TW201209054A - Novel compounds - Google Patents

Abstract

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

Description

201209054 VI. INSTRUCTIONS: [Technical Field of the Invention] The present invention relates to therapeutic compounds useful for the treatment of metabolic diseases including type II diabetes. In particular, the present invention relates to compounds having activity as a GPR1 19 agonist. [Prior Art]

Drugs for disease phylogeny associated with non-insulin dependent Type II diabetes have many possible side effects and are not suitable for dyslipidemia and hyperglycemia in a high proportion of patients. Treatment usually focuses on the needs of individual patients, using foraging, exercise, hypoglycemic agents, and insulin, but still requires novel anti-diabetic agents, particularly anti-diabetic agents with better tolerance and fewer undesirable side effects. Similarly, metabolic syndrome (X syndrome) puts people at high risk of coronary artery disease and is characterized by a large group of risk factors, including central obesity (excessive adipose tissue accumulates in the abdomen), blood sugar intolerance, High triglyceride and low HDL cholesterol, and high blood pressure. Myocardial ischemia and microvascular disease have been identified as pathologies associated with untreated or poorly controlled metabolic syndrome. Obesity is characterized by an excess of adipose tissue mass relative to the body size. Clinically, body fat mass is estimated by body mass index (BMI; body weight (kg) / height (m) 2) or waist circumference. When an individual's BMI is greater than 30, it is considered obese, and overweight has been confirmed to cause medical complications. Consider weight gain, especially caused by abdominal fat, with diabetes 'hypertension, -5-201209054 heart disease, and many other health problems (such as arthritis, stroke, gallbladder disease, muscle and respiratory tract) Medical opinions related to increased risk of problems, back pain and even some cancers have been accepted for some time. There remains a need for novel anti-diabetic agents, particularly anti-diabetic agents that are well tolerated and have fewer adverse side effects, particularly agents that can cause moderate weight or preferably cause weight loss. GPR119 (formerly known as GPR1 16) is a GPCR identified as 3>101^25 in \¥000/50562, which also reveals human and rat receptors, and US 6,468,756 also reveals mouse receptors (accession number) : AAN95194 (human), AAN95195 (rat) and ANN95196 (mouse)). In humans, GPR119 is expressed in the pancreas, small intestine, large intestine, and adipose tissue. The performance profile of the human GPR119 receptor suggests that it may be useful as a target for the treatment of diabetes. 0?11119 agonists have been shown to stimulate gastrointestinal tract release ^1^-1. To this end, GPR1 19 agonists (1) promote the release of glucose-dependent insulin from the pancreas, leading to improved oral glucose tolerance; (2) slowing the progression of the disease by increasing the beta-cell cAMP concentration; and (3) causing Weight loss 'may be the ability to reduce food intake via G LP -1. International Patent Application No. WO 2005/061489, WO 2006/070208, WO 2006/067532, WO 2006/06753 1, WO 2007/003960, WO 2007/00396 1, WO 2007/003962, WO 200 7/003964, WO 2007/ 1 1 6229, WO 2007/ 1 1 623 0, WO 2 00 8/08 1 204, WO 2008/08 1 205, WO 2008/08 1 206, WO 2008/08 1 207 'WO 200 8/0 8 1 208 WO 2009/050 5 05 22, WO 2009/050523, 201209054 WO 201 0/00 1 1 66, WO 20 1 0/004343, WO 20 1 0/004344, WO 201 0/004345 > WO 2010/004346, WO 20 1 0/004347 and WO 20 1 0/004348 disclose GPR119 receptor agonists.

Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous but highly specific serine protease that cleaves the end of a polypeptide with L-proline or L-alanine at the second last position. Dipeptide. Studies of DPP-IV inhibitors have shown that the primary role of DPP-IV is to inactivate GLP-1. By prolonging the duration of action of GLP-1, it stimulates insulin secretion, inhibits the release of glucagon, and slows gastric emptying. DPP-IV inhibitors are used to treat type 2 diabetes, and examples of DPP-IV inhibitors include vildagliptin (vi 1 dag 1 ipti η), sitagliptin (sitag 1 ipti η), alurolide (alogliptin) and saxagliptin (saxagliptin). The possibility of using a combination of GPR1 1 9 agonist and DPP-IV has been suggested, however, this combination requires the administration of two separately formulated products to the patient or the two active ingredients to be formulated together, so that the two activities are achieved The inherent chemistry of the ingredients is inherently problematic in their compatibility with pharmacokinetic and pharmacodynamic properties. WO 2009/034388 discloses a dual combination of a GPR119 agonist and a DPP-IV inhibitor. The compounds of the invention also have dual activities as GPR1 19 agonists and DPP-IV inhibitors. SUMMARY OF THE INVENTION According to the present invention, there is provided a compound of the following formula (I) and a pharmaceutically acceptable salt thereof: -7- 201209054 0(R9hc) (CHR!〇)q Y-X-R11

N R2

NH2 N-

Z

(I) wherein A is a para-substituted phenyl group or a 6-membered heteroaryl ring substituted with 1 to 3 nitrogen atoms; R1 is hydrogen, halo, cyano, Cm alkyl, Cm halo a base, an oxy group or a C2-6 alkoxy group; R2 is: a phenyl group optionally substituted by one or more halo, methyl or methoxy groups, or optionally one or more from C a pyridyl group, an N-pyridone group or a group substituted with an i-alkyl group or a halomethyl group; each of R3 is independently a fluorenyl group, a methyl group or a fluorenyl group; Z is -C(0)0R, - C(〇)R4, -S(〇)2R4, ^(OhNd)R, heteroaryl or -CH2_heteroaryl, when both p and q are 〇, z is also CH2-phenyl' where the phenyl Arbitrarily substituted by one or two independent Si-4, Cu_4 halogen, and halo groups. R4 is aryl, heteroaryl, C2_6 alkyl, C3_6 cycloalkyl, C4, Heterocyclyl Cm alkyl, CM alkoxyalkyl 'aryl & 4 hospital F, C 1 -4, halomethyl fluorenyl, pyrazole 3 alkyl, may be -i selected from 6 heterocycle; , hetero-8- 201209054 aryl C^4 alkyl or C4_6 cycloalkyl C4 alkyl, the cycloalkyl C 4 alkyl is optionally substituted by (^-4 alkyl; wherein Z is Or comprising a heteroaryl group or when R4 is or comprises an aryl or heteroaryl group, the aryl or heteroaryl group may be optionally substituted with one or two groups selected from the group consisting of: a group, a cyano group, an SF5 group , Cm alkyl, C,-4 haloalkyl,

Cu hydroxyalkyl, Cb4 alkoxy, c2_4 alkoxyalkyl, heterocyclic, heterocyclic Ci-4, heteroaryl Cl.4, Ci_4 mercaptoamine, Cl.4 Month-based Ci-4, C3-6 cyclodecyl and - (Ci-3)-(C3-6 ring-based), wherein the cycloalkyl and alkyl are optionally passed one or two Substituted by a group each independently selected from a Cj4 alkyl group, a hydroxyl group or a halogen group: X is selected from the group consisting of CR5H, hydrazine, and NR6, wherein R5 and R6 are each independently hydrogen or a C alkyl group; Y is Y1 or W- Y1, wherein W is a 5-membered heteroaryl ring containing one or more heteroatoms selected from the group consisting of ruthenium, osmium and S, and Y1 is selected from the group consisting of CR7H, ruthenium and NR8' wherein R7 is hydrogen, Cu alkyl, C2 a -6 alkoxyalkyl group or a heterocyclic group; wherein the mountain 2 alkyl group may be optionally substituted by a cyano group, a hydroxyl group or a halogen group, and R8 is a Cm alkyl group or a Cm cycloalkyl group, with the proviso that when Y When W-Y1, X is 〇 and Y1 is CR7H, when Y1 is 〇 or NR8, X is CR5H, and when X is Ο or NR6, Y1 is CR7H; each R9 and R1Q are independently H, halogen , ci-2 alkyl 'C!-2 haloalkyl, C^3 alkoxy or hydroxy; or R9 and R113 linked to form azabicyclo[3.3.1] Alkane, 3-oxa-7-azabicyclo[3.3.1]nonane or azabicyclo[3.2.1]octane; R11 is H, dentate, Ci-2, and Ci-2 Or Ci-3 alkoxy; -9 - 201209054 m is 0, 1 or 2; η is 0 or 1, ρ and q are 〇, 1 or 2, respectively, and the prerequisite is 〇S p + q S 2 ; It is 1 or 2. The compound of the present invention has an activity as a GPR1 19 agonist and is also an inhibitor of DPP-IV, and thus can be used for the treatment of metabolic diseases including type III diabetes. DETAILED DESCRIPTION OF THE INVENTION R5 is suitably hydrogen or methyl. R6 is suitably hydrogen. R8 is suitably a methyl group. Suitably, R11 can be Η. In some systems, R11 can be an alkoxy group, such as a methoxy group. Or 'R11 can be a halo group, including F. In some systems, the compound of the present invention may suitably have a stereochemistry (a compound of the formula (I a)) shown by the following formula; this compound may prove to have a D P P -1V inhibitory activity:

p and q are each independently 0, 1, or 2, with the proviso that p + q does not exceed 2, i.e., forms a 4_, 5 - or 6-membered ring. In some systems, the same can be formed, ie, a 6-membered ring. Suitably both 'p and q are 1. -10- 201209054 R9 and R1Q may be the same or different from each other. Suitably, both... and ruler (7) are Η. When ρ (or q) is 2, the two R9 (or ruthenium) groups may be the same or different from each other. Suitably when one of R9 (or R1Q) is not deuterium, the other may be a 6-membered heteroaryl ring containing one or two nitrogen atoms in the para position. A is suitably pyridine, pyrimidine, pyrazine or pyridazine, usually pyridine or pyrimidine 'for example 2- or 3-pyridyl or 2- or 5-pyrimidinyl, wherein 2-, 3- or 5- meaning pyrrole The point of attachment of a pyridine or piperidine ring. In a group of compounds of the invention, γ is γ1. In this group, 'Y1 can be 〇 and X can be CR5H. Or 'X may be 〇 and Y1 may suitably be CR7H. In this system, therefore, the compounds of the invention are represented by the formula: R2

(lb). In another alternative system, Y1 can be NR8 and X can be CR5H. In yet another alternative system, X can be NR6 and Y1 can be CR7H. In another subgroup of compounds of the invention, Y can be W-Y1, wherein Y1 is CR7H directly bonded to X, and X is 0. W is usually an oxadiazolyl group. In this system, therefore, the compound of the present invention can suitably be represented by the following formula: -11 - 201209054

z

(IC) In each case, A can be selected from: Gossip

In some systems, Z may suitably be -C(0)OR4S(〇)2R4.

'C(0)R4 R4 may suitably be an alkyl group, a Co5 alkoxyalkyl group, a ring-shaped _ _ 赛 or a lysine group, wherein the ring-based base is optionally passed through a C 1 ·4 base Helped # generation.逋 Often, R·4 may be a propyl group, particularly an isopropyl group. Alternatively, Z may be a heteroaryl group which may be optionally substituted by one or two groups selected from the group consisting of: Ci-4 alkyl, C,.4 haloalkyl, Cm hydroxyl, C2_4 alkane An oxyalkyl group, a C3-6 decyl group optionally substituted by a Cw alkyl group or a halogen group, a c, a-4 alkoxy group, a heterocyclic group, a heterocyclic alkyl group, a heteroagonic ginseng, an alkylamino group, Alkylaminoalkyl, cyano and halogen. When Z is a heteroaryl group, suitable heteroaryl groups are oxadiazole, pyrimidine-11-12-12090054, thiazole, tetrazole, benzothiazole and thiadiazole, such as oxadiazole and pyrimidine. Wherein Z may suitably comprise i, 2,4-oxadiazole-3-yl, 1,2,4-oxadiazol-5-yl or pyrimidin-2-yl, which may be substituted by any of the above Substituted by the base. Usually, the 1,2,4-oxadiazole-3-yl or oxadiazolyl can be substituted by a Cl-4 alkyl group such as a propyl group (for example, 3-isopropyl or 5-isopropyl), C!-4® alkyl 'Cl. 5 hydroxyalkyl (e.g., hydrazine-hydroxyethyl), orthoxyalkyl or heterocyclic. Suitably, the Cm hydroxyalkyl group can be a Cl_3 hydroxyalkyl group, such as a transethyl group. The pyrimidin-2-yl group may be unsubstituted or substituted with one or more halo groups, such as 5-chloropyrimidin-2-yl.

In another alternative system, 'Z may suitably be -CH2.phenyl, wherein the phenyl group is optionally independently selected from one or two groups independently selected from the group consisting of Cl-4 alkyl, Ci4dentylalkyl and halo. Replaced by the regiment. In some systems, R1 may suitably be 11 or a C alkyl group, such as a methyl group. In general, a compound wherein R 1 is an anthracene is preferred. R2 may suitably be any substituted phenyl, pyridyl, indole or fluorenyl-pyridinyl group, such as 2-pyridyl. In some systems, 'R2' may suitably be a phenyl group substituted with one, two or three halo groups; the halo group is suitably fluoro. Or 'R2 may be pyridyl, Ν-pyrazolyl or Ν _ substituted by one, two or three halo, methyl or methoxy (usually one or two methyl groups) [1 to -13 - 201209054 ketone base. When W is a 5-membered heteroaryl ring, 2 7ΐΤ local

When W is a 5-membered heteroaryl ring, such as oxadiazolyl, RJM is optionally substituted with one or more halo, methyl or halomethyl groups, based on some systems, when Y is W When -Y1, R2 can be selected from:

Optionally, one or more halo, methyl, halo

a phenyl group substituted by a methoxy group or a methoxy group, or a pyridyl group optionally substituted by one or more _ groups, c 1 -2 alkyl groups or halomethyl groups, wherein the indoleamine, the present group and the pyridyl group are As above. R7 is suitably an alkyl group, usually a methyl group. When 2 is 'C(0)0R4', R7 may be a C02 alkyl group, and R2 may be a phenyl group optionally substituted with one or more mercapto groups, methyl groups or halomethyl groups. When Z is -CH2-phenyl, 'R2" may be phenyl optionally substituted with one or more halo, methyl or dentate methyl groups. The molecular weight of the compounds of the invention is suitably less than about 8000, typically less than about 600. When Z is a heteroaryl group, particularly an oxadiazolyl group, the compound of the present invention can be metabolized in vivo via a ring opening mechanism to form a compound of the formula (Id):

Z (Id) -14 - 201209054 wherein A, R1 to R11, X, Y, m, n, p, q and r are as defined in any one of the above formula (I), (lb) or (Ic); Z is -C(0)R12; and

R12 is -NHC(0)R13 or -NHC(NH)R13, wherein R13 is selected from the group consisting of Ci-4, Ke-4, Ci-5, basal, Ci-4, 〇, 〇 2-4 alkoxyalkyl, heterocyclic, heterocyclic Ch4 alkyl, heteroaryl 4 alkyl, C3-6 cycloalkyl and -(Cu alkyl)-(c3.6 cycloalkyl And wherein the cycloalkyl group and the alkyl group are each optionally substituted with one or two groups each independently selected from the group consisting of a q-4 alkyl group, a hydroxyl group or a halogen group. The compound of formula (Id) may have the stereochemistry of formula (la). These metabolites have been found to have some GPR 11 9 agonist activity, and thus, and their pharmaceutically acceptable salts are encompassed within the scope of the invention, and R1 3 may be <^-4 alkyl, Such as propyl or isopropyl

Suitably, Y1 may be CR7H, wherein 117 is a Cb2 alkyl group, as defined above, although most of the appropriate groups for each variable have been listed above for each variable, respectively, but the compounds of the invention comprise a formula (I) Several or each variable is a compound selected from the group specifically listed for each variable. Accordingly, the present invention is intended to include all combinations of the listed groups, particularly those which are shown to be appropriate or typical. The present invention also encompasses isotopically-labeled compounds which are identical to the compounds of formula (I), (lb), (Ic) and (Id) and the formula below, but one or more of the 201209054 atoms are The atomic weight or the mass of the atom is replaced by an atomic mass or mass. Examples of isotopes to which the compound of the present invention may be added include isotopes of hydrogen, carbon, nitrogen, and fluorine, such as 3H, 11C, 14c, and 18 F. Compounds of the invention and salts of such compounds containing the above isotopes and/or other isotopes of other atoms are encompassed within the scope of the invention. Isotopically labeled compounds of the invention, e.g., compounds incorporating a radioisotope (e.g., 14C), are useful for drug and/or matrix distribution analysis.氚 ′, i.e., 3H, and carbon-14, i.e., 14C, are particularly suitable for their ease of preparation and detectability. The 11 C and 18 F isotopes are particularly useful for P E T (positive emission tomography). PET can be used for brain imaging. In addition, heavier isotopes such as deuterium, ie, 2 Η, may provide some therapeutic benefit due to the greater metabolic stability of these heavier isotopes', such as increased in vivo half-life or reduced dose requirements, and thus may be In some cases, it is preferred that the compounds of the invention of the formula (I), (lb) '(Ic) and (Id) and the formulas below are generally subjected to the following reaction schemes and/or examples. The procedures described are prepared by substituting a non-isotopically labeled reagent with an immediately available isotopically labeled reagent. In one system, the compounds of formula (1), (Ib), (Ie) and (Id) or salts thereof are not isotopically labeled. [In this context, unless otherwise indicated, "alkyl" means straight a carbon chain of a chain or a branched chain. Examples of the alkyl group include an ethyl group, a propyl group, an isopropyl 'T group', a second butyl group, and a third butyl group. In some systems, the hospital base may pass one or more Substituted halo, especially fluorine. Usually the CF3 group can be substituted by SF5 without departing from the invention. -16- 201209054 "Heteroaryl" ring B means 5- or 6-membered nitrogen-containing heteroaryl a base ring, which optionally contains one or more, for example 1, 2 or 3, additional heteroatoms selected from N, 0 and S, or means a fused bicyclic system, which optionally contains one or more , for example 1, 2, 3, 4 or 5, heteroatoms selected from N, fluorene and S. Examples of the heteroaryl ring are pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isomerism Azyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazine<:4_6 cycloalkylane# base (wherein the ring) Alkylalkyl Substituted by Cm alkyl), triazinyl fluorene, tetrazolyl and benzothiazolyl. The compounds described herein may contain one or more asymmetric centers and thus may produce non-image isomers and optical isomers. The present invention encompasses all possible non-image isomers and racemic mixtures thereof, resolved substantially pure mirror image isomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Included are all stereoisomers of the compounds of the invention and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated Q-specific stereoisomers are also encompassed. The product of these steps may be a mixture of stereoisomers during the synthesis step, or when using the racemization step or the isomerization step as is known to those skilled in the art. When the tautomer of the compound of the invention is present The invention includes any of the possible tautomers and pharmaceutically acceptable salts and mixtures thereof, unless otherwise specifically indicated or indicated. When the compounds of the invention and their pharmaceutically acceptable The salt is present in the form of a solvate or polymorph, and the present invention encompasses any possible solvate or poly--17-201209054. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically Acceptable. For example, water, ethanol, propanol, acetone, etc. may be used. "Pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is When acidic, the corresponding salt can be readily prepared from a pharmaceutically acceptable non-toxic base comprising an inorganic base and an organic base. The salt derived from the inorganic base comprises aluminum, ammonium, calcium, copper ( Copper and cuprous), iron, ferrous, lithium, magnesium, potassium, sodium, zinc, etc. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts derived from pharmaceutically acceptable organic non-toxic bases. Salts include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as natural and synthetic substituted amines. Other pharmaceutically acceptable organic non-toxic bases which form salts include arginine, betaine, caffeine, choline, AT, '-dibenzylethylenediamine, diethylamine, 2-diethylamine Ethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, 7V-ethylmorpholine, ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine , aminic acid, methyl reduced glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, standard D, theobromine, triethylamine, trimethylamine, Tripropylamine, tris(hydroxymethyl)methylamine, and the like. When the compound of the present invention is basic, its corresponding salt can be readily prepared from a pharmaceutically acceptable non-toxic acid. The non-toxic acid comprises a mineral acid and an organic acid. The acid includes, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid 'citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, 2 -hydroxyethanesulfonic acid, lactic acid, maleic acid-18-201209054, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, Toluenesulfonic acid, difluoroacetic acid, and the like. Since the compounds of the invention are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 6 % purity, more suitably at least 75% purity, especially at least 98% purity (% based on weight) Calculation) ° The compound of formula (1) can be produced as described below, where rI, r2, r3

R4, R5, r6, R7, r8, r9, r1〇, R11, A, X, Υ, Z, m, n, p, q and r are as defined in the formula (1). Pg is a protecting group 'LG is a leaving group and Hal is a halogen. The compound of the formula (I) can be produced as described in the reaction scheme 1. The compound of the formula (IV) can be subjected to SNAr displacement reaction by a suitable halogenated aromatic compound of the formula (II) and an amine of the formula (111) under standard conditions (for example, DBU and DMSO at 80 to 1 ° C). And manufacturing. Alternatively, the compound of the formula (IV) can be obtained by a suitable halogenated aromatic compound of the formula (II) and an amine of the formula (III) in Buchwald-Hartwig conditions, such as Pd2(dba)3 and XANTPHOS or triisobutyl. The phosphatrane is produced by reacting in a suitable solvent (for example, toluene) at 120 ° C in a microwave reactor. The protecting group PG of the amine functional group can be removed using standard conditions well known to those skilled in the art to give the compound (I). • 19 - 201209054 Reaction Scheme 1 The compound of formula (II) wherein X is hydrazine can be prepared as described in Reaction Scheme 2. The alcohol of formula (V) can be treated with a hydroxyaryl compound of formula (VI) under standard Mitsonobu conditions (for example, using diisopropyl azodicarboxylate and triphenylphosphine in a suitable solvent such as toluene). Compounds of formula (II) wherein X is hydrazine can be prepared from an alcohol of formula (V) by formation of a suitable leaving group. Suitable leaving groups, such as the mesylate of formula (VII), can be used. Manufactured under conditions such as methanesulfonium chloride and triethylamine in DCM. The compound of formula (II) can be obtained from the mesylate of formula (VII) and the hydroxyaryl compound of formula (VI) under standard conditions (eg Prepared by a base (for example, CsF. K2C〇3) in a suitable solvent (such as DMA or DMF) at 60 to 80. 〇. -20- 201209054 Reaction Figure 2

The compound of the formula (IV) wherein X is NR6 and R6 is hydrogen can be prepared according to the reaction scheme 3. The carbonyl compound of formula (VIII) can be used from the alcohol of formula (V) using standard oxidation conditions (eg, DMSO and oxalic acid chloride with a base such as triethylamine, or Dess-Martin Periodinane (periodane) in a solvent (eg, DCM). ) and manufactured. The compound of the formula (IV) can be obtained from a carbonyl compound represented by the formula (VIII) and an amine of the formula (IX) by a reductive amination reaction under standard conditions, for example, using a reducing agent (for example, NaBH(〇Ac)3) and a catalyst. (e.g., AcOH) is produced in a suitable solvent such as DCM. y Υ-ΟΗ Reaction Figure 3 P(RjHcyY=o

VIII

R PG The compound of the formula (IV) can be further reacted with an immediately obtainable aldehyde under the standard conditions as described above to produce a compound of the formula (IV) wherein R6-21-201209054 is an alkyl group. The compound of the formula (IX) can be produced according to the reaction scheme 4 described. The compound of the formula (XI) can be produced by subjecting a halogenated aromatic compound of the formula (X) and an amine of the formula (III) to a SNAr displacement reaction under standard conditions as described above. The compound of the formula (IX) can be produced from a compound of the formula (XI) by a reduction reaction under standard conditions using a catalyst (for example, 10% palladium on carbon) under a hydrogen atmosphere in a suitable solvent such as methanol or ethanol. . Reaction Figure 4

The compound of the formula (Π) wherein X is CR5H and Y1 is 0 can be prepared as described in Reaction Scheme 5. An alkylating agent (for example, a halide of formula (XIII)) (which can be readily obtained or can be obtained by known methods) can be suitably used with an alcohol of formula (XII) under standard conditions, for example using a base such as sodium hydride or tBuOK. The reaction is carried out in a solvent such as THF or DMF. Reaction Figure 5

The compound of the formula (IV) wherein X is CR5H, and Y1 is NR8, and wherein R8 is hydrogen can be produced according to the reaction scheme of Fig. 6. The compound of the formula (XIV) can be produced from an alcohol of the formula (XII) in standard Mitsonobu conditions, for example, using diisopropyl azodicarboxylate and triphenylphosphine in a suitable solvent such as toluene. The compound of the formula (XIV) can be used in a solvent by hydrating the amine (for example, -22-201209054

The reaction in EtOH) is converted into an amine, thus obtaining an amine represented by the formula (XV). The compound of the formula (IV) can be produced by reacting an amine of the formula (XV) with a carbonyl compound of the formula (XVI) under standard reductive amination conditions as described above. Reaction circle 6

p(RrHCV^ _.N>^(CHR1#)q

P(R*HC)

R2 VH PG The compound of the formula (IV) is further reacted with an immediately obtainable aldehyde under standard conditions (using a reducing agent such as NaBH(0Ac)3) and a catalyst (for example, AcOH) in a suitable solvent (for example, DCM). It can be used to prepare a compound of the formula (IV) wherein R6 is an alkyl group.

The carbonyl compound of the formula (XVI) can be produced according to the reaction scheme of Figure 7. The compound of the formula (XVIII) can be produced by subjecting a suitable and immediately obtainable haloaromatic compound of the formula (XVII) to an amine of the formula (III) by subjecting to a SNAr displacement reaction under the standard conditions as described above. The compound of the formula (XVIII) can be reduced to an alcohol of the formula (XIX), for example, using a standard reducing agent (e.g., DIBAL-H) in a solvent such as THF. The carbonyl compound of the formula (XVI) can be produced from an alcohol of the formula (XIX) by an oxidation reaction under standard conditions using a reagent such as Dess-Martin Periodinane (disiodane) in a solvent such as DCM. Alternatively, the carbonyl compound of the formula (XVI) can be subjected to SNAr substitution under the standard conditions as described above by a suitable and immediately available -23-201209054 halogenated aromatic compound of the formula (XX) and an amine of the formula (ΠΙ). Produced by reaction. Reaction Figure 7

Examples and syntheses of compounds of formula (III) have been disclosed in Benbow et. al., W02007 1 48 1 85; Brackes et. al., Bioorg. Med. Chem. Lett., 2007, 1 7 (7), 2005 -20 1 2; Pei et.al., J. Med. Chem,, 2007, 5 0 (8 ), 1 9 8 3 - 1 9 8 7 ; Cox et.al., Bioorg. Med. Chem. Lett. , 2007, 1 7 (1 6), 4579-45 8 3 ; Wright et.al., 5ioorg. Med. C/zew. Lei,., 2007, 17 (20), 5638-5642. The synthesis of building blocks of formula (V) and (XIII) has been disclosed in Fang α/·, W0200 8070692; Walmsley et. al., W0200803801 1 ; Chen et. al., W0200808323 8 ; Wilson et. al, WO2009 1 23992 ; L〇so et. al., W 0 2 0 0 8 0 3 0 2 6 6. Further, the compound of the formula (I) can be produced by a method similar to the above or by a method known from -24 to 201209054. Further details of the preparation of the compounds of formula (I) can be found in the compounds of formula (I) which may be produced individually or as a library of compounds (including at least 2, for example 5 to 1,000, or more preferably 10 to 100) It is produced in the form of a compound of the formula (1). The library of compounds can be made by a combined "split and mix" route or by multiple parallel synthesis using solution or solid phase chemistry using procedures known to those skilled in the art.

All novel intermediates defined in the above reaction schemes or examples are also within the scope of the invention. Thus, according to another aspect of the present invention, a compound of any one of formula (II) '(IV), (IX) and (XVI) as defined above is provided. Preferred groups for the various variables described above for the compound of formula (I) are also applicable to the intermediate compound. As indicated above, the compounds of the invention are useful as GP R 1 1 9 agonists, for example for the treatment and/or prevention of diabetes. For this purpose, the compounds of the invention will generally be administered in the form of a pharmaceutical composition. The compounds of the invention may also be used as dual GPR119 agonists/DPP-IV inhibitors' for example for the treatment and/or prevention of diabetes. For this purpose, 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 medicament. The invention also provides a pharmaceutical composition comprising a compound of the invention in combination with a pharmaceutically acceptable carrier. Preferably, the composition comprises a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. -25- 201209054 Furthermore, the present invention also provides for the treatment of a disease by modulating GPR 1 19 and any IV and thus resulting in a prophylactic or curative treatment of a diabetic composition comprising a pharmaceutically acceptable carrier and a non-toxic treatment. A quantity of a compound of the invention or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may optionally contain other therapeutic ingredients or adjuvants. The composition comprises a composition suitable for oral, rectal, topical, and parenteral (including intramuscular, and intravenous) administration, however, the most pathway in any case will depend on the particular host and will be administered to the active ingredient. The nature and seriousness of it. The pharmaceutical compositions are conveniently presented in unit dosage form and can be made by any methods known in the pharmaceutical art. In fact, the compound of the present invention, or a pharmaceutically acceptable salt active ingredient form thereof, is intimately compatible with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques. The carrier can be in a wide variety of forms depending on the form of preparation desired for administration (e.g., parenteral (including intravenous) administration). Thus, the pharmaceutical compositions may be in discrete dosages suitable for oral administration, such as capsules, sachets or lozenges' which each contain a predetermined amount of the active ingredient. Further, the composition may be in the form of a powder, a granule, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid. In addition to the above conventional dosage forms, the compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be administered in a controlled release method and/or a delivery device. Compositions are prepared by any of the methods of pharmacy. Typically the method comprises the step of combining the activity with a carrier, including one or more essential ingredients. Generally, the article is made by uniformly and intimately mixing the active ingredient with a liquid carrier or a fine solid carrier or both. The product can then be conveniently molded into the form of the DPP-medicine under the effective composition, the appropriate condition, and the -26-201209054 expression of the composition of the component or the component of the emulsion. The compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used can be, for example, a solid, a liquid, or a gas. Examples of solid carriers include lactose, white gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When the composition is formulated into an oral dosage form, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc., can be used to form oral liquid preparations such as suspensions, elixirs and solutions; for example, starch, sugar microcrystalline cellulose, Carriers of diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to form oral solid preparations such as powders, capsules and lozenges. Because of their ease of administration, lozenges and capsules are preferred oral dosage forms, and solid pharmaceutical carriers are employed. Optionally, the ingot Q agent can be coated by standard aqueous or non-aqueous techniques. The lozenge containing the composition of the present invention can be optionally produced by extrusion or molding with one or more auxiliary ingredients or adjuvants. Extruded tablets may be prepared by admixing free-flowing active ingredients (e.g., powders or granules) with a binder, lubricant, inert diluent, surfactant or dispersing agent in a suitable machine. Molded tablets may be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.05 mg to about 5 g of active ingredient, and each pill or capsule preferably contains from about 0.5 mg to about 5 g of active ingredient. -27- 201209054 For example, a formulation for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent in admixture with a suitable and suitable amount of carrier materials in an amount from about 5% to about 95% of the total composition. %. The unit dosage form will usually contain from about 1 mg to about 2 g of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg '8 0 0 Mg, or 1 000 mg o The pharmaceutical composition of the invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water. It may contain a suitable surfactant such as hydroxypropylcellulose. The dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. In addition, preservatives may be included to prevent the harmful growth of microorganisms. The pharmaceutical compositions of the invention suitable for injectable use comprise sterile aqueous solutions or dispersions. Further, the composition may be in the form of a sterile powder for the immediate preparation of the injectable solution or dispersion. In all cases, the final injection form must be sterile and must have effective fluidity for easy injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is preferably 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 (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof. The pharmaceutical composition of the present invention may be in a form suitable for topical use, for example, an aerosol, a cream, an ointment, a lotion, a dusting or the like. Further, the composition may be in a form suitable for use in a transdermal device. Such a mixture can be produced according to a conventional processing method using the compound of the present invention or a pharmaceutically acceptable salt thereof. -28- 201209054 By way of example, a cream or ointment is prepared by mixing a hydrophilic material and water and from about 5 wt% to about 10 wt% of the compound to obtain a cream or ointment having a desired consistency. The pharmaceutical compositions of this invention may be in a form suitable for rectal administration wherein the carrier can be a solid. It is preferred that the mixture form a suppository in unit dosage form. Suitable carriers include cocoa butter and other materials commonly used in the industry. Suppositories can be prepared by first mixing the composition with a softened or molten carrier and subsequently cooling and shaping in a mold. In addition to the above carrier components, the above pharmaceutical compositions may also contain, if appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants. , preservatives (including antioxidants), etc. In addition, other adjuvants may be included to equalize the osmotic pressure of the blend to the blood of the subject in question. The composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof may also be in the form of a powder or a liquid concentrate. Generally, a dose ranging from 0.01 mg/kg to about 150 mg/kg body weight per day or from about 0.5 mg to about 7 g per patient per day can be used to treat the above conditions. For example, 'administering about 0.01 to 50 mg of compound per kilogram of body weight per day, or about 〇·5 mg to about 3.5 g per patient per day, can effectively treat obesity. However, it should be understood that the specific dosage of any particular patient will depend on a number of factors, including age, weight, general health status, gender, foraging, time of administration, route of administration, rate of excretion, combination of drugs, and treatment. The severity of a particular disease. The compounds of the invention are useful in the treatment of diseases or conditions involving GPR119 and any of DPP- -29 - 201209054 IV. The invention therefore also provides a method for treating a disease or condition involving GPR 19 9 and any DPP-IV comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a patient in need thereof step. The diseases or conditions include diabetes, obesity, glucose intolerance, insulin resistance, and diabetes mellitus (e.g., neuropathy, kidney disease, retinopathy, cataract, cardiovascular dysfunction, and dyslipidemia). It also includes treatment for patients who are abnormally sensitive to the intake of fat and cause functional dyspepsia. The compounds of the present invention are also useful in the treatment of metabolic diseases such as metabolic syndrome (X syndrome), glucose intolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, and hypertension. The invention also provides a method of treating Type II diabetes comprising the step of administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. The invention also provides a method for treating obesity, metabolic syndrome (X syndrome), glucose intolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL content or hypertension, including administration An effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a patient in need 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 described above. The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition as described above. "Treatment" in the method of the invention is meant to encompass both curative and prophylactic -30-201209054 treatment. The compounds of the invention may exhibit advantageous properties compared to known compounds or combination therapies for the treatment of diabetes.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in combination with one or more therapeutically active compounds. The other therapeutically active compounds can be used to treat the same disease or condition as the compounds of the invention or to treat different diseases or conditions. The therapeutically active compounds can 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, such as insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides , α2 agonists, glitazones, PPAR-γ agonists, PPAR-α/γ mixed agonists, RXR agonists, fatty acid oxidation inhibitors, α-glucosidase inhibitors, β-agonists, Phosphodiesterase inhibitors, hypolipidemic agents, glycogen phosphorylase inhibitors, anti-obesity agents (eg pancreatic lipase inhibitors, MCH-1 antagonists and CB-1 antagonists (or inverse agonists)) , amyloid antagonists, lipoxygenase inhibitors, somatostatin analogues, glucokinase activators, glucagon antagonists, insulin signaling agonists, P TP 1 B inhibitors , sugar stimulating inhibitors, antilypholytic agents, GSK inhibitors, galanin receptor agonists, anorexia agents, CCK receptor agonists, leptin, serotonergic/dopaminergic anti-obesity Medicine, re-intake Agents (eg, sibutramine), CRF antagonists, CRF-binding proteins, thyroxine compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, -31 - 201209054 NHE-1 inhibitors or Sorbitol dehydrogenase inhibitor. Combination therapy comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one other agent is a further aspect of the invention. The invention also provides a method of treating diabetes in a mammal (e.g., a human) comprising 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 other agents, for the treatment of diabetes. The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in combination with other agents for the treatment of diabetes. The compound of the present invention or a pharmaceutically acceptable salt thereof may be co-administered with one or more other agents, or administered sequentially or separately. Co-administration includes administration of a formulation comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more other agents, or different formulations of the agents, either simultaneously or separately. Co-administration of the two agents is preferred when the compound of the invention, or a pharmaceutically acceptable salt thereof, and the pharmacological profile of the one or more other agents are permitted. The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and other agents for 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 other anti-obesity agents, and a pharmaceutically acceptable carrier. The invention also encompasses the use of the composition in the above methods. All of the publications, including, but not limited to, the patents and patent applications cited herein are hereby incorporated by reference in their entirety in their entirety in their entirety in the the the the the the the The invention will be described in detail with reference to the following examples, which are not intended to limit the scope of the invention. [Embodiment] Materials and methods

Column chromatography was performed on Si〇2 (40-63 mesh) unless otherwise indicated. The LCMS data was obtained from the following conditions: Atlantis 3μ C18 column (3.0 x 20.0 mm, flow rate = 0.85 mL/min), eluted with a solution of 0,1% HC02H in 112〇-1^€]^ for 6 Minutes, detected with UV at 220 nm. Gradient data: 0.0-0.3 minutes 100% H20; 0.3-4.25 minutes: gradually increased to 10% H2O-90% MeCN; 4.25-4.4 minutes: gradually increased to 1〇〇〇/0

MeCN; 4.4-4.9 minutes: maintained at 1 〇〇% MeCN; 4.9-6.0 minutes: back to 100% H20. Mass spectrometry was obtained using an electron spray free source of positive ion (ES + ) or negative ion (ES-) mode. The LCMS-Method 2 data was obtained from the following conditions: Xbridge (: 18 column (2.1 X 50 mm, 2.5 μΜ, flow rate 0.8 mL/min), eluted with MeCN-10 mM NH4HC03 solution for 1.5 minutes, with UV at 2 1 5-3 50 nm detection. Gradient data: 0-0.8 min: 98% MeCN 2% NH4HC03 to 98% NH4HC03 2% MeCN ; Ο·8·1” min: maintained at 98% NH4HC03 2% MeCN. The electrons in the positive ion (ES + ) mode were sprayed from the free source. The LCMS-method 3 data was obtained from the following conditions: Xbridge <: 18 column (2.1 X 5.0 mm, 2.55 μΜ, flow rate 〇·8 mL/min) , elution with MeCN- -33- 201209054 10 mM NH4HC〇3 solution for 5 minutes, UV detection at 2 1 5-350 nm. Gradient data: 〇 - 4 minutes: 9 8 % M e CN 2 % Ν Η 4 HC Ο 3 to 98% NH4HC03 2% MeCN ; 4-4.6 min: maintained at 98% NH4HC03 2% MeCN. Mass spectrometry was obtained by electron spray free source in positive ion (ES + ) mode. LCMS-method 4 data was obtained from The following conditions were obtained: Xbridge 〇 18 column (3.0 X 150 mm ' 5 μΜ, flow rate 1.0 mL/min), eluted with MeCN-10 mM NH4HC03 solution for 5 minutes. UV detection at 2 1 5-3 50 nm. Gradient data: 〇 - 0.1 min: maintained at 5% M e CN 9 5 % NH4HCO3 ; 0.1-3.0 min: 5% MeCN 95% NH4HC03 to 5% NH4HC03 95°/ MeCN; 3.0-3·9 minutes: maintained at 5% NH4HCO3 95% MeCN. Mass spectrometry was obtained by electron spray free source in positive ion (ES + ) mode. LCMS-method 5 data was obtained from the following conditions: Xbridge <;: 18 column (3.0 X 150 mm, 5 μΜ, flow rate 0.5 mL/min), eluted with MeCN-10 mM NH4HC03 solution for 25 minutes, and UV detected at 215-350 nm. Gradient data: 〇-1 5 Minutes: 5 % M e CN 9 5 % N Η 4 HC Ο 3 to 5% NH4HC〇3 95 % MeCN ; 1 5-25 minutes: maintained at 5% NH4HC〇3 95% MeCN. Mass spectrometry was obtained using an electron spray free source of positive ion (ES + ) mode.

The LCMS - Method 6 data was obtained from the following conditions: phenomenex Kinetex C18 column (3_0 X 30 mm, 2.6 μΜ, flow rate 1_0 mL/min) 'washed with Η 20 - M e CN solution containing 0.1 % HC Ο 2 Η The evaluation was carried out at 220 nm with UV for 2 minutes. Gradient data: 〇, 〇 _ 〇 minute: 2% MeCN -34- 201209054 98% H20 to 5% MeCN 95% H20; 0.1-1.50 minutes: gradually increased to 100% MeCN; 1.5-1.75 minutes: maintained at 100% MeCN; 1.75-1.8 min: 100% MeCN to 2% MeCN 98% H20; 1.8-2.0 min: maintained at 2% MeCN 98% H20. Mass spectrometry was obtained using an electron spray free source of positive ion (ES + ) or negative ion (ES_) mode.

The LCMS-Method 7 data was obtained from the following conditions: Waters Atlantis Ci8 column (3.0 x 20 mm, 3 μΜ, flow rate 1.0 mL/min), eluted with 0.1% HC02i^3H2〇-MeCN solution for 6 minutes to UV is detected at 220 nm. Gradient data: 0·00-0.30 minutes: 100% H20; 0.30-4.25 minutes: 100% H20 to 90% MeCN 10% H20; 4.25-4.40 minutes: 90% H20 to 10% MeCN to 100% MeCN; 4.40-4.90 Minutes: maintained at 100% MeCN; 4.90-5.00 minutes: 100% MeCN to 100% H20; 5.00-6.00 minutes: maintained at 100% H20 for rebalancing. Mass spectrometry was obtained using an electron spray free source of positive ion (ES + ) mode. The LCMS-method 8 data was obtained from the following conditions: Waters Xbridge C18 column (4.6 x 50 mm '3.5 μΜ, flow rate 1.5 mL/min) to 112 1-]^ containing 0.2% 1^113〇11 The liquid wash was carried out for 5.5 minutes and detected at 11 ¥ at 220 nm. Gradient data: 0.00-0.30 minutes: 95% H20, 5% MeCN; 0.3 0-3.90 minutes: 100% H20 to 100% MeCN; 3.90-4.90 minutes: Maintain at 100% MeCN; 4.90-5.00 minutes: 100% MeCN to 5% MeCN 95% H20; 5.00-5.5 0 minutes: maintained at 95% H20 5% MeCN for rebalancing. Mass spectrometry uses positive ion (ES + ) mode The electrons were sprayed with a free source. Unless otherwise indicated, LCMS - Method 1 was used for analysis. -35- 201209054 Preparative HPLC purification was performed using standard or basic methods. Standard method: 〇61^1^-\乂(: 18 column (21.2\10〇111111, 5卩1^, flow rate 20 mL/min), eluted with H20-MeCN solution containing 0 1% HC02H, using a gradient of 1 Torr, and UV detection at 220 nm. Sex method: XBridge Prep C18 column (19 X 1〇〇mm, 5 μΜ, flow rate 20 mL/min), eluted with 0.2% ΝΗ4ΟΗ Η20-MeCN solution, use 1 A minute gradient is detected at UV at 220 nm. Standard methods are used for purification unless otherwise indicated. MDP (mass-oriented purification) is performed using an acidic or basic method. Acidic method: XBridge Prep Ci8 column (19 X 50 mm, 5 μΜ, flow rate 20 mL/min), eluted with Η2〇-MeCN solution containing 〇_1% HC02H, using an 8-minute gradient, UV at 220 nm and additionally using mass ion detection. Method of assay: XBridge Prep C18 column (19 X 50 mm, 5 μΜ, flow rate 20 mL/min), eluted with Η20-MeCN solution containing 0.2% ΝΗ4ΟΗ' using an 8-minute gradient, υν at 220 nm and additionally using mass ion detection. Acidic Both the basic and the alkaline methods were used for purification. Palm-HPLC was performed on a Daicel chiralpak IA 250 X 20 mm, 5 μΜ column. Abbreviations and acronyms: AcOH: Acetic acid; ADDP: Azomethyl carbazide卩定;BA: n-butylamine; BOP: hexafluorophosphoric acid (benzotriazin-i_yloxy)tris(dimethylamino)iron; n-BuLi: n-butyllithium; tBu〇K: -36 - 201209054 tert-butanol; lBuOK: potassium t-butoxide; C: carbon; CsF: fluorinated planer; DAST: diethylaminosulfur trifluoride; DBU: 1,8-diazabicyclo[5.4.0]-f--carbon-7-ene; DCM: dichloromethane; DCE: 1,2-dichloro Ethane;

DEA: diethylamine; DEAD: diethyl azodicarboxylate; DIAD: diisopropyl azodicarboxylate; DMA: dimethylacetamide; DME: 1,2-dimethoxyethane; DMF : dimethylformamide; DIPEA: diisopropylethylamine; DMAP: dimethylpyridin-4-amine; DMSO: dimethyl sulfoxide; EDCI: (3-dimethylaminopropyl)ethyl Carbodiimide hydrochloride; Et20: diethyl ether; EtOH: ethanol; EtOAc: ethyl acetate; h: hour; HBTU: hexafluorophosphate 0-(benzotriazol-1-yl)-oxime, hydrazine, hydrazine 'Ν'-tetramethylurea key; HC1: hydrochloric acid; HC02H: formic acid; hydrazine 20: water; hydrazine: 1-hydroxy-7-fluorobenzotriazole; HOBt: 1-hydroxybenzotriazole monohydrate; HPLC: high performance liquid chromatography; H2S04: sulfuric acid; IH: isohexane; IMS: industrial methylated alcohol; IPA: isopropanol; hydrazine: molar concentration; MDP: mass-directed purification; MeCN: acetonitrile MeOH: methanol; MgS04: magnesium sulfate; min: minute; MTBE: methyl tert-butyl ether; NaHC03: sodium hydrogencarbonate; NaOH: sodium hydroxide; Na2S04: sodium sulfate; n-BuLi: n-butyllithium; NH3: ammonia; NH4HC03: ammonium carbonate; NH4OH: ammonium hydroxide; NMP: N-methyl-2-pyridyl Pyridone; Pd: palladium; PE-AX: anion exchange resin; hydrazine: phosphonic acid resin; PPh3: triphenylphosphine; PS: polymer supported; RT: hysteresis time; rt: room temperature; sat: saturated; SCX: Strong cation exchange resin; SiO 2 : tannin; STMAd: succinic resin; TBAD: dibutyl azodicarboxylate; TBAI: tetrabutylammonium iodide; TBME: third butyl methyl ether; THF: tetrahydrofuran; TFA: 37- 201209054 Trifluoroacetic acid; TFAA: trifluoroacetic anhydride; TsOH: p-toluenesulfonic acid monohydrate; wt: weight. The synthesis of the following compounds has been disclosed: (1-benzyl-5-fluoro-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol: Nelson, TD, ei. al., WO 2006069287; (35,45)-3,4-diazido-bubenzylpyrrolidine:

Benbow ef. α/·, WO2007 1 48 1 85; N-hydroxy-2-methoxyacetamidine: Allen, a/., W02004056823; 4-hydroxypiperidine-1-carbonitrile:

Bertram, L·, a/·, WO2007 1 1 6229; (i?)-N-hydroxy-tetrahydrofuran-2-methyl: R ikimaru, K ·, e ί. a / ·, W Ο 2 0 1 0 0 9 5 6 6 3 ; () - 3-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]butan-1-ol: Fyfe ίίΛ, W02008081204; 3-isopropyl-5-trichloromethyl-[1,2,4]oxadiazole: Smith, N., ei. fl/·, W020091 1 742 1 ; (1)-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethyl ester: Fang α/., W02008070692; 4-((/?)-l-methanesulfonate醯oxy-ethyl)-piperidine-isopropyl isopropyl ester: Fang ei a/., W02008070692; piperidine. 4-yl-ethanol acetate: Fang, J. ei α/., W02008070692; , 45·)-3-Tertibutyloxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Johnsοη, J. eί a / _, WΟ2009 1 53 5 54. All other compounds are commercially available from commercial sources. Preparation Example 1: [(1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl Imethanol 4-indole D-methanol (3.45 g, 30 mmol The solution formed in DCM (25 mL) was cooled to 0. </ RTI> was added sodium bicarbonate (24.72 g, 120 mmol). -38 - 201209054 Cyanide bromide (3.82 g, 36 mmol) was added dropwise to the mixture. The solution formed in water (10 mL) was stirred for 15 minutes, then the mixture was stirred at EtOAc for 2 hrs and then at room temperature for 16 hrs. The organic layer was separated and the aqueous layer was taken from DCM (4 X 50 mL) The mixture was extracted with EtOAc (EtOAc m.).

A solution of zinc chloride (3.73 g, 27.43 mmol) in EtOH (20 mL) was added to a solution of intermediate and N-hydroxyisobutylhydrazine (2.80 g, 27.43 mmol) in EtOH (30 mL). The solution lasted 15 minutes. The reaction mixture was stirred at room temperature for 2 hours. Then, 1 2 Μ H C1 (13.3 3 mL) was added, and then the mixture was heated at 50 ° C for 18 hours. After cooling to room temperature, the filtrate was filtered and concentrated under vacuum. The resulting residue was diluted with water (10 mL) then NaHC. The mixture was extracted with EtOAc (3 X 2 00 mL). EtOAc EtOAc (EtOAc) The solvent was removed under vacuum to give the title compound: </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; Preparation 2: 2-Chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine

[(1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl) _4-yl]methanol was cooled to 0 °C (Preparation Example 1 '丨· 13 g' 5. 〇mmo1) and triethylamine (0.77 mL, 5.5 mmol) in DCM (30 mL) were added dropwise -39-201209054 to formamidine sulfonium chloride (0.39 mL, 5.0 mmol). The reaction mixture was then allowed to warm to room temperature for 30 min. The mixture was partitioned between DCM (100 mL) and 1M EtOAc (150 mL). (3-isopropyl[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethyl ester. Add 2-chlorosulfonate to a solution of the intermediate in DMF (50 mL) -5-Alcohol (0.78 g, 6.0 mmol) and cesium carbonate (1·38 g, 10.0 mmol). The reaction mixture was heated to 80 ° C for 16 hr. 3 00 mL). The solution was washed with EtOAc EtOAc (EtOAc) (EtOAc) 3 3 8.1 [M+H]+. Preparation 3: 2-bromo-5-[1-(3-isopropyl-[l, 2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyridine

[(1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation Example 1 ' 1.13 g, 5.0 mmol) and 6-bromopyridine The solution of 3-ol (0.87 g, 5.0 mmol) in toluene (100 mL) was cooled to 0 ° C under argon. Add ADDP (2.52 g, 10.0 mmol), followed by dropwise addition of tri-n-butyl Phosphine (2.46 m L '1 0 · 〇mm ο 1). The resulting mixture was allowed to reach room temperature, then stirred for 1200 hours, then the solvent was evaporated in vacuo. (2 X 200 mL) rinse, then rinse with -40-201209054 brine (2 x 150 mL), and dry (MgS〇4). Purify by column chromatography (111: £ (〇人〇, 60:40) The title compound was obtained: 11 butyl = 2.37 min; m/z (ES + ) = 381.1, 3 8 3 · 1 [M+H] +. Preparation Example 4: 2-bromo-5-[l-(3-iso Propyl-丨1,2,4]oxadiazol-5-yl)piperidine-4-ylmethoxy]pyrazine

[(1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation Example 1) and 5-bromopyrazin-2-ol utilization The reaction was carried out in EtOAc EtOAc (EtOAc (EtOAc) M+H]+. Preparation 5: Methyl 3-(2,5-difluorophenyl)-4-nitrobutanoate

Mixture of (2E)-3-(2,5-difluorophenyl)acrylic acid (21.10 g, 114.7 mmol) in DCM and MeOH (DCM: MeOH, 4: 1,250

To the resulting solution was added a solution of trimethylsulfonyldiazomethane (2M Et 2 〇 solution &apos; 57.34 mL, 114.7 mmol) over 15 min and the mixture was stirred at room temperature until the reaction was complete. AcOH was added dropwise until the reaction turned to colorlessness and solvent was removed in vacuo. The residue was redissolved in MeCN (114 mL) then nitromethane (7.45 mL, 137.6 mmol). The mixture was cooled to 0 ° C then DBU (17.49 mL 201209054, 1 17.0 mmol) was added dropwise over 30 min. The reaction mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed under EtOAc (EtOAc)EtOAc. , 4.91-4.77 (m, 2H), 4.27-4.17 (m, 1H), 3.75 (s, 3H), 2.91 (m, 2H). Preparation 6: (trans)-1-benzyl-4-(2,5-difluorophenyl)-5-nitropiperidin-2-one

Methyl 3-(2,5-difluorophenyl)-4-nitrobutanoate (Preparation 5, 16·27 g, 62.81 mmol), trioxane (1·94 g, 64.63 mmol) and amide The composition (13.7 mL, 1 25.62 mmol) in EtOH was heated to 90 in a sealed tube. (: 16 hours. After the reaction was completed, the mixture was partitioned between EtOAc (400 mL) and 2M EtOAc (600 mL). The organic fractions were separated, washed with brine, dried (MgS04) and solvent Purified by column chromatography (EtOAc EtOAc (EtOAc:EtOAc) 1-benzyl-4-(2,5-difluorophenyl)_3_nitropiperidine hydrochloride

-42- 201209054 in (trans)-bromo-4-(2,5-difluorophenyl)-5-nitropiperidin-2-one under argon (preparation 6, 10.44 g, 30.17 mmol The borane dimethyl sulfide complex (2.OM DCM solution, 45.3 mL, 90.60 mmol) was added to a solution of THF (90 mL) and the mixture was warmed to 70. (: 3 hours. After cooling to room temperature, the mixture was diluted with MeOH (20 mL) and then 1M EtOAc (30 mL). The mixture was stirred for 10 min then solvent was evaporated in vacuo. The reaction mixture was stirred with EtOAc EtOAc (EtOAc m. [(3/?, 4i?)-l-Benzyl-4-(2,5-difluorophenyl)piperidin-3-yl 1carbamic acid tert-butyl ester

(trans)-1-benzylidene_4_(2,5-difluorophenyl)-3-nitropiperazine hydrochloride (Preparation Example 7, 11.12 g, 30.17 mmol) and zinc powder (15.69 g, 241.36) Methyl) The composition in a mixture of AcOH and EtOH (1:1, 110 mL) was heated to 80 〇C. After the reaction was completed, the mixture was filtered and the solvent was removed in vacuo. A solution of the obtained residue in MeOH (30 mL). The resulting material was rapidly precipitated in Et: 2 Torr (x2), followed by rapid precipitation in toluene (χ3) to give the hydrochloride salt of the amine intermediate. This intermediate formed a solution in a mixture of THF (ISO mL) and water (75 mL), cooled to hydrazine, and added triethyl-43-201209054 amine (12.6 mL, 90.51 mmol), followed by the addition of dicarbonate Butyl ester (9.59 g, 45.26 mmol). The mixture was warmed to room temperature and stirred for 16 hours until the reaction was completed. The mixture was partitioned between EtOAc (750 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (500 mL). EtOAc evaporated. Purified by column chromatography (IH: EtOAc, 80: 20), then purified by HPLC (IH: IPA: DEA, 90: 10: 0.1, 15 mL/min, 27〇11111, 11 butyl = 9.8 Minutes, the title compound: 11 butyl = 2.68 min; w/z (ES + ) = 403.2 [M+H]+. Preparation 9: [(3 and 4, 4-dioxo-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester

[(3/?, 4i〇-l-benzyl-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 8, 1.89 g, 4.70 mmol The solution formed in MeOH (94 mL) was passed through a H-Cube hydrogenation apparatus (10% Pd/C Catcart 70, 30 bar, 80 〇C) at a flow rate of 1 mL/min. The solvent was removed in vacuo to give the title compound. : RT = 2_37 min; m/z (ES + ) = 3 1 3 · 2 [Μ + Η] +. Preparation Example 10: 1-piperidinylethanol in α-methyl-4-pyridinemethanol (3.7 g, 30 mmo丨) at EtOH (100 -44- 201209054

To the resulting solution was added AcOH (1.9 mL, &lt;RTI ID=0.0&gt;&gt;&gt; The mixture was filtered and the mash was concentrated in vacuo. A solution of NaOH (1.6 g, 40 mmol) and water (1.6 mL) in MeOH was added to a solution of the residue dissolved in MeOH. The reaction mixture was stirred for 30 min' then the solvent was removed in vacuo and the residue was suspended in Et20 over 30 min. The mixture was filtered, and the EtOAc was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 2H), 2.01-1.92 (m, 2H) &gt; 1.76- 1.69 (m &gt; 1H) &gt; 1.67- 1.54 (m &gt; 2H) &gt; 1.51-1.42 (m , 1H), 1. 1-1 . 14 (m, 3H). Preparation 11: Piperidine-4-ylethanol The title compound was prepared from (&lt;S)-(-)-a-methyl-4-indole steep methanol using the procedure described in Preparation 10: 4 NMR δ Η ( 400 MHz, CDC13): 3.63 -3.5 5 (m,1H), 3.39-3.31 (m,2H),2.7-2.6 (m,2H),2.01-1-92 (m,2H),1.76- 1.69 (m , 1H), 1.67-1.54 (m , 2H), 1.51-1.42 (m, 1H), 1.1-1.14 (m, 3H). Preparation Example 12: Hydroxymethylpiperidine-1·isopropyl isopropylate under argon in a 3-neck flask in 4-piperidinemethanol (12.0 g, 1·4·12 mmol) in DCM (200 mL) DIPEA (23.6 mL, 135.42 mmol) was added to the resulting solution and the mixture was cooled to 0 °C. A toluene solution of isopropyl chloroformate (1 M, 120 mL' 119.79 mmol) was added dropwise over a period of -45 - 201209054 1 s 5 hrs, then the mixture was returned to room temperature and stirring was continued for 2.5 hours. The mixture was partitioned between 1M EtOAc (EtOAc) (EtOAc)EtOAc. The solvent was removed in vacuo to give the title compound: 4 NMR δ δ (400 MHz, CDC13): 4.96-4.8 6 (m, 1H), 4.09-4.25 (m, 2H), 3.5 1 (d, J = 6.2 Hz, 2H ), 2.8 0-2.6 8 (m &gt; 2H) &gt; 1.7 8 - 1.62 (m, 3H), 1.49-1.41 (m, 1H), 1.29- 1.09 (m, 8H). The following compounds were prepared from the appropriate piperidine starting materials using the procedure described in Preparation 12: Preparations No.. &lt;RTI ID=0.0&gt;&gt; NMR δ Η (400 MHz, CDC13): 4.97-4.87 (m, 1H), 4.28-4.14 (m, 2H), 3.66-3.55 (m, 1H), 2.77-2.63 (m, 2H), 1.88-1.81 (m , 1H), 1.67-1.59 (m, 1H), 1.48-1.38 (m, 1H), 1.26-1.16 (m, 11H). 14 丫T〇4-((5)-1-hydroxyethyl)piperidine Isopropyl 1-formate! H NMR δ Η (400 MHz, CDC13): 4.97-4.85 (m, 1H), 4.31-4.10 (m, 2H), 3.64-3.53 (m, 1H), 2.69 (t, 7 =12.69 Hz, 2H), 1.83 (d, 1H), 1.62 (d, 1H), 1.49-1.38 (m, 1 H), 1.30-1.10 (m, 11H). Preparation 15 : 4-(6_bromo Isopropyl pyridin-3-yloxymethyl)piperidine-1-carboxylate

Add tri-n-butylphosphine (4.95 mL, 19.87 mmol) to a dry solution of ADDP (5.01 g, 19-87 mmol) in toluene (200 mL), followed -46-201209054

6-Bromo D was added to the steep 3-ol (1.73 g, 9.94 mmol) and the reaction mixture was cooled to 〇 °C for 5 min. A solution of 4-hydroxymethylpiperidine-1-carboxylic acid isopropyl ester (Preparation Example 12, 2.0 g, 9.94 mmol) in toluene (50 mL) was added dropwise to the solution over a period of 5 min. . (: stirring for 16 hours. Add IH (200 mL), stir the reaction mixture for 1 Torr, then filter the mixture to remove the precipitate. The filtrate was passed through 2 ΜN a Ο Η solution (2 X 150 mL), water (150 (1 mL), 1 Μ HCl solution (2 χ 150 mL), and brine (150 mL), and then dried (MgS04). The solvent was removed in vacuo and purified by column chromatography (IH: EtOAc, 4:1, 3:1 The title compound was obtained: RT = 3_87 min; m &quot; (ES + ) = 3 5 9.1 [M+H] +. Preparation Example 16: (3 s. 4^)-4-azido-1-benzylpyrrole Pyridin-3-amine

Add dropwise to a solution of (3 14^)-3,4-diazido-1-benzylpyrrolidine (15.6 g, 64.10 mmol) in THF (500 mL) cooled to EtOAc. A solution of triphenylphosphine (16.5 g, 62.81 mmol) in THF (100 mL). Bring the resulting mixture back to room temperature and stir 1 6

hour. The reaction solvent was removed in vacuo and the obtained residue was purified eluted eluted eluted The mixture was heated under reflux for 4 hours and then stirred at room temperature for 16 hours. The reaction solvent was removed under vacuum, and the obtained residue was quickly precipitated from Et20. The precipitate was filtered and the filtrate was concentrated in vacuo. The residue was again placed in Et20 and filtered. The filtrate was concentrated under vacuum and purified by column chromatography (EtOAc: EtOAc, EtOAc, EtOAc

The title compound: RT-47-201209054 =0.77 min; m/z (ES+) = 218·1 [from +H]+. Preparation 17: ((3^,4*S)-4_azido-1~-p-pyrrolidinyl-3-yl)-tert-butyl methacrylate

(35,4^)-4-azido-1-benzylpyrrolidin-3-amine (preparative Example 16, 6.0 g, 27.74 mmol) and triethylamine (4.6 mL' 33.29). Mm ο 1) A solution of di-tert-butyl carbonate (7.3 g, 33.29 mmol) in DCM (10 mL) was added dropwise to a solution of DC Μ (1 0 0 m) for 20 min. The resulting mixture was returned to room temperature and stirred for 72 hours. The reaction solvent was rinsed with a saturated NaHC03 solution, followed by brine washing and drying (MgS04). The solvent was removed under EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut elut , 3.84-3.76 (m, 1H), 3.68 -3.59 (m, 2H), 3.12-3.01 (m, 1H), 2.91-2.82 (m, 1H), 2.5 5-2.3 5 (m, 2H), 1.46 ( s ' 9H). Preparation 18: ((3^,4^)-4-amino-1-benzylpyrrolidin-3-yl)carbamic acid tert-butyl ester

The title compound is obtained by the procedure described in W Ο 2 0 0 7 / 1 4 8 1 8 5 from -48 to 201209054 ((3 nt)-4-azido-1-benzylpyrrolidin-3-yl) Prepared with tert-butyl carbazate (Preparation Example I7). Preparation Example I9: -Benzyl-4-(2-ketopiperidin-1-yl)pyrrolidinyl-3-yl]carbamic acid tert-butyl ester

The title compound was obtained from the ((35,45)-4-amino-1-benzylpyrrolidin-3-yl)carbamic acid by a third step using the procedure described in WO 2 0 07/1 4 8 1 8 5 Preparation of butyl ester (Preparation Example 18). Preparation 20: [(3·5,4·5)-4-(2-ketopiperidin-1-yl)pyrrolidin-3-yl]aminocarboxylic acid tert-butyl ester

[(3 nucleus 4-phanyl-1-benzyl-4-(2-ketopiperidin-1-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 19, 2.6 g, 7.07 mmol The solution formed in MeOH (140 mL) was passed through a H-Cube hydrogenation apparatus (10% Pd/C Catcart 70, 10 bar, 90 ° C) at a flow rate of 1 mL/min. The solvent was removed under vacuum to give the title compound. · 4 NMR δ Η (400 MHz, CDC13): 5.25-5.07 (m, 1H), 4.85-4.62 (m, 1H), 4.34-4.07 (m, 1H), 3.49-3.28 (m, 3 H), 3 · 2 4 (s,1 H),2.9 9 (s,1 H), -49- 201209054 2.87-2.73 (m,1H),2.52-2.39 (m,2H) ' 2.3 8-2.22 (m, 2H), 1.9 1.74 (m, 1H), 1-54-1.3 8 (m, 9H). Preparation 21: 4-Methanesulfonyloxymethylpiperidine-1-carboxylic acid isopropyl ester under argon at 4 -Hydroxymethylpiperidine-1-carboxylic acid isopropyl ester (Preparation Example 12, 2.5 g, 12.42 mmol) was added EtOAc (EtOAc (EtOAc) Cool to 0 ° C. Methanesulfonium chloride (1·〇6 mL, 13.66 mmol) was added dropwise over 4 minutes, then the reaction mixture was stirred at 〇 ° C for 30 min. The mixture was diluted with DCM (50 mL) The organic layer was washed with water (2×50 mL), EtOAc (EtOAc) (EtOAc) (EtOAc) , DMSO-d6): 4.95-4.8 5 (m, 1H), 4.25-4.18 (m, 2H), 4.17-4.07 (m, 2H), 3_31 (s, 3 Η ), 2 _ 9 8 - 2.7 9 ( m, 2 Η), 2 · 0 8 - 1 . 9 6 (m, 1 Η), 1.85-1.75 (m, 2 Η), 1.35-1.17 (m, 8 Η). Preparation 22: 4-(4-bromobenzene Isopropyl oxymethyl) piperidine-1-carboxylate

Under argon, in 4-methanesulfonyloxymethylpiperidine-1-carboxylic acid isopropyl ester (Preparation 21 ' 3.40 g ' 12.17 mmol) and 4-bromophenol (2.32 g, 13.39 mmol) in DMF ( 70 mL) of the resulting solution was added potassium carbonate (3.36 g, 24.34 mmol) and the reaction mixture was heated to 90. (: 16 hours. The reaction solvent was removed under vacuum, then the crude residue was dissolved in EtO Ac (200 m) and then rinsed with water (3 x 1 0 0 m). The extract was extracted with EtOAc (5 mL). EtOAc (EtOAc m. RT = 4.36 min; m/z (ES + ) = 5 3 6.2 [M+H] +. Preparation 23: 4_methanesulfonyloxymethylpiperidine-1-carboxylic acid tert-butyl ester

Add triethylamine (5.0 mL, 3 5.9) to a solution of 4-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 23.2 mmol) in DCM (100 mL). Mm). Methanesulfonium chloride was added dropwise to the mixture for 5 minutes, and the resulting reaction mixture was stirred at 0 ° C for 30 minutes. The mixture was rinsed with water, then rinsed with brine and dried (MgS04). The solvent was removed in vacuo to give the title compound: 4 NMR δ δ (400 MHz, CDC13): s. s. s., s., s., s. -2.65 (m, 2H), 1.97-1.8 7 (m, 1H), 1.77-1.71 (m, 2H), 1.46 (s, 9H), 1.29-1.15 (m, 2H).制备 Preparation Example 24: tert-butyl 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-1-carboxylate

In 4-dimethylsulfonyloxymethylpiperidine-1-carboxylic acid tert-butyl ester (Preparation Example 23, 1.47 g, 5.0 mmol) and 2-chloropyrimidine-5-ol (0.65 g, 5.0 mmol) Potassium carbonate (〇·83 g, 6.0 mmol) was added to a solution of DMF (80 mL), and the mixture was heated to 80. (: until the reaction is complete. The solvent is removed under vacuum, and the residue obtained is redissolved in Et0Ac (3 00 mL). Dissolved -51 - 201209054 solution by 1 Μ N a Ο Η solution (200 m L) and brine (2 </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; (s, 1H), 4.18 (b rs, 2 Η), 3 · 9 2 (dd ' • 7 = 6.25, 3.51 Hz, 2H), 2.78 (t, J = 12 · 3 0 Hz, 2H), 2.09- 1.95 (m, 1H), 1.84 (d, 7-128.89 Hz, 2H), 1.49 (s, 9H), 1.4, 1.24 (m, 2H). Preparation 25: 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-1-carboxylic acid isopropyl ester

Add to a solution of 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (Preparation 24, 820 mg '2.51 mmol) in DCM (25 mL) A solution of HCl in dioxane (4M, 2.51 mL, 10.04 mmol). The reaction solvent was removed under vacuum, and the obtained residue was redissolved in TH. The mixture was cooled to zero. C, triethylamine (0.75 mL '5_52 mmol) was added dropwise, followed by a solution of isopropyl chloroformate in toluene (1M, 3.02 mL, 3.02 mmol). The mixture was stirred at room temperature for 2 hours' and then the solvent was concentrated in vacuo. The residue was dissolved in D C Μ, rinsed with a saturated NaH C Ο 3 solution, and then rinsed with a solution of &lt;RTIgt; The solvent was removed in vacuo to give the title compound: &lt;RTI ID=0.0&gt;&gt; Preparation 26: 4-(1-Methanesulfonyloxyethyl)piperidine-1-carboxylic acid isopropyl ester-52-201209054 Under argon, in 4-(1-hydroxyethyl)piperidine-1- Isopropyl formate (Preparation Example 13, 3.02 g, 14.1 mmol), EtOAc (EtOAc, EtOAc) Methanesulfonium chloride (1.20 mL, 15.5 mmol) was added dropwise over 5 minutes, and the reaction mixture was allowed to warm to room temperature and stirred until the reaction was completed. The crude mixture was partitioned between DCM (150 mL) and 1M EtOAc (500 mL). The organic layer was separated, then rinsed with 1M EtOAc (400 mL), dried (MgS04) Compound: 4 NMR δ Η (400 MHz, CDC13): 4.94 (spt &gt; 7 = 6.25 Hz, 1H) ' 4.68 (quin &gt; /=6.2 5 Hz, 1H), 4.38-4.19 (m, 2H), 3.04 ( s, 3H), 2.80-2.67 (m, 2H), 1.86-1.66 (m, 3H), 1.42 (d, J = 6.2 5 Hz &gt; 3H), 1.39-1.24 (m, 8H). Preparation 27: 4-[l-(2-Chloropyrimidin-5-yloxy)ethyl]piperidine-1·isopropyl isopropylate

The title compound was purified by 4-(1-methanesulfonyloxyethyl)piperidine-1-carboxylic acid isopropyl ester (Preparation Example 6 6) and 2-chloropyrimidine-5- using a procedure similar to that described in Preparation. It was prepared by alcohol reaction, but in this case, the reaction mixture was heated to 100. (: : RT = 3_75 min; m/z (ES + ) = 3 28.1 [M+H] +. Preparation 28: 4-((5)-1-methanesulfonyloxyethyl)piperidine-1 -isopropyl formate-53-201209054 4-(()--1-hydroxyethyl)piperidine-1-carboxylic acid isopropyl ester (Preparation Example 14) and methanesulfonyl chloride are similar to those described in Preparation Example 2 The reaction was carried out in EtOAc (50 mL). The solvent was removed in vacuo to give the title compound: 4 NMR δ δ (400 MHz, CDC13): 5.01-4.82 (m,1H), 4.70-4.5 8 (m,1H), 4.3 3-4.08 (m, 2H), 3.01 (s, 3H), 2.82 - 2.5 3 (m , 2H), 1.8 8 - 1.5 5 (m &gt; 3H) &gt; 1.41 (d &gt; J = 6.25 Hz &gt; 3H) &gt; 1 .3 8- 1 .08 (m, 8H). Preparation 29: 4-[(Phantom-1-(2-chloropyrimidin-5-yloxy)ethyl)piperidine-1-carboxylic acid isopropyl ester

In 4-( methanesulfonyloxyethyl)piperidine-1-carboxylic acid isopropyl ester (serving Example 28, 1.85 g, 6.30 mmol) and 2-chloropyrimidin-5-ol (0.69 g, 5.25 mmol) Potassium carbonate (1.45 g, 10.50 mmol) was added to a solution of DMF (40 mL), and the mixture was heated to 100. &lt;: until the reaction is complete. The reaction mixture was poured into a mixture of water (3 mL) and brine (300 mL). The organic layer was combined, washed with brine (1 mL), dried (M gS04), and evaporated in vacuo. Purification by column chromatography (EtOAc (EtOAc:EtOAc:EtOAc):jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 30: 2,4-Difluoro-1-((fluorene)-2-nitrovinyl)benzene 2,4-difluorobenzaldehyde (25.0 g' 〇·18 mol) and nitromethane (11.4 mL, 0.21 Mol) solution in MeOH (53 mL) was cooled under argon

It is up to -15 °C. A solution of NaOH (7.4 g, 0.19 mol) in water (26 m L) was added dropwise over 20 minutes. The resulting mixture was stirred at -1 5 ° C, and a precipitate formed after 30 minutes. More MeOH was added to form a slurry which was stirred for a further 15 minutes before the reaction mixture was allowed to warm to EtOAc. Ice water was added, and the mixture was stirred for 15 minutes, after which 4 M HCl (100 mL) was added. The organic fractions were extracted with DCM (3×3 0 mL) dried (Na2S04) and solvent was evaporated in vacuo. A portion of the residue (1 〇. 〇 g, 50 mmol) was dissolved in acetic anhydride (8.1 mL, 90 mol) under argon and cooled to 0 °C. DMAP (0.4 g, 3 mmol) was added, and the reaction mixture was stirred at this temperature for 20 minutes, then the mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction solvent was removed under vacuum and the residue obtained was dissolved in DCM. Any residual acetic anhydride was destroyed by the addition of a small amount of 1 M NaOH solution, and the resulting solution was dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (〇〇14)' gave the title compound: 1^ = 3.60 min; /2 ( ug 3 + ) = 1 86.1 [M+H]+. Preparation 31: (trans)-1_benzyl_3_(2,4-difluorophenyl)·4_nitropyrrolidine -55- 201209054

A solution of 2,4-difluoro-1-((fluorene)-2-nitrovinyl)benzene (Preparation Example 30, 8.0 g '43.0 mmol) in DCM (250 mL) was cooled under argon to - 30. (:, N-(methoxymethyl)-N-(trimethyldecylmethyl)benzylamine (11.7 mL, 45.0 mmol) was added to maintain the temperature. The reaction mixture was stirred for 1 Torr, then TFA (0.3) was added dropwise. </ RTI> <RTI ID=0.0></RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; ;m/z (ES + ) = 319.1 [M+H]+. Preparation 32: 丨(trans)-1-benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl J tert-butyl carbamic acid

(trans)-1-benzyl-3-(2,4-difluorophenyl)-4-nitropyrrolidine (Preparation 31 '25.0 g '0.08 mol) and zinc powder (17.8 g, 0.28 mol) The mixture formed in a mixture of AcOH and EtOH (1: 1,500 mL) was heated to 70. (: After 45 hours, add another zinc powder (12.0 g, 0.18 m〇i), and continue to heat for 20 minutes. After the reaction is complete, remove the solvent under vacuum. The resulting residue is redissolved in E t OA c, Rinse with a saturated solution of N a HC Ο 3, followed by rinsing with brine, and drying (N a: S Ο 4). The solvent is removed under vacuum to give the product (trans)-1-benzyl- 4-(2,4-Difluorophenyl)pyrrolidine-3-amine: RT = 1.82 min; w/z (ES + ) = 2 8 9.1 [M+H]+.

Triethylamine (20.4 mL, 0.15 mol) was added to a solution of the product in THF (400 mL) under argon, and the solution was cooled to 〇 °C. Diacid-t-butyl vinegar (19.0 g, 0.09 mol) was added over 5 minutes to bring the reaction mixture back to room temperature for 16 hours. The solvent was removed in vacuo and the residue was crystallised eluted eluted eluted eluted Heptane (100 mL) was added to the product. The suspension was sonicated until it was completely dissolved. The solution was allowed to stand for 60 hours to form a precipitate. The solvent was evaporated, and EtOAc (EtOAc m. Preparation 33: 丨(3Λ,45)-1-benzyl-4-(2,4-difluorophenyl)pyrrolidine _3·yl] tert-butyl carbamic acid

The title compound was isolated by palmitic HPLC via [(trans)_1-benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 32). (IH: IPA: DEA 9 6: 4: 0.1 » 15 mL/min, 270 nm, RT = 9.8 minutes). Preparation 34: [(3Λ,4Χ)-4-(2,4-difluorophenyl)pyrrolidin-3-yl]aminoglycolic acid tert-butyl ester -57- 201209054

The title compound was obtained from [(3 and, 4, phantom: 1-benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 33). Prepared in the procedure described in Preparation 20, but at a temperature of 50 ° C: RT = 2.38 min; w/z (ES + ) = 299.1 [M+H]+. Preparation 35: 2,4,5-trifluoro- L-((E)-2-Nitrovinyl)benzene

The title compound was prepared from 2,4,5-trifluorobenzaldehyde using a procedure similar to that described in Preparation 30. After reaction with DMAP, the crude mixture was diluted with a saturated NaHC?3 solution. The resulting precipitate was stirred for 3 minutes, filtered and dried under vacuum to give the title compound: iH NMR δ Η (300 MHz, CDC13): 7.97-7.93 (m'lH), 7.66-7.62 (m,lH),7.42- 7.26 (m ' 1H), 7.16-6.96 (m, 1H). Preparation 36: (trans-di-benzyl-benzyl_3_(2,4,5-trifluorophenyl)_4_nitrosyridylpyridine

The title compound was prepared by the method described in Preparation 31 from 2,4,5-trifluoro-indole ((E)-2-nitrovinyl)benzene (-58-201209054 Preparation Example 35), but the reaction was It is carried out at 〇 °C. Purification by column chromatography (hexane:EtOAc:EtOAc:EtOAc: LCMS Method 2: RT = 0.94 min; w/z (ES+) = 3 37.2 [Af+H]+. Preparation 37: [(trans)-1-benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

(trans)-1-benzyl-3-(2,4,5-trifluorophenyl)-4-nitropyrrolidine (Preparation 36' 11.5 g, 〇_〇3 mol) and zinc powder ( 18.0 g, 0.28 mol) The mixture formed in the AcOH and IMS mixture (1: 1,210 mL) was heated to 65. Hey. After the reaction was completed, the mixture was filtered, washed with EtOAc, and evaporated. The residue was redissolved in EtOAc (EtOAc)EtOAcEtOAcEtOAc The solvent was removed under vacuum and purified by column chromatography (DCM: MeOH, EtOAc: EtOAc: EtOAc: EtOAc: Base) pyridyl-3-amine. LCMS Method 2: RT = 0.82 min; w/z (ES + ) = 3 07.2 [M+H] + 〇 Under argon, diethylamine (3.9) was added to the solution of the product in THF (110 mL). mL, 〇.〇4 mol), the mixture was cooled to 〇 °C. Di-tert-butyl dicarbonate (4.7 g, 0. 02 mol) was added over 5 minutes, then the reaction mixture -59-201209054 was warmed to room temperature and stirred for 16 hours. The solvent was removed in vacuo then EtOAcqqqqqqqqqqqqqq The product was quickly precipitated from heptane and was repeated several times to give the title compound. LCMS Method 3: RT = 3.10 min; m/z (ES+) = 407.3 [M + H]+. Preparation 38: [(trans)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]aminocarbamic acid tert-butyl ester

[(trans)-1-benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester under argon (Preparation Example 37, 40.1 g, 98.8 mmol) of a solution of a mixture of IMS (3 25 mL) and EtOAc (50 mL) was placed in a hot pot. A slurry formed of palladium on carbon (5 %, 4.0 g, 1.9 mmol) in a minimum amount of toluene was added, and then the reaction mixture was placed in a hydrogen atmosphere (50 atm) and stirred for 72 hours. The crude mixture was filtered with EtOAc EtOAc eluting LCMS method 4: RT = 2.42 min; m/z (ES+) = 317.2 [M+H]+. Preparation 39: [(3i?,4iT)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]aminocarbamic acid tert-butyl ester -60- 201209054

[(trans)-4_(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 38' 30.0 g, 95 mmol) suspended in EtOH (100

(mL) and heat to 70 °C. A warm solution mixture of (S)-( + )-naproxen (10_9 g, 47 mmol) in EtOH (100 mL) was added to the suspension and heated to reflux. The heater was removed and the mixture was stirred slowly to room temperature for 16 hours. The resulting precipitate was filtered, and the solid product was partitioned from Et.sub.2 (2400 mL) and 1M NaOH (600 mL). The organic layer was separated, washed with 1 ΜN a Ο Η and brine, then dried (MgS04) and solvent was evaporated in vacuo. A second portion of [(trans)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 38, 29.5 g, 93 mmol) Suspended in EtOH (1 00 mL) and heated to 70 °C. The second batch of the enantiomers enriched in the image is obtained according to the procedure described above, which was treated with a warm solution of (magic (+)-naproxen (10.6 g, 46 mmol) in EtOH (100 mL). The second batch of product was suspended in EtOH (200 mL) and then treated with a hot solution of &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&& To the reflux and repeat the purification procedure to give the title compound: 4 NMR δ Η (4 〇〇 MHz, CD3 OD): 7.3 8 -7.25 (m, 1H), 7.14-7.01 (m '1H) ' 4.20-4.09 (m, lH), 3.30-3.21 (m, 3H), 2.90-2.81 (m '1H), 2.77-2.68 (m, 1H), 1.34 (br.s., 9H) -61 - 201209054 Preparation 40: [(Reverse 1-benzyl-4-(2,3-difluorophenyl)pyrrolidin-3-yl J-tert-butyl ester

The title compound was obtained from 2,3-difluorobenzaldehyde in 3 steps using the synthetic procedure described in Preparation 37. LCMS Method 3: RT = 3·04 min; m/z (ES+) = 3 8 9.3 [Μ+Η]+. Preparation 41: [(3/?,4*S)-1-pyristyl-4-(2,3-propylphenyl)pyrene is slightly steeper-3-yl] tert-butyl carbamic acid

The title compound was isolated via the palm of the formula [(trans)-bromo-4-(2,3-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 40). (IH: IPA: DEA 96.5: 3.5: 〇·1,15 mL/min, 270 nm, RT = 1 0·6 minutes). Preparation 42: 丨(3145)-4-(2,3-difluorophenyl)pyrrolidin-3-yl]aminobutyrate tert-butyl ester -62- 201209054

The title compound was obtained from [(3/?,4&lt;5)-1-benzyl-4-(2,3-difluorophenyl)pyrrolidin-3-yl]amine by the procedure described in Preparation 20 Preparation of tert-butyl formate (Preparation 41), but at a pressure of 30 bar: 'Η ΝΜΙΙδΗ (400 MHz, CDC13): 7.17-6.93 (m, 3H), 4.3 1-4.08 (m, lH), 3.57- 3.39 (m, 2H), 3.38-3.17 (m ' 1H), 3.06-2.81 (m, 2H), 1.40 (br.s., 9H). Preparation 43: [(trans)-1-benzyl-4-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

The title compound was prepared from 4 -chloro-2-fluorobenzaldehyde in 3 steps using the synthetic procedure described in Preparation 37. LCMS Method 3: RT = 3 25 min; m/z (ES+) = 405.4 [M+H]+. 4-(4-Chloro-2-fluorophenyl) Preparation 44: [(trans)-3_t-butoxycarbonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester -63- 201209054

nC^-V Τ 第三 in [(trans)-1-benzyl-4-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 43, 2.03 g, 5.01 mmol) of 1,8-bis(dimethylamino)naphthalene (1.02 g, 4.76 mmol) and 1-chloroethyl chloroformate (1.60 mL, 14.70 mmol). The reaction mixture was heated under reflux for 1 hour and then at room temperature for 16 hours. The crude mixture was passed through a short column of silica gel (DCM: MeOH, 100:0, 10:1, 4:1), and the polar fractions were combined and concentrated under vacuum. The residue obtained was dissolved in MeOH (100 mL)EtOAc. DIPEA (5 mL, 28.7 mmol) was added to the solution, followed by dibutyl succinate (3.02 g, 13.8 mmol), and the mixture was stirred at room temperature for 45 min, then solvent was evaporated in vacuo. The residue was taken up in EtOAc (300 mL)EtOAc. The solvent was removed under EtOAc (EtOAc)EtOAc. Preparation 45: 丨(trans)_4·(4-chloro-2-fluorophenyl)pyrrolidin-3-ylaminobutyl methacrylate

Zinc bromide (5.00 g, 19.6 mmol) in DCM (50 mL) -64- 201209054

The suspension was stirred under argon at room temperature for 16 hours. A portion of the suspension (3.50 mL) was added to [(trans)-3-t-butoxycarbonylamino-4-(4-chloro-2-fluorophenyl)pyrrolidine-benzoic acid tert-butyl ester ( In Preparation 44, 0.25 g, 0.6 mmol), the mixture was stirred for 4 hr. 1 M NaOH solution (1 mL) was added, followed by EtOAc (100 mL) and the mixture was stirred for 10 min then filtered. The filtrate was extracted with EtOAc then EtOAc (EtOAc)EtOAc. Purified by column chromatography (EtOAc EtOAc EtOAc (EtOAc)

Preparation 46: [(trans)-1-benzyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl-J-carbamic acid tert-butyl ester

The U title compound was prepared from the 2,5-dioxybenzophenone in 3 steps using the synthetic procedure described in Preparation 37. 1^]\/18 Method 3: 1^丁 = 3.04 min; m/z (ES + ) = 3 8 9.3 [M+H] + ° Preparation 47: [(3145)-1-benzyl-4- (2,S-difluorophenyl)pyrrolidine_3_yl]carbamic acid tert-butyl ester

-65- 201209054 The title compound is via [(trans)-1-benzyl-4-(2,5-difluorophenyl)-la-l-yl-yl]- carbamic acid tert-butyl ester (Preparation 46) The palmar HPLC separation (IH: IPA: DEA 96: 4: 0·1, 15 mL/min, 270 nm, RT = 10.9 min) was obtained. Preparation 48: tert-butyl phthalate (3β,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamate

The title compound was obtained from [(3 and,4^)-1-benzyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 47) Prepared by the procedure described in Preparation Example 20 except that the reaction was carried out at a pressure of 30 bar. RT = 2_3 5 minutes; m/z (ES + ) = 299.2 [i/+H]+. Preparation 49: (Λ)-3-丨1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]butyric acid

Oxide (vi) (5 g) was added to a concentrated H2S solution (5 mL) with stirring to form a thick brown paste. The paste was added to water (15 mL) and the mixture was cooled to 0 &lt;0&gt;C to afford a bright red/orange solution. The other one is cooled to 〇 °C (i〇-3-[l-(3-isopropyl-[1;2,4]ox-66-201209054 oxazol-5-yl)piperidin-4- Add a drop of red Jones reagent to the solution of butan-1-ol (250 mg, 0.94 mmol) in acetone (100 mL) until the yellow color is no longer observed. Add a few drops of IP A to the reaction mixture. The reaction was quenched and the mixture was evaporated EtOAcjjjjjjjjjjjjjjjjj The mixture was washed with EtOAc (EtOAc m. Piperidine-1-carbonitrile

A solution of NaHC03 (44.0 g) in water (60 mL) was added to a solution of 4-piperidinemethanol (15 g, 0.13 mol) in DCM (60 mL), and the mixture was cooled to 0 °C. A solution of cyanogen bromide in DCM (3M, 48. 5 mL, 0.15 mol) was applied dropwise over 40 min and the mixture was warmed to room temperature for 90 minutes. The mixture was filtered and the organic layer was separated. The aqueous layer was extracted with DCM, then the organic fraction was combined, washed with saturated NaHCO3 and brine, and dried (MgS04). The solvent was removed in vacuo to give the title compound: NMR δ δ 300 (300MHz, CDC13): 3.5 6-3.3 5 (m, 4H), 3.10- 2.91 (m, 2H), 1.85-1.51 (m, 4H), 1.46-1.25 (m, 2H). Preparation 51: [(1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidine-4-yl]methanol 4-hydroxymethylpiperidine-1-carbonitrile ( Preparation 50, 7.5 g, 〇.〇5 m〇1) was mixed with N-pyridinium (5.7 g, 0.06 mol) in EtOH (150 mL). -67- 201209054 Zinc chloride was added to the mixture ( II) (8.8 g, 0.06 mol) in EtOH (10 mL) for 15 min. The reaction mixture was stirred at room temperature for 2 h. then concentrated H.sub.1 (25 m. The reaction mixture was heated under reflux for 4 h. The reaction was concentrated in vacuo. EtOAc was evaporated.jjjjjjjjjjjjjjjj The solvent was removed and purified by EtOAc EtOAcjjjjjjjjjj 3-ethyl-[1,2,4]oxadiazol-5-yl)piperidine-4-ylmethyl ester in [(1-(3-ethyl-[1,2,4]oxadiazole- Drying of 5-yl)piperidin-4-yl]methanol (Preparation 51' 3.50 g, 16.57 mmol) in DCM (95 mL) Triethylamine (4·60 mL, 33.13 mmol) was added to the solution, and the mixture was cooled to 5 ° C. The mixture was added dropwise to a mixture of chlorine (1.30 mL, 16.57 mmol) for 5 minutes. The mixture was stirred and allowed to warm to room temperature. The reaction was completed. The crude mixture was partitioned between EtOAc EtOAc EtOAc (EtOAc m. z (ES + ) = 290.1 [M+H] +. Preparation 53: 2-chloro-5-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidine -4- methoxy a pyrimidine

-68 - 201209054 1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethyl methanesulfonate (Preparation 52, 440 mg, 1.51 mmol) A mixture of 2-chloropyrimidin-5-ol (270 mg '1.81 mmol) and potassium carbonate (417 mg, 3.02 mmol) in DMF (20 mL) was heated to 1 Torr in a microwave reactor. (: 2 hours. The reaction solvent was concentrated under vacuum, and the obtained residue was dissolved in EtO Ac. The solution was washed with 1M NaOH solution (?2) and brine, then dried (MgS04), and then solvent was removed under vacuum. The title compound (4M NMR δ Η (400 MHz, CDC 13): 8.27 (s, 1H), 8.25 (s, 1H), 4.26 - 4.15 (m, 2H), 3.95 -3.85 (m, 2H), 3. 15-3.00 (m, 2H), 2.62-2.50 (m, 2H), 2.15-2.01 (m, 1H), 1.97- 1.85 (m, 2H), 1.52- 1.3 8 (m, 2H), 1.30-1 _ 1 9 (m, 3H). Preparation 54: 4-[l-(6-bromopyridin-3-yloxy)ethyl]piperidine-1-carboxylic acid isopropyl ester

异丙 4-(1-methanesulfonyloxyethyl)piperidine-1-carboxylic acid isopropyl ester (Preparation 26, 967 mg &gt; 3.30 mmo 1) and 6-bromopyridin-3-ol (6 3 2 Mg, 3.6 3 mmol) Potassium carbonate (1366 mg, 9.90 mmol) was added to a solution of DMF (10 mL), and the mixture was warmed to 1 ° C for 16 hours. The solvent was concentrated in vacuo and EtOAcqqqqqqq The product was dissolved in a small amount of MeOH to give crystals. The crystals were collected by EtOAc (EtOAc):EtOAc: 201209054 Preparation 55: 2_Chloro-5-methoxy-4-methylpyrimidine under argon in 2,4-chloro-5-methoxypyranidine (1.5 g, 8.38 mmol) in THF (15 mL) was added to a solution of trimethyltriborotrioxane (1.2 g, 9.22 mmol), dichlorobis(triphenylphosphine) 10 (0.6 g, 0.84 mmol) and phosphoric acid. Potassium (3.6 g, 16.76 mmol) and the mixture was heated under reflux for 16 h. The reaction mixture was diluted with E t Ο A c, washed with water and then dried (Na2SO4). The solvent was removed in vacuo and purified with EtOAc EtOAcjjjjjjjjjjj = 159.0 [M+H] + Preparation 56: 2-chloro-4-methylpyrimidine-5-ol 2-chloro-5-methoxy-4-methylpyrimidine (Preparation 55, 1.1 g, 6.94 mmol The dried solution formed in DCM (20 mL) was cooled to -78 under argon. &lt;3. Boron tribromide (2.63 mL, 27.82 mmol) was added dropwise over 15 minutes, then the reaction mixture was stirred at -78 °C for 20 minutes then stirring was continued at room temperature for 16 hours. The mixture was cooled to -78 ° C, and MeOH was added dropwise thereto to allow the reaction to be quenched. The reaction mixture was allowed to reach room temperature, then NaHC03 was carefully added to adjust to pH 5. The mixture was extracted with EtOAc. The organic layer was washed with brine then dried (Na2SO4). The solvent was removed in vacuo <RTI ID=0.0>: </RTI> <RTI ID=0.0></RTI> -70-201209054 Preparation 57: 2-Chloro-5-[l-(3-isopropyl-[I,2,4]oxadiazole-5-yl)piperidin-4-ylmethoxy]- 4-methylpyrimidine

Cool to 〇. (: by [(1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation Example 1, 1.40 g, 5.84 mmol) and To a solution of triethylamine (0.98 mL, 7.01 mmol) in DCM (20 mL) was added dropwise to a mixture of EtOAc (0.50 mL ' 6.43 mmol), then the ice bath was removed and the reaction was stirred at room temperature 1 The organic layer was separated, dried (Na 2 SO 4 ), and concentrated in vacuo to give the intermediate 1-(3-isopropyl[1,2,4]oxadiazol-5-yl. Piperidin-4-ylmethyl ester. To a solution of the intermediate (0.79 g, 2.61 mmol) in DMF (10 mL) was added 2-chloro-4-methylpyrimidine-5-ol (Preparation 56, 0.38 g, 2.61 mmol) and potassium carbonate (0.72 g, 5. <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Concentration. Purification by column chromatography (EtOAc EtOAcjjjjjjjjjj [1-(5-isopropyl-[I,2,4]oxadi- _3·yl)piperidin-4-yl]methanol in hydroxy Methylpiperidine-1-carbonitrile (Preparation Example 50, 7.00 g, 5 〇 mmol) was dissolved in a solution of IMS (100 mL) in hydroxyamine (50% aqueous solution, 6_06 mL, 100 mmol). The mixture was stirred at room temperature for 30 - 71 - 201209054 minutes. The solvent was concentrated in vacuo and the residue was evaporated and evaporated tolue tolue toluene toluene to afford the amidamine intermediate. In amidoxime (8.66 g, 50 mmol) and DIPEA (36.9) mL, 120 mm ο 1) In a solution of DMF (80 m L), isobutyric acid (4.87 mL, 53 mmol) was added in portions, followed by addition of HBTU (22.70 g, 60 mmol). After stirring at room temperature for 16 hours, the mixture was diluted with water and extracted with EtOAc (EtOAc) (EtOAc). The mixture was heated to EtOAc (3 mL, EtOAc) = 2.25 minutes; m/z (ES + ) = 226.2 [M+H]+. Preparation 59: 1(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethyl methanesulfonate The title compound was obtained using the procedure described in Preparation 52 [1-(5-Isopropyl-[1,2,4]oxadiazol-3-yl)piperidine-4-yl]methanol (Preparation 58). LCMS Method 3: RT = 1.73 min; w/z (ES+) = 304.2 [M+H]+. Preparation 60: 2-Chloro-5-[l-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxyl pyrimidine

1-(5-Isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-yl---72-201209054 ester (Preparation 59) and 2-chloropyrimidine- The 5-alcohol was reacted using the procedure described in Preparation Example 53. Purification by column chromatography (hepthhhhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3.94-3.8 7 (m, 2H), 3_12-3_01 (m &gt; 1H), 2.99-2.8 6 (m &gt; 2H) &gt; 2.13-1.97 (m, 1H), 1.94-1.83 (m, 2H), 1.51-1.39 (m, 2H), 1.35 (d, · / = 7.3 Hz, 6H).

Preparation 61: Piperidin-4-ylethanol The title compound was prepared from (y)-(+)-?-methyl-4-pyridinemethanol using the procedure described in Preparation Example 10 except that the reaction was carried out for 64 hours: iH NMR δ Η (400 MHz &gt; CDC13) : 3.63 -3 .5 5 (m, 1H), 3.39-3.31 (m , 2H), 2.7-2.6 (m, 2H), 2.01 -1 .92 (m &gt; 2H) - 1.76-1 .69 (m &gt; 1H) &gt; 1.67- 1.54 (m &gt; 2H) &gt; 1.51-1.42 (m&gt;1H)&gt; 1.14-1. 1 0 (m, 3H). Preparation 62: (J〇-l-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol

NaHCO3 (1 3 50 mg, 10.08 mmol) was added to a solution of (Pyryl-1-piperidin-4-ylethanol (Preparation 61, 519 mg, 4.02 mmol) in DCM (40 mL) And water (20 mL), the reaction mixture was cooled to 〇 ° C. The solution of cyanogen bromide (511 mg, 4.83 mmol) in -73-201209054 DCM (2 〇mL) was added dropwise for 5 minutes, followed by reaction The mixture was stirred at 0&lt;0&gt;C for 30 min then warmed to EtOAc. EtOAc (EtOAc) The solvent was removed under vacuum to give the cyano intermediate. N-hydroxyisobutyl hydrazine (367 mg, 3.60 mmol) was added to the solution of the intermediate in EtOAc (30 mL). The zinc (II) was stirred and the reaction mixture was stirred at room temperature for 2 hours. Concentrated HCl (EtOAc EtOAc, EtOAc, EtOAc (EtOAc) The mixture was stirred with EtOAc (4×250 mL). Removal of the solvent under vacuum afforded the title compound: RT = 2.72 min; m/z (ES + ) = 240.1 [M+H] + 〇 Preparation 63: 2-chloro-5-((5) -1-11-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine

(i?)-l-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (prepared to 〇 °C) Example 62, 570 mg, 2.38 mmol) and triethylamine (3 90 μιη, 2.86 mmol) in DCM (42 mL) was added methane sulfonium chloride (204 μί, 2.86 mmol) and the mixture was warmed to room The temperature is 1 hour. Additional methane sulfonium chloride (92 μί, 1.19 mmol) and triethylamine (1 9 9 μL, 1.4 3 mm ο 1 ) were added, and stirring was continued for 16 hours. Mixture -74- 201209054

Dispense between DCM (100 mL) and 1M EtOAc (250 mL). Add 2-chloropyrimidin-5-ol (373 mg, 2.86 mmol) and potassium carbonate (985 mg, 7.34 mmol) to a solution of the residue in DMF (15 mL). . The reaction solvent was concentrated under vacuum, followed by azeotropic distillation with toluene. The residue was dissolved in EtOAc (EtOAc)EtOAc. Recrystallization from MeOH, followed by column chromatography (m.p.: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2.1 [Af + Η ] +. Preparation 64: (3 and, 4*5)-4-(2,5-difluorophenyl)-1-[5-(piperidin-4-ylmethoxy) Pyrimidin-2-yl]pyrrolidin-3-amine

T-butyl 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-1-carboxylate (Preparation Example 24, 165 mg, 0.5 mmol) and [(37?, 4 &gt; 5)- A mixture of tert-butyl 4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamate (preparation 48, 100 mg, 0.33 mmol) in DMSO (1 mL). , 0.5 mmol), the reaction mixture was heated to 100 ° C for 225 minutes and then cooled to room temperature. The mixture was diluted with water and extracted with DCM. The organic fraction was washed with brine, concentrated under vacuum and purified by column chromatography (D CM: MeOH, 95:5) to give intermediate product 4-{2-[(3 and Butyloxyaminoamino-4-(2,5-difluorophenyl)pyrrolidin-1 -yl]pyrimidin-5-yloxymethyl}piperidine-1 -carboxylic acid tert-butyl ester: RT = 4.67 min ;m/z (ES + ) = 590.3 [M+H]+. -75- 201209054 TFA (1 mL) was added to a solution of the product in DCM (5 mL), and the mixture was stirred at room temperature for 1 hour. The crude mixture was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut (ES + ) = 3 90. 1 [M+H]+. Preparation 65: 4-cyanopiperidine-1-carboxylic acid isopropyl ester under argon at 4 - cyanopiper (29.74 g, 0.27 Methyl) Triethylamine (57 mL, 0.41 mol) was added to a solution of toluene (300 mL), and the reaction mixture was cooled to 〇 ° C. Toluene solution of isopropyl chloroformate was added dropwise (1M, 29 7 mL, 0.3 0 mol), then the resulting mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated with EtOAc (EtOAc)EtOAc.EtOAc. ' 70 : 30), the title compound: 4 NMR δ Η (400 MHz, CDC13): 4.93 - 4.83 (m, 1 Η), 3.72-3.61 (m, 2H), 3.40-3.31 (m, 2H), 2.83 - 2.74 (m, 1H), 1.90-1.71 (m, 4H), 1_21 (d, 6H). Preparation 66: 4-(N-hydroxymethylmethyl)piperidine-1-carboxylic acid isopropyl ester

Isopropyl 4-cyanopiperidine-benzoate (preparation 65, 47.17 g, 0.24 mol), aqueous potassium carbonate solution (35.38 g, 0.26 mol, 400 mL) and -76-201209054

Hydroxylamine hydrochloride (3 5.5 8 g, 0.51 mol) was added to a mixture of EtOH (225 mL). After cooling to room temperature, EtOH was removed in vacuo and aqueous layer was evaporated elut The combined organic layer was rinsed with water (x2), then with brine, and dried (MgS04). The solvent was removed in vacuo to give the title compound: 4 NMR δ Η (400 MHz 'CDC13): 4.94-4.84 (m, 1H), 4.56 (br s ' 2H), 4.26 - 4.10 (m, 2H), 2.81-2.69 ( m, 2H), 2.31-2.22 (m, 1H), 1.86-

1.78 (m, 2H), 1.61-1.49 (m, 2H), 1.22 (d, 6H). Preparation 67: 4-(5-Hydroxymethyl-[1,2,4]oxadiazol-3-yl)piperidine-1-carboxylic acid isopropyl ester

To a suspension of glycolic acid (1.00 g, 13.15 mmol) in DCM (15 mL) was added carbonyldiimidazole (2.13 g, 13.15 mmol). 4-(N-Hydroxymethylindolyl)piperidine-p-formate isopropyl ester (Preparation 66, 3.01 g' 13.15 mmol) was added to the mixture and stirring was continued for 3 hr. The reaction mixture was then heated to 35 °C for 2 hours and then at room temperature for 16 hours. The reaction mixture was again at 35. C was heated for 16 hours, after which time the reaction mixture was concentrated under vacuum. The crude residue was partitioned between EtOAc (150 mL) The organic layer was separated, washed with brine and dried (MgSO4). The solvent was removed in vacuo to give an oil which was dissolved in toluene and warmed to EtOAc. The solvent was removed in vacuo and purified with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj +H]+. Preparation 68: 4-丨5-(2-chloropyrimidin-5-yloxymethyl)-indole 1,2,4]oxazol-3-yl]piperidine-1-carboxylic acid isopropyl ester

Isopropyl 4-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)piperidine-1-carboxylate in an oven-baked flask under argon (preparation) Example 67, 103 mg, 0.38 mmol) 2-Chloro-pyrimidin-5-ol (50 mg, 0.38 mmol) was added to a solution of THF (5 mL), followed by triphenyl scale (150 mg, 0.57) Methyl), the mixture was cooled to 0 °C. DIAD (112 μιη, 0.57 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 2.5 h. The reaction was removed in vacuo and the residue was crystallisjjjjjjjj The solution was rinsed with water (50 mL), then brine, and dried (M g S Ο 4 ), then solvent was evaporated in vacuo. IΗ was added followed by a minimum amount of E12 Ο to form a precipitate. The solvent was decanted and concentrated under vacuum. The resulting residue was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Preparation 69: 4-(5-{2_[(3Λ,4 Magic-3-Tertoxycarbonylamino-4-(2,5-difluorophenyl)-pyridin-1-yl]pyrimidine- 5-yloxymethyldiphenyl 1,2,4] oxadiazin-3-yl)piperidine-1-carboxylic acid isopropyl ester-78- 201209054

4_[5_(2-chloropyrimidin-5-yloxymethyl)-[1,2,4]oxadiazol-3-yl]pyridin-1-carboxylic acid isopropyl ester (Preparation 68, 38 mg, 0.10 mmol), [(3/?, 4 magic-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tributyl _ (Preparation 9 ' 3 1 mg, 0.1 0 Mm) and DIPEA (1 9 μί ' 〇· 1 1

Mixture of mmol) in tert-butanol Ο niL) was heated at 80 ° C for 40 hours. The reaction mixture was partitioned between EtOAc (5 mL) and brine (50 mL) and then the organic layer was separated and dried (MgS04) And the solvent was removed under vacuum. The crude residue was purified eluting with EtOAc EtOAc EtOAc EtOAc £8 + ) = 65 8.2 [from +1^]+. Preparation 70: (trans)-3-(9H-indole-9-ylmethoxycarbonylamino)-4-(2-fluorocuminyl)pyrrolidine-1-carboxylic acid tert-butyl ester

(trans)-3-amino-4-(2-fluorophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g, 7.13 mmol) and triethylamine (1.59) cooled to 〇 °C. Add 1 - fluoromethyl chloroformate (2.31 g, 8.92 mmol) to a solution of dioxane and water (2:1,75 mL), then -79-201209054 The reaction mixture was allowed to reach room temperature and then stirred for 16 hours. The mixture was diluted with EtOAc, washed with water, 1M EtOAc, sat. NaHCO3 and brine, and dried (Mg S04). The solvent was removed under EtOAc (EtOAc)EtOAc (EtOAcjjjjjjjj M+H]+. Preparation 71: [(trans)-4_(2-fluorophenyl)pyrrolidin-3-yl imidocarboxylic acid 9H-indol-9-ylmethyl ester hydrochloride

In the (trans)-3-(9H-Fran-9-ylmethoxycarbonylamino)-4-(2-fluorophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Preparation Example 70, 1.50 g, 2.98 mmol) A solution of dioxane (4M '30 mL) was added to a solution of dioxane (30 mL), and the mixture was stirred at room temperature for 6 hours, then a precipitate formed. Et20 was added to the mixture until no more precipitate was observed and the solvent was decanted. The residue was resuspended in a portion of Et 2 crucible and stirred for 5 minutes, after which the solvent was decanted. This step was repeated twice more, and the residue obtained was concentrated in vacuo to give the title compound, RT = 2.82 min; /z (ES + ) = 403.1 [M+H]+. Preparation 72: tert-butyl (1-cyanopiperidin-4-yl)carbamate in tert-butyl piperidin-4-ylaminocarbamate (10.0 g, 49.9 mmol) in DCM (130) A solution of NaHC03 (12.6 g, -80-201209054 149·8 mmol) in water (30 mL) was added to the resulting solution, and the resulting mixture was cooled to 〇 °C. A solution of cyanogen bromide (6.4 g, 59.9 mmol) in DCM (15 mL) was added dropwise over EtOAc. The reaction mixture was diluted with water and then layered. The aqueous layer was subjected to DCM extraction. The organic layer was then combined, washed with saturated NaHC 3 solution, then brine, and dried (MgS04). The solvent was removed in vacuo to afford the title compound: RT: 2.93 min; w/z (ES + ) = 226.1 [M+H] + 〇 Preparation 73: 1-(3-isopropyl-[1,2,4 Oxadiazole-5-yl)piperidin-4-amine

Thirteen butyl (cyanopiperidin-4-yl)carbamate (preparation 72, 4.04 g, 17.9 mmol) and N-isobutylpyridinium (2.20 g, 21.5 mmol) in EtOH (50 mL) To the resulting solution was added a solution of zinc(II) chloride (2.93 g, 21.5 mmol) in EtOH (30 mL), and the resulting mixture was stirred at room temperature for 2.25 hours. Concentrated HCl (4.58 mL, 53.8 mmol) was then added and the reaction mixture was warmed to 50 °C for 16 h. The solvent was removed under vacuum and the residue obtained was quickly precipitated from MeCN. The white solid was collected by filtration and washed with EtOAc (EtOAc) eluting eluting EtOAc was added and the resulting emulsion was filtered over celite. The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjjjj H]+. -81 - 201209054 Preparation 74: a solution of (2-chloropyrimidin-5-yl)methanol 2-chloropyrimidine-5-carboxylic acid methyl ester (1.0 g, 5.8 mmol) in THF (30 mL) Cool to -78 °C. DIBAL-H in DCM (1.0 M, 20.3 mL, 20.3 mmol) was slowly added to the solution for 40 minutes. The reaction mixture was allowed to warm to room temperature and then stirred for further 16 hours. Saturated sodium potassium tartrate solution (100 mL) was added slowly, followed by EtOAc. The organic layer was separated, then a further portion of EtOAc was added and then stirred for 1 hour. The organic layer was removed and the aqueous layer was washed with EtOAc EtOAc EtOAc. The whole organic mixture was saturated with sodium saturated sodium tartrate solution, water and brine, and dried (MgS04). The solvent was removed in vacuo to give the title compound: m. Preparation 75: [(3/?,4*y)-4-(2,5-difluorophenyl)-1-(5-hydroxymethylpyrimidin-2-yl)pyrrolidin-3-yl]amine Tert-butyl carboxylic acid

In (2-chloropyrimidin-5-yl)methanol (preparation 74, 2 5 3 mg, 1.75 mmol) and [(37?,45)-4-(2,5-difluorophenyl)pyrrolidine-3 -Based carboxylic acid terpene vinegar (Preparation 48, 574 mg, 1.93 mmol) was added DBU (262 μί, 1.75 mmol) to a dry solution of DMSO (1·6 mL). To 70. C lasted 2 hours. The mixture was diluted with water, -82-201209054 and extracted with EtOAc (X2). The organic layer was combined, washed with a saturated NaHCO.sub.3 solution, then brine, and dried (MgSO.sub.4). The solvent was removed under EtOAc (EtOAc m.) Preparation 76: [(3i?, 4 51)-4-(2,5-Difluorophenyl)-1-(5-methylpyridylpyrimidin-2-yl)pyrrolidinyl-3-yl]carbamic acid Third butyl ester

In 〇°c, in [(3i?,4S)-4-(2,5-difluorophenyl)-1-(5-hydroxymethylpyrimidin-2-yl)pyrrolidin-3-yl]amine Dess-Martin periodinane (5 1) was added to a solution of tert-butyl formate (Preparation 75, 413 mg, 1.02 mmol) and a solution of EtOAc (EtOAc (EtOAc) (EtOAc). 7 mg, 1.22 mmol), the resulting mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residual residue was taken in EtOAc eluting with EtOAc EtOAc (EtOAc). The solvent was removed in vacuo and EtOAcqqqqqqqqqqqqqq Preparation 77: [(3/2,45)-4-(2,5-Difluorophenyl)_1-(5-{[1-(3-isopropyl-[1,2,4]) Zin-5-yl)piperidin-4-ylamino]methyl}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester-83- 201209054

[(3/?,4&lt;S)-4-(2,5-Difluorophenyl)-1-(5-methylindolyl)pyrrolidin-3-yl]carbamic acid tert-butyl Ester (Preparation Example 76 '1〇1 mg' 〇·25 mmol) and 1-(3-isopropyl-[1,2,4]oxadiazole·5-yl)piperidine-4-amine (Preparation Example) 73, 63 mg, 0.30 mmol) An oven-dried molecular sieve (550 mg) was added to a solution of DCE (3 mL). The reaction mixture was heated to 100 °C for 48 hours. Further DCE (5 mL) was added followed by sodium triethylsulfonium hydride (85 mg, 0.40 mmol). The reaction mixture was passed through a c e 1 i t e oven, rinsed with D C ,, and then the combined organic layer was washed with water, dried (MgSCU), and solvent was removed under vacuum. Purification by column chromatography (EtOAc:MeOHMeOHMeOHMeOH LCMS: RT = 2.87 min; w/z (ES+) = 599.4 [M+H]+. Preparation 78: {(3/?,4S)-4-(2,5-difluorophenyl)-l-[5_(Ul_(3_isopropyl-丨1,2,4)oxadiazole-5 -yl) piperidine_4_yl]methylamino}methyl)pyrano-2·yl]pyrrolidine_3_yl}-tert-butyl carbamate

[(3Λ ,45)-4-(2,5-fluorophenyl)-1-(5-{[1-(3-isopropyl _[1,2,4] -84- 201209054

Oxadiazol-5-yl)piperidin-4-ylamino]methyl}pyrimidin-2-yl)pyrrolidin-3-yl]-tert-butyl carbamate (Preparation 77, 75 mg, 0.12 mmol A mixture of formaldehyde (4 mg, 0.14 mmol) and sodium triethoxysulfonium hydride (37 mg, 0.18 mmol) in EtOAc (2 mL) The solvent was removed in vacuo and the residue was crystallised eluted with EtOAc EtOAc EtOAc. The solvent was removed in vacuo and purified with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj + Preparation Example 79: 1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidine-4-carbaldehyde

[(1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol was cooled to 0 °C (Preparation Example 1, 5.44 g, 24.13 mmol) Dess-martin periodinane (12.28 g, 28.95 mmol) was added portionwise to a solution of DCM (150 mL) for 5 min. The reaction mixture was warmed to room temperature and stirred for 2 hr. The solvent was removed and the residue obtained was taken from EtOAc EtOAc EtOAc EtOAc (EtOAc) , 60 : 40) 'The title compound: RT = 2.37 minutes; speak /2 (£3 + ) = 224.1 [from 10 11] +. Preparation 80 : [(3^,45)-4-(2,5 -difluorophenyl)-1_(5-nitropyrimidin-2-yl-85- 201209054) pyrrolidin-3-yl]carbamic acid tert-butyl ester

Under argon, 2-chloro-5-nitropyrimidine (2.00 g, 12.5 mm 〇l) and [(3/?,4*S)-4-(2,5-difluorophenyl)pyrrol Add DBU (1.87 mL, 12.5 mmol) to a solution of pyridine-3-ylaminobenzoic acid tert-butyl ester (Preparation 48, 4.11 g, 13·8 mmol) in anhydrous DMSO (10 mL) The mixture is heated to 60. C lasted for 16 hours. After cooling, the mixture was poured into water (10.5 mL) and the obtained gum was extracted to EtOAc (100 mL then 50 mL). The combined organic fractions were washed with saturated aq. NaHCO.sub.3 (50 mL) then brine (50 mL) and dried (MgS04) and then evaporated. Recrystallization from EtOAc: EtOAc (EtOAc (EtOAc) (EtOAc) :丨(3Λ,4*ί)-1-(5-Aminopyrimidin-2-yl)_4-(2,5-difluorophenyl)pyrrolidin-3-yl1carbamic acid tert-butyl ester

[(3 /?,4Phantom-4 - (2,5-difluorophenyl)_J (5-nitropyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester ( Preparation 80, 1.04 g, 2.47 -86 - 201209054 mmol) A solution of a mixture of THF (20 mL) and MeOH (30 mL) was passed through a Η-Cube hydrogenation apparatus at a flow rate of 1 niL/min (10% Pd/ The solvent was removed in vacuo to give the title compound: RT: 2. <RTI ID=0.0=============================================== 4-(2,5-Difluorophenyl)-1-(5-{[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl Methyl]amino}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

Under argon, in [(3Λ,45&gt; 1-(5-aminopyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid, third Butyl ester (Preparation Example 81, 300 mg, 0.77 mmol) and 1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidine-4-carbaldehyde (Preparation Example) 79,220 mg, 0.99 mmol) To a solution of DCE (20 mL) was added sodium triethyloxy borohydride (276 mg, 1.30 mmol), followed by AcOH (199 μί, 3.50 mmol) After stirring at room temperature for 16 hours, the reaction mixture was washed with EtOAc EtOAc EtOAc. </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 3-isopropyl-[1,2,41oxadiazol-5-yl)piperidin-4-ol-87- 201209054 in 4-hydroxypiperidine-1-carbonitrile (1.08 g, 8.6 mmol) and N a solution of zinc hydroxy(II) (1.40 g, 10.3 mmol) in EtOH (15 mL) in a solution of hydroxyisobutyl hydrazine (1.05 g, 10.3 mmol) in EtOH (20 mL). Stir at room temperature for 2 hours. Concentrated H C1 (4 · 1 9 mL, 49.2 mmol) was added and the mixture obtained was warmed to 50 ° C for 16 hr. solvent was removed under vacuum and water was added to the residue. The mixture was filtered, and the title compound was obtained from EtOAc EtOAc (EtOAc) RT = 2.44 min; w/z (ES + ) = 212.1 [M+H] +. Preparation 84: 2-chloro-5-[l-(3-isopropyl-[1,2,4] Zyrid-5-yl)piperidin-4-yloxymethyl]pyrimidine

Dry solution of 1-(3-isopropyl-[1,2,4]oxadiazol-5(yl)piperidinol (Preparation 83, 432 mg, 2.04 mmol) in THF (4 mL) NaH (60% suspension in '98 mg' 2.44 mmol) in mineral oil was added and the mixture was stirred at room temperature for 25 minutes. A solution of 2-chloro-5-chloromethylpredane (332 mg' 2.04 mmol) in THF (3 mL) was added to the mixture and the mixture was stirred at room temperature for 16 hours. The reaction mixture was heated to 30 ° C for 1.5 hours, followed by another portion of NaH (49 mg &lt;RTI ID=0.0&gt;&gt; The reaction mixture was then heated to 35 ° C for 16 hours. -88-201209054 The solvent was removed under vacuum, the residue was taken up in EtO Ac, rinsed with water, then rinsed with brine and dried (MgS04). The solvent was removed in vacuo and purified EtOAcqqqqqqqq

Preparation 85: ((3 and 45&gt; 4-(2,5-difluorophenyl)-1-{5-[1-(3-isopropyl)[1,2,4]oxadiazole- 3-butyl)piperidin-4-yloxymethyl 1 pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester

2-Chloro-5-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxymethyl]pyrimidine (Preparation Example 84, 24 Mg, 0.07 mmol) and [(3 Λ,4·5)-4-(2,5-difluorophenyl)pyrrolidine-3-yl]carbamic acid tert-butyl ester (Preparation 48, 23 mg, 0.08 mmol) DBU (11 mL, 0.07 mmol) was added to a solution of EtOAc (0.05 mL) and the mixture was warmed to 70 ° C for 16 hours. The mixture was diluted with EtOAc, washed with water (x2) then brine and dried (MgSO. The solvent was removed in vacuo and the residue was purified mjjjjjjjj The resulting product was eluted with EtOAc over EtOAc (EtOAc) eluting with Et. The solvent was removed in vacuo to give the title compound: RT: 4.15 min; m/z (ES+) = 600.3 [M+H]+. Preparation 86: 5-benzyloxy-2-chloropyrimidine-89 - 201209054 2-Chloropyrimidine-5-ol (70% purity '7.5 g, 40 mmol) in DMF (15 mL, 190 mmol) The carbonic acid planer (14.0 g, 43 mmol) was added portionwise under helium to 〇 ° C °, and the mixture was stirred at 〇 ° C for 5 min, then at room temperature for 1 hr. The mixture was cooled to 0 ° C and benzyl bromide (5.1 mL &apos; 43 mmol) was added portionwise. The reaction mixture was stirred at 〇 ° C for 15 minutes, then warmed to room temperature and stirring was continued for 90 minutes. The solvent was removed in vacuo. The organic layer was separated, washed with water: brine (1:1), dried (MgSO.sub.4), and solvent was evaporated from vacuo. The precipitate was rapidly precipitated in a mixture of Et20 and IH. After concentration in vacuo, the title compound was again precipitated from a mixture of Et20 and IH to give the title compound: RT = 3.54 min; w/z (ES + ) = 221.0 [Af+ H]+. Preparation 87: [(3^,45)-1-(5-Benzyloxypyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)pyrrolidine-3-yl]amino group Tert-butyl formate

5-Phenoxy-2-chlorinated chew (preparation 86, 4.4 g, 20 mmol), [(3i?,4(7)-4-(2,4,5-trifluorophenyl)pyrrolidin-3- a mixture of tert-butyl carbazate (preparation 39, 6.0 g, 19 mmol) and DIPEA (4.4 mL, 25 mmol) in MeCN (56 mL, 1100 mmol) in a microwave reactor at 150 ° C was heated for 4 x 60 minutes. The solvent was removed under vacuum and the residue was partitioned between DCM and water. The organic layer was partitioned, the aqueous layer was rinsed with DCM, organic fractions were dried, dried (MgS04), and in vacuo The solvent was removed. The crude material was precipitated from Et2 EtOAc. Minutes; w/z (ES + ) = 501.1 [Μ+Η]+. Preparation 88: [(3Λ,4*5)-4-(2,4,5-trifluorophenyl)-1-(5 -Hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

[(3/?,4 to 1-(5-benzyloxypyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid III A mixture of butyl ester (preparation 87, 4.5 g, 9.0 mmol) and 10% Pd/C (0.1 g, 0.1 mmol) was re-washed, EtOH (100 mL) was added and the mixture was placed in a hydrogen atmosphere for 60 minutes. The mixture was filtered through celite, rinsed with EtOH (2×50 mL) and solvent was evaporated in vacuo. The crude material was quickly precipitated from Et20, filtered through Ij, then rapidly precipitated in DC ' 'filtered and dried under vacuum The title compound was obtained: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 4-based]methanol

7.4 mmol) was added to a solution of (4-methoxyindole) methanolic hydrochloride (1:1) (400 mg, 2.0 mmol) in ϊ-Βυ0Η (3 mL). - 201209054 The mixture should be heated in a microwave reactor at 80 °C for 30 minutes. The mixture is distributed between D C Μ and water and passed through a phase separator. The aqueous layer was washed with D C , then combined organic layers and concentrated in vacuo. Purification by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Preparation 90: [(3/?,4·?)-1-{5-[1-(5-Amphetyridin-2-yl)-4-methoxypiperidin-4-ylmethoxy]pyrimidine -2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]aminobutyl carbamate

Third in [(3i?,4«S)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid Butyl ester (Preparation 88, 50 mg '0.1 mmol) in THF (1 mL) was added to a solution of THF (1 m.sup.2). Allow to stand at room temperature for 5 minutes. A solution of TBAD (31 mg' 0.13 mmol) in THF (0.5 mL) was added and the mixture was stirred at room temperature for 5 min. Adding a solution of Π-(5-chloropyrimidin-2-yl)-4-methoxypiperidine-4-yl]methanol (Preparation 89 '31 mg' 0.12 mmol) in THF (0.5 mL) The mixture was stirred at room temperature for 2 hours. Add another TBAD (31 mg ' 0.13 mmol) and PS - triphenylphosphine (1.52 mmol / g loading; 120 mg, 0.18 mmol)' and heat the reaction mixture to 40 ° C for 2 hours ' then at room temperature Stir 60-92-201209054. The reaction mixture was filtered and the resin was rinsed with DCM and methanol. The filtrate was concentrated under vacuum and then purified by preparative HPLC. The solvent was removed under vacuum to give the title compound: 1^ = 4.80 min; /2 (£8 + ) = 65 0.5 [M+H]+. Preparation 91: [(35,4&lt;S)-1-benzyl-4-(5-bromo-4,4-difluoropentamylamino)pyrrolidine-3-yl]carbamic acid tert-butyl ester

5-Bromo-4,4-difluoropentanoic acid (containing 25% 5-chloro-4,4-difluoropentanoic acid, 3.46 g » 16.82 mmol) ' EDCI (3.87 g &gt; 20.18 mmol) ' H〇AT ( 2.75 g, 20.18 mmol) and a mixture of triethylamine (7.00 mL, 50.45 mmol) in DMF (35 mL). To the reaction mixture Q was added ((3夂4&lt;5)-4-amino-1-benzylpyrrolidine-3-yl)carbamic acid tert-butyl ester (Preparation Example 18, 4.90 g, 16.82 mmol) The solution formed in DMF (35 mL) was heated to 5 EtOAc over 16 s. The DMF was removed under vacuum and the crude residue was placed in water. The mixture was extracted with EtOAc (x3), EtOAc (EtOAc) (EtOAc)EtOAc. : 〇", 96: 4: 〇.1), the title compound · RT - 2.92 min; (es + ) = 490.1, 492.1 [M+H]+. -93- 201209054 Preparation 92: Section _4- (5,5--fluoro-2-ketoindole-t-yl) pyrrolidin-3-yl]-tert-butyl carbamate

[(3*S,45)-1-pyrimidinyl-4-(5-di-_4,4-one pentylamino) hydrazide-thyl-3-yl] carboxylic acid tert-butyl ester (containing 25% [(,, 4*5)-1-pyrimidyl_4-(5-chloro-4,4-difluoropentamylamino)pyrrolidin-3-yl]carbamic acid tert-butyl ester, Preparation 91, 5.60 g, 11.7 mmol) of a solution of DMF (30 mL) was cooled to hydr. c. Sodium hydride (60%&apos; in mineral oil, 0.94 g &apos; 23.4 mmol) was added and the reaction mixture was stirred and slowly warmed to room temperature for 2 hours. The DMF was removed under vacuum and azeotroped with toluene (x3) then the crude residue was partitioned between DCM and water. The aqueous layer was separated and extracted with DCM' followed by organic layers, rinsed with brine, and dried (MgS04). The solvent was removed in vacuo and purified title title title crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LCMS Method 4: RT = 2.90 min; m/z (ES+) = 410.2 [M+H]+. Preparation 93: [(3·5,45&gt; 4-(5,5-difluoro-2-ketopipyridinyl)pyrrolidin-3-yl]-tert-butyl methacrylate

201209054 The title compound was obtained from [(31^)-1-benzyl-4-(5,5-difluoro-2-onepiperidin-1-yl)pyrrolidin-3- using the procedure described in Preparation 20 Preparation of butyl carbamic acid tert-butyl ester (Preparation 92): RT = 2.04 min; m/z (ES+) = 320.2 [M+H]+. Preparation 94: 2-Bromo-5-((5)-1-11-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxylate Pyridine

Under argon, (Fantasy-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)indole-4-yl]ethanol (Preparation Example 62, 1.02) g, 4.24 mmol) Triphenylphosphine (1.66 g, 6.32 mmol) was added to a solution of THF (12.5 mL). The reaction mixture was cooled to 0 ° C. TBAD (1.46 g, 6.32 mmol) was added. To the room temperature, followed by stirring for 20 hours. The reaction solvent was reduced to 5 mL, then purified by column chromatography (Si2, eluted from EtOAc, 4:1, 3:1). LCMS Method 5: RT = 14.07 min; m/z (ES+) = 395.0, 397.0 [M+H]+. Preparation 95: 2-bromo-5-{ (5)-1-(1-(3) -isopropyl-[1,2,4]oxanol-5-yl)piperidine-4-yl]ethoxy}pyrazine

-95-201209054 piperidin-4-yl]ethanol (Preparation 62, 1.10 g, 4.58 mmol) EtOAc (EtOAc) 0 °C. DIAD (1.35 mL, 6.86 mmol) was added in two portions and the mixture was warmed to room temperature then stirred 16 hr. The reaction solvent was reduced in volume under vacuum, and the thick slurry was purified by column chromatography (heptane: £1,8:4:1, 3:1, followed by doping with octa 8 of 8 丨 02, heptane: EtOAc ' 4 : 1 ' 3 : 1). The purification method was repeated to give the title compound. LCMS Method 5: RT = 14.99 min; w/z (ES + ) = 3 96·0, 3 9 8.0 [M+H]+. Preparation 96: (/?)-1-pyridin-4-yl-ethanol in diphenyl-(«S)-pyrrolidin-2-ylmethanol (10.5 g, 41.3 mmol) in THF (800 mL) Trimethoxyborane (5.52 mL, 49.5 mmol) was added to the solution and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 〇 ° C ', borane dimethyl sulfide (78 mL, 825.5 mmol) was added, followed by the addition of 4-ethylpyridylpyridine (50 g, 410.7 mmol) in THF (200 mL). hour. Stirring of the reaction mixture was continued for 1 hour, after which time the reaction was quenched with 2M HCl. After stirring for 10 minutes, the reaction mixture was basified with saturated NaHC03 solution. The precipitate formed was filtered off and the residual filtrate was extracted with EtOAc (EtOAc). The organic layer was combined, dried (MgS 4), and the solvent was removed under vacuum. Purification by column chromatography (EtOAc: EtOAc (EtOAc:EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1H), 3.08-2.8 6 (m, 1 Η), 1. 5 1 - 1.48 (m, 3H). -96 - 201209054 Preparation 97: (and) 1-piperidin-4-ylethanol acetate 9 x/-

AcOH (16.2 mL) was vigorously charged in a solution of pyridin-4-ylethanol (preparation 96, 31.6 g, 0.29 mol) in MeOH (650 mL). Platinum oxide (4.0 g) was added, and the reaction mixture was stirred under a hydrogen atmosphere of 50 atm for 18 hours. The mixture was filtered through celite, washed with MeOH thenEtOAc. The residue was crystallized from EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH &gt; 2H) &gt; 2.77-2.65 (m &gt; 2H) &gt; 2.00-1.92 (m * 4H), 1.76- 1.69 (m, 1H), 1.65-1.40 (m, 3H) &gt; 1.20-1.16 (m , 3 H). Preparation 98: 4-((i?)-l-hydroxyethyl)piperidine-1-carbonitrile

A solution of NaHC03 (106.5 g) in water (175 mL) was added to a solution of piperidin-4-ylethanol acetate (Preparation 97, 60.0 g, 0.32 mol) in DCM (175 mL). The mixture is cooled to 〇 ° C. A solution of cyanogen bromide in DCM (3M, 116.0 mL, 0.35 mol) was then evaporated. The mixture was partitioned between DCM and water, and the organic layer was separated. The aqueous layer was extracted by DCM, then the organic fraction was combined and washed with saturated NaHC03 solution -97-201209054' and dried (MgSCU). The solvent was removed in vacuo to give the title compound::HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1.92- 1.80 (m, 1H)' 1.72-1.30 (m' 4H)' 1.20-1.11 (m, 3H). Preparation 99: N-hydroxypropionamin In a solution of hydroxylamine (15 mL '0.45 mol) in IMS (210 mL), propanonitrile (38 mL '0_ 54 mol) was added and the reaction mixture was heated to 1 0 0 ° C lasted for 16 hours. The solvent was concentrated in vacuo to give the title compound: 4: NMR δ δ δ (400 MHz 'CDC13): 4.75-4.38 (s (br), 2H), 2.20-2.09 (m, 2H), 1. 1 9-1.06 (m , 3H). Preparation Example 100: (β)-1-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol

4-((Pho-O-hydroxyethyl)piperidine-1-carbonitrile (Preparation 98, 28.4 g, 183 mmol) and N-hydroxypropionin (Preparation 99, 19.4 g, 220 mol) in EtOH (570) Into the mixture, a solution of zinc chloride (π) (309 g, 220 mol) in EtOH (40 mL) was added to the mixture for 15 minutes, and the reaction mixture was stirred at room temperature for 2 hours. Concentrated HCl (25 mL) was added for 5 min, and the reaction mixture was heated with EtOAc EtOAc EtOAc EtOAc. The solvent was removed under vacuum. Purified by column chromatography (DCM: MeOH, 95: 5) -98 - 201209054 'title compound. LCMS Method 3: RT = 1.33 min; w/z (ES) =226.1 [M+H]+. Preparation 101: methanesulfonic acid (ϋ)-1-丨1_(3_ethyl-[1,2,4]oxadiazole-5-yl)piperidine_4·yl] Ethyl ester

In (Fantasy-1-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation Example 100, 2.0 g, 8.9 mmol) Diethylamine (1.5 mL, 10.6 mmol) was added to a dry solution of DCM (30 mL), and the mixture was cooled to 0 ° C. Methanesulfonium chloride (〇. 8 mL, 9.8 mmol) was added by a syringe, and the reaction was stirred. The mixture was diluted until DCM (50 mL), EtOAc (EtOAc)EtOAc. (ES + ) = 304.1 [M+H] +. Preparation 102: 2-chloro-5-{(5)-1-[1-(3-ethyl-[1,2,4]oxadiazole- 5-yl)piperidin-4-ylindole ethoxy}pyrimidine

The title compound was prepared from the (i?)-1-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidine-4 methanesulfonic acid by the method described in Preparation 29 -Based on ethyl ester (Preparation Example 101). Purification by column chromatography (IH:EtOAc, 40: EtOAc): -99 - 201209054 Preparation 103: 1-(3-isopropyl-indole, 2,4)oxadiazol-5-yl)-4-oxiranylpiperidine^&gt;-Ν0&lt;ί in iodine Sodium hydride (0.22 g, 5.37 mmol) was added to a solution of trimethylsulfoxonium iodide (1.18 g, 5.37 mmol) in DMSO (10 mL). The resulting solution was stirred at room temperature for 30 minutes, after which 1-[3-(propan-2-yl)-1,2,4-oxadiazin-5-yl]piperidine-4-carbaldehyde was added via a cannula ( Preparation 79, 1.20 g, 5 - 37 mmol) of a solution in DMSO (8 mL). The reaction mixture was stirred at room temperature for 16 hours' and then poured into ice water (400 mL). The mixture was extracted with EtO A c (X 3 ), and the combined organic fraction was washed with water, then brine, and dried (MgS04). The solvent was removed under EtOAc (EtOAc) (EtOAcjjjjjjjj ]+. Preparation 104: 1-[1-(3-Isopropyl-[1,2,4]oxan-5-yl)piperidin-4-yl]-2-methoxyethanol

1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-4-oxiranylpiperidine (Preparation 103, 3 56 mg, 1.50 mmol) in dry MeOH (6 mL) To the resulting solution was added sodium methoxide (85 mg &lt;RTI ID=0.0&gt;&gt; The solvent was removed in vacuo. Separate the water layer to -100- 201209054

The organic fractions of the combined EtOAc (x2) were dried (MgSO4). The solvent was removed under vacuum and purified by EtOAc EtOAc EtOAc EtOAc (td. +H]+. Preparation 105: 1-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethyl methanesulfonate

1-[1-(3-Isopropyl-[1,2,4]Doxaindole-5-yl)piperidin-4-yl]-2-methoxyethanol cooled to 〇 °C (Preparation 104, 217 mg, 0.8 mmol). To a solution of DCM (5 mL) was added triethylamine (190 ML, 1.4 mmol), followed by methane sulfonium chloride (81 μί, 1.0 mmol) The reaction mixture was stirred at 0 ° C for 2 · 5 hours. Water was added to the reaction mixture to quench the reaction, and the organic layer was separated, washed with a saturated NhCl solution, then () washed with brine, and dried (MgS?4). The solvent was removed in vacuo to give the title compound: RT = 3.24 min; w/z (ES + ) = 348.1 [M+H]+. Preparation 106: [(3J?,4*y&gt;-l-(5-benzyloxypyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidine-3-yl]amino group Tert-butyl formate

5-benzyloxy-2-chloropyrimidine (Preparation 86, 3 50 mg, 1.6 mmol), -101 - 201209054 [(3Λ,4^-4-(2,5-difluorophenyl)pyrrolidine-3 a mixture of -butyl carbamic acid tert-butyl ester (Preparation 48, 570 g, 1.9 mmol) and DIPEA (550 μιη, 3.2 mmol) in MeCN (10 mL) in a microwave reactor at ΐ6 ° ° C After heating for 30 minutes, the solvent was evaporated, EtOAcjjjjjjjjjjjj ES + ) = 483.2 [M+H] + Preparation Example 1〇7: [(1) 犮一幻-心口一-二氟苯卜卜--hydroxypyrimidine-;^-yl)pyrrolidin-3-yl]amine Tert-butyl carboxylic acid

[(3i?, 4 5)-1-(5-benzyloxypyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidino-H--3-yl]S-based carboxylic acid table A mixture of dibutyl vinegar (preparative example; 1 〇 6,300 mg, 0.6 mmol) and palladium on carbon (1 〇 wt%, 66 mg, 0.06 mm 〇l) in EtOH (30 mL) was flushed with argon gas, then Placed in a hydrogen atmosphere for 60 minutes. The mixture was filtered over EtOAc EtOAc (EtOAc) Preparation 108: [(3/?,45)-4-(2,5-Difluorophenyl)-isopropyl-[I,2,4]oxadiazole·5-yl)piperidinyl]_2 ·Methoxyethoxy}pyrimidin-2-yl)pyrrolidinyl-3-ylaminobenzoic acid tert-butyl ester-102- 201209054

1-[l-(3-isopropyl-π,2,4]oxadiazol-5-yl)piperidine-4-yl]-2-methoxyethyl methanesulfonate (Preparation Example 105, 80.5 Mg, 0.23 mmol) and [(3i?,4*S)-4-(2,5-difluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]amino T-butyl formate (Preparation 107, 82.7 mg, 0.21 mmol) EtOAc (3 mL, EtOAc) (: stir for 120 hours. Add another serving

CsF (35.0 mg, 0.23 mmol) and TBAI (15.6 mg, 0.04 mmol), and the reaction mixture was warmed to 75 ° C for 16 hours. Add another portion of CsF (35 mg, 0·23 mmol) and 1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-4 -Methoxy-2-ylethyl ester (Preparation 105, 40 mg, 0.12 mmol) in DMA (0.4 mL). (: heating for 16 hours. Additional CsF (35 mg, 0.23 mmol) was added, and the reaction mixture was heated to 85 °C for 120 hours. After cooling, the reaction mixture was diluted with EtOAc, rinsed with water (x3) and then rinsed with brine , and drying (MgS04), then removing the solvent under vacuum.

Chromatography (IH: EtOAc, EtOAc (EtOAc:EtOAc) (ugly 3 + ) = 644.3 [from +: «] +. Preparation 109: [1-(5-ethyl-2-methyl-2H-[1,2,4]triazol-3-yl)piperidin Pyridin-4-yl]methanol-103- 201209054

Formed in [1-(5-ethyl-2H-[l,2,4]triazol-3-yl)piperidin-4-yl]methanol (510 mg, 2.4 mmol) in MeOH (10 mL) The solution was poured into KOH (140 mg, 2.4 mmol) and the mixture was stirred at room temperature for one hour. The methyl pick (170 μί' 2.7 mmol) of the reaction mixture was added dropwise to 60 ° C for 16 hours. The mixture was cooled and another portion of methyl iodide (17 μί, 0.1 eq) was added and the mixture was heated to 60 ° C for 30 minutes. The mixture was again cooled, another portion of methyl iodide (35 μί, 0.2 eq.) was added and the reaction mixture was heated to 60 ° C for 60 minutes. The mixture was again cooled, and another portion of methyl iodide (35 μM, 0.2 eq) was then taken and then KOH (70 mg, 0.5 eq) was added and the mixture was heated to 60 ° C for 60 minutes. The mixture was partitioned between D C Μ and water. The aqueous layer was separated and extracted with EtOAc (EtOAc). The aqueous layer was then extracted with ethyl acetate (x3). The combined organic fractions were dried (MgS04) and the solvent was evaporated in vacuo to give an oil. A small amount of water (3 mL) was acidified with EtOAc (EtOAc) elute The remaining aqueous layer was concentrated under vacuum and the residue was dissolved in a mixture of &lt;RTI ID=0.0&gt;&gt; The mixture was passed through a mortar and the desired fraction was concentrated under vacuum to give an oil. Combine all oily products and dissolve in Me Ο Η. Purification by preparative HPLC (basic) afforded the title compound: m. -104-201209054 Preparation 110: [1-(3-ethyl-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl)piperidin-4-yl]methanol

7-Chloro-3-ethyl-[1,2,4]triazino[4,3-c]pyridinidine (50 mg' 0.3 mmol) and 4-(methylidenemethyl)piperidite (11〇 A mixture of mg, 1.0 mmol) in NMP (250 μL) was at 1 Torr in a microwave reactor. (: heating for 15 minutes. The reaction mixture was diluted with DC hydrazine and rinsed with water, then filtered through a phase separator. The organic layer was eluted with MeOH, eluted with MeOH, then eluted with NH4OH/MeOH to collect basic fractions. The title compound was obtained in vacuo to give the title compound: RT = 2.09 min; m/z (ES + ) = 262.2 [Af+H]+. Preparation 111: [1-(3-isopropyl -[1,2,4]oxadiazol-5-yl)piperidin-3-yl 1 methanol

a mixture of 3-isopropyl-5-trichloromethyl-[1,2,4] chelate dioxime (600 mg, 2.61 mmol) and 3·piperidinemethanol (137 mg, 3.90 mmol) in a microwave reactor Heat at 80 ° C for 60 minutes. The crude mixture was passed through a pad of EtOAc (EtOAc) eluting eluting eluting eluting The material was then taken up in EtOAc EtOAc (EtOAc)EtOAc. -105-201209054 Preparation 112: (3/^45)-4-(2,5-Difluorophenyl)pyrrolidin-3-amine

[(3/?,4 to 4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid dibutyl ester (Preparation 48, 2.5 g, 8.4 mmol) in DCM ( TBA (5 mL) was added to the resulting solution, and the reaction mixture was stirred at room temperature for 3 hours. The crude mixture was passed through SCX, eluted with Me Ο ,, followed by NH 4 〇 H / MeOH The mixture was eluted, and the residue was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ,3 · 5 7 - 3.49 (m, 2 H ), 3.37-3.31 (m, 1H), 3.15-3.07 (m, 1H), 3.04-2.98 (m , 1H), 2.8 2-2.75 (m, 1H) Preparation 113: 4-(()--1-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester

In a solution of (i〇-l-piperidin-4-ylethanol acetate (Preparation 97, 20 g, 69 mmol) in 1,4-diche (150 mL) was added Na2C03 (28 g) , 265 mmol) in water (100 mL), the mixture was cooled to 〇 ° C. Dibutyl succinate (24 g, 11 1 mmol) was added in portions over 10 min. After stirring for 22 hours, the crude mixture was poured into water and extracted with DC Μ (x3), then the combined organic fractions were dried (MgS04) and the solvent was removed in vacuo. Column chromatography -106 - 201209054 Purification (DCM. EtOAc, EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc &gt; 3.62-3.53 (m &gt; 1H) &gt; 2.70-2.58 (m, 2H) ' 1.8 5 - 1.7 8 (m, 1H), 1.64 - 1.50 (m, 3H), 1.48-1.33 (m, 10H) , 1.20-1.15 (m, 3H). Preparation 114: 4-((Λ)-ΐ_methanesulfonyloxyethyl)piperidine-hydrazine-carboxylic acid third

Butyl ester

The title compound was prepared from 4-((70-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (Preparation 113) using the procedure described in Preparation 101: 4 NMR δ Η (400 MHz, CDC13) δ = 4.69-4.60 (m,1Η) &gt; 4.29-4.08 (m,2H),3 ·〇1 (s,3H), 2.73-2.60 (m,2H),1.83- 1 · 6 1 (m ' 3 H), 1.4 6 (s, 9 H), 1 · 4 1 (d, ·· = 6.2 H z,3 H), 1.35-1 . 1 8 (m, 2H). Preparation ll5 : 4- [(*S)-l-(2-chloropyrimidine-S-yloxy)ethyl I piperidine-1-carboxylic acid tert-butyl ester

T-butyl 4-((i?)-l-methanesulfonyloxyethyl)piperidine-1-carboxylate (Preparation Example 114, 1.77 g, 5.76 mmol) and 2-chloropyrimidin-5-ol ( Potassium carbonate (1.1 g, 8.10 mmol) was added to a solution of N.sub.2 (20 mL). (: 16 hours. Anti-107- 201209054 The mixture should be partitioned between Τ Β Μ E and water, and the aqueous layer should be separated and rinsed with Τ Μ Μ E. The organic layer was combined, rinsed with water, then rinsed with brine. The title compound was obtained by EtOAc (EtOAc: EtOAc (EtOAc:EtOAc) s, 2H), 4.25-4.19 (m, 3H), 2.74-2.64 (m, 2H), 1.90- 1.65 (m, 3H), 1.47 (s, 9H), 1.3 9- 1.25 (m, 5H). Example 116: 4-((5)-1-(2-((31^45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidine-5- Benzyl}ethyl)piperidine-1-carboxylic acid tert-butyl ester

T-butyl 4-((&lt;S)-1-(2-chloropyrimidin-5-yloxy)ethyl]piperidine-benzoate (Preparation 115, 1.98 g, 5.79 mmol) and (3) /?, 4S)-4-(2,5-Difluorophenyl)-pi-bromo-3-amine (Preparation 112, 1.67 g ' 8.42 mmol)). DBU was added to a mixture of DMSO (11 mL) (1_30 mL, 8.70 mmol), the reaction mixture was at 80 in a sealed tube. (: heating for 64 hours. The reaction mixture was partitioned between DCM and water. The organic layer was separated, rinsed with water, then rinsed with brine, and dried (MgS 〇 4). The solvent was removed under vacuum to give the title compound: RT = 2.92 minutes; m/z (ES + ) = 504.2 [M+H] + ο Preparation 117 : 4-((5)-1-(2-1(35,4/0-3-(2,5- Difluorophenyl)-4-(9H-fos-9-ylmethoxycarbonylamino)pyrrolidin-1-yl]pyrimidin-5-yloxy}ethyl-108- 201209054 yl)piperidin-1- Tert-butyl formate

4-((&lt;S)-l-{2-[(3i?,4Phase-3-amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidine-5_ Tert-butyl ester of methoxy)ethyl)piperidine-1-carboxylate (Preparation 116, 2.59 g, 5.14 mmol), 9-fluorenylmethyl chloroformate (1.60 g, 6.17 mmol) and NaHC〇3 (1.73) a mixture of g, 20.60 mmol) in 1,4 -2 U hospital (40 mL), water (50 mL) and toluene (20 mL) was stirred at room temperature for 16 hours. Add another portion of chloroformic acid 9-buried Methyl ester (0.16 g, 0.62 mmol), and stirring was continued for 30 minutes. The reaction mixture was separated and the aqueous layer was washed with EtOAc. EtOAc (EtOAc m. Chromatography (IH: EtOAc (EtOAc:EtOAc:EtOAc) ^,45)-4-(2,5-Difluorophenyl)-1-[5-((5)-1-piperidin-4-ylethoxy)pyrimidine-2-yl]pyrrolidine_3 _ base} carbamic acid 9H-Jiang _9-yl methyl ester acetate-109- 201209054

4-((5)-1-{2-[(3&lt;5,4 and)-3-(2,5-difluorophenyl)-4-(911-fluoren-9-ylmethoxycarbonylamine Benzyl pyrrolidine-1-yl]pyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester (Preparation 117, 2.29 g, 3.16 mmol). TFA (8 mL) was added to the solution and the mixture was stirred at room temperature for 16 h. The reaction solvent was removed under vacuum and the residue was dissolved in DCM. The solution was flushed through a pad of EtOAc (EtOAc m.). Preparation 119: {(3/?,4*y)-4-(2,5-difluorophenyl) 4-15-((5)-1-piperid-4-ylethoxy)pyrimidine- 2·yl]pyrrolidine_3_yl}aminocarboxylic acid 9H_蒹_9-yl methyl ester

{(3 and,45)-4-(2,5-difluorophenyl)-bu[5-((5)-1-piperazol-4-ylethoxy)pyrimidin-2-yl]pyrrolidine -3-yl}aminocarbamic acid 9H_莽_9-yl methyl ester acetate (Preparation 118, 0.81 g, 1.2 mmol) MDCM (20 mL) and sat. -110 - 201209054

Dispense between NaHC03 solution (20 mL) and pass through a phase separator. The aqueous layer was washed with EtOAc then EtOAc EtOAc (EtOAc). Preparation 120: 4-((&gt;y)-l-{2-1(3^,45)-3-Tertoxycarbonylamino-4-(2,5-difluorophenyl)pyrrolidine -1-yl]pyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester

T-butyl 4-[(^)-1-(2-chloropyrimidin-5-yloxy)ethyl]piperidine-1-carboxylate (Preparation Example 11S, 190 mg '0.55 mmol) and [(3) /?, 4 phantom 4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (preparation 48, 160 mg, 0.55 mmol) in DMSO (2 mL) Into the mixture

DBU (124 pL, 0.83 mmol), and the reaction mixture was stirred at 100 ° C for 16 hr. The mixture was partitioned between DCM and water and passed through a phase separator. The aqueous layer was rinsed with additional DCM then organic layer and concentrated in vacuo. Purification by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: Preparation 121: (32?,4·5)-4-(2,5-difluorophenyl)-1-[5-((5)-1-piperidin-4-yl-ethoxy)pyrimidine -2-yl]pyrrolidine_3-amine-111 - 201209054

4-((-1-(2-(^3^,4 5)-3-Tertobutoxyamino-4-(2,5-difluorophenyl)pyrrolidin-1-yl] To a solution of pyrimidine-5-yloxy}ethyl)piperidine-1-carboxylic acid as the butyl ester (Preparation 120, 150 mg, 0.25 mmol) in DCM (2.5 mL) The reaction mixture was shaken at room temperature for 16 hours. The crude mixture was passed through a pad of EtOAc (EtOAc) eluting with EtOAc EtOAc (EtOAc) The title compound was obtained: RT = 1.99 min; m/z (ES + ) = 404.1 [M+H]+. Preparations 122: (5,-fluoro-3,4,5,6-tetrahydro-2H-[l , 2fI bipyridyl-4-yl)methanol

A mixture of 2,5-difluoropyridine (0.5 g, 4 mmol) and 4-(hydroxymethyl)piperidine (1.5 g, 13 mmol) was slowly heated to melt in a microwave vial with a heat gun. The reaction mixture was heated in a microwave reactor at 60 ° C for 15 minutes' followed by heating at 100 ° C for 30 minutes. The mixture was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc &lt;&apos;&apos;&apos;&apos;&apos; Purification by column chromatography gave the title compound: RT = i·87 min; (Es + ) = 2 1 1 . 1 [M+H]+. -112-201209054 Preparation Example 123: [1-(4-Methylthiazolyl-2-yl)piperidine-4-yl I methanol

A mixture of 2-chloro-4-methylthiazole (0.25 g, 2 mmol) and 4-(hydroxymethyl)piperidin (0.50 g, 4 mm ο 1) was slowly heated in a microwave vial with a heat gun until melt. The reaction mixture was heated in a microwave reactor at ° C for 15 minutes and then heated at 1 ° C for 30 minutes. The resulting gum was partitioned between D CM and water. organic layer was separated and concentrated in vacuo. The remaining aqueous layer was extracted with EtOAc. The two organic residues were combined and quickly precipitated from EtOAc. The supernatant was separated and purified with EtOAc EtOAc EtOAc: Preparation 124: [(3/?, 4 51)-1-{5-[1-(5-ethyl-2-methyl-211-[1,2,4]triazol-3-yl)piperidin Third butyl butyl 4-(4-methoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)oxaridin-3-yl]carbamate

In the [(3Λ,4*5)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl) phenoxyl-butyryl] carboxylic acid tert-butyl vinegar (Preparation Example 88, 2·3 mg '0.07 mmol) THF (0.6 mL) was added to a solution of THF (0.6 mL) Allow to stand for 5 minutes. A solution of TBAD (18.1 mg, 〇. 〇 8 mmol) in THF (0.3 mL) -113 - 201209054 was added and the mixture was stirred at room temperature for 5 min. [丨, 5-ethyl-2-methyl-2H-[1,2,4]triazol-3-yl)piperidin-4-yl]methanol (Preparation 109, 16 mg, 0.07 mmo 1) The solution formed in THF (0.3 mL) was stirred at room temperature for 2 hours. Another portion of TBAD (18.1 mg '0.08 mmol) and PS-triphenylphosphine (1.52 mmol/g loading; 70.4 mg' 0.11 m m ο 1) were added and the mixture was heated to 40. C lasted 2 hours. The reaction mixture was filtered and the resin was rinsed with EtOAc. The filtrate was concentrated under vacuum and then purified using preparative HP LC. The solvent was removed in vacuo to give title compound: mjjjjjjj Preparation 125: [(3/^,45)-1-15-(5^Fluoro-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-ylmethoxy Pyrimidine-2-yl]-4-(2,4,5-trifluorophenyl)pyrrolidinyl]aminobutyl carbamate

T-butyl ester of [(3 and 45)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid (Preparation Example 88, 50 mg, 〇.1 〇 mmol) and (5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl)methanol (Preparation Example 122, 31 mg, 0.15 mmol) EtOAc (3 mL, EtOAc, EtOAc (EtOAc) The mixture was stirred at room temperature for 5 minutes. TBAD (5 1 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 16 h. Another portion of TBAD (51 mg, 0.22 mmol) and PS-triphenyl scale-114-201209054 (1.94 mmol/g loading; 113_mg, 0.22 mmol) were added, and the mixture was heated to 40 °C for 2 hours, after which it was in the chamber. Stir for 60 hours under temperature. The reaction mixture was filtered, and the EtOAc was washed with EtOAc. The resulting residue was partitioned between DCM and water and passed through a phase separator. The aqueous layer was rinsed with D CM then the organic layers were combined and solvent was evaporated in vacuo. Rapid precipitation in MeOH gave the title compound: RT = 4.50 min; w/z (ES+) = 603.3 [M+H]+.

Preparation 126: [(3Λ,4·?)-1-{5-[1-(4-methylthiazol-2-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}-4 -(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

In [(3i?,4S)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)

Pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 50 mg, 0.10 mmol) and [1-(4-methylthiazol-2-yl)piperidin-4-yl]methanol (Preparation Example 123, 31 mg, 0.15 mmol) EtOAc (3 mL) Stir at room temperature for 5 minutes. TBAD (51 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 16 h then heated to 40. (: 2 hours. Another PS-triphenylphosphine (1.94 mmol/g loading; 113 mg, 0.22 mmol) and TBAD (51 mg, 0.22 mmol) were added, and the reaction mixture was then heated at 40 °C. Hour, -115- 201209054 and then allowed to stand at room temperature for 60 hours. The reaction mixture was over-boiled, the resin was rinsed with Me Ο ,, and the filtrate was concentrated under vacuum. The residue was partitioned between DC and water and passed. The aqueous layer was washed with EtOAc (EtOAc) (EtOAc) M+H]+. Preparation 127: [(3 and 419)-1-{5-[1-(3-ethyl-[1,2,4]triazolo[4,3-c]pyrimidine -7-yl)piperidin-4-ylmethoxy]pyrimidin-2-ylbu 4-(2,4,5-trifluorophenyl)pyrrolidine-3-yl]carbamic acid tert-butyl ester

Triethylamine (40 pL, 0.3 mmol) and methanesulfonyl chloride (20 μί, 0.2 mmol) were added to [1-(3-ethyl-[1,2,4]diwax[4,3-c The reaction mixture was shaken at room temperature for 2 hours in a solution of the compound formed in DCM (1 m L). . The mixture was rinsed with 1 Μ H C1 (1 m L) and passed through a phase separator. The aqueous layer was rinsed with DC hydrazine, then combined organic layer &lt; and concentrated under vacuum. [(3/?,4·5)-4-(2,4,5-Trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid A solution of tributyl ester (Preparation 88 '50 mg' 〇.12 mmol) in DMF (1 mL) was added to the crude residue, followed by K2C〇3 (50 mg '0.40 mmol). The mixture was heated to 80. C lasted for 16 hours. The mixture was distributed between D c M and water' and passed through a -116-201209054 phase separator. The aqueous layer was washed with DCM then combined organic layers and concentrated in vacuo. Purified by preparative HPLC to give the title compound: RT == 3.93 min; m/z (ES + ) = 654.3 [M+H]+

Preparation 128: [(3/^,45)-1-(5-(1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-3-yl) Oxy]pyrimidin-2-yl b 4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]aminobutyl carbamate

The title compound was obtained from [1-0-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-3-yl]methanol (Preparation 111) using the procedure described in Preparations. Formation of the mesylate intermediate followed by [(3 and,^)·4,2,4,5·trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidine-3- Prepared by the reaction of butyl carbamic acid tert-butyl ester (Preparation 88): RT = 4.53 min; m/z (ES + ) = 618.3 [Λ/+Η]+. Preparation 129: methanesulfonic acid (/?)-dipen-(3-isopropyl-indole-1,2,4) oxadiazol-5-yl)piperidine-4-yl]ethyl ester

(i〇-l-[l-(3-isopropyl-indol, 2,4)oxadiazolyl)piperidin-4-yl]ethanol (Preparation 62, 4.0 g, 16.7 mmol) in DCM ( 50 mL) The solution of -117-201209054 was added to the solution of triethylamine (2.8 mL '20.0 mmol). The mixture was cooled to 0 ° C. Methanesulfonium chloride (1.6 mL, 20.0 mmol) was added for 10 minutes. After stirring for 2 hours at 0 ° C then water was added to quench the reaction. The mixture was washed with brine (x2), dried (Na.sub.2SO.sub.) and the solvent was removed in vacuo to give the title compound: lH NMR δ Η (4G() MHz' CDC13) : 4.73-4.65 (m &gt; 1 H) &gt; 4.17-4.18 (m, 2H) ' 3.08 - 2.97 (m , 5H), 2.93 - 2.84 (m, lH), 1.94-1.74 (m'3H) '1.53- 1.35 (m, 5H), 1.29 (d, / = 7.0 Hz '6H). Preparation 130: [(3^,45)-4-(2,5-difluorophenyl)-1-( 5_{(·5)-1-[1-(3-isopropyl-[1,2,4] chewedin-5-yl) shouting steep-4-yl]ethylamino}pyran- 2 -yl)pyrrolidin-3-yl]aminobutyl carbamate

In [(3i?,4&lt;S)-l-(5-Aminopyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrole-3-yl]carbamic acid third Butyl vinegar (preparation 81' 256 mg, 0.65 mmol) was added with methanesulfonic acid (phana-1-[3-(3-isopropyl-indenyl), 2,4]oxadiazol-5-yl)piperidine a solution of -4-yl]ethyl ester (preparation 129, 208 mg '0.65 mmol) in MeCN (5.5 mL). K2C03 (99.4 mg, 0.72 mmol) was added, and the reaction mixture was heated under reflux. 1 6 hours. The mixture was concentrated under vacuum to a volume of 2 mL 'heated in a microwave reactor at 1 ° C for 3 hours' and then heated under reflux for 1 44 hours. The solvent was removed under vacuum, followed by residue The product was dissolved in EtOAc <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Purification by HPLC to give the title compound: 111: = 3.95 min; / /2 ( ug 3 + ) = 613.3 [M+H] +. Preparation 131: [(3^,45)-1-(5-11 -(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidine-4-yloxy]pyrimidin-2-yl}-4_(2,4 ,5-trifluorophenyl)pyrrolidine-3-

In 2-chloro-5-[l-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-butylation (Preparation Example 53, 162 Mg' 0.5 mmol) and [(3/?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 158 mg , 0.5 mmol) DBU (75 μί, 0.5 mmol) was added to a solution of DMSO (1 mL) and the mixture was warmed to 1 ° C for 72 hours. The mixture was diluted with DCM and flushed with brine to pass a sifter. The solvent was removed under EtOAc (EtOAc m.)

Preparation 132: [(3/?,4*5)-1-{5-[1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine _4_ Methoxy]pyrimidin-2-yl}_4-(2,4,5-trifluorophenyl)pyrrolidinyl-3(yl)carbamic acid tert-butyl ester-119- 201209054

The title compound was subjected to the procedure described in Preparation 131 via 2-chloro-5-[1 -(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy Pyrimidine (preparation 60) and [(3/?,4S)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]amine

The third butyl formate (Preparation Example 39) was prepared by reaction. Purification by column chromatography (EtOAc EtOAc EtOAc) Preparation 133: 2-((E)·2-Nitrovinyl)pyridinepyridine-2-carbaldehyde (10.0 g, 93 mmol) The solution was cooled to -15 °C under argon. A solution of NaOH (3.9 g, 98 mmol) in water (10 mL) was added dropwise over 20 min. The resulting pale yellow precipitate was stirred under the crucible for 1 minute. Ice water (60 mL) was added, and the mixture was stirred for 15 minutes, after which a saturated NH 4 C 1 solution (7 mL) was added. The organics were extracted with DCM (X), dried (NazSCU), and solvent was removed in vacuo. The residue was dissolved in acetic acid liver (1 mL, 195 mmol) under air and cooled to 0 C. DMAP (0.8 g' 6 mmol) was added and the ice bath was removed and the mixture was stirred at room temperature for 16 h. The reaction solvent was extracted with D c ’ &lt;&gt; The resulting residue was redissolved in -120-201209054 DCM' solution and rinsed with 2M NaOH solution, then rinsed with brine and then dried (MgS04). The solvent was removed in vacuo to give the title compound: </RTI> </RTI> NMR: NMR δ δ (300 MHz, CDC13): 8.74-8.60 (m &gt; 1H) &gt; 8.07-7.85 (m, 2H), 7.82-7.72 (m, 1H), 7.50- 7.43 (m, 1H), 7.40-7.32 (m, 1H). Preparation 134: 2-((trans)-l-benzyl-4-nitropyrrolidin-3-yl)pyridine

The title compound was prepared from 2-((E)-2-nitrovinyl)pyridine (Preparation 13 3) by the method described in Preparation 31, except that the reaction mixture was carried out at 〇 °C. Purification by column chromatography (hexane:EtOAc:EtOAc:EtOAc: LCMS Method 2: RT = 0.84 min; m/z (ES+) = 284.2 [M+H]+. Preparation Example I35: ((trans)-1-benzyl-4-pyridine-2-ylpyrrolidinyl-3-yl)carbamic acid tert-butyl formate

2-((trans)-1-pyryl-4-nitropyrrolidine-3-yl)pyridine (Preparation Example 134 '15·3 g '54 mmol) and zinc powder (28 〇g, 432 mm 〇imAcOH with

The mixture formed in the EtOH mixture (1: 1 '3 00 mL) was heated at 60 ° C -121 - 201209054 for 1 hour. After the reaction was completed, the mixture was cooled and filtered, and then rinsed with &lt;RTIgt; The residue obtained was redissolved in DCM, washed with brine and dried (Na2S04). The solvent was removed under vacuum and purified by column chromatography (DCM: MeOH, 100: EtOAc, 98: 2, 95: 5) to give intermediate (trans)-1-benzyl- 4-pyridine-2- Base-pyrrolidin-3-amine. LCMS method 2: RT = 0.63 min; m/z (ES + ) = 254.3 [M+H]+. Under a argon atmosphere, triethylamine (5.5 mL, 39 mmol) was added to a solution of the product in THF (100 mL), and the mixture was cooled to 0 °C. Di-tert-butyl dicarbonate (5.2 g, 24 mmol) was added, then the reaction mixture was allowed to reach room temperature and stirred for 16 h. The solvent was removed in vacuo and the residue was crystallised eluted eluted elut elut The product was quickly precipitated from heptane, which was repeated several times to give the title compound. LCMS Method 3: RT = 2.35 min; w/z (ES+) = 354.3 [M+H]+. Preparation 136: ((trans)-4-pyridin-2-ylpyrrolidin-3-yl)carbamic acid tert-butyl ester

((trans)-1-benzyl-4-pyridin-2-ylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 135, 500 mg, 1.42 mmol) in MeOH (28 mL) The resulting solution was passed through a H-Cube hydrogenation unit (10% Pd/C Cat cart 30, 30 bar, 90 ° C) at a flow rate of 1 mL/min. The solution was dissolved in EtOAc (EtOAc: EtOAc: EtOAc: EtOAc) +H]+. Preparation 137 : 4-Methanesulfonyloxymethylpiperidine-1-carboxylic acid benzyl ester λ0

〇L〇TiX Benzyl 4-hydroxymethylpiperidine-1-carboxylate (16.2 g, 65 mraol) and sulfonium chloride (8_2 g, 71 mmol) in DCM (80 mL) cooled to 4 °C The resulting solution was added dropwise to a solution of triethylamine (7.6 g, 75 mmol) in DCM (20 mL). hour. The resulting reaction mixture was stirred for 30 minutes. The mixture was washed with EtOAc (EtOAc) (EtOAc) (Br.s, 2H), 4.10 (m, 2H), 3.05 (s, 3H), 2.84 (t, 2H), 2.04-1.92 (m , 1H), l_8〇 (m, 2H), 1.34-1.21 ( m, 2H). Preparation 138 : 4-(2-Chloropyridin-5-yloxymethyl)piperidine-l-carboxylic acid benzyl ester

4_ Benzylsulfonyloxymethylpiperidine-1-carboxylic acid benzyl ester (Preparation Example 137 '20.2 g, 61 mmol), 2-chloropyrimidine _5-alcohol (containing 30% 2-bromopyrimidine-5-

A mixture of alcohol '10.5 g' 73 mmol) and potassium carbonate (11.8 g, 85 mmol) in DMF (200 mL) was heated to 80. C lasted for 16 hours. The reaction mixture was diluted with water - EtOAc (300 mL). Additional water (100 mL) and brine (5 〇〇 mL) were added and the organic layer was separated. The aqueous layer was extracted with EtOAc (x3). All the organic fractions were combined, rinsed with 1 M NaOH solution (500 mL) and then rinsed with brine (5 〇 0 mL) and dried (MgS 〇 4). The solvent was removed under vacuum to give a crude residue. The remaining aqueous layer was extracted again with EtOAc (EtOAc). The organic layer was washed with 1M NaOH solution (250 mL) then brine (250 mL) and dried (MgS04). The solvent was removed under vacuum to give a crude residue. The two crude residue fractions were combined and purified with EtOAc EtOAcjjjjjjjj Mixture of benzyl-1-acetate and benzyl 4-(2-bromopyrimidin-5-yloxymethyl)piperidine-1-carboxylate (64 : 3 6) : *H NMR δ Η (400 MHz, CD C13 ) : 8 · 3 0 (s, 1.4H), 8.26 (s, 0.6H), 7.41-7.31 (m, 5H), 5.17 (s, 2H), 4.28 (Br.s, 2H), 3.93 (d, · / = 6·2Ηζ, 2H), 2_86 (m, 2H) &gt; 2.10-1.99 (m, 1H), 1.87 (d &gt; / = 12.8Hz, 2H), 1_35 (m, 2H). Preparation 139: 4-{2-[(31^,45)-3-Tertoxycarbonylamino-4-(2,5-difluorophenyl)pyrrolidinyl}pyrimidin-5- Benzyloxymethyl}piperidine-1-carboxylic acid benzyl ester

4-(2-chloropyrimidin-5-yloxymethyl)piperidine-1-carboxylic acid benzyl vinegar (containing -124-201209054 36% 4-(2-bromopyrimidin-5-yloxymethyl)per Benzene-1-carboxylic acid benzyl ester 'Preparation 138, 13.22 g, 35 mmol) and [(3i?,4S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]aminocarboxylic acid Tributyl ester (Preparation Example 48, 5.45 g' 18·3

Methyl) DBU (3·60 mL, 24.4 mmol) was added to a solution of DMSO (150 mL) and the mixture was warmed to 100 ° C for 16 hours. A second portion of [(3Λ,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 0.55 g, 1.8 mmol), Continue heating for 4 hours. A third portion of [(3i?,4&lt;S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester was added (Preparation 48, 4.00 g, 13.4 mmol) ) and DBU (1_57 mL '11 mmol), the reaction continued for 16 hours. After cooling, the mixture was diluted with water (600 mL) andEtOAc. The combined organic fractions were rinsed with brine and dried (MgS04). The solvent was removed under EtOAc (mjqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 5H), 7.02-7.21 (m , 2H), 7.0-6.93 (m ' 1H), 4, 71 (Br.s, 1H), 5.17 (s, 2H), 4.47 (Br.s, 1H), 4.28 ( Br.s, 2H), 4.22-4.07 (m, 2H), 3.83 (d '/ = 6·2Ηζ, 2H), 3.70-3.60 (m, 2H), 3.4 1 (m ' 1 H) 2.8 6 (m ' 2 H) ' 2 · 0 6 -1 · 9 5 ( m,1 H),1 · 8 6 (d,&gt;/ = 14Hz, 2H), 1.43 (s,9H), 1.33 (m,2H) . Preparation 140: {(3/?,4*S)-4-(2,5-difluorophenyl)-l-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl] Pyrrolidine _3_yl} carbamic acid tert-butyl ester-125- 201209054

Preparation 139, 13.7 g, 22 mmol) palladium on carbon (1 〇 wt% ' 4.1 g ' 50% water) was added to a solution of ethanol (230 mL). The reaction mixture was stirred for 1 hour under an ammonia atmosphere. The mixture was filtered and the solvent was removed in vacuo to give the title compound: NMR (400 MHz 'CDCI3) · 8·14 (s, 2 Η), 7.12-7.01 (m, 2 Η), 7·〇_6·93 (m , 1Η), 4.72 (Br.s, 1Η), 4.47 (Br.s, 1Η), 4.22-4.07 (m, 2Η), 3.80 (d, ·· = 6·5Ηζ, 2Η), 3.69-3.60 (m ' 2Η), 3.42 (m ' 1Η) 3.17 (m, 2H), 2.68 (m ' 2H) ' 2.00- 1.75 (m, 4H) ' 1.43 (s, 9H), 1 · 33 (m, 2H). Preparation 141: [(3i?,4»S)-l-[5-(l-Cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-di Fluorophenyl)pyrrolidin-3-yl]aminobutyl carbamate

{(3^,45)-4-(2,5-Difluorophenyl)-1-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]pyrrolidine-3-yl} Tert-butyl carbazate (Preparation Example 14 〇 '1〇.4 g, 21.3 mmol) and NaHC03 (5.3 7 g, 63.8 mmol) were added to water (3〇-126- 201209054)

In a mixture of mL) and DCM (30 mL), the mixture was cooled to 0 °C. Another portion of water (20 mL) and DCM (20 mL) were added to the resulting slurry. The solution of cyanogen bromide (2.5 g, 23.6 mmol) in DCM (30 mL) was added dropwise over 15 min while maintaining the temperature below 5 °C then stirring the mixture for one hour at 〇 ° C, then Stirring was continued for 16 hours at room temperature. The mixture was separated and the aqueous layer was extracted with DCM (x2). The organic layer was combined, washed with a saturated NaHC03 solution, then brine, and dried (MgS04). The solvent was removed under EtOAc (EtOAc mEtOAcqqqqqqq , 2H), 7.0-6.93 (m, 1H), 4.71 (Br.s &gt; 1H) &gt; 4.47 (Br.s &gt; 1H) &gt; 4.22-4.07 (m, 2H), 3_83 (d &gt; J = 6.1 Hz, 2H), 3.69-3.60 (m, 2H), 3.53 (m, 2H), 3.42 (m, 1H) 3.10 (m, 2H), 2.0-1.85 (m, 3H) ' 1.55 (m, 2H) ), 1.43 (s, 9H). Preparation 142: ((3i^,41S)-4-(2,5-difluorophenyl)-l-{5-[l-(2H-tetrazol-5-yl)piperidin-4-yl Third butyl oxy)pyridin-2-yl}pyrrolidin-3-yl)carbamate

Under argon, [(3i?,4S)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluoro Phenyl)pyridin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 300 mg, 0.60 mmol) was added portionwise to a solution of -127-201209054 in DMF (5 mL). 47 mg, 0.87 mmol). Sodium azide (57 mg, 0.87 mmol) was then added portionwise, and the mixture was stirred at room temperature for 20 min then heated to 1 〇 〇. C lasted for 6 hours. After cooling, the mixture was diluted with a mixture of water and brine and extracted with EtOAc. The combined organic fractions were rinsed with brine, dried (M g S Ο 4 ), and the solvent was removed in vacuo. Rapid precipitation in D C , gave the title compound: RT = 3 · 6 2 min; m/z (ES + ) = 5 5 8.3 [Μ+Η]+. Preparation 143: ((3/?,45)-4-(2,5-difluorophenyl)-1-{5-[1-(2-isopropyl-2-yt-tetrazole-5) Piperidine_4_ylmethoxy]pyrimidin-2-yl}pyrrolidinyl-3-yl)carbamic acid tert-butyl ester

Under argon, at ((3i?,4*y)-4-(2,5-difluorophenyl)-1-{5-indole-(2Η-tetrazol-5-yl)piperidine _4· D-butyl benzyloxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamate (preparation 142, 196 mg, 0.35 mmol) and acetone (2.5 mL) in DMF (0.5 mL) K2C03 (146 mg, 1.05 mmol) was added to the solution followed by isopropyl iodide (70 μί, 0.70 mmol). The reaction mixture was heated to 50 ° C for 3.5 hours and then concentrated under vacuum. A mixture of water and brine was added to the residue. The combined organic layers were washed with brine, dried (MgSO4), and evaporated in vacuo. Purification by preparative HPLC (basic method) gave the title compound: RT = 4.53 min; w/z (ES+) = 201209054 600.4 [M+H]+. Preparation 144: ((3;?,4 magic-4-(2,5-difluorophenyl)-l-{5-[l-(5-isopropyl-[1,3,4] oxa 2 Tetylene-2-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester

In the 丨^ and /"-bu-(a)-difluorophenylbubupipiperidino-indole-ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid tert-butyl ester (Preparative Example, 70 mg, 0.10 mmol). Add 5-isopropyl-3H-[1,3,4]oxadiazol-2-one (27 mg' 0.21 tnmol) to a solution of DMF (4 mL) ), followed by

BOP (95 mg &gt; 0.21 mm ο 1) and D IP E A (50 μL y 〇 · 2 8 mmol) were added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (EtOAc). The combined organic fractions were taken up in EtOAc EtOAc (EtOAc) eluting eluting The residue obtained was taken up in EtOAc (EtOAc) eluting with EtOAc EtOAc. Two fractions were collected and concentrated under vacuum. Purification by preparative HP LC gave the title compound: RT = 4.09 min; m/z (ES+) = 600.3 [M+ Η]+. Preparation 145 : ((3/^,45)-4-(2,5-difluorophenyl)-1-{5-[1-(indolyl-hydroxymethylindenyl)piperidine-4-yloxy Base 1 pyrimidine_2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester-129- 201209054

[(3/?,4Fanta-1-[5-(cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidine_ The solution of 3-benzyl]-tert-butyl carbamate (Preparation 141, 4.0 g, 7.8 mmol) dissolved in EtOH (40 mL) was warmed to 50. (:, then EtOH (35 mL) was added until a solution was formed. The solution was cooled to 40 ° C, and a solution of hydroxylamine (50% aqueous solution '〇·5 mL' 7.8 mmol) in EtOH (5 mL) was added dropwise for 10 minutes. The reaction mixture was stirred at this temperature. After 6 hours, a white precipitate formed. The mixture was dried and the solid obtained was quickly precipitated from EtOAc (c) to give the title compound: 4 NMR δ Η (400 MHz 'CDC13): 8.13 (s' 2H) ' 7.10-7.02 (m, 2 Η ), 7 · 0 - 6 · 9 3 (m ' 1H) ' 4.80 (br s ' 1 H) ' 4 64 (br.s, 1H), 4.47 (br.s ' 1H) ' 4.22-4.07 (m ' 2H,)' 3.80 (m, 2H) ' 3.74-3.67 (m, 2Η), 3·67-3·59 (m, 2H) ' 3·42 (m , 1H) 1 2.79-2.69 (m 1 2H) &gt; 2.00-1.80 (m ' 3H) ' 1.48- 1.34 (m, 11H). Preparation 146: 3-methoxy-2-methylpropanoic acid

Add NaOH (1_4 g' 34 mmol) in water (30 mL) to a solution of methyl 3-methoxy-2-methylpropanoate (3.0 g' 20 mmol) in EtOH (30 mL) The resulting solution 'reaction mixture was heated to 60 ° C for 2 hours - 130 - 201209054. After cooling, EtOH was removed in vacuo and residue was partitioned betweenEtOAc and water. The mixture was acidified with EtOAc (EtOAc)EtOAc. The solvent was removed in vacuo to give the title compound: NMR δ Η 400 (400 MHz &gt; CDC13): 3.64-3.59 (m,1H), 3.52-3.48 (m.,1H), 3.40 (s,3H), 2.8 5-2.75 (m, 1H), 1.22 (d &gt; J=7.01 Hz &gt; 3H).

Diterpene-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)_4_(2,5-difluorophenyl)pyrrolidin-3-yl]-tert-butyl carbamate

In ((3 and, 45&gt;)-4-(2,5-difluorophenyl)-1-{5-[1-(1^-hydroxymethylindolyl)piperidin-4-ylmethoxy] Pyridin-2-yl}pyrrolidin-3-yl)carbamic acid terpene oxime ester (Preparation 145, 50 mg, 0.09 mmol) in a solution of DMF (3 mL) Propionic acid (is mg, 0.16 mmol) was added followed by HOBt (28 mg, 0.18 mmol), and finally EDCI (35 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 90 min. The solvent was removed under vacuum, and the obtained residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 148: (5·)-Ν·hydroxyl_2_methoxypropene-131 - 201209054

Hydroxylamine (50% in water, 1.55 mL ' 23.52 mmol) was added to a solution of (5)-2-methoxypropionitrile (910 mg, 10.69 mmol) in MeOH (10 mL). . (: 16 hours. After cooling, the solvent was removed in vacuo, the product was recrystallized from heptane:EtOAc (1:1). The mother liquor was concentrated in vacuo and crystallized for a second time. The title compound was obtained by EtOAc EtOAc: EtOAc (EtOAc)

F Hydroxylamine (50% aqueous solution, 792 μΐ^, 13.18 mmol) was added to a solution of 2,2-difluoropropionitrile (1 mg, 10.98 mmol) in IMS (30 mL). To 90. (3) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , CDC13): 4.78 (br.s - 1H) - 1 .90- 1 -73 (m - 3H) Preparation 150 : ((3Λ,4^-4-(2,5-difluorophenyl)-l -{5-[l-(5-ethyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl ) butyl methacrylate-132 - 201209054

In methoxyacetic acid (l〇mg, 0.2 mmol) and ((3i?,45)-4-(2,5-difluorophenyl)-1-{5-[1-(Ν-hydroxymethyl fluorenyl) Tetylene butyl piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidinyl-3-yl)carbamate (preparation 145, 50 mg, 0.1 mmol) in DMF (3 mL, 40 mmol HOBt (28 mg, 0.18 mmol) was added to the mixture, followed by EDCI (35 mg, 0.18 mmol). The mixture was stirred at room temperature for 180 minutes and then heated to 70 ° C for 90 minutes. After cooling, the solvent was removed under vacuum. The residue obtained was purified by preparative EtOAc (EtOAc) elute elute elute elute elut The following compounds were prepared via the procedure described in Preparation 150 via ((37?,415)-4-(2,5-difluorophenyl)-1-{5-[1-(hydroxyhydroxymethyl)pyridinium. -C) tert-butyl 4-methylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamate (Preparation Example 145) was prepared by reacting with an appropriate acid building block: Name LCMS 151 ^:ν^0&lt;να^ [(3 足45&gt; 1-{5-[1-(5-Difluoromethyl-[1,2,4]oxadiazol-3-yl)piperidine) T-butyl -4-ylmethoxy]pyrimidin-2-yl}-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid RT = 4.52 min; Wl/z ( ES+) = 608.2 [M+H]+. -133- 201209054 152 [(3i?,4S&gt;4-(2,5-difluorophenyl)-1-(5-{1 -[5-(1 - Methylcyclopropyl)-[1,2,4]glyoxazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid Butyl ester RT = 4.77 minutes; m/z (ES ten) = 612.3 [M+H]+. 153 I.J:KK cf^F 〇 。 ( (3 feet 45)-4-( 2,5-difluorophenyl)-1-{5-[1-(5-ethoxymethyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy Tert-butyl pyrimidin-2-yl}pyrrolidin-3-yl)carbamate RT = 4.43 min; w/z (ES+) = 616.3 [M+H]+. 154 f^^nO^〇^ VnCC °Λ [(3/?,45)-4-(2,5-difluorophenyl)-1-(5-{1-[5-(1-fluoro-1-methylethyl)-[ 1,2,4] Oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)3⁄4rrrr-3-yl]carbamic acid tert-butyl ester RT = 4.60 min; m/z (ES+) = 618.3 [Μ+ηγ ° 155 〇乂. ((37?,45)-4-(2,5-Difluorophenyl)-1-{5-[1-(5-three Fluoromethyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrole (1 -3-yl)carbamic acid tert-butyl Ester RT = 4.78 min; w/z (ES+) = 626.3 [M+H]+ ° 156 F/KK{K^ [(3 feet 4S)-l-(5-{l-[5-(3,3 -difluorocyclobutyl)-[1,2,4]oxadiazol-3-yl]piperazin-4-ylmethoxy}pyrimidin-2-yl)-4-(2,5-difluorobenzene Tert-butyl bromid-3-yl]carbamic acid tert-butyl ester RT = 4.56 min; m/z (ES+) = 648.3 [M+H]+ ° 157 Ρ:Κ&gt;Λ&lt;Κ^ [(3 Foot 45)-4-(2,5-difluorophenyl)-1-(5-{1-[5-(3-methylisoxazol-5-ylmethyl)-[1 , 2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrole D-but-3-yl]carbamic acid tert-butyl ester RT = 4.32 min; m /z (ES+) = 653.3 [M+Hf ° Preparation 158: 2-chloro-5-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine _ 4_yloxy]pyrimidine-134- 201209054

Add 3-B in a solution of 1-(3-isopropyl-hydrazide, 2,4)-glyoxazol-5(yl)piperidin-4-ol (Preparation 83, 422 mg '2.0 mmol) in DCM Amine (3 24 pL, 2.4 mmol) 'The mixture was cooled to 〇〇C. Methane sulfonium chloride (1 71 μL, 2 · 2 mm 〇 1) was added to bring the reaction mixture to room temperature for 5 minutes, then stirring was continued for 15 minutes. The mixture was partitioned between DCM and HCl solution and dried using a phase separator. The solvent was removed under vacuum to give the intermediate product 1-indole-isopropyl-indole, 2,4]oxadiazol-5-yl)piperidin-4- ester in the intermediate and 2-chloropyrimidine-5 To a mixture of D.sub.2 (20 mL), EtOAc (EtOAc, EtOAc. The solvent was removed in vacuo then the residue was taken in MeOH and filtered. The filtrate was passed through a pad of EtOAc (EtOAc) eluting with EtOAc, eluting with EtOAc EtOAc. Purification by column chromatography (EtOAc EtOAc (EtOAc:EtOAc) -5-yl)piperidin-4-yloxy]pyrimidine): RT = 3.20 min; /«/2 (8 +) = 324.1 [from +11]+. Preparation 159 : ((3^,45)-4-(2,5-difluorophenyl)-1-{5-[ 1-(5-dimethylaminomethyl-oxime I, 2, 4 Oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidine-2-yl}pyrrolidinyl-3-(yl)aminocarbamic acid tert-butyl ester-135- 201209054

In dimethylaminoacetic acid (17 mg '〇·16 mmol) and ((3/?,4 S)-4-(2,5-difluorophenyl)-1-{5-[1-(&gt ;^-hydroxymercapto)piperidin-4-ylmethoxy;|pyridin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 145, 50 mg, 0.09 mmol) HOBt (28 mg, 0.18 mmol) was added to a mixture of DMF (3 mL), followed by EDCI (35 mg, 0.18 mmol), and the mixture was stirred at room temperature for 16 hrs and then heated to 70 ° C for a period of time 90 minutes. After cooling, the solvent was removed under vacuum. The resulting residue was purified by preparative EtOAc (EtOAc) elute elut elut elut elut elut elut The following compounds were subjected to the procedure described in Preparation 159 via ((3i?, 4 5)-4-(2,5-difluorophenyl)-1-{5-[1-(Ν-hydroxymethylhydrazine). Preparation of tert-butyl piperidine-4-yloxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamate (Preparation Example 145) by reaction with a suitable carboxylic acid building block: Preparation Example No. Structure Name LCMS 160 [(3/?,4S)-4-(2,5-Difluorophenyl)-1-(5-{1-[5-((8)-1-methoxyethyl)- [1,2,4]oxazolidine]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester RT = 4.43 min; m/ z (ES+) = 616.2 [M+H]+. -136- 201209054 161 /KK min f [(3 foot 45)-4-(2,5-difluorophenyl)-1-(5-{1- [5-(Tetrahydrofuran-3-yl)-[1,2,4]oxadiazol-3-yl]-1,4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-yl Tert-butyl carbazate RT = 4,24 min; m/z (ES+) = 628.2 [M+H]+. 162 [(3/?,4S)-4-(2,5-difluorobenzene Base)-1-(5-{1-[(5&gt;5-(four Hydrofuran-2-yl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid Tributyl ester RT = 4.35 min; τη/ζ (ES+) = 628.2 [M+H]+. 163 〇. [(3 foot 45)-4-(2,5-difluorophenyl)-1-( 5-{1-[5-(1-methoxy-1-methylethyl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidine- 3-butyrrolidin-3-yl]carbamic acid tert-butyl ester RT = 4·59 min; m/z (ES+) = 630.2 [M+H]' 164 dCK min C^F ((3 ft 45 )-4-(2,5-difluorophenyl)-1-{5-[1-(5-pyrrolidin-1-ylmethyl-[1,2,4]oxadiazol-3-yl) T-butyl butyl piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamate RT = 2.98 min; w/z (ES+) = 641.2 [M+H]+. 165. Af af [(3 foot 45)-4-(2,5-difluorophenyl)-1-(5-{1-[5-(1-methylpyrrolidin-2-yl)-[1 , 2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-yl] carbamic acid tert-butyl ester RT = 3,00 min; /n/z (ES+) = 641.2 [M+H]+. -137- 201209054 166

[(3i?,45)-4-(2,5--phenyl)-1-(5-{1-[5-(tetrahydropyran-4-yl)-[1,2,4] Oxadiazol-3-yl]piperidine-4-yloxy}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester RT = 4.43 min; m/z (ES+) = 642.2 [M+H]+. Preparation 167: N-hydroxy-2-methoxyethylhydrazine OHNH2 〇Λ methoxyacetonitrile (5.3 mL, 70.42 mmol) in EtOH (10 mL) Hydroxylamine solution (50% aqueous solution, 4.6 mL, 70.42 mmol) was added and the reaction mixture was heated under reflux for 16 h. The solvent was removed in vacuo and the title title compound: NMR δ Η (400 MHz, CDC13): 5.29 (s, 1H), 4.87 (br.s., 2H), 3.92 (s, 2H), 3.33 (s, 3H). Preparation 168: N-Hydroxy-tetrahydrofuran-3_ formazan

Hydroxylamine (5 〇% aqueous solution, 750 μL, 11.3 mmol) was added to the solution of tetrahydrofuran-3-carbonitrile (loom mg, 10.3 mmol) in IMS (7 m L). Heated under reflux for 16 hours. After cooling, the solvent was removed under vacuum to azeotrope with toluene. The residue was purified by EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj s -138- 201209054,2H), 4_l〇-3.85 (m, 2H), 3.80-3.60 (m, 2H), 3.03-2.82 (m, 1H), 2.3 0- 1.90 (m, 2H). Preparation Example 1β9: 2,2-Difluoro-N-hydroxyethylhydrazine

Add hydroxylamine solution (50% aqueous solution, 2.08 mL, 31.6 mm ο 1) to a solution of difluoroacetonitrile (2.21 g, 28.7 mmol) in EtOH (5 mL). hour. After cooling, the solvent was removed under vacuum and azeotroped with toluene (χ3). The residue obtained was partitioned between DCM and water to isolate organic layer. The aqueous layer was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ]+. Preparation 170: N-Hydroxy-1-methylcyclopropanecarbamidine

Pyridine (2.5 mL, 3 0.26 mmol) was added to a solution of 1-methylcyclopropanecarbamide (1.50 g, 15.13 mmol) in THF (225 mL). Stir under 1 hour. TFAA (10. 5 mL, 75.66 mmol) was then added to the mixture and the mixture was stirred at EtOAc for 15 min. Saturated NaHC(R) 3 solution was added until pH 8 was reached and the mixture was then diluted with DCM. The organic layer was separated and the aqueous layer was extracted with DCM (x2). The organic fractions were combined, dried (Na2SO4) </RTI> - </RTI> &lt;RTI ID=0.0&gt;&gt; A hydroxylamine solution (50% aqueous solution, 0.9 mL, 13·7 mmol) was added to the product IMS solution (ISO mL) and the reaction mixture was heated to 90 °C for 16 hours. After cooling, the solvent was evaporated in EtOAcqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .s, 1H), 4.57 (br.s, 2H), 1.29 (s' 3H), 0.96-0.90 (m &gt; 2H) &gt; 0.59-0.51 (m , 2H). Preparation Example 171: 2-Fluoro-N-hydroxy-2-methylpropionamidine

DAST (4.65 mL '35.3 mmol) was added dropwise to a solution of 2-hydroxy-2-methylpropanenitrile (2.00 g, 23.5 mmol) in DCM (240 mL) cooled to -78 °C. minute. The reaction mixture was warmed to room temperature and stirring was continued for 16 hours. Water and a saturated NaHCO 3 solution were added, and the organic layer was separated and washed with a saturated Na 2 H Ο 3 solution. The aqueous layer was combined and extracted with DCM. Then the organic fractions of all the combined organics were dried (Na.sub.2.sub.4) and the solvent was removed in vacuo to give the intermediate product 2-fluoro-2-methylpropionitrile: 1 NMR δΗ (3 00MHz ' CDC13) : 1.80 (s, 3Η), 1.73 (s, 3Η) ο Add hydroxylamine (50% aqueous solution, 1 · 4) to the solution formed in the product IΜ S (50 m L) 1 m L, 2 3 _ 3 0 mm ο 1), the reaction mixture was heated to 85 ° C for 16 hours. After cooling, the solvent was removed under vacuum and azeotroped with toluene -140 - 201209054 (X2). Purification by column chromatography (heptane:EtOAc (EtOAc:EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 8 (d, ·/ = 22 · 5 Hz , 6H). Preparation 1 72: 2-Ethoxyethylamine v^nh2 To a solution of ethoxyacetic acid (2.07 g, 19.85 mmol) in DCM (20 mL) cooled to 0 ° C 2.02 mL, 23.82 mmol) 'Subsequent force [j into DMF (2 drops), the reaction mixture was stirred at this temperature for 1 hour and then stirred at room temperature for 2 hours. The mixture was cooled to 0.degree. C. and aq. MeOH (17%, 50 mL). The solvent was removed under vacuum and DCM was added. The mixture was filtered, washed with EtOAcqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 93 (s, 2 Η), 3.6 1 - 3.5 0 (m , 2H), 1.27-1.20 (m, 3H). Preparation 173 2-Ethoxy-N-hydroxyacetamidine

N, C, ΝΗ, ΝΗ, pyridine (3.0 mL) was added to a solution of 2-ethoxyethylamine (preparative 172' 184 g, 17.84 mmol) in THF (290 mL) cooled to 0 °C. , 3 7.09 mmol)' followed by the addition of TFAA (12.90 mL '92.73 -141 - 201209054 mmol) and the reaction mixture was stirred at 0 °C for 15 min. The solution was saturated with NaHC03 until pH 8 ' was reached and the mixture was extracted with DCM (x2). The organic layer was combined, washed with a 1 M HCl solution, then dried (Na2SO4) and solvent was evaporated in vacuo to give the intermediate product 1-methylcyclopropanecarbonitrile. A hydroxylamine solution (50% aqueous solution, 1 · 〇 8 m L, 1 7 · 9 8 m m ο 1) was added to the solution of the product in IMS (170 mL), and the reaction mixture was heated to 90. (: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ): 5.89 (s, 1H), 4.98 (br. s, 2H), 4 · 02 (s, 2H), 3.5 7-3.48 (m, 2H), 1. 26-1 · 19 (m, 3H). Preparation 174: (/?)-N-hydroxytetrahydrofuran-2-carboxamidine

The title compound was prepared from (i?)-tetrahydromethane-2-carbonitrile using the procedure described in Preparation 168. Purification by column chromatography (heptane:EtOAc:EtOAc:EtOAc:EtOAc , 2.20- 1.80 (m , 4H). Preparation 175: [(3Λ,4&lt;5)-1-(5-bromo-3-cyanopyridin-2-yl)-4-(2,5-difluorophenyl)pyrrolidine_3_yl] Tert-butyl carbazide-142- 201209054

DBU (3 3 8 pL, 2.26 mmol) was added in one portion to a solution of 5-bromo-2-pyridyl-3-cyanoindole ratio (300 mg, 2.00 mmol) in MeCN (2 mL). BOP (1000 mg, 2.26 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM and (1 brine) and layered. The aqueous layer was extracted with DCM (X2) and then the organic fractions were passed through a phase separator and concentrated under vacuum. IH: EtOAc, EtOAc: EtOAc: EtOAc: EtOAc: -1-13-cyano-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]-4 -(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

In argon, a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethyl (1:1) (15.2 mg, 0.02 mmol) , [(3i?,4S)-1-(5-bromo-3-cyanopyridin-2-yl)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid Tributyl ester (Preparation 175, 299.0 mg, 0.62 mmol), bis(pinacolato)diboron (174.2 -143- 201209054 mg, 0-69 mmol), and KOAc (183.7 mg, 1.87 mmol) To the mixture was added 1,4·dioxane (3 〇 mL) and the reaction mixture was heated to 80 ° C for 16 hours. The solvent was removed in vacuo and EtOAcqqqqqqq The layers were separated and the aqueous layer was extracted with EtO A c. The combined organic fractions were washed with EtOAc (EtOAc m.) Preparation 177 : 5-Bromo-2-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-3.cyano Pyridine

Under argon in [(1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1, 272 mg, 1.20 mmol To a solution of anhydrous THF (5 mL) was added 5-bromo-2-hydroxy-3-cyanopyridine (200 mg, 1.01 mmol), followed by triphenylphosphine (477 mg, 1.82 mmol). The suspension was cooled to 〇 °c for 20 minutes, then TBAD (419 mg, 1.82 mmol) was added portionwise. After the addition, the reaction mixture was stirred at 0 ° C for 20 min, then warmed to room temperature and stirred again. The solvent was removed in vacuo and purified with EtOAc EtOAc EtOAc EtOAc (EtOAc) H]+. Preparation 178: (4-hydroxymethyl-piperidin-1-yl)-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-methanone-144 - 201209054

Add piperidin-4-yl to a solution of 3-isopropyl-5-trichloromethyl-[1,2,4]oxadiazole (500 mg '2.0 mmol) in IPA (10 mL) - Methanol (380 mg, 3.3 mmol), the resulting mixture was heated at 50 ° C for 16 h then heated at 90 ° C for 5 h. Add water (0.5 mL) and at 90. Heating was continued for 16 hours at C. The reaction mixture was purified by preparative </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Preparation 179: [(3Λ,45)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-pulse-methyl-4-yl Oxyl]-cyclohexan-2-yl}-4-(2,4,5-diphenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

(4-Hydroxymethyl-piperidin-1-yl)-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-methanone (Preparation 178' 36 mg, 0.14 Methyl)triethylamine (4 μμ [' 0.30 mmol) and methanesulfonyl chloride (20 pL, 〇·2〇mmol) were added to a solution of DCM (1 mL). The mixture was stirred at room temperature. After 2 hours, rinse with 2 MH C1 aqueous solution and concentrate under vacuum to give 1-(3-isopropyl-indole, 2,4)oxadiazolecarbonyl)-piperidin-4-ylmethyl methanesulfonate. . Addition of [(3i?,4&lt;y)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid A solution of tributyl ester (Preparation 88, 50 mg, 0.12 - 145 - 201209054 mmol) in DMF (1 mL) and EtOAc (50 mg, 0.40 mmol). . The reaction mixture was cooled to room temperature and partitioned between DCM and water. The organic layer was separated, EtOAc (EtOAc m. Preparation 180: [(3/?,4·5)-1-{5-[1-(3-methyl-butanyl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}- 4_(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

Add three to a solution of 1-(4-hydroxymethyl-indole-1-yl)-3-methyl-butan-1-indole (28 mg, 0.14 mmol) in DCM (1 mL) Ethylamine (40 pL '0.3 mmol) and methanesulfonyl chloride (20 pL, 0.2 mm ο 1), and the resulting mixture was shaken at room temperature for 2 hours. The reaction mixture was washed with aq. EtOAc (1 mL). Adding tert-butyl ester from [(3 and,4 *5)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidinyl]carbamic acid (Preparation Example 88' 50 mg, 0.12 mmol) in a solution of DMF (1 mL) and potassium carbonate (50 mg, 0.40 mmol). Stir for 16 hours at C. The reaction mixture was cooled to room temperature and partitioned between 〇 c Μ and water. The organic layer was separated, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Preparation Example Ιβί : 4-((Phantom-1-yl-ethyl)-_steep-1-carboxylic acid ester ester Gentleman

Add sodium carbonate (58.8 g, 555 mmol) and water (280) to a solution of (Λ)-1-岐卩定_4_yl-ethanol acetate (35 g, 185 mmol) in DCM (300 mL) [mL) 'Subsequent to the dropwise addition of chloroformic acid ester (25.] mL, 176 mmol), the resulting reaction mixture was stirred at room temperature for 16 hours. The aqueous layer was separated and extracted with DCM (2×). EtOAc (EtOAc) Purification by column chromatography (EtOAc: EtOAc (EtOAc:EtOAc): EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 2). Preparation 182: methanesulfonyloxy-ethyl)-piperidine-benzyl benzoate (...) vinegar o. 〇Tc/x at 0 ° CT, at 4-((i?)-l-hydroxy-B Benzyl-piperidine-l-carboxylic acid benzyl ester (Preparation 181 '21.3 g, 80.7 mmol) was added to a solution of DCM (250 mL), triethylamine (17.9 mL, 129 mmol). Stir under C for 0.5 hours. Methanesulfonium chloride (8_〇9 mL, 1〇5 mm〇1) was added and the resulting reaction mixture was stirred at 0 °C for 2 hours, followed by stirring at room-147-201209054 for 2 hours, followed by the addition of water ( 300 mL) and DCM (100 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 3 50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc EtOAc EtOAc (EtOAc) Preparation 183: 4-[(5&gt;1-(2-Chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-1-carboxylic acid benzyl ester .frCi

〇L〇YiX°^N ο Benzyl 4-((i?)-l-methanesulfonyloxy-ethyl)-piperidine-1-carboxylate (Preparation 182, 27.6 g, 80.8 mmol) in DMA (800 mL) The resulting solution was charged with 2-chloro-pyrimidine-5-ol (10.9 g, 130 mmol) and fluorinated (12.7 g, 8 3 · 4 mm ο 1). Stir for 9 hours at C. Additional fluorination (7.50 g, 49.7 mmol) was added, and at 60. &lt;3 stirring was continued for 72 hours. After cooling, the reaction mixture was poured into water (1 500 mL). The layers were separated and EtOAc (2×EtOAc The combined organic layers were rinsed with water: brine (1: 1 s 4 X 500 mL) dried (Na2S04), filtered and concentrated in vacuo. Purified by column chromatography (DCM: MeOH, EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc Compound: RT = 0.87 min; m/z (ES + ) = 376.1 [M+H] + (LCMS, Method 2). -148- 201209054 Preparation 184 : 4-(1-((5)-24(3/^4^)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) Benzyl pyrrolidin-1-yl]-pyrimidine _5-yloxy}-ethyl) piperidine-1-carboxylate

X under argon in [(trans)-4·(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 38' 6.41 g, 20.3 Methyl) 4-1(5)-1-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-benzoic acid benzyl ester was added to a solution of anhydrous DMSO (50 mL). Preparation 183, 6.00 g, 16.0 mmol), followed by DBU (2.51 mL, 16.8 mmol), and the resulting solution was stirred at 90 ° C for 49 hours and then at 100 ° C for 16 hours. Additional [(trans)-4_(2,4,5-trifluorophenyl)pyrrolidinyl-3-yl]carbamic acid tert-butyl ester (Preparation 38, 864 g, 2.70 mmol), and obtained The solution is at 120. (: heating under 8 hours. Further adding [(trans)-4_(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 38, 2.0 g, 6.32 mmol), and the resulting solution was heated at 110 ° C for 16 hours and at 140 ° (20 ° C. The reaction mixture was poured into water (25 mL) and extracted with EtOAc (2 X 100 mL) The combined organic extracts were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHH 1.53 minutes; m/z (ES + ) = 656.00 [M+H] + (LCMS - Method 6). Preparation 185: [(3Λ,4·9)-1-[5-((5*)-1 -piperidin-4-yl-ethoxy)-149- 201209054 pyridin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid Third butyl ester

4-(1-{ (5)-24(3/2,4 5)-3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1 Benzyl-pyrimidin-5-yloxy}-ethyl)-piperidine-1-carboxylate (Preparation 184, 7.44 g ' 11.3 mmol) was added 10% to a solution of EtOH (210 mL). The resulting mixture of pd/C (2.11 g, 58.6 mmol) in EtOH (20 mL) was stirred for 3 hours under hydrogen atmosphere and room temperature, and stirred at 50 ° C for 2 hours. After cooling, the reaction mixture was filtered through celite and the residue was washed with methanol. The concentrate was concentrated in vacuo to give the title compound: RT: </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Preparation 186: Butane-1 sulfonyl)piperidin-4-yl]-ethoxypyrimidin-2-yl)-4-(2,4,S-trifluorophenyl)-pyrrolidinyl 3-butyl]-amino carboxylic acid tert-butyl ester

In [(3/?,4Phantom-l-[5-((S)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5- Tributyl phenyl)-pyrrolidin-3-yl-p-aminocarbamic acid tributyl ester (manufactured by -150-201209054, 185, 75 mg, 0.14 mmol) was added to a solution of DCM (5 mL). Amine (30 mL, 0.22 mmol) and n-butanesulfonium chloride (27 mg, 0.17 mmol). The title compound was isolated <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;

Preparation 187: [(3Λ,45)-1-(5-((5)-1-11-(2-methylpropan-1-sulfonyl)-piperidine-4-yl]-ethoxy }-Pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidinyl-3-yl]-carbamic acid tert-butyl ester

The title compound was obtained from [(3/?,4&lt;S)-l-[5-((S)-l-piperidin-4-yl-ethoxy)-pyrimidine-2 by the procedure described in Preparation 186. Preparation of 3-butyl-4-(2,4,5-trifluorophenyl)-pyrrolidinyl]-carbamic acid tert-butyl ester (Preparation 185) and 2-methylpropane-1-sulfonyl chloride: RT = 1.44 min; w/z (ES + ) = 642.54 [M+H] + (LCMS - Method 6). Preparation 188: [(3Λ,45)-1-(5-{(5·)_ι_[ι_(propane-2-sulfonyl)-piperidin-4-yl]-ethoxy}-pyrimidine_2 ·)) 4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester-151 - 201209054

The title compound was obtained from [(3i?,4*^)-1-[5-((&lt;5)-1-piperidine-4-yl-ethoxy)-pyrimidine by the procedure described in Preparation 186. 2_yl]_4_(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl ester (Preparation 185) and decane-2-sulfonyl chloride Preparation: rt = 1.38 min; m/z (ES + ) = 62 8.54 [M+H] + (LCMS - Method 6). Preparation 189: trans-3-t-butoxycarbonylamino-4 hydroxy-pyrrole-1-carboxylic acid tert-butyl ester

Add triethylamine (8.00 mL) to a solution of trans-3-amino-4-hydroxy-pyrrolidine-benzoic acid tert-butyl ester (5·〇〇g, 24.7 mmol) in THF (50 mL) , 57.4 mmol). The reaction mixture was cooled to 〇 ° C. and then di-n-butyl dicarbonate (6.47 g, 29.7 mmol). The resulting reaction mixture was at 0. Stir for 15 minutes at C and at room temperature for 3 hours, then dilute with D C , and rinse with water and brine. The organic extract was dried (MgS04), filtered, concentrated in vacuo, and quickly dried. The obtained solid was collected by filtration to give the title compound: iH NMR δ Η (400 MHz, DMSO): 7.09 (s ' 1H), 5_23 (s ' 1H) ' 3.95 (m ' 1H) ' 3_71 (m, 1H), 3.42 ( m ' 2H) ' 3.08 (m ' 2H) ' 1_41 (s ' -152- 201209054 1 8H). Preparation 190: 3,6-diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-t-butyl ester, ry^°^ under argon and 〇°c' in trans- 3-tert-butoxyalkylamino group _4_ fluorenyl) pyridine-pyrrolidine-1-carboxylic acid tert-butyl ester (Preparation 189 '4·00 g' 13_2 mmol) and triethylamine (3.00 mL' 21.5 Methane) Methanesulfonium chloride (I.10 mL, 14.2 mmol) was added dropwise to a solution of THF (40 mL) for 5 min. The reaction mixture was poured into water and extracted with DC EtOAc (3×). The combined organic extracts were washed with brine, dried (MgSO.sub.sub.sub.sub. Tert-butyl formate. The crude product was dissolved in THF (40 mL), washed with argon and cooled to EtOAc. Sodium hydride (0.53 g, 13.2 mmol) was added portion wise over 5 min and the resulting mixture was poured into water and extracted w. The organic extract was washed with EtOAc (EtOAc) (EtOAc m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (s, 2H) ' 1.49 (s, 9H), i .46 (s, 9H). Preparation 191: trans)_4_Amino-pyrrolidin-3-yl)--fluoro--pyridin-2-one -153- 201209054

In 3,6-diaza-bicyclo[3·1·〇]hexane-3,6-dicarboxylic acid di-t-butyl vinegar (preparation 190, 330 mg, 1.20 mmol) and 5-fluoropyridine-2 ( 1 H)-_ (656 mg ' 5.80 mmol) was added to a solution of NMP (3 mL), tBuOK (521 mg, 4.64 mmol), and the resulting mixture was heated under microwave irradiation for 30 minutes at 1 °C. The reaction mixture was diluted with EtOAc, washed with water, 1M aqueous NaOH and brine and then passed through a phase separator. The organic layer was concentrated in vacuo and the crude intermediate was purified eluting with EtOAc EtOAc. TF A (400 μιη, 5.00 mmol) was added to a solution of the mixture in DCM (2 mL), and the resulting mixture was shaken at room temperature for 3 hrs and then placed on EtOAc. The oxime was eluted with MeOH then EtOAc (EtOAc) eluted eluted eluting m,1H), 7.21-7.28 (m ' 1H), 6.46 -6.5 6 (m,1H),4.8 2-4.90 (m, 1H), 3.45 - 3 5 5 (m,2H),3 · 3 7- 3.44 (m,1 H),3 _ 1 2 (dd, •/=11.72, 2.73 Hz, 1H), 2.70 (dd, *7=10.35, 6.05 Hz -1H). Preparation Example l92 : 1-((trans)-4-amino-pyrrolidin-3-yl)-1H-pyridin-2-one

The title compound was obtained from the 3,6-diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-t-butyl ester using a procedure similar to that described in Preparation 191 (Preparation-154- 201209054 190,3 3 0 mg, 1.20 mmol) and pyridin-2-one (5 52 mg, 5.80 mmol) were synthesized: 4 NMR δ Η (400 MHz, CDC13): 7.55 (dd, "7=7.03, 1.95 Hz, 1H), 7.28-7.37 (m &gt; 1H) &gt; 6.56 (d , 7 = 8.9 8 Hz, 1H), 6.10-6.27 (m &gt; 1H) &gt; 4.77-4.94 (m &gt; 1H), 3.48- 3.5 8 (m &gt; 2H) &gt; 3.39 (dd · 7 = 10.93 &gt; 6.64 Hz &gt; 1H), 3.16 (dd, 7 = 12.1, 3.51 Hz, 1H) &gt; 2.71 (dd, 7 = 10.93, 6.25 Hz * 1H).

Preparation 193: 1-((trans)-4-Amino-pyrrolidin-3-yl)-4-methyl-1H-pyrido-2-immun NH2 (+/-) title compound utilization and preparation A similar procedure as described for 191 from 3,6-diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-t-butyl ester (Preparation Example 190, 3 30 mg, 1.20 mmol) and 4 -Methyl-2-P was synthesized over steep alcohol (633 mg, 5.80 mmol): NMR δ Η (400 MHz, CD3OD): 7.59 (d, / = 7.07 Hz, 1H), 6.41 (s &gt; 1H) &gt; 6.3 1-6.39 (m &gt; 1H) &gt; 4.72-4.84 (m &gt; 1H) &gt; 3.66-3.76 (m &gt; 1H) &gt; 3.41-3.53 (m, 2H) &gt; 3.17 (dd, 7= 12.25 » 5.18 Hz, 1H), 2.78 (dd, /=11.78 &gt; 7.07 Hz &gt; 1H), 2.26 (s, 3H). Preparation 194: 1-((trans)-4-amino-pyrrolidin-3-yl)-5-methyl-1H-pyrypyr-2 -嗣 -155- 201209054

The title compound was subjected to a procedure similar to that described in Preparation 191 from 3,6-diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-t-butyl ester (Preparation 190) and 5- Synthesis of methyl-2-pyridinol: RT = 0.24 min; m/z (ES + ) = 1 94.1 1 [M+H]+. Preparation 195: 1-((trans)-4-amino-pyrrolidin-3-yl)-5-fluoro-1H-pyridin-2-one

Nh2(+/_) The title compound was obtained from the 3,6-diaza-bicyclo[3·1·0]hexane-3,6-dicarboxylic acid di-t-butyl ester using a procedure similar to that described in Preparation 191. (Preparation 190) and 5-fluoro-2-pyridinol were synthesized: RT = 0.20 min; m/z (ES+) = 1 98.09 [M+H]+. Preparation 196 : (5)-1-11-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol

The title compound was synthesized from (p-[pi]-pi-piperidine-4-ylethanol (Preparation 11) using a procedure similar to that described in Preparation 62: RT = 2.72 min; mlz (ES + ) = 240.1 [M+H ]+. -156- 201209054 Preparation 197: 3-Chloro-6-{(S)-l-[l-(3-isopropyl-indenyl-1,2,4)oxadiazol-5-yl)- Piperidin-4-yl]ethoxy oxazine

Add (*S)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin to potassium tert-butoxide (3 95 mg, 3_52 mmol) A solution of pyridine-4-yl]ethanol (843 mg, 3.5 2 mmol) in THF (20 mL) was evaporated. A solution of 3,6-dichloro-1,2-diazine (500 mg, 3.4 mmol) in THF (10 mL) was added and the mixture was stirred at room temperature for 60 min then stirred at 60 ° C 16 hours. After cooling, the solvent was removed in vacuo and residue was partitioned between EtOAc (EtOAc) The organic layer was separated, washed with brine (200 mL) and evaporated. Purification by column chromatography (EtOAc:EtOAc:EtOAc) Preparation 198: [(3^,45)-1-(5-Bromo-4-methoxy-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidine-3 -yl]-tert-butyl carbamic acid

T-butyl [(31451)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid (preparation 48, 1.49 g, 5.00 mmol) in DMSO (10 mL) DBU (748 μί, 5.00 mmol) and 5-bromo-2-chloro--157-201209054 4-methoxypyrimidine (1.12 g ' 5.00 mmo丨) were added to the resulting solution, and the resulting reaction mixture was at 80 °C. Heat for 19 hours. After cooling, EtOAc (300 mL) and brine (EtOAc) Recrystallization from MeOH (35 mL) EtOAc (EtOAc) Preparation 199: [(31^,45)-4-(2,5-Difluoro-phenyl)4-(5-hydroxy-4-methoxy-pyrimidin-2-yl)-pyrrolidin-3- Tert-butyl carbamic acid

In [(3/?,4 5&gt; 1-(5-bromo-4-methoxy-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl Add a solution of tributyl hydroxycarbamate (Preparation 198, 650 mg, 1.30 mmol) in THF (21 mL). A solution of n-BuLi in hexane (1.6 M, 1.8 mL, 2.90 mmol) was added at <RTI ID=0.0># </ RTI> </ RTI> </ RTI> The reaction mixture was stirred at -78 °C for 1 hour, then water was added to quench the reaction and warmed to room temperature. The mixture was partitioned between EtOAc (EtOAc) (EtOAc)EtOAc. , 1. 3 mL, 3.30 mmol) and hydrogen peroxide (30% aqueous solution, 0.34 mL, 3.30 mmol). The reaction mixture was stirred at 0 ° C for 30 min and poured into EtOAc (250 mL) and brine (250 mL) The organic layer was separated and concentrated under vacuum. purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 2 (ugly 8 + ) = 423.2, 48 7.1 [Λ/+Η]+. Preparation 200: ((3Λ,45&gt; 4-(2,5-difluoro-phenyl)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazole_ 5_yl)-piperidine·4·ylmethoxy]-4-methoxy-pyrimidin-2-ylpyrrolidin-3-yl)-carbamic acid tert-butyl ester

1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethyl methanesulfonate (33.1 mg' 109 μπιοί), [(3i?, 4S) )-4-(2,5-difluoro-phenyl)-1-(5-hydroxy-4-methoxy-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl The ester (Preparation Example 199 '46.1 mg, 109 μιηοΐ) and potassium carbonate (45.2 mg, 327 μηηοΐ) were dissolved in DMF (ΐ·〇mL), and at 80. (The next heating was carried out for 10 hours. The DMF was removed in vacuo and toluene (3 x 10 mL) was evaporated. The residue was dissolved in DCM (100 mL), washed with brine (150 mL) and concentrated in vacuo. Column chromatography purification (IH: EtOAc; 7:3 to 4: 6) afforded title title: s.! - 3.77 min; „ /2 (£8 + ) == 63 〇 3 [from +11 ]+〇Preparation Example 2〇ι: 仁丨)·1, 2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidin-1-carboxylic acid isopropyl ester and pyrimidine _5-yloxy) Ethyl] piperidine _ 1-isopropyl formate

CI/Br 201209054 4-((i?)-l-methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acid isopropyl ester (2.93 g, 9.99 mmol), potassium carbonate (4.14 g, 30.0 mmol) , and a mixture of 2-bromo-5-hydroxypyrimidine (68 2 mg, 3.90 mmol) and 2-chloro-5-hydroxypyrimidine (861 mg, 6.25 mmol) in DMF (20 mL) at 80 ° C. hour. EtOAc (3 50 mL) and brine (250 mL) was evaporated. Purification by column chromatography (EtOAc EtOAc (EtOAc): EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 0 8 [ M+H ] +. Preparation 202: 4-((5)-1-(2-1(35,45)-3-Tertoxycarbonylamino-4-(2-keto-piperidin-1-yl)-pyrrole Iridin-1-yl]-pyrimidine-5-yloxybuethyl)-piperidine-1-carboxylic acid isopropyl ester

T-butyl [(315,4&lt;5)-4-(2-ketopiperidin-1-yl)pyrrolidin-3-yl]carbamic acid (Preparation Example 20, 70 mg, 247 μιηοΐ) , 4-[(5)-1-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-1-carboxylic acid isopropyl ester (Preparation Example 201, 49.8 mg, 152 μιηοΐ) and 4 -[(〇-1-(2·Bromo-pyrimidin-5-yloxy)-ethyl]-piperidine-1-carboxylic acid isopropyl ester (Preparation Example 201, 35 mg, 95 μηιοί) in DMSO (594 μ DBU (37.6 mg, 247 μm ο 1 ) was added to the solution formed, and the resulting reaction mixture was heated at 80 ° C for 48 hours. After cooling, the reaction mixture was poured into DCM (150 mL) and The organic layer was isolated from EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) Preparation + 203 : 4-((^)-1-(24(3145)-3-Tertidinoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-1 -yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-1-carboxylic acid

Benzyl 4-[(&lt;5)-1-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-1-carboxylate (Preparation Example 83' 3.00 g, 7.98 mmol) [(3i?,4&lt;S)-4-(2,5-Difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 3.57 g, 12.0 mmol) in DMSO ( DBU (1.19 mL, 7.98 mmol) was added to a solution of 16 mL), and the obtained mixture was heated at 90 ° C for 40 hours. After cooling, the reaction mixture was poured with EtOAc EtOAc m. Purification by column chromatography (EtOAc: EtOAc: EtOAc) Preparation 204: {(3 and, 4*5)-4-(2,5-difluoro-phenyl)-1-[5-((*ί)-1-piperidin-4-yl-ethoxy Base)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester-161 - 201209054

4-((1S)-l-{2-[(3Λ,4&gt;S)-3-Tertidinoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidinyl-l-yl ]-Pyridine-5-yloxy}-ethyl)-piperidine-l-carboxylic acid (Preparation 203, 5·03 g '7·89 mmol) was added Pd/C (1 0) to a solution of EtOH (71 mL). %, 1.5 g, 42 mmol), the resulting reaction mixture was stirred under a hydrogen atmosphere for 1.5 hr. The reaction mixture was filtered with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH [(3/^45)-1-(5-1(5)-1-(1-cyano-piperidin-4-yl)-ethoxypyrimidin-2-ylbu 4-(2,5 -Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

In {(3/^4S)-4-(2,5-difluoro-phenyl)-l-[5-((15)-piperidin-4-yl-ethoxy)-pyrimidine-2- Addition of NaHC03 (1.00 g' 11.9 mmol) to a solution of dimethyl s-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 2.00 g, 3.97 mmol) in DCM (10 mL) The solution formed in H2〇 (1〇mL). The reaction mixture was cooled to 〇 ° C </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The resulting reaction mixture was stirred at 0&lt;0&gt;C for 30 min then warmed to room temperature and diluted with DCM (40 mL). The organic layer was separated, EtOAc (EtOAc m.

Preparation 206: [(3^,45)-1-(5-((5)-1-(1-cyano-piperidin-4-yl)-ethoxy]-pyrimidine_2-yl b 4 -(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound was obtained from [(3Λ,45)-[[5-((5)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-) using a procedure similar to that described in Preparation 205. Synthesis of tert-butyl 4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid (Preparation 185, 1.11 g, 2.13 mmol): RT = 1.30 Minutes; w/z (ES + ) = 547.5 [M+H]+ (LCMS-method 6). Preparation 2〇7 : 1-Fluoro-4-methoxy-2-((5)_2-nitro-vinylbenzene

To a solution of 2-fluoro-5-methoxybenzaldehyde (1.00 g, 6.49 mmol) in MeOH (2 mL) was added nitrosamine (420 pL, 7.8 mmol) -163 - 201209054 To -10 °C. A solution of Na〇H (272 mg, 6.8 1 m m ο 1) in Η 2 ◦ (1 m L) was added dropwise, and the resulting mixture was at -10. (: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Acetic anhydride (1.22 mL, 1 3.0 mmol) was added to the residue, then the mixture was cooled to 0 ° C. 4 - dimethylaminopyridine (55.5 mg, 454 μιηοΐ) was added, and the mixture was stirred at room temperature 16 The reaction mixture was stirred at room temperature. The precipitate was collected by filtration, washed with H20 and dried under vacuum. Purified by column chromatography (IH: EtOAc; To 9: 1), the title compound was obtained: 4 NMR δ Η (400 MHz, CDC13): 8.02 (d- 7=13.67 Hz &gt;1H)&gt; 7.71 (d- /=13.67 Hz, 1H) - 7.06-7.20 (m , 1H), 6.86-7.06 (m, 2 H), 3 8 4 (s, 3H). Preparation 2: 8: (trans)-1-benzyl-3-(2-fluoro-5-methoxy Base-phenyl)-4-nitro-pyrrolidine

At 0 〇C 'in 1-fluoro-4-methoxy-2-((penta)-2-nitro-vinyl)-benzene (Preparation 207, 330 mg, 1.70 mmol) in D CM (8 To the solution formed by adding TFA (26 kL, 0.33 mmol), followed by dropwise addition of N-benzyl-N-methoxymethyl-N-(trimethylmethyl)methylamine (0.51 mL, 2.0 - 164-201209054 mmol) The resulting reaction mixture was stirred under ankle for 90 minutes over 5 minutes. Purification by column chromatography (EtOAc: EtOAc: EtOAc (EtOAc) ;w/z (ES+) = 331.27 [M+H]+. Preparation 2:9: (trans)-4-(2-fluoro-5-methoxy-phenyl)-pyrrolidine_3_amine

(trans)-1-benzylidene-3-(2-fluoro-5-methoxy-phenyl)-4 nitro-indolebiidine (130 mg '0.39 mmol) in MeOH (5 mL) The solution was passed through a H-Cube hydrogenation unit (l〇e/.pd/C Catcart 70, 100 psi' 50 °C) at a flow rate of 1 mL/min. The solvent was removed in vacuo to give the title compound: mjjjjjjjj Preparation Example 21: 4_trimethyldecyl ethynyl-1H-eyelid

Add (trimethylammonium) b (7.28 mL, 51.6 mmol), N-ethylethylamine (15 mL') to a solution of 4- iodine (2 g, 10 mmol) in THF (15 mL). 140 mmol), dichlorobis(triphenylphosphine)palladium (η) (10 g, 1.5 mmol) and copper iodide (I) (〇_28 g, 1.5 mmol). The mixture was stirred at room temperature and room temperature for 16 hours, and the solvent was removed under vacuum. Residue soluble

EhO, filtered to remove insoluble impurities. The filtrate is concentrated under vacuum and dissolved

MeOH' was filtered to remove insoluble impurities. The filtrate was concentrated under vacuum and purified by column chromatography (IH: EtOAc: 4:1 to 0:1). The title compound was obtained by column chromatography on pure - 165 - 201209054 (Et20: IH; 1 : 〇 to 1:1): RT = 3.40 min; τη/z (ES + ) = 1 65.09 [Af+H] +. Preparation 211: 4-ethynyl-1H-pyrazole in a solution of 4-trimethyldecylethynyl-1-indole-pyrazole (Preparation 210, 400 mg '2.4 mmol) in THF (3 mL) A solution of lithium hydroxide (58 mg, 2.4 mmol) in H.sub.2 (0.6 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 7 with acetic acid and concentrated in vacuo. The residue was partitioned between EtOAc EtOAc (EtOAc). Preparation M2: 4-ethyl-1H-pyrazole

A solution of 4-ethynyl-1H-pyrazole (Preparation 210, 170 mg, 1.8 mmol) in EtOH (18 mL) was passed through a H-Cube hydrogenation apparatus at a flow rate of 1 mL/min (1% pd/C Catcart 70, 1 bar, room temperature). The solvent was removed in vacuo to give the title compound:····················· Preparation 213: (trans)-3-tert-butoxycarbonylamino-4-tetrabutyl 4-(4-ethyl-pyrazol-1-yl)-pyrrolidine-1-carboxylate -166-201209054

3,6-diaza-bicyclo[3_1·〇] ancex-3,6-dicarboxylic acid di-t-butyl vinegar (preparation 190, 0.207 g '0.728 mmol) and 4-ethyl-1H-shadow ( A mixture of Preparation </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; The reaction mixture was diluted with DCM and washed with NaOH aqueous (2M) and brine. The organic layer was dried (MgSO4) filtered and concentrated in vacuo. Purification by preparative HP LC gave the title compound: EtOAc: EtOAc: Preparation 214: (trans)-4-(4-ethyl-pyrazol-1-yl)-pyrrolidin-3-amine

In the (trans)-3-tert-butoxycarbonylamino-4-(4-ethyl-pyrazol-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (Preparation Example 213, 79 mg, TPA (250 μM, 3.2 mmol) was added to a solution of DCM (2 mL), and the obtained mixture was stirred at room temperature for 4 hr. The reaction mixture was placed on a SCX crucible, eluted with MeOH then eluted with NH3/MeOH. The basic fractions were concentrated in vacuo to give title titled:jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3.5 9 (m,2H),3.2 5-3.3 8 (m,1H), 2.70-2.86 (m ' 1H), 2.49 (q,·Ζ=7·55 Hz, 2H), 1.19 (t, •7= 7.62 Hz, 3H). 167-201209054 Preparation 215: Ethyl 5-trichloromethyl-[1,2,4]oxadiazole-3-carboxylate

Add perchloroacetic anhydride (1.74 mL, 9.54) to a suspension of ethyl 2-oximinooxamate (1.26 g, 9.54 mmol) in toluene (13 mL, 120 mmol). (mmol), the resulting reaction mixture was heated at 1 1 ° C for 17 hours, then the solvent was removed in vacuo. The residue was dissolved in EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjjjjj , 2H), 1.50 (t, 7 = 7.2 2 Hz &gt; 3H). Preparation 216 : 5-14-((5)-1-(24(31^,45)-3-Tertidinoxycarbonylamino-4- 4-(2,4,5-triphenyl)- Slightly steep-1-yl]-pyranyloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazole-3-carboxylate

[(3i?,4S)-l-[5-((S)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro Benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 250 mg '0.48 mmol) and 5-trichloromethyl-[1,2,4]oxadiazole-3 A solution of ethyl formate (preparation 215' 186 mg, 0.719 mmol) in DMF (1 - 5 mL) was warmed at 5 ° C for 2 h. After cooling, the solvent was evaporated in EtOAc EtOAc (EtOAc) The organic layer was separated, washed with brine (10 mL) and concentrated in vacuo. Purified by column chromatography (IH: E t Ο A c ; 7 : 3 to 4 : 6) 'title compound: RT = 1.41 min; m/z (ES + ) = 662.43 [M+H] + (LCMS - Method 6).

Preparation 217: [(3 and 415)-1-[5-((*?)-1-{1-[3-(1-)-yl-1-methyl-ethyl)-[1,2 , 4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]_ 4_(2,4,5-trifluorophenylpyrrolidin-3-yl 】-T-butyl carbamic acid

At -20 °c, in 5-14-((5)-1-(2-1(3^,45)-3-3 butyloxycarbonylamino-4-(2,4,5-three) Ethyl fluorophenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazole-3-carboxylate (Preparation 216, Cj 171 mg, 0.258 mmol) EtOAc (EtOAc) (EtOAc) (: stirring for 90 minutes, then adding another portion of Et20 solution of methylmagnesium bromide (3M, 0.172 mL, 0.516 mmol). The resulting reaction mixture was stirred at -20 °C for 90 minutes, then a saturated aqueous solution of NH4C1 ( 5 mL) The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Purification by HPLC to give the title compound: RT: 1.29 min; w/z (ES+) = 648.47 [M+H] + -169 - 201209054 (LCMS - Method 6). Preparation 218: 丨 1-(3- Propyl-[I,2,4]oxadiazol-5-ylmethyl)-azetidine_3_yl I-methanol

Add 5-(chloromethyl)-3-isopropyl-1 to a solution of azetidin-3-ylmethanol hydrochloride (0.5 g, 4 mmol) in DMF (5 mL) 2,4-oxadiazole (0.78 g, 4.8 mmol) and triethylamine (1·7 mL, 12 mmol), and the obtained mixture was stirred at 40 ° C for 16 hours. The reaction mixture was partitioned between EtOAc EtOAc m. The combined organic extracts were flushed with brine and placed on a pad of EtOAc (EtOAc) eluting with EtOAc EtOAc. The basic fractions were concentrated in vacuo and purified by preparative EtOAc EtOAc EtOAc (EtOAc: Hz, 2H), 3.42-3.55 (m, 2H) ' 3.16-3.27 (m, 2H) ' 2.94-3.13 (m, 1H), 2.64-2.74 (m, 1H) ' 1.30 (d ' J=7.03 Hz, 6H) o Preparation 219: [(3^,45)-1-(5-(1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-aza Cyclobutane-3-ylmethoxy]-pyrido-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester -170- 201209054

Preparation of [(314^)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (preparation Example 88, 49 mg, 0.12 mmol) was taken in THF (1 mL) EtOAc (EtOAc: EtOAc) The resulting reaction mixture was stirred at room temperature for 5 min. then a solution of THF (31 mg, 0.13 mmol) in THF (0.5 mL). After stirring at room temperature for 5 minutes, [1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-azetidin-3yl]- A solution of methanol (Preparation 218, 25 mg, 0.12 mmol) in THF (0.5 mL) Additional TBAD (31 mg, mmol) and PS-PPh3 (1.52 mmol/g, 119 mg, 0.181 mmol) were added and the resulting mixture was stirred at 40 ° C for 120 min. After cooling, the reaction mixture was filtered, and EtOAc EtOAc m. Purified by preparative HPLC to give the title compound: 1^ = 3. 〇〇 min; /2 (£3 + ) = 604.26 [from +^1] + Preparation 220: (trans)-3-third Oxycarbonylamino-4-(4-methyl-pyrazole-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester-171 - 201209054

Xc

The title compound was obtained from the 3,6-diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-t-butyl ester using a procedure similar to that described in Preparation 213 (Preparation Example 190, 0·500 g , 1.76 mmol) and 4-methyl-1H-pyrazole (0.433 g, 5.28 mmol): RT = 3.72 min; w/z (ES + ) = 3 67 24 [Af+H]+. Preparation 221: (trans)-4-(4-methyl-pyrazole-yl)-pyrrolidine_3_amine

The title compound was obtained from (trans)-3-tert-butoxycarbonylamino-4-(4-methyl-pyrazol-1-yl)-pyrrolidin-1 using a procedure similar to that described in Preparation 214. Synthesis of tert-butyl formate (Preparation 220, 1 mg, 0.273 mmol): RT = 0-36 min; m/z (ES+) = 167.11 [M+H]+. Preparation 222: 2,2-difluorohydroxy-propionium

Hydroxylamine (50% aqueous solution, 7 9 2 mg '1 3.2 mmol) was added to a solution of 2,2-difluoro-propionitrile (1.00 g, 11.0 mmol) in IMS (30 mL). Heat at 16 °C for 16 hours. After cooling, the solvent was evaporated under EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , J=1 9. 1 Hz, 3H). Preparation 223: 2,2,2-Trifluoro-N-hydroxy-acetamidine

A solution of aqueous hydroxylamine solution (50%, 3·9 mL, 63 mmol) in EtOH (80 mL) was placed in a 600 mL Paar apparatus at 35. (: and 15 PSi under the solution of trifluoroacetonitrile (5 g, 50 mmol). Stir the reaction mixture for 45 minutes' and then add trifluoroacetonitrile (5 g, 5 0 mm ο 1 at 35 ° C and 15 PSi) The resulting reaction mixture was stirred for 16 hours at 35 ° C. The solvent was removed in vacuo and the residue was crystallised eluted from Et20 (3 X 50 mL). NMR δ η (400 MHz, d6-DMSO): 1 0 · 3 0 (s, 1 H), 6.2 5 - 6.3 5 (bs, 1H). Preparation 224: N-hydroxy (2HS)

A solution of propionitrile-D5 (250 mg, 4.2 mmol) and a solution of aqueous amine (50%, 0.3 mL, 5.0 mmol) in EtOH (5 mL). After cooling, the solvent was removed in vacuo to give the title compound: 4 NMR δ Η (400 MHz, d6-DMSO): 8.67 (s, 1H), 5.20-5.30 (bs, 1H). -173- 201209054 Preparation 225 : Ν·hydroxy (3,3,3-2H3) propyl hydrazine

IX (3,3,3 -2 Η 3)propanenitrile (2 4 0 mg ' 4 · 2 mm ο 1) and a solution of a solution of amide (50%, 0.3 mL, 5.0 mmol) in EtOH (5 mL) The solution is at 60. (The next heating was carried out for 5 hours. An aqueous solution of hydroxylamine (50% '0.13 mL, 2.1 mmol) was further added, and the obtained mixture was stirred at 60. (5 hr under stirring. After cooling, solvent was removed under vacuum to give the title compound: lH NMR δ Η (400 MHz, CDC13): 8.10-8.60 (bs '1Η) ' 4.50-4.80 (bs, 1 Η), 2.1 7 (s, 2H). Preparation 226: [(3i?, 4S)-4-( 2,5-Difluoro-phenyl)-1-(5-{(·5)-1-[1-(indolyl-hydroxymethyl)-piperidin-4-yl]-ethoxypyrimidine- 2_yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

[(3 and 415)-1-{5-[(15)-1-(1-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-(2 , 3 -Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 205, 100 mg, 0-2 mmol) and aqueous hydroxylamine (50%, 13 pL, 0.22 mmol) The solution formed in EtOH (4 mL) was heated at 60 °C for 3 hours. The solvent was removed in vacuo and aq. EtOAc (EtOAc):jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -174-201209054 Preparation 227: [(3^,45)-1-(5-((5)-1-(1-hydroxy)hydroxyl-yl)-piperidin-4-yl]-ethoxy }-Pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl ester

The title compound was obtained from [(3 &, 4 51)-1-{5-[(5)-1-(1-cyano-piperidin-4-yl)-B using a procedure similar to that described in Preparation 226. Oxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 206, 100 mg, 0.2 Mm): RT = 2.93 min; m/z (ES + ) = 580.1 9 [M+H] + 〇 Preparation 228: [(3Λ,45&gt;4-(2,5-difluoro-phenyl)- 1-(5-((5)-1-(1-(4-methyl-thiazol-2-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidine 3-yl]-tert-butyl methacrylate

{(3i?,4S)-4-(2,5-Difluoro-phenylpiperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid A solution of the third butyl ester (Preparation Example 204' 30 mg, 0.06 mmol) and 2-chloro-4-methyl-1,3-thiazinium (80 mg, 0.6 mmol) in DCM (2 mL) . (: Microwave-175-201209054 Radiant heating for 30 minutes, followed by microwave irradiation for 60 minutes at 140 ° C. The reaction mixture was placed on SCX crucible, eluted with MeOH (2 X 4 mL), followed by NH3 / MeOH (3.5 M, 2 X 4 mL). EtOAc (EtOAc: EtOAc) · 5 1 [M+H]+. Preparation 229: [(3 and, 4*5)-4-(2,5-difluoro-phenyl)-1-(5-{(15)_1-[ 1-(1H-tetrazole-S-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-tert-butyl carbamate

In [(3i^,41S)-l-{5-[(1S)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-( Adding chlorine to a solution of 2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 200 mg, 0-4 mmol) in DMF (4 mL) The money (30 mg, 0.57 mmol) was added followed by sodium azide (37 mg, 0.57 mmol). The obtained mixture was stirred at room temperature for 20 min and stirred at 100 ° C for 16 h. After cooling, the reaction mixture was partitioned between EtOAc (EtOAc) The organic layer was separated, washed with brine (30 mL), dried (MgS04), filtered and evaporated. The title compound was obtained by RT.sub.3, mp. Preparation 230: 1(3Λ,4Χ)-4-(2,5-difluoro-phenyl)-1-(5-((5)-141--176- 201209054 (3-ethyl-1H-four T-butyl butyl-5-yl)-piperidin-4-yl]-ethoxypyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid

F

At room temperature, in [(3 and 45)-4-(2,5-difluoro-phenyl)·b (5-{(5)-1-tetrazol-5-yl)-piperidine- Tert-butyl 4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid (Preparation Example 229 '160 mg' 0·28 mmol) in DMF (0.5 mL Potassium carbonate (120 mg, 0.84 mmol) was added to a solution of acetone (2.5 mL), then ethyl iodide (45, 0.56 mmol) was added portionwise, and the resulting mixture was heated at 50 ° C for 3.5 hours. The solvent was removed in vacuo and EtOAcqqqqqqqqq The organic layer was separated, washed with brine (40 mL) dry The residue was purified by preparative EtOAc EtOAc (EtOAc) The basic fraction was concentrated in vacuo to give the title compound: &lt;RTI ID=0.0&gt;&gt; Preparation 231: [(3^,45)-1-(5-((5)-1-11-(211-tetrazol-5-yl)-piperidin-4-yl]-ethoxypyrimidine _2_yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester-177- 201209054

The title compound was obtained from [(3 &, 4 5)-1-{5-[(&lt;5)-1-(1-cyano-piperidin-4-yl) by a procedure similar to that described in Preparation 229. -Ethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 206, 200 mg , 0.4 mmol): RT = 3.82 min; m/z (ES + ) = 5 90.1 9 [M+H]+. Preparation 232: [(3/2,45^-1-(5-((5)-1-11-(2-ethyl-2H-tetrazol-5-yl)-piperidin-4-yl] -Ethoxypyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound was obtained from [(3i?,4S)-l-(5-{(S)-l-[l-(2H-tetrazol-5-yl)-piperidine by a procedure similar to that described in Preparation 230. 3-butyl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (preparation Example 231, 200 mg, 0.3 mmol) was synthesized: 尺丁 = 4.49 min; 坩/2 (£3 + ) = 618_19 [from +1^+. Preparation 233: [1-(6-Ethyl-pyridazin-3-yl)-piperidin-4-yl]-methanol

-178- 201209054 3-Bromo-6-ethylpyridazine (300 mg, 2 mmol) and 4-(hydroxymethyl)piperidine (650 mg, 5.6 mmol) - heated by microwave irradiation at 1 °C 20 minutes. The reaction mixture was diluted with DCM (10 mL) &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& The aliquots were concentrated in vacuo and purified EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH +H]+.

Preparation 234: [(3Λ,4*5)-1-{5-[1-(6-ethylpyridazin-3-yl)-piperidin-4-ylmethoxy]-pyrimidine-2-yl }-4_(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-tert-butyl carbamic acid

[(3Λ,4·5)-4-(2,4,5-Trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl The ester (Preparation 88' 50 mg, 0.122 mmol) was added to a solution of THF (1 mL). &lt;RTI ID=0.0&gt;&gt; A solution of 31 mg, 0.134 mmol) in THF (0.5 mL). [1-(6-Ethyl-pyridazin-3-yl)-piperidin-4-yl]-methanol (Preparation 233, 27 mg, 0.12 mmol) The solution, and the resulting reaction mixture were stirred at room temperature for 2 hours. Additional TBAD (31 mg, 0.134 mmol) and PS-PPh3 (1-52 mmol/g, 120 mg, 0.183 mmol) were added, and the reaction mixture was stirred at 40 °C -179 - 201209054 for 2 hours. The reaction mixture was filtered and the resin was rinsed with Me Ο 。. The filtrate was concentrated in vacuo and purified EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Preparation 235: [(3/?,4S)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-3-yl Methoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester hydrochloride

Formed in [1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidinyl]methanol (Preparation 111, 32 mg, 0.140 mmol) in DCM (1 mL) To the solution were added triethylamine (40 μί, 0.3 mmol) and agar (20 pL, 0 · 2 mm ο 1 ), and the resulting mixture was shaken at room temperature for 2 hours. The reaction mixture was flushed with aqueous HCI (1 EtOAc) and concentrated in vacuo. Add [(3Λ,4·5)-4-(2,4,5-trifluorophenyl)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl The ester (preparation 88, 50 mg, 0.122 mmol) in EtOAc (1 mL). Stir for 16 hours at C. The reaction mixture was partitioned between DCM and water. Purification by preparative <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Preparation 236: (trans)-1-benzylnitro-4-phenyl-pyrrole steep -180- 201209054

TFA (0.10 mL, 1.3 mmol) was added to a solution of ((5)-2-nitro-vinyl)-benzene (1 g 1 7.0 mmol) in DCM (10 EtOAc). N-(Methoxymethyl)-N-(trimethylmethylidenemethyl)benzylamine (2.0 mL '8.0 mmol) was added dropwise. The resulting reaction mixture was in hydrazine. (: Stir for 1-5 hours and stir at room temperature for 1 hour. Add N-(methoxymethyl)-N-(dimethylmethylmethyl)-amine (〇·8 mL, 3·2) Ment) and TFA (0.1 mL, 1-3 mmol), and the reaction mixture was stirred at 〇 ° C for 3 min. The reaction mixture was diluted with DCM (40 mL) and water (50 mL) Concentration in vacuo, EtOAc (EtOAc: EtOAc (EtOAc) Preparation 237: (trans)-4-phenyl-pyrrolidine_3_amine (+/-)

P ην0^ν, (trans)-1-benzyl-3-nitro-4-phenyl-pyrrolidine (Preparation Example 236' 275 mg, 0.974 mmol) was hydrogenated by H-Cube at a flow rate of 1 mL/min. Device (10% Pd/C, 100 bar, 75 °C). The reaction mixture was taken on a pad of EtOAc (EtOAc) eluting with EtOAc (EtOAc) The basic fraction was concentrated under vacuum to give the title compound: RT = 2.98 min; w/z (ES + ) = 1 63.01 [M+H]+. -181 - 201209054 Preparation 238: 5-Bromo-2-((5)-1-11-(3-isopropyl-indole, 2,4)oxadiazol-5-yl)-piperidine-4- Ethyl pyrimidine

(Fantasy-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 0.50 g, 2.1 mmol) , a solution of 5-bromo-pyrimidin-2-ol (0.36 g, 2.1 mmol) and PPI13 (0.66 g, 2.5 mmol) in THF (20 mL) was added dropwise DEAD (0.39 mL, 2.5 mmol) over 15 The resulting reaction mixture was stirred at room temperature for 16 hours, then added PPh3 (0.33 g, 1.25 mmol), (i?)-l-[l-(3-isopropyl-[1,2,4] Diazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 0.20 g, 0.84 mmol) and EtOAc (0· 20 mL, 0.43 mmol), and the obtained mixture was stirred at room temperature for 72 hours. The solvent was removed under EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -(4-methyl-pyridine-2-yl)-ethyl acrylate

The reaction was carried out by adding phosphinic acid triacetate (5.38 g, 24.0 mmol) dropwise to a solution of sodium hydride U·1 g '26.0 mmol) in THF (120 mL) at 0 〇C. The mixture is at 0. Stir for 30 minutes at C. A solution of 4-methyl-pyrido-2-methyl-fermentation (1.5 g, 12 mmol) in THF (30 mL) - 182 - 201209054 was added dropwise, and the resulting mixture was warmed to room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with EtOAc EtOAc. The combined organic extracts were dried (MgSO4) filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAcjjjjjjjjj Example 24: (trans)_1_benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidine·3-carboxylate

Ethyl (5)-3-(4-methyl-pyridin-2-yl)-acrylate (Preparation 239, 1.97 g, 10.3 mmol) and N-(methoxymethyl) at 0 °C To a solution of -N-(trimethylmethyl)benzylamine (3.0 mL, 12.4 mmol) in EtOAc (EtOAc) (EtOAc) Stir for 1 hour and stir at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous solution of NaHC.sub.3 and extracted with DCM (3x). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc (EtOAc): EtOAc: EtOAc (EtOAc: EtOAc) Method 2). Preparation 241: (trans)_; [_benzyl_4_(4-methyl-pyridin-2-yl)-pyrrolidine-3-carboxylic acid -183- 201209054

In (trans)-1-benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidine-3-carboxylic acid ethyl acetate (Preparation Example 240' 3.26 g, 10.06 mmol) in MeOH (30 mL To the resulting solution was added a solution of NaOH (68 0 mg '12.0 mmol) in water (5 mL), and the resulting mixture was stirred at room temperature 'Add HCl aqueous solution (6M, 2.8 mL), and under vacuum The solvent was removed, and the title compound was obtained from mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Preparation 242: [(3Λ,4·?)-1-benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

In (trans)-1-benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-carboxylic acid (Preparation 241, 2.96 g, 10 mmol) in 1,4-dioxin Diethylamine (2.1 mL, 15 mmol) was added to a solution of hexane (40 mL), and the obtained mixture was cooled to 0 °C. Diphenylphosphonium azide (2.59 mL, 12 mmol) was added and the reaction mixture was stirred. (: stirring for 45 minutes, then adding third butanol (5 mL). After stirring at 0 °C for 5 minutes, the reaction mixture was warmed to room temperature. Stir at room temperature for 2 hours and at 85 ° C. 1 6小时。 The reaction mixture was diluted with EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. Purification by column chromatography (EtOAc: heptane; 5:1 to 1 : 0), the crude product was quickly precipitated from heptane to give [(trans)-1-benzyl-4-(4-methyl-pyridine) Tert-butyl 2-methyl)-pyrrolidin-3-yl]-carbamic acid. Purified by palm chromatography (MTBE: MeOH: BA; 98: 2: 0.1, 15 mL/min, 265 nm, RT = 5.1 min), the title compound was obtained: RT = 3.03 min; /«/ (ugly 3 + ) = 368.2 [from +11] + (1^1^3-method 4). Preparation 243: [(3i?, 45&gt;4-butyl 4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl-p-aminocarbamate

In [(3,4 S) -1 -benzyl-4 -(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl

Adding palladium hydroxide (7.6 mg, 54 μπιοί) to a solution of EtOH (12 mL) and AcOH (1 mL). The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between DCM (2 mL) The organic layer was washed with brine &apos; dried (MgSO4) filtered and evaporated. Purification by preparative HPLC (basic method) gave the title compound: RT: 1.90 min; m/z (ES+) =27 8.1 1 [M+H]+. Preparation 244: 5-bromo-2-{(8)-1-[1-(3-isopropyl-indenyl-1,2,4]oxadiazol-5-yl)-piperidin-4-yl] -ethoxy}-pyridine-185- 201209054

In (i?)-l-[l-(3-isopropyl-indole, 2,4)oxadiazol-5-yl)piperidin-4-yl]ethanol at 0 ° C (Preparation Example 62) , 400 mg, 2 mmol), 5-bromo-2-hydroxyindole (290 mg, 1.7 mmol) and PPh3 (660 mg, 2.5 mmol) in THF were added to TBAD 3 times (5 8 0 mg, 2.5 mmol) A solution of THF (0.5 mL) over 20 min. The resulting reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc (EtOAc)EtOAc. Purification by preparative EtOAc (m.) (m. Preparation 245 : 5-Bromoisopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyridine

The title compound was obtained from (Λ)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4- using a procedure similar to that described in Preparation 244. Synthesis of ethanol (preparative Example 62, 400 mg, 2 mmol) and 5-bromo-2-hydroxy-4-methylpyridine (310 111 LV, 1.7 111111 〇1): 11 butyl = 4.72 min; 2 (£8 + ) = 409.1, 4 1 1 · 1 [M+H]+. Preparation 246: [(3Λ,4Λ)-4-(2,5-Difluoro-phenyl(3-ethyl-[1,2,4]oxadiazol-5-yl)-piperidine-4- Base]-ethoxy}-pyrimidine_2--186- 201209054

[(3i?,4i〇-4-(2,5-Difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 9, 60 mg, 0.192 mmol) and 2-chloro -(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 102, 54.1 mg, 0.160 mmol) in DMSO (0.32 mL To the resulting solution was added DBU (2 4 · 4 mg, 1 6 Ο μ m ο 1), and the resulting reaction mixture was stirred at 90 ° C for 144 hours. After cooling, the reaction mixture was poured into DCM (175 mL) , </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 614.5 [M+H]+.

Preparation 247: [(3/?, 415)-1-(5-{(1?)-1-[1-(3-isopropyl-[1,2,4] oxaindole-5-yl) )--Sp.--4-yl]-ethoxy}•pyran-2-yl)-4-(4-methyl-U-pyridin-2-yl)-pyrrolidinyl-3-yl]-amino Tert-butyl formate

[(3Λ,45)-4-(4-Methyl-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 243, 55.0 mg, 0.198 mmol), 2 -Chloro-5-{(5)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy-187- 201209054 The solution of pyrimidine (Preparation 63, 78.6 mg '0.198 mmol) and DBU (29.6 μM &gt; '0.198 mmol) in DMSO (4 mL) was heated at 80 ° C for 96 hours. After cooling, the reaction mixture was diluted with EtOAc (EtOAc) The title compound was obtained by preparative EtOAc (m.p.). Preparation 248: 6-Bromo-3-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-methyl Base-pyridine

In 6-bromo-2-methyl-B than steep-3-ol (250 mg, 1.33 mmol), [(1-(3-isopropyl-[1,2,4]oxadiazol-5-yl) Piperidin-4-yl]methanol (Preparation 1, 314 mg, 1.40 mmol) and PPh3 (384 mg, 1-46 mmol) in THF were added 3 times to TBAD (337 mg, 1.46 mmol) The reaction mixture was stirred at room temperature for EtOAc (EtOAc) (EtOAc) (EtOAc) Rinse with brine (50 mL), dry (MgSO4), EtOAc (EtOAc) = 3 9 5.1 〇, 397.09 [M+H]+ ° Preparation 249 : ((3Λ,4&lt;!〇-4·(2,5-Difluoro-phenyl)·1_{5·[1-(3 -isopropyl-[1,2,41oxadiazol-5-yl)-piperidin-4-ylmethoxy]_6-methyl-pyridine-2- -188- 201209054 phenylpyrrolidin-3- Tert-butyl carbamic acid

[(3/^,45)-4-(2,^Difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 272 mg, 0.911 mmol), 6-bromo- 3-[l-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-methyl-pyridine (() Preparation 248,300 mg, 0.759 mmol), biphenyl-2-yl (di-tert-butyl)phosphine (45.3 mg, 0.152 mmol) and potassium butoxide (106 mg, 0.949 mmol) in toluene (10 mL) In the sealed tube at 150. (The next heating was carried out for 16 hours. After cooling, the reaction mixture was taken on EtOAc EtOAc (EtOAc) eluting eluting eluting Method), the title compound was obtained: RT = 3.83 min; m/z (ES + ) = 613.21. [M+H] + 〇I' Preparation 250: 1-benzyl-4-hydroxymethyl-piperidine-3- alcohol

CLCC;H In the case of a fast vertical stirrer, add 1-benzyl-3-keto-anthracene-4-carboxylic acid to sodium borohydride (50 g, 1.31 mmol) at 0 °C A solution of the ethyl ester hydrochloride (20 g, 67.2 mmol) in MeOH (3 50 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added and stirring was continued for 4 hours, then the solvent was removed in vacuo. The residue was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 2.27 minutes; speak /2 (ugly 3 + ) = 222.1 [from +11] + (LCMS method _ 4 ). Preparation 251: (cis)-4-ethenyloxymethyl-1-benzyl-piperidin-3-acetate

Acetic anhydride (70 mL) was added to a solution of 1-benzyl-4-hydroxymethyl-piperidin-3-ol (Preparation 250) in pyridine (140 mL). 24 hours. The solvent was removed in vacuo, EtOAc (EtOAc) (EtOAc (EtOAc) ES + ) = 306.1 [M+H]+ (LCMS Method - 4). Preparation 252: Acetic acid (trans)_4_ethyloxymethylbenzyl-piperidine-3-ester

The title compound was synthesized by the method described in Preparation 25i: RT = 2.82 min; /n/z (Es + ) = 306.1 [M+H] + (LCMS Method-4) -190 - 201209054 Preparation Example 253: Acetic acid (cis)-4-ethyl oxymethyl-pipeline steep_3_acetic acid difluoroacetate

Acetic acid (cis)_4_ethyloxymethyl-1-_1-benzyl-indole-3-ester (Preparation 251, 2.00 g, 6.5 5 mmol) MEtOH (300 mL) and TFA (3 mL) The resulting solution was passed through a chemical unit at a flow rate of 1 mL/min (10% Pd/C Catcart 70' 50 atm '70 °C). The solvent was removed in vacuo and aq. EtOAc (EtOAc) EtOAc (EtOAc) Preparation 254: acetic acid (trans)-4_ethyloxymethyl-anthracene-3-ester tri-glycolate

A. The title compound was obtained from EtOAc (V.s.). Mm): RT = 1.52 min; w/z (ES + ) = 2 1 6 · 1 1 [M+H]+. Preparation 255: (cis-chloro-pyrimidine-2-yl)-4-hydroxymethyl-piperidine-3-ol-191 - 201209054 c,-C}-nQ^〇h OH (+/-) acetic acid ( Cis)-4-ethoxycarbonylmethyl-piperacetone difluoroacetate (preparation 253, 0.690 g' 2.10 mmol), 2,5-dichloromethane (0.375 g, 2.5 1 mmol), Potassium carbonate (0.724 g, 5.24 mmol), NMP (8 mL) and water (4 mL, 200 mmol) were mixed in a microwave tube and stirred at room temperature for 5 min. The reaction mixture was heated by microwave irradiation at 100 Torr for 1 minute' followed by release pressure. The reaction mixture was further heated by microwave irradiation at 150 ° C for 10 minutes and then heated for another 20 minutes to release the pressure between the steps. The reaction mixture was poured into water (300 mL) and extracted with Et20 (4×200 mL). The combined organic extracts were washed with brine, dried (M g S Ο 4), filtered and concentrated in vacuo. The resulting oil was crystallized from EtOAc EtOAc (EtOAc) Preparation 256: (trans)-1 (5-chloro-pyrimidin-2-yl)-4-hydroxymethyl-piperidin-3-ol

OH (+/-) The title compound was obtained from the (yield)-4-ethyloxymethyl-piperidine-3-ester trifluoroacetic acid salt using a procedure similar to that described in Preparation 255 (Preparation 254, 0·130 g, 〇·3 9 5 11101〇1) Synthesis: RT = 2.57 minutes; ml z (ES ) = 244.1 1 [^γ/+Η]+ 〇-192- 201209054 Preparation 257 :( Cis)-1_(5_Chloro_[Just]······························· Bromo-mute ·2_yl)_4_(2_chloro-spray-5-yloxymethyl)-piper-3-ol

In (cis)-1-(5-chloro-gamma-2-yl)-4-ylmethyl-indole-3-ol (Preparation 255, 〇·449 g, 1.84 mmol) ' 2- a solution of chloropyrimidine-5-ol (0.144 g, 1·10 mmol), 2-bromopyrimidin-5-ol (0.129 g, 0.737 mmol) and PPh3 (0.725 g, 2.76 mmol) in THF (35 mL) TBAD (0.467 g, 2.03 mmol) was added. The resulting reaction mixture was stirred at 50 ° C for 3 hours. The solvent was removed in vacuo. EtOAc (EtOAc) (EtOAc) The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Preparation 258: (trans)-1-(5-chloro-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5-yloxymethyl)-piperidinol and (trans, ^( ^Bromo-pyrimidin-2-yl)_4_(2_chloro-pyrimidin-5-yloxymethyl)-piperidine-3-ol

The title compound was obtained from (anti-193-201209054)-1-(5-chloro-pyrimidin-2-yl)-4-hydroxymethyl-piperidin-3-ol by a procedure similar to that described in Preparation 257 ( Preparation 256, 0.306 g, 1.26 mmol): mp::::::::::::::::::::::::::::::::::::::::::::::::::::::::: (3/2,45)-: 1-(5-1(3^,45)-1-(5-chloro-pyrimidin-2-yl)-3-hydroxy-piperidin-4-ylmethoxy] · pyrimid-2-yl}-4-(2,5-di-phenyl)_11-tert-pyridin-3-yl]-carbamic acid tert-butyl ester

In (cis)-1-(5-chloropyran-2-yl)-4-(2-chloro-m-stamp-5-yloxymethyl)-piperidin-3-ol (Preparation Example 257' 0.204 g' 0.573 mmol), (cis)-l_(5-bromo-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol (Preparation Example 257' 0" 36 g' 〇·339 mmo1) and [(3Λ,45&gt;)-4·(2,5-difluorophenyl)pyrrol-3-yl]carbamic acid tert-butyl The ester (Preparation Example 48, 0.427 g, 1.43 mmol) was taken in a solution of THF (2.5 mL) and DBU (0.143 <RTIgt; Heat at 48 for 48 hours. The reaction mixture was poured into EtOAc (3 mLEtOAc)EtOAc. The residue was purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: Tert-butyl ester of methoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidinyl-3-yl]-carbamic acid. Purification by palm Η PLC (M ec Ν : τ HF ; 8 4 : 1 6,1 5 -194 - 201209054 mL/min &gt; 250 nm) gave the title compound: RT = 4.27 min; w/z (ES + ) = 6 18.29 [M+H]+. Preparation 260: [(31?,45)-1-{5-[(38,41〇-1-(5-chloro-pyrimidin-2-yl)-3-hydroxy-piperidin-4-ylmethoxy) Tert-butyl]pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid

The title compound was obtained from (cis)-indole-chloro-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5-yloxymethyl)-piperidine-3 using the procedure described in Preparation 259. -Alcohol and (cis-iso-D D- 2 -yl-gas-free H疋-5-yloxymethyl)-piperidin-3-ol (Preparation 257) were synthesized: RT = 4.34 min; /z (ES + ) = 6 1 8.29 [M+H]+.

Preparation 261: [(3/^,45)-1-(5-1(3^, 4i?)-l-(5-chloro-pyrimidin-2-yl)-3-carboxyl-purine-4 -methylmethoxy]-propan-2-yl}-4-(2,5- _--phenyl-phenyl)-pyrrolidin-3-yl-p-aminocarbamic acid tert-butyl ester

[(3Λ,45·)-1-{5-[(trans)-1-(5-chloro-pyrimidin-2-yl)-3-hydroxy-piperidin-4-ylmethoxy]-pyrimidine- The 3-butyl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared by the procedure described in Preparation 259 (anti-195-201209054) 1-(5-chloro-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol and (trans)-1-(5) -Bromo-pyrimidin-2-yl)-4-(2-chloro-pyrimidinyloxymethyl)-piperidin-3-ol (Preparation 258) was synthesized. Purification by palm chromatography (DCM: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: . Preparation 262: [(3^,45)-1-(5-((35,45)-1-(5-chloro-pyrimidin-2-yl)_3_hydroxy-piperidin-4-ylmethoxy]] -pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound was obtained from (trans)-1 -(5-chloro-pyrimidin-2-yl)-4 -(2-chloro-pyrimidin-5-yloxymethyl)-piper by the procedure described in Preparation 261 Pyridin-3-ol and (trans)-1-(5-bromo-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol (preparation Example 258) Synthesis: RT = 4.32 min; m/z (ES + ) = 618.28 [M+H]+. Preparation 263: yl)-l-deep-l-yl]-mouth steep-5-yloxymethylindole-1_(5-gas-m-steep_2-yl)-piperidin-3-ol

-196 201209054 The title compound was obtained from [(3i^,4lS)-l-{5-[(3S,4&gt;S)-l-(5-chloro-pyrimidin-2-yl)- 3-hydroxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4·(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid dibutyl Vinegar (Preparation 262, 55 mg, 0.089 mmol) was synthesized: RT = 2.70 min; /2 (£3 + ) = 518.20 [from +11]+. Preparation 264: (cis)-4-hydroxymethyl-piperidin-3-ol

〇In a solution of (cis)-4-ethenyloxymethyl-1-benzyl-piperidine-3-ester (Preparation 251, 3.00 g, 9.82 mmol) in MeOH (60 mL) Potassium carbonate (1 3.6 g, 98.24 mmol) was added and the resulting mixture was stirred at room temperature for 10 min. Water (50 mL) was added and the~~~~~~ The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford (3?,4&gt;5)-1-benzyl-4-(hydroxymethyl)piperidin-3-ol. The product was dissolved in EtOH (100 m L), passed through a H-Cube hydrogenation apparatus at a flow rate of 1 mL/min (10% Pd/C, 50 atm, 70% (:) twice. The solvent was removed in vacuo to give the title compound. : NMR δ Η (400 MHz, DMSO-c? 6): 4 · 0 7 - 4.4 0 (m, 2 Η ), 3.6 2 (br.s, 1 Η), 3.14 - 3.52 (m, 3 Η), 2.71 2.96 (m, 2 Η), 2.29-2.46 (m, 1H), 1.52 (m, 1H), 1.12-1.43 (m, 2H). Preparation 265: (3/?, 4 magic-3-hydroxy-4- Hydroxymethyl-piperidine-1-carbonitrile OH (+/-) -197 201209054 in (cis)-4-hydroxymethyl-piperidin-3-ol (Preparation 264 '0.8 80 g, 6.71 mmol) Add NaHC03 (1.69 g, 20.1 mmol) and water (5 mL) to a solution of DCM (30 mL). The mixture obtained was cooled to 〇 ° C. Cyanide bromide (0.853 g ' 8.05 mmol) was added to DCM ( 10 mL) of the resulting solution, and the resulting reaction mixture was stirred at room temperature for 16 hours. Add NaHC03 (1 g, 1 1.9 mmol) and MgS〇4 (1 〇g)' and the reaction mixture was stirred at room temperature 1 After </ RTI> </ RTI> </ RTI> <RTI ID=0.0></RTI> H NMR δ Η (400 MHz, DMSO-A): 4.04 (br.s, 1 Η) ' 3.5 9-3.76 (m, 2 Η) ' 3.3 0-3.5 2 (m, 2H), 2.92-3.14 (m, 3H ) ' 2.29 (br_s ' 1H) , 1.8 6 -2.09 (m, 1H), 1.5 0- 1.66 (m, 1H), 1.31-1.47 (m , 1H). Preparation 2 66: (cis)-4- Hydroxymethyl-1-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-3-ol I OH (+/-) at (3i?,4S)- 3-Hydroxy-4-hydroxymethyl-piperidine-1·carbonitrile (Preparation 265, 0.637 g, 4.67 mmol) and N-hydroxyisobutylhydrazine (〇_57 g, 5.6 mmol) in EtOH (10 mL) A solution of zinc chloride (0.63 7 g, 4.67 mmol) in EtOH (1 mL) was added dropwise to the resulting solution for 5 minutes, and the resulting mixture was stirred at room temperature for 2 hr. An aqueous solution of HCl (1 2 · 5 Torr, 5 m L) was added, and the reaction mixture was at 8 Torr. Heat at C for 4 hours. The solvent was removed under vacuum, and P H to P Η 7 was adjusted with a saturated aqueous solution of NaH? -198- 201209054 The title compound was obtained from EtOAc (EtOAc: EtOAc (EtOAc) + ) = 242.1 6 [M+H]+. The guest liquid was passed through the salt column to the minute of the column; mlz;-[1,2,4]. Preparation Example 267: Methanesulfonic acid (3145)-3-hydroxy-1-(3-isopropyldiazole-5- Piperidin-4-ylmethyl ester

In cis ° C, in (cis)-4-hydroxymethyl-1-(3-isopropyloxadiazol-5-yl)-piperidine-3-ol (Preparation 266 '0.170 mmol) and three Ethylamine (0.118 mL, 0.845 mmol) was added dropwise to a solution of DCM toluene (54.5 EtOAc, EtOAc············· The title compound was obtained after aq. EtOAc (EtOAc: EtOAc: EtOAc. Η]+. Preparation 268: (cis)-4-(2-chloro-pyrimidin-5-yloxymethylpropyl-[1,2,4]oxadiazol-5-yl)-piperidine- 3-alcoholyl-[1,2,4] g, 0.704 (10 mL) 704 mmol) The mixture was washed with water and purified by chromatography for s.

Add methanesulfonic acid (37?, 4&gt) to a solution of 2-chloro-5-hydroxypyrimidine (59 mg' 0.45 mmol) and potassium carbonate (75-199 - 201209054 mg, 0.54 mmol) in DMF (2 mL) ;5)-3-Hydroxy-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethylacetate (Preparation 267, 0.145 g, 0.454) Methyl) solution in DMF (3.8 mL). Further potassium carbonate (31.3 mg, 〇·23 mmol) was added, and the reaction mixture was heated at 80 ° C for 24 hours. The solvent was removed in vacuo and EtOAc (EtOAc)EtOAc. Purification by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc) Preparation 269: 2-Chloro-5-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methoxy-piperidine- 4-methylmethoxy]-pyrimidine

In (cis)-4-(2-chloro-pyrimidin-5-yloxymethyl)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidyl Pyridin-3-ol (Preparation 268, 49 mg, 0.14 mm ο 1) was added sodium hydride (6 〇% mineral oil dispersion '11 mg' 0.28 mmol) to a solution of THF (10 mL). The resulting reaction mixture was stirred at room temperature for 10 minutes. Methyl hydrazine (43 μΐ^, 0.69 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hr. Further, sodium hydride (6 〇 % mineral oil dispersion '11 mg' 0.28 mmol) and methyl iodide (87 μΐ, 1.4 mmol) were added, and the reaction mixture was stirred at room temperature for 48 hours. Water (5 〇 m l ) was added and the reaction mixture was extracted with EtOAc (3 X 100 mL). The combined organic extracts were washed with aq. sat. NaHCO3 and brine, dried (MgSO4), filtered and evaporated. Purified by column chromatography (EtOAc: EtOAc:EtOAc:EtOAc:EtOAc:jjjjjjjjjjjjjjjjjjjjjj (3^,45)-1-(5-1(32^,45)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methoxy -piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4_(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

2-Chloro-5-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methoxy-piperidin-4-yl Add [[3J?,4S)-4-(2,4,5-trifluorophenyl) to a solution of methoxy]-pyrimidine (Preparation 269, 61 mg, 0.16 mmol) in DMSO (2.5 mL) Pyrrolidin-3-yl]carbamic acid tert-butyl ester (preparation example)

39, 0.105 g, 0.332 mmol) and DBU (24.8 μί, 0.166 mmol), the resulting reaction mixture was heated at 75 ° C for 48 hours and then at 85 ° C for 72 hours. The reaction mixture was poured into EtOAc (3 mL)EtOAc. Purification by column chromatography (DCM: MeOH; 95: 5) afforded [(3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Dioxo-n--5-yl)-3-methoxy-indole D-1,4-methyloxy]-3⁄4'deep-2-yl}-4. (2,4,5-trifluorophenyl -Pyrrolidin-3-yl]-carbamic acid tert-butyl ester. Purified by palm chromatography (MeOH: THF; 93: 7 &gt; 12 mL/min, 250 nm) -201 - 201209054 RT = 1.41 min; m/z (ES + ) = 64 8.5 7 [M+H] + (LCMS Method-6). Preparation 271: [(3^,45)-1-(5-((35, 4/2)-1-(3-isopropyl-[1,2,4]oxo-•indol-5-yl)-3-methoxy-oxime-4-ylmethoxy]-mute -2-yl}-4_(2,4,5-trifluorophenyl)-pyrrolidin-3-yl-p-aminocarbamic acid tert-butyl ester

The title compound was prepared from 2-chloro-5-[(cis)-1 -(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3 using the procedure described in Preparation 270. Synthesis of -methoxy-piperidin-4-ylmethoxy]-pyrimidine (Preparation 269): RT = 1.41 min; m/z (ES + ) = 648.57 [M+H]+ (LCMS Method - 6 ). Preparation 272 : 4-fluoro-3-((^)-2-nitro-vinyl)-benzoic acid methyl ester

The title compound was synthesized from 4-fluoro-3-carbamimido-benzoic acid methyl ester (10.0 g, 53.5 mmol) using a procedure similar to that described in Preparation 35 using IPA instead of MeOH: iH NMR δ Η (300 MHz, CDC13) ): 8.25-8.22 (m,1H), 8.20-8.10 (m &gt; 1H) &gt; 8.07 (d ' 7-13.7 Hz &gt; 1H), 7.27 (d, /=13.7 Hz, 1H), 7.29-7.23 (m, 1H), 3.92 (s, 3H). -202 - 201209054 Preparation 273: 3-((trans)_1_benzyl_4_nitro-pyrrolidine_3_yl)_4_fluoro-benzoic acid methyl ester

The title compound was prepared from 4-fluoro_3_((5)-2-nitro-vinyl)-benzoic acid methyl acetate (Preparation 272) using a procedure similar to that described in Preparation Example 3 i, except that the reaction was in 〇° Under C. Purification by column chromatography (heptane:EtOAcEtOAc:EtOAc) RT = 3.15 min; m/z (ES + ) = 3 59.2 [M+H] + (LCMS Method-4). Preparation 274: (trans)_1_benzyl_4_(2-fluoro-5-methoxycarbonyl-phenyl)-pyrrolidin-3-amine

Methyl 3-((trans)-1 -benzyl-4-nitro-pyrrolidin-3-yl)-4-fluoro-benzoate at 50 ° C (Preparation 273, 14.7 g » 4 5小时。 After the addition of zinc powder (3.88 g, 243 mmol) was added to the solution of AcOH (225 mL) for 1.5 hours. The resulting reaction mixture was heated at 50 °C for 15 hours. After cooling, the reaction mixture was filtered with EtOAc EtOAc EtOAc EtOAc The residue was taken up in aq. EtOAc (EtOAc) (EtOAc) The combined organic extracts were rinsed with water (7550 mL) and brine (500 mL) - 203 - 201209054 &apos; dried (MgS 〇 4) filtered and concentrated in vacuo. Purification by column chromatography (MeOH: DCM; EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 2.93 minutes; m/z (ES + ) = 329.2 [M+H]+ (LCMS method _4). Preparation 275: 3-((trans).ι_benzyl·4_t-butoxycarbonylamino-pyrrolidine-3-yl)-4-fluoro-benzoic acid methyl ester

In (trans)-1-benzyl-4-(2-fluoro-5-methoxycarbonyl-phenyl)-pyrrolidin-3-yl-amine at 0 °C (Preparation 274, 2.37 g , a solution of 7.22 mmol) and triethylamine (3 mL, 21.7 mmol) in THF (30 mL) was added di-dibutyldicarbonate (2.36 g, 10.83 mmol). Stir! After an hour, the mixture was stirred at room temperature for 6 hours. The solvent was removed in vacuo and EtOAc EtOAc m. The residue was crystallized from EtOAc EtOAc (EtOAc) Preparation 276: [(trans)_;!_benzyl_4_(2-fluoro-5-hydroxymethyl-phenyl)-pyrrolid-3-yl]-carbamic acid tert-butyl ester-204 - 201209054

3-((trans)-1-benzyl-4-t-butoxycarbonylamino-pyrrolidin-3-yl)-4-fluoro-benzoic acid methyl ester at -10 °C (Preparation Example) 275, 1.95 g, 4.55 mmol) of lithium hydride added to a solution of THF (7 mL)

(1 M, 2.3 mL, 2.3 mmol) over 3 min, the obtained mixture was stirred at -10 °C for 100 min. Add EtOAc (30 mL) and a saturated aqueous solution of Rochelle salt (1 〇 m L ) and the reaction mixture at -1 0. Stir for 16 hours at C. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated. Purification by column chromatography (DCM: EtOAc; 1:1) gave the title compound: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Preparation 277: [(312,45)-1-Benzyl-4-(2-fluoro-5-fluoromethyl-phenylpyridinyl)-l-yl)-carboxylic acid carboxylic acid tert-butyl ester

[(trans)-1-pyryl-4-(2-fluoro-5-exogenicmethyl-phenyl)-pyrrolidin-3-yl]-carbamic acid third at -78 °C Butyl ester (Preparation Example 276, 1.34)

g, 3.35 mmol) DAST (0.66 mL, 5.02 mmol) was added to a solution of DCM (20 mL), and the obtained mixture was stirred at -78 °C for 2 hours. Water and a saturated aqueous solution of NaH.sub.3CO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. Purified by column chromatography (DCM: EtOAc; 6:1 to 5:1) to yield [(trans) s s. Pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl vinegar. Purification by palm chromatography (IH: IPA: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: + ) = 403.3 [M+H]+ (LCMS Method-3). Preparation 278: [(3/^,45)-4-(2-Fluoro-5-fluoromethyl-phenyl)pyrrolidin-3-yl]-carbamic acid tert-butyl ester

[(3i?,45)-1-Benzyl-4-(2-fluoro-5-fluoromethyl-phenyl)-pyrrolidine-3-yl]-carbamic acid tert-butyl ester (Preparation Example 277 , 0.092 g, 0.23 mmol) Triethyl chloroformate (47.2 μί, 0.343 mm〇i) was added dropwise to a solution of DCE (11 mL) and DIPEA (0_32 mL, 1.8 mmol). Heat under reflux for 2 hours. The solvent was removed under vacuum. The residue was dissolved in AcOH (2 mL) and zinc (5 〇 mg, 0.7 6 m ο 1) was added portionwise. The resulting reaction mixture was stirred at room temperature for 2 hours, and M e Ο Η (10 m L) was added and the reaction mixture was passed through a c e 1 i t e. The broth was concentrated under EtOAc (EtOAc) EtOAc (EtOAc) -206- 201209054 Preparation Example 2·79: 1-(2-Fluoro-5(methyl-phenyl)_2-nitro-ethanol

At 0 ° C, in a solution of 2-fluoro-5-methyl-benzaldehyde (5.0 g, 36.2 mmol) and nitromethane (2.35 mL, 43.5 mmol) in MeOH (90 mL) A solution of NaOH (1.52 g, 38.0 mmol) in H.sub.2 (15 mL) was added dropwise over 10 min and the mixture was stirred at room temperature for 50 min. The reaction mixture was poured into a saturated aqueous solution of EtOAc (EtOAc). The combined organic layer was washed with EtOAc (EtOAc m. , 1H), 7.0-6.9 (m, 1H), 5.71-5.70 (m, 1H), 4.63-4.57 (m, 2H), 2.93 (br.s, 1 H), 2.3 3 (s, 3 H). Preparation 28: 1-fluoro-4_methyl_2_((penta)-2-nitro-vinyl)-benzene

Add 1-(2·fluoro-5-methyl-phenyl)·2-nitro-ethanol (preparation 279, 7.18 g, 36.1 mmol) to a solution of acetic anhydride (6.8 mL, 22.2 mmol) DMAP (300 mg '2_5 mmol), the obtained mixture was stirred at room temperature for 19 h. The reaction mixture was slowly poured into a saturated aqueous solution of &lt;RTI ID=0.0&gt; The solid was collected, washed with a saturated aqueous solution of NaH.sub.3.sub.3, and then rinsed with Η2 , to give the title compound H NMR δ η (3 0 0 Μ Η ζ ' CDCI3) · 8.04-7.99 (d, J=13 76 - 207- 201209054

Hz, 1H) ’ 7.74-7.69 (d, J=13.7 6 Hz, 1H), 7.30-7.26 (m , 2H), 7.1-7.0 (m, 1H), 2.36 (s, 3H). Preparation 281: (trans-benzyl·3_(2-fluoro-5-methyl-phenyl)nitro-pyrrolidine

Formed in DCM (70 mL) at 10 ° C in 丨-fluoro-cardomethyl-2_((5)-2-nitro-vinyl)-benzene (Preparation 280' 6.38 g, 35.3 mmol) TFA (0.27 mL, 3.52 mmol) was added to the solution, followed by dropwise addition of N-(methoxymethyl)-N-(dimethylmethylmethyl) amide (9.52 mL, 38.8 mmol) in DC ( 30 m L ) of the resulting solution. The resulting reaction mixture was stirred at room temperature for 1.5 hours, poured into a saturated NaHCO^Jc solution and extracted with DCM (3x). The combined organic extracts were washed with EtOAc EtOAc (EtOAc m. (m, 2H), 7.0-6.9 (m &gt; 1H) &gt; 5.04-5.02 (m &gt; 1H) &gt; 4.17-4.15 (m * 1H) &gt; 3.77-3.65 (m ' 2H) ' 3.5-3.46 (m ' 1H), 3.3-3.26 (m, 1H), 3.1-3.0 (m, ih), 2.65-2.60 (m, 1H), 2.30 (s, 3H). Preparation 282: (trans)benzyl_4_(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-amine -208-201209054

'(trans)_;!_benzyl_3_(2_fluoro-5-methyl-phenyl)_4_nitro-pyrrolidine at 30 °C (Preparation 281, 1 1 · 4 g, 3 5.3 mm ο 1) Zinc (13·8 g, 212 mmol) was added in portions to a solution of A c Ο Η (90 mL) for 30 minutes. The resulting reaction mixture was at 3 Torr. Stir for 1 hour at c, then filter with celite and rinse with Ac. The filtrate was concentrated in vacuo and the residue was taken in EtOAc (30 mL). The resulting mixture was stirred at room temperature for 6 hours, EtOAc (EtOAc) The combined organic extracts were dried (MgSO4), 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) to give the title compound: RT = 3.06 min; + ) = 285.1 [Μ+Η]+ (LCMS Method - 4). Preparation 283: [(trans)-1-benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidinyl-3-yl]-aminobenzoic acid tert-butyl ester

(trans)-1-benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolid-3-amine at 〇 ° C (Preparation 282, 5.6 g ' 19.7 mmol To a solution of THF (80 mL) was added a solution of triethylamine (5.65 mL '40 mmol) and dibutyl succinate (5.15 g, 23.6 mmol) in THF (30 mL). The resulting reaction mixture was stirred at room temperature for 2 1 hour. The reaction mixture was poured into EtOAc (3 mL). EtOAc (EtOAc) (EtOAc) The resulting oil was dissolved in EtOAc (EtOAc) EtOAc (EtOAc). (LCMS Method-4). Preparation 284: [(3AO-1-Benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound is via [(trans)-1-hexyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 2) 8 3 ) was obtained by palm HPLC separation (IH: IPA: DEA 96:4: 0.1-15 mL/min, 270 nm, RT = 8.2 min). Preparation 285: 丨(3Λ,45&gt;-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

[(37?, Benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 284, 2.4 g, 6.2 mmol The solution formed in MeOH (124 mL) was passed through a H-Cube hydrogen-210 - 201209054 apparatus (10% Pd/c Cate art 70, 100 bar, 50 ° C) at a flow rate of 1 mL/min. The solvent was removed to give the title compound: RT: 2.42 min; m/z (ES + ) = 2 9 5.3 2 [Af+H]+. Preparation 28: 1-(2,4-difluoro-5-methyl- Phenyl)-2-nitro-ethanol

F

At 0. (:, in a solution of 2,4-difluoro-5-methyl-benzaldehyde (15.0 L'96_1 mmol) and Nitromethine (7.33 g, 120 mmol) in IP A (150 mL) The solution of NaOH (5.22 g, 131 mmol) in H20 (20 mL) was added dropwise over 1 min, and the obtained mixture was stirred at room temperature for 1 hour. Water (90 mL) and saturated aqueous NH4C1 (105 mL) And extracted with DCM (3 X 250 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purified by column chromatography (IH: EtAOc, 9:1 to 7 : 1 to 4 : 1 to 3 : 1), the title compound: NMR δ Η (300MHz, CDC13): 7.38-7.34 (m, 1H), 6.82-6.76 (m, 1H), 5.69-5.66 (m, 1H) ), 4.61-4.51 (m , 2H), 2.95 (s, 1H), 2.28 (s, 3H). Preparation 287: 1,5-difluoro-2-methyl- 4-((5)-2- Nitro-vinyl)-benzene

F

The title compound was obtained from 1-(2,4-difluoro-5-methyl-phenyl)-2-nitro-ethanol using a procedure similar to that described in Preparation 280 (Preparation 286' 14.5 g -211 - 201209054 , 66.9 mmol): NMR δ Η (400 MHz, CDC13): 7.99-7.96 (d, J=13.73 Hz, 1H), 7.68-7.65 (d, J=13.73 H z, 1 H ), 7.3 4 - 7 · 3 (m, 1 H ), 6.9 1 - 6 _ 8 9 (m, 1 H), 2.2 7 ( s ' 3H). Preparation 288: (trans)-i-benzyl_3_(2,4-difluoro-5-methyl-phenyl)-4-nitro-pyrrolidine

F

The title compound was obtained from 1,5-difluoro-2-methyl-4-((penta)-2-nitro-vinyl)-benzene using a procedure similar to that described in Preparation 281 (Preparation 287, 12.0 g '60.3 mmol) was synthesized: rt = loo min; w/z (ES + ) = 333 · 2 [M+H] + (LCMS Method - 2).

Preparation 289: (trans)-i-benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-amine

The title compound was obtained from (trans)-1-indolyl-3-(2,4-difluoro-5-methyl-phenyl)·4-nitro- using a procedure similar to that described in Preparation 289. Pyrrolidine (Preparation 288 ' 21.0 g, 63.3 mmol &amp; mp = 〇 = 93 min; w/z (ES + ) = 303.2 [M+H] + (LCMS Method _2). -212 - 201209054 Preparation 290 : [(trans)_1_benzyl_4_(2,4-difluoro-5-methyl-phenyl)-la-rrolidine-3-yl]-tert-butyl carbamate

The title compound was obtained from (trans)-1-benzyl-4-(2,4-difluoro-5-methyl-phenyl)-la-bromodin-3-amine using a procedure similar to that described in Preparation 283. Preparation 289, 9.5 g, 31.5 mmol): rt = 3.25 min; m/z (ES+) = 403.3 [M+H]+ (LCMS _3). Preparation 291: [(3 and 45)-1-benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidine-3-yl]-carbamic acid tert-butyl ester

The title compound is prepared from [(trans)-1_pyringyl_4_(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (preparation) Example 2 9 〇) was obtained by palm HPLC separation (IH: IPA: DEA 96: 4: 0.1, 15 mL/min '270 nm, RT = 9.0 min). Preparation 292: 丨(3/?,4 5)-4-(2,4-difluoro-5-methyl-phenyl)pyrrolidin-3-yl]-carbamic acid tert-butyl ester-213- 201209054

[(3Λ,45)-1-Benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidine-3-yl]-carbamic acid tert-butyl ester (preparation example) A solution of 291, 1.97 g, 4.9 mmol) in MeOH (100 mL) was passed through a H-Cube hydrogenation apparatus (10% Pd/C Catcart 70, 80 bar, 50 ° C) at a flow rate of 1 mL/min. The solvent was removed in vacuo to give the title compound <RTI ID=0.0></RTI> </RTI> <RTIgt; Preparation 293: 3,N-Dimethoxy-N-methyl-pyridine-4-carboxamide

A suspension of 3-methoxypyridine-4-carboxylate (5.48 g, 28.9 mmol) in sulfoxide (40 mL) was heated under reflux for 6 hours. After cooling, the solvent was removed in vacuo. N,0-Dimethylhydroxylamine hydrochloride (5.64 g &gt; 57.8 mmol), and the suspension was cooled to 〇 ° C, then added triethylamine (16.1 m L, 1 1 6 ) Mm ο 1). The reaction mixture was further stirred at room temperature for 18 hours, after which the solvent was removed in vacuo. The residue was partitioned between EtOAc (EtOAc) (EtOAc) The combined organic extracts were concentrated with EtOAc EtOAc EtOAcjjjjjjjjj ), -214- 201209054 7.14-7.21 (m, 1H), 3.96 (s, 3H), 3.49 (br.s., 3H), 3.37 (br.s. - 3H). Preparation 294: 1-(3-methoxy-pyridin-4-yl)-ethanone at 0 ° C in 3,N-dimethoxy-N-methyl-pyridine-4-carboxamide (Preparation Example 293, 4.83 g, 24.6 mmol) MeOH (40 mL). (The mixture was stirred for 90 minutes. A saturated aqueous solution of NH4C1 (50 mL Compound: 'H NMR δ Η (400 MHz, CDC13): 8.48 (s, 1H), 8.36 (d &gt; 7 = 4.69 Hz, 1H), 7_49 (d &gt; /=5.08 Hz , 1H), 4.04 (s, 3H), 2.63 (s, 3H). Preparation 295: (i?)_l-(3-methoxy-pyridin-4-yl)-ethanol

Trimethyl borate (0.335 mL ' 2.95 mmol) was added to a solution of diphenyl [(25)-pyrrolidin-2-yl]methanol (623 mg, 2.46 mmol) in THF (25 mL). Stir at room temperature for 1 hour. Add borane-dimethyl sulfide complex (4.67 mL, 49.2 mmol), and the resulting reaction mixture was stirred at room temperature for 15 min then slowly added 1-(3-methoxy-pyridin-4-yl)- A solution of ethyl ketone (Preparation 294, 3.72 g, 24.6 mmol) in THF (5 mL) The reaction mixture was further stirred at -215 - 201209054 for 1 hour at room temperature. Then, an aqueous HCI solution (1 2 Μ) was added dropwise thereto to acidify, and the reaction mixture was stirred at room temperature for 20 minutes. The pH was adjusted to pH 8 with aq. EtOAc (EtOAc) (EtOAc) The combined organic extracts were concentrated under vacuum and the residue was analyzed by palm HLPC (IH: MTBE: MeOH; 75: 20: 5, 1 mL/min, 2 8 5 η Μ ), showing the ratio of mirror image isomers For &gt; 9 : 1. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc: EtOAc ; 1H) , 8.20 (s, 1H), 7.35 (d &gt; 7=4.98 Hz - 1H), 5.12 (q, /=6.2 7 Hz &gt; 1H), 3.93 (s, 3H), 1.4 7 (d, 6.6 3 Η z,3H) o Preparation 296: (cis)-4-((Λ)-1-hydroxy-ethyl)-3-methoxy-piperidine-1-carbonitrile

To a solution of (/0-1-(3-methoxy-pyridin-4-yl)-ethanol (Preparation 29S, 3.67 g, 24.0 mmol) in MeOH (100 mL) 26_4 mmol), followed by the addition of lead dioxide (0.381 g, 1.68 mmol). The reaction mixture was placed under a hydrogen atmosphere (about 8 〇〇 Psi) and stirred for 22 hours. AAc〇H (1_50 mL '26.4 mmol) and Platinum dioxide (0·381 g, 1.68 mmol), and the reaction mixture was stirred under a hydrogen atmosphere (about 800 Psi) at 40 ° C for 6 hours 'at room temperature for 15 hours' and stirred at 40 ° C for 1 hour. And stirring at room temperature for 8 3 hours. The reaction mixture was filtered -216-201209054, and the filtrate was concentrated in vacuo to give (i?)-l-((cis)-3-methoxy-piperidine-4- Base)-ethanol acetate. The product was dissolved in DCM (100 mL), and a solution of NaHC03 (10.1 g, 0.12 mol) in H20 (1 00 mL) was added. The reaction mixture was cooled to 0 ° C and cyanogen bromide was added. (2.80 g, 26.4 mmol) in EtOAc (EtOAc)EtOAc. tOAc : IH ; 1 : 1 to 1 : 0), title compound: 4 NMR δ Η (500 MHz, CDC13): 3.79-3.8 7 (m - 1H) * 3.75 (br.s.,1H), 3.68-3.74 (m, 1H), 3.47-3.5 2 (m, 1H), 3.46 (s, 3H), 3.05 (td, 7 = 12.85 &gt; 3.04 Hz, 1H), 2.89 (dd, /=13.82, 1.11 Hz, 1H ), 2.37 (d, 7 = 7.19 Hz, 1H), 2.07-2.13 (m, 1H), 1.3 8- 1.49 (m, 2H), 1.25 (d, J~ 6.08 Hz » 3H) o

Preparation 297: (i?)-l-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methoxy-piperidine -4-kib ethanol

The title compound was obtained from (cis)_4·((Λ)-1-hydroxy-ethyl)-3-methoxy-piperidine-1-carbonitrile using a procedure similar to that described in Preparation 266 (Preparation 296 Synthesis: NMR δ Η (500 MHz, CDC13): 4.46-4.54 (m &gt; 1 H) &gt; 4.18-4.23 (m, 1 H), 3 · 7 6 - 3 · 8 6 (m, 2 H ) , 3.4 2 (s, 3H), 3.08 (td, /=12.99, 2.76 Hz, 1H), 2.95 (dd, /=14.37, 1.11 Hz - 1H), 2 · 84-2.93 (m, 1H), 2.48 ( d, -217- 201209054 «7=7.19 Hz,1H),1 .94-2.05 (m ' 1 H), 1.46- 1.57 (m,2H) ' 1.29 (d,/=6.63 Hz,6H), 1.26 (d · 7 = 6.08 Hz &gt; 3H) ° Preparation 298 : 2-Chloro-5-{(*S)-l-[(cis)-1-(3-isopropyl-[1,2 , 4]oxadiazol-5-yl)_3·methoxy-piperidine _4_ylbuethoxypyrimidine

(Fantasy-1-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methoxy-piperidin-4-yl] - PPh3 (0.390 g, 1.48 mmol) was added to a solution of ethanol (Preparation 297, 0.2 g, 0.7 mmol) and 2-chloro-5-hydroxypyrimidine (0.121 g, 0.928 mmol) in THF (6 mL) TBAD (0.342 g '1 · 4 8 mm ο 1 ). The resulting reaction mixture was heated to 60 ° C and stirred for 2.5 hr. </ RTI> </ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 382.4 [M+H] + (LCMS Method-6). Preparation 299: 4-(2-chloro-pyrimidine-5-yloxymethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

2-Chloro-5- in a solution of 1-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (1.61 g, 7-55 mmol) in DMF (10 mL) -218- 201209054 Hydroxypyrimidine (1.08 g, 8.30 mmol) and potassium carbonate (1·56 g ' 11.3 mmol). (The mixture was heated for 20 hours. The solvent was evaporated in vacuo and EtOAc mjjjjjjjjjjjjjjjj Concentration. Purification by column chromatography (EtOAc:EtOAc:EtOAc:HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 6).

Preparation 300: 4-(2-Chloro-pyrimidin-5-yloxymethyl)-piperidin-4-ol hydrochloride

In the 4-butyl 2-(2-chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-h-formate (Preparation 299 '0.566 g, 1.65 mmol) in 1,4 - dioxole A solution of HCl in 1,4-dioxane (4M, 5 mL &lt;RTI ID=0.0&gt;&gt; The solvent was removed in vacuo to give the title compound: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Preparation 301: 4-(2-Chloro-pyrimidin-5-yloxymethyl)_4-hydroxy-piperidine-^carbonitrile in 4-(2-chloro-pyrimidin-5-yloxymethylpiperidine - 'Alcohol hydrochloride (Preparation - 219 - 201209054 Example 300, 0.432 g, 1.54 mmol) in DCM (15 mL) was added NaHC03 (0.389 g, 4.63 mmol) in H2 (15 mL) The solution was cooled to 〇 ° C, cyanogen bromide (0.196 g, 185 mmol) was added, then the mixture was warmed to room temperature and stirred for 5 hr. The aqueous layer was separated to DCM (2 mL) The combined organic layers were concentrated in vacuo to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -Chloro-pyrimidin-5-yloxymethyl)-1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol JCK^. -(2-Chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-1-carbonitrile (Preparation 301 '0.391 g, 1.46 mmol) and N-hydroxypropionium (0.154 g, 1 _75 mmol) A solution of zinc dichloride (0.238 g, 1.75 mmol) in EtOH (2 mL) was added dropwise to a solution of EtOH (6 mL). The reaction mixture was stirred at room temperature for 2.5 h. EtOAc (1M, &lt;RTI ID=0.0&gt;&gt; The title compound was obtained in EtOAc (3 mL, EtOAc) (EtOAc) (ES + ) = 34〇3〇[M+H]+ (LCMS Method-6). -220 - 201209054 Preparation 303: 2-chloro-5-[l-(3-ethyl-[1,2, 4] Ethylene-5-yl)-4-methoxy-piperidin-4-ylmethoxy]-pyrimidine

2-chloro-5-[l-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-methoxy-piperidin-4-yl at 0 °C A solution of methoxy]-pyrimidine (Preparation 302' 100 mg, 0.294 mmol) in anhydrous DMF (3 mL) was added portionwise NaH (60% mineral oil dispersion, 12.9 mg, 0.324 mmol). The mixture was stirred at 0-5 ° C for 15 minutes. Methyl iodide (36.6 μ): '0.589 mmol) was added, and the obtained mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was cooled to 〇 ° C, then NaH (60% mineral oil dispersion &apos; 12.9 mg, &lt;RTI ID=0.0&gt; The reaction mixture was warmed to room temperature and stirring was continued for 19 h. The solvent was removed in vacuo and EtOAcqqqqqqqq The organic layer was separated, washed with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj . Preparation 3〇4: tert-butyl 4-(2-chloro-pyrimidin-5-yloxymethyl)-4-fluoro-piperidine-1-carboxylic acid

4-(2-Chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-1-carboxylic acid second butyl vinegar at 0 ° C (Preparation 299, 500 mg, 1 mmol To a solution of DCM-221 - 201209054 (10 mL) was added dropwise diethylamine trifluorosulfide (0.23 mL, 1.7 mmol). The resulting reaction mixture was stirred at 0 - 5 °C for 1 hour then a saturated aqueous solution of &lt;RTI ID=0.0&gt;&gt; Purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc) . Preparation 305: 4-(2-Chloro-pyrimidin-5-yloxymethyl)_4-fluoro-piperidine--carbonitrile

The title compound was subjected to the procedure described in Preparation 3 〇 and Preparation 3 〇1 from 4-(2-chloro-pyrimidin-5-yloxymethyl)-4-fluoro-piperidine-i-carboxylic acid. Synthesis of butyl ester (Preparation 304, 410 mg, 1.2 mmol): rt = 0.87 min; w/z (ES+) = 271.25 [M+H]+ (LCMS -6). Preparation 306: 2-Chloro-5-[l-(3-ethyl-[124]oxadiazole-5-yl)4fluoro-piperidin-4-ylmethoxy]-pyrimidine

01

RT crude title compound was prepared from 4-(2-chloro-pyrimidin-5-yloxymethyl)_4-fluoro-piperidine-hydrazin-carbonitrile using a procedure similar to that described in Preparation Example 32. 305, 〇·231 g, 〇_8 53 mmol) was synthesized. Purification by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc) ό). Preparation 307 : 5-Bromo-2-[1-(3-isopropyl-[1,2,4]oxadiin-5-yl)--pyridin-4-ylmethoxy]-pyridine

The title compound was obtained from [(1 -(3-isopropyl-indol, 2,4)oxadiazol-5-yl)piperidin-4-yl]methanol by a procedure similar to that described in Preparation 244. 1 ' 777 mg, 3.45 mmol) and 5-bromo-2-pyridylpyrazine: RT = 4.28 min; w/z (ES + ) = 381.06 ' 383.05 [M+H]+° Preparation 308 : ( (31?,4*9)-4-(2,5-difluoro-phenyl)·1-{6-[1·(3-isopropyl-[1,2,4]oxadiazole_5 _yl)-piperidinyl-4-yloxy]-pyridin-3-ylpyrrolidin-3-yl)-carbamic acid tert-butyl ester

[(3 and, 4, 4,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 3 〇〇 mg, 1.00 mm 〇l), 5-bromo-2-[1-(3-isopropyl-[1,2,4]oxadiazole·5·yl)-piperidin-4-ylmethoxy]-pyridine (Preparation Example 307, 0.320 a mixture of g, 〇.838 mmol), sodium butoxide (96.6 mg, 1.00 mmol) and biphenyl (di-dibutyl)phosphine (50 mg '0.168 mmol) in toluene (5 mL) The tube was degassed with argon for 20 minutes. Tris(dibenzylideneacetone)dipalladium (38.4 mg, 41·9 μπιοί) was added, and the obtained anti-223-201209054 mixture was heated at 90 ° C for 6 6 hours. After cooling, the reaction mixture was taken on EtOAc EtOAc (EtOAc) eluting eluting eluting eluting The title compound: RT = 4.55 min; m/z (ES + ) = 599.3 6 [M + H]+. Preparation 309: 2-chloro-4-(1-ethoxy-vinyl)-5. Base-pyrimidine

〇V

Potassium carbonate (19.13 g, 138.5) was added to a solution of 2,4-dichloro-5-methoxypyrimidine (12.39 g, 69.22 mmol) in 1,4-dioxane (0.5 L, 6000 mmol). Methyl) a solution formed in H20 (20 mL). The solution was degassed by argon for 10 minutes, and 1-ethoxyvinyltri-n-butyltin (25.0 g, 69.2 mmol) and Pd(PPh3)2Cl2 (2.43 g, 3.46 mmol) were added. The mixture was heated to 100 ° C for 30 minutes and the solvent was removed under vacuum. The residue was partitioned between DCM (5 50 mL) and H20 (600 mL), and organic layer was isolated and concentrated under vacuum. Purification by column chromatography (EtOAc EtOAc: EtOAc:EtOAc) Preparation 310: Ethyl 2-chloro-5-methoxy-pyrimidine-4-carboxylate 〇-/

-224- 201209054

2-Chloro-4-(1-ethoxy-vinyl)-5-methoxy-pyrimidine (Preparation 309 ' 4.00 g, 18.6 mm 〇l) in 1,4-dioxane (300 mL) A solution of potassium periodate (8.57 g, 37. 3 mmol) in H2 (90 mL) was added to the resulting solution. Potassium permanganate (294 mg, 1.86 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was poured into DCM (400 mL) and organic layer was separated. The aqueous layer was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) 1 7.1 [M+H]+. Preparation 311: [(3 and 415)-1-(4-Aminomethylamino-5-methoxy-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrole Third butyl pyridine-3-yl]-carbamic acid

A saturated aqueous solution of hydrogen peroxide (20 mL) was added to ethyl 2-chloro-5-methoxy-pyrimidine-4-carboxylate (preparation 310' 1.310 g, 6.047 mmol) at EtOAc. The mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum and the residue was purified EtOAc EtOAc. The crude product was dissolved in DMSO (5 mL). Add [(3^4^)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid 2 butyl ester (Preparation 48, 462 mg, 1.55 mmol) and DBU (〇 771 mL, 5.16 mmol), and the resulting reaction mixture was stirred at room temperature for 1 hour and at 95 ° C for 3 hours. The solvent was removed in vacuo and the residue was crystallised from EtOAc and MeOH. The solid was collected by filtration to give the title - 225 - 201209054 compound. RT = 3.40 min; w/z (ES + ) = 450.23 [M+H]+. Preparation 312: 2-[(3/?,4*ϊ)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidinyl-1-yl]-5-hydroxy-pyrimidine- 4_Metamine

[(3Λ,4 5)-1-(4-Aminomethylindenyl 5-methoxy-pyrimidin-2-yl)-4-(2,5-fluoro-phenyl)-pyrrolidin-3-yl a mixture of -butyl carbamic acid triester (preparative example 311, 1.7 g' 3.8 mmol) and lithium pentaline (6.00 g, 44.8 mmol) in 2-methylpyridinium (30 mL) The microwave is radiantly heated at 〖2% in the sealed tube. The solvent was removed in vacuo and the residue was partitioned between EtOAc (EtOAc) (EtOAc). The layers were separated and the aqueous extracted with EtOAc EtOAc. The combined organic extracts were washed with brine (50 mL) dried (MgSO4). Purified by preparative HP LC to give the title compound: RT = 2 - 23 min; w/z (ES + ) = 3 3 6.1 7 [M+H]+. Preparation 313: [(3 i?,4S)-1-(4-Aminomethylindol-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidine 3-butyl]-carbamic acid tert-butyl ester

In 2-[(3i?,4S)-3-amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]-5-hydroxypyrimidin-4-carbamidamine ( Preparation 312, 135 mg, 0_403 -226- 201209054

Methyl) Triethylamine (U2μΐ^, 0.805 mmol) and dibutyltributate dicarbonate (132 mg' 0.604 mmol) were added to a solution of THF (10.0 mL). The resulting reaction mixture was heated at 1 〇 ° C for 2 hours. After cooling, the reaction mixture was partitioned between EtOAc (EtOAc) (EtOAc) The layers were separated and the aqueous extracted with EtOAc EtOAc. The combined organic extracts were rinsed with brine (20 mL), dried (MgSO4) filtered and concentrated in vacuo. Purification by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 4*5)-1-(4-cyano-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid Tributyl ester

At 0 ° C, in [(3/?,45·)-1-(4-aminocarbamimido-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl Pyridine (63 μΐ, 0.78 mmol) was added to a solution of tributyl butyl pyrrolidin-3-yl]-carbamic acid (preparation 313, 85 mg, 0.20 mmol) in THF (5 mL) TFAA (110 μί, 0.78 mmol), the obtained mixture was stirred for 10 min. Additional TFAA (55 μ!^, 0.39 mmol) was added and the reaction mixture was stirred for 1 hour. Aqueous potassium carbonate (10%, 20 mL) and EtOAc (50 mL). The layers were separated and EtOAc (30 mL). The combined organic extracts were washed with brine (30-227 - 201209054 mL), dried (MgSO4), filtered and concentrated in vacuo. Purified by column chromatography (DCM:M e Ο Η ; 9 5 : 5 ) 'title compound: R τ = 3 · 8 7 min; w/z (ES + ) = 418.38 [·Μ&quot;+Η]+ . Preparation 315: [(3Λ,45·)-4-(2-Fluoro-5-methyl-phenyl)-1-(5-((5)-1-[1-(3-isopropyl)- [1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrido-2-yl)-disgusty-3-yl]-aminocarboxylic acid Dibutyl vinegar

2-Chloro-5-{(illus-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation Example 63, 60 mg '0.17 mmol) and [(3/?,4S)-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid DBU (25 5 · 4 μL, Ο . 1 7 mm ο 1) was added to a solution of butyl ester (Preparation 285, 100 mg, 0.3 mmol) in DMSO (3.4 mL). After stirring for 9 hours, the reaction mixture was partitioned between EtOAc (EtOAc m. RT = 4.67 min; m/z (ES + ) = 61. </RTI> [M+H] +. Preparation 316: 2-chloro-5-{l-[l-(3-isopropyl-[1,2, 4]oxazol-5-yl)-piperidin-4-yl]-2-methoxy-ethoxypyrimidine and 2-bromoisopropyl-purine 1,2,4]oxadiazole-5 -yl)-piperidin-4yl]-2-methoxy-ethoxy}-pyrimidine-228- 201209054 V:k&gt;4nv

In l-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethanol (Preparation 104, 3.477 g, 12.91 mmol), 2-chloro-pyrimidine-5-ol (1·45 g, 1 1.1 mmol), 2-bromo-pyrimidin-5-ol (0.88 g, 16·1 mmol) and PPh3 (6.77 g, 25.8 mmol) TB AD (5.94 g, 25.8 mmol) was added to a solution of THF (150 mL), and the obtained mixture was stirred at 60 ° C for 75 min. Additional TBAD (2.97 g, 12.9 mmol) and PPh3 (3·39 g, 12.9 mmol) were added and the reaction mixture was heated at 60 °C for 30 minutes. The solvent was removed in vacuo and EtOAc EtOAc m. The residue is rapidly incubated in Et2〇. The precipitate was collected by a furnace and the filtrate was concentrated under vacuum. Purified by column chromatography (EtOAc EtOAc EtOAc:EtOAc:EtOAc:HHHHHHHHHHHHHHHHHHHHHHHHHHH 11: 5: RT = 3.67 min; m/z (ES + ) = 382.10, 426.05, 428.05 [M+H]+. Preparation 317: [(3/?,4&lt;S)-l_(5-{l-[l-(3-isopropyl 412,4)-glycin-5-yl)-piperidin-4-yl -2-methoxy-ethoxy}-m-stamp-2-yl) 4-(2,4,5-trifluorophenyl)-pyrrolidine_3_yl-p-aminocarboxylic acid tert-butyl vinegar 229- 201209054

Chewing on 2-chloro-5-(2-methoxy-propan-2-yl)-l,2,4-oxadiazole-5-yl]piperidin-4-ylethoxy) Example 316, 335 mg '0.877 !11111〇1), 2-bromo-5-(2-methoxy-1-1-[3-(propan-2-yl)-1,2,4-oxadiazole -5-yl]piperidin-4-ylethoxy)pyrimidine (Preparation 316, 170 mg, 0.399 mmol) and [(3Λ,45)-4-(2,4,5-trifluorophenyl)pyrrole To a solution of pyridine-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.484 g, 1.53 mmol) in DMSO (5 mL), DBU (0.191 mL, 1.28 mmol) Stir at °c for 16 hours. Further, [(3^?, 4 magic-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 39, 96 mg '0.30 mmol) 'And the reaction mixture was stirred at 80 ° C for 80 hours. After cooling, the reaction mixture was poured into water and extracted with Et0 Ac (3 X). The combined organic extracts were dried (MgS04), filtered and evaporated. Concentration. Purification by column chromatography (EtOAc:EtOAc:EtOAc) elute elut elut elut elut elut elut elut H]+. Preparation 318: 4·Ethylene oxide-piperidine-i-benzyl formate

The title compound was obtained by a procedure similar to that described in Preparation Example 1-3, from -230 - 201209054 formeryl-indole-1 -carboxylic acid ester (15.0 g, 60.6 mmol): 11 s = 3.47 min; „&quot;(£5 + ) = 262.2 [from +11]+. Preparation 319: 4-(1-hydroxy-2-methoxy-ethyl)-piperidine-benzoic acid benzyl ester (r° cv〇) The title compound was obtained from EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc m/z (ES + ) = 294.3 [M+H] + (LCMS Method·6). Preparation 320: 4-[1_(2-chloro-pyrimidin-5-yloxy)_2-methoxy-B Benzylpiperidine-1-carboxylate

The title compound was obtained from benzyl 4-(1-hydroxy-2-methoxy-ethyl)-piperidine-l-carboxylate (m.p. Synthesis with 2-chloro-5-hydroxypyrimidine (0.556 g, 4.26 mmol): RT = 1.23 min; /z (ES + ) = 406.4 [M+H]+ (LCMS -6). Preparation 321 : 4·(1_丨2_K3i?, 4 magic-3-tert-butoxycarbonylamino-4-(mono-trifluorophenylpyrrolidinyl)-pyridyl-pyridyloxy卜 methoxy · -231 - 201209054 ethyl)-piperidine-1-carboxylic acid benzyl ester

The title compound was obtained from 4-[1-(2-chloro-pyrimidin-5-yloxy)-2-methoxy-ethyl]-piperidine-1-carboxylic acid benzyl using a procedure similar to that described in Preparation 317. Ester (Preparation Example 320, 1.00 g, 1.48 mmol) and [(3/?,4&lt;5)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid The butyl ester (Preparation 39, 0.7 〇 1 g, 2.22 mmol) was obtained: RT: 1.48 min; m/z (ES+) = 68 6.6 [M+H]+ (LCMS -6). Preparation 322: 4-((^)-1-(2-1(3/^,4^)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) Benzyl pyrrolidine-1-yl]-pyrimidin-5-yloxy}-2-methoxy-ethyl)-piperidine-1-carboxylate

The title compound is composed of 4-(1-{2-[(3Λ,4·5)-3-t-butoxycarbonylamino-4-(2,4,5-digas)-- -1 -yl]- y Φε-5-yloxy}-2-methoxy-ethyl)-piperidine-1-carboxylic acid benzyl ester (Preparation 321) by palm chromatography HPLC (MeOH: THF; 80 : 2 0,14 mL/min, 2 5 0 nm, RT = 7_5 min) and single exit: RT = 1.48 min; m/z (ES + ) = 686.6 [M+H] + (LCMS Method-6) . * The center's stereochemistry has been specified. -232 - 201209054 Preparation 323 : ((15,25)-2-(5,5-Difluoro-2-keto-piperidin-1-yl)_4- {5-[1-(3-isopropyl Base-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]_4_methyl-pyrimidin-2-yl}-cyclopentyl)-carbamic acid tert-butyl ester

In a sealed tube, in 2-chloro-5-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-4-A Pyrimidine (Preparation 57, 15 mg, 0.43 mmol) and [(3·5,4·5)-4-(5,5-difluoro-2-ketopipridin-1-yl)pyrrolidine- To a solution of 3-benzyl]-tert-butyl carbamate (preparation 93, 270 mg, EtOAc. EtOAc) (EtOAc) Stir at °C for 1 20 hours. After chilling, EtOAc (EtOAc m. Purification by column chromatography (EtOAc: EtOAc) 〇

Preparation 324: [(3Λ,4·5)-4-(2,5-Difluoro-phenyl)-1-(5-((5)-1-(1-(3-isopropyl-)-[ I,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyrimidin-2-yl)-pyrrolidin-3-yl]-amino Tert-butyl formate-233- 201209054

In the sealed tube 'in methanesulfonic acid (i?)-l-[l-(3-isopropyl-[I,2,4]oxadiazol-5-yl)piperidin-4-yl]ethyl ester (Preparation Example 129, 250 mg, 1.7 mmol) and 2-chloro-4-methylindole-5-ol (250 mg, 1.7 mmol) in DMA (15 m L) Planed (260 mg, 1. 7 mm ο 1), and the resulting reaction mixture was stirred at 65 ° C for 72 hours. Additional fluorinated planer (26 mg, 1.7 mmol) was added and the reaction mixture was heated at 70 °C for 24 hours. Additional gasification planer (260 mg, 1.7 mmol) was added and the reaction mixture was heated at 80 °C for 24 hours. After chilling, the EtOAc~~~~~~~~~~~~~~~~~~~ The residue was dissolved in DMSO (2.5 mL). &lt;RTIgt;[(3i?,4S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 143 mg, 0.478 mmol) and DBU (40_9 μί, 0.273 mmol), and the obtained reaction mixture was stirred at 80 ° C for 16 hours. After chilling, EtOAc EtOAc EtOAc EtOAc. ES + )= 628.1 6 [M+H]+. Preparation 325: (31?,4S)-3-tert-butoxycarbonylamino-4-(5-chloro-2-fluoro-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester -234- 201209054

The title compound was synthesized in a multi-step synthesis from 5-chloro-2-fluorobenzaldehyde using a procedure similar to that described in Preparation 44: RT = 4.40 min; m/z (ES + ) = 415.12 [M+H] +.

Preparation 326 : (3^,45)-4-(5-chloro-2-fluoro-phenyl)-pyrrolidin-3-amine

The title compound was obtained from (3/?,4 to -3-t-butoxycarbonylamino-4-(5-chloro-2-fluoro-phenyl)-pyrrolidine-- using a procedure similar to that described in Example 205. Synthesis of tert-butyl benzoate (Preparation 325, 1.21 g, 2.92 mmol): RT = 1.42 min; m/z (ES + ) = 21 5.00 [M+H]+.

Preparation 327: [(3/^,45)-1-(5-((5)-1-11-(3-ethyl-[1,2,4]oxadiazol-5-yl)-peripiped Tributyl butyl 4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid

The title compound was obtained from 2-chloro-5-{(5)-1-[1-(3-ethyl-[1,2,4]oxadiazol-5- using a procedure similar to that described in Preparation 31. Benzylpiperidin-4-yl]ethyl-235-201209054 oxy}pyrimidine (Preparation 102) and [(3/?,4 5)-4-(2-Fluoro-5-methyl-phenyl)- Synthesis of tert-butyl pyridin-3-yl]-carbamic acid (Preparation 285): RT = 4.47 min; w/z (ES+) = 5 96.20 [M+H]+. Preparation 328: [(3Λ,45)-1-(5-Bromo-pyrimidin-2-yl)-4-(2,5·difluorophenyl)-pyrrolidin-3-yl]-carbamic acid Tributyl ester

Add [(314^)4-(2,5-difluorophenyl)pyrrolidine-3- to a solution of 5-bromo-2-chloropyrimidine (1.0 g, 5.17 mmol) in DMSO (10 mL) Tert-butyl carbamic acid terephthalate (Preparation 48, 2.31 g, 7.75 mmol) and DBU (0.773 mL, 5.17 mmol), and the obtained mixture was stirred at 80 ° C for 6 hours. After cooling, the reaction mixture was poured EtOAc EtOAc EtOAc > The organic extract was washed with brine (25 mL) dried (MgSO4). Recrystallization (EtOAc) gave the title compound: EtOAc: EtOAc: EtOAc: ester

Add n-BuLi dropwise at -20 °C in a suspension of methyltriphenylphosphonium bromide (2.23 g, 6.25 mmol) in THF (75 mL) -236-201209054

The resulting reaction mixture was taken up in hexanes (1.6M, 3. <RTI ID=0.0; (The mixture was stirred for 30 minutes. A solution of 4-methylmercapto-piperidine-i-formic acid benzyl ester (1.03 g, 4.16 mmol) in THF (9 mL) was added, and the mixture was warmed to room temperature and stirred 1 The reaction mixture was poured into water (100 mL) and extracted with Et.sub.2 (2.times.50 mL). The organic extracts were dried (MgSO.sub.4), dried and evaporated. Chromatography (IH:EtOAc (EtOAc:EtOAc): 2-(2-1(312,4^)-3-Tertidinoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidinyl-l-yl]-pyrimidine-1 2· Benzyl}-vinyl) benzyl piperidine-1-carboxylate

1 - B-supplemental-staple-l-carboxylic acid vinegar (preparation 329, 109.0 mg, 0.444 mmol), [(3i?, 45)-l-(5-bromo-picryt-2-yl)-4 -(2,5-Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 328, 101 mg 2 , 0.222 mmol), Pd(PPh3) 4 (25 mg, 0.022 mmol) and triethylamine (62 μΙ&gt;, 0.444 mmol) in DMF (0.5 mL) in a sealed tube at 115 °. Heat at C for 3 hours. After cooling, the reaction mixture was partitioned between water and EtOAc (EtOAc). The residue was applied to a reverse phase silica gel eluting with EtOAc EtOAc: EtOAc (EtOAc: EtOAc: - 201209054 [M+H]+. Preparation 331 : {(3/2,45)-4-(2,5-Difluoro-phenyl)-l-[5-(2-piperidin-4-yl-ethyl)-pyrimidine-2- Tert-butyl pyrrolidin-3-yl}-carbamic acid

In 4-((5)-2-{2-[(3i?,4S)-3-t-butoxycarbonylamino-4-(2,5-difluoro-phenyl)pyrrolidin-1 Pd/C (10) was added to a solution of benzyl]-pyrimidin-5-yl}-vinyl)-piperidine-1 -carboxylate (Preparation 330, 82.0 mg, 0.132 mmol) in EtOH (1 mL) %) The suspension formed in EtOH (1 mL), the resulting mixture was stirred under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Preparation 332: [(3Λ,4*9)-1-(5-{2-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-ethylpyrimidine-2 -yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

In a sealed tube, at {(3/?,4^)-4-(2,5-difluoro-phenyl-238- 201209054 piperidin-4-yl-ethyl)-pyrimidin-2-yl]- Pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 331 '64.0 mg' 0.131 mmol) in t-BuOH (2.5 mL) was added 2,5-dichloropyrimidine (19.6 mg) '0.131 mmol) and triethylamine (79 μί' 0.567 mmol). The resulting reaction mixture is

The microwave was heated at 110 ° C for 30 minutes. The reaction mixture was taken on EtOAc EtOAc (EtOAc) elut elut elut elut elut elut elut elut ) = 600.22 [M+H]+. Preparation 333: [(3Λ,45)-1-{5-[2-(1-Cyano-piperidin-4-yl)-ethyl]-pyrimidin-2-yl}-4-(2,5 _Difluoro-phenyl)-pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl ester

Addition of NaHC03 (52.7) to a solution of -pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 331, 102 mg, 0.209 mmol) in DCM (2 mL) A solution of mg, 0.628 mmol) in H20 (1 mL), and the mixture was cooled to 0 °C. A solution of cyanogen bromide (24.4 mg, 0.23 mmol) in DCM (1 mL) was added dropwise, and the obtained mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM and water. &lt;RTI ID=0.0&gt;&gt; Purified by column chromatography (DCM: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: Method-6) Preparation 334: 丨(cis)-3-fluoro-1-(3-isopropyl-[1,2,4]glycin-5-yl)-piperidin-4-yl] -methanol

Add Pd to a solution of (1-benzyl-5-fluoro-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.172 g, 0.777 mmol) in MeOH (3 mL) /C (10%) was slurried in M e Ο Η (2 m L ), and the resulting reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered with EtOAc EtOAc EtOAc. The residue was dissolved in DCM (2 mL). EtOAc (EtOAc) C. A solution of cyanogen bromide (3 8 · 5 g ' 0 · 3 6 3 mmol) in DCM (0.5 mL) was added dropwise, and the mixture was stirred at 0 ° C for 30 min and at room temperature for one hour. . The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was dissolved in EtOH (8 mL). EtOAc (EtOAc:EtOAc. The reaction mixture was stirred at room temperature for 16 hours. A solution of 1,4-dioxane in HCl (4M, 0.332 mL, 1.33 mmol) was added, and the mixture was stirred at 70 ° C for 5 hours. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic layer was dried (MgSO4) filtered and concentrated in vacuo. Purified by column chromatography (DCM: MeOH; 98: 2): ield: RT: 0.75 min; m/z (ES + ) = 244.28 [M+H]+ (LCMS Method-6) . Preparation 335: 2-Chloro-5-[(cis)-3-fluoro-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine-4- Methoxy]-pyrimidine

In [(cis)-3-fluoro-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-methanol (Preparation Example 334, TBAD (92.3 mg, 0.401 mmol) was added to a solution of 65 mg, 0.27 mmol), 2-chloro-5-hydroxypyrimidine (35 mg, 0.267 mmol) and PPh3 (105 mg, 0.401 mmol) in THF (3 mL) The resulting reaction mixture was stirred at 50 ° C for 4 hours. A PPh3 (25 mg, 0.095 mmol) and TBAD (25 mg' 0.109 mmol) were added and the resulting mixture was stirred at 60 ° C for 2 hours. Further, PPh3 (25 mg, 0.095 mmol) and TBAD (25 mg, 0.109 mmol) were added and the resulting reaction mixture was stirred at 60 ° C for 1 hour. The solvent was removed under EtOAcqqqqqqqlilililililililililili (LCMS Method-6) ° Preparation 336: [(3/?,45)-1-{5-[(3;?,45&lt;)-3-fluoro-1-(3-isopropyl-[1 , 2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxypyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidine_3 _ base]•T-butyl carbamic acid-241 - 201209054

2-Chloro-5-[(cis)_3_fluoro-l-(3-isopropyl-[I,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy] -pyrimidine (Preparation 335, 99 mg, 0.28 mmol), [(3/?,4 Magic-4-(2,4,5-Trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl The solution of the ester (Preparation 39, 176.176 g' 0.556 mmol) and DBU (41.6 pL, 0.278 mmol) in DMSO (1. oo mL) was stirred at 90 ° C for 16 hours, then at HO °C After stirring for 8 hours, the reaction mixture was poured into EtOAc EtOAc (EtOAc)EtOAc. [(cis)-1-{5-[(3/?,4·5)-3-fluoro-1-(3-isopropyl-[1,2,4]oxadiazole-5-yl) --piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester Purification by palm chromatography (MeOH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: Method -6) Preparation 337: [(3/^45)-1-(5-1(35,4/0-3-fluoro-1-(3-isopropyl-[1,2,4]] Oxadiazole-5_yl)_piperider -4_ ylmethoxy] pyrimidin-_ 4 · -2_ yl} (2,4,5-trifluorophenyl) pyrrolidine _3_ _-yl] - carbamic acid tert-butyl ester -242-201209054

The title compound of NH is from [(cis)-1-(54(3/2,45)-3-fluoro-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl) --piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (See Preparation 336) via palm HPLC (MeOH: MTBE; 60: 40 &gt; 15

mL/min, 250 nm) and single exit: RT = 1.38 min; m/z (ES + ) = 63 6.5 [Λ/+Η]+ (LCMS method, 6). Preparation 338: [((-(3-isopropyl-indole I,2,4)oxadiazol-5-yl)-3-methyl-piperidin-4-yl]-methanol

Potassium carbonate (0.263 g, 1.90 mmol) was added to a solution of s-n-Boc-3-methyl-piperidine-4-carboxylic acid (0.463 g, 1.90 mmol) in DMF (8 mL). Methyl iodide (0.142 mL, 2.28 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was poured into aqueous potassium carbonate (10%) and EtOAc (EtOAc) The combined organic extracts were washed with brine (2×2 5 m L), dried (M g S Ο 4), and concentrated under vacuum to give (cis)-3-methyl-piperidine-1 , 4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester. The intermediate was dissolved in THF (3 mL) and cooled to 0 ° C.

A solution of LiAlH4 (73 mg, 1.92 mmol) in THF (3 mL). -243- 201209054 The resulting reaction mixture was warmed to room temperature. </ RTI> EtOAc (5 mL) was added, and the mixture was cooled to 0 ° C, followed by aqueous Na Ο Η (1 5 %, 7 3 μL) and water (2 93 μΙ〇. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of MgS〇4, followed by filtration and concentration in vacuo to give (cis) _4_yl-methyl-3-methyl-pyridin-1 - formic acid table dibutyl vinegar. This intermediate was dissolved in HCl in 1,4-dioxane (4M, 3_0 mL, 12.0 mmol) and the mixture was stirred at room temperature for 1 hour. (cis)_3-Methyl-acridin-4-yl)-methanol hydrochloride. NaHC03 (0.608 g, EtOAc) 7.24 mmol) of a solution of Ηζ0 (5 mL), followed by dropwise addition of a solution of cyanogen bromide (〇 211 g, 1.99 mmol) in DCM (3 mL). After 1 hour, and stirring at room temperature for 2 hours, the organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in EtOH (25 mL)脒 (0.183 g, 1.79 mmol), followed by the addition of a solution of zinc dichloride in Et20 (1M, 1.79 mL, 1.79 mmol). The reaction mixture was stirred at room temperature for 2 hours, then HCl 1 was added. The mixture was stirred for 6 hours at 70 ° C. After cooling, the solvent was removed in vacuo and the residue was partitioned between DCM and water. Drying (M.sub.4), EtOAc (EtOAc) (EtOAc). +H]+ (LCMS Method-6). Preparation 339: 2-chloro-5-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazole-5- 244- 201209054 yl)-3-methyl-piperidin-4-ylmethoxy]-pyrimidine

In [(羼-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methyl-piperidin-4-yl]-methanol (Preparation 338, 0.106 g) '0.443 mmol), 2-chloro-5-hydroxypyrimidine (57.8 mg, 0.443 mmol) and PPh3 (0.174 g, 0.664 mmol) in THF (5 mL) in a solution of TBAD (0.153 g, 0.6 64) The resulting mixture was stirred at 50 ° C for 3 h. EtOAc (EtOAc) (EtOAc) Concentration. Purification by column chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc Example 340: [(3Λ,45&gt; 1-{5-[(cis)-1-(3-isopropyl-[1,2,4]oxadin-5-yl)-3-methyl- Tert-butyl-4-ylmethoxy]-male-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl ester

2-Chloro-5-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methyl-piperidin-4-yl Oxy]-pyrimidine (Preparation 339, 89 mg, 0.25 mmol) and [(3i?,4S)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid DBU (37.8 μί, 0.253 mmol) was added to a solution of tributyl ester (Preparation 39, 0.16 g, 0.50 mmol) in DMSO (1 mL), and the reaction mixture was stirred at 70 °C from -245 to 201209054. 48 hours. Further added [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.10 g, 0.31 mmol) The solution formed by DMSO (0.5 mL) and the reaction mixture were at 1000. Stir for 16 hours at C. After cooling, the reaction mixture was poured into water (25 mL). The organic extract was washed with brine (2×10 mL), dried (MgSO4), filtered and evaporated. Purification by column chromatography (EtOAc EtOAc (EtOAc:EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH LCMS method - 6). Preparation 341: [(31^,45)-1-15-((5)-1-(1-1(^-3-(tetrahydrofuran-3-yl)-[l,2,4]oxadiazole) -5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-amine Tert-butyl carboxylic acid

Amino-峨U-1,4-phenyl)-ethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid The third butyl ester (Preparation 206, 660 mg ' 1.21 mm 〇i) and N-hydroxy-tetrahydrofuran-3-carboxamide (Preparation 168, 0.188 g ' 1.45 mmol) were formed in EtOH (0.72 mL, 1.45 mmol). A solution of zinc dichloride in EtOH (2M, 0.724 mL, 1.45 mmol) was then weighed. HCI solution in 1,4-dioxane (4 Μ, 1 _ 5 1 m L '6.04 mmol) was added and the reaction mixture was heated to 80 ° C for 6 hours. Cooling -246- 201209054

The reaction mixture was poured into DCM (200 mL) and saturated aqueous NaHCOs (200 mL). The organic layer was separated, dried (MgSO.sub.4), filtered and concentrated in vacuo to afford &lt;(31^)-1-15-((^)-1-(1-1^-(tetrahydrofuran-3-yl)- [1,2,4]oxadiazole_5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-difluorophenyl) _ Pyrrolidine _3_amine. The intermediate was dissolved in tHf (15 mL) and H20 (15 mL), and triethylamine (0.252 mL, 1.81 mmol) and dibutyl carbonate-dibutyl ester (0.395 g, 1.81) The resulting reaction mixture was stirred at room temperature for 16 h. then EtOAc was evaporated in vacuo. EtOAc EtOAc EtOAc. The organic extracts of hydrazine were concentrated in vacuo and purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 3-(Tetrahydrofuran-3-yl)-[1,2,4]oxadiazin-5-yl]-piperidin-4-yl}-ethoxy)-mute-2-yl]-4- (2,4,5-Trifluorophenyl)-pyrrole π-3-yl]-carbamic acid tert-butyl ester. Purified by palmitic HPLC (MTBE: THF; 75: 25, 12 〇 11/111 丨11,25〇11111'11丁=13.9 minutes) 'The title compound: 11 butyl = 1.35 minutes; m/z (ES + ) = 660.5 [M+H]+ (LCMS Method -6). Preparation 342: [(3^,45)-1-15-((5)-1-(1-1(5)-3-(tetrahydro)咲 · · 3_ base)-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)·pyrimust-2_kib 4-(2,4, 5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl vinegar

The title compound is obtained from tetrahydroanthracene-247-201209054-anthyl-3-yl)-[1,2,4]oxadiazol-5-yl]-piperidin-4-ylethoxy)pyrimidin-2-yl ]-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (see Preparation 341) via palmitic HPLC (MTBE: THF; 75: 25) , 12 mL/min, 250 nm, RT = 12.2 minutes) and single exit: RT = 1.35 minutes; m/z (ES + ) = 660.5 [M+H]+ (LCMS Method - 6). Preparation 343: 244-((5)-1-(2-1(3^,45)-3-Tertidinoxycarbonylamino-4- 4-(2,5-difluoro-phenyl)-pyrrolidine -1-yl]-pyrimidine _5·yloxyethyl)-piperidin-1-yl]-oxazole-4-carboxylic acid ethyl ester

In {(3i?,4 5)-4-(2,5-difluoro-phenyl)-1-15-((5)-1-piperidin-4-yl-ethoxy)-pyrimidine-2 · -Pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 250 mg, 0.50 mmol) and 2-chlorooxazole-4-carboxylic acid ethyl acetate (109 mg, 0.620 mmol) DIPEA (108 μί, 0.620 mmol) was added to a solution of DMSO (1.5 mL, 21 mmol), and the resulting mixture was heated under microwave irradiation at 120 ° C for 30 min. The reaction mixture was partitioned between EtOAc (EtOAc) (EtOAc)EtOAc. Purification by column chromatography (EtOAc (EtOAc: EtOAc: EtOAc: EtOAc) . -248- 201209054 Preparation 344 : Third butoxycarbonylamino group _ poison-"^-difluoro-phenylpyrrolidinyl-pyridylpyrimidine-bupyoxy-ethyl-ethyl-peptidyl-l-yl]-[ 1,2,4】啰二哩-3-carboxylic acid ethyl vinegar

F

The title compound was obtained from {(3/?,4&lt;5)-4-(2,5-difluoro-phenyl)_1_[5-((5|)-) using a procedure similar to that described in Preparation Example 2 16 1-tert-decyl-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation Example 2〇4) and 5-trichloromethyl Synthesis of thio-[1,2,4]oxazol-3-carboxylate (Preparation 215)

Obtained: RT = 1.37 min; m/z (ES + ) = 644.42 [M + Η] (LCMS Method-6). Preparation 345: [(3 and, 4 &lt; 5)-1-(5-{(5·)-1-[1-(3-ethylindenyl][[,2,4]oxadiazol-5-) -(piperidin-4-yl)-ethoxy}-pyrimidin-2-yl)-4-(2,5-difluoro-(J-phenyl)-pyrrolidin-3-yl]-carbamic acid Third butyl ester

At -78 °C, in 5-[4-((&lt;S)-l-{2-[(3i?,U)-3-Tertidinylamino-4-(2,5) -difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidine-11--5-yloxy-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazole·3·carboxylic acid Ethyl ester (Preparation 344, 1.24 g, 1.93 mmol) EtOAc (EtOAc) (EtOAc) Stir at °C to -6 5 °C for 4 hours. A saturated aqueous solution of NHCI (5 mL) was added to the mixture, and the mixture was stirred and evaporated to room temperature, and the mixture was partitioned between EtOAc (25 mL) and EtOAc. The aqueous layer was separated and extracted with EtOAc (2 X 25 mL). The combined organic extracts were passed through a water repellent sintered glass filter and the solvent was removed under vacuum. Purification by column chromatography (Et OA c: EtOAc: 3 5 : 6 5 to 3 : 1 ) to give the title compound: RT = 1.35 min; tm/z (ES + ) = 614.46 [M+H]+ ( LCMS Method-6). Preparation 346: {(3Λ,45·)-4-(2,5-Difluoro-phenyl)-1-[5-((5·)-1-{1-[3-(1-hydroxy-) 1-Methyl-propyl)-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}·ethoxy]pyrimidin-2-yl]-pyrrolidine-3 -yl}-tert-butyl methacrylate

At -70 °C, in [(37^45)-1-(5-((5)-141-(3-ethylindolyl-[l,2,4]oxadiazol-5-yl)- Piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester ( Preparation 345, 200 mg, 0.326 mmol) EtOAc (3 mL) EtOAc (EtOAc (EtOAc) The mixture was stirred for 3 hours. Aq. aq. EtOAc (2 mL) was evaporated. The organic extracts were combined and purified by preparative HPLC to give the title compound: rt = 1 · 32 min; (ES + ) = 644.49 [M+H] + (LCMS Method-6). Preparation 347: [3-(1-cyclopropyl-l-carbyl-ethyl)-indole 1,2,4]oxadiazol-5-yl]-piperidine _ 4_Kipyloxy)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound was obtained from [(3i^,41S)-l-(5-{(1S)-l-[l-(3-ethylindolyl-[l,2,4]) by the procedure described in Preparation 346. Diazide·5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- Synthesis of tert-butyl carbazate (preparative example 5) and cyclopropyl magnesium bromide: RT = 1.35 min; m/z (ES + ) = 656.49 [M+H]+ (LCMS Method-6) Preparation Example 348: (i?)-N-Hydroxy-2-methoxy-propionium

(2 phantom-2-methoxypropionitrile (1 〇〇 mg' k0 mmo1) and hydroxylamine (50% aqueous solution '86 μί, 1.4 mmol) in EtOH (5 mL '80 mmol) solution at 60 ° The mixture was heated under C for 4 hours. The solvent was removed under vacuum. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; N-dihydroxy-2,2-dimethyl-propionate

n"OH

HO 3-carbyl-2,2-dimethylpropionitrile (0.500 g' 5.04 mmol) and residue amine (50% aqueous solution, 0.371〇11^, 6.05 111111〇1) at £1〇11 (5.89 1111_1) The resulting solution was at 60. Heat at C for 4 hours. Additional hydroxylamine (50% aqueous solution, 0.155 mL, 2.52 mmol) was added and the reaction mixture was heated at 60 °C for 3 hours. The solvent was removed in vacuo to give the title compound:jHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , 2H), 1.04 (s, 6H). Preparation 350: {(3/2,45)-4-(2,5-difluorophenyl)-l-[5-((*S)-lU-[3-(1-hydroxy-1-methyl) -ethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}- Tert-butyl carbamic acid

The title compound was obtained from 5-[4-((5)-1-(2-1^3/^,45^-3-3 butyloxy)-amino-4 -(2,5-difluoro-phenyl)-pyrrolidinyl-1 -yl]-pyrimidin-5-yloxyethyl)-piperidin-1 -yl]-[1,2,4]oxadiazole- Synthesis of ethyl 3-formate (Preparation 344): RT = -252 - 201209054 1.32 min; m/z (es + ) = 63 0.52 [M+H]+ (LCMS Method-6). Preparation 351: 4 -((^)-ip-〗 (31^4 5)-3-Tertioxetine-amino- 4-(2,4-difluoro-5.methyl-phenyl)-pyrrolidin-1 -yl]-pyrimidine-S-yloxy}-ethyl)-piperrol-1-carboxylic acid ester

4-[(Phosphate-1-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-1-carboxylic acid benzyl ester in a sealed tube (Preparation 183, 0-400 g' 1.06 mmol) [(3i?,4&lt;S)-4-(2,4-Difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 292, A solution of 0.399 g, 1.28 mmol) and DBU (0.159 mL, 1.06 mmol) in DMSO (2 mL) was evaporated. Extracted with EtOAc (3×50 mL). EtOAc (EtOAc:EtOAc. 'title compound: RT = 1.58 min; w/z (ES + ) = 652.50 [M+H]+ (LCMS method _6).

Preparation 352 : {(3Λ,45)-4-(2,4-Difluoro-5-methylphenyl)-1_[5-(()) 1-piperidin-4-yl-ethoxy (3)-pyrimidinyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester-253- 201209054

The title compound was obtained from 4-((^^{2-[(3/?,4 5)-3-3 butyloxycarbonylamino-4-(2, Benzyl 4-difluoro-5-methyl-benyl)-l-dodec-1-yl]-physin-5-yloxy}-ethyl)-pulsin D-carboxylate Example 351, 0.600 g, 0.921 mmol): mp. )-1-(2^(3^,45)-3-Tertidinoxycarbonylamino-4-(2,4-carb-5-methyl-phenyl)-disc-1-yl ]-Ethyl 5-methyloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazole-3-carboxylate

The title compound was obtained from {(3 and 4 to 4-(2,4-difluoro-5-methyl-phenyl)-1-[5-(( 15) 1-butylpiperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 352) and 5-trichloromethyl Synthesis of ethyl-[1,2,4]oxazol-3-carboxylate (Preparation 215): RT = 1.44 min; (ES + ) = 658.48 [M+H]+ (LCMS Method-6). Preparation 354: {(3Λ,45)-4-(2,4-difluoro-5-methyl-phenyl)-1-[5-((5&gt; 1-{1-[3-(1- Hydroxy-1-methyl-ethyl)-[1,2,4]oxadiazol-5-yl]-piperidine·-254- 201209054 4-yl}-ethoxy)-pyrimidine_2-yl] -pyrrolidin-3-ylp-aminocarboxylic acid tert-butyl ester

The title compound was obtained from 5 -[4-((1y)-l-{2-[(3i^41S)-3-tributoxycarbonylamino-4-) using a procedure similar to that described in the preparation of Example 2 17 (2,4-difluoro-5-methyl-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxyethyl)piperidine-!-yl]-[1,2,4] Synthesis of oxadiazole _3_carboxylic acid ethyl ester (Preparation 353): RT = 1.32 min; m &quot; (ES + ) = 644.52 [M+H]+ (LCMS Method-6). Preparation 355: 4-Fluoro-benzoic acid 1-carboxy-cyclopropyl ester

Add 4-fluoro-benzazole to a solution of 1-hydroxy-1-cyclopropanecarboxylic acid (0·500 g, 49〇mmo1) in pyridine (U5 mL) and chloroform (1 mL) at 0 °C Chlorochloride (0.608 mL, 5.14 mmol) was obtained and the obtained mixture was stirred at 70 ° C for 40 min. After cooling, the reaction mixture was poured into water (2 mL) and extracted with chloroform (3 x 15 mL). The combined organic extracts were washed with 2M EtOAc (20 mL). The combined NaHC03 extract was adjusted to pH 1 with 12 M HCl and then extracted into chloroform (3 X 2 〇 mL). The combined organic extract was passed through a water repellent sintered glass filter&apos; and the solvent was removed under vacuum. Purification by column chromatography (EtOAc: EtOAc: EtOAc (EtOAc:EtOAc): EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH _6). Preparation 356: 4-Fluoro-benzoic acid 1-aminoformamidin·cyclopropyl ester

EDCI (0.434 g, 2.26 mmol) and HOBt in a solution of 1-fluoro-benzoic acid 1-carboxy-cyclopropyl ester (Preparation 355, 0.423 g, 1.89 mmol) in THF (13 mL) The resulting reaction mixture was stirred at room temperature for 10 minutes. NH3 in 1,4-dioxane (0.5 M, 37.74 mL, 18.87 mmol) was added and the mixture was stirred at room temperature for 72 hr. The solvent was removed in vacuo and the residue was crystalljjjjjjjjjj The organic layer was separated, washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated under vacuum: RT = 0.82 min; m/z (ES + ) = 224.19 [M+H]+ (LCMS - 6). Preparation 357: 1-(5-trichloromethyl-(1,2,4)oxadiazole-3-yl)-cyclopropyl 4-fluoro-benzoate

At 0. (:, in a solution of 4-fluoro-benzoic acid 1-aminoformamido-cyclopropyl ester (Preparation 356, 0.290 g, 1.30 mmol) in THF (10 mL), diethylamine (0.54 mL) , 3.9 mmol), followed by the addition of TFAA (0·28 mL, 1.9 mmol), and the resulting reaction mixture was stirred for 1 hour. Water (50 mL) was added to the reaction mixture 256-201209054 to quench the reaction and extract To DCM (2 x 70 mL), the combined organic extracts were passed through a water-repellent sintered glass filter and concentrated under vacuum. The residue was dissolved in EtOH (10 mL). 6, 143 mm 〇 1" obtained in 6 反应

Heat at ° C for 1.5 hours, then remove the solvent under vacuum. The residue was dissolved in toluene (20 mL). &lt;RTI ID=0.0&gt;&gt; The solvent was removed under EtOAc (EtOAc)EtOAc. -6). Preparation 358: 1-(5-(4-((5)-1-)(24(312,45)-3-3 butyloxycarbonylamino-4-(2,5-) Difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-yl }-cyclopropyl ester

{(3Λ,4^-4-(2,5-Difluoro-phenyl)-1-[5-((5)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl) ]-Pyrrolidin-3-yl-p-aminocarbamic acid tert-butyl ester (Preparation Example 204, 0.276 g, 0.547 mmol) and 4-fluoro-benzoic acid 1-(5-trichloromethyl-[1,2,4 The solution of oxadiazol-3-yl)-cyclopropyl ester (Preparation 357, 0.100 g, 0.274 mmol) in DMSO (1 mL) was stirred at room temperature for 16 hr. Extracted with EtOAc (3×5 mL). EtOAc (EtOAc) (EtOAc) 201209054, title compound: RT = 1.55 min; speak &amp; (ES + ) = 750.50 [Μ + H] + (LCMS Method-6). Preparation 359: 1-cyano-cyclobutyl benzoate

DBU (0.182 mL) was added to a solution of α-ketobenzeneacetonitrile (4.00 g, 30.5 mmol) and cyclobutanone (4.02 mL, 61.0 mmol) in toluene (30 mL). Stir for 20 hours. The solvent was removed under EtOAcqqqqqqqlilililililililililili ),7 · 6 2 - 7 · 6 8 (m,1 Η ), 7.4 8 - 7 · 5 5 ( m, 2H), 2.90-3.02 (m, 2 H ), 2 · 5 7 - 2.7 1 (m , 2 H), 2 · 1 7 - 2.2 9 (m, 1H), 2.09-2.17 (m, 1H). Preparation 360: 1-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclobutyl benzoate

Addition of a base amine (5 〇%) to a suspension of benzoic acid cyano-cyclobutyl ester (Preparation 359, 3 84 g, 19" mm ο 1) in E t Ο Η (50 m L) Aqueous solution, 1.29 mL, 21 - 0 mmol). The solvent was removed under vacuum and the residue was suspended in toluene -258 - 201209054 (50 mL). Perchloroacetic anhydride (3.49 mL, 19.1 mmol) was added, and the reaction mixture was heated under reflux for 3 hours. The solvent was removed under EtOAcqqqqqqqqlililililililili ]4 (LCMS Method-6). Preparation 361: 1-(5-14-((5)-1-(2-1)(3145)-3-3 butyloxycarbonylamino) 4-(2,5-difluoro-phenyl) benzoate )-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[I,2,4]oxadiazole_3_ylbubutylbutyl ester

Tetyl butyl)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid (Preparation Example 204 '0.20 g, 0.397 mmol) and 1-(5-trichloromethyl-benzoate) A solution of [1,2,4]oxadiazol-3-yl)-cyclobutyl ester (Preparation 360' 0.215 g, 0.596 mmol) in DMF (0.8 mL). The solvent was removed in vacuo and the residue was purified eluting elut elut elut elut elut elut elut eluting Preparation 362 : {(3Λ,4·5)-4-(2,5-Difluoro-phenyl[3-(1-hydroxy-cyclobutyl)_[ι,2,4]oxadiazole-5 ·-]Piperidin-4-yl}-ethoxy)-pyrimidinyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester-259- 201209054

Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidinyl}}ethyl)-piperidine-1-yl]-[1,2,4 Oxadiazole-3-yl}-cyclobutyl vinegar (preparative Example 3 6 1 '80 mg, 0.11 mmol) in THF (2 mL), Me 〇H (1 mL) and H.sub.2 (1 mL) Lithium hydroxide monohydrate (5 · 4 mg '〇·13 mmol) was added to the solution, and the resulting reaction mixture was stirred at room temperature for 2 hr. Additional lithium hydroxide monohydrate (5.4 mg, 0.13 mmol) was added and the reaction mixture was heated at 5 ° C for 1.5 hours. The solvent was removed in vacuo and the residue was partitioned between DCM (20 m) The organic layer was passed through a water-repellent sintered glass filter and the solvent was evaporated to give the title compound: RT: 1.29 min; m/z (ES + ) = 642.52 [M+H]+ (LCMS -6). Preparation 363: 1-{5-[4-((^)-1-(2-((3/^,4*9)-3-3 butyloxycarbonylamino-4-(2,2, 4,5·Trifluorophenyl)·Zyrazol-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[I,2,4]啰二哩_3_基}-cyclobutyl ester

The title compound was obtained from [(3145)-1-15-((5)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]_4_ using a procedure similar to that described in Preparation 395. (2,4,5-Trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 0.88 g' 1.7 mmol) and 1-(5-trichloromethyl)benzoate -[1,2,4]oxo-260- 201209054 oxazol-3-yl)-cyclobutyl ester (Preparation 360' 0.303 g, 0.8 3 9 mmol) was synthesized: RT = 1.61 min; m/z (ES + ) = 764.54 [Μ +H] + (LCMS Method -6). Preparation 364: 3,N-Dihydroxy-3-methyl-butane

A solution of hydroxylamine (50% aqueous solution, 1.24 mL &apos; 40.4 mmol) and 3-hydroxy-3-methyl-butyronitrile (1 g, 10.1 mmol) in EtOH (10 mL) was stirred at room temperature for 1.5 hr. The solvent was removed in vacuo to give title titled: EtOAc (EtOAc: EtOAc: Preparation 365: [(3Λ,4*!?)-4-(2,5-difluoro-phenyl)-l-(5-{(*S)-l-[l-(2H-tetrazole) -5-yl)-piperidin-4-yl]-ethoxypyrimidin-2-yl)-pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl ester

In [(3/^,4 5)-1-(54(5)-1-(1-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4·( Adding chlorine to a solution of 2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 300 mg, 0.6 mmol) in DMF (5 mL) The money (4 7 mg, 0.8 7 m π χ ο 1) and sodium azide (57 mg, 0.87 mmol) were stirred at room temperature for 15 minutes and at 1 ° C for 7 hours. After the reaction mixture was diluted with water (1 〇-261 - 201209054 mL) and brine (10 mL), and extracted with EtOAc (2 x 20 mL). The organic extracts were rinsed with brine and dried (MgS〇4) , </ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Example 366 : 2-(5-14-((5)-1-(2-1(3^,45)-3-3 -butoxycarbonylamino-4-(2,5-difluoro-phenyl) )-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-tetrazol-2-yl}-2-methyl-propionic acid ethyl ester

[(3/?,4*5)-4-(2,5-difluoro-phenyl)-1-(5-{(幻-1-[b(211-tetrazol-5-yl)-peri T-butyl pyridine-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid (Preparation 365, 0.126 g, 0.220 mmol), 2-bromo- Ethyl 2-methyl-propionic acid (98.5 μί, 0.661 mmol), potassium (3.7 mg, 22 μιηοΐ) and triethylamine (0.50 mL) were heated in DMF (0.50 mL) at 70 °C for 16 hours. After cooling, the reaction mixture was partitioned between EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH :RT = 1_51 min; m/z (ES + ) = 68 6.52 [Μ +H] + (LCMS Method-6) Preparation 367: {(3Λ,45)-4_(2,5-difluoro-benzene ))-1-丨5-((S)-l-{l-[2-(2-hydroxy-1,1-dimethyl-ethyl)-2H-tetrazol-5-yl]-piperidine -4-yl}- -262- 201209054 ethoxylated)-pyrimidin-2-yl]-pyrrolidin-3-yl-p-aminocarbamic acid tert-butyl ester

At -20 °C, 2-{5-[4-((·5)-1-{2-[(3Λ,4&gt;5)-3-3 butyloxycarbonylamino] 4-(2) ,5-difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-tetrazol-2-yl}-2- A solution of ethyl-propionate (Preparation 366, 65 mg, 95 μηιοί) in THF (2 mL) was added to a solution of LiAlH4 in THF (1M, 95 μm, 95 μιηοο), and the resulting mixture was at -20. The mixture was stirred for 1 hour. A saturated aqueous solution of NH.sub.4Cl.sub.sub.sub.sub. (IH : E t OA c ; 2 : 1 to 1 : 1), the title compound: RT = 1.32 min; τκ/ζ (ES + ) = 644.48 [尨+11]+(1^]^3 method-

Trimethyl borate (0.27 mL, 2.4 mm ο 1 ) was added to a solution of diphenyl[(2S)-pyrrolidin-2-yl]methanol (0.50 g' 2.0 mmol) in THF (22.1 mL). The resulting reaction mixture was spoiled for 1 hour at room temperature. Borane-dimethyl sulfide ((3.76 mL '39.7 mmo1) was added dropwise, and the reaction mixture was stirred for 15 min, then i-(3-fluoro-byryl-4-yl)ethanone (2.76 g, 19.8 mmol). The solution formed in THF (22 mL) was over 1 hour. Reverse-263-201209054 The mixture was stirred at room temperature for 90 minutes, then aqueous HCl (12M) was added to allow the reaction to be stopped and stirred for 30 minutes. The mixture was extracted with EtOAc (2×50 mL), and the combined organic extracts were passed through a water-repellent sintered glass filter and concentrated under vacuum. DCM: MeOH) EtOAc: EtOAc: EtOAc: Fluoro-4-((/?)-1-hydroxy-ethyl)-pyridinium bromide

Addition of benzyl bromide (2 · 0 4) to a solution of (phantom-1-(3-fluoro-pyridin-4-yl)-ethanol (preparation 368, 2.20 g, 15.6 mmol) in acetone (35 mL) m L, 1 7 . 1 mm ο 1), the obtained mixture was stirred for 10 hr under reflux. The solvent was evaporated to give the title compound: RT = 0.48 min; / / / / / [M]+ (LCMS Method - 6). Preparation 370: (i-l-l-(l-benzyl-5-fluoro-1,2,3,6-tetrahydro-pyridin-4-yl)-ethanol

1-Benzyl-3-fluoro-4-((M-Ph-hydroxy-ethyl)-pyridinium bromide (Preparation 369, 4.86 g, 15.6 mmol) in MeOH (80 mL) Sodium borohydride (1.92 g '50.6 mmol) was added portionwise to the resulting solution and the obtained mixture was stirred at room temperature for 16 h. solvent was removed in vacuo -264 - 201209054 'Residue in EtOAc (50 mL The title compound was obtained from rt = EtOAc = EtOAc = EtOAc: 0.50 min; m/z (ES + ) = 23 6.22 [M + H] + (LCMS Method-6). Preparation 371: (and)-1-[(cis)-1-(3-ethyl- [1,2,4]oxadiazin-5-yl)-3-fluoro-piperidin-4-yl]-ethanol

The title compound was obtained from (Λ)-1-(1-benzyl-5-fluoro-1,2,3,6-tetrahydro-pyridin-4-yl)ethanol using a procedure similar to that described in Preparation 334. Preparation 37 〇) and N-pyridinium were synthesized: RT = 0.72 min; m/z (ES + ) = 244.24 [M + H] + (LCMS Method-6). Preparation 372: methanesulfonic acid (phanuary_1_[(cis-ethyloxadiazole-5-yl)-3-fluoro-piperidin-4-yl]-ethyl ester

At 0 ° C, in (Λ)-1-[(cis)-i_(3-ethyl-[1,2,4]oxadiazol-5-yl)-3-fluoropiperidine-4 -Alkyl-ethanol (Preparation 371, 0184 g, 0.756 mmol) and triethylamine (0.211 mL, 1.51 mmol) in DCM (10 mL) 0.908 mmol) The resulting reaction mixture was stirred at 0 °C for 15 minutes and at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of NaHCO.sub.3 (2.times.10 mL), 265-201209054, passed through a water-repellent sintered glass filter, and concentrated under vacuum. Purification by column chromatography (EtOAc: EtOAc = EtOAc (EtOAc) Preparation 373: 2-Chloro-5-{(*ί)-1-[(cis)-1-(3-ethyl-丨^彳]oxadiazol-5-yl)-3-fluoro-piperidin Pyridin-4-ylethyloxy}-pyrimidine

Methanesulfonic acid (Λ)-1-[(cis)-1-(3-ethyl-[1,2,4]pyridin-5-yl)-3-fluoro-piperidin-4-yl] - ethyl ester (preparation 372, 0.23 0 g, 0.716 mmol), 2-chloro-5-pyranosyl (96.2 mg '0.737 mmol) and fluorinated (〇·ιΐ2 g' 0.737 mmol) in DMA (7) The resulting solution was heated at 60 ° C for 16 hours. Additional fluorinated planer (0.1 1 2 g, 0.7 3 7 m m ο 1) was added and the reaction mixture was heated at 60 ° C for 16 hours. Additional cesium fluoride (0.112 g, 0.737 mmol) was added to the reaction mixture at 60. (The reaction mixture was stirred for EtOAc EtOAc (EtOAc)EtOAc. The solution was dissolved in DMA (5 mL) and cesium fluoride (0.112 g, 0_737 mmol) was added, and the mixture was heated at 60 ° C for 16 hours. Then added fluorinated planer (0.1 1 2 g, 0.737 mmol). The mixture was heated at 60 ° C for 16 hours. A fluorinated slab (0.112 g, 0.737 mmol) was added and the reaction mixture was stirred at 60°. The organic layer was partitioned, and the organic layer was separated, washed with brine, dried (MgSO.sub.sub.sub.sub.ssssssssssssssssssssssssssssssssss Purification by HPLC to give the title compound: mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (5-((5)-1-((35,4^)-1-(% ethyl-[1,2,4] chewed diazin-5-yl)-3- gas- shouting steep -4- ]]-ethoxy}-chew-phen-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidine- 3-yl]-tert-butyl methacrylate

2-Chloro-5-{(S)-l-[(cis)-1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-3-fluoro-piperidine- 4-yl]-ethoxy}-pyrimidine (Preparation 373, 21 mg, 59 4〇1〇1), [(3/?, 45|)-4-(2,4,5-trifluoro | benzene a solution of the tert-butyl-3-ylaminocarbamic acid tert-butyl ester (Preparation 39, 98 mg '0.31 mmol) and DBU (17.6 pL, 0.118 mmol) in DMSO (1 mL) Heat at 80 ° C for 16 hours, followed by heating at 90 ° C for 8 hours. After cooling, water (10 mL) and EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH = 1.36 minutes; w/z (ES + ) = 636.43 [Μ +H] + (LCMS Method-6) ° Preparation 375 : [(3 &,45)-1-(5-((5)-1-) 1(31^,45)-1-(3-ethyl-[l,2,4]oxadiazol-5-yl)-3-fluoro-piperidin-4-yl]-ethoxy}-pyrimidine -2-yl)- 4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester-267- 201209054

The title compound was synthesized using the procedure described in Preparation 374: RT = 1.36 min; w/z (ES + ) = 636.43 [ Μ +H] + (1^1^3 Method-6) ° Preparation 376 : (3/?,45)-1-{5-[(*9)-1-(1-benzoxazol-2-yl-piperidin-4-yl)-ethoxy]-pyrimidine-2- Tert-butyl 4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid

{(3i?,4 5)-4-(2,5-Difluoro-phenyl)-l-[5-((*S)-l-piperidin-4-yl-ethoxy)pyrimidine_ 2·yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 50 mg, 0.1 mmol), 2-chlorobenzophthalic acid (20 mg, 0.1 mmol), third a mixture of sodium alkoxide (14 mg, 0.15 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (14 mg, 20 μιηοΐ) in toluene (2.5 mL) at 130 °C Heated under microwave radiation for 60 minutes. The solvent was removed in vacuo and EtOAc m. Preparation 377: [(3^,45)-1-(5-((5)-Bu[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-peripiped Pyridin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl ester- 268- 201209054

The title compound was obtained from 5-[4-((·5)-1-{2-[(3Λ,45)-3- 3 -butoxycarbonylamino-4-(4-). 2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)piperidin-1-yl]_ [1,2,4] Ethyl azole-3-carboxylate (Preparation 26) was synthesized: RT = 1.37 min; m/z (ES+) = 632.5 [M+H]+ (LCMS -6). Preparation 378: [(3/?,45)-1-[5-(($)-1-{1-[3-(1-cyclopropyl-1-hydroxy-ethyl)-[1,2 ,4]oxadiazin-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine- 3-butyl]-amino carboxylic acid tert-butyl ester

The title compound was obtained from [(3i^41S)-l-(5-{(5I)-l-[l-(3-ethylindolyl-[l,2,4]) by the procedure described in Preparation 346. Zyrid-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]- Synthesis of tert-butyl carbazate (Preparation 377) and cyclopropylmagnesium bromide: RT = 1.37 min; m/z (ES + ) = 674.5 [M+H]+ (LCMS Method-6) 〇 Preparation 379 : 7-Benzyl-3-oxa-7-aza-bicyclo[3.3.1]壬-9-keto-269- 201209054

Benzylamine was added dropwise at 65 ° C in a solution of tetrahydropyran-4-one (24 g, 240 mmol) and trioxane (18 g, 600 mmol) in IPA (600 mL). A solution of 28.8 mL of '264 mmol) and acetic acid (15.2 mL, 264 mmol) in IPA (600 mL) was stirred for 1.5 hours, and the resulting mixture was stirred at 65 ° C for 1 hour. After cooling, the solvent was removed under vacuum and the residue was diluted with water (1 L) and EtOAc (1 M &lt; The aqueous layer was basified to pH 13 with aqueous NaOH (1 EtOAc, 2L) and EtOAc (3 EtOAc). The combined EtOAc extracts were dried (EtOAc EtOAcjjjjjjjjjjj Preparation 380: 7-Benzyl-3-oxa-7-aza-bicyclo[3.3.1]decane-9-carbonitrile

7-Benzyl-3-oxa-7-aza-bicyclo[3.3.1]non-9-one (Preparation 379, 10 g, 43.3 mmol) and toluenesulfonyl group at 0 °C Potassium terp-butoxide (11.65 g, 103.9 mmol) was added portionwise to a solution of DME (146 mL) and EtOH (4 mL) over 20 min. Stir at 〇 °c for 1.5 hours' followed by stirring at 40 ° C for 1 hour. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (EtOAc)EtOAc. Purified by column chromatography (DCM: MeOH; EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: (LCMS Method-4). Preparation 381 : 7 -benzyl-3-oxo-7-aza-bicyclo[3.3.1] brothel-9-formate ethyl ester 0

7-Benzyl-3-oxa-7-aza-bicyclo[3.31]nonane-9-carbonitrile (Preparation Example 3 80, 10.0 g '41.3 mmol) in HCl (12 mL, 80 mL) The resulting solution was heated under reflux for 6 hours. The solvent was removed under vacuum and the residue was dissolved in EtOAc (EtOAc) (EtOAc) The reaction mixture was concentrated to aq. The organic extract was washed with EtOAc EtOAc (EtOAc)EtOAc. Preparation 382: (7-Benzyl-3-oxa-7-aza-bicyclo[3.n]}-9-yl)-methanol

(TN〇^〇H

Add 7-benzyl-3-oxax-7-aza-bicyclo[3.3.] to a suspension of lithium aluminum hydride (10.26 g, 0.27 mmol) in THF (1 40 mL). 1] A solution of broth-9-formic acid ethyl ester (Preparation Example 381, ΗG, 67.47 -271 - 201209054 mmol) in THF (160 mL) over 40 min. The resulting reaction mixture was heated at 60 ° C for 4.5 hours. The reaction mixture was cooled to 〇 γ and Na 2 SO 4 .H 2 加入 was added portionwise until boiling completely stopped. EtOAc was added, and the mixture was evaporated EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4). Preparation 383 : (3-oxa-7-aza-bicyclo[3.3.1]fluoren-9-yl)-methanol

Pd/ was added to a solution of (7-fluorenyl-3-oxo-7-aza-bicyclo[3_3_1]fluoren-9-yl)-methanol (Preparation 382' 2.2 g, 9.1 mmol) in MeOH. C (5%), the resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered with EtOAc EtOAc EtOAc (EtOAc) 3.15-2.95 (m, 2H), 2.5-2.2 (m ' 4H), 1.6-1.5 (m, 1H). Preparation 384: 9·Hydroxymethyl-3_oxa-7-aza-bicyclo[m]decane-7-carbonitrile

In 3-(oxa-7-aza-bicyclo[3.3.1]fluoren-9-yl)-methanol (Preparation 383 ' 4.05 g, 17.7 mmol) in DCM (35 mL) Add NaHC03 (4.46 g, 53.1 mmol) and H20 (35 mL) to the resulting solution -272- 201209054

. A solution of cyanogen bromide (2.25 g, 21.3 mmol) in DCM (15 mL) was added slowly, and the obtained mixture was obtained. (The mixture was stirred for 45 minutes, then stirred at room temperature for 16 hours. The reaction mixture was extracted with DCM (3×), and the organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purified (EtOAc) to give the title compound: 4 NMR δ δ 300 (300 MHz, CDC13): 4.2-4.1 (m, 1 Η), 4.0 - 3 · 7 (m, 4 Η), 3.65-3.4 (m, 3 Η), 3.4 -3.3 (m, 1 Η), 2.2-1.85 (m, 1 Η), 1.85-1.7 (m' 2H), 1.6-1.5 (m, 1H). Preparation 385: [7-(3-ethyl-[1 , 2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]fluoren-9-yl]-methanol title compound is similar to that described in Preparation Example 51 The procedure was synthesized from 9-hydroxymethyl-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carbonitrile (Preparation 384) and N-hydroxypropionium: rt = 1.77 min. ;w/z (ES + ) = 2 5 4.1 [M+H]+ (LCMS Method-4). Preparation 386: (15·,5ϋ)-9-(2-chloro-pyran-5-yloxy) Methyl)-7-(3-ethyl-[I,2,4]oxadiazole_5.yl)_3_oxa-7-aza-bicyclo[3.3.11 decane

In the 2-air-5-base spray (130 mg, 0.99 mmol), [7-(3-ethyl-[1,2,4]嚷_•哩-5-yl)-3-oxa- 7-Aza-bicyclo[3.3.1]壬-9-yl]- -273- 201209054 Methanol (Preparation 385, 250 mg, 0.99 mmol) and PPh3 (777 mg, 2.96 mmol) in THF (20 mL) To the resulting solution was added 1,1'-(azodicarbonyl)dipiperidine (0.747 g, 2.96 ramol), and the resulting reaction mixture was heated at 60 ° C for 2 hr. Further PPh3 (259 mg, 0.99 mmol) and 1,1'-(azodicarbonyl)dipiperidine (249 mg, 0.99 mmol) were added, and the reaction mixture was stirred at 60 ° C for 4 hours. Further PPh3 (2 5 9 mg, 0.99 mmol) and 1,1'-(azodiyl)dipiperidine (249 mg, 0.99 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. Purification by column chromatography (EtOAc: EtOAc:EtOAc) Preparation 387 : ((3/?,45·)-4-(2,5-mono-phenylethyl-[1,2,4]oxadiazol-5-yl)-3-oxa-7 -aza-bicyclo[3.3.1] 壬-9-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester

In (l*S,5i?)-9-(2-chloro-pyrimidin-5-yloxymethyl)-7-(3-ethyl-[1,2,4] Uoxadia-5- ))-3-oxa-7-aza-bicyclo[3.3.1] brothel (preparation 386 '70.63 mg ' 0-1931 mmol) and [(3i?,45)-4-(2,5 - __ gas-based) pyrrolidin-3-yl]carbamic acid tert-butyl ester (preparation 48 '60 mg' 〇.2 mmol) in DMSO (0.8 mL) was added DBU (58 μί , 0 , 3 8 6 mmol), the resulting reaction mixture was heated at 85 for 12 hrs. After chilling, the mixture was diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) Purified by column chromatography (EtOAc: EtOAc:EtOAc: EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH LCMS Method-6). Preparation 388: 1-Fluoro-2_((penta)-2-nitro-vinyl)-benzene

The title compound was synthesized from 2-fluorobenzaldehyde by a procedure similar to that described in Preparation 30: 4 NMR δ Η (3 00 MHz, CDC 13): 8.05 (d, J = 13.8 Hz, 1H), 7.73 (d, J = 13_8 Hz, 1H), 7.4-7.6 (m , 2H), 7. 1 - 7.3 (m, 2H). Preparation 389 · (trans)-1-pyryl-3-(2- gas-phenyl)-4-nitro-oxime ratio slightly steeper

The title compound was synthesized from hydrazine-fluoro- 2 -((5)-2-nitro-vinyl)-benzene (Preparation 388) using a procedure similar to that described in Preparation 31: rt = 0.93 min; m/z (ES + ) = 301.2 [M+H]+ (LCMS Method-2). Preparation 39: [(trans)-i-benzyl_4_(2-fluoro-phenyl)-pyrrolidin-3-yl]-tert-butyl methacrylate - 275 - 201209054

The title compound was synthesized from (trans)-1-benzyl-3-(2-fluoro-phenyl)-4-nitro-pyrrolidine (Preparation 389) using a procedure similar to that described in Preparation 32: RT = 2.99 min; m/z (ES + ) = 371.3 [Af+H]+ (LCMS Method-3). Preparation 391: [(3J?,4*S)-1-benzyl-4-(2-fluoro-phenyl)-pyrrolidin-3-yl I-carbamic acid tert-butyl ester

The title compound was isolated by palmitic HPLC via [(trans)-1-benzyl-4-[2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 390). (IH: IP A: BA; 96 : 4 : 0.1, 1 5 m L/min, 2 70 nm, RT = 1 0 · 6 minutes). Preparation 392: [(3 and 4,4-hearted 4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

-276- 201209054 [(3i?,4*S)-l-Benzyl-4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 391, A solution of 8 80 mg, 2.38 mmol) in MeOH (47.5 mL) was passed through a H-Cube hydrogenation apparatus (10% Pd/C Catcart 30, 30 bar, 90 ° C) at a flow rate of 1 mL/min. The solvent was removed in vacuo to give title compound: EtOAc: EtOAc: , Preparation 393: (/?)-1-{1-[3-((5)-1_methoxy-ethyl)-[1,2,4]

I I azole _5_yl]-piperidin-4-yl}-ethanol

The title compound was synthesized from 4-hydroxyethyl)piperidine-1-carbonitrile (Preparation Example 98) and hydroxy-2-methoxypropane (Preparation 148) using a procedure similar to that described in Preparation Example 1 :rt = 0.58 min; m/z (ES + ) = 256.2 [M+H]+ (LCMS Method _2). Preparation 394: Methoxy-ethyl bromide [1,2,4]oxadiazol-5-yl]-piperidin-4-ylethane

The title compound was obtained from (/?) _ 1-{1-[3-((5)-1-methoxy-ethyl)_π,2,4], using a procedure similar to that described in Preparation Example 1 〇i Synthesis of oxazol-5-yl]-piperidine-4-yl}-ethanol (Preparation 3 ί&gt; 3): rt = 0.65 min; m/z (ES + ) = 334.2 [M+H]+ (LCMS method _ 2). -277- 201209054 Preparation 395 : 2 -Chloro-5-(()5)-1-(1.丨3-(0)-1-methoxyethyl)-[I,2,4] Zyrid-5-yl]-piperidine-4-yl-ethoxymethyl]-pyrimidine

The title compound was obtained from methanesulfonic acid (/0-1-{1-[3-((^)-1-methoxy-ethyl)), 2,4], using a procedure similar to that described in Preparation 373. Synthesis of the oxazol-5-yl]-piperidin-4-yl}-ethyl ester (Preparation 394). Purified by column chromatography (DCM: MeOH; 99: 1 to 96: 4): RT = 2.09 min; Zn/z (ES + ) = 3 68_2 [M+H]+ (LCMS Method-3). Preparation 396: {(3Λ,45)-4-(2-fluoro-phenyl)-l-[5- ((S)-l-{l-[3-((5)_1-methoxy-ethyl)-丨1,2,4]oxadiazol-5-yl]-piperidin-4-yl} -ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester

In 2-chloro-5-((&lt;5)-1-{1-[3-((&lt;5)-1-methoxy-ethyl)-[1,2,4]oxadiazole- Add 5-[i]-piperidin-4-yl}-ethoxy)-pyrimidine (Preparation 395, 131 mg, 0.35 7 mmol) in DMSO (0.72 mL). *S)-4_(2-Fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 392, 150 mg, 0.535 mmol), and the obtained mixture was heated at 80 ° C. 88 hours. After cooling, the reaction mixture was partitioned between DCM (150 mL) and sat. The organic layer was separated, washed with brine (100 mL) and concentrated in vacuo. The residue was purified by preparative EtOAc EtOAc: EtOAc (EtOAc: Preparation 397 · 4-Gas-Dibenzoic acid butylamino-4-(2,4,s-trifluorophenyl)pyrrolidin-1-yl]-pyrimidine-5-yloxy}- Ethyl)-峨 steep-;U-based]·丨1,2,4]oxadiazole_3_yl}_cyclopropyl ester

The title compound was obtained from [(3^,45)-1-15-((5)-1-piperidine-4-yl-ethoxy)-pyrimidin-2-yl] using a procedure similar to that described in Preparation 358. _4·(2,4,5-trifluorophenyl)-la-rrolidine_3_yl]-butylic acid tert-butyl ester (Preparation Example 185) and 4-fluorobenzoic acid 1-(5-trichloro) Synthesis of methyl-[12,4]oxadiazol-3-yl)-cyclopropyl ester (Preparation 357): rt = 1.58 min; w/z (ES + ) = 7 6 8 · 5 1 [ Af + Η ] + (LCMS method _ 6).

Preparation 398: 4-((5&gt;1-{2-[(3/?,415)-3-Tertidinoxycarbonylamino-4-(2-fluoro-5-methyl-phenyl)-pyrrole Benz-1-yl]-pyrimidine·5-yloxyethyl)-piperidine-benzyl benzoate

The title compound was prepared from 4-[(5)-1-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-1-carboxylic acid benzyl ester using a procedure similar to that described in Preparation 351. Example 183) and [(3^,45)-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-amine-279- 201209054 butyl terephthalate (preparation example) 285) Synthesis: RT = m@ m/z (ES + ) = 634.49 [M+H]+ (LCMS Method - 6). Preparation 399: {(3,45)-4-(2-Fluoro-5-methyl-phenyl)-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidine- 3-butyl}-aminocarboxylic acid tert-butyl ester

The title compound was obtained from 4-((&gt;S)-l-{2-[(3i^,41S)-3-tert-butoxycarbonylamino)4- using a procedure similar to that described in Preparation 185. Synthesis of (2-fluoro-5-methyl-phenyl)-pyrrolidin-1 -yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-1 -carboxylic acid benzyl ester (Preparation 398) : rt = 0.87 min; m/z (ES + ) = 500.46 [M+H] + (LCMS Method. 6) 〇 Preparation 400: 4-fluoro-benzoic acid tert-butoxycarbonylamino group _4_(2- Fluoro-5-methyl-phenyl)-pyrrolidine-;!-ylpyrimidin-5-yloxy}-ethyl)-piperidine _ 丨_ kib [] L, 2, 4] oxadiazole _3 kib propyl ester

The title compound was obtained from {(3i?,4 5)-4-(2-fluoro-5-methyl-phenyl)-diindole-^bipidine- 4 using a procedure similar to that described in Preparation 358. Benzyl-ethoxy)-pyrimidin-2-yl]-pyrrolidine-3-yl-p-aminocarbamic acid tert-butyl ester (Preparation -280 - 201209054 Example 399) and 4-fluoro-benzoic acid 1-(5 Synthesis of trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclopropyl ester (Preparation 357): RT = 1.61 min; m/z (ES + ) = 746.5 8 [M +H]+ (LCMS Method-6).

Preparation 401: 4-((^)-1-{2-[(3/?,4*5)-3-Tertoxycarbonylamino-4-(2-fluoro-phenyl)-pyrrolidine -1-yl]-pyrimidine-5-yloxyethyl)-piperidine-1-carboxylic acid benzyl ester

The title compound was obtained from benzyl 4-[(5)-1-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-1-carboxylate using a procedure similar to that described in Preparation 351 ( Preparation 1S3) and [(3Λ,4^)-4.(2-Fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 392) were synthesized: RT = 1.50 Minutes; w/z (ES + ) = 620.47 [M+H]+ (LCMS Method-6). Preparation 402: {(3Λ,45&gt;4-(2-Fluoro-phenyl)-1-[5-((phana-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl] -pyrrolidin-3-yl}-carbamic acid tert-butyl ester

The title compound was obtained from 4-((5)-1-{2-[(3),43)-3-t-butoxycarbonylamino-4-4-(2-) using a procedure similar to that described in Preparation 185. Synthesis of fluoro-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxyethyl)-piperidine-benzoic acid benzyl ester (Preparation 401): RT = 0.80 min; w/z (ES + ) = 486.44 -281 - 201209054 [M+H]+ (LCMS Method-6). Preparation 403: 1-(5-(4-((5)-1-)2-((3^,45)-3-3 butyloxycarbonylamino-4-(2-fluoro-benzene) () pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-oxime I, 2,4]oxadiazol-3-yl}-cyclobutane ester

The title compound was obtained from {(3^,45)-4-(2-fluoro-phenyl)-l-[5-((*S)-l-piperidine-4 using a procedure similar to that described in Preparation 358. -butyl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 402) and 1-(5-trichloromethyl-[1] benzoate , 2,4]oxadiazol-3-yl)-cyclobutyl ester (Preparation Example 360) was synthesized: RT = 1.59 min; m/z (ES + ) = 728.57 [M+H]+ (LCMS method - 6). Preparation 404: 1-{5-[4-((5)-1-{2-[(3;?,45&gt;)-3-)-tert-butoxy-amino-4-(benzoic acid)-4-(2- Gas-5-methyl-phenyl)-disgustyl-1-yl]-mute-5-yloxyethyl)-piperidin-1-yl]-[1,2,4]oxadiazole- 3-yl}-cyclobutyl ester

The title compound was obtained from {(3/?,4 5)-4-(2-fluoro-5-methyl-phenyl)-1-[5-((5)-) using a procedure similar to that described in Preparation 358. T-butyl 1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid (Preparation 399) and 1-(5-triphenyl)benzoate Synthesis of chloromethyl-[1,2,4]oxadiazol-3-yl)-cyclobutane-282-201209054 ester (Preparation Example 360): rT = 162 min; w/z (ES 742.56 [M+ H]+ (LCMS method _6). Preparation 4〇5: N-trans-l-methyl-methyl propyl methacrylate

A solution of the base amine (50% aqueous solution, 0.41 mL, 6.69 mmol) and 1-(methylidene)cyclopropanecarbonitrile (〇5〇g, 5.15 mmol) in EtOH (20 mL) at 60 ° Heat at C for 4 hours. Additional hydroxylamine (5% aqueous solution, 0.78 9 mL ' 12.9 mmol) was added, and the reaction mixture was at 60. (The mixture was stirred for 4 hours. The solvent was evaporated in vacuo to give the title compound: iH NMR δ Η (400 MHz, DMSO-de): 8.83 (s, ΙΗ), 5.25 (br.s., 2 Η), 4.64 (t, 1H), 3.44 (d &gt; J = 5.5 Hz, 2H), 0.77-0.75 (m &gt; 2H), 0.56-0.54 (m, 2H). Preparation 406: 5-14-((5)-1- (2-1(3^:,45)-3-Tertidinoxycarbonylamino-4- 4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-1-yl]-pyrimidine·5_ Methyloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazole-3-carboxylic acid methyl ester or ethyl ester

{(3 and 415)-4-(2-Fluoro-5-methyl-phenyl)-1-[5-((51)-1-piperazin-1-1,4-yl-ethoxy)- Pyrimidin-2-yl]-pyrrolidin-3-yl-p-aminocarbamic acid butyl ester (Preparation 399, 120 mg, 0.240 mmol) and 5-trichloromethyl-[1,2,4]U- 283-201209054 A solution of the oxazol-3-carboxylate (preparative 215, 312 mg, 〇12 mmol) in EtOAc (1 mL) was stirred at room temperature for s. The reaction mixture was placed on a SCX crucible (this SCX® was previously eluted with MeOH, followed by elution with aqueous HCl (1M) and then eluted with MeOH). The reaction mixture was eluted with MeOH then EtOAc (EtOAc)EtOAc. Purification by column chromatography gave 4:1:jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Preparation 407: {(3/?,4 5·) _4-(2-Fluoro-5-methyl-phenyl{1-[3-(1-hydroxy-1-methyl-ethyl)-[1 , 2,4]oxazol-5-yl]-piperidinyl ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl-p-butyl carbamate

The title compound was obtained from 5-[4-((5)-l-{2-[(3i?,45)-3-3 butyloxycarbonylamino-4-(2) using a procedure similar to that described in Preparation 217. -fluoro_5_methyl-phenyl)-pyrrolidin-1 -yl]-pyrimidin-5-yloxy} •ethyl)-piperidine-;!_yl]_[I,2,4] Methyl -3-3-formic acid methyl ester or ethyl ester (Preparation Example 4 〇 6) was synthesized: RT = 1.30 min; m/z (ES + ) = 626.5 [M+H]+ (LCMS method _6) Preparation 408: (/?)-l-[l-(5-ethyl-pyrimidin-2-yl)-piperidine_4_ylbuethanol-284- 201209054

(Formula-1 piperidin-4-ylethanol (Preparation Example 61, 0.50 g' 3.87 mmol) and 2-bromo-5-ethylpyrimidine (0.693 g, 3.70 mmol) in DBU (0.6 mL) Heated under microwave irradiation for 30 minutes at 100 ° C. After cooling, the reaction mixture was poured into water and extracted with EtOAc (3×). The organic extracts were washed with brine, dried (MgS04), filtered and Concentration in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> The similar procedure was carried out by reacting (Pyrann-1-piperidin-4-ylethanol (Preparation 61) with 2-chloro-5-ethylpyrazine or 2,5-dichloropyrimidine: Preparation Example Name LCMS (Method 6) 409 (i?)-l-[l-(5-Ethyl-pyrazin-2-yl)-piperidin-4-yl]-ethanol RT = 0.75 min; w/z (ES+ ) - 236.29 ΓΑ/+ΗΓ. 410 c,^VCKh (exo 1-[1-(5-chloro-piperidin-2-yl)-piperidin-4-yl]-ethanol RT = 0.98 min; m/Z (ES+) = 242.22 [M+H]+. Preparation 411: m-sulfonic acid (and)-1-[1-(5-ethylpyrimidin-2-yl)-piperidin-4-yl]-ethyl ester

In ( ° C, (Methylidene-pyrimidin-2-yl)-piperidin-4-yl]-ethanol (Preparation 408 '0·484 g, 2. 〇 6 mmol) and triethylamine (0.40) mL, 2.87 mmol) methane-285-201209054 sulfonium chloride (0.20 mL ' 2.58 mmol) was added to a solution of DCM (30 mL) and the resulting mixture was stirred for 30 min. The reaction mixture was washed with EtOAc EtOAc EtOAc EtOAc. The following compounds were prepared by reacting a suitable alcohol building block (Preparation 409 or 410) with methanesulfonyl chloride using a procedure analogous to that described in Preparation 4-11: Preparations Structural Name LCMS (Method 6) 412 methanesulfonic acid (Λ)-1-[1-(5-ethyl-pyrazine-2-yl)-piperidin-4-yl]-ethyl ester RT = 0-98 min; m/z (ES+) = 314.30 [M+ Hf. 413 ci^y~\y^〇-P methanesulfonic acid (Λ)-1-[1-(5-chloro-pyrimidin-2-yl)-piperidinol]-ethyl ester RT = 1.16 min; m /z (ES+) = 320.23 ΓΜ+Hf. Preparation 414: 2-chloro-5-(15)-1-11-(5-ethylpyrimidin-2-yl)piperidin-4-yl J ethoxy Pyrimidine

Methanesulfonic acid (Fantasy_[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-ethyl ester (Preparation Example 411, 1.36 g, 4.34 mmol), 2-chloro a solution of -5-hydroxypyrimidine (1 _ 13 g, 8.68 mmol) and cesium carbonate (1·50 g, 10.8 mmol) in DMF (8 mL) was heated in a sealed tube at 80 ° c for 16 hours. After cooling, the reaction mixture was partitioned between EtOAc (EtOAc) and EtOAc (methanol). ;w/z (Es + ) = 348·29 [from +H] + -286- 201209054 (LCMS Method-6) The following compounds were constructed via the appropriate mesylate using a procedure similar to that described in Preparation 414. The block (Preparation Example 412 or 413) was reacted with 2-chloro-5-hydroxyl to give a steep reaction: Preparation Example Structure Name LCMS (Method 6) 415 2-Chloro-5-{(5)-l-[l-( 5-ethyl-pyrazin-2-yl)-piperidin-4-yl]-ethoxy}-pyrimidine RT = 1.06 min; m/z (ES+) = 348.28 [M+Hf. 416 c'-crCK&lt;;Vc. 5-Chloro-2-(4-(5)-1-[(2-chloropyrimidin-5-yl)oxy]ethylpiperidin-1-yl)pyrimidine RT = 1.37 min; mlz (ES+ ) = 354.21 ΓΜ+Η Preparation 417: (Fanta--1-{1-[3-(1,1-difluoro-ethyl)-[1,2,4]oxadiazole-5-yl]-piperidin-4-yl }-ethanol

The title compound was obtained from 4-((Λ)-1-hydroxyethyl)piperidine-1-carbonitrile (Preparation 98) and 2,2-difluoro-N-hydroxy- using a procedure similar to that described in Preparation 100. Synthesis of propylene (Preparation 222): NMR δ Η (300MHz, CDC13): 4.3-4.2 (m, 2H), 3.7-3.6 (m, 1H), 3.1-3.0 (m, 2H), 2.1-1.9 (m) , 4H)' 1.8-1.7 (m, 1H), 1.6-1.3 (m, 3H), 1.2 (d, J = 6.43 Hz, 3H). Preparation 418 : 2-chloro-5-((*S)-l-{l-[3-(l,l-difluoro-ethyl)-[l,2,4]oxadiazol-5-yl 】-piperidin-4-ylethyloxy)-pyrimidine-287- 201209054

In 2-chloro-5-hydroxypyrimidine (82.4 mg ' 0.632 mmol), (/?)-l-{l-[3-(1,1-difluoro-ethyl)-[1,2,4] Add TBAD to a solution of oxazol-5-yl]-piperidin-4-yl}-ethanol (Preparation 417 '150 mg, 0.57 mmol) and PPh3 (226 mg, 0.861 mmol) in THF (6 mL) (198 mg, 0.861 mmol), the obtained mixture was stirred at room temperature for 16 hr. The reaction mixture was partitioned between EtOAc (EtOAc m. Purification (chromatography) gave the title compound: EtOAc: EtOAc. The following compounds were reacted with the appropriate amidoxime via 4-((i?)-l-hydroxyethyl)piperidine-1-carbonitrile (Preparation 98) using a procedure similar to that described in Preparation 100. Preparation: Preparation Example structure name 'H NMR δ Η (300 MHz &gt; CDC13) 419 F (i?)-l-[l-(3-trifluoromethyl-[1,2,4]oxadiazol-5- Base)-piperidin-4-yl]-ethanol 4.26-4.22 (m, 2H), 3.61-3.65 (m, 1H), 3.20-3.00 (m, 2H), 1.95-2.04 (m, 1H), 1.80- 1.70 (m, 1H), 1.60-1.45 (m, 1H), 1.45-1.25 (m, 3H), 1.23-1.21 (d, 3H). 420 ^VnCHh (8)-l-[l-(3-third -[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethanol 4.20-4.15 (m, 2H), 3.64-3.60 (m, 1H), 3.03-2.90 (m , 2H), 1.96-1.91 (m, 1H), 1.75-1.65 (m, 1H), 1.55-1.40 (m, 1H), 1.40-1.25 (m, 12H), 1.25-1.15 (d, 3H). The compound was prepared by reacting a suitable alcohol building block (Preparation Example 419 or 420) with methane sulfonium chloride using a procedure similar to that described in Preparation Example 41 to -288-201209054

Preparation Example structure name spectrum 419 methanesulfonic acid (and trifluoromethyl-[1,2,4]oxadiazin-5-yl)-piperidin-4-yl]-ethyl ester RT = 0.80 min; m/z (ES+)= 344.4 [MfH]+ (1^:]^3 Method-2). 420 methanesulfonic acid (i?)-l-[l-(3-tert-butyl-[1,2,4] Oxadiazol-5-yl)-piperidin-4-yl]-ethyl ester! H NMR δ Η (300MHz, CDC13): 4.70-4.65 (m, 1H), 4.23-4.13 (m, 2H), 3.05-2.90 (m, 5H), 1.90-1.70 (m, 3H), 1.56-1.35 (m, 5H), 1.30 (s, 9H). Preparation 421: 2-chloro-5-{(5&gt;l-[l- (3-trifluoromethyl-[1,2,4]glycin-5-yl)-piperidin-4-yl]-ethoxypyrimidine

F

In methanesulfonic acid (and trifluoromethyl-oxime 1,2,4) chewed bismuth-5-yl)piperidin-4-yl]-ethyl ester (Preparation Example 419, 1.34 g, 3.90 mmol) and 2 -Chloro-5- was added to a solution of the basal D (1.13 g' 8.68 mmol) in DMA (27 mL). Toluene (1.19 g, 7.81 mmol) was obtained. Stir for 7 hours at C. After cooling, the reaction mixture was diluted with EtOAc EtOAc (EtOAc) The combined organic extracts were washed with brine (8x), dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc EtOAc EtOAc EtOAc (EtOAc) z(ES + ) = 378·4 [M+H]+ (LCMS Method-3). Preparation 422 : 5-((5)-1-丨1-(3-Terbutyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy -2--chloro-pyrimidine

The title compound was obtained from methanesulfonic acid (i〇-l-[l-(3-tert-butyl-[1,2,4]oxadiazol-5-yl) using a procedure similar to that described in Preparation 42 1 . -piperidin-4-yl]-ethyl ester (Preparation 420) and 2-chloro-5-hydroxypyrimidine were synthesized: RT = 2.65 min; w/z (ES + ) = 366.4 [M+H]+ (LCMS Method - 3) Preparation 423: [(3 and 45)-1-[5-((^-1-{1-[(*5)-2-(tetrahydrofuran-3-yl)-2H-tetra Zyrid-5-yl]-piperidin-4-yloxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-ylamino Tert-butyl formate

[(3i2,4S)-l-(5-{(&lt;S)-l-[l-(2H-tetrazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine_ 2_yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 231 '0.250 g' 0.424 mmol), 3-iodine A solution of tetrahydrofuran (0.252 g, 1.27 mmol) and triethylamine (1 mL '7 mmol) in DMF (1 mL) was warmed at 80 ° C for 28 h. After cooling, EtOAc (50 mL) solution was added and washed with water (30 mL) and brine (2 X 30 -290 - 201209054 mL) The residue was purified by preparative HPLC to give (tetrahydrofuran-3-yl)-2H-tetrazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-( T-butyl 2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid. Purification by palm chromatography (MeOH: MeCN: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc - 6). Preparation 424: [(3Λ,45&gt;1-[5-((5)·1-{1-[(π)-2-(tetrahydrofuran-3-yl)-2Η-tetrazol-5-yl]-) Piperidin-4-yl}-ethoxy)-pyrimidin-2-ylbu-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound was obtained from [(3/?,4&lt;S·)-1-(5-((5)-141-(211-tetrazol-5-yl)-piperidine- 3-butyl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)pyrrolidinyl-3-yl]-carbamic acid tert-butyl ester (preparation example) 231) Synthesis: rt = 1.39 minutes; m/z (ES + ) = 660.50 [M+H]+ (LCMS method _6). Example 1: (3/^,45)-4-(2,5- Difluorophenyl)-1_{5-[1-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyridin-2_ Pyrrolidin-3-amine hydrochloride-291 - 201209054

Under argon, 2-chloro-5-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (preparation) Example 2, 67 mg, 0.20 mmol) and [(3Λ,4 magic-4_(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 48 '60 mg' 0.20 mmol) DBU (30 μιη, 0.20 mmol) was added to a solution of DMSO (0.4 mL), and the mixture was heated to 100 ° C for 16 hours. Another portion of 2-chloro-5-[l-(3- Isopropyl-[1.2.4]oxadiazol-5-yl)piperidine-4-ylmethoxy]pyrimidine (Preparation 2, 2 mg, 0.06 mmol), and heating was continued for 8 hours. The mixture was partitioned between EtOAc and EtOAc (EtOAc) (EtOAc m. The mixture was stirred at room temperature for 1 hour. The crude reaction mixture was purified by EtOAc (EtOAc) eluting eluting eluting eluting MeOH, 98: 2) to give the title compound as a free base, which was dissolved in 4M EtOAc in dioxane. The solvent was removed to give the title compound: 1^ = 2.82 min; / «/2 ( ug 3 + ) = 500.2 [from +11] +. Example 2: (3/?, 4ii)-4-(2,5- Fluorophenyl)-1-{5-[1-(3-isopropyl-[1.2.4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}piperidin Pyridine-3-amine hydrochloride-292- 201209054

'n^.HCI F The title compound was obtained from 2-chloro-5-[ 1-(3-isopropyl-[I,2,4]oxadiazol-5-yl)piperidine using the procedure described in Example 1. -4-ylmethoxy]pyrimidine (Preparation Example 2) and [(3i?,4/?)-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl Preparation of vinegar (Preparation Example 9): RT = 2.88 minutes; w/2 (ES + ) = 514·3 [Μ+Η]+. Example 3: (3Λ,45·)-4-(2,5·difluorophenyl)-1-15-443-isopropyl_[1,2,4]oxadiazol-5-yl)piperidine -4-ylmethoxy]pyridin-2-yl}pyrrolidine_3_amine hydrochloride

2-bromo-5-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyridine (Preparation Example 3' 38 mg, 〇.1〇mmol), [(3Λ,45)-4-(2,5-difluorophenyl)pyrrolidinyl]carbamic acid tert-butyl ester (Preparation Example 48, 36 mg, 0·12 mmol) , sodium butoxide (34 mg, 0.35 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane A mixture of (3 mg, 〇·〇 1 mmol) in toluene (3 mL) was degassed with argon for 1 min. Add bis(a benzylidene acetonide)-pin (9 mg, 0_01 mmol), and the mixture was degassed by argon for 10 minutes and then at 120 in a microwave reactor. (The mixture was heated for 30 minutes. The reaction mixture was partitioned between DCM (1 mL) and brine (100 mL), then the organic layer was separated, dried (Mg S04), and solvent was removed under vacuum-293-201209054. An intermediate product protected with a butyl butyl sulphate. The crude product was dissolved in DCM (5 mL). EtOAc (5 mL). Purification by column chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc ;m/z (ES + ) = 499.3 [M+H]+. Example 4: (3/ί,4β)-4-(2,5-difluorophenyl)-5'-[l-(3- Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-3,4,5,6-tetrahydro-2H-[1,2'] Pyridine-3-amine hydrochloride

The title compound is obtained from 2·bromo-5-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyridine (Preparation Example 3) And [(3Λ,4^-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 9) was prepared using a method similar to that described in Example 3. 'Through the third butyl-protected amine intermediate was purified by column chromatography (IH: EtOAc ' 60: 40). To a solution of the product in DCM (5 mL), TFA (5 mL) Stir at room temperature for 20 minutes. The crude reaction mixture was eluted directly with MeOH (EtOAc) eluting with EtOAc (EtOAc) eluting with NH.sub.4OH/MeOH, and the basic fractions were collected. The residue was dissolved in HCl in dioxane (4M) The solvent was then removed in vacuo to give the title compound: RT = 2.63 min; m/z (ES + ) = 513.3 [M+H] +. -294 - 201209054 Example 5: (3/^,45^-4 -(2,5-di-phenylphenyl)-1-{5-[1-(3-isopropyl-[1,2,4]-glycyl-5-yl)pyro-_4-methoxyl Base] shamexiao_2_base Η slightly steeper · 3_ amine hydrochloride

2-bromo-5-[1-(3-isopropyl-indolyl 2,4]oxadiazol-5(yl)piperidin-4-ylmethoxy]pyrazine (Preparation Example 4 ' 1 15 mg , 0·30 mmol), [(3i^,41S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 48 '107 mg' 0.36 Ment), dibutanol (1〇1 1.05 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-phosphobicyclo[3.3.3; - A mixture of alkane (10 mg, 0.03 mmol) in dioxane (4 mL) Tris(diphenylideneacetone)dioxane (9 mg' 〇.01 mmol) was added and the mixture was degassed by gas for 5 minutes and then at 120 in a microwave reactor. (The next heating is carried out for 30 minutes. The reaction mixture is directly passed through EtOAc EtOAc (EtOAc) elute The product was dissolved in EtOAc (4M) EtOAc (EtOAc) (EtOAc:EtOAc: 3Λ,45&gt;1-{5-[1·(3-isopropyl-[1,2,4]oxadiazol-5-yl)acridin-4-ylmethoxy]pyrazin-2-yl }-4-(2,4,5-trifluorophenyl)pyrrolidine_3_amine hydrochloride-295- 201209054

2-Bromo-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrazine (Preparation Example 1) and [ (3 Λ , 4^)-4-(2,1,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39) using a procedure similar to that described in Example 5. The reaction was carried out except that the reaction mixture continued at 1 2 0. Heat at C for 30 minutes. After purification by SCX, EtOAc (EtOAc) After stirring at room temperature for 15 minutes, the reaction mixture was passed directly through EtOAc (EtOAc) eluting with MeOH then eluting with &lt;RTIgt; Purification by column chromatography (DCM: MeOH EtOAc:EtOAc: The product was dissolved in HCl in dioxane (4 EtOAc) and then solvent was evaporated in vacuo to give the title compound: RT = min; m / z ( ES + ) = 5 1 8 · 4 [ Μ + Η ] + 〇 Example 7 : 4-(6-1(35,45)-3-Amino-4-(2-ketopiperidin-1-yl)pyrrolest. 1-yl]pyridin-3-yloxymethyl}peri Pyridine-1-carboxylic acid isopropyl ester hydrochloride

-296- 1 - (6-bromopyridin-3-yloxymethyl)piperidin-1 -carboxylic acid isopropyl ester (Preparation 15, 107 mg, 0.30 mmol), [(35,45)-4-( 2 - Regiving 峨U-I-yl) pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 2〇' 1〇9 mg '〇·3 5 mmol), 9,9-dimethyl a mixture of bis- 4,5-bis(diphenylphosphino)oxaxan (1 〇 mg' 〇·02 mmol) and sodium butoxide sodium (101 mg, 1.05 mmol) in toluene (4 mL) 201209054 Argon was bubbled through for 15 minutes. Tris-(dibenzylideneacetone)dipalladium (6 mg' 0.01 mmol) was added, and the resulting mixture was heated to 100 °C for 24 hours. The crude mixture was filtered and diluted with EtOAc. The organic mixture was washed with a saturated NaHC03 solution, dried (MgSO.sub.4) and solvent was evaporated. Purification by column chromatography (DCM: MeOH, EtOAc) The product was redissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) Example 8: 4-{6-[(3i?,45&gt;3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]pyridin-3-yloxymethyl}piperidin Pyridine-l-formic acid isopropyl ester hydrochloride

4-(6-Bromopyridin-3-yloxymethyl)piperidine-1-carboxylic acid isopropyl ester (Preparation 15) and [(3;?, 4 S)-4-(2,5-difluoro Phenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 48) was reacted using a procedure similar to that described in Example 7. The crude reaction mixture was partitioned between DCM and brine, then the organic layer was separated, dried (MgS04). Purification by column chromatography (DCM: MeOH, 98: 2, 96: 4, 92: 8, 90: 10) The product was redissolved in EtOAc (3M) (EtOAc) elute Example 9: 4-[(3i?,4/0-3-Amino-4-(2,5-difluorophenyl)-3,4,5,6-tetra-297- 201209054 Hydrogen - 2H-丨1,2,]bipyridyl-5,-yloxymethyl]piperidine-1-carboxylic acid isopropyl ester hydrochloride

4-(6-bromopyridin-3-yloxymethyl)piperidine-:!-carboxylic acid isopropyl ester (Preparation 15) and [(3/?, 4i?)-4-(2,5-di The third butyl fluorophenyl)piperidin-3-yl]carbamate (Preparation Example 9) was reacted using a procedure similar to that described in Example 7, except that the reaction mixture was heated to 90 °C. The crude mixture was concentrated in vacuo, taken up in MeOH and filtered. The filtrate was passed through a pad of SCX, eluted first with MeOH then eluted with NH.sub.4OH/MeOH and basic fractions were collected. This material was purified by preparative HPLC, and the obtained product was eluted with EtOAc EtOAc (EtOAc) The basic fractions were collected and concentrated under vacuum. The product was dissolved in EtOAc (4M) (EtOAc) elute Example 10: 4-{4-丨(3/?,4Phase-3-amino-4-(2,5-difluorophenyl)piperidin-1-yl]phenoxymethyl}piperidine- 1-carboxylic acid isopropyl ester hydrochloride

Isopropyl 4-(4-bromophenoxymethyl)piperidine-1-carboxylate (Preparation Example 22, 96 mg '0_3 mmol), [(3i?, 4 magic-4-(2,5-difluoro) Phenyl phenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 9, 31 mg, 0_1 mmol), triethylamine (41-298-201209054)

A mixture of pL, 0.3 mmol), copper acetate monohydrate (20 mg, 0.1 mmol) and 4A molecular sieves in DCM (6 mL) was stirred at room temperature for 80 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was redissolved in MeOH and washed with EtOAc (EtOAc) eluting with EtOAc EtOAc. TFA (2 mL) was added to a solution of EtOAc (EtOAc). This material was passed through a second SCX oxime, eluted first with MeOH then eluted with NH.sub.4OH/MeOH and basic fractions were collected. Purification by preparative HPLC gave the free amine as the title compound. The product was dissolved in EtOAc (EtOAc) (EtOAc)EtOAc. Example 11: 4-(2-1(3^45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidinyl-pyridylpyrimidin-5-yloxymethyl}piperidine Isopropyl formate hydrochloride

Isopropyl 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-1-carboxylate under argon (Preparation 25 '47 mg' 0.15 mmol) and [(3^,45) Addition of tert-butyl 4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamate (preparation 48, 45 mg, 0.15 mmol) in DMSO (0.3 mL) DBU (23 μί, 0.15 mmol), the mixture was heated to 100. (: 16 hours. After cooling to room temperature, the mixture was partitioned between DCM (100 mL) and brine (1 mL), then the organic layer was separated and concentrated in vacuo. 10 mL), TFA (3 mL) was added, followed by stirring at room temperature -299 - 201209054 for 1 hour. The crude mixture was passed through EtOAc (EtOAc) eluting with MeOH then eluting with NH.sub. The fractions were purified by EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH : RT = 2.88 min; m/z (ES + ) = 476.3 [M+H] +. Example 12: 4-((5)-1-(2-((3^,45)-3-amino)- 4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid isopropyl ester hydrochloride

Under argon, 4-[1-(2-chloropyrimidin-5-yloxy)ethyl]piperidine-1-carboxylic acid isopropyl vinegar (Preparation 27, 113 mg, 0.31 mmol) and [(3) /?, 4 5) -4-(2,5·difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 112 mg, 0.38 mmol) in DMSO (0.63 mL) DBU (47 pL, 0·20 mmol) was added to the resulting solution and the mixture was warmed to 100 ° C for 72 hours. The mixture was cooled to room temperature and partitioned between EtOAc and brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purified by column chromatography (IH: EtOAc, 60: 40), eluted with EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 4-(1-{2-[(3/?,4(7)-3-Tertidinoxycarbonylamino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidin-5-yl) Ethyloxyethyl}piperidine-1-carboxylic acid isopropyl ester: RT = 4_55 min; w/z (ES + ) = 590.3 [M+H] + -300 - 201209054 The product in DCM (5 mL) TFA (1 mL) was added to the resulting solution and the mixture was stirred at room temperature until the reaction was completed. The crude mixture was passed through EtOAc, eluted with MeOH, eluted with NH4OH/MeOH, and basic fractions were collected. The solvent was removed in vacuo to give EtOAcqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ m/z (ES + ) = 490.2 [M+H]+ °

Example 13: (3J?, 4*y)-4-(2,4-difluorophenyl)-1-{5·[1-(3-isopropyl-[1,2,4]oxadiazole -5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-amine hydrochloride

Under argon, 2-chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperazin-4-ylmethoxy]-furfuryl (Preparation Example 2, 54 mg '0_15 mmol) and [(3^?,4&lt;5)-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester ( Preparation 34, 54 mg '0.18 mmol) <RTI ID=0.0>#</RTI> The mixture was cooled to room temperature&apos; and partitioned between EtOAc and brine. The organic layer was separated, washed with brine (3×1 50 mL), dried (MgSCU) and concentrated under vacuum. Purified by column chromatography (IH:

EtOAc, 60: 40) gave intermediate ((3i?,4*S)-4-(2,4-difluorophenyl)- isopropyl-[1,2,4]oxadiazole-5- Tert-butyl ester of piperidine_4·ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid: RT = 4.47 min -301 - 201209054; w/z (ES + ) = 600.3 [M+H]+. TFA (1 mL) was added to a solution of the product in DCM (5 mL), and the mixture was stirred at room temperature until the reaction was completed. The crude mixture was passed through a pad of SCX eluting with MeOH then eluting with &lt The solvent was removed in vacuo to give the title compound, m. The title compound was obtained from EtOAc (EtOAc) (EtOAc) The following examples were made by reacting a suitable 2-chloropyrimidine building block with the appropriate amine building block using procedures analogous to those described in Example 13: Example Structure Name LCMS 14 /Heart. -οκέ (3 feet 45)-4-(2,3-difluorophenyl)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl Piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-amine hydrochloride RT = 2.77 min; mlz (ES^ = 500.2 [M+H]+ 15 4-((8)-1 -{2-[(3Λ,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidin-5-yloxy}ethyl)piperidine-1 - isopropyl formate hydrochloride RT = 2.79 min; mlz (ES+) = 490.2 [M+H] + 16 (3, 45)-4-(2,5-difluorophenyl)-1-{5- [1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-amine hydrochloride RT = 2.57 minutes; mlz (ES+) = 486.2 [M+H]+ -302- 201209054 (3/?,45)-4-(2,5-difluorophenyl)-1-(5-{(5) -1-[1-(3-isopropyl-RT-2.81 min 17 [1,2,4]oxadiazol-5-yl)piperidine-;mlz (ES^ = 1 ^nh^HCI 4-yl ]ethoxy}pyrimidin-2-yl) 514.4 [M+H]+pyrrolidin-3-amine Example 18: (3Λ,45&gt;1-{5-[1-(3-isopropyl-[1, 2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-

Under argon, in 2-chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (preparation Example 2, 199 mg, 0.56 mmol) and [(3/?,4*5)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester ( Preparation 39' 269 mg, 0.85 mmol) EtOAc (4 mL) EtOAc. The mixture was cooled to room temperature and diluted with EtOAc. The organic solution was rinsed with water, then with brine, dried (MgSO4) and then solvent was evaporated from vacuo. Purification by column chromatography (IH:EtOAc, 1: 1.5) to give intermediate ([(3^,4 5)-1-(5-(:1-(3-isopropyl-[1,2,4] Oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid Third butyl ester: RT = 4.53 min; / (£3 + ) = 618.2 [on + old +. Add TFA (2.5 mL) to the solution of the product in DCM (10 mL). Stirring was continued until the reaction was completed. The reaction mixture was crystallized from EtOAc EtOAc EtOAc (EtOAc). The organic fractions were washed with brine, dried (MgSO4), and evaporated in vacuo. The title compound: 11 butyl = 2.77 min; /«/2 (ES + ) = 500.2 [M+H]+. Example 19. ((3^,45^-4-(4-chloro-2-phenyl) 1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidine- 3-amine

Under argon, in 2-chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (preparation Example 2, 130 mg, 0.37 mmol) and [(trans)-4-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 45, 110 Mb, 0.0.35 mmol) DBU (55 μί, 0.37 mmol) was added to a solution of DMSO (2 mL), and the mixture was heated to 85 ° C for 120 hours. The mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with water, then with brine, dried (MgSO.sub.4) and then evaporated. Purification by column chromatography (IH: EtOAc, 1 : 1.5) &lt;&gt;&gt;&lt;[&gt;&gt;&gt; 37?,4 5&gt; 4-(4-Chloro-2-fluorophenyl)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl) Piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)aminomethyl-304- 201209054 acid tert-butyl ester: RT = 4.64 min; w/z (ES + ) = 616.3 [Af + H] + 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The mixture was partitioned between EtOAc EtOAc (EtOAc m. = 2.93 minutes; /«/2(£3 + ) = 516.2[尨+11]+. Example 20: ((3*5,4 and)-4-(4-chloro-2-fluorophenyl)-1 -{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidine

The title compound was obtained from 2-chloro-5-[Bu(3·isopropyl-[I,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy] using the procedure described in Example 19. Pyrimidine (Preparation Example 2) and [(trans)-4-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl]carbamic acid dibutyl ester (Preparation Example 45) were prepared. Palm HPLC: MTBE: THF 80 : 20 ' 12 mL/min, 23 5 nm, RT: 9.1 min. LCMS: RT = 2.85 min; m/z (ESI+) = 516.2 [M+H]+. Example 21: 4-((/?)_ι_{6_[(3Λ4ι5)_3-Amino-4-(2,5-difluorophenyl)lahydroidin-1-yl]pyridine_3_yloxy} Ethyl) piperidine-1-carboxylic acid isopropyl ester strontium salt-305- 201209054

The title compound was obtained via 4-U-(6-bromopyridin-3-yloxy)ethyl]piperidine-1 -carboxylic acid isopropyl ester (Preparation 5 4) and [( It was prepared by reacting 3i?,4&gt;S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 48). At the end of the first step, the reaction mixture was passed directly through S C X 匣, eluted first with Me Ο ,, then with N Η 4 〇 H / M e Ο , , and the basic fraction was collected. TFA (5 inL) was added to a solution of the residue in DC EtOAc (5 rnL), and the mixture was stirred at room temperature for 30 min. The crude reaction mixture was passed through a pad of EtOAc (EtOAc) eluting with MeOH, eluting with NH. Purified by column chromatography (DCM: MeOH, 97.5: 2.5), followed by purified by HPLC (MTBE: MeOH: BA; 80: 20: 0.1, 13 mL/min, 250 nm, RT: ίο. 5 Min.), the free amine of the title compound. The product was dissolved in Et20 and a few drops of HCl in dioxane (4M). The solvent was removed under vacuum to give the title compound: </ RTI> = 2.54 min; /2 (£3 + ) = 489.2 [from +?1]+. Example 22: 4-((5)-1-(6-((3^,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyridine-3- Isopropyl}ethyl)piperidine-1-carboxylic acid isopropyl ester hydrochloride

The title compound was prepared using the procedure described in Example 21: Palm HPLC: MTBE: MeOH: BA; 80: 20: 0.1, 13 mL/min, -306 - 201209054 250 nm, RT: 14_4 min. LCMS: RT = 2. 54 min; w/z (ES+) = 489.2 [M+H]+. Example 23: (3Λ,4·ϊ)-4-(2,5-difluorophenyl)-l-{5-[l-(3-isopropyl-[1,2,4]oxadiazole- 5-yl)piperidinylmethoxy]_4_methylpyrimidin-2-ylpyrrolidine_3_amine p-toluenesulfonate

2-Chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-4-methyl chelate (Preparation 57, 89 mg, 0.25 mmol) and [(3i?,4*S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (preparation) Example 48, 150 mg, 0.50 mmol) DBU (39 pL, 0·25 mmol) was added to a solution of DMSO (4 mL), and the mixture was heated at 80 ° C for 7 days in a sealed tube. The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc (EtOAcjjjjjjjjj [1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-4-methylpyrimidin-2-yl}pyrrolidine-3 -Base) tert-butyl carbazate: RT = 4.51 min; m/z (ES + ) = 614.5 [M+H]+. The solution of the product in DCM (5 mL) was cooled to &lt;RTI ID=0.0&gt;&gt;&gt;&gt; A saturated NaHC03 solution was added to quench the reaction, and the organic layer was separated, passed through a phase separator, and concentrated under vacuum. Purification by column chromatography, followed by purification with mp. - 307-201209054 A solution of EtOAc (EtOAc) EtOAc (EtOAc) +H]+. Example 24: (3 and 45)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-4-ylmethoxy] _4_Methylpyrimidine_2_ylbu-4_(2,4,5-trifluorophenyl)pyrrolidin-3-amine p-toluenesulfonate

Preparation of 2-chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-4-methylpyrimidine Example 57, 83 mg, 0.24 mmol) and [(3Λ,4^-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 150 mg, 0.47 mmol) DBU (36 pL, 0.24 mmol) was added to a solution of DMSO (4 mL). The reaction mixture was heated in a sealed tube at 80 ° C for 7 days. The mixture was diluted with EtOAc and rinsed with brine. , drying (MgS04), and removing the solvent under vacuum. Purified by preparative HPLC to give intermediate product [(3/?,4S)-l-{5-[l-(3-isopropyl-[1,2 , 4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-4-methylpyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidine- 3-butyl] butyl carbamic acid tert-butyl ester: RT = 4.53 min; w/z (ES + ) = 63 2.26 [M+H]+. Under argon, the product formed in Et20 (5 mL) A solution of HCl in dioxane (4M, 5 mL) was obtained, and the mixture was stirred at room temperature for 16 hrs. The solvent was concentrated under vacuum. then saturated NaHC03 solution and MeOH (2 mL). , organic layer -308- 2012 Drying (NaaSCU), EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjj A solution of TsOH (leq.) in MeOH was added to a solution of MeOH in MeOH then EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 11]+.

Example 25: (312,45)-4-(2,5-Difluorophenyl)-1-{5-[1-(5-isopropyl-[l,2,4]oxazolidine-3- Benzylpiperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-amine hydrochloride

Under argon, in 2-chloro-5-[1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidine (preparation Example 60, 249 mg, 0.70 mmol) and [(3i?,4&lt;S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 48) D209 (104 pL, 0.70 mmol) was added to a solution of EtOAc (EtOAc) (EtOAc). The mixture was cooled to room temperature and partitioned between EtOAc and brine. The organic layer was separated, dried (MgSO4), and solvent was evaporated in vacuo. Purification by column chromatography (IH: EtOAc '70: 30) gave intermediate ((3/?, 41?)-4-(2,5-difluorophenyl)-1-{5-[1- (5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid third Butyl ester: RT = 4.69 min; m/z (ES + ) = 600.2 [M+H]+. TF A (2 mL) -309 - 201209054 was added to a solution of the product in DC EtOAc (8 mL), and the mixture was stirred at room temperature for one hour. The crude mixture was passed through a pad of EtOAc (EtOAc) eluted with EtOAc EtOAc EtOAc EtOAc The residue was passed through SCX (POH) hydrazine for repeated purification. The basic fractions were collected and concentrated in vacuo to give the title compound as a free amine. The product was redissolved in a small amount of Et20 and a solution of HCl in dioxane (4M). The solvent was removed in vacuo to give the title compound:jjjjjjjjjjjj Example 26: (3/?,415)-1-{5-丨1-(5-chloropyrimidin-2-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}-4-(2 ,5-difluorophenyl)pyrrolidin-3-amine

(3/?, 4 phantom-4-(2,5-difluorophenyl)-1-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl] is slightly steep _3_ Amine (Preparation Example 64' 21 mg' 〇.05 mm〇l), 2,5-dichloropyrimidine (8&quot;18'〇.〇5111111〇1) and triethylamine (3〇01^'0·2 mmol) The mixture in the third butanol U mL) was at 11 Torr in a microwave reactor. (The mixture was heated for 50 minutes. The mixture was cooled to room temperature' directly through SCX (POH) EtOAc, eluted with MeOH then eluted with 10% NH4OH/MeOH. The basic fractions were collected and concentrated under vacuum. The title compound was obtained: RT = 2.93 min; w/z (ES + ) = 502.2 [Λ/+Η]+. Example 27: 4-(5-{2-[(3i?,45)-3-Amino- 4-(2-Phenylphenyl)rudopyridin-1-ylpyrimidine-5-yloxymethyldiphenyl 1,2,4]oxazol-3-yl)piperidine-isopropyl isopropylate P-toluene acid salt-310- 201209054

4-[5-(2-Chloropyrimidin-5-yloxymethyl)-[1,2,4]oxadiazol-3-yl]piperidine-1-carboxylic acid isopropyl ester (Preparation 68' 125 mg, 0.33 mmol), [(trans)-4-(2-fluorophenyl)pyrrolidin-3-yl]carbamic acid 9H-indol-9-ylmethyl ester hydrochloride (Preparation 71, 143 The mixture of mg, 0-33 mmol) and DIPEA (120 pL, 0.69 mmol) in tert-butanol (2 mL) was heated to 80 °C for 72 hours. The reaction mixture was concentrated in vacuo and purified eluting with EtOAc EtOAc Purification by palm chromatography (MTBE: MeOH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: A solution of Τ s Ο Η (1 eq.) in MeOH (2 mL), EtOAc (EtOAc) [M+H]+.

Example 28: 4-(5-{2-[(3Λ,47?)-3-Amino-4·(2,5-difluorophenyl)piperidin-1-yl]pyrimidin-5-yloxy Methyl}-丨1,2,4]oxazol-3-yl)piperidine-1-carboxylic acid isopropyl ester hydrochloride

4-(5-{2-[(3i?,4i?)-3-Tertidinoxycarbonylamino-4-(2,5-difluorophenyl)piperidin-1-yl]pyrimidine-5 -yloxymethyl}-[1,2,4]oxadiazol-3-yl) -311 - 201209054

TPA (2 mL) was added to a solution of EtOAc (EtOAc m. The crude mixture was passed through a pad of EtOAc (EtOAc) eluting eluting The basic fractions were collected and concentrated in vacuo to give the title compound as a free amine. The product was redissolved in Et20 followed by a solution of HCl in dioxane (4M). The solvent was removed in vacuo to give the title compound: RT: 2.87 min; m/z (ES+) = 558.2 [Af+H]+. Example 29: {2-[(32?,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidin-5-ylmethyl}-丨1- (3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]methylamine

In {(3 and,45)-4-(2,5-difluorophenyl)-1-[5-({[1-(3-isopropyl-[1,2,4]oxadiazole- 3-butyl)piperidin-4-yl]methylamino}methyl)pyrimidin-2-yl]pyrrolidine-3-yl}carbamic acid tert-butyl ester (Preparation 78, 49.3 mg, 0.08 mmol) TFA (0.2 mL) was added to a solution of DCM (1.0 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was passed through a pad of EtOAc (EtOAc) eluting with MeOH then eluting with &lt;RTIgt; The solvent was removed in vacuo to give the title compound: RT = 2.27 min. Example 30: {2-[(3Λ,45:)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyridyl_5_yl b[1-(3 -isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethyl-312- 201209054 amide

The title compound was obtained from [(3 and, 4 &lt;5)-4·(2,5-difluorophenylisopropyl-[1,2,4]oxadiazol-5-yl) using the procedure described in Example 29. Preparation of tert-butyl piperidin-4-ylmethyl]amino}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid (Preparation 82): RT = 2.62 min; m/z (ES) + ) = 499.3 () [Αί+Η]+. Example 31: (3Λ,4·ί)-4-(2,5-difluorophenyl)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazole- 5-yl)piperidin-4-yloxymethyl]pyrimidin-2-yl}pyrrole steep-3-amine

In ((3/?,4S)-4-(2,5-difluorophenyl)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazole-5 -butyryl-4-yloxymethyl]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation Example 85, 11.7 mg '0.02 mmol) in DCM (2 The solution formed at 50 μM was forced into TFA (50 μ! 〇 ' mixture was stirred at room temperature for 8 〇 minutes. The crude mixture was passed through SCX 匣 ' first eluted with MeOH, then eluted with NH 4 OH / MeOH The title compound was obtained after EtOAc (EtOAc:MeOHMeOHMeOHMeOH z (ES + ) = 500.3 [M+H]+. -313- 201209054 Example 32: (3/?,4*9)-1-{5-[1-(5-chloropyrimidin-2-yl)- 4-methoxypiperidin-4-yloxy]pyrimidin-2-yl}-4_(2,4,5-trifluorophenyl)pyrrolidine-3-amine

In [(3Λ,4(S)-l-{5-[l-(5-chloropyrimidin-2-yl)-4-methoxypiperidin-4-ylmethoxy]pyrimidin-2-yl} Tetrabutyl 4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamate (preparation 90, 4.9 mg, 0.01 mmol) in DCM (1 mL) TFA (0.1 mL) was added to the solution and the mixture was stirred at room temperature for 16 hours. The crude mixture was passed through EtOAc (EtOAc) eluting with MeOH, then eluting with &lt;RTI ID=0.0&gt; Concentration under vacuum gave the title compound: RT = 2·98 min; w/2 (ES + ) = 5 50.5 [M+H]+. Example 33: 1-[(3*5,45)-4-amine 1-(5-{(5)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy} Pyrimidin-2-yl)pyrrolidine-3-yl]-5,5-difluoropiperidone hydrochloride

Under argon, 2-chloro-5-((^)-1-11-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl] Ethoxy}pyrimidine (Preparation Example 63' 171 mg '0.49 mmol) and [(35,45).4-(5,5- _ Mirror (-2-indolyl-1-yl) 3⁄4[: T-butyl carbamic acid tert-butyl amide (Preparation Example 93' 155 mg' 〇.49 mmo1) at -314- 201209054

DBU (74 pL, 0.49 mmol) was added to a solution of DMSO (1.0 mL) and the mixture was warmed to &lt The reaction mixture was diluted with DCM (50 mL) EtOAc (EtOAc)EtOAc Purification by column chromatography (DCM: MeOH, EtOAc: EtOAc: EtOAc (EtOAc) (5-{(·?)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidinyl]ethoxy}pyrimidin-2-yl) Pyrrolidin-3-yl]carbamic acid tert-butyl ester. TFA (1 mL) was added to a solution of EtOAc (EtOAc). Another portion of TFA (1 mL) was added and the mixture was stirred for 20 min. The crude mixture was taken up in EtOAc (EtOAc) eluting eluting eluting Purification by column chromatography (D CM: MeOH, 95: 5, 90: 10) The product was redissolved in Et20 (2 mL) and EtOAc (4M, 5). The solvent was removed in vacuo to give the title compound: RT = 2.67 min; </RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 34: l-[(3*S,4S)-4-Amino-1-(5-{(5·)-1-[1-(3-isopropyl-[1,2,4]) Oxazol-5-yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)pyrrolidine·3-yl]piperidine-2-one hydrochloride 0.

• HCI-315-201209054 oxazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 63 '171 mg, 0.49 mmol) and [(35,45)4-(2-ketopiperine) Add DBU (81 μί, 0.54) to a solution of pyridine-1-yl)pyridin-3-yl]carbamic acid tert-butyl ester (Preparation 20, 160 mg, 0.56 mmol) in DMSO (1.0 mL) Mm〇l), the reaction mixture was heated to 80. &lt;: Lasted 144 hours. The reaction mixture was diluted with DCM (50 mL), washed with brine (x3), dried using a phase separator and solvent was evaporated from vacuo. Purification by column chromatography (DCM: MeOH, 98: 2) afforded intermediate (35,45)-1-(5-((5)-141-(3-isopropyl-[1,2,4 Oxadiazole-5-yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)-4-(2-ketopiperidin-1-yl)pyrrolidin-3-yl]amino Tefane formic acid was added to a solution of EtOAc (1 mL), EtOAc (EtOAc) Then, eluted with NH4〇H/MeOH, the basic fraction was collected and concentrated under vacuum. The residue was purified by SCX(POH) hydrazine. The basic fractions were collected and concentrated under vacuum. The title compound was dissolved in EtOAc (2 mL). (ugly 3 + ) = 499.3 [^/&gt;+11]+. Example 35: 14(35,45)-4-amino-ΐ·(5-{(5&gt;)_ι_[ι_(3-isopropyl -[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyridin-2-yl)pyrrolidin-3-yl]piperidin-2-indole

-316- 201209054 2-Bromo-5-{(5)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]B The oxygen ratio is steep (Preparation Example 94, 200 mg, 0·50 mmol), [(3^,4^)-4-(2-ketopiperidin-1-yl)pyrrolidin-3-yl]amino group T-butyl formate (preparation 20, 170 mg, 0.61 mmol), sodium butoxide (170 mg, 1.77 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetra Aza-1-phosphabicyclo[3·3·3]~[--•院 (17 mg, 0.05 mmol) in 1,4 - dioxin (6 mL)

The mixture was degassed by argon for 10 minutes. Tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) was added, and the mixture was again degassed with argon for 10 minutes and then heated at 120 ° C for 2 x 30 min in a microwave reactor. The reaction mixture was filtered, washed with MeOH and solvent was evaporated in vacuo. Purification by preparative HPLC and column chromatography (DCM: MeOH, 95:5), followed by purification by EtOAc (MeOH: THF: BA; 80: 20: 0.1, 12 mL/min, 250 nm, RT = 13.0 min), the title compound: RT = 1.83 min; m/z (ES + ) = 498.5 [Af+H]+. Example 36: 1-[(3*5,4*ί)-4-Amino-l-(5-{(S)-l-[l-(3-isopropyl-[1,2,4] Oxadiazole-5-yl)piperidin-4-yl]ethoxy}pyrazine-2·yl)pyrrolidin-3-yl]piperidin-2-one

0_ 2-Bromo-5-{(phantom::1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy} Pyrazine (Preparation Example 95' 200 mg' 〇.51 mmo1), [(3·5,4*5)-4-(2-ketopiperidinyl-pyridyl)pyrrolidin-3-yl]aminocarboxylic acid Third vinegar (preparation 20, 172 mg, 〇·61 mmol), sodium butoxide (170-317-201209054 mg, 1.77 mmol) and 2,8,9-triisobutyl·2,5, A mixture of 8,9-tetraaza-l-pyridinium bicyclo[3.3_3]undecane (17 mg, 0.05 mmol) in 1,4-dioxane (3 mL) was degassed with argon for 10 min. Tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) was added, and the mixture was again degassed by argon for 10 minutes, then at 120 in a microwave reactor (: heating for 2 x 30 minutes). By SCX, first eluted with MeOH, followed by &amp; NH4〇H/Me〇H elution, and the basic fraction was collected. The solvent was removed under vacuum to give an intermediate product [(3 isopropyl-[1,2, 4]oxazol-5-yl)piperidin-4-yl]ethoxy}pyrazin-2-yl)-4-(2-ketopiperidin-1-yl)pyrrolidine-3-yl] T-butyl carbamic acid. Add TFA to the solution of the product in DCM (5 mL) (1 mL), the reaction mixture was stirred at room temperature for 20 minutes. Another portion of TFA (1 mL) was added and stirring was continued for 20 minutes. The reaction mixture was passed through SCX, eluted first with Me Ο ,, then n Η 4 Ο H / M e Ο Η elution, collect the alkaline fraction, and concentrate under vacuum. The residue was passed through SCX (POH), eluted with MeOH, then eluted with NH 4 OH / MeOH And concentrated under vacuum. Prepared by preparative HPLC (basic method), SCX oxime, preparative HPLC (standard method) and followed by SCX oxime purification, the solvent was removed under vacuum between each purification step to give the title Compound: RT = 2.63 min; m/z (ES + ) = 499.4 [M+H] +. Example 37: (3/?,4S)-4-(2,5-difluorophenyl)-1-( 5-((5)-1-11-(3-ethyl-oxime I,2,4)oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine-2-yl)pyrrole Pyridine-3-amine hydrochloride-318 - 201209054

Under argon, in 2-chloro-5-{(Λ)-1-[1-(3-ethyl-Π,2,4]oxazol-5-yl)piperidin-4-yl]B Oxy)pyrimidine (Preparation Example 102, 1 82 mg '0.54 mmol) and [(3i?,4S)-4-(2,5-difluorobenzyl)pyrrole-3-yl]carbamic acid III Butyl ester (Preparation 48, 160 mg, 54·54 mm 〇1) was added to a solution of DMS (1.1 mL). DBU (8 1 μιη, 〇·49 mmol) ' f ! The reaction mixture was heated to 8 〇. . C lasted 7 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (x3), dried using a phase separator, and solvent was removed under vacuum. Purification by column chromatography (IH: EtOAc, 60: 40) to give intermediate (3i?,4S)-4-(2,5-difluorophenyl)-l-(5-{(S)-l -[l-(3-ethyl-[1,2,4]B oxazepine-5-yl)peptidyl-4-yl]ethoxy}pyran-2-yl)Ubiridine- 3-butyl] butyl methacrylate: RT = 4.39 min; w/z (ES + ) = 600.5 [M+H]+. Add TFA (1 mL) to the solution of the product in DCM (5 mL)

The reaction mixture was stirred at room temperature for 20 minutes. Another portion of TFA (1 mL) was added and stirring was continued for 20 min. The reaction mixture was taken up in EtOAc (EtOAc) eluting eluting eluting The residue was taken up in EtOAc (EtOAc) eluting with EtOAc (EtOAc) The solvent was removed in vacuo to give the title compound as a free amine. The product was redissolved in Et20 (2 mL). The solvent was removed in vacuo to give the title compound: RT: 2.70 min; m/z (ES+) = 500.3 [M+H]+. -319-201209054 The following example was made using the procedure described in Example 37 via reaction of the chloropyrimidine building block with the desired pyrrolidine building block: Example structure name LCMS 38 (3^,45)-1-(5- {(5)-1-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)-4 -(2,4,5-trifluorophenyl)pyrrolidine-3-amine hydrochloride RT = 2·70 min m/z (ES+) = 518.3 [M+H]+. 39 (3Λ,45) 1-(5-{(5)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine -2-yl)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine hydrochloride RT = 2.85 min; m/z (ES+) = 532.2 [M+H]+. 40 : (3Λ,4*9)-4-(2,5-difluorophenyl)-1-(5-{1-[1-(3-isopropyl-[1,2,4] evil two Zyrid-5-yl)piperidin-4-yl]-2-methoxyethoxy}pyrimidin-2-yl)pyrrolidin-3-amine

The title compound was obtained from [(3/?,45)-4~(2,5-difluorophenyl)-1-(5-{1-[1-(3-isopropyl). -[1,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethoxy}anranyl)pyrrolidyl-3-yl]aminocarbamic acid Preparation of the third butyl ester (Preparation Example 1 〇 8): RT = 2.76 min; w/z (ES + ) = 544.3 [M+H]+. -320-201209054 Example 41: (3Λ,45·)-4-(2,5-difluorophenyl)-1-(5-{(5·)-1-[1-(3-isopropyl)- [1,2,4]spirobimethyl)piperazin-4-yl]-2-methoxyethoxy}pyran-2-yl)pyrrolidin-3-amine

The title compound is via (3Λ,4^)-4_(2,5-difluorophenyl)_1_(5_{1 — [1-(3-isopropyl-indenyl), 2,4]oxadiazole-5- Palmitic HPLC separation of MT) piperidine_4_yl]_2-methoxyethoxy}pyrimidin-2-yl) thiazolidine-3-amine (Example 4〇) (MTBE: MeOH: TiiF: n-butyl Obtained by limb 80: 15 . 5 . 01, mL/min, 250 nm). Example 42: (3Λ,4Χ)-4-(2,5-difluorophenyl)-1_(5-{(Λ)-1_[1·(3_isopropyl-[1,2,4] evil two Zyrid-5-yl)piperidine-4-indole-2-methoxyethoxy}pyrimidine_(J 2-yl)pyrrolidin-3-amine

[1-(3-isopropyl-oxime, 2,4]oxadiazol-5-yl)piperidinyl]2-methoxyethoxy}pyrimidin-2-ylpyrrolidin-3-amine ( Example 40) Palm HPLC separation

(Μ T B E : M e O H : T H F ··n-butylamine·' 8 〇 : 1 5 . 5 · 0 · 1,1 · G mL/min, 250 nm). -321 - 201209054 The following examples were prepared by reacting the appropriate building block containing the butyl butyl carbamate with TFA using the procedure described in Example 29. Example fiber name LCMS 43 cc?F (3/?, 45 )-1-{5-[ 1-(5-ethyl-2-methyl-2H-[1,2,4]triazol-3-yl)piperidin-4-ylmethoxy]pyrimidine-2 -yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine RT = 2.34 min; w/z (ES+) = 517.2 [M+H]' 44 (3 feet 45)- 1-[5-(5,-Fluoro-3,4,5,6-tetrahydro-2H-[l,2']bipyridin-4-ylmethoxy)pyrimidin-2-yl]-4-( 2,4,5-trifluorophenyl)pyrrolidin-3-amine RT = 2.62 min; m/z (ES+) = 503.1 [M+U]+ ° 45 (3 feet 45)-1-{5-[ 1-(4-Methylthiazol-2-yl)-piperidin-4-ylmethoxy]pyrimidine-2-yl H-(2,4,5-trifluorophenyl)pyrrolidin-3-amine RT = 2.29 minutes; τη/ζ (ES+) = 505.1 [Λ/+Η]+ ο 46 ^fN*o FrtF (3 feet 4S)-1 - {5-[ 1-(3-isopropyl-[1, 2,4]oxadiazol-5-yl)piperidin-3-ylmethoxy-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine RT = 2.75 minutes; w/z (ES+) = 518.3 [M+H]+ 〇 Example 47: (3i?, 4 5)-1-(5-(1-(3 -ethyl-[1,2,4] Triazolo[4,3-c]pyrimidine _7_yl Piperidinylmethoxy]pyrimidin-2-yl}_4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine

The title compound of FF was obtained from [(3 A,4 5 ) -1"5 - -322- 201209054 [1-(3 -ethyl-[1,2,4]triazolo[ 4,3-c]pyrimidin-7-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl] Prepared with tert-butyl carbazate (Preparation 127). Purification by preparative HPLC (basic method) gave the title compound: RT = 2.57 min; m/z (ES+) = 554.3 [Af+H]+.

Example 48: (3^,45)-4-(2,5-Difluorophenyl)-1-(5-((5)-1-(1-(5-isopropylpyrimidin-2-yl)) Piperidin-4-yl]ethoxy}pyrimidine_2-yl)pyrrolidin-3-amine

Nh2 Add 2-chloro-5-isopropyl chelate (19 mg, 0.12 mmol) and DBU (37 μΐ^, 0_25 mmol) to (3i?,4S)-4-(2,5-difluorophenyl) 1-l-[5-((&lt;S)-1-piperidin-4-yl-ethoxy)pyrimidin-2-yl]pyrrolidin-3-amine (Preparation 121, 50 mg, 0.1 mmol) The reaction mixture was heated in a microwave reactor at 100 ° C for 3 minutes in a solution of DMSO (1 mL, 10 mmol). The mixture was partitioned between DCM and water and passed through a phase separator. The water layer is then rinsed with DCM. The organic layers were combined, concentrated under vacuum and purified by preparative HPLC. The fractions containing the desired product were passed through a pad of SCX, eluted with MeOH then eluted with NH.sub.4OH/MeOH. The solvent was removed in vacuo to afford the title compound: RT: 2.92 min; m/z (ES + ) = 524.3 [M+H] + ° Example 49: 4-((5&gt;)_1-{2-[(3 , 4*5)-3-amino-4-(2,5-difluorophenyl)pyrrolidin-1-ylpyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid propyl ester- 323- 201209054

Pyridine (14 μί, 0.17 mmol) and n-propyl chloroformate (19 μΙ&gt; '0.17 mmol) were added to the stirred by {(3π,4·5)-4-(2,5-difluorophenyl) 1-[5-((&lt;5)-1-piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9Η-莽-9-ylmethyl ester (Preparation 119, 35 mg, 0.06 mmol) EtOAc m. The mixture is rinsed with water and passed through a phase separator. The aqueous layer was rinsed with DCM then the organic layer was combined and &lt;RTI ID=0.0&gt;&gt; The reaction mixture was further stirred at room temperature for 16 hours. The mixture is rinsed with water and passed through a phase separator. The aqueous layer was washed with additional DCM, then the organic layer was combined and concentrated in vacuo. Purification by preparative HPLC (basic method) gave the title compound: EtOAc: 2. s. Example 50: 4-((5|)-1-{2-[(3 and,41?)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidine _5·yloxy}ethyl)piperidine-1·carboxylic acid cyclopropylmethyl ester

Triphosgene (12 mg' 0.04 mmol) was dissolved in DCM (0.25 mL' 3.9 mmol) and cooled to 0 °C. A mixture of cyclopropylmethanol (9.6 pL, 0"2 mmol) and EtOAc (9.7 μί, 0.12 mmol) in DCM (0.25 mL) was added dropwise to the mixture and the mixture was warmed to room temperature. After 1 hour, add {(3^,45)-4-(2,5-difluorophenyl)-1-[5-((51)-1-piperidin-4-yl) dropwise-324-201209054 Ethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester (Preparation 119, 25 mg, 0.04 mmol) and mp (9.7 pL, 0.12 mmol) The solution formed in DCM (0.5 mL) was stirred at room temperature 16

hour. The mixture is rinsed with water and passed through a phase separator. The aqueous layer was rinsed with DCM then EtOAc (EtOAc). The reaction mixture was stirred at room temperature for 16 hours. The mixture is rinsed with water and passed through a phase separator. The aqueous layer was washed with EtOAc EtOAc (EtOAc m. +H]+. Example 51: (3Λ,45)-4-(2,5-Difluorophenyl)-1-(5-{(·5)-1-[1-(5-fluoropyrimidin-2-yl)piperidine 4-yl]ethoxy}pyrimidin-2-ylpyrrolidin-3-amine formate

The title compound is composed of {(3/?,4 5&gt; 4-(2,5-difluorophenyl)-1-[5-((5)-1-piperidin-4-ylethoxy)pyrimidine- 9-yl]pyrrolidin-3-yl}carbamic acid 9-fluorenyl-9-ylmethyl ester (Preparation Example 119) was prepared by reacting 2-chloro-5-fluoropyrimidine in a similar manner to that described in Example 48. After the purification treatment, the crude residue was purified by preparative HP LC after eluting with MeOH, eluting with MeOH, then eluting with NH4 〇H/MeOH. , the title compound of the formate: 111' = 2.97 minutes; ^ (ugly 3 + ) = 500_ 1 [M + H] + -325- 201209054 Example 52: 4-((15)-b {2- [(3/?,45)-3-Amino-4-(2,5-difluorophenyl)lahydroidin-1-yl]pyrimidin-s-yloxy}ethyl)piperidine-i- Cyclopentyl formate

Add cyclopentanol (19.8 μιη, 0.22 mmol) and 2,6-dimethyloladium (25 pL, 0.22 mmol) to a solution of triphosgene (22 mg, 0.07 mmol) in DCM (1 m L) The mixture was stirred at room temperature for 3 minutes. In another container, {(3i?,4S)-4-(2,5-difluorophenyl)-1-[5-((phana-1-piperidin-4-ylethoxy)pyrimidine- 2·ylpyrrolidin-3-yl}carbamic acid 9H-burial-9-ylmethyl ester acetate (Preparation 118, 50 mg, 0.07 mmol) in DCM (2 niL) (1 mL) rinse, and passed through a phase separator to give {(3A,4S)-4-(2,5-difluorophenyl)-1-[5-((---l-l-piperidin-4-yl) a solution of the free base of 9H-fluoren-9-ylmethyl ethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid. The cyclopentanol mixture is added to the {(3Α,4^) -4-(2,5-monofluorophenyl)-1-[5-((5|)-1-piperidin-4-ylethoxy)pentan-2-yl]pyrene slightly steep-3 a solution of -yl}carbamic acid 9H-inden-9-ylmethyl ester followed by 2,6-dimethyl B ratio (8.4 μί, 0.07 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was rinsed with water and passed through a phase separator. The aqueous layer was rinsed with DC ' then the organic layer was combined and then the mixture was added (2 〇〇μl, 2 mmol). After stirring at room temperature for 60 hours, the mixture was passed. Rinse with water and pass through a phase separator. The water layer is rinsed with DC ,, then The organic layer was combined and concentrated under vacuum. Purified by preparative ΗPLC (basic method) to give the title compound: </ RTI> = 2.94 min; 7 « /2 ( ug 8 + ) = 516.4 [from +1^+ -326-201209054 Example 53: 4-((5)-1-(2-1(3/^,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1 -yl]pyrimidin-5-yloxy}ethyl)piperidine-butyl butylate

{(3;?,41?)-4-(2,5-Difluorophenyl)-1-[5-((*5)-1-piperidin-4-ylethoxy)pyrimidin-2- The solution of the pyridyl-3-yl}carbamic acid 9H-burden-9-yl methyl ester acetate (Preparation 118, 50 mg, 0_07 mmol) in DCM (2 mL) was saturated. Rinse NaHC03 solution (1 mL) and rinse through DCM (0.5 mL) through a phase separator to give {(3Λ,45)-4-(2,5-difluorophenyl)-1-[5-(( 5) A solution of the free base of 9H-indol-9-ylmethyl ester of 1-piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid. N-butyl chloroformate (3 0.5 pL, 0.24 mmol) and 2,6-dimethyl smear (9.2 μιη, 0.08 mmol) were added to the solution, and the mixture was stirred at room temperature for 60 minutes. The mixture is distributed between DCM and water and passed through a phase separator. The aqueous layer was washed with additional EtOAc then EtOAc (EtOAc &EtOAc). The mixture is rinsed with water and passed through a phase separator. The aqueous layer was washed with additional DCM, then the organic layer was combined and concentrated in vacuo. Purification by preparative HPLC (basic method) gave the title compound: RT: 2.97 min; w/z (ES+) = 504.2 [M+H]+. Example 54: 4-((5)-1-{2-[(31?,415)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidine_5 · oxyethyl}ethyl)piperidine-1-carboxylic acid isobutyl ester-327- 201209054

The title compound was obtained from the procedure of Example 53 from {(3 Α 45·)-4-(2,5-difluorophenyl)-1-[5-((5)-1-piperidin-4-yl. Ethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9-fluoren-9-ylmethyl ester acetate (Preparation Example 118) and isobutyl chloroformate Preparation: ruler = 2.87 min; /2 (£8 + ) = 504.2 [Μ+Η]+. Example 55: 4-((5)-1-(2-1(37^,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidine_5 _ yloxy}ethyl)piperidine-1-carboxylic acid cyclobutyl ester

Cyclobutanol (17 mg, 0.24 mmol) and 2,6-lutidine (28 μί' 0.24 mmol) were added to a solution of triphosgene (24 mg, 0.08 mmol) in DCM (1 mL). Shake for 30 minutes at room temperature. In another container, {(3i?,4S)-4-(2,5-difluorophenyl)-145-((5)-:1-piperidin-4-ylethoxy)pyrimidine-2 -Pyrylpyridin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester acetate (Preparation 118 '50 mg, 0.07 mmol) in DCM was washed with saturated NaHC 3 solution, and By means of a phase separator, {(3/?,4 5)-4-(2,5-difluorophenyl)-:1^5-((5)-1-piperidin-4-ylethoxy A solution of the free base of pyrimidine-2-yl]pyrrolidin-3-yl}carbamic acid 9H-inden-9-ylmethyl ester. Adding a cyclobutanol mixture to the {( 3 i?, 4 &gt; 5) - 4 - (2,5 -difluorophenyl)-1 - [ 5 - ((S) - :1 -峨D- 4 - ethoxylated) chewred - 2 -yl]pyrrolidine-3-amine}amine-328- 201209054 carboxylic acid 9H- and -9-yl methyl ester solution, the reaction mixture at room temperature Shake for 60 minutes. The mixture was rinsed with water, passed through a phase separator and the aqueous layer was rinsed with D CM. The organic layer was combined, piperidine (2 〇〇 0, 2 mm ο 1) was added, and the reaction mixture was shaken at room temperature for 16 hours. The mixture is rinsed with water and passed through a phase separator. The aqueous layer was washed with D C ,, combined organic layers and concentrated under vacuum. Purification by preparative HP LC (basic method) gave the title compound: &lt;RTI ID=0.0&gt;&gt;

The following examples were carried out using the procedure described in Example 55 via {(3 and, 4)5b 4_(2'5-monochato)-1-[5-((5&gt;)-1-indol-4-yl Ethoxy) mouth-steep 2-1-yl]-l-r-hexyl-3-yl}aminocarbamic acid 9H-indol-9-ylmethyl ester acetate (Preparation 118) was prepared by reaction with an appropriate alcohol:

L -329- 201209054 Example structure name LCMS 56 4-((5&gt;1-{2-[(3)45)-3-Amino-4-(2,5-difluorophenyl)-pyrrolidin-1 (yl)pyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid (8)-dibutyl butyl ester RT = 2.92 min; m/z (ES+) = 504.2 [M+H]+. 57 4-( (5)-1-{2-[(3 Foot 45)-3-Amino-4-(2,5-difluorophenyl)-pyrrolidin-1-yl]pyrimidin-5-yloxy}B ()) piperidine-1-carboxylic acid (5)-dibutyl butyl ester RT = 2.87 min; m/z (ES+) = 503.1 [M+Hf. 58 4-((5)-1-{2-[(3 feet 45 )-3-amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid cyclobutylmethyl ester RT = 2.90 min ;m/z (ES+)= 516.2 [M+H]+. 59 4-((5)-1-{2-[(3,45)-3-amino-4-(2,5-difluoro) Phenyl)pyrrolidin-1-yl]pyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid 1-methyl-cyclopropylmethyl ester RT = 2.92 min; m/z (ES+) = 516.2 [M+H]+. 60 ο^°^{Κχ众Ν νη2 4-((5)-1-{2-[(3 Foot 45)-3-Amino-4-(2,5-difluoro Phenyl)pyrrolidin-1-yl]pyrimidin-5-yloxy}ethyl)piperidine-1-carboxylic acid (5)-(tetrahydrofuran-3-yl)ester RT = 2.57 min; m/z (ES+) = 518.2 [M+H]+. 61 0, ΚΗ普^F 4-((5)-1-{2-[(3足45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrimidine_5_yl (Ethyl)ethyl)piperidine-1-carboxylic acid (8)-(tetrahydrofuran-3-yl)ester RT = 2.57 min; m/z (ES+) = 518.2 [M+H]+. -330- 201209054 62 4-( (5)-l-{2-[(3i?,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyridyl_5-yloxy} Ethyl) piperidine-1-carboxylic acid 3-methyloxetan-3-yl methyl ester RT = 2.63 min; mlz (ES-1} = 532.2 [M+H]+. 63 ck a 〒 F 4-((S)-l-{2-[(3-branched 4S)-3-amino-4-(2,5-difluorophenyl)pyrrolidin-1-yl]pyridinyl-5-yl Ethoxy}ethyl)piperidine-1-carboxylic acid 2-methoxy 4,1-dimethyl-ethyl ester RT = 2.84 min; mlz (ES+) = 534.2 [M+H]+.

Example 64: (3Λ,45·)-4-(2,5-diphenyl)-l-(5-{(S)-l-[l-(5-ethylpyrimidin-2-yl)piperidin Acridine-4-yl]ethoxyl}pyrimyl_2_yl)pyrrole steep _3_amine

In {(3Λ,45)-4-(2,5-difluorophenyl)-bu[5-((5)-piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidine -3-yl}aminocarbamic acid 9H-inden-9-ylmethyl ester (preparation 119, 50 mg, 0.08 mmol) and 2-chloro-5-ethyl chelate (11 〇mg Cj, 0.08 mmol) in DMSO DBU (36 pL, 0.24 mmol) was added to a mixture (1 mL) and the mixture was stirred at 100 ° C for 30 min. The mixture was partitioned between DCM and water and passed through a phase separator. The aqueous layer was rinsed again with DCM. The organic layers were combined, concentrated under vacuum and purified by preparative HPLC. The fractions containing the desired product were combined, concentrated under vacuum and purified by preparative ΗPLC (basic method) to give the title compound: 111' = 2.82 min; 坩/2 ( ug 8 + ) = 510.3 [尨+11]+. Example 65: {6-[4_((&lt;5)-1-{2-[(3 and 415)-3-Amino-4-(2,5-difluorophenyl-331 - 201209054) pyrrole Acridine-1-yl]pyrimidin-5-yloxy}ethyl)piperidin-1-yl]pyridazin-3-yl}dimethylamine

The title compound was obtained via the procedure of Example 48 via (2,5-difluorophenyl)-1-[5-((^)-1-piperidin-4-ylethoxy)pyrimidin-2-yl] Preparation of pyridin-3-yl}carbamic acid 9H-Fran-9-ylmethyl ester (Preparation 119) by (6-chloropyridazin-3-yl)dimethylamine: 111' = 2.85 min ;/„/2斤 3 + ) =524.3 [M+H]+. Example 66: (3Λ,4*5)-4-(2,5-difluorophenyl)-1-(5-((5) -1-11-(5-propylpyrimidin-2-yl)piperidine-4-yl]ethoxy}pyrimidin-2-yl)pyrrolidin-3-amine

The title compound is from {(3Λ,45)-4-(2,5-difluorophenyl)-1-[5-((5)-1-piperidin-4-ylethoxy)pyrimidin-2- 9-ylpyridin-3-ylmethyl carbamate (preparative Example 119) and 2-chloro-5-propylpyrimidine were prepared by a similar reaction to that described in Example 48, except After heating the reaction mixture at 100 ° C for 30 minutes in a microwave reactor, another portion of 2-chloro-5-propylpyrimidine (1 eq.) was added, and the reaction mixture was at 150. (: heating for 30 minutes: RT = 2.97 minutes; m/z (ES + ) = 524.3 [M+H]+. Example 67: {2-[(3/?,4·9)-3-amino- 4-(2,5-difluorophenyl)pyrrolidin-1-yl-332- 201209054 ]pyrimidine-5-yl b{(S)-l-[l-(3-isopropyl-[1,2 ,4]oxadiazol-5-yl)acridin-4-yl]ethyl}amine

In [(3i?,4S)-4-(2,5-difluorophenyl)-1-(5-{(5)-1-[1-(3_isopropyl-[1,2,4] Oxadiazol-5-yl)piperidin-4-yl]ethylamino}pyrimidin-2-yl)-le-bromo-3-yl]amino carboxylic acid tert-butyl ester (Preparation Example 130, 6 mg, TFA (30 μί, 0.4 mmol) was added to a solution of EtOAc (EtOAc). The crude mixture was passed through a pad of EtOAc (EtOAc) eluting eluting eluting eluting This material was then purified by preparative HP LC and the product containing fractions were concentrated under vacuum and reduced. This material was again taken up in EtOAc (EtOAc) eluting elut elut elut elut elut elut elut elut elut elut elut 513.3 [M+H]+. Example 68: (3Λ,4·5)-1·{5-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidine-4-yloxy] Pyrimidine_2_yl}_4_(2,4,5-trifluorophenyl)pyrrolidine_3_amine hydrochloride

[(3 heart 45)-1-{5-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine-2 -yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]amine-333- 201209054

The carboxylic acid table - 'butyl vinegar (Preparation 131, 171 mg, 0.28 mmol) was added to a solution of DCM (5 mL), and the mixture was stirred for 20 min. Add another portion of T F A ' and continue to stir for 2 minutes. The crude mixture was taken up in EtOAc EtOAc (EtOAc) eluting eluting The material was then passed through a pad of EtOAc (EtOAc) eluting with MeOH then eluting with NH4OH / MeOH. The residue obtained was purified by column chromatography (DCM: MeOH, 98: 2), eluted with preparative HPLC, and product fractions were concentrated in vacuo. The residue was again taken up in EtOAc (EtOAc) elute elut elut elut elut elut elut elut A solution of HCl in dioxane (4M, 5 drops) was added to a solution of the above compound in Et20 (2 mL). The solvent was removed in vacuo to give the title compound: &lt;RTI ID=0.0&gt;&gt; Example 69: (37?,4*S)-l-{5-[l-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy Pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine p-toluenesulfonate

In [(3i?,4S)-l-{5-[l-(5-isopropyl-[1,2,4]oxadiazin-3-yl)piperidin-4-ylmethoxy]pyrimidine 2-3-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 132, 1 〇 3 mg, 0.17 mmol) in DCM ( To a solution of 5 mL) was added TFA (1 mL) 'Reaction mixture - 334 - 201209054 and stirred at room temperature for 20 min. Add another portion of TFA (1 mL) and continue to stir for 20 minutes. The crude mixture was passed through a pad of EtOAc (EtOAc) eluting eluting with EtOAc EtOAc. TsOH (25 mg, 0.13 mmol) was added to a solution of EtOAc (2 mL) The solvent was removed in vacuo to give the title compound:jjjjjjjjj

Example 70: (3^,45)-1-(5-((5)-1-11-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-4 -yl]ethoxy}pyrimidin-2-yl)-4-pyridin-2-ylpyrrolidin-3-amine hydrochloride

2-Chloro-5-((5)-1-(:1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy Pyrimidine (Preparation 63, 81 mg '0.23 mmol) and (( Ο trans)-4 -pyridin-2-ylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 136, 61 mg, DBU (39 μΐ^, 0.23 mmol) was added to a solution of DMSO (0.5 mL). The mixture was heated to 1 ° C for 48 hours. The mixture was diluted with DCM and rinsed with brine. The solvent was removed by passing through a sifter, then EtOAc (EtOAc) EtOAc (EtOAc: EtOAc, EtOAc (EtOAc) ; 15 m L/min, 2 5 0 nm, RT = 11.46 min), intermediate compound [(3145)-1-(5-((5)-1-(1-(3-isopropyl-[1] , 2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)-4- -335- 201209054 pyridin-2-ylpyrrolidin-3-yl]amine To the solution of the product in dioxane (0.1 mL), a solution of THF (dichloromethane) (4 Μ, 0·1 mL) was added and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo to give the title compound:jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj )-1-{5-[1-(2-isopropyl-2H-tetrazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidine-3-amine hydrochloride salt

((37^,41S)-4-(2,5-Difluorophenyl)-l-{5-[l-(2-isopropyl-2H-tetrazol-5-yl)piperidine-4 -Dimethyl methoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation Example 143, 110 mg, 0.18 mmol) was added to a solution of D CM (5 mL) TFA (1 mL), the reaction mixture was stirred at room temperature until the reaction was completed. The crude mixture was passed through a pad of EtOAc (EtOAc) eluting with EtOAc then eluting The solvent was removed in vacuo to give the title compound, md. A solution of HCl in dioxane (4M, 230 μί, 0.92 mmol) was added and the mixture was stirred for 30 min. The solvent was removed in vacuo to give the title compound: &lt;RTI ID=0.0&gt;====================================================== -基)峨 steep_4_ylmethoxy]pyran-2-yl}pyrene ratio steep_3_amine

In ((3Λ,4&lt;5)-4-(2,5-monofluorophenyl)-1 - { 5 - [ 1 - ( 5 -isopropyl-[1,3,4]oxadiazole-2 -butyl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidinyl-3-ylaminobenzoic acid tert-butyl ester (Preparation 144, 19 mg, 〇·03 mmo1) in DCM (2.5 mL To the resulting solution was added TFA (0.5 mL), and the mixture was stirred at room temperature until the reaction was completed. The crude mixture was passed through a pad of EtOAc (EtOAc) eluting with MeOH then eluting with NH? The solvent was removed in vacuo to give the title compound: </RTI> <RTIgt; </RTI> <RTIgt; The following examples were made using the procedure described in Example 72 via reaction of a suitable building block containing a third butyl carbamate with TFA: Example Structure Name LCMS 73 Ν (3/?, 45)-4-(2,5 -difluorophenyl)-1-{5-[l-(5-dimethylaminomethyl-[1,2,4]oxazol-3-yl)piperidin-4-ylmethoxy ] pyrimidin-2-yl}pyrrolidin-3-amine RT = 2.25 min; /w/z (ES+) = 515.3 [M+H]' 74 NHj (3/?,45)-4-(2,5- Difluorophenyl) small (5-{1-[5-((8)-1-methoxyethyl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy Base}pyrimidin-2-yl)indolepyridin-3-amine RT = 2.77 min; τη/ζ (ES+)-516.3 [M+H]+. -337- 201209054 75 (3/?,4S&gt;4-(2,5-Difluorophenyl)-1-(5-{l-[5-(tetrahydrofuran-3-yl)-[1,2,4 Oxadiazol-3-yl]-piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidine-3-amine RT = 2.72 min; /w/z (ES+) - 528.3 [M+H ]+. 76 (3/?,4S)-4-(2,5-difluorophenyl)-1-(5-{1-[(5)-5-(tetrahydrofuran-2-yl)-[1 , 2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidine-3-amine RT = 2_73 min; w/z (ES+) = 528.3 [M +H]+. 77 .Ο^ν〇-Ο&lt;να^ (3 feet 45)-4-(2,5-difluorophenyl)-1-(5_{1_[5_(1_methoxy-) Μmethylethyl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidine-3-amine RT = 2.92 min; w /z (ES+) = 530.3 [M+H]+. 78 N (3i?,45)-4-(2,5-difluorophenyl)-1-{5-[1-(5-pyrrolidine- 1-ylmethyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-amine RT = 2.23 min; m/ z (ES,= 541.3 [MfH]+. 79 (3 brothers 45)-4-(2,5-difluorophenyl)·1-(5_{1_[5-(1-methylpyrrolidine D- 2-yl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrole-thran-3-amine RT = 2.22 min; m/z(ES+) = 541.3 [Af+H]+. 80 (3 ft. 45)-4-(2,5-difluorophenyl)-1-(5-{1-[5-(tetrahydropyran-4) -yl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidine-3-amine RT = 2.70 min; w/z ( ES+) = 542.3 [M+H]+ ° Example 81: (3^,45)-4-(2,5-difluorophenyl)-1-(5-{1-[5-(2-methoxy) Base-l-methylethyl)-[l,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-amine-338- 201209054

Add ((3Λ,45)-4-(2,5-) to a solution of 3-methoxy-2-methylpropanoic acid (Preparation 146, 8.4 mg, 0.07 mmol) in DMF (1.5 mL) Difluorophenyl)-1-{5-[1-(1^-hydroxycarbamimido)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid Tributyl ester (Preparation Example 145,

30 mg' 0.05 mmol) followed by HOBt (12 mg, 0.08 mmol) and finally EDCI (16 mg, 0. 08 mmol). The reaction mixture was stirred at room temperature for 16 hours and then at 80 ° C for 3 hours. The solvent was concentrated in vacuo and the residue was partitioned between DCM and water. The organic layer was separated, washed with a saturated NaHC03 solution, and solvent was removed in vacuo to give intermediate product [(3i?,4&lt;S)-4-(2,5-difluorophenyl)-b (5-{1) -[5-(2-methoxy-1-methylethyl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrole Tributyl butyl-3-yl]carbamic acid. TFA (0.1 mL) was added to a solution of EtOAc (1 mL). The crude mixture was taken up in EtOAc (EtOAc) eluting eluting eluting The residue was purified by MDP (acidic conditions) and the product fractions were eluted with EtOAc (EtOAc) eluting with EtOAc. The basic fractions were collected and concentrated in vacuo to give title compound: RT = 2.80 min; m/z (ES + ) = 530 </ s> [M+H]+. Example 82: (3 and, 4*5)-1-(5-{1-[5-(1,1-difluoroethyl)-[1,2,4]oxadiazole-3-yl]piperidin Acridine-4-ylmethoxy}pyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrim-339- 201209054 slightly steep-3-amine

Chesing 3-(3-yl)piperidin-4-ylmethoxy at [(3^,43)-1-(5-(145-(1,1.difluoroethyl)-oxime, 2,4] Pyrimidine-2-yl)-4-(2,5-difluorophenyl)blotyridin-3-yl]carbamic acid tert-butyl ester (Preparation 147, 38 mg 〇·06 mmol) in DCM (2 mL) of the resulting solution was poured into a solution of TFA (0.2 mL). The reaction mixture was stirred at room temperature for 2 hours. The crude mixture was passed through EtOAc (EtOAc) eluting with MeOH and eluting with NH4OH/MeOH The aliquots were collected and concentrated in vacuo. EtOAc was purified eluting with EtOAc EtOAc: EtOAc: And, 4*5)-4-(2,5-difluorophenyl)-1-{5-[1-(3-isobutyl-[1,2,4]oxadiazol-5-yl) Piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrole steep _3·amine hydrochloride

[(3i?,4&lt;S)_[[5-(1-Cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrole Butyl-3-yl] butyl methacrylate (preparation 141, 50 mg, 〇.1 〇 mmol) and N-hydroxy-3-methylbutanthene (14 mg 〇 -12 mmol) in EtOH ( A 2 mL) mixture was added with a solution of zinc(II) chloride Et2 (1M, 〇.12 mL '〇·ΐ2 mm〇l). The reaction mixture was stirred at room temperature for 90 minutes. Concentrated HC1 (12M '44 μί, -340 - 201209054 0·53 mmol) was added to the mixture, and stirring was continued at room temperature for 90 minutes, and then the reaction mixture was at 100 in a microwave reactor. (The next heating is carried out for 30 minutes. The crude mixture is eluted with MeOH in EtOAc, followed by elution with EtOAc, EtOAc, EtOAc. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The crude mixture was purified directly in M.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. The reaction mixture was stirred at room temperature for 30 min then EtOAc (EtOAc)

Example 84: (3i?,4*S)-4-(2,5-difluorophenyl)-l-(5-{l-[3-((5)-1-methoxyethyl)- [1,2,4]oxadiazol-5-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-amine hydrochloride

In [(3 and, 4, Fanta-1-[5-(1-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidine 3-butyl] butyl methacrylate (Preparation Example 141, 150 mg, 〇·29 mmol) and (&lt;S)-N-hydroxy-2-methoxypropionamidine (Preparation 148, 46 mg , 0.3 5 mmol) in a mixture of EtOH (3 mL) with zinc chloride (11) in 2 〇 solution (1M, 〇·35 mL '0·35 mmol) 'anti-341 - 201209054 After stirring for 60 minutes, a concentrated HCl solution (12 M '0.13 mL, 1.6 mmol) was added to the mixture, and stirring was continued at room temperature for 5 minutes, after which the reaction mixture was heated at 80 ° in a microwave reactor for 30 minutes. The solvent was removed in vacuo and the title compound was purified eluting elut elut elut elut elut elut elut A solution of HCl in dioxane (4 mL, 0.2 mL, 0.9 mmol) eluted elute elute + ) = 516.1 [from +11]+. Example 85: (3 and 45)-1-(5-{1-丨3-(1,1-difluoroethyl)-[1,2,4]oxadiazol-5-yl]piperidine- 4-ylmethoxy}pyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidine-3-amine hydrochloride

In [(3i?,4S)-l-[5-(1-Cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidine -3-yl]aminobutyl carbamate (Preparation 141, 150 mg, 0.29 mmol) and 2,2-difluoro-N-pyridinyl (Preparation 149, 43 mg, 0.35 mmol) in EtOH A solution of zinc chloride (Π) in Et20 (1 M, 0.35 mL, 0.35 mmol) was added to a mixture (3 mL). The mixture was stirred at room temperature for 60 min. A solution of HCl in dioxane (4M, 0.36 mL, 1.4 mmol) was added to the mixture and the mixture was taken at 80 in a microwave reactor. (: heating for 30 minutes, then increasing the temperature to 10 〇 and heating for 30 minutes. Add a second portion of HC1 in dioxane solution (4M, 0.36 mL - 342 - 201209054 '1.4 mmol)' and the reaction mixture in the microwave reactor The mixture was heated at 12% for 30 minutes. The solvent was removed under vacuum' and the residue obtained was partitioned between dcm and sat. NaHC.sub.3 solution. The organic layer was separated, dried (M.sup.4) and removed under vacuum. Solvent. The crude mixture was passed through EtOAc (EtOAc) eluting with EtOAc (EtOAc) eluting with EtOAc EtOAc. The fractions were concentrated in vacuo. EtOAc EtOAc EtOAc. To a solution of DCM (2 mL), EtOAc (EtOAc m. «/203 + ) =522.6 [M+H]+. Example 86: (31^,45)-4-(2,5-difluorophenyl)-1-{5-[1-(5-ethyl-

[l,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-amine

In ((37?,4&lt;5)-4-(2,5-difluorophenyl)-1-{5-[1-(5-ethyl-[1,2,4]oxadiazole-3 -yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)amine

TCA (0.15 mL) was added to a solution of dimethyl succinate (preparation 150, 25 mg, 0.04 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 90 min. The quality mixture passes through SCX匣, first with -343- 201209054

The MeOH was stripped&apos; followed by elution with NH.sub.4OH/MeOH. The resulting product was stirred in a mixture of MeCN and water (1:1 &lt;RTI ID=0.0&gt;&gt; + ) = 486.3 [Λ/+Η]+. The following examples were prepared by reacting the corresponding B〇c protected building blocks with TFA using the procedure described in Example 86: Example Λ I | γ Η γ Structure Name LCMS 87 I---- 1~1 (3 feet 45 -1{5-[1-(5-Difluoromethyl-[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}- 4-(2,5-difluorophenyl)pyrrolidine-3-amine RT = 2.85 min; w/z (ES+) = 508.2 [Μ+Η]+· 88 (3 feet 45)-4-(2, 5-difluorophenyl)-1-(5-{1-[5-(1-methylcyclopropyl)-[1,2,4]oxadin-3-yl]piperazin-4-yl Methoxy}pyrimidin-2-yl)pyrrolidine-3-amine RT = 2.92 min; w/z (ES+) = 512.3 [Μ+ηγ. 89 (3 feet 45)-4-(2,5-difluoro Phenyl)-1-{5-[1-(5-ethoxymethyl·[1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2- }}pyrrole B--3-amine RT = 2.75 min; w/z (ES+) = 516.3 [M+H]+. 90 ~- ~ (3 ft 45 &gt; 4-(2,5-difluorophenyl) 1-(5-{1-[5-(1-fluoro-1-methylethyl)-[1,2,4]oxadiazol-3-yl]piperazin-4-ylmethoxy} Pyrimidin-2-yl)pyrrolidin-3-amine RT = 2.90 min; /m/z (ES+) = 518.3 [M+H]' -344- 201209054 91 (3/?,45)-4-(2, 5-difluorophenyl)-1-{5-[1-(5-trifluoromethyl- [1,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-amine RT = 3.02 min; ?n/z (ES^ = 526.2 [M+R]+. 92 F (3i?,45)-l-(5-{l-[5-(3,3-difluorocyclobutyl)-[1,2,4]oxadiazole 3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)-4-(2,5--phenylphenyl)pyrrolidine-3-amine RT-2.88 min; m/z ( ES+) - 548.3 [M+H]' 93 (3 foot 4S)-4-(2,5-difluorophenyl)-1-(5-{1-[5-(3-methylisoxazole- 5-ylmethyl)-[1,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyridin-2-yl)pyrrole-thran-3-amine RT = 2.75 min ;m/z (ES+) = 553.3 [M+H]+. Example 94: (3i?,4S)-4-(2,5-difluorophenyl)-l-{5-丨1-(3- Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]pyrimidin-2-yl}pyrrolidin-3-amine

2-Chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]pyrimidine (containing 40% 2-bromo- 5-[l-(3-Isopropyl-[1,2,4]oxadiazole-5-yl)piperidin-4-yloxy], chew, preparation 158, 55 mg, 0.16 mmol) And [(314^)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 59 mg '0.20 mmol) in DMSO (0.33 tnL) DBU (25 μί, 0.16 mmol) was added to the mixture and the mixture was heated to 80 ° C for 16 hr. The mixture was diluted with DCM, washed with brine and concentrated in vacuo. Purified by column chromatography (IH: EtOAc, 1:1) to give -345 - 201209054 intermediate ((3/^,45)-4-(2,5-difluorophenyl)-1-{5- [1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid Third butyl ester: RT = 4.37 min; w/z (ES + ) = 5 8 6.2 [M+H]+. TFA (2 mL) was added to a solution of EtOAc (EtOAc). The reaction mixture was purified by EtOAc (EtOAc) eluting elut elut elut elut elut elut elut elut 486.2 [M+H]+. Example 95: (3^,45)-4-(2,5-Difluorophenyl)-1-(5-(1-[3-(2-methoxyethyl)-[1,2,4 Oxadiazole-5-yl]piperidin-4-ylmethoxy}pyrimidinylpyrrolidin-3-amine hydrochloride

A solution of hydroxylamine (50% aqueous solution, 3.1 mL, 5 1.2 mmol) was added to a solution of 3-methoxypropionitrile (1_07 mL, 11.8 mL) in EtOH (7 mL). 6 hours. The solvent was removed under vacuum to azeotrope with toluene to give the intermediate product N-hydroxy-3-methoxypropane. In one part of the intermediate (41 mg, 〇. 4 mmol) and [(3i?,4&lt;S)-l-[5-(1-cyanopiperidin-4-ylmethoxy)pyrimidine-2_ Addition of tert-butyl [4,5-difluorophenyl)pyrrolidin-3-yl]carbamate (preparation 141, 150 mg, 0.29 mmol) in EtOH (2.5 mL) Zinc chloride (π) -346- 201209054

Et20 solution (1 M, 0.35 mL' 〇·35 mm 〇i), and the mixture was stirred at room temperature for 6 hr. Concentrated HCl solution (12 M, 0.13 mL, 1·6 mmol) was added to the mixture. The mixture was heated in a microwave reactor at 8 Torr for 30 minutes. The solvent was removed under vacuum and the residue obtained was partitioned between dcm and sat. NaHC. The organic layer was separated and the aqueous layer was extracted with dcM. The combined organic fractions were concentrated in vacuo to purified titled EtOAc (EtOAc) A solution of the HCl in dioxane (4M, 0.36 mL, 1.4 mmol The solvent was removed in vacuo to give title compound: EtOAc: EtOAc: Example 96: (3^,45)-4-(2,5-Difluorophenyl)-1-{5-[1-(3·methoxymethyl-[1,2,4]oxadiazole _5-yl) piperidine_4_ylmethoxy]pyrimidin-2-yl}pyrrolidine-3-amine hydrochloride

In hydrazine-hydroxy-2-methoxyacetamidine (Preparation 167, 36 mg, 0.35 mmol) and [(3/?,45·)-1-[5-(1-cyanopiperidin-4- Tert-butyl ester of methoxymethyl)-4-methyl]-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamate (preparation 141, 150 mg, 0.29 mmol) A solution of zinc(II) chloride in Et2 (1 M '0.35 mL, 0.35 mmol) was added to a solution of EtOH (2.5 mL), and the mixture was stirred at room temperature for 60 min. Concentrated HCl solution (12 M, 0.13 mL, 1.6 mmol) was added to the mixture. The reaction mixture was heated in a microwave-347-201209054 reactor at 80 ° C for 30 minutes. The solvent was removed in vacuo and the residue was partitioned between DCM and sat. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were concentrated in vacuo to purified title title title title A solution of HCl in dioxane (4M, 0.36 mL, 1.4 mmol). The solvent was removed in vacuo to give title compound: EtOAc: EtOAc: The following examples were carried out by the procedure described in Example 96 from [(3i?,4, phantom-indole-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2, 5-di) Manufacture of butyl fluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 141) by reaction with an appropriate hydrazine intermediate: Example structure name LCMS 97 (3i?, 45)-4-(2, 5-difluorophenyl)-1-(5-{1-[3-(tetrahydrofuran-3-yl)-[1,2,4]oxadiazol-5-yl]piperidin-4-ylmethoxy }}pyrimidin-2-yl)pyrrolidine-3-amine hydrochloride RT = 2.60 min; m/z (ES+) = 528.3 [M+H]+. 98) 仏(3 足45)-4-(2 ,5-difluorophenyl)-1-{5-[1-(3-propyl-[1,2,4]oxadiazole-5-yl)piperidin-4-ylmethoxy]pyrimidine- 2-yl}pyrrolidine-3-amine hydrochloride RT = 2_7 knives; m/z (ES+) = 500.3 [M+H]+. 99 (3/?, 4 for 4-(2,5-two) Fluorophenyl)-1-{5-[1-(3-isopropoxymethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine- 2-yl}pyrrole-threo-3-amine hydrochloride RT = 2.68 min; m/z (ES+) = 530.3 [M+H]+. -348- 201209054 (3i?,45)-l-{5-[ 1-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)piperidine RT = 2.72 min 100 pyridine-4-ylmethoxy]pyrimidin-2-yl}-4-(2 , 5-difluoro Phenyl)pyrrolidin-3-amine hydrochloride* miz (ES+) = 498.3 [M+H]+. Example 101: (3 and, 41^)-1-{5-[1-(3- two gas Methyl-[1,2,4]spiro-indol-5.yl)indole-4-ylmethoxy]pyranyl-2_yl}_4_(2,5-difluorophenyl) 3-amine

In 2,2-difluoro-N-hydroxyacetamidine (Preparation 169, 38 mg, 0.35 mmol) and [(3i?,4S)-l-[5-(l-Chloryl-deep-4-yl) Oxy) chelate tert-yl-2-yl]-4-(2,5-difluorophenyl)pyrrolidinyl-3-yl]carbamic acid tert-butyl ester (Preparation 141, 150 mg, 0.29 mmol) in EtOH (2.5 mL) The solution formed was added with a solution of zinc(II) chloride in Et.sub.2 (1M, 0.35 mL, 0.35 mmol). The mixture was stirred at room temperature for 60 min. Concentrated HCl solution (12 M, 0.13 mL '1.6 mmol) was added to the mixture and the mixture was stirred at 80 ° C for 30 min. The solvent was removed in vacuo and the residue was partitioned between DCM and sat. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic fractions were concentrated under vacuum to purify with MDP (basic conditions). The fractions containing the product were concentrated under vacuum and purified by M D P (acidic conditions). The saturated fractions containing the product were eluted with EtOAc (EtOAc) eluting with EtOAc (EtOAc) eluting Rapid precipitation in EUO, titled compound -349-201209054: RT = 2.70 min; ^(ES + ) = 5〇8-2[M+H]+° Example 102: (3Λ,45·)-4" 2,5-fluorobenylmethylcyclopropyl)-[1,2,4]oxadiazolyl]piperidine-4-yloxypyrimidin-2-yl)pyrrolidin-3-amine in N -Phenyl-1-methylcyclopropanol (Preparation Example 170 '40 mg, 0.35 mmol) and [(3/2,0)4-1^5-0-cyanopiperidin-4-yl- Oxy)chr-2-yl-2-(2,5-difluorophenyl)pyrrolidyl-3-ylaminobenzoic acid tert-butyl ester (Preparation 141, 150 mg, 〇.29 mmol To a solution of EtOH (3.5 mL) was added zinc chloride ((1) Et2 〇 solution (1 Μ, 〇·35 mL, 〇35 mmol), and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was heated in a microwave reactor at 80 ° C for 30 minutes. The solvent was removed in vacuo and the residue was partitioned between DCM and sat. NaHC. The organic layer was separated, and the aqueous layer was extracted with DCM. The organic fractions were combined and concentrated in vacuo and purified by MPP (acidic conditions). The product-containing fractions were removed in vacuo to give title compound: RT = 2.89 min; w/z (ES + ) = 5 1 2.5 [M+H]+. Example 103: (3/?, 4 -4-(2,5-difluorophenyl丨1·(3_ethoxymethyl-[1,2,4]chh-indole-5-yl)indole-4-ylmethoxy] spray Steep-2-yl} scheacidine-3-amine formatate-350 - 201209054

2-Ethoxy-N-hydroxyacetamidine (Preparation 173) and [(3Λ,4&lt;?)_[5-(1-Cyanopiperidinylmethoxy)pyrimidin-2-yl]-4_ (2,5-Difluorophenyl)pyrrolidine-3-ylaminobenzoic acid tert-butyl ester (Preparation Example 141) was reacted using the procedure described in Example 1-2. The solvent was removed in vacuo to give the title compound: EtOAc: EtOAc. Example 104: (3Λ,45)-4-(2,5-Difluorophenyl)-l-(5-{l_[(i?)-3-(tetrahydrofurazan-2-yl)-[1 , 2,4]oxadiazole·5-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidine-3-amine formate

(/?)-Ν-hydroxytetrahydrofuran-2_formamidine (Preparation 174) and [(μ,κ)-;!-[5-0-Cyanopiperidin-4-ylmethoxy)pyrimidine-2 -Methyl 4-(2,5-difluorophenyl)pyrrolidin-3-ylcarbamic acid tert-butyl ester (Preparation Example 141) was reacted using a method similar to that described in Example 102. The title compound was obtained from the residue (yield: EtOAc): EtOAc (EtOAc: EtOAc) Example 105: (3Λ,45)·4_(2,5-difluorophenyl)-1-(5-{1-[3-(1-fluoro-b-methylethyl)-[1,2,4] Diazol-5-yl]piperidine-4-yloxypyrimidinyl)pyrrolidin-3-amine-351 - 201209054

The title compound was obtained from 2-fluoro-N-hydroxy-2-methylpropanium (Preparation 171) and [(3Λ,4·ϊ)-1-[5-(1-Cyanopiperidin-4-yl) Third butyl oxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamate (Preparation Example 141) using a procedure similar to that described in Example 102 Prepared by reaction, except that the purification was carried out using MDP (basic conditions): RT = 2.75 min; m/z (ES + ) = 5 1 8.2 [M+H]+. Example 106: (3Λ,4 5&gt; 1-{5-[1-(3-t-butyl-[1,2,4]oxadiazole-5-yl)piperidine-4-yloxy] Pyrimidin-2-yl}-4_(2,5-difluorophenyl)indyrrolidine-3-amine

The title compound is obtained from Ν-hydroxy-2,2-dimethylpropanindole and [Oi?,4*?)-;!-[5-(1-cyanopiperidin-4-ylmethoxy)pyrimidine- T-butyl 2-methyl]-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamate (Preparation Example 141) was prepared by a similar reaction procedure as described in Example 102. The purification was carried out using MDP (basic conditions): RT = 2.87 min; m/z (ES+) = 514.2 [M+H]+. Example 107: 2-1(311,4 5)-3-Amino-4-(2,5-difluorophenyl)pyrrolidinyl-1-yl]-5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]-3-cyanopyridine-352- 201209054

In [(1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1, 23 mg, 0.10 mmol) and [(3Λ ,45)-1-[3-cyano-5-

(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]-4-(2,5-difluorophenyl Triethyl propyl pyrrrolidin-3-yl]carbamate (Preparation 176, 109 mg, 0.21 mmol), EtOAc (EtOAc m. Copper (II) acetate monohydrate (22 mg, 0.1 1 mmol). The flask was sealed and the reaction mixture was stirred at room temperature for 5 days. TFA (5 mL) was added directly to the reaction mixture and stirring was continued for 1 hour. The reaction mixture was poured directly into SCX(R) pre-activated (pre-activated with 1 M HCl followed by MeOH), eluted first with MeOH, followed by elution with 7.5% NH4OH/MeOH to collect basic fractions and Concentrate under vacuum. The residue obtained is purified by column chromatography (IH: E t OA c : M e Ο Η, 80: 20: 0-0: 100: 〇, then 〇: 95: 5), and the product-containing fraction is And concentrated under vacuum. Purification by preparative HP LC (basic method) gave the title compound: RT = 2.97 min; m/z (ES+) = 524.3 [M+H]+. Example 108: 5-[(3圮45&gt;3-Amino-4-(2,5-difluorophenyl)pyrrolidinyl]_2_丨1-(3-isopropyl-[1,2,4 Oxadiazole _5_yl) piperidin-4-ylmethoxy b 3-cyanopyridine

-353- 201209054 Add [(3i?,4*S)-4-(2,5-difluorophenyl)pyrrole in an oven-sealed tube equipped with a magnetic stirrer under argon Tributyl butyl-3-yl]carbamate (Preparation Example 48' 61.7 mg, 0.21 mmol), 5-bromo-2-[l-(3-isopropyl-[I,2,4] Zol-5-yl)piperidine-4-ylmethoxy]-cyanopyridine (Preparation 177, 70.0 mg '0.2 mmol), sodium butoxide (19.9 mg, 0.21 mmol) and biphenyl-2 - Base (di-t-butyl) o- (10.3 mg '0.03 mmol) followed by toluene (2 mL). The resulting solution was vigorously stirred and aerated with argon for 20 minutes. Next, bis(dibenzylideneacetone)palladium (7.89 mg, 0.01 mmol) was added, and the tube was completely sealed, followed by heating at 75 ° C for 19 hours. The reaction mixture was poured directly into SCX(R) pre-activated (pre-activated with 1 M HCl followed by MeOH), eluted first with MeOH, then eluted with 7.5% NH.sub.4OH/MeOH. Concentrated under. TFA (5 mL) was added to aq. The crude mixture was poured directly into SCX PCT, pre-activated (pre-activated with 1 M HCl followed by MeOH), eluted first with MeOH, then eluted with 7.5% NH.sub.4OH/MeOH. Concentrate under vacuum. Purification by preparative hydrazine P L C (basic method) gave the title compound: RT = 2.95 min; m/z (ES+) = 524.3 [M+H]+. Example 109: (4-{2-[(311,48)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidine·5-yloxy Methylpiperidin-1-yl)-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-methanone-354- 201209054

In [(37^45)-1-{5-[ 1-(3-isopropyl-[1,2,4]oxadiazol-5-carbonyl)-piperidin-4-ylmethoxypyrimidine -2_yl}_4_(2,4,5-trifluorophenyl)-pyrrolidine-3-yl]-carbamic acid tert-butyl ester (Preparation 179, 35 mg, 53.6 μιηοΐ) in DCM (2.0 mL The solution obtained by adding TFA (0.2 mL, 2 mmol) was added to the resulting solution and stirred at room temperature for 2 hours. The crude mixture was passed through a pad of EtOAc (EtOAc) elute elute elut elut elut elut elut elut elut elut elut elut elut 1^ = 2.75 minutes; /«/2(£3 + )= 546.23 [M+H]+. Example 110 ·· 1-(4-{2-[(32?,4*5)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]- Pyrimidin-5-yloxymethyl}-piperidin-1-yl)-3-methyl-but-1-

In [(3/?,4 5)-1-{5-[1-(3-methyl-butenyl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2 , 4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid terpene vinegar (preparation 93, 25 mg, 42.6 μιηοΐ) was added to a solution of DCM (2.0 mL). (0.2 mL, 2 mmol), the resulting solution was stirred at room temperature for 2 hr. The crude mixture was purified by EtOAc (EtOAc) eluting eluting elut elut elut elut elut elut /z (ES + ) = 492.26 [Af+H]+. Example 111: (3/^,45)-1-(5-((5)-1-11-(butane-1-sulfonyl)-piperidine-4-yl]-ethoxy bromide -2-yl)-4-(2,4,5-trifluorophenyl)-indole slightly steep-3-amine hydrochloride

In [(3 and,45)-1-(5-{(5)-1-[1-(butane-1-sulfonyl)-piperidin-4-yl]-ethoxy}-pyrimidine- T-butyl 2-(meth)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl-p-aminocarbamate (Preparation 186, 60 mg, 90 μιηοΐ) in DCM (2 mL To the resulting solution was added TFA (0.2 mL), and the obtained mixture was stirred at room temperature for 4 hr. The crude mixture was passed through a pad of EtOAc (EtOAc) eluting eluting eluting The product was dissolved in DCM (3 mL), and 4M EtOAc (yield: &lt;RTIgt;&lt;/RTI&gt; The resulting reaction mixture was stirred at room temperature for 5 hours, then the solvent was evaporated in vacuo to give the title compound: </ RTI> </ RTI> = 2.93 min; / /2 ( ug 3 + ) = 542.1 4 [Μ+Η]+. 112 : (3^,45)-1-(5-((5)-1-11-(2-methyl-propan-1-sulfonyl)-piperidine-4-yl]-ethoxy} -pyrimidin-2-yl)-4_(2,4,S-trifluorophenyl)-pyrrolidine-3-amine hydrochloride-356- 201209054

The title compound was obtained from [(3/?,45)-1-(5-{(*5)-1-[1-(2-methyl-propan-1-sulfonyl)) using the procedure described in Example 111. -piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl Preparation of the ester (Preparation 187): Ruler 1' = 2.92 min; 77^ (ug. 3 + ) = 542.1 3 [M+H]+. Example 113: (3i^, 41S)-l-(5-{(S)-l-[l-(propane-2-sulfonyl)-piperidin-4-yl]-ethoxy}-pyrimidine- 2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride

The title compound was subjected to the procedure described in Example 111 from [(37?,4&lt;s)-l-(5-((5)-1-(^1-(propyl)-2-mineral)-峨 steep -4-yl]-ethoxy}-, 卩疋-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl Preparation of the ester (Preparation 188): RT = 2 - 80 min; w/z (ES + ) = 528.12 [M+H] +. Example 114: 1-[(35,4·5)-4-amino-1- (5-{(5&gt;1-[1-(3-ethyl-[1,2,4]oxadiin-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine-2 -yl)-pyrrolidin-3-yl]-5-fluoro-1H-pyridin-2-one-357- 201209054

In 2-chloro-5-{(S)-l-[l-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation Example 102, 110 mg, 325 μιηοΐ) and 1-(trans)-4-amino-pyrrolidin-3-yl)-5-fluoro-1 fluorene-pyridine-2-one (Preparation Example 1 9 1 ' 32.0 mg, 0.162 mmol) DBU (32 μΐ^, 210 μπιοί) was added to a solution of DMSO (1 mL), and the resulting mixture was heated under microwave irradiation at 120 ° C for 65 minutes. The reaction mixture is partitioned between D C hydrazine and water and passed through a phase separator. The organic layer was concentrated under vacuum and the crude material was purified by preparative HPLC and applied to EtOAc. The hydrazine was eluted with methanol, followed by elution with 3.5 Μ NH3 / MeOH, and the basic fractions were collected and concentrated under vacuum to give 1-[(trans)-4-amino-1-(5- {(5)-1-[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl )-Pyrolidin-3-yl]-5-fluoro-1H-pyridin-2-one. Purification by palm chromatography (MTBE: MeOH: THF: n-butylamine; 50: 30: 20: 0.1, 12mL/min, 250 nm) afforded the title compound: 11 s = 2.45 min; = 499.19 [from +11]+. Example 115: 1-[(35,4Χ)-4-amino-1-(5-{(5·)-1-[1-(3-ethyl-[1,2,4]oxadiazole- 5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-1Η-pyridin-2-one

1_[(trans)-4-Amino- l-(5-{(S)-l-[l-(3-ethyl-[1,2,4] chew-358- 201209054 azole-5-yl) )-piperidin-4-yl]-ethoxypyrimidin-2-yl)-pyrrolidin-3-yl]-1H-pyridin-2-one was prepared from 丨_( using a procedure similar to that described in Example ι 14 (trans)-4-amino-pyrrolidin-3-yl)·ιη-pyridin-2-one (Preparation Example 192) and 2-chloro-5-{(5)-1-[1-(3- Ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation Example 1 0 2) was synthesized. Purification by palm chromatography (M e Ο Η : THF: n-butylamine; 80: 20: 0.1, 13 mL/min, 250 nm) to give the title compound. RT = 2.37 min; m/z (ES + ) = 481_19 [M+ H]+. Example 116: 14(35,45)-4-amino-1-(5-{(5&gt;1-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)) -piperidin-4-ylethyloxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-4-methyl-1H-pyridin-2-one

1·[(trans)-4-amino-1-(5-{(5)-1-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)- Piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-4-methyl-1H-pyridin-2-one is similar to that described in Example 114. The procedure consists of Ια trans)-4-amino-pyrrolidin-3-yl)-4-methyl-1H-pyridin-2-one (Preparation Example 193) and 2-chloro-5-{(S)-b [1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)piperidine-4-yl]ethoxy}pyrimidine (Preparation Example 1〇2) was synthesized. Purification by palm chromatography (MeOH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc (ES + ) = 495.25 [M+ H]+. Example 117: 1-1(35,45)-4-amino-1-(5-((5)-1-^-(3-ethyl--359- 201209054 #β I i-Rft 略【1 , 2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine_2-fan; pyridine-3-yl]-5-methyl-1H-pyridine-2 -ketone

1 p·适*·*^&quot;* 1-[(trans)-4-amino-l-(5-{(S)-l-[ 1-(3-ethyl-Π'2'4 ] / ^ certain 1 - 5 -oxazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidine-^-m-methyl-1H-pyridin-2-one Using a procedure similar to that described in Example 114 from 1 ((trans)-4-amino-pyrrolidin-3-yl)-5-methyl-1 H-pyridine-2-indole (Preparation 194) and 2-Chloro-5-{(S)-l-[l-(3-ethyl-[1,2,4]oxadiazol-5-yl)anthran-4-yl]ethoxy}pyrimidine Preparation Example 1 〇 2) was synthesized. Purification by palm chromatography (MeOH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 2.45 min; m/z (ES + ) = 495.24 [Λ/ + H]+. Example 118: 1-((3·5,4«ϊ)-4-amino-1-{5-[1-(3-isopropyl-[nq oxadiazole-S-yl)-piperidine _ 4_ylmethoxy]-pyrimidin-2-ylpyrrolidinyl_3_yl)_5_fluoro-1H-pyridin-2-indole

1-((trans)-4-amino-1-{5-[1-(3-isopropyl-[1,2,4]oxadiindole-5-yl)-piperidin-4-yl-methyl Oxy]-pyrimidin-2-yl}-pyrrolidinyl-3-yl)-5-fluoro-1H-pyridin-2-one was synthesized by a procedure similar to that described in Example 114; [_((trans)_4 - 360- 201209054 Amino-pyrrolidin-3-yl)-5-fluoro-1indole-pyridin-2-one (Preparation 195) and 2-chloro-5-[1-(3-isopropyl-[1 , 2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation Example 2) was synthesized. Purification by HPLC (MTBE: MeOH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc + )= 499.25 [M+ H]+.

Example 119: (3Λ,4·5)-4-(2,5-difluoro-phenyl)-1-(5-{(5&gt;1-[1-(3-isopropyl-[1,2] , 4]oxadiazol-5-yl)-piperidin-4yl]-ethoxypyrazin-2-yl)-thiazolidine-3-amine hydrochloride

2-bromo-5-((5)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrr Pyridine (Preparation Example 95, 150 mg, 380 μηηοΐ), [(3Λ,4*5)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (preparation) Example 48' 140 mg, 460 μπιοί), sodium butoxide (110 mg, 1.1 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphonium Bicyclo [3.3.3] Eleven (13 mg, 38 μπιοί) was mixed in toluene (2 mL) in a sealed tube and degassed with argon for 10 minutes. Add tris(dibenzylideneacetone)dipalladium (0) Chloroform adduct (20 mg, 19 μπιοί), and the reaction mixture was degassed by helium for 5 minutes, followed by 120° (: microwave irradiation for 1 hour. The reaction mixture was cooled to room temperature and placed on SCX®. It was then eluted with MeOH, EtOAc (EtOAc) (EtOAc (EtOAc) 361 - 201209054 Stir at room temperature for 30 minutes. The reaction mixture was placed on SCX crucible, followed by elution with MeOH, followed by elution with NH3/Me〇H (7M), basic fraction Concentration under vacuum. Purification by preparative HP LC (basic method) afforded (3^4^)-4-(2,5-difluoro-phenyl)-1-(5-((5)-1 ^1-(3-Isopropyl-[1,2,4]oxadiazole·5-yl)-indole-4-yl]-ethoxy}-disc-2-yl)-卩bill D--3-amine, dissolved in DCM (1 mL), EtOAc (EtOAc (EtOAc) ) =5 1 4· 1 [M+H]+. Example 120: (3^,45)-4-(2,5-difluoro-phenyl)-1-(6-{(5)-1- [1-(3-Isopropyl-[1,2,4]oxadiazole_5-yl)-piperidin-4-yl]-ethoxydoxazin-3-yl)-pyrrolidine-3 -amine hydrochloride

3-Chloro-6-((5)-1-11-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy} -pyridazine (Preparation Example 197, 115 mg, 327 μιηο1), [(3Λ,4·5)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester ( Preparation 48, 117 mg, 392 μιηοΐ) and 1,8-diazabicyclo [5.4.0]-f--carbon-7-ene (59_7 mg, 392 μπιοί) in DMSO (654 μΙ〇 in a sealed tube) Heating at 80 ° C for 72 hours, followed by heating at 100 ° C for 24 hours. After cooling, the reaction mixture was poured into DCM (200 mL), washed with brine (200 mL) and concentrated in vacuo The residue was redissolved in EtOAc (EtOAc) (EtOAc)EtOAc. 201209054 NH3/MeOH (7M) was eluted. The basic fraction was concentrated in vacuo and the residue was taken up in MeOH EtOAc EtOAc EtOAc EtOAc EtOAc The basic fraction was concentrated under vacuum and purified by column chromatography (DCM: MeOH; 96: 4) to afford (3i?,4&gt;S)-4-(2,5-difluoro-phenyl) -1-(6-( (5)-1-11-(3-Isopropyl-[1,2,4]oxadiindole-5-yl)-azetro-4-yl]-ethoxy}-pyridazine-3- And the product was dissolved in 1,4-dioxane (4M, 0.3 mL) EtOAc. = 2.55 min ; m/z (ES + ) = 5 1 4.2 [M+H]+. Example 121: (3/f, 45)-4-(2,5-difluoro-phenyl)-1-{ 5-[1-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-4-methoxy-pyrimidin-2-yl Bupiryridine-3_amine hydrochloride

In ((37?,4&lt;5)-4-(2,5-difluoro-phenyl)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazole -5-yl)-piperidin-4-ylmethoxy]-4-methoxy-pyrimidin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (Preparation Example 200, 68.7 mg, 109 μηιοί) was added to a solution of DCM (5 mL), and the mixture was stirred at room temperature for 30 min. Additional TFA (1 mL) was added and the mixture was stirred at room temperature for one hour. The reaction mixture was taken on a pad of EtOAc (EtOAc) eluting eluting The basic fraction was concentrated under vacuum and purified by column chromatography (DCM: MeOH; 195: 5) to afford (3/?,45)-4-(2,5-difluoro-phenyl)-1 -{5-[1- -363- 201209054 (3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine-4-ylmethoxy]-4-methoxy -pyrimidin-2-yl}-pyrrolidin-3-amine. The product was redissolved in DCM (2 mL). EtOAc (EtOAc) The solvent was removed in vacuo to give the title compound: RT: 2.67 min; m/z (ES+) = 530.3 [M+H]+. Example 122: (3Λ,45&gt; 4-(2,5-difluoro-phenyl)-1-(5-((5)-1-11-(3-isopropyl-丨1,2,4) Oxadiazole-5-yl)-piperidin-4-yl]-ethoxypyridin-2-yl)-pyrrolidine-3-amine hydrochloride

Toluene (2 mL) was added to 2-bromo-5-{(S)-l-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-4 -yl]ethoxy}pyridine (Preparation Example 94, 1 50 mg, 3 80 μηιοί), [(3/?,4&lt;S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl Tert-butyl carbazate (Preparation 48' 150 mg, 0.49 mmol), sodium butoxide (110 mg, 1.1 mmol) and 2,8,9-triisobutyl-2,5,8, In 9-tetraaza-phosphabicyclo[3.3.3]undecane (14 mg, 0.041 mmol), the obtained reaction mixture was degassed with argon for a minute. Add tris(dibenzylideneacetone)dipalladium (ruthenium) chloroform adduct (2 〇mg '19 μιηοΐ) 'The reaction mixture was degassed by argon for 5 minutes, then heated under microwave irradiation at 1 2 〇 ° C. hour. After cooling, the 'reaction mixture was placed on a SCX crucible' and first eluted with MeOH followed by elution with NH3/Me〇H (7M). The basic fraction was concentrated under vacuum to redissolve in DCM (1OmL) and then taken to TFA (2mL). The resulting reaction mixture was stirred at room temperature for 30 min &lt;&lt;&gt;&gt;&lt;&apos;&gt;&gt; The basic fraction is concentrated under vacuum, and the residue is purified by preparative HPLC (basic method) to give (3,,,,,,,,,,,,,,,,,,,,,,,,, -{(*5)-1-[1-(3-isopropyl-[1,2,4]glycin-5-yl)-piperidin-4-yl]-ethoxy}-decan -2 -yl)-pyridyl 3-amine. The product was dissolved in d C Μ, and a solution of 1,4-dioxane (4 Torr) added to HCl. The solvent was removed under vacuum to give the title compound: RT = 2.54 min; w/2· (ES + ) = 513.29 [Μ+Η]+. Example 123: 4-((5)-1-(2-丨(3&lt;5,4&lt;5)-3-Amino-4-(2-keto-piperidine-i_)

Base) pyrrolidin-1-yl I-pyrimidine-5-yloxybuethyl)-piperidine-1-carboxylic acid isopropyl

4-((5)-1-{2-[(3 51,4&lt;5)-3-Tertidinoxycarbonylamino-4-(2-keto-piperidin-1-yl)-pyrrole Isopropyl-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-p-formate isopropyl ester (Preparation 202, 57 mg '99 μπιοί) in DCM (1 I ) rnL) A solution of HCl in 1,4-dioxane (4 Torr, 0.1 mL) was added to the solution, and the obtained mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum to give the title compound: RT = 2.62 min; m/z (ES + ) = 47 5.2 [M+H]+. Example 124: 2-{5-[4-((5·)-1-{2-[(3Λ,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidine -l-yl]-pyrimidin-5-yloxy}-ethyl)-piperazin-1-yl]-[1,2,4]oxadiazol-3-yl}-ethanol hydrochloride-365- 201209054

In [(3 and, 4 5')-1-{5-[(5&gt;)-1-(1-cyano-indole|1-1-4-yl)-ethoxy]-mute steep_2_ __(2,5-Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid terpene vinegar (Preparation 2 05, 150 mg '0.28 mmol) and 3,N-dihydroxy - A solution of zinc dichloride (Et2) solution (1M, 〇.34 mL '〇.34 mmo1) was added to a solution of propylene (35 mg, 0.34 mmol) in EtOH (15 mL) at room temperature. Stir under 3 hours. The I4-digestilate solution of HC1 (4M, 0.35 mL, 1.4 mmol) was added and the reaction mixture was heated by microwave irradiation at 110 °C for 3 Torr. The reaction mixture was taken on a pad of EtOAc (EtOAc) eluted with EtOAc (EtOAc) The product was taken on a pad of <RTI ID=0.0></RTI> <RTI ID=0.0> The basic fraction was concentrated under vacuum, redissolved in DCM (1 mL), and HCI1 s. The resulting reaction mixture was stirred at rt for EtOAc (3 mL), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidine l-yl]- Pyrimidin-5-yloxy}-ethyl)-piperidine-l-yl I-[l,2,41 oxadiazole-3-yl}-ethanol hydrochloride

-366-201209054 The title compound was obtained from [(3^,45)-1-(1-(1)-(5)-1-(1-cyano-piperidin-4-yl). )-Ethoxy]-pyrimidine-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-aminocarboxylic acid tert-butyl ester (Preparation Example 205, 150 mg '0.28 mmol) and 2,N-dihydroxy-propanthene (35 mg, 0.34 mmol) were synthesized: RT = 2.48 min; m/z (ES + ) = 516.5 [M+H]+.

Example 126: 1-(5-(4-((5)-1-(2-((3/2,45)-3-amino-4-(2,4,5-trifluorophenyl)-) Pyrrolidin-1-yl]-pyrimidine-S-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-yl}-ethanol

In [(3/?,4 to -1-(54(5)-1-(1-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-(2) , 4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl vinegar (Preparation 206' 50 mg' 0.09 mmol) and 2,N-dipyridyl-propionate (11 Mg, 0.11 mmol) A solution of the molecule (1 g) and zinc dichloride in Et20 (0.1 1 mL, 0.11 mmol) was added to a solution of EtOH. The obtained mixture was stirred at room temperature for 2 hours. I,4-two-noise solution (4M, 0.11 mL '0.46 mmol), and the reaction mixture was heated at 11 Torr for 30 minutes. The reaction mixture was placed on SCX(R), first eluted with MeOH, followed by It was eluted with NH3/MeOH (3.5M, 2.4 mL), then the basic fraction was concentrated in vacuo and purified by preparative HPLC. The product was placed on _SCX(s), eluted with MeOH, followed by NH3/ MeOH (3.5 M, 2 4 mL) eluted EtOAc (EtOAc:EtOAc) ]+. Example 127: 2-(5-14-((5)-1-(2-1(3^,45)-3-Amino-4-(2,4,5-trifluorophenyl)) -pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl - piperidin - L-yl] - [1,2,4] oxadiazol-3-ethanol hydrochloride Ji Bu

The title compound was obtained from [(37?,4 5)-1-{5-[(5)-1-(1-cyano-piperidin-4-yl)-ethoxylate using a procedure similar to that described in Example 124. Tert-butyl pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid (Preparation 206, 150 mg, 0.28 mmol And 3,N-dihydroxy-propanthene (34 mg, 0.33 mmol): RT = 2.52 min; m/z (ES + ) = 534.1 4 [M+H]+. Example 128: (^-1-(5-(4-((5)-1-(2-1(3^,45)-3-amino-4-(2,4,5-trifluorophenyl) )-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiin-3-yl}-ethanol hydrochloride salt

(^4-(544-((5)-1-(24(3^45)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidinyl)-pyrimidine -5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-yl}-ethanol is derived from 1-(5-4-((5) 1-(2-((3/^,45)-3-amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy }}- -368- 201209054 Ethyl)-piperidin-1-yl]-indole, 2,4]oxadiazol-3-yl}-ethanol (Example 126, 145 mg, 0.272 mmol) via palmitic HPLC ( MTBE: MeOH: THF: BA; 60: 20: 20: 0.1, 12 mL/min, 250 nm) and isolated. The product (66.8 mg, 0.125 mmol) was dissolved in DCM (0.5 mL). (2M '80 μί, 0.160 mmol), EtOAc (mjqqqqqq ]+ (LCMS side

Example 129: (5)-1_{5-[4-((8)-1-{2-[(3Λ,45·)-3-amino-4-(2,4,5-trifluorophenyl) )-pyrrolidin-1-yl]pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-yl}-ethanol hydrochloride salt

The title compound was obtained from 1-{5-[4-((*5)- 1-{2-[(3Λ,4·?)-3-amino-4-(2,4) using the procedure described in Example 128. ,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazole-3 -Base}-Ethanol (Example 126, 145 mg, 0.272 mmol): mp.: EtOAc: EtOAc: EtOAc: Example 130: 4-((5)-l-{2-[(3i?,4S)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidine-bu] -pyrimidine-5-yloxyethyl)piperidine-1-sulfonic acid isopropyl-methyl-decylamine hydrochloride-369- 201209054

T-butyl ester of piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]-carbamic acid (Preparation 185 '75 mg, 〇· 14 mmol). To a solution of DCE (5 mL) was added triethylamine (40 pL, 0.29 mmol) and methyl (propan-2-yl)aminosulfonyl chloride (30 mg '0.17 mmol), the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and EtOAc (EtOAc). The product was dissolved in EtOAc (2 mL)EtOAcEtOAcEtOAcEtOAc The solvent was removed in vacuo to give the title compound: RT: 2.87 min; Example 13 1 : (3^,45)-4-(2-Fluoro-5-methoxy-phenyl)-l-{5-丨1-(3-isopropyl-[1,2,4] Oxadiazole-5-yl)-piperidin-4-ylmethoxypyrimidin-2-yl}-pyrrolidin-3-amine

In (trans)-4-(2-fluoro-5-methoxy-phenyl)-pyrrolidin-3-amine (Preparation Example 2〇9, 43 111§, 2〇〇01^〇1) and 2 -Chloro-5-[1-(3-isopropyl-[1,2,4]oxadiazin-5-yl)piperazin-4-ylmethoxy]pyrimidine (Preparation Example 2, 69 mg, 200 Μιηοΐ) DIPEA (53 μί, -370-201209054 3 10 μηιοί) was added to a solution of MeCN (2 mL), and the resulting reaction mixture was heated under microwave irradiation at 170 ° C for 30 minutes. The solvent was removed under vacuum and the residue was purified (EtOAc). Purification by palm chromatography (IH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: Speak / 2 kg 3 + ) = 512.5 [from +^1]+.

Example 132: (351,4 Magic-4-(2-Fluoro-5-methoxy-phenyl)-1-{5-[1-(3-isopropyl-[1,2,4] oxa 2 Zyrid-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-amine

0 in (trans)-4-(2-fluoro-5-methoxy-phenyl)-pyrrolidin-3-amine (Preparation 209, 43 mg, 200 μιηο 1) and 2-chloro-5 - [ 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2, 69 mg, 200 μπιοί) in MeCN (2 Add DIPEA (53 pL, to the solution formed)

3 10 μιηοΐ), the resulting reaction mixture was heated by microwave irradiation at 170 ° C for 30 minutes. The solvent was removed under vacuum and the residue was purified (EtOAc). Purification by palm chromatography (IH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: ;w/z (ES + ) = 512.24 [M+H]+. Example 133: (35,45)-1-(5-((5)-1-(1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-piperidine-4 - kib ethoxypyrimidin-2-yl)-4-(4-ethyl-pyrazole-l-yl)-pyrrolidin-3-amine-371 - 201209054 2-chloro-5-{(15)- 1-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation Example 102, 130 mg, 380 μιηοΐ), (anti _ 4-(4-Ethyl-pyrazol-1-yl)-pyrrolidin-3-amine (Preparation 214, 34 mg, 190 μπιοί) and DBU (37 μΐ^, 240 μιηοΐ) in DMSO (1) The resulting solution was heated by microwave irradiation at 120 ° C for 65 minutes. The reaction mixture was diluted with D CM and H20, and the organic layer was separated and concentrated in vacuo. The residue was purified by preparative HPLC and then placed on SC. Top, eluted with MeOH, followed by elution with NH3 / MeOH. The basic fraction was concentrated in vacuo and purified by chromatography (MeCN: THF: BA; 70:30:0.1, 15 mL/min, 250 nm , RT = 12.8 minutes). The crude product is placed on the SCX匣 to

The MeOH was eluted and then eluted with NH3/MeOH. The basic fraction was concentrated in vacuo to give the title compound: RT: 2.65 min; m/z (ES+) = 482.22 [M+H]+. Example 134: 2-(5-14-((5)-1-(2-1(31^,45)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidine -1-ylpyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-ylpropan-2-ol tosylate

In [(3 and, 4 5)-1-[5-((*5)-1-{1-[3-(1-hydroxy-1-methyl-ethyl)_[1,2,4] Oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4- -372- 201209054 (2,4,5-trifluorophenyl)-pyrrolidine -3_yl]-tert-butyl carbamic acid tributyl methacrylate (Preparation 217, 0.178 g, 0.275 mmol) was added to a solution of DCM (4 mL), and the mixture was stirred at room temperature. 90 minutes. The solvent was removed in vacuo and EtOAcqqqqqqqq The aqueous layer was separated and extracted with DCM (15 mL). The combined organic layers were concentrated with EtOAc (EtOAc)EtOAc. The solvent was removed in vacuo to give title compound: EtOAc: EtOAc: Example 135: (3/?,45)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-azetidine- 3-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine

In [(37?,4&lt;5)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-azetidine- 3-butylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 219 TFA (0.2 mL) was added to a solution of DCM (1 mL), and the obtained mixture was stirred at room temperature for 1 hour. The reaction mixture was applied to a pad of EtOAc (EtOAc). The basic fraction was concentrated in vacuo to give the title compound: RT = 2 · 15 min; m/z (ES + ) = 504.17 [M+H]+. -373-201209054 Example 136: (31S,41S)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl Methoxy]-pyrimidin-2-yl}-4-(4-methyl-pyrazol-1-yl)_II-pyridin-3-amine

2-Chloro-5-[l-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation Example 53, 0.11 g' 0.32 Ment), (trans)-4-(4-methyl-pyrazol-1-yl)-pyrrolidin-3-amine (Preparation 221, 35 mg '〇·21 mmol) and DBU (40 μ!^) The solution of 0.268 mmol) in DMSO (1.5 mL) was heated under microwave irradiation at 120 °C for 60 minutes. After cooling, the reaction mixture was placed on a pad of phosphonic acid SCX, eluted with MeOH then eluted with EtOAc (EtOAc) EtOAc (EtOAc) The basic fraction was concentrated in vacuo and purified with EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: ;w/z (ES+) = 468.40 [M+ Η ] +. Example 137: 4-((5)-1-(24(3^,45)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidine -5-yloxy}-ethyl)-piperidine-1-sulfonic acid ethyl-methyl-decylamine hydrochloride

The title compound was chewed from 201209054 [(3i?,4iS)-l-[5-((&lt;S)-l-indole-4-yl-ethoxy)-- using the procedure similar to that described in Example 30 D-butyl-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-tert-butyl methacrylate (Preparation 185, 75 mg, 0.14 mmol) Ethyl (methyl)aminosulfonyl chloride (0.027 g, 〇·17 mmol) was synthesized: RT = 2.80 min; w/z (ES + ) = 543.1 2 [Af+H]+. Example 138: (3Λ,45)-4-(2,5-Difluoro-phenyl)-1-15-((5-1-11-13-((^)-1-methoxy-ethyl) )-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-amine hydrochloride

In [(3 145)-1-(5 4(5)-1-U-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-(2,5- Tert-butyl difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid (Preparation Example 205' 120 mg '0.230 mmol) and (5)-indole-hydroxy-2-methoxypropanthene ( Preparation 148, 33 mg '0.27 ramol) was added to a solution of EtOH (6 C,) mL) in a solution of zinc dichloride in Et20 (1M, 0.27 m, 0.27 mm ο 1). Stir at room temperature for 3 hours. A 1,4-dioxin solution of HCl (4M, 0.28 mL, 1.1 mmol) was added, and the reaction mixture was heated at 100 ° C for 30 minutes under microwave irradiation. The reaction mixture was taken up in EtOAc (EtOAc) (EtOAc) The residue was purified by preparative EtOAc EtOAc EtOAc (EtOAc) The residue was dissolved in DCM (3 mL), then -375 - 201209054 was added to H C1 of 1,4 - 2 chewable solution (4 Μ, 0 · 14 m L) and the resulting mixture was stirred at room temperature for 3 〇. minute. The solvent was removed under vacuum to give the title compound: RT = 2.72 min; m/z (ES + ) = 5 3 0.26 [M+H]+. The following examples were constructed using the appropriate (1-cyano-piperidin-4-yl-ethoxy)-pyrimidin-2-yl building block with the appropriate amidoxime using a procedure analogous to that described in Example 138. Manufactured by reaction: Example leg name LCMS 139 * NHj · ΠΙΙ (3/?, 45) -4-(2,5-difluoro-phenyl)- 1- (5-{(S)-l-[l- (3-Isopropoxymethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine-2-yl)-pyrrolidine-3 -amine hydrochloride RT = 2.79 min; mlz (ES4^ = 544.28 [M+H]+ ο 140 (3Λ,45)-4-(2,5-difluoro-phenyl)-1-[5-( (3)-1-{1·[(5)-3-(Tetrahydrofuran-2-yl)-[1,2,4]oxadiazol-5-yl]-a-D-1,4-yl}-ethoxy )-pyrimidin-2-yl]-lahydropyridin-3-amine hydrochloride RT = 2·70 min; mlz (ES+) = 542.27 [M+H]+ ο 141 (3 feet 45 &gt; 1-(5- {〇S&gt;l-[ 1-(3-cyclopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl )-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2.84 min; mlz (ES+) = 530.22 [M+H]+ o 142 ΝΗΖ .HCI (3 /?,45)-l-(5-{CS&gt;l-[l-(3-difluoromethyl-[1,2,4]oxadiazol-5-yl)-piperidine·4·yl] -ethoxy}-pyrimidin-2-yl)-4-(2 ,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2_80 min; mlz (ES+) = 540.19 [M+nf o -376- 201209054

143 (3i?,45)-1-[5-((5)-l-{l-[3-(1-methyl-cyclopropyl)-[l,2,4]oxadiazole-5- ]]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2.98 Minutes; m/z (ES+)= 544.22 [M+H]+ ο 144 1 \=N .HCI (3/?,45)-l-[5-(〇S)-l-{l-[3- (1-fluoro-1-methyl-ethyl)-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]Μα4 , 5-trifluorophenyl)-lahydropyridin-3-amine hydrochloride RT = 2.90 min; mlz (ES+) = 550.18 [M+H]+ o 145 V^NH2 .HCI (3 feet 45 &gt;(5-{(5&gt;1-[1-(3-ethoxymethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}- Pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride RT = 2.79 min; w/z (ES+) = 548.22 [M+H]+ o 146 vIKKac?1: FF \=N^ ^NH2.HC (3/?,45)-1-[5-((5)-1-{1-[3-(1,1-difluoro-B) Base]-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro Phenyl)-pyrrolidin-3-amine hydrochloride RT = 2.88 min; m/z (ES+) = 554.15 [M+H]+ o 147 (3Λ,45)-1 -(5- {(5&gt; 1 -[ 1 -(3 -propyl-[1,2,4]oxadiazol-5-yl)-piperidine-4- ]-Ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride RT = 2.80 min; m/z (ES+) = 532.14 [M+H]+ o 148 (3Λ,45)-1-[5-((5)-1-{1-[3-(〇S&gt;l-methoxy-ethyl)-[1, 2,4] Oxadiazole-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine -3-amine hydrochloride RT = 2.68 min; m/z (ES+) = 548.15 [M+H]+ o -377- 201209054 149 Ηα (3 feet 4S)-l-[5-(〇S)-l -{l-[(i?)-3-(tetrahydrofuran-2-yl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidine _2-yl]-4_(2,4&gt;trifluorophenyl)-pyrrolidin-3-amine hydrochloride RT = 2·75 min; mlz (ES+)-560.15 [M+H]+ ο 150 (3 Foot 45)-1-(5-{(5)-1-[1-(3-isopropoxymethyl-[1,2,4]oxadiin-5-yl)-piperidine-4- ]]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)irondophene-3-amine hydrochloride RT = 2.80 min; mlz (ES+) = 562.15 [M+H]+ o 151 1 ^Nh2.HCI (3 feet 45)-1-[5-((5)-1-{1-[3_((Λ)-1-methoxy-ethyl) -[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl )-pyrrolidin-3-amine hydrochloride RT = 2.77 Clock; mlz (ES+) = 548.14 [M+H]+ o 152 (3i?,45)-1-[5-((5)-1-{1-[(5)-3-(tetrahydrofuran-2- Base]-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro Phenyl)-pyrrolidin-3-amine hydrochloride RT = 2.70 min; mlz (ES+) = 560.17 [M+Hf o 153 .HCI (3 feet 4 has-1-(5-{(5)-1- [1-(3-Methoxymethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4- (2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2.72 min; mlz (ES+) = 534.14 [M+Hf o 154 ^Nh2 .HCI (3/?, 4S) -l-[5-((5)-l-{l-[3-(2-methoxy-ethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-4 -yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2.65 min; mlz (ES+)= 548.15 [M+H]+ o -378- 201209054 155 .HCI (3i?,4S)-l-(5-{(5)-l-[l-(3-methyl-[1,2,4] Oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine Hydrochloride RT = 2.63 min; m/z (ES+) = 504.10 [M+H]+ 0 156 ^JXIK{VC^F Un ^^NH2 .HCI (3旯4习-4-(2,5-two Fluoro-phenyl)-1-(5-{(5)-1-[1-(3- -[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidine-3-amine hydrochloride RT = 2_82 Minutes; m/z (ES+) = 514.54 [Af+H]+ 0 157 (3i?,4S)-l-(5-{〇S)-Hl-(3-cyclopropyl-[1,2,4 Oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolididine-3 -amine hydrochloride RT = 2.83 min; m/z (ES+) = 512.58 [MfH]+ o 158 νϊΚκ^να^ F \=N \^νΝΗ:Ηα (3/?,4S&gt; 1-(5-( (5)-1-[1-(3-Difluoromethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine-2- 4-(2,5-Difluoro-phenyl)-pyrrolidine-3-amine hydrochloride RT = 2.85 min m/z (ES^ = 522.50 [M+H] + o 159 v ^NHj HC| (3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-(〇S)-l-{l-[3-(l-methyl-cyclopropyl)- [1,2,4]oxadiazol-5-yl]-indolyl-4-yl}-ethoxy)-chewing steep 2·yl]-pyrrolidine-3-amine hydrochloride RT = 2.92 min ;m/z (ES+)~ 526.25 [M+ H]+ o 160 νΚΚ{Νν&lt;χ°&quot; N NH2 ,HCI (3/?,45)-4-(2,5-difluoro-phenyl)- L-[5-(〇S)-l-{l-[3-(l-fluoro-1-methyl-ethyl)-[1,2,4]oxadiazol-5-yl]-acridine _4-yl}_ethoxy)-pyrimidine _2·yl]-lahydropyridin-3-amine hydrochloride RT = 2.84 min; m/z (ES+) = 532.23 [M+H]+ o -379- 201209054 161 ^ ^ΝΗ,-ΗΟί (3 feet 45) 4-(2,5-difluoro-phenyl)-l-(5-{〇S&gt;1-[l-(3-ethoxymethyl-[1,2,4]oxadiazole-5 -yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-lahydro-t--3-amine hydrochloride RT = 2.67 min; m/z (ES+) = 530.24 [M+ H]+ ο 162 (3Λ,45)-1-[5-((5)-1-{1-[3-(1,1-difluoro-ethyl)-[1,2,4] Zyrid-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-lado-throm-3-amine Acid salt RT = 2.82 min; mlz (ES+) = 536.21 [M+H]+ o 163 (3i?,4S)-1-(5-{(5)-1-[1-(3-trifluoromethyl) -[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrido-2-yl)-4-(2,4,5-trifluorobenzene ))-pyrrolidine-3-amine hydrochloride RT = 3.05 min; m/z (ES+) = 558.11 [M+H]+ o 164 sVKKrK?1: DD, N^SlHrHCI (3Λ,45)-1- (5-{(5)-1-[1-(3-(2Η5)ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride RT 2·72 min; m/z (ES+) = 523.20 [M+ H ]+ o 165 ddUK H{VnC^: \=N ^^ΝΗ,.ΗΟΙ(3i?,4S)-l-(5-{〇S)-l-[l-(3-(2,2,2-2H3)ethyl -[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl )-pyrrolidin-3-amine hydrochloride RT = 2.72 min im/z (ES+) = 521.18 [M+Hf o 166 VKK P &lt; £: (3 feet 45)-1-(5-{(5) 1-[1-(3-(2H5)ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl) -4-(2,5-Difluoro-phenyl)-pyrrolidin-3-amine hydrochloride RT = 2.67 min; m/z (ES+) = 505.13 [M+H\+ 0 -380- 201209054 167

NH, -HCI (3 feet 45)-l-(5-{〇S)-l-[l-(3- (2,2,2-23⁄4)ethyl-[1,2,4] oxadi-RT = 2.65 min oxazol-5-yl)-piperidine-4-yl]-ethoxy; w/z (ES+)= yl}-pyrimidin-2-yl)-4-(2,5-di 503.22 [M+ H ]+Fluoro-phenyl)-pyrrolidine-3-amine hydrochloride. Example 168: (3^,45)-4-(2,5-Difluoro-phenyl)-1-15-((5)-1-(1-((5)-3-(tetrahydro!! -3-3-yl)-[1,2,4] chew a 哩-5-yl]-峨 steep-4-yl}-ethoxy

-pyrimidin-2-yl]-pyrrolidin-3-amine

In [(3Λ,41S)-l-{5-[(1y)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-(2) , 3 -difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 205, 240 mg, 0.45 mmol) and N-pyridyl-tetrahydrofuran-3 -formamidine (preparation) Example 168, 71 mg, 0.54 mmol) in EtOH (12

To the resulting solution was added a solution of zinc dichloride in Et20 (1M &lt;RTI ID=0.0&gt;&gt; A solution of HC1 in 1,4-dioxane (4M, 0.57 mL, 2.3 mmol) was added, and the obtained mixture was obtained at 1 〇. Heated under microwave irradiation for 30 minutes. After cooling, the reaction mixture was applied to EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) And purified by preparative HPLC. The purified product was added to SCX(R), eluted with MeOH (3×5 mL), eluted with NH3/MeOH (3.5M, 2 x 5 mL), and concentrated in vacuo. ,4S)-4-(2,5-difluoro-phenyl)-l-[5-((S)-l-n_[3-(tetrahydrofuran-3-yl)-[1,2,4] -381 - 201209054 Diterpenoid-5-yl]-hydrazin-4-yl}-ethoxy)-pyridin-2-yl]-pyrrole steep-3-amine. The product was purified by palm chromatography (MeOH: IH: THF: ΒΑ; 50: 25: 25: 0.1, 15 mL/min, 250 nm), then dissolved in DCM (3 mL). Alkane solution (4 Μ '3 mL). The resulting reaction mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated in vacuo. The residue was purified by preparative EtOAc EtOAc (EtOAc) The basic fraction was concentrated in vacuo to give the title compound: RT: 2.60 min; m/z (ES+) = 542.31 [Af+H]+. Example 169: (3Λ,45)-4-(2,5-Difluoro-phenyl)-1-[5-((*5)-1'{1-[(/?)-3-(four gas Furan-3-yl)-[1,2,4] succinyl _5-yl]-oxime _4_yl ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-amine

The title compound was obtained from [(3,4 51) - 1 -{5-[(5)-1-(1-cyano-piperidin-4-yl)-ethoxy) using the procedure described in Example 168. ]-pyrimidin-2-yl}_4_(2,5·

- tert-butyl carbamic acid ester (Preparation 205 '240 mg, 0.45 mmol) and hydrazine-hydroxy-tetrahydrofuran_3_ formazan (preparation 168, 71 mg, 0.54 mmol): RT = 2.60 min; /z (ES + ) = 542.32 [M+ H]+. Example 170: (3Λ,4·ϊ)-4-(2,5-Difluoro-phenylphanyl-3-(tetrahydrofuran-2-yl)-[1,2,4]oxadiazol-5-yl] - piperidine_4·kibethoxy)-pyrimidin-2-yl]-pyrrolidin-3-amine-382- 201209054

In [(3/2,45)-1-(5-1(5)-1-(cyanopiperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-( 3,5-Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 205, 150 mg, 0.28 mmol) and (i〇-N-hydroxy-tetrahydrofuran) Molecular sieves (1 g) were added to a solution of formazan (44 mg, 0.34 mmol) in EtOH (12 mL), followed by a solution of zinc dichloride in Et 2 (1, 0.34 mL, 0.34 mmol). The resulting reaction mixture was scrambled for 2 hours at room temperature. A solution of HCl in 1,4-dioxane (4M, 0.35 mL, 1.4 mmol) was added, and the mixture was heated under microwave irradiation at 110 ° C for 30 minutes. Add to SCX(R), elute with MeOH (4.times.5 mL), then elute with NH3 / MeOH (3.5M, 2 X 5 mL), and the basic fractions are concentrated in vacuo and purified by preparative HPLC. The purified product was taken up in EtOAc (3×5 mL) eluted with EtOAc (EtOAc (EtOAc) Compound: r τ = 2_62 min; w/z (ES + ) = 542.1 7 [M + H] + </RTI> Example 171: (3jR,45)-4-(2,5-difluoro-phenyl)ethyl-[ I, 2, 4] evil two Zyrid-3-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-amine hydrochloride

In [(3 and, 41^)-4-(2,5-difluoro-phenyl)-1-(5-{(5)-1-[1-(1^-hydroxy-383- 201209054 formazan) Tert-butyl 3-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid (Preparation Example 226' 102 mg, 0.181 mmol) HOBt (55.5 mg, 0.362 mmol) and EDCI (69.4 mg '0.362 mmol) were added to a solution of propionic acid (24.2 mg, 0·326 mmol) in DMF (4 mL). The mixture was stirred at 80 ° C for 3 hours and at room temperature for 72 hours. The reaction mixture was partitioned between EtOAc EtOAc m. The product was dissolved in EtOAc (2 mL). The reaction mixture was added to a phosphonic acid SCX oxime, eluted with MeOH (4 X 4 mL), eluted with NH3 / MeOH (3.5M, 3 X 3 mL), and the basic fraction was concentrated under vacuum. The residue was dissolved in DCM, EtOAc (EtOAc m. The solvent was removed in vacuo and aq. EtOAc (EtOAc): Example 172: (3/J,4S)-l-(5-{(Friend)-1-[1-(5-ethyl-[1,2,4]oxadiazol-3-yl)-piperidine 4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride

The title compound was obtained from [(3145)-1-(5-((5)-:141-(1^hydroxymethylmethyl)-piperidin-4-yl]-ethoxyl. }}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-aminomethyl-384-201209054 acid tert-butyl ester (Preparation Example 227, 105 mg, 0.181 mmol): RT = 2.84 min; /m/z (ES + ) = 518.13 [Μ+ Η]+ = Example 173: (3^,45)-4-(2,5- Difluoro-phenyl)-1-(5-{(·?)-1-[1-(4-methyl-thiazol-2-yl)-piperidin-4-yl]-ethoxy}-pyrimidine -2-yl)-pyrrolidin-3-amine

In [(3 and 4, 4-(2,5-difluoro-phenyl)-l-(5-{(1S)-l-[l-(4-methyl-thiazol-2-yl)) -piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 228, 8πlg '10 μm Ol) in DCM (2 mL To the resulting solution was added TFA (0.1 mL, 1 mmol). The obtained mixture was stirred at room temperature for 3 hours. The reaction mixture was applied to SCX®, eluted with MeOH (2 X 4 mL), followed by NH3 /MeOH (2 X 4 mL)

The extract was eluted with EtOAc (EtOAc: m. Example 174: (3 and, 4*5)-4-(2,5-difluoro-phenyl)-1-(5-{(illus-1-[1-(3-ethyl-[1,2) ,4]thiadiazole-5-yl)-piperidine-4-yl]-ethoxypyrimidin-2-yl)·puppyridin-3-amine hydrochloride

{(3/?,4&gt;5)-4-(2,5-difluoro-phenyl)-bu [5-((&gt;5)-1-piperidin-4-yl-ethyl-385- 201209054 Oxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation Example 204, 75 mg, 0.15 mmol) and 5-di-3-ethyl-1,2 A solution of 4 -thiazepine (170 mg, 0.89 mmol) was heated under microwave irradiation at 140 °C for 30 minutes. Purification by preparative HPLC gave [(3i^,4&lt;S)-4-(2,5-difluoro-phenyl)-l-(5-{(S)-l-[l-(3-B) -[l,2,4]thiadiazole·5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid Tributyl ester. This intermediate was dissolved in DCM (2 mL). The reaction mixture was taken up in EtOAc (EtOAc) (EtOAc (EtOAc) The residue was dissolved in DCM, EtOAc (EtOAc m. The solvent was removed in vacuo and aq. EtOAc (EtOAc: EtOAc) Example 175: (3Λ,45)-1-(5-{(5·)-1-[1-(3-ethyl-[1,2,4]thiadiazol-5-yl)-piperidine _ 4·yl]-ethoxypyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride

The title compound was obtained from [(3Λ,45)-1-[5-((5)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl using a similar procedure as described in Example 1 74. Synthesis of tert-butyl 4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamate (Preparation 185, 170 mg, 0.86 mmol): RT = 2.75 min ;w/z -386- 201209054 (ES + ) = 534.10 [Λ/+ H]+. Example 176: (3/?, 419)-4-(2,5-difluoro-phenyl)-1-(5-{(*5)_1-[1-(2-ethyl-2H-tetrazole) -5-yl)-piperidin-4-yl]-ethoxypyrimidin-2-yl)-pyrrolidin-3-amine dihydrochloride

In [(3/2,45)-4-(2,5-di-diphenyl)-1-(5-((5)-1-(1-(3-ethyl- 1 H-tetrazole) -5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 230' 40 mg, 0.07 To a solution of EtOAc (3 mL 4 mL), EtOAc (EtOAc) This was followed by elution with NH3 / MeOH (3.5M, 3 X 4 mL) and EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 20 min. EtOAc was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjj )-1-(5-((5)-1-[1-(2-ethyl-2H-tetrazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine_2_ 4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine dihydrochloride

-387- 201209054 The title compound was obtained from [(3i?,4S)-l-(5-{(*S)-l-[l-(2-S)-l-[l-(2-ethyl- 2H - 4) using a procedure similar to that described in Example I76 Zyrid-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]- Synthesis of tert-butyl carbazate (Preparation Example 232, 30 mg '0·05 mmol): 11 deg = 2.75 min; / «/2 ( ug 3 + ) = 518.12 [from +11] +. Example 178: (31^,45)-1-(5-((5)-1-11-(propan-1-sulfonyl)-piperidin-4-yl]-ethoxy}-pyrimidine-2 -yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride

In [(3i?,4 5)-1-[5-((5)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5 -Trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75 mg '0.14 mmol) and triethylamine (40 μί ' 0.29 mmol) in DCM (4 mL) n-Propylsulfonium chloride (24 mg, 0.17 mmol) was added to the resulting solution, and the obtained mixture was stirred at room temperature for 16 hr. The reaction mixture was partitioned between DCM (10 mL) and water (8 mL). Purified by preparative HPLC to give [(37?,4&lt;S)-l-(5-{(*^)-l_[l_(丙院-I-矿矿基珀氏-4-yl]-ethoxy Benzyl-butyryl-2-yl)-4-(2,4,5-trifluorophenyl)-indole succinyl-3-yl]-carbamic acid tert-butyl ester. Product soluble in DCM (2 mL) 'TFA (0. 2 mL ' 2.0 mmol) was added, and the obtained mixture was stirred at room temperature for 3 hr. The reaction mixture was taken to EtOAc (3 X 4 mL) and eluted It was eluted with NH3/MeOH (3.5M, 3 X 3 mL), and the basic fraction was concentrated under vacuum - 388 - 201209054. The residue was dissolved in DCM (2 mL). Solution (25 μ [, 0.10 mmol]. The reaction mixture was stirred for 20 min. 1 [in + H] +. The following example was obtained from [(3Λ,4ι5)-piperidine-4-yl-ethoxy)-pyrimidin-2-yl]_4_ (2) using a procedure similar to that described in Example I78 , 3,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 18 5) 13⁄43⁄4 when manufactured by the sulfonium chloride building block reaction: Example 179 Structure name LCMS __ --- (3 feet 4S)-l-{5-[〇S)-l-(l-cyclopentylmethanesulfonyl-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl H-( 2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2.95 min; m/z (ES4) = 568.10 [M+H]+. 180 ------* ( 3 feet 45)-1-(5-{(5)-1-[1-(2-methoxy-ethanesulfonyl)-piperidin-4-yl]-ethoxy}-chew-steep 2-yl)-4_(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride RT = 2.60 min; m/z (ES+) = 544.12 [M+H]+. 181 _ —^— 9Γ〇^{κχ^ N hh2 .hci (3 feet 45)-1-{5-[(5)-1-(1-cyclohexyl expanded base-峨 steep-4-yl)-B Oxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine hydrochloride RT = 2.93 min; m/z (ES+) = 568.11 [M +H]+. 182 ——^ u 〇^=N .HCI (3疋45)-1-{5-[(5)-1-(1-cyclopentanesulfonyl-piperidin-4-yl )-ethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolethran-3-amine hydrochloride RT = 2.92 min; m/z (ES+)= 554.12 [M+H]+. -389- 201209054 183 N nh2 .hci (3i?,4S)-l-(5-{(6&gt;l-[l-(tetrahydropyran-4-sulfonyl)) -piperidin-4-yl]-ethoxyindole-pyrimidin-2-yl)-4-(2, fluorenylphenyl)-pyrrolidine-3-amine hydrochloride RT = 2.67 Minutes; m/z (ES+) = 570.1 [M+H]+. 184 (3 ft 45)-1-(5-{(5)-1-[1-(2-ethoxy-ethanesulfonate) (M)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2.82 Minutes; m/z (ES+) = 558.11 [M+H]+. 185 (3 feet 45)-1-(5-{(5&gt;1-[1-(3-methoxy-propane-1-sulfonate) Mercapto)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride RT = 2.67 minutes; mlz (ES+) 558.11 [M+H}\ Example 186: (3 and, 4*5)-1-(5-{(&lt;^)-1-[1-((/?)-院-2-扩扩基)-Spotter-4-yl]-ethoxybutanth-2-yl)-4-(2,4,5-difluorophenyl)-indole slightly steep-3 -amine guanidine hydrochloride

(3R,4S)-l-(5-{(S)-l-[l-(丁院-2-增酸基)-峨卩定-4-yl]-ethoxy}_峨Π定- The 2-yl)-4-(2,4,5-trifluorophenyl)-salt-deep-3-amine system was synthesized from [(3Λ,4lS)-l-[5-( (1S)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-amino Tributyl carboxylic acid ester (Preparation 185 '75 mg, 0.14 mmol) and secondary butyl sulfonium chloride (27 mg, 0.17 mmol) were synthesized. The product was purified by palmitic HPLC (MeOH: THF: BA; 75: 25: 〇.1, 13 mL/min, -390 - 201209054 250 nm) and then added to SCX(R), eluted with MeOH (3 x 4 mL) Then, eluted with NH3/MeOH (3.5M, 3 X 3 niL), and the basic fraction was concentrated under vacuum. The residue was dissolved in DCM (2 mL) and EtOAc (EtOAc) The reaction mixture is stirred at room temperature

The solvent was removed in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI></RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The methanol-containing fractions were concentrated in vacuo to give title crystalljjjjjjjjjjjjjjjjj Example 187: (32^,45)-1-(5-((5)-1-11-((5)-butane-2-sulfonyl)-piperidin-4-yl]-ethoxy Pyrimidine-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine

The title compound was subjected to the procedure described in Example 186 by [(3 i?, 4 -1 -

[5-((5)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-yl Synthesis of -3 -butyl carbamic acid (preparative 185, 75 mg, 0.14 mmol) and butyl sulphonyl chloride (27 mg, 0.17 mmol): RT = 2.90 min; m/z (ES + ) = 542.13 [M+H]+. Example 188: (3^45)-1-(5-((5)-1-[1-((幻-Pentane-2-sulfonyl)-piperidin-4-ylethoxy}}- Pyrimidine_2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride-391 - 201209054

戊院-2-), 峨 -4--4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3- The amine was subjected to a procedure similar to that described in Example 178 from [(3/^4^)-145-((^)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4 -(2,4,5-Trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75 mg, 0.14 mmol) and 2-pentylsulfonium chloride (0.029) g, 0.17 mmol) was synthesized. The product was purified by palmitic HPLC (MeOH: THF: BA; 75: 25: 0.1, 13 mL/min, 25 0 nm), then applied to EtOAc (3 x 4 mL) eluted with NH3 /MeOH (3.5 M, 3 X 3 mL) was eluted and the basic fraction was concentrated in vacuo. The residue was dissolved in DCM (2 mL) and EtOAc EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 20 min. EtOAc was evaporated. (mL) elution. The methanol-containing fractions were concentrated in vacuo to give title compound: EtOAc: EtOAc: Example 189: (3^,45)-1-(5-((5)-1-[1-((5)-pentane-2-sulfonyl)-piperidin-4-yl]-ethoxy Bispyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

-392-201209054 The title compound was obtained from [(3Λ,4ι5)_1_[5-((^)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]. -4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 185 '75 mg '0.14 mmol) and 2-pentylsulfonium chloride (0.029 g' 0.17 mmol): RT = 3.05 min; w/z (ES + ) = 5 56.1 5 [M+H]+. Example 190: (tetrahydrofuran-3-yl)sulfonate

Mercapto]-piperidine-4-ylbuethoxy-pyrimidin-2-ylbu 4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

(3/?,4&lt;S)-l-(5-{(&gt;S)-l-[l-(tetrahydrofuran-3-yl)-piperidinyl-4-yl]-ethoxy} -Pyridine-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine was synthesized from [(Μ,45)-1 - [ using a procedure similar to that described in Example 178. 5-((S)_ 1-indolyl-4-yl-ethoxy)-picky-t-yl]-4-(2,4,5-difluoro-based)-indolerolidine-3 -Based --tert-butyl carbamic acid ester (Preparation 185 '75 mg '0.14 mmol) and tetrahydrofuran-3-ylsulfonyl chloride (29 mg, 0.17 mmol). The product was purified by palmitic HPLC (MTBE: MeCN: THF: BA; 40:30: 30: 0.1 * 14 mL/min, 250 nm), then added to SCX PCT, eluted with MeOH (3 X 4 mL) It was eluted with NH3/MeOH (3·5 Μ, 3×3 mL) and the basic fraction was concentrated in vacuo. The residue was dissolved in DCM (2 mL). &lt;EMI ID=9.1&gt;&gt; The reaction mixture was stirred at room temperature for 20 min and the solvent was evaporated in vacuo. EtOAc EtOAc EtOAc (EtOAc) M, 3 X 3 mL) eluted. The methanol-containing fractions were concentrated in vacuo to give title compound: RT: 2.67 min; m/z (ES+) = 5 56.1 1 [M+H]+. Example 191: (37?,45&gt;1-[5-((5)-1-{1-[(幻-(tetrahydrofuran-3-yl)sulfonyl)-piperidin-4-ylethoxy) )-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride

The title compound was obtained from [(3i?,4^)-l-[5-((^)-1-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]. T-butyl -4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid (Preparation 185, 75 mg, 0.14 mmol) and tetrahydrofuran-3-ylsulfonium Synthesis of chlorine (29 mg, 0.17 mmol): RT = 2_68 min; m/z (ES + ) = 556.12 [M+H]+. Example 192: (3i?,4*S)-l-{5-[l-(6-ethyl-pyridazin-3-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl }-4-(2,4,5-trifluorophenyl)-thiazolidine-3-amine

In [(3i?,4S)-l-{5-[l-(6-ethyl-pyridazin-3-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4 -( 2,4,5-Trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 234, 22 mg, 36 μ! in DCM (2 mL) - 394- TFA (0.2 mL, 2 mmol) was added to a solution of EtOAc (EtOAc) (EtOAc) (EtOAc). Elution, the basic fraction was concentrated in vacuo to give title compound: RT: 2.18 min; w/z (ES+) = 5 1 4.2 1 [M+H]+. Example 193: (3^,45)-1 -(5-((5)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-3-ylmethoxy]-pyrimidin-2-yl }-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine

The title compound is obtained from (3^2,4^)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-3-yl Oxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine (Example 46) via palmitic HPLC (MTBE: MeOH: BA; 80: 20: 0.1 , 13 1111^/1^11, 25〇11111, ruler 1' = 15.7 minutes) and single exit: RT = 2_75 minutes; m/z (ES + ) = 518.25 [M+H]+. * The stereochemistry of the center has been specified. Example 194: (3Λ,4·ϊ)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy -pyrimidin-2-yl}-4-phenyl-pyrrolidin-3-amine

-395- 201209054 Add 2-chloro- in a solution of (trans)-4-phenyl-pyrrolidin-3-yl-ammonium (Preparation 237, 50 mg, 0.3 mmol) in MeCN (2 mL) 5-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2' 83 mg, 0.25 mmol) Following the addition of DIP EA (64 pL, 0.37 mmol), the resulting reaction mixture was heated under microwave irradiation at 170 ° C for 30 min. The solvent was removed in vacuo and the residue was purified by preparative HPLC. The crude product was taken on EtOAc (EtOAc) eluting eluting The title compound was obtained as a title compound: 1 〇' = 2.68 min, eluted with EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc ;w/z (ES + ) = 464.26 [M+H]+. Example 195: 1-[(3·5,4·Γ)-4-amino-1-(5-{(5&gt;1-[1-(3-isopropyl-[1,2,4])) Diazol-5-yl)-piperidin-4-yl]-ethoxypyridin-2-yl)-pyrrolidin-3-yl]-5,5-difluoro-piperidin-2-one hydrochloride salt

-396- 1 -Bromo-5 - {(^) -1 - [ 1 - ( 3 -isopropyl-[1,2,4 ]oxadiazol-5-yl)piperidin-4-yl]ethoxylate Base} batch steep (preparation 94' 50 mg' 〇·ι mmol) ' 2 [(35,4^)-4-(5,5-fluoro!-? Slightly steep-3-yl]-tert-butyl carbamate (preparation 93, 48 mg '0.15 mmol), sodium butoxide (42 mg '〇·44 mmol) and 2,5,8,9 -4 Aza- 2,8,9-trimethyl-1-phosphabicyclo[3·3·3]^--alkane (2.7 mg' 13 μιηοΐ) is dissolved in hydrazine, 4-dioxane (2 mL), The resulting reaction mixture was degassed by argon for 1 min. Join three (two sub-sections 201209054

The base acetone) dipalladium (12 mg, 13 μιηοΐ), and the reaction mixture were degassed by argon for 10 minutes. The reaction mixture was heated by microwave irradiation at 120 °C for 60 minutes, followed by filtration with celite. The filtrate was concentrated in vacuo and dissolved in DCM (5 mL The resulting reaction mixture was stirred at room temperature for 30 min then EtOAc (1 mL). The reaction mixture was taken on a pad of EtOAc (EtOAc)EtOAc. The residue was taken on EtOAc (EtOAc) elute The residue was purified by column chromatography (EtOAc EtOAc EtOAc EtOAc The solvent was removed under vacuum and the residue was purified by EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: Compound: RT = 2_45 min; w/z (ES + ) = 534.27 [M+H]+. Example 196 : (3Λ,4·5)·1-(5-{(*5)-1-[1-(3-isopropyl-[1,2,4]oxadiazole_5_yl) -piperidin-4-yl]-ethoxypyrazine-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

The title compound was obtained from 2-bromo-5-{(S)-l-[l-(3-isopropyl-[丨,2,4]oxadiazol-5-yl using a procedure similar to that described in Example 119. Piperidin-4-yl]ethoxy}pyrazine (Preparation Example 95, 300 mg, 0.8 mmol) and [(3145)-4-(2,4,5-trifluorophenyl)pyrrolidine-3 -Based: tert-butyl carbamic acid ester (Preparation - 397 - 201209054 39, 290 mg, 0.91 mmol): mp = 2.92 min; w/z (ES + ) = 532.53 [M+H]+. Example 197: (3Λ,4·5)-1-(2-{(5·)-Bu [1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-peripipeline Pyridin-4-yl]-ethoxypyrimidin-5-yl)-4-(2,4,5-trisphenyl)-pyrrolidine-3-amine hydrochloride

5-bromo-2-{(5)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy }-pyrimidine (Preparation Example 238, 177 mg '0.447 mmol), [(3/?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid III Butyl vinegar (Preparation 39 '170 mg' 0.54 mmol), sodium butoxide (52 mg, 0.54 mmol) and 2-(di-t-butylphosphino)biphenyl (27 mg, 89 μπιοί) in toluene The resulting solution was degassed by argon for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (20 mg, 22 μηιοί) was added, and the reaction mixture was again degassed by argon for 1 Torr, and at 75. (The mixture was heated for 96 hours. The reaction mixture was filtered with EtOAc EtOAc EtOAc m. TFA was added for another 30 minutes (1 mL) and stirring was continued for 20 minutes at room temperature. The reaction mixture was placed on a SCX crucible, first eluted with MeOH, followed by N Η3 / M e Ο Η ( 7 Μ ) The basic fraction was concentrated under vacuum. The residue was dissolved in EtOAc EtOAc (EtOAc (EtOAc) 2.82 minutes; mlz (ES + ) = 532.51 [M+H]+. -398- 201209054 Example 198: (3i?,4 5)-l-(5-{(&lt;y)-l-[1-( 3-ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxypyrimidin-2-yl)-4-(4-methyl-pyridine- 2-yl)-pyrrolidin-3-amine hydrochloride

2-Chloro-5-{(*S)-l-[l-(3-ethyl-[1,2,4]oxadiazol-5-yl)piperidine-4-(yl)ethoxy Pyrimidine (Preparation Example 102 '30.4 mg, 90 μπιοί), [(3i?,4 5)-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid Tributyl ester (Preparation Example 243 '31.3 mg ' 113 μιηοΐ) and DBU (13.7 mg, 90 μιηοΐ) were heated in a sealed tube at 980 ° C for 96 hours in DMSO (1 mL). After cooling, the reaction mixture was diluted with EtOAc EtOAc m. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 4]oxazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine-2-(J-yl)-4-(4-methyl-pyridin-2-yl)-pyrrolidine -3-yl]-carbamic acid tert-butyl ester. This intermediate was dissolved in DCM (5 mL), EtOAc (1 mL), and the mixture was stirred at room temperature for 20 min. The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was taken on EtOAc EtOAc (EtOAc) eluting (2 mL), and Et2 solution (5 drops) with HCl. The solvent was removed in vacuo to give the title compound: RT = 0.70 min; m/z (ES + ) = 479.50 [M+H]+ (LCMS-method 6) -399- 201209054 Example 199: (3R,4S)-4-(2,5-Difluoro-phenylisopropyl-[1,2,4]oxadiazole·5·yl)·piperidine _4·yl l-ethoxydipyridin-3-yl)-pyrrolidin-3-amine dihydrochloride

In the sealed tube 'in the [(3/?,4 $)-4-(2,5·difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation Example 48, 78.9 mg, 0.264 mmol), 5-bromo-2-{(S)-l-[l-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl] -ethoxy}-pyridine (preparation 244, 87.1 mg, 0.220 mmol), sodium butoxide (25.4 mg, 0.264 mmol) and biphenyl-2-yl (di-tert-butyl)phosphine (13.2 mg, Toluene (2 mL, 20 mmol) was added to 44.1 μηιοί). The reaction mixture was degassed with argon for 15 minutes, followed by the addition of bis(dibenzylidenepropanone)palladium (10.1 mg, 11.0 μηιοί). The reaction mixture was degassed for 5 minutes and at 80. Heat at C for 40 hours. After cooling, the reaction mixture was taken on EtOAc (EtOAc) eluting eluting with EtOAc (EtOAc). The fractions were concentrated in EtOAc (EtOAc)EtOAc. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was taken on a pad of EtOAc (EtOAc) eluting eluting The basic fraction was concentrated in vacuo and the residue was purifiedjjjjjjjjj The product was dissolved in Et20 (2 rnL) and a solution of THF in 1,4-dioxane (0.2 mL). The solvent was removed in vacuo to give the title compound: RT: 2.80 min: w/z (ES+) = 513.3 [M+H]+. Example 200: (3/?,45)-4-(2,5-difluoro-phenyl)-1-(6-{(5&gt;1-[1-(3-iso-400-201209054 propyl-) [1,2,4]oxadiazole_5_yl)piperidin-4-yl]-ethoxy}-4-methyl-pyridine-3-yl)-pyrrolidin-3-amine dihydrochloride salt

The title compound was obtained from [(3Λ,4^-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid, the third T. Preparation 48' 71.6 mg' 〇·24 mmol)) and 5-bromo-2-{(*S)-l-[l,(3-()isopropyl-[1,2,4] snail -5-yl)-hydrazin-4-yl]-ethoxy}-4-carboxamidinepyridine (Preparation Example 245, 81.9 mg, 〇. 20 mmol): RT &lt; 2.65 min; (£8 + ) = 527.3 [尨+11]+. Example 201: (3i?,4*S)-4-(2,5-difluoro-phenyl).1-(2-((5)-1-(1-(3-)-propyl-[I , 2,4]oxadiazole_5_yl)-piperidine_4_yl]-ethoxypyrimidine_5_棊V pyrrolidine-3-amine dihydrochloride

The title compound was obtained by a procedure similar to that described in Example 19 7 from 5-(2-(3-)-[1,2,4]oxadiazole_5_ Base)-piperidine-4-yl]-ethoxypyrimidine (Preparation Example 238'110„^,〇28_〇1) and [(3/?,4幻-4 - (2,5-fluorine) Synthesis of phenyl)pyrrolidinyl-3-ylaminocarbamic acid tert-butyl ester (preparative example mmol) was obtained by RT = 2 79 min; speaking / (ES + ) = 5 1 4.6 [Af + H] + .

201209054 --[1,2,4]oxadia-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-piperidin-3-amine hydrochloride

The title compound was obtained from [(3i?,4i?)-4-(2,5-difluoro-phenyl)-1-(5-{(&gt;5)-1) using a procedure similar to that described in Example 1 76. -[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-piperidine-3 -Based --tert-butyl carbamic acid ester (Preparation 246, 85.0 mg, 0.138 mmol): RT = 0.83 min; /z (ES + ) = 514.4 [M+H] + (LCMS Method-6 ). Example 203: (3^,4 5)-1-(5-((5)-1-11-(3-isopropyl-[1,2,4]oxadiin-5-yl)-piperidine 4-yl]-ethoxypyrimidin-2-yl)-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-amine hydrochloride

[(3Λ,45)-1-(5-((5)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-indole D--4 -yl]-ethoxy}-&amp; dense, 卩疋-2-yl)-4-(4-methyl-disindol-2-yl)-pyrrolidin-3-yl]-carbamic acid A solution of tributyl ester (Preparation 247, 50 mg, 84 μηιοί) in 1,4-dioxin solution (4M, 5 mL, 20 mmol) from EtOAc was stirred at room temperature for 16 h under vacuum. The solvent was removed and azeotroped with DCM (2x) and Et.sub.2 (2x) to give the title compound: RT = 2.52 min; Claws/2 ( ug 3 + ) = 493.3 2 [like +:»] + -402 - 201209054 Examples 204 : (3Λ,4·5)-4-(2,5-difluoro-phenyl)-1-{5-[1-(3-isopropyl-[1,2,4] chewable diterpene- 5-(yl)-piperidin-4-ylmethoxy]-6-methyl-pyridin-2-yl}-pyrrolidin-3-amine dihydrochloride

((3/?,4*5)-4-(2,5-difluoro-phenyl)-1-{5-[1-(3-isopropyl-[1,2,4] D哩-5-yl)-hydrazin-4-ylmethoxy]-6-methyl-D is more than Π疋-2-yl}-D dul () pyridine-3-yl)-carbamic acid A solution of tributyl acrylate (Preparation Example 249 '40.0 mg, 65 3 μπιπιοί) in 1,4-di D solution (4M '10.0 mL, 4〇.〇mmol) of HC1 was stirred at room temperature for 2 hours. . The solvent was removed in vacuo and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Example 205: (3 and 45)-4-{2-[(3 and 415)-3-amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]- Pyrimidin-5-yloxymethylchloro-pyrimidin-2-yl)_CJ piperidin-3-ol

Under the armpit, in [(3π,4·?)-1-{5-[(3/?,4·5)-1-(5-chloro-pyrimidin-2-yl)-3-hydroxy-piperidine T-butyl -4-methylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid (Preparation Example 259 , 55 mg, 89 μιηοΐ) TFA (1.5) was added dropwise to the solution formed in DCM (8 mL)

mL). The resulting reaction mixture was stirred at room temperature for 2 h. then was taken on EtOAc (EtOAc) EtOAc (EtOAc) The basic fraction was concentrated in vacuo to give the title compound: RT = 2.6 8 min; τη / ζ (ES + ) - 518.21 [Μ+Η]+. Example 206: (35,470-4-(2-1(3^, 45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidine-5- Hydroxymethyl}-1-(5-chloro-pyrimidin-2-yl)-piperidin-3-ol

The title compound was obtained from [(3 &,45)-1-{5-[(33,4 ft)-1-(5-chloro-pyrimidin-2-yl)-3- Hydroxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester ( Preparation 260 '54 mg ' 87 μπιοί): RT = 2.70 min; m/Z (ES + ) = 518.21 [Μ+Η]+. Example 207: (3145)-1-(5-1(35,4^)-1-(5-chloro-pyrimidin-2-yl)-3-methoxy-piperidin-4-ylmethoxy] -pyrimidine_2-yl}-4_(2,5-difluoro-phenyl)-pyrrolidin-3-amine

In (3S,4/?)-4-{2-[(3/?,4S)-3-amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]- Pyrimidine-5-yloxymethyl}-1 - (5-chloro-pyrimidin-2-yl)-piperidin-3-ol (Example 206, 62 mg < 0.10 mmol) in THF (1 mL) -404- 201209054 NaH (60% mineral oil dispersion, 6.0 mg, 0.15 mmol) was added to the solution.

The resulting reaction mixture was stirred at room temperature for 10 minutes. Add methyl iodide (50 pL

'0.80 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Further, sodium hydride (60% mineral oil dispersion, 6.0 mg, 0.15 mmol) and methyl ketone (50 kL, 0.80 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hr. Water was added cautiously to the reaction mixture and the product was extracted EtOAc (3x). The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. Purified by preparative HPLC to give [(3/?,4 magic-1-{5-[(3·5,4/?)-1-(5-chloro-pyrimidin-2-yl)-3-methoxy Tert-butyl ester of phenyl-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid. The product was dissolved in DCM (5 mL) EtOAc (EtOAc)EtOAc. NH3/MeOH (10%) eluted. EtOAc (EtOAc: EtOAc) 2.1 5 [M+H]+ The following examples were carried out using the procedure similar to that described in Example 207 from the appropriate 4-{2-[(3;?,4S)-3-amino-4-(2,5- Difluoro-phenyl)-pyrrolidino-pyl]-pyrimidin-5-yloxymethylchloro-pyrimidin-2-yl)-piperidin-3-ol building block (Example 205 or Preparation 261 or Preparation Example) 262) Manufactured by reaction with methyl iodide: -405- 201209054 Instance name LCMS 208 (3R, 4S)-l-{5-[(3R,4S)-l-(5-chloro-pyrimidin-2-yl)- 3-methoxy-piperidin-4-ylmethoxy]-furan-2-yl}-4-(2,5-difluoro-phenyl)-laoxaridin-3-amine RT = 2.88 minutes; m/z (ES+) = 532.24 [M+H]+. 209 (3/?,45)-1-{5-[(3Λ,4/?)-1-(5-chloro-pyrimidine- 2-yl)-3-methoxy-piperidin-4-ylmethoxy]-zincidine-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidine-3 -amine RT = 2.88 min; m/z (ES+) = 532.45 [M+H]+. (LCMS Method-7). 210 (3Λ,45)-1-{5-[(35,45)-1-(5-Chloro-pyrimidin-2-yl)-3-methoxy-piperidine-4 -methylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidine-3-amine RT = 2.95 min; m/z (ES+) 532.43 [M+ H]+. Example 211: (3/^45)-1-(5-((3/^,45)-1-(3-isopropyl-[1,2,4]oxadiindole-5- 3-)-3-methoxy-indole-4-ylmethoxy]-mute-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride salt

In [(3;?,4 5)-1-(5-((3^2,4 5)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl) 3-methoxy-piperidine 4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-amino TCA (1.0 mL) was added to a solution of EtOAc (EtOAc EtOAc EtOAc (EtOAc) (EtOAc) The residue was dissolved in DCM (1 mL). EhO solution (2 mL), and the reaction mixture was stirred for 5 min. The solvent was removed <RTI ID=0.0> Example 212: (3^,45)-1-(5-1(35,4 and)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)- 3-methoxy-piperidinylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

The title compound was obtained from [(3^45)-1-(5-1:(314/0-1-(3-isopropyl-[1,2,4]), using a procedure similar to that described in Example 21 1 Diazol-5-yl)-3-methoxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidine- Synthesis of 3-butyl]-aminocarbamic acid tert-butyl ester (Preparation 271, 30 mg, 0.046 mmol): RT = 0.83 min; m/z (ES+) = 548.53 [M+H]+ (LCMS - 6) Example 213: (31^45)-1-(5-((5)-1-(1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-per Pyridin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2-fluoro-5-fluoromethyl-phenyl)-pyrrolidin-3-amine

In a sealed tube, in [(3i?,4&lt;S)-4-(2-fluoro-5-fluoromethyl-phenyl)-pyridin-407- 201209054 sclerosyl-3-yl]-carbamic acid Tributyl ester (Preparation Example 278, 10.1 mg, 32.3 μM and 2-chloro-5-{(·?)-1-[1-(3-ethyl-[1,2,4]oxadiazole-5 Add DBU (5 μιη, 32.3 mm ο 1) to a solution of DMSO (0.2 mL) in DMSO (0.2 mL). The resulting reaction mixture was stirred at 8 ° C for 8 h. The mixture was poured into water (25 mL) and EtOAc (3 X 40 mL). </ RTI> <RTIgt; -1-11-(3-ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxypyrimidin-2-yl)-4-(2 -Tr-butyl-5-fluoromethyl-phenyl)-pyrrolidine-3-yl]-carbamic acid tert-butyl ester. The product was dissolved in ι,4-dioxane (1 m L) and cooled to hydr. c, Add H C1 in 1,4 - dioxin solution (4 Μ, 1 mL). The resulting reaction mixture was stirred under the arm for 1 hour. After the addition of HCl in 1,4-dioxane (4 mL, 1 mL), EtOAc (EtOAc) The aqueous solution (5 mL) was washed with EtOAc EtOAc (mjjjjjjjjjj + ) = 514.48 [M+H]+ (LCMS Method-6). Example 214: (3/?, 4 5)-4-(2,4-difluoro-5-methyl-phenyl)-1- (5-{(15)-Bu [1-(3-ethyl-[1,2,4]oxadiazole_5_yl)-piperidine-4-yl]-ethoxy}-pyrimidine-2 _ base) - shame steep _3_amine hydrochloride -408- 201209054

In 2-chloro-5-{(&gt;S)-l-[l-(3-ethyl-[1,2,4]oxadiazin-5-yl)piperidin-4-yl]ethoxylate Pyrimidine (Preparation Example 102, 1 〇〇 mg, 〇. 3 mmol) was added to a solution of DMSO (2 mL). [(3 Λ,4*S) - 4 - (2,4-difluoro-5) -Methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 292, 0.139 g, 0.444 mmol) and DBU (44.3 pL '0.296 mmol) 'C &gt; Stir at 8 5 ° C for 8 9 hours. After cooling <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; The residue was purified by preparative HPLC to give [(3,4,5)-4-(2,4-difluoro-5-methylphenyl)-b (5-{(5)-1-[1- (3-ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]- Tert-butyl carbamic acid. This compound was dissolved in DCM (5 mL), EtOAc (EtOAc) The solvent was removed in vacuo and the residue was purified (EtOAc EtOAc EtOAc EtOAc. The residue was taken up in vacuo to dryness crystals crystals crystals crystals crystals crystals RT = 0.83 min; m/z (ES + ) = 514.49 [M+H] + (LCMS Method-6). Example 215: isopropyl _ [1,2,4]oxadiazol-5-yl)- 3-methoxy-piperidine-4-yl-2-ethyloxy}-pyrimidine--409- 201209054 2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine Hydrochloride

2-Chloro-5-{(*S)-l-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-3-methoxy Base-piperidin-4-yl]-ethoxypyrimidine (Preparation 298, 50 mg, 0.1 mmol) and [(3/?,4&lt;S)-4-(2,4,5-trifluorobenzene) Addition of DBU (19.6 μί, 0.131 mmol) to a solution of pyridine (1,62.1 mg, 0.196 mmol) in DMSO (1 mL). The mixture was heated at 85 ° C for 89 hours. After cooling, the reaction mixture was crystalljjjjjjjjjjjjjjj Purification by preparative HPLC gave [(3/?,4α-1-(5-{(·5)-1-[(cis)-1-(3-isopropyl-[1,2,4]] Oxadiazol-5-yl)-3-methoxy-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)- Pyrrolidin-3-yl]-carbamic acid tert-butyl ester. Purified by palmitic HPLC (MTBE: MeOH: 90: 10, 15 mL/min ' 2 50 nm) to give [(3^,45)- 1-(5-((5)-1-((3/^, 45)-1-(3-isopropyl-[1,2,4]oxadiazole-5-yl)-3-methoxy Methyl-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid Butyl ester. The product was dissolved in DCM (1 mL), EtOAc (EtOAc, EtOAc (EtOAc) Azeotropic distillation with MeOH (3×1 mL) gave the title compound: RT = 0.84 min; w/z (ES+) = 562.50 [M+H] + (LCMS Method-6) -410-201209054

Example 216: (3 and 45&gt; 1-(5-{(5)-1-[(38,411)-1-(3-isopropyl-[1,2,4] chelate-哩-5-yl) 3-methoxy-oxime-4-yl]-ethoxy}_slightly steep-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrole steep _3_amine salt Acid salt

The title compound was obtained from the procedure described in Example 2 15 from 2-chloro-5 -{(&gt;?)-1-[(cis)-1-(3-isopropyl-[1,2,4] Oxadiazol-5-yl)-3-methoxy-piperazin-4-yl]-ethoxybuproster (Preparation 298, 50 mg, 0.1 mmol) and [(3i?, 4^)- Preparation of 4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid terpene vinegar (Preparation 39): RT = 0.83 min; m/z (ES + ) = 562.51 [ M+H]+ (LCMS Method-6). Example 217: (3^,45)-1-(5-(1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-methoxy-piperidine-4 -ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride

2-Chloro-5-[l-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-methoxy-piperidin-4-ylmethoxy]-pyrimidine (Preparation Example 303, 0.103 g, 0.29 mmol) and [(3;?,4^)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl vinegar (Preparation 39, 0.138 g, 〇 435 mmol) EtOAc (EtOAc) The resulting reaction mixture was heated to 85. C and stir for 19 hours. After cooling, the reaction mixture was crystalljjjjjjjjjjjjjjj The residue was purified by preparative HPLC then EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at room temperature for 4 hours' and the solvent was removed in vacuo. The residue was purified by preparative EtOAc (EtOAc): The organic layer was separated, concentrated in vacuo and EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj X 2 mL) azeotropic distillation to give the title compound · RT = 0.77 min; m/z (ES + ) = 534.50 [Af + Η ] + (LCMS Method-6). Example 218: (3^,45)-1 -(5-11-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-fluoro-piperidine-4-yloxy]-pyrimidine_2-yl}- 4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

The title compound was obtained from 2-chloro-5-[1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-fluoro-piperidine using a procedure similar to that described in Example 217. Synthesis of -4-ylmethoxy]-pyrimidine (Preparation 306, 0.137 g, 0.401 mmol): RT = 0.79 min; m/z (ES+) = 522.48 [M+H]+ (LCMS - 6) . Example 219: (3/?, 41?)-4-(2,5-difluoro-phenyl)-1_{6-[1-(3-isopropyl-[1,2,4]oxadiazole -5-yl)-piperidin-4-ylmethoxy]-pyridin-3-yl}-pyrrole-412- 201209054 pyridine-3-amine

The title compound was obtained from ((35,4/?)-4-(2,5-difluoro-phenyl)-1-{6-[1-(3-isopropyl) using a procedure similar to that described in Example 205. -[1,2,4]oxazol-5-yl)-piperidin-4-ylmethoxy]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (Preparation Example 308, 60 mg, 0.1 mm ο 1): (. RT = 2.80 min; m/z (ES + ) = 499.3 1 [Af+H]+. Example 220: 2-[(3i ?,45&gt;3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidinyl-l-yl]-5-{(1S)-l-丨l-(3-ethyl-[ l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine-4-carbonitrile

In [(3i?,45)-1-(4-cyano-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-thiazolidin-3-yl] - tert-butyl carbazate (preparation 314, 2 〇. 〇mg, 47.9 μιηοΐ) and methanesulfonic acid (/?)-1-[1-(3-ethyl-[1,2,4] chew Potassium carbonate (18.7 mg ' 0.12 mmol) was added to a solution of dim-5-yl)piperidin-4-yl]ethyl ester (Preparation 101, 17.4 mg, 57.5 μιηοΐ) in DMF (3 mL). The reaction mixture was heated at 90 ° C for 66 hours. After cooling, the reaction mixture was partitioned between EtOAc (EtOAc) The layers were separated and EtOAc (2×20 mL). The combined organic extracts were washed with brine (50 mL) dried (MgSO4), filtered and evaporated. -413- 201209054 The residue was purified by column chromatography (D C </RTI> : M e Ο Η; 1 : 0 to 5 : 9 5 ) and the crude product was dissolved in DCM (10 mL). TFA (5 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was taken up in EtOAc (EtOAc) eluting eluting The basic fractions were concentrated in EtOAc (EtOAc m.) Example 221: 2-[(3Λ,45.)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]·5-[1-(3-isopropyl -[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxypyrimidine-4-carbonitrile

The title compound was obtained using the same procedure as described in Example 22 (S.sup.3). ((3/?, 4-phan-1-(4-cyano-5-hydroxy-pyrimidin-2-yl)-4-(2,5 -Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 314 '25 mg '59·9 μιηοΐ) and 1-(3-ethyl-[1] , 2,4]oxadiazol-5-yl)piperidine-4-ylmethacetic acid (Preparation 52, 21.8 mg, 0.0719 mmol) was synthesized. RT 2.92 min: w/z (ES + ) = 5 2 5 · 2 3 [M+H ] +. Example 222: (311,48)-4-(2-fluoro-5-methyl-phenyl)-1-(5-{(3)-1-[1 (3_isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-domain steep 2-yl)-pyrrolidine-3-amine -414- 201209054

[(3i?,4S)-4-(2-Fluoro-5-methyl-phenyl)-1-(5-{(幻-1-[1-(3-isopropyl-[1,2] , 4] oxadiazole-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (preparation example) 315,45 mg, 74 μιηοΐ) HCl (1 mL) was added to a solution of EtOAc (2 mL, 5 mL). The resulting mixture was stirred at room temperature for 2 hrs. The solvent 'residue was purified by preparative HPLC (basic method) to give the title compound: 11 s = 2.88 min; / /2 ( ug 3 + ) = 510.33 [M+H]+. Example 223: (35,45 )-1-(5-(1-11-(3.isopropyl 412,4)oxadiazol-5-yl)-oxime _4_yl]-2_methoxy-ethoxy} Pyrimidine-2_yl)_4(2,4,5-trifluorophenyl)-pyrrolidin-3-amine

The title compound was obtained from [(3 and 415)-1-(5-{1-[1-(3-isopropyl-[1,2,4]) Azole_5_yl)-piperidine-4-yl]-2-methoxy-ethoxypyrimidine-2-yl)_4_(2,4,5-trifluorophenyl)-pyrrolidin-3- Synthesis of tert-butyl carbazate (preparative example 317, 466 mg, 0.704 mmol): Rt = 2.84 min; s (ES + ) = 562.2 1 [M+H]+. -415- 201209054 Example 224: (3^,45)-1-(5-((/2)-1-11-(3-isopropyl-[1,2,4]oxadiazol-5-yl) )-piperidin-4-yl]-2-methoxy-ethoxypyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine

The title compound is obtained from (3i?,4^-1-(5-{1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine-4- 2-yl-2-ethoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine (Example 223) via palmitic HPLC (MTBE : MeOH : BA ; 50 : 50 : 0.1, 17 m L / mi η, 2 5 0 nm) and synthesized: RT = 2.84 min; m/z (ES + ) = 5 62.2 1 [M+H] + Example 225: (3^,45)-1-(5-(8)-1-(1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine 4-yl]-2-methoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine

The title compound is obtained from (3i?,4S)-1-(5-{1-[ 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine-4- 2-yl-2-ethoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine (Example 223) via palmitic HPLC (MTBE: MeOH: BA; 50:50: 0.1, 17 mL/min - 25 0 nm) and synthesized: 111' = 2.84 min; Claw/2 (£3 + ) = 562.21 [from +; 9] + - 416- 201209054

Example 226: 4-((/?)-1-{2-[(3 and 415)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidine·1·yl 】-Pyridine-5-yloxy}-2-methoxy-ethyl)-piperidine-1-carboxylic acid benzyl ester

The title compound was obtained from 4-((/?)-l-{2-[(3i?,4 5)-3-t-butoxycarbonylamino-4-(2, 4,5-Trifluorophenyl)-pyrrolidin-1 -yl]-pyrimidin-5-yloxy}-2-methoxy-ethyl)-piperidine-1 -carboxylic acid benzyl ester (Preparation Example 322, 6.3 mg, 9.2 μιηοΐ): RT = 0.90 min; w/z (ES + ) = 5 8 6.5 [M+H]+ (LCMS Method-6). * The stereochemistry of the center has been specified.

Example 227: 1-((15,25)-2-Amino-4-{5-[1·(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine 4-ylmethoxy]-4-methyl-pyrimidin-2-ylbupentyl)-5,5.difluoro-piperidin-2-indole

In ((1&lt;5,25|)-2-(5,5-difluoro-2-keto-indenyl-1-yl)-4-{5-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-4-methyl-pyrimidin-2-yl}-cyclopentyl)-aminocarboxylic acid tert-butyl The ester (Preparation Example 323 '150 mg, 0.24 mmol) was added to a solution of DCM (2 mL), THF - 417 - 201209054 dioxane (4M, 5 mL). 6 hours. The solvent was removed in vacuo and the residue dissolved in DCM eluted with EtOAc (2M). The organic layer was separated, dried (MgSO4), filtered and evaporated. Purified by preparative HP LC to give the title compound: RT = 2.70 min; w/z (ES + ) = 53 5.1 6 [M+H]+. Example 228: (3Λ,45&gt;4-(2,5·difluoro-phenyl)-l-(5-{(&lt;S)-l-[l-(3-isopropyl-[I,2 , 4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyrimidin-2-yl)-pyrrolidine-3-amine hydrochloride

In [(3/?,4S)-4-(2,5-difluoro-phenyl)-1-(5-{(5)-1-[1-(3-isopropyl-[1,2] , 4]oxazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid third Butyl ester (Preparation 324, 125 mg '0.199 mmol) was added to a solution of EtOAc (EtOAc m. 1 6 hours. The solvent was removed in vacuo and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Example 229: (3Λ,4·ϊ)-4-(5-chloro-2-fluoro-phenyl)-1-{5-[1-(3-isopropyl-[1,2,4] Zyrid-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-ylpyrrolidin-3-amine tosylate-418- 201209054

(3i?, 4*s)-4-(5-chloro-2-fluoro-phenyl)-pyrrolidin-3-amine (preparative example 326, 210 mg, 0.98 mmol) and 2-chloro-5- [ 1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2, 220 mg, 0·67 mmol) in DMSO (2 mL) of the resulting solution was added DBU (99.8 ML, 0.667 mmol). Stir for 120 hours at C. After cooling, the reaction mixture was taken with EtOAc EtOAc m. The combined organic extracts were flushed with brine, dried (MgSO4), filtered and evaporated Di-tert-butyl dicarbonate (500 mg, 2.29 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was purified mjjjjjjjjjj Purified by palm Η PLC (MeOH : IH : THF ; 80 : 17 : 3 , 12 mL / min, 250 nm, RT = 4.55 min), ((3i?,4S)-4-(5-chloro-2) -fluoro-phenyl)-1-{5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyrimidine T-butyl 2-methyl}-pyrrolidin-3-yl)-carbamic acid. TFA (2 mL) was added to aq. The solvent was removed under EtOAc (EtOAc)EtOAc. The residue was dissolved in EtOAc (2 mL) EtOAc (EtOAc) The solvent was removed in vacuo to give the title compound:jjjjjjjj -419- 201209054 Example 230: (3 and, 4*9)-4-(2,5-difluoro-phenyl)-1-{5-[1-(5-methoxy-pyrimidin-2-yl) )-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-amine

(3Λ,4^-4-(2,5-Difluorophenyl)-1-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]pyrrolidine-3-amine (preparation Example 64, 45 mg, 0.12 mmol) 2-Chloro-5-methoxypyrimidine (50 mg, 0.35 mmol) and DBU (21 mg, 0.14 mmol). The reaction mixture was heated under microwave irradiation for 90 minutes at 100 ° C. After cooling, the reaction mixture was diluted with DCM and rinsed with water. The organic extract was placed on a succinic acid SCX and eluted with MeOH, followed by NEt3/MeOH (2%), EtOAc (3%). An example using a procedure similar to that described in Example 230 from (3/?,4&lt;S)-4-(2,5-difluorophenyl)-1-[5-(piperidin-4-ylmethoxy) Pyrimidine-2-yl]pyrrolidin-3-amine (Preparation Example 64) is reacted with an appropriate chlorine or bromoaryl building block to form a cerium. Example structure name LCMS 231 NHj (3i?, 4S&gt;4 -(2,5-difluoro-phenyl)-1-{5-[1-(3-morpholin-4-yl-[1,2,4]thiadiazol-5-yl)-piperidine- 4-ylmethoxy]-furan-2-ylindole Strepto-3-amine RT = 2.72 min; mlz (ES+) = 559.23 [M+H]+. -420- 201209054 232 (3 feet 45)-4-(2,5-difluoro-phenyl)-1- {5-[l-(5-ethoxy-pyrimidin-2-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-amine RT = 2.80 min; m /z (ES+)= 512.29 [M+H]' 233 ^=N plant (3i?,4S&gt;4-(2,5-difluoro-phenyl)-1-{5-[1-(5-B -[l,3,4]thiadiain-2-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-amine RT = 2.59 min; m/z (ES+)= 502.24 [M+H]+. 234 (3i?,4S)-4-(2,5-Difluoro-phenyl)-1-{5-[1-(5-ethyl-嗦嗦-2-yl)-acridin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-amine RT = 2.28 min; mlz (ES+) 496.30 [M+H]+. Example 235: (3Λ,45)-1-[5-(1-benzothiazol-2-yl-piperidin-4-ylmethoxy)-mute-2-yl]- 4-(2,5-difluoro -Phenyl)-卩 is slightly steeper than _3.amine

NH«

In { ( 3/?,4&lt;S) - 4 - ( 2,5 -difluorophenyl)-1-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]pyrrolidine 2-Chloro-1,3-thiazol-5-carbonitrile was added to a solution of -3-yl}-tert-butyl carbazate (preparation 140, 48.9 mg, 0.1 mmol) in DMSO (1 mL) (25·4 mg, 0.15 mmol) and DBU (22 mg, 0.15 mmol), and the obtained mixture was heated at 100 ° C for 30 min. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative EtOAc EtOAc (EtOAc) TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 2 hr and then placed on SC

The MeOH was stripped and washed with NH3/MeOH (10%). The basic fraction was concentrated in vacuo to give the title compound: RT = 2·80 min; w/z (ES + ) = -421 - 201209054 523.24 [M+H]+. Example 236: 2-(4-{2-[(3/?,4 5)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidine- 5-yloxymethyl}-piperidin-1-yl)-thiazole-5-carbonitrile

The title compound was obtained by a procedure similar to that described in Example 235 from {(3/?, 415)-4-(2,5-difluorophenyl)-1-[5-(piperidin-4-ylmethoxy) Pyridin-2-yl]pyrrolidinyl-3-yl}amino carboxylic acid tert-butyl ester (Preparation Example 14) and 2-chloro-1,3-thiazole-5-carbonitrile were synthesized: RT = 2.75 min; m/z (ES + ) = 498.1 6 [M+H]+. Example 237: 4-(2-1(3145)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxymethyl} - piperidine-1-carboxylic acid benzyl ester

The title compound was obtained from 4-{2-[(37^,45)-3-t-butoxycarbonylamino-4-(2,5-difluorophenyl)pyrrolidine using a procedure similar to that described in Example 205. Benzyl-1-yl]pyrimidin-5-yloxymethyl}piperidine-1-carboxylate (Preparation 139) was synthesized to 1": 111' = 2.93 min; / «/2 (£3 + ) = 524.22 [From +; «]+. Example 238: 4-(2-1(3(45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxymethyl Keipiperidine-1-carboxylic acid 2-isopropoxy-ethyl-422- 201209054

A solution of triphosgene (0.1 mmol) in DCM was added to a solution of 2-isopropoxy-ethanol (0.3 mmol) in DCM (1 mL). After stirring at room temperature for 20 minutes, the solution was added to the stirred by {(37?,4*5)-4-(2,5-difluorophenyl)-1-[5-(piperidine-4) -T-butyloxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid tert-butyl ester (Preparation 140, 48.9 mg, 0.1 mmol) in DCM (1 mL). The solution was stirred at room temperature for 16 hours 'diluted with DCM' washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative EtOAc EtOAc (EtOAc) TFA (1 mL) was added and the mixture was stirred at room temperature for 2 hr then applied to EtOAc. The hydrazine was eluted with MeOH (EtOAc) (EtOAc) eluted eluted +H]+. Example 239: 4-{2-丨(3i?,4&lt;S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-ylpyrimidin-5-yloxy Methyl}-piperidine-1_carboxylic acid (5)-2-methoxymethyl-ethyl ester

-423-201209054 The title compound was obtained from a step similar to that described in Example 238 from {(3/?,4 5)-4-(2,5-difluorophenyl)-1-[5-(piperidin-4 Synthesis of tert-butyl 3-methyloxypyrimidin-2-yl]pyrrolidin-3-yl}carbamate (Preparation Example 140) and hydrazine-1-methoxypropan-2-ol: 11 D = 2.67 minutes; / «/2 (ugly 3 + ) = 5 06.24 [M+H]+. Example 240: (3/^,45)-1-(5-((5)-1-(1-(3-ethyl-[1,2,4]oxadiazol-5-yl)- shouting steep 4-yl]-ethoxy}-pyran-2-yl)-4-(2-propane-5-methyl-phenyl)-pyrrolidin-3-amine hydrochloride

The title compound was obtained from [(3145)-1-(5-((5)-1^1-(3-ethyl-[1,2,4]oxadiazole-5] using a procedure similar to that described in Example 228. -yl)-piperidin-4-yl]-ethoxy}-, 卩疋-2 -yl)-4-(2-3⁄4 -5-methyl-phenyl)-D than acridine-3 -Based --tert-butyl carbamate (Preparation 237): RT = 2.80 min; w/z (ES + ) = 496.23 [M+H]+. Example 241: (3;?,45) 1-(5-(2-(1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl-ethylpyrimidin-2-yl)-4-(2,5-difluoro-benzene) Pyrrolidin-3-amine

[(3 Λ,4 S) -1 - ( 5 - { 2 - [ 1 - ( 5 -chloro-pyrimidin-2-yl)-piperidin-4-yl]-ethyl}-pyrimidin-2-yl )-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-aminomethyl-424- 201209054

TCA (0.3 mL) was added to a solution of EtOAc (EtOAc, EtOAc, m. The reaction mixture was taken on a pad of EtOAc (EtOAc) eluting eluting The residue was purified with EtOAc EtOAc EtOAc EtOAc. Purification by palm chromatography (MTBE: MeOH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: /2 (ES + ) = 500.1 6 [M+H]+ 〇 Example 242 : (3Λ,45)-4-(2,5-Difluoro-phenyl)-1-(5-{2·[1 -(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]ethyl}pyrimidin-2-yl)-pyrrolidin-3-amine Hydrochloride

In [(3 and, 4 phantom-1-{5-[2-(1-cyano-piperidin-4-yl)-ethyl]-pyrimidin-2-yl}-4-(2,5-di Addition of N-hydroxyisobutyl hydrazine to a solution of fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 333, 69 mg, 0.135 mmol) in EtOH (5 mL) (17 mg, 0.162 mmol), followed by dropwise addition of a solution of zinc dichloride in Et20 (1M, 0.162 mL, 0.162 mmol). The obtained mixture was stirred at room temperature for 16 hr. Alkane solution (4M, 0.168 mL, 0.673 mmol), EtOAc m. And the basic fraction was concentrated under vacuum in -425 - 201209054. The residue was purified by preparative ΗPLC, applied to EtOAc (EtOAc) eluting with MeOH eluting with NH3/MeOH (7M) and base The residue was concentrated in vacuo. EtOAc EtOAc (EtOAc m. RT = 0.86 min; m/z (ES + ) = 49 8.5 [M+H]+ (LCMS Method-6). Example 243: (3Λ,Fluoro-1-(3-isopropyl-[1,2,4]oxadiazole-5-yl)-piperidine-4-ylmethoxypyrimidine- 2_yl}_4_(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

In [(3^,45)-1-(5-((35,4/0-3-fluoro-1-(3-isopropyl-[1,2,4] oxazide--5-yl) )-峨B-1,4-methylmethoxy]-furo D-yl-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid Tributyl ester (Preparation 337, 27 mg, 0.042 mmol) was added to a solution of DCM (2 mL). The residue was dissolved in MeOH (1 mL) and EtOAc (1 mL) After 50 minutes, the solvent was removed in vacuo to give the title compound: RT: </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; (3145)-1-(5-1(3145)-3•fluoro-1-(3_isopropyl-[124]-426- 201209054 oxadiazol-5-yl)-piperidin-4-ylmethoxy -pyrimidin-2-yl}-4-(2,4,5-trisylphenyl)-pyrrolidine-3 amine hydrochloride

The title compound was obtained from [(3/?,4&gt;5)-1-{5-[(3/?,4 5)-3-fluoro-1-(3-isopropyl) using a procedure similar to that described in Example 243. -[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)_ Synthesis of tert-butyl pyridinium (1 -rrolidin-3-yl)-carbamic acid (Preparation 336): RT = 0.8 7 min; speak /2 (£8 + ) = 53 6_4 [from +11] + ( 1^&gt;/18 method-6). Example 245: (31?,45)-1-{5-[(3 and, 41?)-1-(3-isopropyl-[1,2,4 Oxazol-5-yl)-3-methyl-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidine 3-amine hydrochloride

In [(3/2,45)-1-{5-[(cis)-1-(3-isopropyl-[1,2,4]oxadiazole-5-yl)-3-methyl -piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester ( Preparation 340, 92 mg '0.14 mmol) <RTI ID=0.0>################################################################################# The extract was eluted with NH3/MeOH (7 EtOAc) eluted with EtOAc (EtOAc) (EtOAc) Residue -427-201209054 Purified by palm of hand HPLC (MeCN: MeOH: BA; 50 ·· 50 : 0.1, 15 mL/min, 250 nm). Compound dissolved in MeOH (1 mL). 2M, 50 μ! 〇, and the solution was stirred at room temperature for 15 minutes. The solvent was evaporated in vacuo to give the title compound: RT = 0.91 min; m/z (ES + ) = 5 32.4 [M+H]+ (LCMS Method-6). Example 246: (3^,45)-1-(5-((38,48)-1-(3-isopropyl-[1,2,4]oxadiazol-5-yl) )-3-methylpiperidin-4-ylmethoxy]-pyrimidine _2_ yl} -4- (2,4,5-yl) - pyrrolidin-3-amine hydrochloride

The title compound was obtained from [(3i?,4^)-l-{5-[(cis)-1-(3-isopropyl-[i,2,4]carbazide by the procedure described in Example 245. -5-yl)-3-methyl-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl Synthesis of -3 -butyl hydroxyacetic acid (preparation 340, 92 mg, 0.14 mmol): RT = 0.90 min; w/z (ES + ) = 53 2.4 [M+H]+ (LCMS Method-6) . Example 24 7 : (3^,45)-1-15-((5)-1-(1-[(幻-3-(tetrahydrofuran-3-yl)-[l,2,4]oxadiazole- 5_yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

-428- 201209054 The title compound was obtained from [(3/?, 415)-1-[5-((^-1-{1-[( -yl)-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-tri Synthesis of fluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 341): RT = 0.81 min; m/z (ES + ) = 560.4 [M+H]+ (LCMS Method -6).

Example 248: (3^,45)-1-(5-((5)-1-(1-1(5)-3-(tetrahydrofuran-3-yl)[l,2,4]oxadiazole- 5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine-3-amine hydrochloride

The title compound was obtained from [(3 &,4 5)-1-[5-((5)-1-{1-[())-3-(tetrahydrofuran-3-yl). )-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-Ci Synthesis of phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 342): RT = 0.81 min; m/z (ES + ) = 560.4 [M+H]+ (LCMS method -6). Example 249: 2-{2-[4-((S)-l-{2-[(3i?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidine -l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-yl]-oxazol-4-yl}-propan-2-ol tosylate-429- 201209054

45)-3-di Dibutyl ore-based amine-amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1.yl]-pyrimidin-5-yloxy}-ethyl)·peripipeline Acridine-1·yl]-spiroquinone-4-formic acid ethyl acetate (Preparation 343 '〇.203 g, 0.316 mmol) The solution in anhydrous THF (3 mL) was cooled to -30 ° C under argon. Methylmagnesium bromide (3M solution of Et 2 hydrazine '0.527 mL, 1.5 8 mmol) was added to the solution, and the obtained mixture was stirred at _3 () ° C for 2 hr. A saturated aqueous solution of NH.sub.4Cl.sub.1 (5 mL) was added to the mixture and the mixture was allowed to warm to room temperature. The mixture was partitioned between EtOAc (25 mL) and EtOAc. The organic layer was separated, washed with brine (25 mL), passed through a water-repellent sintered glass filter, and concentrated under vacuum. The residue was purified by preparative EtOAc EtOAc (EtOAc) TFA (0.5 mL, 6 mmol) was added and the mixture was stirred at room temperature for 90 min. The reaction mixture was taken on a pad of EtOAc (EtOAc) eluting eluting The residue was purified by column chromatography (EtOAc EtOAcjjjjjjj A solution of TsOH (25 mg, 0.13 mmol) elut elut elut elut elut elut elut elut elut LCMS Method-6). Example 250: (5·)-2-{5-[4-((5)-1-{2-丨(3/?,4*y)-3-Amino-4-(2,5-di) Fluoro-phenyl)-pyrrolidinyl]-pyrimidin-5-yloxyethyl)-piperidine-1_yl]_-430- 201209054 [1,2,4]oxadiazol-3-yl}-butyl - 2_ alcohol tosylate

In {(3145)-4-(2,5-difluoro-phenyl)-1-[5_((5)-1-{1-[3-(dihydroxy-1_methyl-propyl) -[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid third To the solution of butyl ester (Preparation 346, 100 mg, 0.156 mmol), EtOAc (EtOAc) The reaction mixture was taken on a pad of EtOAc (EtOAc) eluting eluting The residue was purified by EtOAc (MeOH: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc It was eluted with NH3/MeOH (2M). The basic fraction was concentrated in vacuo and the residue was taken eluted eluted eluted eluted eluted The solvent was removed in vacuo to give title compound: EtOAc: EtOAc: Example 251: 45)-3-Amino-4-(2,5-monofluoro-benyl)-indole-slightly steep-1-yl]-molecule_5-yloxy}•ethyl)_峨Steep-1_ base]-[I,2,4]oxadiazole_3-kibbut-2-ol alcohol toluene

The title compound was obtained by the procedure described in Example 25, from {(314^)-4- -431 - 201209054 (2,5-difluoro-phenyl)-1-[5-(( [3-(1-Hydroxy-1-methyl-propyl)-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidine-2 Synthesis of tert-butyl]pyrrolidin-3-yl}-carbamic acid (Preparation 346): RT = 0.77 min; m/z (ES + ) = 544.48 [M+H]+ (LCMS - 6) Example 252: (·5)-1-{5-[4-((5·)-1-{2-[(3 and,45)-3-Amino-4-(2,5-) Difluoro-phenyl)-asaridyl-1-yl]-pyrimidin-5-yloxyethyl)piperidin-1-yl]-[1,2,4]oxadiazol-3-yl b -cyclopropyl-ethanol tosylate

[(3145)-1-(5-((5)-1-(143-((5)-1-cyclopropyl-1-hydroxy-ethyl)-[1,2,4]oxadiazole- 5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-amino The tert-butyl formate is composed of [(3145)-145-((5)-1-(1-(3-0-cyclopropyl-1-hydroxy-ethyl)-[1,2,4] Zyrid-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-amine The third butyl carboxylic acid ester (Preparation Example 347, 136 mg, 0.208 mmol) was isolated by HPLC (IH: MeOH: THF; 60: 30: 10, 18 mL/min, 250 nm). Compound dissolved in DCM (2 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was placed on EtOAc (EtOAc) eluting with MeOH, eluting with NHs/MeOH (2M) The residue was concentrated in vacuo <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; + (LCMS Method - 6) -432- 201209054 Example 253: (72)-1-(544-((5)-1-(2-((3),45)-3-Amino-4-( 2,5-一·气-本基)_啦略陡-1 -基】- Steep -5---yloxy} - ethyl) -1_ Jibu steep Bauer [1,2,4] oxadiazol-3 - cyclopropyl Ji Bu - ethanol toluenesulfonate

The title compound was obtained from [(3i^,4S)-l-[5-((ίy)-l-{l-[3-(l-cyclopropyl-l-hydroxy-ethyl). )-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl Synthesis of tert-butyl pyridin-3-yl]-carbamic acid (Preparation 347): RT = 0.80 min; w/z (ES + ) = 5 56.45 [M+H]+ (LCMS method) -6). Example 254: 2-(5-14-((5)-1-^2-1(31^,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidine- L-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-yl]-[1,2,4]oxadiazol-3-yl-2-methyl-propan-1- Alcohol hydrochloride

In [(3/?,4Phantom-1-{5-[(5)-1-(1-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4- (2,5-Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid terpene vinegar (Preparation Example 205' 〇·150 g' 〇·284 mm〇i) and 3,Ν_二经Base 2,2-dimethyl-propan-Chen (Preparation 349, 45. 〇mg, 0·340 mmo1) was added dropwise to a solution of EtOH (5 mL) (38.7 mS' 0.284 Methyl) solution of MEtOH (1 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. HCl solution of 1,4-dioxane (4M, 〇·2 mL '0.6 mmol) was added. And the reaction mixture was heated at EtOAc (EtOAc) (EtOAc) (EtOAc) Dry (M.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss The mixture was stirred at room temperature for 1 Torr and the solvent was removed in vacuo to give the title compound r τ =0.79 min; m/z (ES + ) = 544.45 [M+H]+ (LCMS Method-6). Example 255: 2-(5-14-((5)-1-(24(3^) ,45)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidinyloxyethyl)-piperidin-1-yl]_ [1, 2,4]oxadiazol-3-yl}-2-methyl-propan-1-ol hydrochloride

The title compound was obtained from [(3/?,4 5)-1-{5-[(5)-Bu(1-cyano-piperidin-4-yl)-ethoxylate using a procedure similar to that described in Example 254. Tert-butyl]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 2❶6) and 3,Ν- Dihydroxy-2,2·dimethyl-propionamidine (Preparation 349) was synthesized: RT = 0.80 min; w/z (ES + ) = 562.44 [Μ+Η] + (LCMS Method-6). Example 256: 2-{5-[4-((S)-b{2-[(3Λ,45)-3-amino-4-(2,5-difluoro-phenyl)-pyrrolidine-l -yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-yl]- -434- 201209054 [I,2,4]oxadiazol-3-ylpropan-2-ol toluene Sulfonate

The title compound was obtained from {(3/2,45)-4-(2,5-difluoro-phenyl)-1-[5-((幻_卜{1_[3_) using a procedure similar to that described in Example 134. (1_Hydroxy-1·methyl-ethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-4-ylethoxy)-chelinyl-2-yl]-pyrrolidine -3_yl}-tert-butyl carbamic acid ester (Preparation Example 350) was combined to give: RT = 0.76 min; m/z (ES + ) = 53 〇 46 [Af+H] + (LCMS method _ 6). Example 257: 2-(5-14-((5)-1-(2-1(3^, 45)-3-amino]_4_(2,4-difluoro-5-methyl- Phenyl)-pyrrolidine-l-yl l-pyrimidin-5-yloxy}-ethyl)-piperidine-l-yl]-[1,2,4]oxadiazol-3-ylpropan- 2-alcohol hydrochloride

The title compound was obtained from {(3/?,4&lt;5)-4-(2,4-difluoro-5-methyl-phenyl)-1-[5- using a procedure similar to that described in Example 243. ((15)-1-{Bu[3-(1-hydroxy-1-methyl-ethyl)-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}- Ethyl ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 354) was synthesized: rt = 0.90 min; m/z (ES + ) = 544.44 [ M+H]+ (LCMS Method-6). Example 258: 1-{5-[4-((5)-1-{2-[(3Λ,45)-3-Amino-4-(2,5-difluoro--435- 201209054 phenyl) -pyrrolidin-1-yl]-pyrimidin-5-yloxyethyl)-piperidine- l-yl]-[1,2,4]oxadiazol-3-ylcyclopropanol hydrochloride

4-fluoro-benzoic acid 45)-3-tert-butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy} -ethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-yl}-cyclopropyl ester (Preparation 358, 0.121 g, 0.161 mmol) in THF (5.0 mL) To a solution of MeOH (2.50 mL) and H20 (2.50 mL) The reaction mixture was acidified with 2M EtOAc and solvent was evaporated in vacuo. The residue was dissolved in DCM (10 mL). &lt;:, then TFA (1.5 mL, 19 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc EtOAc EtOAc EtOAc The residue was purified by column chromatography (EtOAc:EtOAc:EtOAc) Product soluble

MeOH (0.5 mL) was added to a solution of EtOAc (2M, &lt;RTI ID=0.0&gt;&gt; The solvent was removed in vacuo to give the title compound: RT: </RTI> &lt;RTI ID=0.0&gt;&gt; -(2-1(3^,45)-3-amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-ylpyridin-5-yloxy}-ethyl )-piperidine-1-carboxamide-436- 201209054 Ο '-f Ο

In [(3^,45)-1-(5-((^-1-(1-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-(2) , 3,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 206, 0.250 g, 0.457 mmol) and 2,N-dihydroxy-propanthene (57 mg) A solution of zinc dichloride (62 mg, 0.46 mmol) in EtOH (17 mL) was added to a solution of EtOAc (EtOAc) 1,4-Dioxane solution of HC1 (4M, 0.572 mL, 2.29 mmol), and the mixture was stirred at 80 ° C for 1 hour. The solvent was removed in vacuo and the residue was purified and purified Extraction with EtOAC (3 X 50 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purified by column chromatography (DCM: MeOH; 9:1 to 17:3) , title compound: RT = 0.69 min; tw/z (ES + ) = 465.37 [Λ/+Η]+ (LCMS Method-6). Example 260: 1-{5-[4-((5)-1 -{2-[(3Λ,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidinyl-l-yl]-pyrimidin-5-yloxy}-ethyl) - piperidine-l-yl]-[I,2,4]oxadiazole- 3-kib cyclobutanol tosylate

In {(3i?,4&gt;S)-4-(2,5-difluoro-phenyl)-1-[5-((&lt;5)-1-{1-[3-(1-hydroxy- Cyclobutyl)-[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidine-437- 201209054 pyridine_2_yl]-pyrrolidine-3 -Base}-T-butyl carbamic acid (Preparation 362 '55 mg' 0.086 mmol) 1,4-dioxane solution of HCl in 1,4-dioxane (1 mL) (4M, 1 mL, 8 mmol). The solvent was removed in vacuo and EtOAcqqqqqqqq The organic layer was separated, concentrated under vacuum and purified EtOAc EtOAc. The product was dissolved in DCM (1 mL) and a solution of EtOAc (EtOAc, EtOAc (EtOAc) The solvent was removed in vacuo to give the title compound: RT: 0.76 min; m/z (ES+) = 542.45 [M+H] + (LCMS -6). Example 261: 1-(544-((5)-1-(24(3^,45)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidinylpyrimidine _ 5_yloxybuethyl)-piperidine-bukib [1,2,4]oxadiazole_3_pybbutanol hydrochloride

The title compound was subjected to a procedure similar to that described in Example 258 from &lt;RTI ID=0.0&gt;&gt; -Baseoxy}-ethyl)-piperidin-1-yl]-[I,2,4]oxadiazol-3-yl}-cyclobutyl ester (Preparation 363): RT = 0.79 min; w/z (ES + ) = 560.40 [M+H]+ (LCMS Method-6). Example 262: (5^-1-(5-(4-((5)-1-12-((3/2,45)-3-amino-4-(2,5-di-438- 201209054 Fluoro-phenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine- l-yl b[1,2,41oxadiazol-3-ylpropan- 2-alcohol

A solution of 3-hydroxybutyronitrile (98.5 mg, 11.6 mmol) and hydroxylamine (50% in water, 0.851 mL, 13.9 mmol) in EtOH (20 mL) was heated at 60 ° C for 5 h then at 70 ° C Heat for 10 hours. Further, f! is used as a base amine (50% aqueous solution, 0.10 mL, 1.63 mmol), and the reaction mixture was heated at 70 ° C for 10 hours. The solvent was removed in vacuo and the residue was purified eluting elut Add [(3/?,4S)-l-{5-[(&lt;S)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}- T-butyl 4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid (preparation 205, 0.10 g, 0.189 mmol), followed by the addition of Et20 of zinc dichloride Solution (1 M, 0.227 mL, 0.227 mmol). An additional Et20 solution of zinc dichloride (1 M, 25 μί, 25 μχηοΐ) was added, and the reaction mixture was stirred at room temperature for 4.5 hours at Cj. A solution of HCl in 1,4-dioxane (4M, 0.236 mL, 0.946 mmol) was obtained, and the mixture was heated at 60 ° C for 7 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The residue was purified by preparative HPLC then purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc The compound was taken on EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut elut elut elut 53 0.42 [M+H]+ (LCMS Method-6). * Center Stereo -439- 201209054 Chemistry has been specified. Example 263: 1-(5-14-((5)-1-(2-1(3/^,45)-3-Amino-4-(2,5-difluorophenyl)-pyrrolidine- L-yl]-pyrimidine-S-yloxy}-ethyl)-piperidine-l-yl]-[1,2,4]oxadiazol-3-yl}-2-methyl-propan-2 -alcohol hydrochloride

The title compound was obtained from [(372,45)-1-(5-1^(5)-1-(1-chloro-indole-4-yl)-ethoxylate using a procedure similar to that described in Example 254. a group of 3-butyl-2-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 205) and 3,N -Dihydroxy-3-methyl-butanthene (Preparation 364) was synthesized: RT = 0.77 min; m/z (ES + ) = 544.44 [M+H]+ (LCMS Method-6). Example 264: 2 -{5-[4-((5)-1-{2-[(3/?,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-1- -pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-tetrazol-2-yl-2-methyl-propan-1-ol

The title compound was obtained by a procedure similar to that described in Example 205 from {(3/?,4 magic-4-(2,5-difluoro-phenyl)-1-[5-(( [2-(2-Hydroxy-1,1-dimethyl-ethyl)-2H-tetrazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]- Synthesis of pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 367): RT = 0.82 min; m/z (ES + ) = 544.42 [M+H] + 201209054 (LCMS Method·6) The following examples were made by a similar procedure as described in Example 243 via deprotection of a suitable third butoxycarbonyl protected intermediate (Preparation 374 or 375 or 376): Example Structure Name LCMS 265 (3/? ,45)-l-(5- {(5)-1-[(35,4/?)-1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-3 -Fluoro-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride RT = 0.83 Minutes; m/z (ES^ = 536.38 [M+H]+ (LCMS Method-6). 266 (3i?,4S)-l-(5-{〇S&gt; 1-[(3/?,4S) 1-(3-ethyl-[1,2,4]oxadiazol-5-yl)-3-oxo-piperidin-4-yl]-ethoxyindole-2-yl)- 4-(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride RT = 0.83 min; m/z (ES+) = 536.42 [M+H]+ (LCMS Method-6). 267 σκκ 分c$I: (3i?,4S)-l-{5-[〇S)-l-(l-benzoxazol-2-yl -piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-amine RT = 2.90 min m/z (ES+ ) = 521.15 [M+H]+. Example 268: 4*ϊ)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidine_5 _ yloxy}-ethyl)-piperidin-1-yl]_π, 2,4] oxadiazol-3-yl}-1-cyclopropyl-ethanol hydrochloride

[OR/S)-1-[[((Wd-UD-UShl-cyclopropyl-1-yl-ethyl)0 oxadiazin-5-yl]-hyperptic-4-yl}-ethoxy 4-(2,4,5-trifluorophenyl)-pyrrolidine-3-yl]-carbamic acid tert-butyl ester (12.1 mg, 18) Ιιηοΐ) is derived from cyclopropyl-1-hydroxy-ethyl)-[1,2,4]oxadiazole-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl ]-4-(2,4,5-trifluorophenyl)-pyridyl-3-yl]-carbamic acid tert-butyl ester (Preparation 378) via palm chromatography HPLC (MTBE: MeCN: MeOH; 70 : 20: 1 0, 14 mL/min, 25 0 nm) and isolated, and dissolved in DCM (2 mL). An Et20 solution of HC1 (2M, 16.5 μί, 33 μιηοΐ) was added, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was crystallisjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs Example 269: (and)-1-(5-14-((5)-1-(2-1(31^45)-3-amino-4-(2,4,5-trifluorophenyl)) -pyrrolidin-1-yl]-pyrimidine_5-yloxyethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-yl}-1-cyclopropyl-ethanol Hydrochloride

The title compound was obtained from [(3Λ,4·5)-1-[5-((5)-1-(1-(:3-)-cyclopropyl-1-hydroxy-B) using the procedure described in Example 268. Base)-[1,2,4]oxadiazin-5-yl]-piperidin-4-yl}-ethoxy)pyrimidin-2-yl]-4-(2,4,5-trifluoro Phenyl)·glycidin-3-yl]-carbamic acid tert-butyl ester (Preparation 378) was synthesized: RT = 0.83 min; w/z (ES + ) = 574·5 [M+H]+ (LCMS Method .6) Example 270: (3Λ,45&quot;)-4-(2,5-Difluoro-phenyl 201209054 (3-ethyl-[1,2,4]oxadiazol-5-yl) 3-oxa-7-aza-bicyclo[3.3.1]non-9-ylmethoxy]·•pyrrol-2-ylpyrrolidin-3-amine hydrochloride

(3 i?,45*) - 4 - (2,5-difluoro-phenyl)-1 _ { 5 - [ (1/?,5 *5,951) - 7 - (3 -ethyl-[1, 2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-ylmethoxy]-pyrimidin-2-yl}-pyrrolidine-3 -Amines from ((314^)-4-(2,5-difluoro-phenyl)-1-{5-[(1Α,55)-7-(3-ethyl-[1,2,4 Oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-yl) - Tributyl methacrylate (Preparation 387) was isolated by palmitic HPLC (MTBE: MeOH; 80: 20, 13 mL/min, 250 nm) and dissolved in Et20 (1 mL) ). An Et20 solution of HC1 (2M, 29 μί, 57 μηαοί) was added, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum to give the title compound: RT = 0.73 min; w/z (ES+) = 528.4 [M+H]+ (LCMS -6). Example 271: (3Λ,45)-4-(2,5-Difluoro-phenyl)-1-{5-[(1Λ, (3-ethyl-[1,2,4]oxadiazole_5_ Base)_3_oxa_7_aza-bicyclo[3.3.1] 壬-9_ylmethoxy]-pyrimidine_2-yl}-pyrrolidine_3_amine hydrochloride

The title compound was obtained from ((3/?,4 magic-4-(2,5-fluoro-phenyl)_1_{5_[(1 and 55)_7_(3_ethyl) using the procedure described in Example 27A. _[12,4]oxadiazole_5-yl)_3_oxa-7-aza-bicyclo[3S1]i_9_ylmethoxypyrimidine-443- 201209054 }-pyrrolidin-3-yl) Synthesis of -3 -butyl methacrylate (Preparation 387): RT = 0.73 min; zn / z (ES + ) = 528.4 [M+H] + (LCMS Method _6) Example 272: (3 Λ, 45 &gt; 4-(2-Fluoro-phenylmethoxyethyl)-[1,2,4]oxadiazole_5-yl]-piperidin-4-ylethyloxy)-pyridinium_2_ Pyrrolidin-3-amine hydrochloride

The title compound was obtained by a procedure similar to that described in Preparation 243 from {(3/?,4 5)-4-(2-fluoro-phenylmethoxy-ethyl)-[1,2,4]. Synthesis of azole-5-ylpiperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 396): RT = 0.78 min; m/z (ES + ) = 512.4 [M+H] + (LCMS Method _6) 〇 The following example was carried out using a procedure similar to that described in Example 258 via the appropriate third-butoxycarbonyl-protected intermediate Manufactured by deprotection of Preparation (Preparation 397 or 400 or 403 or 404): Example Structure Name LCMS (Method 6) 273 1 - {5-[4-((5)-1 - {2-[(3/? ,45)-3-Amino-4-(2,4,5-trifluorophenyl)-azulidine-1-yl]-pyrimidin-5-yloxy}-ethyl)--decate-1 -yl]-[1,2,4]oxadiazol-3-yl}-cyclopropanol hydrochloride RT = 0.78 min; w/z (ES+) = 546.39 [Μ+Ηγ. -444- 201209054 274 1 - {5-[4-((5)-1 - {2-[(3i?,45)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-1 -yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazol-3-yl}-cyclopropanol hydrochloride RT = 0.77 Minutes; tw/z (ES+) = 524.48 [Μ+Ηγ. 275 1 - {5-[4-(〇S)-1 - {2-[(3i?,4S)-3-Amino-4-(2-fluoro-phenyl)-pyrrolidin-1-yl]-chew Pyridin-5-yloxy}-ethyl)-acridin-1-yl HU,4]oxadiazol-3-yl}-cyclobutanol hydrochloride RT = 0.77 min; m/z (ES+) = 524.47 [M+H]+. 276 1 - (5-[4-((5)-1 - {2-[(3Λ,45)-3-Amino-4-(2-fluoro-5-methyl) -phenyl)-[!byridine-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-1-yl]-[1,2,4]oxadiazole-3- Base}-cyclobutanol hydrochloride RT = 0.85 min; /w/z (ES^ = 538.44 [M+H]' Example 277: (l-{5_[4-((*y)-l-{2 -[(3i?,4S)-3-amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)- Piperidin-1-yl]-[1,2,4]oxadiazol-3-yl}-cyclopropyl)-methanol hydrochloride

The title compound was subjected to a procedure similar to that described in Example 254 from {5-[(S)-1 1-(1-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}-4 -(2,4,5-trifluorophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation Example 20 6) and N-hydroxy-1-hydroxymethyl-cyclopropanecarbamidine (Preparation Example 4 05) Synthesis: RT = 0.79 min; w/z (ES + ) = 560.43 [M+H] + (LCMS -6). -445- 201209054 Example 278: 2-(5-14-((5)-1-(24(31^,45)-3-Amino-4-(2-fluoro-5-methyl-phenyl)) -pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-1_yl]-[1,2,4]oxadiazol-3-yl}-propan-2- Alcohol hydrochloride

In {(3^,4 5)-4^2-fluoro-5-methyl-phenyl)-1-[5-((幻-1-{1-[3-(1-hydroxy-1-) -ethyl)_[1,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}- Add a solution of HCl (3 mL, 1 mL, 2 mmol) in MeOH (0.25 mL). Stir for 1 hour under warm conditions. The solvent was removed in vacuo to give the title compound: EtOAc: EtOAc. Example 279: 1-((35,45)-4-amino-1-(5-{(S)-l-[1-(5-ethyl-pyrimidin-2-yl)- shouting-4) ]]-ethoxy}-mute-2-yl)-shame-deep-3-yl]-5-methyl-1 Η-pyridine-2-one

2-Chloro-5-(l*S)-:l-[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]ethoxypyrimidine (Preparation 414' 123 mg, 0.353 Mm〇l) and 1-(trans)_4_amino-pyrrolidin-3-yl)-5-methyl-1H-pyridin-2-one (Preparation Example 194, 4〇.〇

The solution obtained by adding the DBU (50 μ!&gt;, 0.334 mmol) was added to a solution of DMSO (1 mL) in DMSO (1 mL). The mixture was heated at 120 ° C for -95 - 201209054 for 1 95 minutes. After cooling, the reaction mixture was poured into water and EtOAc (EtOAc) The combined organic extracts were dried in a phase separator and concentrated under vacuum. The residue was dissolved in MeOH and taken on EtOAc EtOAc (EtOAc) The basic fractions were concentrated in vacuo and purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: RT = 0.77 minutes; w/z (ES + ) = 505.44 [M+H] +

(LCMS Method-6). Example 280: 1-1(35,45)-4-amino-1-(5-{(5&gt;1-[1-(5-ethyl-pyrazin-2-yl)-piperidin-4- ]]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-5-methyl-1H-pyridin-2-one

The title compound is 2-chloro-5-{(&lt;5)-1-[1-(5-ethyl-pyrazin-2-yl)-(J piperidin-4-yl)-ethoxy} -pyrimidine (Preparation 415) and 1-(trans)-4-amino-pyrrolidin-3-yl)-5-methyl-1H-pyridin-2-one (Preparation Example 194) utilized and Example 279 A similar procedure was synthesized, except that the palmitic HP LC conditions were changed as follows: (MeOH: THF: BA; 6 5: 3 5: 0.05, 15 mL/rnin, 250 nm, RT = 10.1 min): RT = 0.78 min; m/z (ES + ) = 505.43 [M+H]+ (LCMS Method-6). Example 281: 45)-4-Amino-1-(5-{(5)_1-[1-(5-chloro-pyrimidin-2-yl)-piperidine-4-yl-ethoxypyrimidine- 2-yl)-pyrrolidin-3-yl b-5-methyl--447- 201209054 1 Η-pyridine-2-one

The title compound is 5-chloro-2-(4-π)-1-[(2-chloropyrimidin-5-yl)oxy]ethylpiperidin-1-yl)pyrimidine (Preparation 416) and 1- (trans)-4-amino-pyrrolidin-3-yl)-5-methyl-1H-pyridin-2-one (Preparation 194) was synthesized using a procedure similar to that described in Example 279. The HPLC conditions were as follows: (MeCN: THF: BA; 50: 50: 0.05, 16 mL/min, 250 nm, 11 butyl = 12.5 min): 11 deg = 0.87 min; 7 « /2 (£3 + ) = 511.37 [M+H]+ (LCMS Method-6). Example 282: 1-((35,45)-4-amino-1-15-((5)-1-(1-丨3-(1,1-difluoro-ethyl)-[1,2 ,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl b-5-methyl-1H-pyridine-2- ketone

The title compound is 2-chloro-5 -((*S) -1 - { 1 - [ 3 - (1,:1 -difluoro-ethyl)-[1,2,4]oxadiazole_5- ]]-piperidin-4-yl}-ethoxy)-pyrimidine (Preparation 418) and 1-(trans)-4-amino-pyrrolidin-3-yl)-5-methyl-1H- Pyridin-2-one (Preparation Example 194) was synthesized using a procedure similar to that described in Example 297, except that the conditions of the palm of the HPLC were changed as follows: (MeCN: THF: BA; 65: 35: 0.05, 15 mL/ Min, 250 nm, RT = 8_6 min): RT = 0_81 min; w/z (ES + ) = 531.41 [M+H]+ (LCMS Method - 6). -448- 201209054 Example 283 : 1-[(3*5,45&gt;4-Amino-1·(5-{(5&gt;1-[1-(3-isopropyl][1,2,4] Oxadiazol-5-yl)-piperidin-4-yl]-ethoxypyrimidin-2-yl)-pyridolidin-3-yl]-5-methyl-1Η-pyridin-2-one

The title compound is obtained by 2-chloro-5-{(»5)-1-[1-(3-isopropyl-[1,2,4]-c-coxazol-5-yl)piperidin-4-yl Ethoxy}pyrimidine (Preparation Example 63) and 1-(trans)-4-amino-pyrrolidin-3-yl)-5-methyl-1indole-pyridin-2-one (Preparation Example I&quot;) The synthesis was carried out using a procedure similar to that described in Example 279, except that the conditions of the palm of the hand were changed as follows: (MeOH: THF: ΒΑ; 85:1 5: 0.05, 12 mL/min '250 nm &gt; RT = 1 6 · 0 min ): RT = 〇· 7 9 minutes; w/z (ES +) = 509.46 [M+H]+ (LCMS Method -6).

Example 284: 1-[(35.,4·5)-4-amino-1-(5-{(5)-1-[1-(3-trifluoromethyl-[1,2,4] Oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-5-methyl-1H-pyridine-2-one

The title compound is 2-chloro-5-{(幻_1'[1-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-piperidine-4- ]]-ethoxy}-pyrimidine (Preparation 421) and 1-(trans)-4-amino-pyrrolidin-3-yl)-5-methyl-1Η-pyridine-2-one (Preparation Example) 194) Synthesized using a procedure similar to that described in Example 279, except for the change of palm-449-201209054 HPLC conditions as follows: (MeOH: THF: BA; 85: 15: 0.05, 12 mL/min, 250 nm, RT = 12.9) Minutes): RT = 0.87 minutes; m/z (ES + ) = 53 5.43 [M+H]+ (LCMS Method -6). Example 285: 1-[(35,45)-4-amino-1-(5-{(·5)-1-[1-(3-t-butyl-[1,2,4]oxadi Zyrid-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl b 5-methyl-1 fluorene-2-pyridin-2-one

The title compound is 5-{(*S)-l-[ 1-(3-t-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-B Oxy}-2-chloro-pyrimidine (Preparation 422) and 1-(trans)-4 -amino-pyrrolidin-3-yl)-5-methyl-1 oxime-pyridine-2-one (preparation Example 194) was synthesized using a procedure similar to that described in Example 279, except that the conditions of the palm of the HPLC were changed as follows: (MTBE: THF: MeOH: hydrazine; 60: 30: 10: 0.05 - 12 mL/min, 2 50 nm, RT = 11.5 minutes): RT = 〇·85 minutes; w/z (ES + ) = 523.45 [M+H]+ (LCMS Method - 6). Example 286: (3/^,4 5)-1-[5-((5)-1-{1-[(~-2-(tetrahydrofuran-3-yl)_ 2 H-tetrazol-5-yl) • Piperidine_4_ylbuethoxy)-pyrimidin-2-yl]_4_(2,4,5-trifluorophenyl)-pyrrolidin-3-amine hydrochloride

The title compound was obtained from [(,4^)-1 -450- 201209054 [5-((5)-1-{1-[(&lt;5)-2-(tetrahydrofuran-3-) by the procedure described in Example 2U. -211-tetrawa-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-pyrrolidine Synthesis of -3-yl]-carbamic acid tert-butyl ester (Preparation 423): RT = 0.8 4 min; m/z (ES + ) = 560.47 [M+H]+ (LCMS Method-6). Example 287: (372,45)-1-15-((5)-1-(1-1(^-2-(tetrahydrofuran-3-yl)-2H-tetrazol-5-yl]-piperidine- 4-ylethyloxy)-pyrimidin-2-yl]-4-(2,4,5-

The title compound was obtained from [5-((5)-1-(1-10)-2-(tetrahydrofuran-3-yl)-2H-tetrazol-5-yl]-piperidine. 4-butyl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluorophenyl)-thiazolidin-3-yl]-carbamic acid tert-butyl ester (preparation Example 424) Synthesis: RT = 0.8 2 min; w/z (ES + ) = 560.49 [M+H]+ (LCMS Method-6). The biological activity of the compounds of the present invention can be tested by the following analytical system. GPR119 Yeast Reporter Gene Analysis Yeast Reporter Gene Analysis Yeast cell-based reporter gene analysis has been disclosed in the literature (for example, see Mir et J. J. et al, 2 002, J · B i ο 1 · Chem ·, 2 7 7 : 6 8 8 1 -68 8 7 ; Campbell RM et al, 1 9 9 9, Bioorg. Med. Chem. -451 - 201209054

Lett., 9: 24 1 3 -24 1 8 ; King K. et al, 1 990, Science, 2 5 0: 121-123); WO 99/14344; WO 00/1 2704; and US 6,1 00,042 ). Briefly, yeast cells have been genetically engineered such that the endogenous yeast G-alpha (GPA1) has been removed and replaced with G-protein chimeras constructed using a variety of techniques. In addition, the endogenous yeast GPCR, Ste3, has been removed to allow heterologous expression of the selected mammalian GPCR. In yeast, molecules that are highly retained in the pheromone signaling pathway of eukaryotic cells (eg, the mitogen-activated protein kinase pathway) drive the performance of Fusl. By placing P-galactosidase (LacZ) under the control of the Fusl promoter (Fuslp), a system has been developed in which receptor activation leads to enzymatic read-out. Yeast cell lines are transformed by a modification of the lithium acetate method disclosed by Agatep et al. (Agatep, R. et al, 1998, Transformation of S accharomyces cerevisiae by the lithium acetate/single-stranded carrier DNA/polyethylene glycol (LiAc/) ss-DNA/PEG) protocol. Technical Tips Online, Trends Journals, Elsevier). Briefly, yeast cells were grown overnight on yeast yeast trypsin (YT). Vector single-stranded DNA (10 pg), 2 pg each? 1^11&gt;-1^ to report plastids (one with 1; 11 eight screening markers and the other with TRP), 2 GPR1 19 (human or murine receptor) in yeast expression vector (2 The original) and lithium acetate/polyethylene glycol/hydrazine buffer were pipetted into an Eppendorf microtube. The yeast containing the recipient/non-receptor control showed a plastid with a LEU marker. Yeast cells were seeded in this mixture and the reaction was carried out at 30 ° C for 60 minutes. The yeast cells were then subjected to heat shock treatment for 15 minutes at 42-452-201209054 °c. This cell is then rinsed and dispersed on a selection plate. The screening plate is a yeast-specific medium (no LEU, UR A and TRP) (SD-LUT). After incubation for 2-3 days at 30 °C, the colonies grown on the screen were screened and tested in the LacZ assay.

For the luciferase assay of β-galactosidase, yeast cells carrying the human or murine GPR119 receptor were grown in liquid SD-LUT medium overnight to an unsaturated concentration (β卩, the cells still split and did not reach static period). 90 μί yeast cells were added to a 96-well black polystyrene dish (Costar) by diluting to the optimal assay concentration in fresh medium. The compound was dissolved in DMS0 and diluted to a 10X concentration in 10% DMS0 solution. The compound was applied to a dish and the tray was placed at 30 ° C for 4 hours. After 4 hours, the substrate of β-galactosidase was added to each well. In these experiments, luciferin di(β-D-galactopyranoside) (FDG) was used, and the luciferin was released as an enzyme to read the fluorescent data. Add 500 μΜ FDG/2.5% Triton XI 00 at 20 μί / well (requires detergent to penetrate the cells). After incubation of the cells with the substrate for 60 minutes, 1 Μ sodium carbonate was added at 20 pL/well to stop the reaction and boost the fluorescence signal. The signal from the disc is then read at 48 5/53 5 nm in a fluorometer. Several representative examples of the compounds of the present invention and their pharmaceutically acceptable salts were tested in this assay and found to be active, resulting in an increase in the fluorescence signal to the background signal (ie, in the presence of 1% DMSO but no compound present). At least ~1.5 times the signal); some of the example compounds get at least a 5-fold increase in signal. We found that some of the sample compounds tested had human yeast IC50 値 less than 1 μΜ, while other example compounds had IC5Q値 less than 10 μΜ. -453- 201209054 Based on this data, as well as other data described below, it is expected that all of the compounds of the invention will have at least comparable activity. cAMP analysis A stable cell line expressing recombinant human G P R 1 19 was confirmed, and this cell line was used to examine the effect of the compound of the present invention on the intracellular content of cyclic AMP (cAMP). The cell monolayer was washed with phosphate-buffered saline and stimulated for 30 minutes at 37 °C with various concentrations of the compound in stimulation buffer and 1% DMSO. The cells were then lysed and the cAMP content was determined using a Perkin Elmer AlphaS creenTM (Amplified Luminescent Proximity Homogeneous Assay) cAMP kit. The buffer and analytical conditions are as described in the manufacturer's protocol. Several representative examples of the compound of the present invention and pharmaceutically acceptable salts thereof were tested and found to exhibit a concentration-dependent increase in intracellular cAMP content, and usually EC5Q値 was &lt;10 μΜ; some example compounds were analyzed by cAMP It shows that EC 5 〇値 is less than 1 μ Μ. DPP-IV analysis method DPP-IV activity was measured by monitoring the cleavage of the fluorescent peptide H-Gly-Pro-7-amino-4-methylcoumarin (GP-AMC), utilized in 3 The 80 iim was excited and the fluorescence at 460 nm was illuminated to quantify the product 7-amino-4-methylcoumarin. In a 96-well plate (Black OptiPlate-96F) with a total volume of 100 μΐ^/well (containing 50 mM Tris pH 7.6 '100 μΜ GP-AMC '10-25 μυ recombinant human D Ρ Ρ - IV and finally Analysis of the different dilutions of -454-201209054 inhibitors in 1% D Μ S Ο). After incubation at 37 ° C for 30 minutes, the signal of the disk was read in a fluorescence meter. Recombinant human DPP-IV residue Asn29-Pro766 was purchased from BioMol. All of the above Examples 1 to 2 87 were tested in this analysis and found to be active, and found to have an IC5Q値 &lt; 20 μΜ. Some example compounds were found to have DPP-IV EC5〇値 less than 1 μΜ; other example compounds have EC5Q値 less than 20 μΜ °

The activity of the representative compound group tested in the human yeast assay and the DPP-IV assay is shown in Table 1 below: Table 1. Example number margin yeast ec50 &lt;1 μΜ Am yeast ECS0 1 μΜ to 10 μΜ DPP- IV IC5o &lt;1μΜ DPP-IV IC5〇1 μΜ to 20 μΜ 2 + + 7 + + 8 + + _ 12 + + 19 + + a 26 + + Representative compound group tested in cAMP analysis and DPP-IV analysis The activity of the group is shown in Table 2 below: -455 - 201209054 Table 2. Example number cAMP ECs〇&lt;1 μΜ cAMP ECs〇1 μΜ to 10 μΜ DPP-IV IC5〇&lt;1 μΜ DPP-IV IC5〇1 μΜ 20 μΜ 109 + + 110 + + 112 + + 115 + + 124 + + 128 + + 130 + + 131 + + 133 + + 135 + + 140 + + 158 + + 175 + + 176 + + 196 + + 197 + + 198 + + 200 + + 218 + + 223 + + 235 + + 242 + + 249 + + 280 + + Metabolites Metabolites of the compounds of the invention can be identified by incubation in liver microsomes: 5 μΜ of the compound of interest Concentration in mice, liver or human particles - 456 - 201209054 in the body at 37 ° C Foster for 60 minutes. Compound cultures at Τ = 0 were also prepared to determine the amount of parent compound prior to any metabolism. A matrix control group was prepared to determine which compound was the matrix component, and a thermo-stability control group was also prepared to confirm that any metabolite observed in the compound culture was not a thermolabile product. All solutions were extracted into MeCN and analyzed by LC/MSMS using UV detection. Additional MSMS analysis was performed to confirm and structurally analyze the measured metabolites.

For example, via this method, Compound 1 below was identified as a metabolite of Example 3S. Compound 1 was synthesized and tested to find that the EC50値 in the GPR1 19 cAMP assay was 9 μΜ and the IC5〇値 in the DPP-IV analysis was &lt;1 μΜ Compound 1:4-((5)-1-{2- [(3 and 415)-3-Amino-4-(2,4,5-trifluorophenyl)-pyrrolidin-1-yl]-pyrimidin-5-yloxy}-ethyl)-piperidyl Pyridin-1-carboxylic acid propyl decyl amide

Anti-diabetic efficacy of the compounds of the invention in an in vitro model of pancreatic beta cells (ΗΙΤ-Τ15) - 457 - 201209054 HIT-T15 cells (follow-up algebra 60) obtained from ATCC, supplemented with 10% fetal calves Serum and 30 nM sodium selenite were cultured in RPMI1640 medium. All experiments were performed on cells with a subcultured population of less than 70. According to this literature, the nature of cell lines with a surviving algebra above 81 would change (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes. 1 98 9 Jan; 3 8 ( 1 ): 44-8) cAMP assay 1111 '-1 [15 cells in standard medium at 1 000,000 cells / 〇.11111 ^ / well The amount was planted in a 96-well plate and cultured for 24 hours, followed by discarding the medium. The cells were incubated for 15 minutes at room temperature with 100 μί stimulation buffer (Hanks buffered saline, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4). Discard the buffer and replace it with a dilution of 0.001, 0.003, 0.01, 0.03, 0.1, 0 · 3, 1, 3, 10, 30 μΜ of the compound in the stimulation buffer (in 0.5% DMSO) Exist). The cells were incubated for 30 minutes at room temperature. Next, 75 μL of lysis buffer (5 mM HEPES, 0.3% Tween-20, 0.1% BSA, pH 7, 4) was added to each well and the plate was shaken at 900 rpm for 20 minutes. The pellets were removed by centrifugation at 3 000 rpm for 5 minutes, then the samples (each duplicate) were transferred to a 384 well plate and processed according to the Perkin Elmer AlphaScreen cAMP assay kit instructions. Briefly, make 25 μί of the reaction containing 8 μί sample, 5 μί acceptor bead mixture, and 12 μ]: detect the mixture, so that the concentration of the final reaction component and the kit instructions are -458-201209054 the same. The reaction was incubated for 150 minutes at room temperature and the signal of the disk was read using a Packard Fusion instrument. The measured 値 of caMP is compared to the known cAMP concentration (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 1 〇〇, 300, 1 000 nM) standard curve to convert the reading to the absolute concentration of CAMP . Data was analyzed using the XLfit 3 software. Representative compounds of the invention have been found to increase cAMP by less than 10 μΜ EC5C値. Compounds showing EC5Q値 less than 1 μΜ in cAMP analysis

Good. Insulin secretion analysis ΗΙΤ-Τ15 cells were seeded in a 1 2 well plate in a standard medium at a rate of 106 cells/1 ml/well, and cultured for 3 days, followed by discarding the medium. Supplemented Krebs-Ringer buffer (KRB) (containing 119 mM NaCl, 4.74 mM KC1, 2.54 mM CaCl2, 1.19 mM MgS04, 1.19 mM KH2P〇4' 25 mM NaHC03, 10 mM HEPES, pH 7.4, and 0.1% bovine Serum albumin) washed the cells twice. The cells were incubated with 1 mL of KRB for 30 minutes at 37 °C, followed by KRB. Following a second incubation with KRB for 30 minutes, the basal insulin secretion of each well was collected and measured. The compound dilutions (〇, 0.1, 0.3, 1, 3, 10 μΜ) were then added to the well (replicated in duplicate) in 1 ml of KRB supplemented with 5·6 mM glucose. After incubation at 37 ° C for 30 minutes, the sample was removed to measure its insulin content. Insulin measurements were made using the Mercodia Rat Insulin ELISA kit according to the manufacturer's instructions with a known insulin concentration standard curve. For each well, the insulin content was corrected by subtracting the basal secretion from the pre-incubation amount -459 - 201209054 in the absence of glucose. Data was analyzed using the XLfit 3 software. Preferably, the compound of the invention has an E C 5 增加 which increases insulin secretion by less than 10 μΜ. Oral Glucose Tolerance Test The efficacy of the compounds of the invention against oral glucose (Glc) tolerance can be assessed using male Sprague-Dawley rats. Food was taken 16 hours before the administration of Glc and no food was supplied during the entire study period. Rats were given free access to water during the study period. An incision was made in the tail of the animal, followed by blood collection (1 drop) to measure the basal Glc content, and Glc was administered after 60 minutes. Next, the rat body weight was weighed, and the test compound or vehicle (20% hydroxypropyl-β-cyclodextrin aqueous solution) was orally administered to the rats, and another blood sample was collected after 45 minutes, and treated with Glc loading ( Oral 2 g kg-1). Blood samples were collected from the incision of the tail at 5, 15, 30, 60, 1 2 0, and 180 minutes after administration of Glc. Blood glucose sputum was measured immediately after collection using a commercially available glucose meter (OneTouch® UltraTM, purchased from Lifescan). Preferably, the compounds of the invention are statistically reduced in Glc levels at a dose of S 1 〇〇 mg kg-1. The efficacy of the compounds of the invention for oral glucose (Gle) tolerance is assessed using male C57B1/6 mice or male DIO C57BL/6J mice or male mice. Food was taken 5 hours before the application of Glc and no food was supplied during the entire study period. The mice were free to consume water during the study period. An incision was made in the tail of the animal, followed by blood collection (2 μμΙ〇 to measure the basal Glc content, followed by G1 c after 45 minutes. Then 'weigh the mouse' and give the mice oral test compound or vehicle (2 0% hydroxypropyl-β-cyclodextrin aqueous solution or -460- 201209054

25% Gelucire 44/14 in water), another blood sample was collected after 30 minutes (20 μΙ〇, and treated with Glc loading (oral 2-5 g kg·1). 25, 50 after taking Glc Blood samples (20 μί) were collected at 80, 120, and 180 minutes. 20 kL of blood sample for measuring Glc content was collected from the incision of the tail to a disposable micropipette (D ade D iag η 〇stics I n c., In P uert 〇Rico), the sample is added to 480 pL of hemolytic agent. Then, duplicate 20 μl of diluted hemolyzed blood is added to the 180 μί Trinders Glucose Reagent (Sigma Sigma) in the 96-well analysis plate. In the Trinder colorimetric method, after mixing, the sample was allowed to stand at room temperature for 30 minutes, and then the data was read by the Glc standard method (Sigma glucose/urea nitrogen binding standard test group). The compound of the present invention was statistically The dose of S 1 0 0 mgkg _1 reduced the G1C content. Example 16 (30 mpk po) was evaluated in male DIO C57BL/6J mice in the oral glucose tolerance test. Relative to the vehicle (2% hydroxypropyl-β- Cyclodextrin aqueous solution), active blood glucose AUC (0-1 20 minutes) At least 44% (ρ = 0.002) ° -461 -

Claims (1)

201209054 VII. Patent application scope: 1 · A compound represented by formula (1) Or a pharmaceutically acceptable salt thereof, wherein A is a para-substituted base or a para-substituted 6-membered heteroaryl fluorene having 1 to 3 nitrogen atoms; r1 is ammonia, cumyl, oxy , C^-4 yard base, Cm halogen yard base, Ci-4 hospital base or ^2-6 courtyard oxygen base, R2 is: , Ν. '(CHA J (R3)m phenyl optionally substituted by one or more halo, methyl, halomethyl or methoxy, or optionally by one or more halo, Cl-2 alkyl or Halomethyl substituted pyridyl, N-pyridone or N-pyrazolyl; R3 is each independently halo, methyl or halomethyl; Z is -C(0)0R4, -C(0)R4 , -S(0)2R4, -SCOhNiCu alkyl)R4, anthracenyl or -CH2 -heteroaryl" and when both p and q are fluorene, Z may also be -CH2-phenyl, wherein the phenyl group Optionally substituted with one or two groups each independently selected from the group consisting of Cu alkyl, halo-4 haloalkyl, and halo; R4 is aryl, heteroaryl, C2-6 alkyl, c3.6 cycloalkyl, C4-6 heterocyclic group, heterocyclic group (^.4 alkyl, C2_6 alkoxyalkyl, aryl Cl.4 alkyl, hetero-462 - 201209054 aryl Cu alkyl or C4-6 cycloalkyl d.4 An alkyl group, the cycloalkyl group (^_4 alkyl group optionally substituted by a Cu4 alkyl group; Wherein when Z is or comprises a heteroaryl group or when R4 is or comprises an aryl or heteroaryl group, the aryl or heteroaryl group may be optionally substituted with one or two groups selected from the group consisting of halo, cyanide Base, SF5, &lt;^-4 alkyl 'Ci-4 haloalkyl, Ci-5 hydroxyalkyl' Cm alkoxy, C2-4 alkoxyalkyl, heterocyclyl, heterocyclyl Cm alkyl , heteroaryl 匕 alkyl, Cm alkyl amine, Cm alkylamino Cm alkyl, C3-6 cycloalkyl and -(Cu alkyl)-(C3-6 cycloalkyl), wherein the ring The alkyl group and the alkyl group are each optionally substituted by one or two groups each independently selected from the group consisting of (^-4 alkyl, hydroxy or halo; X is selected from CR5H, hydrazine, and NR6' wherein R5 and R6 are each independently The ground is ammonia or a C 1 _2 hospital base; Y is Y1 or W-Y1, wherein w is a 5-membered heteroaryl ring containing one or more heteroatoms selected from N, oxime and S, and Y1 is selected from CR7H, hydrazine and NR8, wherein R7 is hydrogen, Cu alkyl, C2-6 alkoxyalkyl or heterocyclic; wherein the C,-2 alkyl group may be optionally substituted by cyano, hydroxy or halo' R8 is Cj-4 alkyl or Cw cycloalkyl, with the proviso that when Y is W-Y1, X is 〇 and Y1 is CR7H, when Y1 is 〇 or NR8' X is CR5H, and when X is deuterium or NR6, Y1 is CR7H; each R9 and R1Q are each independently H, halo, Cu alkyl, Ci-2 haloalkyl, Cm alkoxy or hydroxy; or R9 And R1C) are bonded to form nitrogen bicyclo[3.3.1]nonane, 3-oxo-7-azabicyclo[3.3.1]nonane or nitrogen bicyclo[3.2.1]xin; R11 is H, dentate, Cl -2 yard base, Ci-2 halogen yard base or Ci-3 court base; -463- 201209054 m is 0, 1 or 2, η is 0 or 1; ρ and q are 0, 1 or 2 'preconditions respectively Is 0 SP + q S 2 ' and r is 1 or 2. 2. A compound according to claim 1, wherein the compound has a stereochemistry (compound represented by formula (la)) as defined by the formula: 3. For example, if you apply for a compound of category 丨 or 2, where? And q are each independently 0, 1, or 2, with the proviso that p + q does not exceed 2. 4. A compound as claimed in claim 3, wherein P and q are the same as each other. 5. A compound as claimed in claim 3, wherein both p and q are 1. 6. A compound as claimed in claim 1 wherein γ is γ 1 . 7. A compound according to claim 6 wherein Y1 is deuterium and X is CR5H. The compound of any one of claims 1 to 6, wherein Y is γΐ, X is Ο, and γ1 is CR7h. 9. The compound of claim 8 is as follows: (b) is the following formula (Ib) -464 - 201209054 R2 A compound according to any one of claims 1 to 5, wherein Y is W-Y1, and Y1 is CR7H directly bonded to X. 11. The compound of claim 10, wherein X is hydrazine. 12. A compound according to claim 10, wherein W is an oxadiazolyl group. 13. The compound of claim 12, which is represented by the following formula (Ic): (Ic). 14. A compound according to claim 1 wherein A is selected from the group consisting of pyridine, pyrimidine, pyrazine and pyridazine. 1 5. The compound of claim 14, wherein A is 2- or 3--465-201209054 pyridinyl or 2- or 5-pyrimidinyl, wherein the 2-, 3- or 5--pyrrole The junction of a steep or piperidine ring. 1 6 · If the compound of claim 9 or 13 is applied, 'A' is selected from the following: A compound according to claim 1 wherein Z is -C(0)0R4, _c(〇)R4, s(〇)2R4 or s(〇)2N(Ci 3 alkyl)r4. 18. The compound of claim 17, wherein R 4 is selected from the group consisting of C2-6 fluorenyl, C4·5 alkoxyalkyl, C3.6 cycloalkyl, and C4-6 cycloalkyl Ci-4 1 兀', wherein the cycloalkyl group is optionally substituted with a cu 4 hospital base. 19. A compound according to claim 18, wherein R4 is propyl or isopropyl. 2. A compound according to claim 1, wherein 2 is a heteroaryl Ge 2 aryl group which is unsubstituted or substituted with one or two groups selected from the group consisting of: SF5, Cl 4 alkane Base, Ci, haloalkyl, hydroxyalkyl, C2-4 alkoxy group. -6 cycloalkyl, (CM alkyl γ η cycloalkyl), heterocyclic group, heterocyclic group C 4 alkyl, heteroaryl Ci "alkyl, Cl. 4 alkylamino, C1M alkylamino匕 4-alkyl, cyano and dentate; wherein the cycloalkyl and alkyl are each optionally substituted by one or two groups each independently selected from a c14 alkyl, hydroxy or halo group. -466- 201209054 21 'A compound as claimed in claim 20, wherein Z is a heteroaryl group selected from the group consisting of oxalopyrazole, pyrimidine, pyridazine, thiazole, tetrazole, benzothiazole and thiadiazepine. A compound of claim 20 or 21 wherein Z is 1,2,4-oxaxazole-3-yl, 12,4-oxadiazol-5-yl or pyrimidine-2-yl. a compound of which 2 is 1,2,4-oxazol-3-yl or benzyl, 2,4-oxadiazole-5-yl, and which is subjected to Cl**alkyl, [μf)halane Substituted with a Cl_5 hydroxyalkyl group, a Cm hydroxyalkyl group, a C2-4 alkoxyalkyl group or a heterocyclic group. 24. A compound according to the scope of claim 4, wherein z is pyrimidine_2_yl' and it is not Substituted or substituted with one or more halo groups. 2 5 · If applying for a patent A compound according to the item 1, wherein Z is -c Η 2 -phenyl' wherein the phenyl group is unsubstituted or one or two are each independently selected from the group consisting of Ci-4 alkyl, Ci-4 haloalkyl and halogen The compound of claim 1, wherein R is a η or Cl 2 〇 院 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 A compound of claim 1 wherein R 2 is unsubstituted or substituted phenyl, pyridyl, N-pyrazolyl or N-pyridinone. 2 9. A compound according to claim 28 Wherein R 2 is phenyl substituted with one 'two or three halo' or when W is a 5-membered heteroaryl ring, R 2 may be unsubstituted phenyl or via one or more halo, Methyl or halomethyl-substituted phenyl. 3 0 · A compound of claim 28, wherein r 2 is a s-467-201209054-based, fluorenyl-pyrazole or N-pyridinone group, and It may be substituted with -, two or three halo's methyl or methoxy. 3 1 _ as claimed in claim 1, wherein R7 is Η or C _2 院. 3 2 . The compound of any one of clauses 17 to 19, wherein R7 is a Cl.2 alkyl 'r2 is a phenyl group which is unsubstituted or substituted with one or more halo, methyl or halomethyl groups. 3 3 · A compound of claim 25, wherein R 2 is phenyl which is unsubstituted or substituted with one or more halo, methyl or halomethyl. 34. A compound wherein R5 is hydrogen or methyl. 3 5. A compound according to claim 1, wherein R6 is hydrogen. 3. 6. The compound of claim 1, wherein r8 is methyl. The compound of claim i, wherein r 1 1 is an anthracene, a halogen or an alkoxy group. 3 8. The compound of claim 1, wherein ^ and r μ are the same as each other. 3 9. The compound of claim 38, wherein R9 and R10 are both Η. 4. A compound as claimed in claim 1, wherein Ρ (or q) is 2' and two R9 (or R1Q) are identical to each other. 41. The compound of claim 40, wherein in the R9 (or R1 (&gt;), the test is not Η, and the other is Η. 42.~ a compound of the formula (Id), or Pharmaceutically acceptable salt -468- 201209054 Wherein A, R1 to R11, X, Y, m, n, p, q and r are as defined in claim 1; Z is -C(0)R12; and R12 is -NHC(0)R13 or - NHC(NH)R13, wherein R&quot; is selected from the group consisting of Cj-4 alkyl, (^-4 haloalkyl, Cu hydroxyalkyl, Ci.4 alkoxy, C2_4 alkoxyalkyl, heterocyclyl, a heterocyclic group is a 4-alkyl group, a heteroaryl s-alkyl group, a C3.6 cycloalkyl group, and a -(C-alkyl)-(C3.6 cycloalkyl group), wherein the cycloalkyl group and the alkyl group are optionally Substituting one or two groups each independently selected from a Ci-4 alkyl group, a hydroxyl group or a halogen group. 43. A compound according to claim 42 wherein the rule 13 is a Cm alkyl group. The compound of claim 42 or 43, wherein Y1 is CR7H, wherein 117 is Cw alkyl. 4 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in a therapeutic manner A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diabetes. 47. The compound of claim 1 or Pharmacologically available -469- 20 1209054 Salt used to treat or prevent obesity, metabolic syndrome (sputum syndrome), glucose intolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension 48. A pharmaceutical composition or composition comprising a compound according to any one of claims 1 to 44 and a pharmaceutically acceptable carrier thereof. A pharmaceutical composition of claims 1 to 4 The use of a compound according to any one of the items 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of diabetes. 50. The use of claim 49, wherein the diabetes is Type II. The use of a compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, for the manufacture of an obesity, metabolic syndrome (X syndrome) , glucose intolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension. -470 - 201209054 4 IV. Designated representative map: (1) Representative Pictured: None (b) of FIG element symbols representative of this briefly described: None 201209054 V. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: (I) 1 -4-