TW200302094A - 3 - (imidazolyl) -2- alkoxypropanoic acids - Google Patents

Abstract

Compounds according to formula (I) wherein n is 0-3, R1 is optionally substituted C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, Heterocycle, Aromatic heterocycle, Aryl or hydrogen and R2, R3, R4, R5, R6, R7, R8 and R9 are each independently selected from hydrogen and optionally substituted C1-6 alkyl, or R5 and R8 are an alkylene chain, are novel. They are useful in the treatment of thrombotic conditions and other pathologies associated with fibrin deposition.

Description

200302094 Π) 发明 Description of the invention [Technical field to which the invention belongs] The present invention relates to a series of 3- (imidazolyl) -2- (ω-aminoalkoxy) -propionic acid derivatives, and the compounds are TAFIa inhibitors are also inhibitors and can be used in the treatment of diseases. [Prior Art] [Background of the Invention] If a blood vessel is injured, a complicated mechanism in a mammalian body is developed to repair the body and stop blood flow. Injured blood vessels contract to reduce blood flow to the injured site, platelet aggregation reduces blood loss to the injured site, fibrinogen splits to produce fibrin, and fibrin polymerizes to form a blood clot. This blood clot covers the site of blood vessel damage and prevents blood loss. Polymerized cellulose also provides a temporary matrix that enhances subsequent repairs. Once the blood vessels are repaired, the blood clot will dissolve. This sequence of blood clots leads to the tandem effect of coagulation, and the sequence of fibrinolysis leads to the lysis of fibrin. Imbalances in the blood coagulation process are thought to be the origin of many different conditions, which are linked by unwanted cellulose accumulation. The scale of cellulose aggregation can be determined by a delicate balance between two biochemical tandem effects in the human body. So agents that can adjust the balance between coagulation and fibrinolysis may be valuable in the treatment of these conditions. Studies have shown that coagulation and fibrinolysis are linked through the production of alpha-thrombin. Alpha-thrombin is the final product of the tandem effect of blood clotting -6-(2) (2) 200302094, and can transform fibrinogen into fibrin. In addition to mediating coagulation, alpha-thrombin can also reduce the rate at which blood clots are broken down by serine protease fibrinolytic enzymes. The anti-fibrinolytic effect of thrombin is TAFI (thrombin-activated fibrinolytic inhibitor). TAFI is a 00 kDa glycoprotein found in human plasma. TAFI is also considered to be procarboxypeptidase B, carboxypeptidase B, plasma carboxypeptidase B, carboxypeptidase U, and carboxypeptidase R. After the onset of the coagulation tandem effect, TAFI is converted into an activated form (TAFIa), and TAFIa then acts on the fibrin matrix that develops the blood clot to prevent the blood clot from dissolving. TAFI is circulated in general plasma in an inactive form at a concentration of about 75 nM. Thrombin converts an inactive zymogen to active TAFI (TAFIa), and the response is increased approximately 1 250 times by thrombomodulin. Once activated, TAFIa develops from a fibrin clot that cleaves both the carbon-terminal arginine and lysine groups. Removal of these dibasic amino acids from the surface of the fibrin matrix reduces blood clot dissolution. This is achieved by inhibiting fibrinolysis: tissue plasminogen (tPA) and its substrates, blood fibers. Prolysin is a key mediator of plasmin precursors. Both tPA and plasminogen contain structural features (known as kringle domains) that are tightly bound to the carbon-terminal lysine group. The removal of these binding sites prevents the formation of a ternary complex between tPA, plasminogen, and plasmin, and inhibits the conversion of plasminogen to plasmin, thus inhibiting Protects blood clots from rapid degradation. In the presence of a DFIa inhibitor, TAFIa is not able to play a role in inhibiting the development of fibrin coagulation in the development of fibrin clots as described above. So TAFIa inhibitors should be sufficient to enhance fibrinolysis. We can see that the general balance between coagulation and fibrinolysis is chaotic and favors coagulation. Fibrin is more common than normal. This makes patients more likely to develop more than one symptom involved in thrombosis. Such patients can be expected to benefit from treatment with plasminogen. Mckay et al. (Biochemistry 1978, 17, 401) revealed experiments with many compounds that could be used as competitive inhibitors of pancreatic-derived bovine carboxypeptidase. Inhibition is achieved by protecting the active sites of tyrosine and ammonium glutamate B from the irreversible alkylation of bromoacetamidine-D-arginine or bromoacetamine butylguanidine. The following is implied: these inhibitors can act as bradykinin synergists. Bovine pancreas-derived enzymes are very different from those found in human plasma, so it is impossible to predict that inhibitors of one will inhibit the others. In addition, these types of inhibitors have very different uses. This disclosure therefore does not provide teaching of TAFIa inhibitors or their uses.

Redlitz et al. (J. Clin. Invest. 1 995, 96, 2534) teaches that plasma carboxypeptidase B (pCPB, or TAFI) is involved in the formation of blood clots. In the presence or absence of pCPB, the dissolution of the blood clot, we found that the presence of pCPB slows the dissolution of the blood clot. To determine the relationship between PCPB, we performed two control reactions; one was to repeat the dissolution test in the presence of pCPB and potato carboxypeptidase inhibitor (PCI), and the second was to perform the dissolution reaction in the presence of pCPB-removed plasma. . Dissolution of both reactions proceeded unchecked. B off a et al. (L Biol · Chem. 1 99 8, 27 3, 2127) compared plasma glycosylation, activation, thermostability, and enzymatic properties of plasma (4) (4) 200302094 and recombinant TAFI and TAFIa . Inhibition constants were determined for three competitive inhibitors: 6-aminohexanoic acid (U-ACA), 2-guanethinosuccinic acid (GEMSA), and potato carboxypeptidase inhibitor (PCI). We have many carboxypeptidases (that is, enzymes that cleave the carbon-terminal amino acids from peptides). The enzymes can be divided into acidic, neutral or alkaline enzymes, depending on the type of amino acid that they cut. Alkaline carboxypeptidases can cut arginine, lysine and histidine. TAFIa is a member of a specific subgroup of alkaline carboxypeptidases. For the purposes of the present invention, the inhibitors disclosed above by Re d 1 tz et al. And Bo f f a. Are too weak, non-specific, and are not suitable for consideration as therapeutic TAFIa inhibitors. Furthermore, when the role of TAFIa is explained in the context of blood clot dissolution, it is not implied that TAFIa inhibitors can be used to treat the disease. US-A-5993815 teaches the use of a peptide that binds to TAFI zymogen, thereby inhibiting the activation of the peptide, to treat diseases from which the carbon-terminal lysine or arginine of the complete peptide is cleaved. Suitable diseases: arthritis, septicemia, thrombosis, stroke 'deep vein thrombosis and myocardial infarction. The peptide used is an antibody or a functionally active fragment. The peptide should be used in an amount that promotes fibrinolysis in vivo. WO 00/66550 and WO 00/6655 7 disclose many types of compounds that can be used as inhibitors of carboxypeptidase U. Carboxypeptidase U inhibitors are required to promote fibrinolysis, so the compounds are required for the treatment of thrombosis. Although details of appropriate analyses are given, no data support this claim. -9- (5) (5) 200302094 WO 00/66 1 52 discloses a blend which contains a carboxypeptidase U inhibitor and a thrombin inhibitor. Suitable carboxypeptidase U inhibitors are compounds in WO / 66550. The blend is required to be used mainly in the treatment of thrombosis. W0 1/1 9 83 6 discloses a series of phosphates and their analogs which can act as carboxypeptidase U inhibitors, which compounds are suitable for the treatment or prevention of thrombosis. W02 / 14285 discloses a series of α · imidazolylmethyl-ω-aminocarboxy φ acids and Nα- (ω-aminoalkyl) -histidine derivatives (inhibitors of TAFIa). The above compounds are considered to be potentially useful in the treatment of many symptoms. The present invention discloses another class of TAFIa inhibitors. [Summary of the Invention] [Description of the Invention] The first aspect of the present invention provides compounds such as the general formula ⑴

-10- (6) (6) 200302094 η is 0, 1, 2 or 3; R1 is selected from the following groups: (a) —A linearly or branched Ci.6 alkyl group optionally substituted , (B) — an optionally substituted straight or branched C2-6 alkenyl group, (c) an optionally substituted straight or branched C2.6 alkynyl group, (d) an aryl group, (e ) Aromatic heterocycle, (0 heterocycle, (g) hydrogen; wherein any of the above groups (a), (b) and (c)) is selected from the group consisting of: Cm cycloalkyl , Aryl, aromatic heterocyclic ring, heterocyclic ring, OR1., NR1% 11, S (〇) PR10, OC (〇) R ", co2Ri., Comon10Rn, SChNR1.! 11, halogen and NHS 〇2R1 (), wherein p is 〇, I or 2; R2, R3, R4, R6, R7, and R9 are each independently selected from the following groups: hydrogen and arbitrarily substituted by 〇1 and halogen R 6 and R 8 are each independently selected from the group consisting of hydrogen and a straight or branched (C: -6) alkyl group optionally substituted with OR " or halogen , Or both together, is C 2 · 6 Extender base chain; R1Q and R11 are each independently selected from the following groups: hydrogen and straight or branched C 1 · 6 yuan; aryl is a 6-1 4 section aromatic monocyclic or fused polycyclic carbocyclic group, which is optionally substituted by ~ more than one substituent selected from the following groups: R " 'Halogen, 0R13, NR1'3R14, NR13C〇2r12, cChR · 13, (7) (7) 200302094 NR] 3S〇2R] 2, CN, haloalkyl, 0 (haloalkyl), SR13, S (〇) R12, s〇2r12, 〇c (〇) r13, 〇2nr13r14, c (〇) nr13R14, C3.7cycloalkyl, 〇 (C3-7 环 院 基), R15 and 〇R1S, of which R12 is a linear or branched C! .6 alkyl group, and R13 and R14 are each independently selected from the following groups: hydrogen and a linear or branched C! .6 alkyl group 'R15 is R12, OR13, A halogen or haloalkyl optionally substituted phenyl; an aromatic heterocyclic ring is a 5- to 7-membered aromatic ring that contains 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. The ring is arbitrarily substituted by one or more groups selected from the group consisting of OR13, NR13R14, Co2R13, NR13Co2R12, R12, halogen, CN, haloyl, 〇 (haloalkyl), SR13 , S (〇) R12, SChR12, 〇c (〇) R13, N R13S〇2R12, S〇2NR13R14 and C (〇) NR13R14; and the heterocyclic ring is a 3 to 8-membered ring, which contains 1 to 3 heteroatoms independently selected from the following groups: oxygen, sulfur and nitrogen The ring is a saturated or partially saturated ring, and the ring is further arbitrarily substituted with one or more substituents selected from the group consisting of 〇r13, NR13R14, CChR13, NR13C02R14, R12, halogen, CN, Haloalkyl, 0 (haloalkyl), SR13, S (〇) R12, S02R12, OC (〇) R13, Nrhs〇2Ru, or a tautomer of a compound of formula (I) 'or A pharmaceutically acceptable salt or solvate of a compound of formula (I) or another tautomer thereof. Used in this specification: i) Halogen includes: fluorine, chlorine, bromine, and iodine-12- (8) (8) 200302094 Η) Haloalkyl includes: monohaloalkyl, polyhaloalkyl, and perhaloalkyl ' Examples are 2-bromoethyl, 2,2,2-trifluoroethyl, chlorodifluoromethyl and trichloromethyl. lH) Unless otherwise specified, alkyl includes: straight or branched chain. We should understand that in compounds of the general formula (I), R1 and C (R2) (R3) (amino acid) groups Can be linked to form a covalent bond at any one of the atoms of the imidazole ring, and does not mean that the formula should be interpreted as limiting R1 to the C2 and N3 positions, nor should C (R2) (R3) (amino The acid) groups are confined to the C4 and C5 positions. I further understand that the two groups cannot be connected to the same atom of the imidazole ring together, and that only one of the nitrogen atoms of the imidazole ring (labeled as N1 by convention) can form a covalent bond. So possible substitution patterns are 1,2-; 1,4-; 1,5-; 2,4- and 2,5-. When the imidazole is substituted with 2,4- or 2,5-, a hydrogen atom is attached to the N1 position. Several compounds such as formula (I) may exist in more than one tautomeric form. If the imidazole of the general formula (I) is substituted at the 2 and 4 positions, the 2,4-disubstituted imidazole can be tautomerized to form the corresponding 2,5-di-substituted imidazole. In addition, when a compound including an aromatic heterocyclic ring is substituted with a hydroxyl group, it may exist in the form of an 'oxo' tautomer. The tautomeric relationship between 2-hydroxypyridine and 2-pyridone is a well-known example of this phenomenon. These tautomers of compounds such as formula (1) (including their mixtures) are included in the scope of the present invention. For example, the compound of formula (I) contains more than one asymmetric carbon atom (centre palm), and it can have two or more types of optical isomers (such as isomeric 200302094 0). Species and epimers). Such as formula (I): The compound contains a carbon-carbon double bond, and the cis (Z) / trans (E) stereoisomerism can also occur. Various stereoisomers and mixtures (including racemic mixtures) of compounds of formula (I) are included within the scope of the present invention. The various stereoisomers can be separated from the mixture by conventional methods such as the stepwise crystallization or delamination of a mixture of compounds or suitable salts or derivatives. In particular, various paraisomers such as compounds of formula (I) can be produced in an isolated manner, such as by applying HPLC to a corresponding racemic mixture of a suitable para-supporting Φ or a suitable optically active acid or The diastereomeric salts formed by the reaction of the base (if necessary) with the corresponding racemic mixture are crystallized in steps. Various palmar isomers can also be obtained from the corresponding optically pure intermediates prepared by the isolation method. These general principles are described in J. Jacques and A. Collet (" Enantiomers, Racemates and Resolutions', Wiley, NY, 1981) and in W. Liu (" Handbook of Chiral Chemicals ", D. Ager (ed.), M. Dekker, NY, 1999; chapter 8) is discussed in more detail. · It will be understood that the compounds of formula (I) have acidic and basic functional groups. Therefore, in addition to the uncharged forms described in the general formula, compounds such as formula (I) may exist in the form of internal salts (zwitterions). In addition, compounds such as formula (I) can form pharmaceutically acceptable salts with acids or bases. These zwitterions and salts are included in the scope of the present invention. The pharmaceutically acceptable salts of the compound of formula (I) can be rapidly manufactured by mixing the compound of formula (I) and the desired acid or base (if necessary) together. A salt is precipitated from the solution, and the salt is collected by filtration or (-14) (10) 200302094 or collected by evaporating the solvent. Salts can also be manufactured by ion exchange, e.g. equilibrating a compound of formula (I) with a suitable ion exchange resin. Ion exchange can also be used to convert one salt form (a pharmaceutically unacceptable salt with an acid or base) of a compound of formula (I) to another salt form. These methods are usually familiar to those skilled in the art. Suitable acid addition salts are made from acids that form non-toxic salts. Examples of such salts are hydrochloride, hydrobromide, hydroiodate, sulfate, bisulfate, Nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, succinate, benzoate Acid salt, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and palmitate. Suitable basic salts are made from bases which form non-toxic salts. Examples of such salts are: sodium, potassium, aluminum, calcium, magnesium, zinc, and diethanolamine salts. For reviews of pharmaceutically acceptable salts, see Berge et al. (J. Pharm. Sci., 1 97 7, 66, 1). Compounds of formula (I) can form pharmaceutically acceptable solvates (including hydrates). These solvates may also be included within the scope of the present invention. Compounds of formula (I) may exist in more than one crystalline form. These polymorphs (including mixtures thereof) may also be included within the scope of the present invention. The scope of the present invention further includes prodrugs of the compound of formula (I), that is, pharmaceutically acceptable derivatives of the compound Among them, more than one of the above functional groups have been modified. He was transformed into a parent compound (11) 200302094 in vivo. Suitable prodrugs are discussed below: Drugs of Today 1 9 83, 19, 499-538 and Annual Reports in Medicinal Chemistry 1975, 10, 306-326. The absolute stereochemistry of a compound such as formula (I) can be described in formula (IA) or formula (IB) below. Traditionally, the absolute stereochemistry at the center of the palm of (IA) is designated as 'S', and the center of the palm of (IB) is designated as 'R'. Formula (ΙΑ)

(IA) (Old) Suitable compounds of formula (I) include the following compounds: imidazole in C2

Or the C4 position is substituted with a C (R2) (R3) (amino acid) group to obtain compounds of formulae (IC) and (ID), respectively. Particularly suitable compounds of formula (I) are the following compounds: R1 is attached to the C4 position of the imidazole moiety, and C (R2) (R3) (amino acid) group is attached to the C2 position to obtain the formula The 2,4-disubstituted imidazole or R1 of (1C1) is attached to the N1 position of the imidazole moiety, and the C (R2) (R3) (amino acid) group is attached to the C4 position to obtain the formula (ID1) 1,4-disubstituted imidazole. The most suitable compound of formula (I) is the following compound: R1 is attached to the N1 position of the imide (I sitting part, and C (R2) (R3) (amino acid) group is attached to the γ position This gives 1,4-disubstituted imidazole of formula (ID1).

R1 is preferably hydrogen, aryl, or Cl.6 alkyl or Ch6 alkenyl optionally substituted by one or more groups selected from the group consisting of: C3.7 cycloalkyl, aryl, and aromatic heterocyclic ring , Heterocycle, 〇R1 (), NRWR11, S (〇) PR1 (), 〇C (〇) R ", CO2R10, CONRUR11, SChNR1. ! ^ 11, halogen and NHS〇2R ". R1 is more preferably hydrogen, aryl, or C! .6 alkyl or CM alkenyl optionally substituted by one or more groups selected from the group consisting of: C3d cycloalkyl, aryl, and aromatic heterocyclic ring 〇R1G, CO2R1Q, halogen and NHS〇2R1 [. R1 is more preferably hydrogen, aryl, or Cu alkyl arbitrarily substituted by one or more groups selected from the group consisting of: Cw cycloalkyl, aryl, aromatic heterocyclic ring, OR1Q, CO2R " And NHSChR ". R1 is more preferably hydrogen, aryl, or an optionally substituted Cu alkyl group selected from cyclohexyl and aryl groups. R] more preferably -17- (13) (13) 200302094 is hydrogen or C !. 3 alkyl. R] is more preferably hydrogen. R2 and R3 are each preferably independently selected from hydrogen and C1 · 6fluorenyl. R and R are more hydrogen. R4 is preferably hydrogen or Cw alkyl. R4 is more preferably hydrogen. R6, R7 and R9 should each be independently selected from hydrogen and c] · 6 courtyards. R6, r7 and R9 are preferably independently selected from hydrogen and Ci.3 alkyl. R6 and r9 are more preferably independently selected from hydrogen and methyl. R6, R7 and R9 are most preferably all hydrogen. When R5 and R8 do not form a C2 · 6 extension base, then R is preferably gas or alkyl, more preferably hydrogen or C! .3 alkyl, more preferably hydrogen or methyl, and most preferably methyl. R8 is preferably hydrogen or <: 6 alkyl, more preferably hydrogen or Cl. 3, and more preferably hydrogen or methyl, most preferably hydrogen. When R5 and R8 form a C2.6 alkylene group, the alkylene group is preferably a C2-3 alkylene group, and more preferably a C2 alkylene group. R1 and R11 are each preferably independently selected from hydrogen and Ci · 3 alkyl. R1. And R11 are preferably each independently selected from hydrogen and methyl. Aryl includes optionally substituted phenyl, naphthyl, anthracenyl, and phenanthryl. Aryl is preferably phenyl or naphthyl optionally substituted with 1-3 groups selected from the group consisting of: R12, halogen, OR13, nr13r14, NR13c02Rl2, co2Rl3, NR13S02R12, CN, Halo base, 〇 (halo base), SR13, S (〇) R12, SCbR12, 〇C (〇) R13, S〇2NR13R14, C (〇) NR " R14, C3-7 ring grafting group, 〇 (C3 -7 Huanyuanji), R15 and OR15. Aryl is more preferably a radical optionally substituted by a group selected from the group consisting of Cl-6, halogen, 0 (Cl.6), CF3, C3-7 ring, and 〇 ( CH cycloalkyl), R15 or OR15, R15 is a phenyl group optionally substituted with a (14) (14) 200302094 group selected from the group consisting of: · Cl. 6 alkyl, halogen, 〇 (Cl · 6 alkyl) or CF3. Aryl is more preferably phenyl optionally substituted with a group selected from the group consisting of: Cl.6 alkyl, CF3, cyclohexyl, 0 (cyclohexyl), R15 or OR15, and R15 is a group selected from The phenyl group optionally substituted by a group in the group: Cw alkyl, chlorine, fluorine, 0 (C! -6 alkyl) or CF3 ° aryl is most preferably phenyl. The aromatic heterocyclic ring is preferably an aromatic ring of 5 or 6 members, which contains 1 or 2 heteroatoms each selected from oxygen, sulfur and nitrogen. The heterocyclic ring includes: optionally substituted furanyl, thionyl , Pyrrolyl, chewizolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperazinyl Triazinyl, the heterocyclic ring is arbitrarily substituted by 1-3 groups selected from the group consisting of 〇R13, NR13R14, C〇2R13, NR13C02R12, R12, halogen, CN, haloyl, (Halofluorenyl), SR] 3, S (〇) R12, S02Ri2, OC (〇) R13, NR13S02R12, S02NR13R14, C (〇) NR13R14. The aromatic heterocyclic ring is more preferably a 5- or 6-membered aromatic ring containing 1 or 3 heteroatoms each selected from oxygen, sulfur, and nitrogen. The heterocycle is 1-3 from 3¾ of the following groups. Arbitrary substitution of groups in: OR13, NR13R14, Co2R13 'NR13Co2R12, R12, halogen, CN, haloalkyl, 〇 (haloalkyl), SR13, S (〇) R12, S〇2R12, 〇C (0) R13, nr13s〇2r12, so2NR13R14, C (〇) NR13R14. The aromatic heterocycle is most preferably an unsaturated 5- or 6-membered aromatic ring that contains one or two heteroatoms each selected from oxygen, sulfur, and nitrogen. The heterocyclic ring is preferably a 3 to 8-membered ring, which contains 1 or 2 heteroatoms each selected from oxygen, sulfur, and nitrogen. The ring is a saturated or partially saturated ring. Any group selected from the following groups is optionally substituted: 〇Rl 3, -19- (15) (15) 200302094 NRi3R14, Co2R13, NR13Co2R12, R12, halogen, CN, haloalkyl, 〇 ( Haloalkyl), SR13, S (〇) R12, S〇2R12, 〇C (〇) R13, NR13s〇2R12, SO2NR13R14, c (〇) nr13r14. A heterocycle is most preferably an unsaturated 5- or 6-membered ring containing one or two heteroatoms each selected from oxygen, sulfur, and nitrogen. The ring is a saturated or partially saturated ring. Heterocycles include: ethylene oxide, azetidinyl, tetrahydrofuranyl, thiaalkyl, pyrrolidinyl, dioxocene, dihydropyranyl, tetrahydropyranyl, morpholinyl, piperidyl And piperazinyl. A suitable compound of the present invention is: (2S)-(-)-2- (2-aminoethoxy) -3- (1-phenyl- 1Η-imido-4 · yl) propionic acid (Example 6 ); (23) -2-{[(11〇-2-amino-1-methylethyl] oxy} _3- [1- (2-cyclohexylethyl) -1Η-imidazol-4-yl ] -Propionic acid (Example 15); (2S) -2-{[(lR) -2-amino-1-methylethyl] oxy 丨 _3- (1-phenyl-1H-imidazole- 4-yl) propanoic acid (Example π); (2S) -2-{[((2S) -2-aminopropyl] oxyl 3- [1- (2-cyclohexylethyl) -1H- Imidazol-4-yl] propanoic acid (Example 34); (2 S)-2-(2-Aminoethoxy) -3-(1 fluorene-imidazol-4-yl) propionic acid (Example 50) ; (2S) -2-{[(lR) -2 -amino-1-methylethyl] oxyb 3- (1H-imidazol-4-yl) propanoic acid (Example 5 1); (2S ) -2-{[(lR) -2_I Women's-1-methylethyl] oxypyridine) -1H-imidazol-4-yl] -propionic acid (Example 52). Particularly suitable compounds are (2S) -2-{[(1R) · 2-Amino-1-methylethyl (16) (16) 200302094] oxyb 3- (1Η-imidazol-4-yl) Propionic acid (Example 51). Compounds of formula (I) are inhibitors of TAFIa. The inhibitory effect of TAFIa can be confirmed by analysis according to the method of Boffa et al. (U. Biol. Chem. 1 99 8,273, 2127) mentioned below. The compound's activity was identified by the method of calculating Ki 値. Generally, the compounds of the present invention have Ki 以下 of 10 // M or less. The preferred compounds are Ki // below 1 μM, and even below 100 nM. The most suitable compound is Ki 値 below 25 nM. For example, compounds of formula (I) are selective for other carboxypeptidases (especially carboxypeptidase N (cPN)). The inhibitory effect of undesired CPN is considered to be the most likely cause of unwanted side effects in clinical applications. The selectivity can be expressed as the ratio of Ki 値 of TAFIa to Ki 値 of CPN. Generally, the compounds of the present invention have a selectivity ratio 値 of at least 5. Preferred compounds have a selectivity ratio of at least 10%. The best compounds have a selectivity ratio of at least 50%. The compound of formula (I) can be produced according to a general method as described below in the Examples and Preparation Examples section. These methods provide another aspect of the invention. However, those skilled in the art will understand that the compounds of the present invention can be manufactured by methods other than those described in this specification, modifications of the methods described in this specification, and / or in this art Modifications of many known methods. We should understand that the synthetic transformation methods specifically mentioned in this manual can be performed in various orders so that the required compounds can be efficiently combined. Chemists skilled in the art will use their judgment and skills to provide the most efficient reaction sequence for the target compounds provided by the synthesis. -21-(17) 200302094 Those skilled in the art will understand that during the synthesis of the compounds of the present invention, sensitive functional groups must be protected and deprotected. This can be achieved by traditional methods, such as in T.W. Greene and P. G. M_ Wuts (" Protective Groups in Organic Synthesis ", 3rd edition,

Wiley-Interscience, NY, 1 999). Compounds of formula (I) can be prepared from corresponding esters of formula (II) (wherein P1 is lower alkyl, benzyl or other carboxy protecting group).

P1 is preferably a lower alkyl (e.g. methyl or ethyl), where suitable conditions for this step include treatment with sodium hydroxide in dioxane solution for 1-3 days.

Compounds of formula (II) can be made from the corresponding protected amines of formula (III) (wherein P2 is tert-butoxycarbonyl, benzyloxycarbonyl or fluorenylmethylcarbonyl, or other amine protecting group). When R9 is hydrogen, the preparation involves only a deprotection step. When R9 is not hydrogen, another step is required to introduce R9 (for example, reduction amination reaction). -22- (18) 200302094 P2 R7 I rM ^ N \ r8

(HI) p1

R8 P1 (ll) produces the corresponding acid (Iv) in order to obtain the compound of formula ⑴. P2, R8 R R, Ν '

(Ml)

P I

Compounds of formula (III) can be derived from imidazole acetic acid derivatives of formula (V) (wherein X is a leaving group (such as a chlorine, bromine or iodine atom), or a methanesulfonate complex or tri-23- (19) 200302094 fluorine Methanesulfonate complex) is made by reacting with an alcohol of formula (VI).

(Mi) A compound of formula (V) (wherein X is bromine) can be prepared from a corresponding hydroxy acid derivative of formula (VII) or by direct halogenation of an ester of formula (VIII).

〇,

Compounds such as formulae (VI), (VII) and (VIII) are known or can be prepared by a method similar to the method used to produce these known compounds. In addition, a compound such as formula (III) can be obtained by combining an α-hydroxyimide acetic acid derivative such as formula (VII) with a compound such as formula (IX) (wherein γ is a leaving group (such as a chlorine, molybdenum, or iodine atom), Or methanesulfonate complex or trifluoromethanesulfonate complex). -24- 200302094

(III) A compound such as formula (II) (wherein R8 and R9 are not hydrogen) can also be made from a compound such as formula (X). When R3 is hydrogen, the conversion can be achieved by hydrogenation in the presence of a suitable catalyst. When R3 is not hydrogen, conversion can be achieved using R3-M (where M is a metal, such as lithium or magnesium) reagent in the presence of a cuprous salt.

Compounds of formula (X) can be prepared by dehydrogenation of compounds of formula (XI). Conversion can be achieved using methanesulfonyl chloride and triamines. The

-25- 200302094

(XI)

Compounds of the formula (XI) can be prepared by reacting an alkoxy ester of the formula (XII) with an aldol of the aldehyde or ketone of the formula (χιπ) in the presence of a strong base (such as lithium diisopropylamidide). . (? Η2) γ

〇

R6yN, R

○ (XU ') Rii ^ > r Ya, (XII) Compounds of the formula (XIIi) are generally familiar, or can be prepared by a method similar to the published method. The compound of formula (XII) can be used to react the corresponding amine alcohol RsR9NC (R6) (R7) (CHONc (R4) (R5) OH with bromoacetate BrCHWChP1 in the presence of a base such as sodium hydride). Compounds of formula (I) (wherein R9 is hydrogen) can also be prepared by hydrolysis of peptamine in formula (XIV). -26- (22) (22) 200302094

Compounds of formula (XIV) can be made from corresponding unsaturated compounds of formula (XV). When R3 is hydrogen, the conversion can be achieved by hydrogenation in the presence of a suitable catalyst. When R3 is not hydrogen, this conversion can be achieved using R3-M (where M is a metal, such as lithium or magnesium) reagent in the presence of a cuprous salt.

Compounds of formula (XV) can be made from dehydrogenation of alcohols of formula (XVI).

Compounds of formula (XVI) can be prepared by reacting an aldehyde or ketone of formula (XIII) with lactam of formula (XVII) in the presence of a strong base (such as lithium diisopropylamide) ) 200302094%. r (XIII)

(XVII)

The compound of formula (XVII) can be prepared by reacting an amine alcohol of formula (XVIII) with chloroacetamidine chloride. Compounds of formula (XVIII) are generally familiar or can be prepared by modification of generally known methods.

(XVIII)

When R8 is hydrogen, the previous method may be problematic 'especially in the steps involving the reaction of compounds such as formulae (XIII) and (X VII). Protected amine alcohols of the formula (X Villa) (where P3 is a nitrogen protecting group) can generally be used. A particularly useful embodiment of P3 is 4-methoxybenzyl. P3 can be removed by ammonium nitrate thorium treatment (XlVa).

(XVIIIa)

-28- (24) 200302094 When R1 is hydrogen, R1 must or can protect the triphenyl derivative as the triphenyl derivative. Therefore, when R1 is hydrogen, compounds of formula (χιχ), (χχ), or (XXI) can be used to obtain compounds of formula (XX) by dehydration. (III) compounds.

This approach can also be used for the manufacture of several compounds of formula (I) in which R1 is attached to the N1 position of the imidazole ring. Compounds of formula (III) (where R1 is hydrogen) can be alkylated or arylated to give compounds of formula (III) (where R1 is not hydrogen and R1 is attached to the N1 position). -29- (25) (25) 200302094

. Suitable conditions for this step include: treatment with 1.1 equivalents of carbonic acid and 1.1 equivalents of an alkylating agent in N, N-dimethylformamide solution, or treatment with sodium hydride and 1.1 equivalents of an alkylating agent in THF. . Suitable alkylating agents include: R] -C1, R] -Br, R] -I, R ^ OSChCiL · ^] R'OSOaCFs. When R1 is an aryl group or an aromatic heterocyclic ring, R1 can be introduced into an arylation reaction. Suitable conditions for this step include: treatment with 2 equivalents of aryl-B (0H) 2 or aromatic heterocycle-B (〇H) 2 in the presence of 1.5 equivalents of copper acetate, 2 equivalents of pyridine, air, and 4 human molecular sieves. . Compounds of formula (I) (wherein the imidazole is 2,4 or 2,5-disubstituted) may also or must use a protecting group at the N1 position. Compounds of formula (I) can be used as therapeutic agents. Compounds of formula (I) are generally formulated to be administered to a patient via a chosen route. Another aspect of the present invention provides a pharmaceutical composition, which contains a compound of formula (I) or a stereoisomer, such as a tautomer of a compound of formula (I) or a pharmaceutically acceptable salt, solvate Or prodrug, and a selected pharmaceutically acceptable excipient, diluent, or carrier related to the desired route of administration and standard pharmaceutical practice. For example, a compound of formula (I) can be administered orally, bucally or sublingually in the following (26) (26) 200302094 forms: tablets, capsules, oocysts, elixirs, solutions or suspensions. These blends can contain flavoring or coloring agents and can be applied to immediate release, delayed release, modified release, continuous release, pulsed release or controlled release. Tablets may contain: excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium diphosphate and glycine, disintegrants such as starch (preferably corn flour, potato flour or cassava flour) ), Sodium starch glycolate, crosearmellose sodium and several complex oxalate salts, and granulating binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl fiber (HPC), sucrose, gelatin and acacia gum. In addition, lubricants include: magnesium stearate, stearic acid, glyceryl dialkanoate, and talc. Similar types of solid compositions can also be used as gelatin capsules. Suitable excipients include: lactose, starch, cellulose and derivatives thereof, lactose and high molecular weight polyethylene glycols. With regard to solutions, suspensions and esters, compounds such as formula (I) can be combined with: various sweeteners or flavoring agents, colorants or dyes, emulsifiers and / or suspending agents, diluents (such as water , Ethanol, propylene glycol, and glycerin), and a combination of the above. A compound such as formula (I) may also be filled with a soft or hard gelatin capsule filled with a solution or suspension. These capsules are generally made of gelatin, glycerin, water and sorbitol. Hard capsules differ from soft capsules in that hard capsules contain less water and therefore have a stronger shell. Additional excipients suitable for use in these capsules include: propylene glycol, ethanol, water, glycan -31-(27) (27) 200302094 oil and edible oil. Compounds of formula (I) can also be administered by the following routes: intravenous injection, arterial injection, intraperitoneal injection, intrathecal injection, intraventricular injection, intraurethral administration, intrasternal injection, intracranial injection, intramuscular injection or Subcutaneous injection. These administrations can be a single large injection or a short or long injection. For parenteral administration, a compound such as formula (I) can be prepared as a sterile solution with water or another suitable solvent or mixture of solvents as the solvent. The sterile solution may contain other substances such as salts (especially sodium chloride), sugars (especially glucose or mannitol) in order to make an isotonic solution with blood; buffers (such as acetic acid, citric acid) And phosphoric acid and its sodium salt) so that the pH of the solution is between 3 and 9; and preservatives. The manufacture of suitable parenteral blends under aseptic conditions is easily accomplished using standard medical techniques familiar to those skilled in the art. Compounds of formula (I) can also be administered intranasally or inhaled, and can be conveniently delivered in the following forms: dry powder inhalers or air from pressurized containers, pumps, sprayers, nebulizers or sprayers Sol sprays, with or without the use of suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkanes, such as 1,1,1,2-tetrafluoroethane (HFA 134ATM) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EATM), carbon dioxide or other suitable gas. In the case of pressurized aerosols, the dosage unit can be determined by means of a metered delivery. Pressurized containers, pumps, sprayers, atomizers or sprayers may contain solutions or suspensions of the active compounds, for example a mixture of ethanol and propellant as a solvent, and may also contain lubricants (such as sorbitan tri-oil Acid ester). Glue-32- (28) (28) 200302094 capsules (made of gelatin) for use in inhalers or insufflators can be formulated to contain a compound of formula (I) and a suitable powder base (such as Lactose or starch) powder mixture. In addition, a compound such as formula (I) can be administered via a sheath or rectal route in the form of a suppository or vaginal suppository, or a compound such as formula (I) can also be administered via a skin or transdermal route using a skin patch. Alternatively, a compound such as formula (I) can be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. Suitable ointments may contain the active compound suspended or dissolved in a mixture of more than one of the following: mineral oil, liquid stone emulsion, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsified tincture and water. Suitable lotions or creams may contain the active compound suspended or dissolved in a mixture of more than one of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polymer Sorbitol 60, hexadecyl hydrazone, hexadecanol, 2-octyldodecanol, benzyl alcohol and water. In addition, compounds such as formula (I) can be administered via the ocular route. For ophthalmic use, a compound such as formula (I) can be formulated into the following forms: a micronized suspension with an isotonic, pH-adjusted sterile saline solution as a solvent, or an isotonic, pH-adjusted A solution of a sterile sterile saline solution with a preservative (such as chlorinated iron) (optional) as a solvent. Alternatively, a compound such as formula (I) can be prepared in an ointment such as vaseline. Compounds of formula (I) can also be used with cyclodextrin. Cyclodextrins are known to form inclusion bodies and non-inclusion body complexes with drug molecules. The generation of drug-cyclodextrin complexes can modify the solubility, dissolution rate, bioavailability, and / or stability of drug molecules. Drug-cyclodextrin complexes are generally -33- (29) (29) 200302094 for most dosage forms and routes of administration. In addition, cyclodextrins can be used as auxiliary additives (such as carriers, diluents, or solubilizers) due to their direct interaction with drugs. Alpha, / 3 and r cyclodextrin are most commonly used, suitable examples are described in WO 91/1 1172, WO 94/025 1 8 and WO 98/55 1 48. Since compounds such as formula (I) are inhibitors of TAFIa, compounds such as formula (I) can be used as therapeutic agents (in pathologies where TAFIa's inhibitory effect is beneficial). Another aspect of the present invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or prodrug thereof that can be used as a medicament. In particular, the present invention provides the use of a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or prodrug thereof for a condition selected from the group consisting of In the manufacture of therapeutic or preventive drugs: thrombosis, atherosclerosis, adhesions, skin scarring, cancer, fibrosis, inflammation, and disorders that benefit from maintaining or increasing bradykinin levels in the body. TAFIa inhibitors for the treatment of thrombosis are derived from the potential of TAFIa inhibitors to promote fibrinolysis without interfering with coagulants. In most clinically relevant cases, thrombosis is subacute, meaning that thrombosis is slow. Traditional antithrombotic agents block blood clotting channels and thus prevent thrombus growth. However, it is inevitable that antithrombotic agents will also prevent blood coagulation, which is responsible for blood vessel damage (thus causing an unexpected increase in bleeding). The promotion of fibrinolysis' accelerates the dissolution of the developing thrombus without impeding the coagulation reaction. Accordingly, a suitable embodiment of the present invention provides a compound such as formula (1) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt thereof, and the like. -34- (30) (30) 200302094 Or prodrugs for the manufacture of drugs for the treatment of thrombosis selected from the group consisting of myocardial infarction, deep vein thrombosis, stroke, juvenile stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral vascular disease , Angina pectoris and other acute coronary syndromes, disseminated intravascular coagulation, 'septicemia, pulmonary embolism, arrhythmic secondary embolism, prevention or intervention of cardiovascular disease after interventional surgery, or use of reduced blood The coagulation method promotes the results of organ transplantation and maintains the function of the organ. Cardiovascular events following interventional surgery include symptoms after intervention (such as restenosis or reclosure), and the interventional procedures such as percutaneous transluminal coronary angioplasty, transplantation, drainage strip placement, coronary vessels Shunt surgery or other types of vascular reconstruction surgery or interventional surgery. Disseminated intravascular coagulation includes all symptoms of intravascular activation due to the coagulation process. This condition can occur sharply, due to abnormal blood contact (infections, burns, extracorporeal circulation, transplantation) leading to the release of precoagulant (eg obstetric emergency, snake bite, crush damage to malignant tumors), or through blood Procoagulant production (transfusion reaction, leukemia); or chronic diseases (such as toxemia, malignant hypertension, severe liver cirrhosis). Deep venous thrombosis includes the 'economy class syndrome', which has formed blood clots in patients who have been forced to tolerate a narrow environment for a period of time (for example, sitting in an economy class seat in an aircraft). The role of thrombosis in the pathophysiology of atherosclerosis has recently been emphasized by several independent groups. Non-closed thrombus not only restricts the blood (causes myocardial ischemia and angina pectoris), but because of incomplete endogenous dissolution, it can be inserted into the arterial wall to become a solidified patch that enhances the atherosclerotic process material. Long-term administration of TAFla inhibitors promotes the development of thrombolysis in (31) (31) 200302094 and provides safe and effective treatment. TAFIa inhibitors can reduce the symptoms of angina pectoris when the progress of the underlying disease is compromised. Traditional treatment of myocardial ischemia in clinically stable coronary artery disease is primarily designed to reduce cardiac workload and improve blood flow. These methods neatly reduce myocardial ischemia and improve the quality of life. However, these strategies have little effect on the pathogenesis of coronary atherosclerosis, which is a chronic procedure in response to the continuous reconstruction of the vascular tree that changes the degree of vascular damage. Therefore, another suitable embodiment of the present invention provides the manufacture of a medicament for treating or preventing atherosclerosis using a compound of formula (I) or a pharmaceutically acceptable salt, solvate and prodrug thereof. These include peripheral vascular disease, insulin resistance, and atherosclerosis caused by X syndrome, as well as myocardial ischemia and angina due to atherosclerosis. Atherosclerosis includes primary and secondary coronary artery disease, where atherosclerosis restricts the supply of blood to the heart. The main prevention of coronary artery disease is the prevention of ischemic syphilis syndromes, such as myocardial infarction in patients who have no history of coronary artery disease but have more than one risk factor. Secondary prevention of coronary artery disease refers to prevention of ischemic episodes in patients with established coronary artery disease (eg, patients with previous myocardial infarction). The X 徴 group is a noun that is often used to bring together many related diseases. The first phase of the X syndrome is composed of insulin resistance, abnormal cholesterol and triglyceride levels, obesity, and hypertension. Any of these symptoms can be used to diagnose the onset of the X syndrome. Then one symptom causes the development of the other to progress the disease. For example, insulin resistance is accompanied by high blood lipid levels, hypertension and obesity. The development of each additional symptom then increases -36- (32) (32) 200302094 The risk of developing more severe diseases also causes a cascade of effects. This can lead to the development of diabetes, kidney disease and heart disease. These diseases can cause strokes, myocardial infarction and organ failure. Atherosclerosis is a common disease in patients with the X syndrome. TAFIa inhibitors are also effective in preventing the formation of adhesions in the body. Most surgical procedures and physical trauma cause blood to flow into the cavities between the tissues. The blood collected at these locations then coagulates to form a fibrin-rich thrombus. These thrombi connect the gaps between adjacent tissues and serve as a focal point for the accumulation of inflammatory cells and fibroblasts. The invading fibroblast cells drop a collagen-rich extracellular matrix that strengthens the adhesions that produce strongly bonded tissues, which restricts movement. Adhesions have been identified based on their location and can occur after any surgery (such as laparoscopic surgery, orthopedic surgery, neurological surgery, cardiovascular surgery, and eye surgery). This unsuitable surgery or post-traumatic tissue adhesion is a major result, which can lead to various results, such as " pain ", " tingling ", local inflammation, restricted mobility, pain, intestinal obstruction Sometimes, it can lead to the worst situation, death. In the case of gynecological surgery, infertility can result. Increased blood clots forming fibrin-rich thrombi are implicated in skin scarring and restenosis. Without being bound by any theory, I am convinced that when insufficient fibrinolysis causes increased and sustained coagulation to form, adhesion formation is enhanced. Treatment with TAFIa inhibitors near and / or after surgical intervention can increase fibrinolysis of fibrin-rich thrombus and therefore inhibit thrombus formation, growth, and stabilization to inhibit adhesion formation. I can see that TAFIa inhibition by local or systemic administration (33) (33) 200302094 is helpful within the scope of the surgical procedure. In addition, administration of TAFIa inhibitors can be used to treat adhesions caused by other types of non-surgical physiological injury (causing internal bleeding). Examples of such injuries include sports injuries or other injuries that cause tears, cuts, abrasions, or induration of the body. Therefore, another suitable embodiment of the present invention provides a medicament for treating or preventing adhesion or skin scar formation by using a compound of formula (I) or a pharmaceutically acceptable salt, solvate and prodrug thereof. Manufacture. TAFIa inhibitors are also effective in inhibiting tumor maturation, progression and metastasis. Without being limited by any theory, I am convinced that the hemostatic system is involved in several levels of cancer pathology, including angiogenesis, cell replacement from early tumors, invasion of blood supply, adhesion of blood vessel walls, and metastasis Growth of sexual position. We believe that the effectiveness of TAFIa inhibitors stems from the ability to reduce fibrin deposition near solid tumors and thus inhibit the aforementioned procedures. Therefore, another suitable embodiment of the present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof in the manufacture of a therapeutic or prophylactic drug for cancer. < 1 TAFIUW system J is effective in the treatment of any symptoms of fibrosis as a contributing factor. Suitable symptoms of fibrosis include pancreatic cystic fibrosis, pulmonary fibrosis (such as chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), fibromuscular dysplasia and fibrous lung, and during eye surgery Fibrin deposition of the eye. Thus, another suitable embodiment of the present invention provides the use of a compound of formula (I) and its pharmaceutically acceptable salts, solvates and prodrugs for the treatment or prevention of fibrotic diseases In particular, for the manufacture of drugs for the treatment or prevention of fibrotic symptoms: pancreatic cystic • 38-(34) (34) 200302094 Fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), respiratory distress symptoms in adults Group (ARDS), fibromuscular dysplasia, fibrous lung and fibrin deposition in the eye during eye surgery. TAFIa inhibitors are effective in the treatment of the following conditions: inflammation, treatment of inflammatory diseases (including asthma, arthritis, intrauterine Heterotopic disease, enteritis, psoriasis, and atopic dermatitis) and neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease). Therefore, the present invention is another A convenient embodiment provides the use of a compound of formula (I) and its pharmaceutically acceptable salts, solvates and prodrugs for the manufacture of drugs for the treatment or prevention of the following conditions: inflammation, inflammatory diseases such as asthma , Arthritis, endometriosis, enteritis, psoriasis, and atopic dermatitis) and neurodegenerative diseases (such as Alzheimer's and Parkinson's disease). TAFIa combines bradykinin And destruction (Tan et al., Biochemisto 1 99 5, 34, 5811). There are many known conditions that benefit from maintaining or increasing bradykinin levels: hypertension, colic, heart failure, pulmonary hypertension, Renal failure or organ failure. Thus, another suitable embodiment of the present invention provides the use of a compound such as formula (I) and its pharmaceutically acceptable salts, solvates and prodrugs to benefit from bradykinin levels. Manufacture of a medicament for the prevention or treatment of a condition that is maintained or elevated. Another aspect of the present invention provides a method for the treatment or prevention of the following conditions: thrombosis, atherosclerosis, adhesion, skin scar formation, cancer, fiber change Disorders, inflammation, and disorders that benefit from the maintenance or increase of bradykinin levels in the body, the method comprising: administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a steric variant thereof (35) (35) 200302094 structures, or pharmaceutically acceptable salts, solvates, or prodrugs. Another suitable embodiment of the present invention provides methods for the treatment or prevention of the following conditions: Thrombosis, especially myocardial infarction, deep vein thrombosis, stroke, juvenile stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral vascular disease, angina pectoris and other types of acute coronary syndromes, disseminated intravascular coagulation, failure Hematopathy, pulmonary embolism, arrhythmic secondary embolism, and prevention of cardiovascular disorders after interventional surgery, the method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or Its stereoisomers, tautomers or pharmaceutically acceptable salts, solvates or prodrugs. Patients with thrombosis suitable for the treatment modalities of the present invention include patients with conditions related to the following symptoms: hypercoagulability, such as factor V mutation, antithrombin deficiency, heparin II cofactor deficiency , Protein C deficiency, protein S deficiency, and polycythemia vera, and conditions exhibiting homocystinemia or homocystinuria. Another suitable embodiment of the present invention provides a method for the treatment or prevention of atherosclerosis, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof Compounds, tautomers or pharmaceutically acceptable salts, solvates or prodrugs. Another suitable embodiment of the present invention provides a method for the treatment or prevention of adhesions or skin scar formation, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula VII or a stereoisomer thereof Compounds, tautomers or pharmaceutically acceptable salts, solvates or prodrugs. Another suitable embodiment of the present invention provides a method for the treatment or prevention of cancer, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of -40- (36) (36) 200302094, such as formula (I) Or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof. Another suitable embodiment of the present invention provides a method for treating or preventing fibrosis, such as pancreatic cystic fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disease (CDPD), and adult respiratory distress syndrome (ARDS). ), Fibromuscular dysplasia and fibrous lung and fibrin deposition during eye surgery, the method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) and its stereoisomers Compounds, tautomers or pharmaceutically acceptable salts, solvates or prodrugs. Another suitable embodiment of the present invention provides a method for treating or preventing inflammatory diseases such as asthma, arthritis, endometriosis, enteritis, psoriasis and atopic dermatitis, or neurodegeneration. STD, such as Alzheimer's disease and Parkinson's disease, the method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer Or a pharmaceutically acceptable salt, solvate or prodrug. Another convenient embodiment of the present invention provides a method for the treatment or prevention of a condition that benefits from maintaining or increasing bradykinin levels, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of formula (I) Or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof. I should understand that all the treatments mentioned in this manual include ... curative therapy, palliative therapy and preventive therapy. The amount of compound to be administered and the frequency of administration will be determined by: the physician should pay attention to the characteristics of the patient: age, weight, health status, and the required -41-(37) (37) 200302094 Degree of inhibition of TA FI a. Generally, the total daily dose for a 70 kg adult is generally between 1 mg and 5 g, preferably between 10 mg and ig, and more preferably between 50 mg and 750 mg. The total dose may be a single dose or a divided dose. The compounds of the present invention can be used alone or in combination with other therapeutic agents. When used with another therapeutic agent, the two agents can be administered simultaneously or sequentially. Simultaneous administration includes administration of a single dosage form containing two agents and administration of the two agents separately at substantially the same time. Consecutive administration includes administration of two drugs according to different schedules, and there should be overlap during treatment. Suitable agents for administration with a compound of formula (I) include: antithrombotic agents, including antiplatelet agents, anticoagulants, and plasminogens. Suitable antithrombotic agents include: aspirin, PlavixTM, chlorobenzidine, piperidine, coumadinTM, unisolated heparin, lepirudinTM, streptokinase, urokinase, recombinant tissue Plasminogen activator (tPA), dipyridamole, ReoproTM, AggrastatTM, and IntegrilinTM. Compounds of formula (I) can also be administered with antihypertensive agents and with agents for treating dyslipidemia (e.g. fixins such as LipitorTM). Further suitable types of drugs for co-administration include factor X inhibitors and antiarrhythmic drugs (such as amiodarone or digoxin). Thus, a further aspect of the present invention provides the use of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof together with an antithrombotic agent for the treatment In the manufacture of drugs for thrombosis. A suitable embodiment is that the antithrombotic agent is a plasminogen. More suitably -42- (38) (38) 200302094 The antithrombotic agent is a recombinant tissue plasminogen activator (tPA). A further aspect of the present invention provides a method for treating or preventing thrombosis, The method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound such as formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof with Comprehensive antithrombotic. A suitable embodiment is that the antithrombotic agent is a plasminogen. A more suitable manifestation is that the antithrombotic agent is a recombinant tissue plasminogen activator φ (tPA). A further aspect of the invention provides a kit comprising: a) a composition comprising a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable Salts, solvates or prodrugs and pharmaceutically acceptable diluents or carriers; b) a composition comprising an antithrombotic agent and a pharmaceutically acceptable diluent or carrier; c) a container. _ The components of this kit can be administered separately, simultaneously or sequentially. The present invention also provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable Salts, solvates or prodrugs as coatings on intravascular devices (such as indwelling catheters, replacement heart valves or arterial drainage strips for dialysis); and as extracorporeal blood circulation devices (such as heart, lung and kidney dialysis) Coating) to prevent thrombosis, especially myocardial infarction, deep vein thrombosis, stroke, juvenile stroke, cerebral infarction, large -43- (39) (39) 200302094 cerebral thrombosis, cerebral embolism, peripheral vascular disease, Angina pectoris and other acute coronary syndromes, disseminated intravascular coagulation, sepsis, pulmonary embolism, secondary arrhythmia, prevention of cardiovascular disease after interventional surgery, such as percutaneous transluminal lumen Coronary angioplasty, alternative drainage strips, coronary bypass surgery or any other type of vascular reconstruction or interventional surgery. The invention provides a device in a blood vessel, and a part of the device in the blood vessel is covered with a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate thereof. Or prodrugs; and extracorporeal blood circulation devices, such as heart, lung, and kidney dialysis machines, parts of the machine that are in direct contact with the patient's blood are covered with a compound of formula (I) or a stereoisomer thereof, Tautomers or pharmaceutically acceptable salts, solvates, or prodrugs. The compounds of the present invention are TAFIa inhibitors, and their use is mainly to prevent the reaction between developing thrombus and TAFla. We have discovered that the compounds of the present invention can also bind to unactivated TAFI molecules at positions involved in the reaction between TAFIa and a developing blood clot. The use of TA FI a inhibitors described in the manner above in scope and use includes the combination of these TAFIa inhibitors with TAFI. [Embodiment] The present invention is further illustrated by the following non-limiting examples. The melting point is confirmed in the Ga 11 e n k a m p melting point device (using a glass capillary), which is considered to be a non-positive tritium. Unless otherwise specified, all reactions -44-(40) (40) 200302094 were performed using a commercially available anhydrous solvent under a nitrogen atmosphere. "0.88 ammonia" represents a commercially available aqueous ammonia solution having a specific gravity of about 0.88. Thin layer delamination (TLC) is performed on a glass-lined pre-coated Merck silicone (60 F254) plate. Silicone column delamination is performed using 40-63 // m silicone (Merck silicone 60). Ion exchange lamination is performed using a designated ion exchange resin (washed with deionized water in advance). Proton NMR spectra were measured on a Varian Inova 300, Varian Inova 400, or Varian Mercury 400 spectrometer (in a designated solvent). In the NMR spectrum, only non-exchangeable protons (represented in a state different from the solvent spikes) are reported. Low-resolution mass spectra were recorded on a Fisons Tdo 1000 (positive ionization using thermal spray) or Finnigan Navigator (positive or negative ionization using electronic spray). High-resolution mass spectra were recorded on Brukei * Apex II FT-MS (positive ionization using electrospray). Flammability analysis was performed by Exeter Analytical UK. Ltd., Uxbridge, Middlesex. Optical rotation was measured at 25 ° C using a Perkin Elmer 341 polarimeter (using the specified solvent and concentration). When measured in a suitable solvent, the compounds of the examples labeled as (+) or (-) optical isomers are designated according to the sign of optical rotation. -45- (41) 200302094 Abbreviations and definitions Arbocel ™ Amberlyst® 15 atm Biotage ™ BocC br C cat d dd Degussa® 101 Dowex® ee HRMS Hyflo ™ filter from J. R e 11 enmaier & S, Germany ο li ne Ion exchange resin, obtained from Aldrich Chemical Company at atmospheric pressure (latm = 760 Torr = 101.3 kPa) delamination method, and implemented the broad peak optical rotation of tert-butoxycarbonyl group with Flash 75 silicone column of Biotage, UK The concentration used was measured in g / 100ml (lmg / mlC 0.10). The double peak of the catalyst consisted of a double peak of 10 wt% IG / activated carbon catalyst, Degussa E 1 0 1 type, obtained from Aldrich Chemical Company. Ion exchange resin from Aldrich Chemical

Company Isomer Excess Excess High Resolution Mass Spectrometry (Positive Scanning by Electrospray Ionization)

Hyflo super cel® from Aldrich Chemical Company (42) 200302094

liq LRMS LRMS (ES ') m m / z MCI ™ gel p s i q Rf

Sep-Pak® TLC 5 liquid low-resolution mass spectrometry (electrospray or thermal spray ionization positive scan) low-resolution mass spectrometry (electrospray ionization negative scan) multiple peak mass spectrometry peak high porosity polymer, CHP 20P 75- 1 50 // m, pounds per inch from Mitsubishi Chemical Corporation (lpsi = 6.9kPa) retention factor for TLC on TLC single peak reverse phase Cis sand rubber column, Waters Corporation produces a triplet thin layer delamination Chemical shift

Example 丄 Amine ethoxy) -3- (1-propyl-1H-imidazol-4-yl) propionic acid

A 6 M hydrochloric acid (35 ml) solution of the compound of Preparation Example 88 (437 mg, -47- (43) (43) 200302094 1.96 mmol) was heated under reflux for 72 hours, then cooled, and concentrated under reduced pressure. The residue was dissolved in water (2 ml), and the solution was purified on a Dowex® 50WX8-200 ion exchange resin using a column of water: 0.88 ammonia and elution (100: 98 to 98: 2). The product containing the fractions was combined, evaporated under reduced pressure, and the product was freeze-dried to give the title compound (456 mg). j-NMI ^ CDCh, 400MHz) 5: 0.82 (t, 3H), 1.70 (ιη, 2H), 2.80 (m, 1Η), 3.01 (m, 3Η), 3.44 (m, 1Η), 3.78 (m, 3Η), 3.89 (dd, 1H), 6-70 (s, 1H), 7.35 (s, 1H) 0 LRMS: m / z (ES +) 2 64 [Mna +]. Measured by microanalysis: c, 49.04; H, 8.17; N, 15.51. ChHi9N3〇3; ι · 6Η20 theory 値: C, 49 · 04; Η, 82.8; Ν ′ 15.60%. [a] D = -33.43 (c = 0.193, methanol). Examples 2 to 4 Compounds of the following general formula were made from the corresponding morpholinone compounds following the procedure of Example 1.

-48-(44) 200302094 Example R Yield (%) Data 2 37 Sticky solid] H-NMR (D20, 400MHz) 5: 0.76 (t, 3H), 1.10 (m, 2H), 1.60 (m , 2H), 2.75 (dd, 1H), 2.82 (dd, 1H), 3.00 (m, 2H), 3.55 (m, 2H), 3.62 (t, 2H), 3.90 (dd, 1H), 6.83 (s, lH), 7.48 (s, lH). LRMS: m / z (TSP +) 25 6.2 [MH +]. Measured by microanalysis: C, 5 3.59; H, 8.35; N, 15.57. C12H2iN3 03; 0.75 H2〇 theory: C, 5 3.62; H, 8.44; N, 15.63%. 3 48 viscous colloid 1H-NMR (D2, 300MHz) 5: 0.82 (m, 2H), 1.05 (m, 4H) , 1.57 (m, 7H), 2.77-2.97 (m, 2H), 3.05 (m, 2H), 3.59 (m, 2H), 3.95 (m, 3H), 6.94 (s, lH), 7.59 (s, lH ). LRMS: m / z (ES +) 310 [MH +] ·

(49) 200302094 Example R Yield (%) Data 4 cr " 61 IH-NMR (CDCh, 400 MHz) 5: 2.80 (dd, lH), 2.99 (m, 5H), 3.42 (m, lH) , 3.80 (m, lH), 3.92 (m, lH), 4.02 (t, 2H), 6.64 (s, lH), 7.01 (d, 2H), 7.20 (m, 4H) · LRMS: m / z (ES, +) 304 [MH +]. Measured by microanalysis: C, 5 8.93; H, 7.17; N, 12.82. Ci6H21N3O3; 1.27 H2O theoretical: C, 58.91; H, 7.27; N512.88%. Example 5 (2S)-(-)-2- (2-Aminoethoxy group)

〇 A concentrated hydrochloric acid (5 ml) solution of the compound of Preparation Example 133 (72 mg, 0.25 mmol) was heated at 110 ° C for 18 hours, then cooled, and concentrated under reduced pressure. The residue was dissolved in water, and the column was eluted on a Dowex® 50WX8-200 ion exchange resin with water: 0.88 ammonia: methanol (95: 5: 0 to 90: 5: 5) step by step -50- (46) 200302094 The solution was purified by delamination. This product was dissolved in water (5 ml) and freeze-dried 'to give the title compound as a sticky colloid (^^). !! ^ NMR (CD3OD, 400MHz) δ: 0.99 (η, 2H), 1.21 (m, 4H), 1.61-1.78 (m, 7H), 2.86 (dd, 1H), 3.02 (m, 3H), 3.58-3.70 (m '2H), 3.98 (m, 3H), 6.93 (s, 1H), 7.50 (s, 1H). LRMS: m / z (ES +) 310 [MH +]. Micro-analytical 値: c, 59.56;;, 8.76; N, 12.91. C16H27N3 03; 0.75 75 2 theory 値: C, 59.51; Η, 8.90; N, 13.01%. [a] D = -23.34 (c = 0.102, methanol). Example 6 (2S)-(-)-2- (2-Aminoethoxyphenyl-1H-imidazol-4-yl) propionic acid

/ ΝΗ2 OH 〇

Following the procedure of Example 5, the title compound was obtained as light yellow-brown solid from the morpholinone of Preparation Example 104 (yield 87%). W-NMIUDW, 400MHz) 5 2.88 (dd, 1H), 3.00 (dd, 1H), 3.10 (t, 2H), 3.62 (t, 2H), 4.02 (m, 1H), 7.30 (s, 1H) , 7.39 (m, 1H), 7.45 (m, 4H), 7.98 (s, 1H). LRMS: m / z (ES +) 29 8 [MNa +]. Measured by microanalysis: C, 59.15; H, 6.39; N, 14.71. C " H "N3〇3; 0.5 H2O theory 値: C, 59 · 14; Η, 6.38; N, 14.78%. [a] D = -16.8 (c = 0.10, methanol). Example 7 -51-(47) 200302094 (2S) -2- (2-aminoethylethyl) -3-ί 1- "3,5-_bis (trifluoromethyl) benzazole-4- Propionate

nh2 Following the procedure in Example 5, the title compound was obtained as white solid (yield 45%) from morpholinone in Preparation Example 106. W-NMIUCDsOD,

400MHz) 5: 3.00-3.18 (ιη, 3H), 3.65 (m, 1H), 3.75 (m, 1H), 4.04 (m, 2H), 7.58 (s, 1H), 7.98 (s, 1H ), 8.22 (s, 2H), 8.30 (s, 1H). LRMS: m / z (ES +) 410 [M-H ·]. Micro-analytical method Measured ，: C, 43.95; Η, 3.79; N '9.99. CwH! 5F6N3O3; 1.25 H2O theory 値: C, 44.30; Η, 4.07; N, 9.69%. Example 8 (2RS) -2-"(2- (methylamino) ethoxy) -3- (1-propyl-1H-imidazole-4-some ^

Propionic acid

Following the procedure of Example 1, the title compound was prepared from the morpholinone of Preparation Example 51. 1H-NMR (D2O, 400MHz) 5 · 0.70 (t, 3H), 1.62 (11), 2H), 2.56 (s, 3H), 2.76 (dd, 1H), 2.84 (dd, 1H) 3.05 (m, 2H), 3.53-3.63 (m, 2H), 3.80 (t, 2H), 3.94 (dd, 1H), 6.84 (s, 1H), 7.50 (s, 1H). LRMS: m / z (TSP +) -52- (48) (48) 200302094 25 6.2 [ΜΗ +]. Example 9 (2RS) -2-"(2- (Di-methylamine, certain oxy) -3-Π-propion-1, 1-imidazole-4-some) propionic acid

A solution of the protected acid (200 mg, 0.62 mmol) in trifluoroacetic acid (5 ml) and dichloromethane (5 ml) of Preparation Example 142 was stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The residue was dissolved in water, and the solution was purified by column-type separation on a Dowex® 5 OWX 8-200 ion exchange resin with water: 0.88 ammonia (9 6: 4). The fraction-containing product was concentrated under reduced pressure, and the residue was dissolved in water and lyophilized to obtain the title compound (100 mg) as a viscous colloid. W-NMRdO, 400MHz) 5: 0.66 (t, 3H), 1.60 (m, 2H), 2.60-2.7 8 (m, 7H), 2.82 (dd, 1H), 3.14 (m, 2H), 3.57 (m, 1H), 3.61 (m, 1H), 3.78 (t, 2H), 3.92 (m, 1H), 6.82 (s, 1H), 7.48 (s, 1H) o LRMS: m / z (TSP +) 270.2 [MH +]. Measured by microanalysis: C, 54.41; H, 8.72; N, 14.58. C "H23N3〇3; H2O theory: C, 54 · 34; H, 8.77; N, 14.62% Example 1 0 -53- 200302094 (2RS) -3- (l-propyl-1H-imidazole-4 -A certain V2-K3R) -pyridin-3-yl chloride some 1 propionic acid

Concentrated hydrochloric acid (3 ml) was added to a solution of the protected amino acid (232 mg, 0.55 mmol) in dioxane (2 ml) of Preparation Example 143, and the mixture was stirred at room temperature for 18 hours, and then under reduced pressure. concentrate. The residue was dissolved in water (lml), and the solution was purified by column-type column separation on a Dowex® 50WX8-200 ion exchange resin with water: 0.88 ammonia (100: 0 to 98: 2). The product was freeze-dried to give the title compound (67 mg) as a white solid. iH-NMIUDsO, 400MHz) (Diastereoisomeric mixture) 5: 0.72 (m, 3H), 1.63 (m, 2H), 1.80, 1.98, 2.08 (3xm, 2H), 2.65, 2.84 (2xm, 3H) ), 3.03-3.3 8 (m, 3H), 3.81 (m, 2H), 3.94 (m, 1H), 4.14 (m, 1H), 6.89 (m, 1H), 7.53 (m, 1H). LRMS: m / z (ES +) 290 [MNa +]. Example 1 1 (2RS) -2- (2-Aminoethoxy) -3- (142- (4'-ethyl "1,1 fluorene-biphenyl")-4-yl 1ethyl 丨- 1H-imidazol-4-yl 1 propanoic acid

-54- 200302094 A mixture of the compound of Preparation 121 (170 mg, 0.43 mmol) and concentrated hydrochloric acid (2 ml) was heated at 110 ° C for 18 hours, then cooled, and concentrated under reduced pressure. The residue was azeotroped with ethanol, methanol, and dichloromethane, followed by column stripping on a Dowex® 50WX8-200 ion exchange resin with water: 0.88 ammonia (100: 0 to 9 8: 2). The residue was purified by a formula delamination method to obtain the title compound (15 mg). OH-NMR iCDsOD, 400 MHz) 5: 1.22 (t, 3 ，), 2.62 ", 2H), 2.82 (m, 1H), 2.98 (ιη, 3H), 3.02 (t, 2H), 3.50-3.62 (m, 2H), 3.90 (m, 1H), 4.18 (t, 2H), 6.86 (s, Xin 1H), 7.14 (d, 2H), 7.20 ( d, 2H), 7.30 (s, 1H), 7.43 (ιη, 4H). Measured by microanalysis: C, 64.05; H, 6.99; N, 9.35. C25H29N3O3; 2.7 H2O Theoretical C: C , 64.28; Η, 7.21; N, 8.99% o Examples 12 to _jj Compounds of the following general formula are made from the corresponding morpholine hydrazones according to the procedure of Example 11 φ

-55 (51) 200302094 Example R Yield (%) Data 12 / a \ 35 ^ -NMRiCDsOD ^ OOMHz) 5: Q white 2. 15 (m, 2H), 2.62 (t, 2H), 2.90 (η solid dd, lH), 3.02 (m, 3H), 3.60 (m, lH), 3.66 (m, lH), 3.98 (m, 3H), 6.96 (s, lH), 7.25 (m, 3H), 7.40 (m , 2H), 7.54 (m, 3H), 7.58 (d, 2H). LRMS: m / z (ES ') 392 [MH *]. 13 H, C \ 17 1H-NMR (CD3OD, 400MHz) 5 : White bubbles 2.09 (m, 2H), 2.34 (s, 3H), 2.59 (m, 2H), 2.86 (m, 1H), 3.00 (m, 3H), 3.60 (m, 2H), 3.97 (m, 3H), 6.96 (s, 1H), 7.19 (m, 4H), 7.40-7.60 (m, 5H). LRMS: m / z (ES +) 430 [MNa +] · -56- (52) 200302094 Examples R Yield (%) Data 14 Η ") 21 Yellow ^ -NMRCCDsOD, 400MHz) 5: 2.18 (m, 2H), 2.78 (t, 2H), 2.88 solid (dd, 1H), 3.02 (m, 3H), 3.58 · 3.72 (m, 2H), 3.97 (m, 3H), 6.95 (s, lH), 7.40 (m, 2H), 7.50 (s, lH), 7.60 (s, lH), 7.78 (m, 3H) · LRMS: m / z (ES ') 366 [MH *]

Example 1 5 (2S) -2- {f (lR) -2 -Amino-1-methylethyl 1hexyl 丨 -3 · "1- (2-cyclohexyl) -1 Η- Mic-4-1-propionic acid

Following the procedure of Example 11 to obtain the title compound from the morpholinone of Preparation Example 9 2 (yield 45%). W-NMIUCDAD, 400MHz) 5: 0.94 (m, 4H), 1.18 (m, 4H), 1.59-1.76 (m, 7H), 2.72 (m, 2H), 2.96 (m, 1H), 3.03 (m , 1H), 3.26 (m, 1H), 3.55 (m, 1H), 3.98 (m, 3H), 6.88 (s, 1H), 7.48 (s, 1H) 〇LRMS: m / z (ES +) 3 24 [MNa +]. Measured radon by microanalysis: C, 5 8.97; H, -57- (53) 200302094 Measured radon · C, 5 8.97; 8., 9.01; N, 1 1.85. Ci7H29Nh〇3; 1.2 H2O theory 値: C, 59.18; Η, 9.17; N, 12.18%. Example 1 6 (2RS) -2- (2-Amine ethoxy) · 3- (1-phenyl · 1Η-imidazol-4-yl) propionic acid

A concentrated hydrochloric acid (2 ml) solution of the compound of Preparation Example 99 (70 mg, 0.27 mmol) was heated at 110 ° C for 18 hours, then cooled, and concentrated under reduced pressure. The residue was azeotroped with water, and then purified by column chromatography using Dowex® 50WX8-200 ion exchange resin with water: 0.88 ammonia (95: 5) to obtain the title compound (50 mg) as a pale yellow solid. . W-NMIUCDsOD, 400MHz) 5 ·· 2.93-3.14 (m, 3H), 3.24 (in, lH), 3.59-

3.73 (m, 2H), 4.00 (m, 1H), 7.35 (m, 2H), 7.45 (m, 4H), 7.98 (s, 1H) 0 LRMS: m / z (ES +) 29 8 [MNa +] . Example 1 7 (2S) -2- 丨 KlR) -2-amine-1-1-methyl-1ethyl-1oxyl 3- (1-benzazine-4-yl) propionic acid

58- (54) (54) 200302094 Following the procedure of Example 16 '6, the title compound was prepared from the morpholinone of Preparation Example 10 (yield 75%), except for the following: methanol: water: 0.88 Ammonia (20: 80: 5 to 3 0: 65: 5) was eluted step by step for ion exchange lamination. UMRWO, 400MHz) 5: 0.90 ((1, 3H), 2.80 (m, 2H), 3.00 (m, 2H), 3.59 (m, 1H), 4.14 (dd, 1H), 7.26 ( s, 1H), 7.37 (m, 1H), 7.42 (m, 4H), 7.96 (s, 1H). LRMS: m / z (ES +) 2 8 8 [MH ·]. Measured by microanalysis: c , 5 8.76; H, 6.72; N '13.37 ° CmH "N3O3; H2O theory 値: c, 58.63; Η, 6.89; Ν, 13.67%. [Cx] d = -83.0 (c = 〇.i, Methanol). Example 1 8 (2S) -2- {"(lR) -2-amino group_1-methyl Z certain 1 hydrogen group 丨 -3-" 1- (3, 4, 4, dioxo Π Biphenyl 1-3-yl) -11 imi-4--4-propionic acid

Following the procedure of Example 17 to obtain the title compound as a white bubble from morpholinone of Preparation Example 1 15 except for the following differences: water: methanol: 0.88 ammonia (75: 20: 5 to 15: 80: 5) stepwise elution and ion exchange lamination. 1H-NMR (CD3OD, 400MHz) 5: 1. 〇 Ο (d, 3 Η), 2.77 (dd, 1H), 2.92 (m, 2H), 3.15 (dd, 1H), 3.59 (ηι , 1H), 4.10 (m, 1H), 7.42 (s, 1 H), 7 · 5 0-7 · 6 2 7 (m, 5 H), 7 · 7 8 (s, -59- (55) ( 55) 200302094 1H), 7.86 (s, 1H), 8.10 (s, 1H). LRMS: m / z (ES +) 434, 436 [MH +]. Example 1 9 (2S) -2-i "(lR) -2 · Amine-Phenylethyl 1oxyb- 3-Π- (4-phenoxybenzene

A solution of morpholinone (130 mg, 0.36 mmol) in concentrated hydrochloric acid (10 ml) of Preparation Example 111 was heated at 110 ° C for 18 hours, then cooled, and concentrated under reduced pressure. The residue was purified by column chromatography using Dowex® 50WX8-200 ion exchange resin with water: methanol: 0.88 ammonia (70: 30: 5). The residue was dissolved in water and lyophilized to obtain the title compound (70 mg) as a non-pure white powder. l-NMRiCDsOD, 400MHz) 5 ·· 1.00 (d, 3H), 2.78 (dd, 1H), 2.86_3.00 (m, 2H), 3.17 (dd, 1H), 3.60 (m'1H), 4.15 (dd , 1H), 7.02 (d, 2H), 7.08 (d, 2H), 7.17 (m, 1H), 7.30 (s, 1H), 7.39 (m, 2H), 7.50 (d, 2H), 7.95 (s, 1H). LRMS: m / z (ES +) 404 [MNa +]. Measured by micro-analysis: C, 62.70; R, 6.22; N, 10.30. C "H23N3〇4; 1.2 H2O theoretical 値: C, 62.5 8; Η, 6.35; N, 10.43%. [A] D = -5 0.9 (c = 0.117, methanol). -60- (56) 200302094 Examples 20 to 31 Compounds of the formula

R

A solution of morpholinone (0.2 to 0.4 mmol) in concentrated hydrochloric acid (2 ml) was heated for 18 hours to concentrate the cooled solution, and the residue was mixed with ethanol, ethyl acetate and dichloromethane.

Example R 共 Data 20 q:-(CH〇2-^-NMRCCDsOD, 400MHz) 5: 1.22 (d, 6H), 2.90 (m, 1H), 3.10-3.22 (m, 6H), 3.78 ( m, 2H), 4.36 (m, 1H), 4.45 (t, 2H), 7.18 (d, 2H), 7.24 (d, 2H), 7.44 (m, 3H), 7.52 (d, 2H), 8.62 (s , LH) · Measured by microanalysis: C, 5 6.65; H, 7.03; N, 7.92. C25H3iN3〇4; 2HC1; 2H2O theory: C, 56.60; Η, 7.03; Ν, 7.92% .

-61-(57) 200302094 (57)

Example RY data 21 F Cl η-(CH2) 2- 1H-NMR (CD3OD, 400 MHz) 5: 3.18 (m, 5H), 3.78 (m, 3H), 4.15 -4.38 (m, 1H), 4.44 (m, 2H), 7.21 (m, 3H), 7.50 (m, 4H), 7.63 (m, lH), 8.5 8- 8.65 (m, lH) · LRMS: m / z (ES +) 432, 434 [ MH +]. 22 q-(CH2) 2- ^ -NMRiCDsOD, 400MHz) 5: 3.10-3.30 (m, 4H), 3.78 (m, 4H), 4.30 (m, 1H), 4.46 (m, 2H ), 7.24 (m, 2H), 7.50 (m, 1H), 7.60 (m, 2H), 7.74 (m, 4H), 8.62 (m, 1H). Measured by microanalysis: C, 50.27; H, 5.39 ; N, 7.34. (: 231124? 31 ^ 〇3; 2) 1 (: 1; 1.7112〇 theory: C, 50.14; H, 5.38; N, 7.63%. -62- (58) 200302094 Implementation Example R Υ Data 23-(CH〇2-1H-NMR (CD3OD54 00MHz) 5: 3.18 (m, 3H), 3.21 (m, 2H), 3.76 (m, 0.5H), 3.80 (m, 2H) , 4.20 (m, 0.5H), 4.32 (m, 1H), 4.48 (m, 2H), 7.20 (m, 4H), 7.30 (d, 1H), 7.50 (ΐΉ, 2Η), 7.60 ( η, 1Η), 7.76 (m, 1H), 8.60 (m, 1H) · HRMS: m / z (ES +) 448.1 842 [M ΗΊ. 24 \ CI Λ-(CH2) 2- 1H-NMR (CD3. D, 400MHz) 5: 3.18 (m, 2H), 3.20 (m, 2H), 3.74 (m, 1H), 3.80 (m, 2H), 4.2 0 (m, lH), 4.35 (m, lH), 4.48 (t, 2H), 7.21 (m, 2H), 7.26-7.40 (m, 4H), 7.48 (m, lH), 7.52 (m, lH) , 8.5 9-8 · 6 5 (m, 1 H). Measured by microanalysis: C, 50.18; H, 5.15; N? 7.32. C22H23Cl2N3〇3; 2HC1; H2O theory: C, 50.02; H, 5. 1 1; N, 7. 61%. -63- (59) 200302094 Example RY data 25 HC V-ch3 Me〇 '1-(CH2) 2-^-NMRCCDsOD, 400MHz) (5: 1.20 ( m, 6H), 2.81 (m, 1H), 3.17 (m, 6H), 3.70 (m, 2H), 3.78 (m, 2H), 4.18 (m, 1H), 4.30 (m, 1H), 4.46 (m , 2H), 6.78-7.16 (m, 5H), 7.39 (d, 1H), 7.44 (m, 2H), 8.60 (m, 1H). 26-(CH2) 2- 1H-NMR (CD3OD, 400MHz) ) (5: 3.17 (m, 4H), 3.78 (m, 3H), 4.18 (m, 1H), 4.30 (m, 1H), 4.45 (m, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.56 (m, 5H), 8.61 (m, 1H) · Microanalytical measurement 値: C, 52.64; Η, 5.82; ,, 7.91.〇22 Η 2〇1N3 〇3; 2HC1; H2O theory C: C , 52.34; Η, 5. 5 9; N, 8.3 2%. -64- (60) 200302094 Example R 数据 Data 27 H3CV CH3 Λ-(CH2) 2- ^ -NMRCCDsOD, 400MHz) 5: 2.24 (d, 6H), 3.07- 3.22 (m, 5H), 3.77 (m, 3H), 4.30 (m, lH), 4.42 (m, 2H), 7.23 (d, lH), 7.30 (s, lH), 7.45 (m, 3H), 8.60 (2xs, lH). Micro Analytical measurement 値: C, 57.44; H, 6.74; N, 8.02. C24H29N3O3; 2HC1; 1.3H2〇 Theoretical 値: C, 57.21; H, 6.72; N, 8.34%. 28 η3Α-(CH〇2- ] H-NMR (CD3OD, 400MHz) 5: 3.12-3.23 (m, 8H), 3.75 (m, 1H), 3.80 (m, 2H), 4.32 (m, 1H), 4.45 (m, 2H), 6.90 (m, lH), 6.99 (m, lH), 7.10 (m, lH), 7.19 (m, 4H), 7.50 (s, lH), 8.61 (m, lH) · Measured by microanalysis: C, 54.72; H36.14; N, 7.96.C23H26FN3〇3; 2HC1; 1.2H2〇 theory: C, 54.59; H, 6.06; N, 8.30%. -65- (61) 200302094 Implementation Example R Υ Data 29-(CH2) 2- 1H-NMR (CD3OD5400MHz) 5: 1.00 (t, 3H), 2.56 (q, 2H), 3.19 (m, 5H), 3.80 (m, 2H), 4.19 (m, lH), 4.30 (m, lH), 4.46 (m, 2H), 7.04 (d, lH), 7.19 (m, 7H), 7.50 (m, lH), 8.62 (2xs, lH) 30 q- (CH2) 3- 1H-NMR (CD3OD, 400 MHz) 5: 2.23 (m, 2H), 2.70 (t, 2H), 3.17 (m, 3H), 3.21 (m, 1H), 3.80 (t , 2H), 4.22 (m, 2H), 4.30 (m, 1H), 7.25 (m, 2H), 7.40 (d, 2 H), 7.48- 7.64 (m, 5H), 8.62 (m, 1H). Measured by microanalysis: C, 51.77; H, 5.72; N, 7.61. C23H26ClN3O3; 2HC1; 2H2O Theoretical 値: C, 51.46; H, 6.01; N, 7.83% · -66- (62) (62) 200302094 Example RY data 31-(CH2) 3- 1H-NMR (CD3OD, 400MHz) 5: 2.23 (m, 2H) , 2.74 (m, 2H), 3.17 (m, 4H), 3.80 (m, 2H), 4.22 (m, 3H), 7.05 (m, 1H), 7.18 (m, 2H), 7.29 (m, 2H), 7.44 (m, 2H), 7.58-7.70 (m, lH), 8.82 (s, lH) · Microanalytical measurement 値: C, 50.15; H55.3 8; N, 7.39. C23H25F2N3〇3; 2HC1; 2.5H2 〇Theoretical 値: C, 50.46; H, 5.89; N, 7.68%. Example 3 2 (2RS) -2- (2-aminoethoxy) -3-Π- (3-Π, 1'-linked Benzene 1-3-propylpropyl)-

By following the procedure of Example 20, the title compound was obtained as an impure white bubble body from the compound of Preparation Example 45. 1H-NMR (CD3OD, 400MHz) δ: 2.25 (m, 2Η), 2.75 (π, 2Η), 3.14 (2ι, 2Η), 3.27 (m, -67- (63) 200302094 1H) , 3.74 (m, 1H), 3.78 (m, 2H), 4.22 (m, 3H), 7.18 (m, 1H), 7.25-7.42 (m, 6H), 7.45 (s, 1H), 7.58 (d, 2H ), 8.80 (s, 1H). LRMS: m / z (ES +) 394 [MH +]. Measured 値 by microanalysis: C, 54.03; Η, 6.73; N, 8.09o C23H27N3O3; 2HC1; 2.4 H2O theoretical 値: C, 54.21; Η, 6.68; N, 8.24%. Example 33 (21 ^)-2- (2-Aminoethoxy) -3- "1- (3-" 1,1'-biphenylb-2-ylpropanyl) -1 fluorene-imidazole- 4-yl-1 propanoic acid dihydrochloride

νη2.2HCI The title compound was obtained as an impure white bubble from the compound of Preparation Example 46 by following the procedure of Example 20 (yield: 30%). W-NMIUCDsOD, 400MHz) ά: 1.96 (m, 2H), 2.60 (t, 2H), 3.05-3 · 23 (ιη, 4Η), 3.79 (ηι, 2Η), 4.02 (t, 2Η) , 4.48 (m, 1Η), 7.14 (d, 1H), 7.19-7.30 (m, 6H), 7.36 (m, 3H), 8.62 (s, 1H). Measured 値 by microanalysis: C, 54.89; Η, 6.24; N, 8.35. C23H27N3O3; 2HC1; 2H2O theory 値: C, 54.98; Η, 6.62; N, 8.36%. Example 3 4 ----- 1-^.,.,.)-2-1 ^ 28) -Amine-propyl] oxy) -3- "1- (2-cyclohexylethyl) -11 m (64) 200302094 H3C ,, / NH2

Following the procedure of Example 20, the title compound was prepared from the morpholinone of Preparation Example 95 (yield 64%). W-NMIUCDAD, 400MHz) 5: 0.80-

.2HCI OH

1.32 (m, 9H), 1.60-1.80 (m, 7H), 3.20 (ι, 1H), 3.57 (m, 3Η), 3.80 (m, 1Η), 4.20 (m, 2Η), 4.35 (m, 1Η), 7.48 (s, 1H), 8.86 (s, 1H). HRMS: m / z (ESl) 324.2280 [MH +]. Example 3 5 (210-2- 丨 "(210-Aminopropyl 1oxyb 3-3-1- (2-cyclohexyl) -111-imidazol-4-yl 1 propanoic acid dihydrochloride Salt 丨 h3c, ^ nh2

• 2HCI OH

0 Following the procedure of Example 20 to prepare the title compound from the morpholinone of Preparation Example 96. 1H-NMR (CD3OD, 400MHz) 5: 0.80-1.3 2 (m, 9Η), 1.60-1.80 (m, 7H), 3.20 (m, 1H), 3.57 (m, 3H), 3.80 (m, 1H ), 4.20 (m, 2H), 4.35 (m, 1H), 7.48 (s, 1H), 8.86 (s, 1H). HRMS: ni / z (ESl) 3 24.2275 [MH +]. Example 3 6 (2RS) -2- (2-Aminoethoxymethylphenyl) -1'-imidazol-4-yl 1 -69- (65) 200302094 Propanoic acid dihydrochloride

A solution of morpholinone (100 mg, 0.37 mm) in concentrated hydrochloric acid (2 ml) of Preparation Example 100 was heated at 110 ° C for 36 hours, then cooled, and concentrated under reduced pressure. The residue was mixed with methanol and dichloromethane. Chlorochloromethane was azeotroped to give the title compound. J-NMIUCD ·, 400MHz) 6: 2.10 (s, 3H), 3.19 (m, 2H), 3.26 (m, 1H), 3.39 (m, 1H), 3.82 (t , 2H), 4.42 (η, 1H), 7.40 (m, 2H), 7.46 (m, 2H), 7.62 (s, 1H), 9.14 (s, 1H). HRMS: m / z (ESl) 290.1 502 [MH +]. Example 37 (2 feet) -2- 丨 "(18) -2-amino-methylmethylethyloxyl 3-" 1- (2-cyclohexylethyl) -1 H-imidazol-4-yl 1 propionic acid dihydrochloride

Following the procedure of Example 20, the title compound was prepared from the morpholinone of Preparation Example 91. 1H-NMR (CD3OD, 400MHz) 5 ·· 1.01 (m, 5Η) ’

1/21 (m, 4H), 1.74 (m, 7H), 2.93-3.14 (m, 3H), 3.25 (m '1H), 3.79 (m, 1H), 4.21 (1,2, H), 4.38 (m, 1H), 7.55 (s, 1 Po, 8.90 (s,] H). LRMS: m / z (ES.) 3 2 2 [MH ·]. Microanalysis method -70- (66) 200302094 Measurement: C, 47.73; H, 7.85; N, 9.66. CnHasNsCh; 2HC1; 1.6 H2O theory: C, 48.02; H, 8.11; N, 9.88%. Example 3 8 (2S) -2- 丨 "(lR) -2-Amino-p-methylethyl 1oxy) -3-Π42- (4,4-dimethylcyclohexyl) ethyl 1- 1Η-imidazol-4-yl 丨 propionic acid dihydrochloride

.2HCI

Following the procedure of Example 20, the title compound was obtained from the morpholinone of Preparation Example 93 (yield: 83%). 'H-NMIUCD ^ OD, 400MHz) 5: 0.88 (s, 6H), 1.04 (d, 3H), 1.17-1.34 (m, 5H), 1.40 (m, 2H), 1.60 (m, 2H), 2.97- 3.18 (m, 3H), 3.30 (m, 1H), 3.81 (m, 1H), 4.24 (m, 2H), 4.40 (m, 1H), 7.58 (s, 1H), 8.94 (s, 1H). HRMS: m / z (ES +) 374.2484 [MNa +]. Example 39 (2S) -2-H (lR) -2-amino-1-methylethyl 1oxyb 3- "l- (3-cyclohexyl- 3-methylbutyl) -1'- Imidazol-4-yl 1 propanoic acid dihydrochloride

-71-(67) 200302094 Following the procedure of Example 20, the title compound was prepared from the morpholinone of Preparation Example 94. 1H-NMR (CD3OD, 400MHz) 5: 0.94 (s, 6H), 0.98] .30 (m, 10H), 1.62 (m, 1H), 1.78 (m, 6H), 2.90-3.15 (m, 3Η ), 3.78 (m, 1Η), 4.20 (mη, 2Η), 4.38 (m, 1Η), 7.52 (s, 1H), 8.90 (s, 1H). LRMS: m / z (ES +) 366 [MH +] 〇 Example 4 0

2- (2-Aminoethane, a phenoxyphenyl group) -1H-imidazole-4-some1propionic acid dihydrochloride

.2HCI The concentrated hydrochloric acid (5 ml) solution of Preparation Example 102 morpholinone (25 mg, 0.07 mmol) was heated at no ° C for 18 hours, then cooled, and concentrated under reduced pressure. The residue was dissolved in water and lyophilized to obtain the title compound (35 mg) as a pale yellow-brown solid. , 400MHz) 5: 3.04 (m, 3H), 3.18 (dd, 1H), 3.63 (t, 2H), 4.19 (m, 1H), 6.98 (d, 2H), 7.06 (η, 3H), 7.19 (d, 1H), 7.46 (dd, 2H), 7.50 (dd, 1H), 7.54 (s' 1H), 8.87 (s, 1H). LRMS: m / z (ES +) 3 6 8 [MH +]. Example 4 1 to 4 4 Compounds of the following general formula follow the procedure of Example 40 from the corresponding -72- 200302094

Example R Data 41 ^ -NMRCDaO, 400MHz) 5: Η 3.01-3.20 (m, 4H), 3.65 (m, 2H), 4.21 Q (m, 1H), 7.10 (m, 2H), 7.25 (s, 1H ), 7.32 (m, 3H), 7.54 (m, 3H), 7.61 (m, lH), 8.59 (s, lH). LRMS: m / z (ES +) 35 2 [MH +]; 374 [MNa + ]. 42 // \ 1H-NMR (D20, 400MHz) 5: 3.18-3.35 (m, 4H), 3.80 (t, 2H), 4.30 (dd, 1H), 7.60 (m, 3H), 7.77 (s , LH), 7.9 8 (m, 2H), 8.04 (m, 2H), 9.06 (s, 1H) • LRMS: m / z (ES +) 34 8 [MNa +] · Measured by microanalysis: C , 49.16; H, 5.60; N, 9.54. ChB19N3O3; 2HC1; 2.3H2O theory: C, 49.18; H, 5.65; N, 9.58%.

-73- (69) 200302094 Example R Data 43 (> ρ CI 1H-NMR (D2, 400MHz) 5: 3.17-3.35 (m, 4H), 3.79 (m, 2H), 4.30 (m, 1H) , 7.40 (m, 2H), 7.52 (m, 2H), 7.60 (m, 2H), 7.70 (m, 3H), 9.02 (s, lH). LRMS: m / z (ES +) 3 86 [MH4] 44 Cl CI ^ -NMRCDiO, 400 MHz) 5: 3.20-3.35 (m, 4H), 3.80 (m, 2H), 4.30 (t, 1H), 7.42-7.75 (m, 8H), 9.05 (s, lH) .LRMS: m / z (ES +) 420,422 [MH +].

Example 45

(2S) -M-2- (2-Amine, an ethylamino) -3- "l- (4-tert-butylphenyl) -1'-imidino-4-yl 1 propanoic acid dihydrochloride

Following the procedure of Example 40, the title compound was obtained as light yellow-brown solid from the morpholinone of Preparation Example 105. 1 ^ 1 ^^ 020,400 ^ 41 ^) 5 ... 丄 2〇 (s, 9H), 3.04-3.35 (m, 4H), 3.79 (m, 2H), 4.38 (m, 1H), 7 41 (m, 2H), 7.58 (m '2H), 7.61 (s, 1H), 8.98 (s,, u, τ ΌΜς. η / ζ (Ε $ Ί33 2 [ΜΗΊ. Microanalytical measurement 値: C, ϊ n) ° L Μ)-"-74- (70) 200302094 49.5 8; Η, 6.75; N, 9.84. Cl8H25N3O3; 2HC1; 1.75 H2O theoretical 値 · C, 49.5 8; Η, 7.06; N, 9.64%. [A] D = _2.00 (c = 0.30, methanol). Examples 46 to 48 Compounds of the following general formula follow the procedure of Example 40 from the corresponding Morpholones are manufactured.

9H3

R

Data_ H-NMR (D2〇, 400MHz) ά: 1.00 (d) 3H)

, 1.16-1.4 (m, 6H), 1.64 (m, lH)? L.78 (m, 3 Η), 2 · 5 9 (ιώ, 1 Η), 2.89-3 · 1 7 (η, 4 Η ), 3.68 (m, lH), 4.30 (m, lH), 7.44 (m, 4H), • 66 (s, lH), 8.98 (s, lH). LRMS: m / z (ES ") 372 [MH +]. Measured by microanalysis: C, 5 2.74; H, 7.27; N, 8.54. C2iH29N3O3; 2HCl; 2 H2O Theoretical 値: C, 5 2 · 50; H, 7.34; N, 8.7 5% ._ -75- (71) 200302094 Example 47

R

48

__mm_ 1H-NMR (D20, 400MHz) 5: 0.98 (d, 3H), 2.90 (m, 1H), 3.05 (m, 2H), 3.24 (m, 1H), 3.78 (m, 1H), 4.38m, lH), 7.02 (d, 2H), 7.15 (m, 3H), 7.26 (d, lH), 7.38 (m, 2H), 7.48 (m, lH), 7.62 (s, lH), 8.99 (s, lH ). LRMS: m / z (ES +) 382 [MH +]. [A] D = -72.0 (c-0.05, methanol). 1H-NMR (D2, 400MHz) 5: 1.01 ((1, 3H) , 2.98 (m, lH), 3.15 (m, 2H), 3.29 (m, lH), 3.79 (m, lH), 4.37 (m, lH), 7.40 (m, 2H), 7.58 (d, 2H) ), 7.62 (m, 2H), 7.75 (m, 3H), 9.05 (s, 1H). LRMS: m / z (TSP +) 400.2 [MH +]. Measured by microanalysis: C, 47.90; H, 5.48; N, 7.90. C2iH2 2ClN3O3; 2HCl; 3H2O theory: C, 47.8 8; H, 5.74; N, 7.98%.

Dou Example 49 (2S ')-2-i "(1RV2-amino-1-methylethyl1oxy) -3-U-" 4- (cyclohexyloxy) phenyl 1-1 Η- Imidazole-4 -yl 丨 propionic acid

200302094 A solution of a mixture of the protected amino acid of 2N hydrochloric acid (1 ml), water (1 ml) and dioxane (1 ml) in Preparation Example 1 20 was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was dissolved in water and purified on a Dowex® 50WX8-200 ion exchange resin with a column of water: methanol: 0.88 ammonia (48: 48: 4). The product was dissolved in water and lyophilized to obtain the title compound (25 mg). W-NMRiDA, 400 MHz) 5: 0.94 (d, 3H), 1.35 (m, 4H), 1.55 (m, 3H), 1.72-2.01 (m, 3H), 2.7 8-2.97 (m, 2H), 3.10 (m, 2H), 3.60 (m, 1H), 4.01 (m, 1H), 4.21 (m, 1H), 6.92 (d, 2H), 7.01 (s, 1H), 7.20 (d, 2H), 7.62 (s, 1H). LRMS: m / z (ES +) 3 88 [MH +]. Measured 値 by microanalysis: C, 5 9.3 3; Η, 7.65; N, 9.80. C2iH29N304; 2H2O theory 値 · C, 5 9.5 6; Η, 7.85; N, 9.92%. Example dS) -2- (2-Aminoethoxy) -3- (1 H-imidazole-4_-yl) propionate

A mixture solution of morpholinone (90 mg, 0.24 mmol) and lithium hydroxide (32 mg, 1.33 mmol) in water (2 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 18 hours, and then reduced at room temperature. Concentrated under pressure. The residue was suspended in concentrated hydrochloric acid (3 ml), and the mixture was heated at 110 ° C for 18 hours. (73) 200302094 It was then cooled and concentrated under reduced pressure. The residue was triturated with acetone, and the resulting solid was collected, dried, and then recrystallized from methanol / acetone to obtain the title compound (12 mg) as a white solid. j-NMIUCDsOD, 400MHz) 5: 3.20 (m, 2H), 3.30 (m, 2H), 3.83 (m, 2H), 4.37 (m, 0.5 ·), 4.41 (m, 0.5Η), 7.41 (s , 1H), 8.81 (s, 1H) o LRMS: m / z (ES_) 198 [MH-] 0 Example 5 1 (2S) -2- {f (lR) -2-amino-1-methyl Ethyl 1oxy 丨 -3-ΠΗ-imidazol-4-yl) propionic acid? H3

A solution of morpholinone (320 mg, 1.64 mmol) in concentrated hydrochloric acid (5 ml) of Preparation Example 105 was heated at 110 ° C for 18 hours, then cooled, and diluted with water (80 ml). The resulting solution was purified on a Dowex® 50WX8-200 ion-exchange resin by column-layer desorption with water: 0.88 ammonia (100: 0 to 9 5: 5). The product was dissolved in water and freeze-dried to give the title compound (290 mg) as a colorless foam. ] H-NMR (D20, 400MHz) 5: ◦ • 90 (d, 3H), 2.80 (dd, 2H), 2.98 (dd, 2H), 3.57 (m, 1H), 4.04 (m, 1H), 6.84 (s, 1H), 7.60 (s, 1H). LRMS: m / z (ES +) 2 3 6 [MNa ”. Microanalytical measurement: ，: C, 46.00; H, 7.41; N, 17.81. C9H” N3〇4; 1.25 H2O Theoretical 値: C, 45.85- 78- (74) 200302094; Η, 7.48; N, 17.82% o [a] D = -94.62 (c = 1.72, water). In another synthesis method, the protected mesitylamine (1.58 g, 4 · 4 2 mm ο 1) and methylamine sulfonic acid (6 · 5 m 1) were prepared in Example 5 5 a at 70 ° C. The mixture was heated for 2.5 hours. The cooled solution was diluted with diethyl ether (40 ml) and the mixture was stirred 'and the ether was poured off. Repeat this procedure 2 times. Water was added and the mixture was stirred vigorously, followed by filtration. The filtrate was allowed to stand at room temperature for 24 hours, and then the filtrate was purified by column-type delamination on a Dowex® 50WX8-200 ion exchange resin with water ···· 88 ammonia (95: 5), and the pressure was reduced under reduced pressure. The obtained fractions were evaporated at a water bath temperature below 33 ° C. The obtained product was dissolved in concentrated hydrochloric acid (5 ml), and the solution was heated at 100 t for 18 hours, then cooled, and diluted with water (30 ml). The solution was purified by washing on Dowex® 50WX8-200 ion exchange resin with water: 0.88 ammonia (95: 5). The product was stirred in acetonitrile (10 ml) for 1 hour, filtered, and dried in vacuum for 18 hours. Measured 値 by microanalysis: C, 46.5 8; Η, 7.50; N, 17.98. C9H " N3.1 H2O theory 値: C, 46.75; Η, 7.41; N, 18.17%. Example 5 2 (23) -2- 丨 [(110-2-Amino-bromomethyl ethyl 1-oxymethyl 3- "1- (2-pyridyl) -1'-imidazol-4-yl 1propane Acid dihydrochloride

〇-79- (75) (75) 200302094 The concentrated hydrochloric acid (3 ml 1) solution of morpholinone (72 mg, 0.26 mmol) in Preparation Example 152 was heated at 100 ° C for 18 hours, then cooled and diluted with water. And concentrated under reduced pressure. The residue was purified on a Dowex® 50WX8-200 ion-exchange resin by column-level delamination with water: 0.88 ammonia (100: 0 to 95: 5). The product was dissolved in 2N hydrochloric acid, and the resulting solution was concentrated under reduced pressure. The residue was dissolved in water (10 ml) and lyophilized to obtain the title compound (58 mg) as a solid. 400MHz) (mixture of local isomers of imidazole) 5: 0.79, 0.99 (2; cd, 3H), 2.56, 2.92 (2xm, 1H), 3.02-3.44 (m, 3H), 3.58, 3.78 (2xm, 1H ), 7.55 (m, 1H), 7.71 (m, 1H), 7.96-8.19 (m, 2H), 8.52, 8.61 (2xm, 1_H), 9.03, 9.38 (2xs, 1H). LRMS: m / z (ES +) 291 [MH +]. Example 5 3 (23) -2-{[((11〇-2-amino-1-methyl certain ethyl 1 gas some) -3- (1-propane-1} ^ enazol-4-yl) Propionic acid

A concentrated hydrochloric acid (10 ml) solution of the compound of Preparation Example 157 (560 mg, 2.36 mm) was stirred at 110 ° C for 18 hours. The cooled solution was concentrated under reduced pressure, and washed on a Dowwe X ® 50 WX 8-2000 ion exchange resin with water: 0.88 ammonia (100: 0 to 95: 5) in steps. The residue was purified by column chromatography to obtain (76) 200302094 the title compound (3 50 mg) as a foam. W-NMI ^ DaO, 400MHz) 5: 0.66 (t, 3H), 0.81 (d, 3H), 1.60 (m, 2H), 2.60- 2.7 8 (m, 2H), 2.80-2.98 (m, 2H), 3.45 (m, 1H), 3.78 (t, 2H), 3.98 (dd, 1H), 6.82 (s, 1H), 7.43 (s, 1H). LRMS: m / z (ES +) 27 8 [MNa +]. Measured 値 by microanalysis: C, 53.44; H, 8.13; N, 15.40 C12H21N3O3; 0.8 H2O Theoretical 値: C, 53.44; H, 8.45; N, 15.58%. [α] 〇 = · 86 · 93. (C = 0.11, methanol).

Example 54 (2R) -2-H (lR) -2-amino-1-methyl certain ethyl 1oxyb 3- (1Η-imidazole-4-some) propionic acid

A mixture of pramine (80 mg, 0.50 m mol) and 2N hydrochloric acid (2 ml) in Preparation Example 158 was heated at 110 ° C for 16 hours, then cooled, and diluted with water (10 ml). This solution was purified on a Dowex® 50WX8 resin using a column of water: 0.88 ammonia (95: 5). The product was triturated with acetone, and the resulting solid was dried in vacuo to give the title compound (68 mg) as a brown solid. j-NMRiDsO, 400 MHz) 5: 1.0 (d, 3H), 2.76 (dd, 2H), 2.83 (m, 2H), 3.60 (m, 1H), 3.86 (m, 1H), 6.79 (s, 1H), 7.57 (s, 1H). -81-200302094 Preparation Example 1 n-propyl-1H-imidazole-4-carbaldehyde

Add mili-4 -formic acid (30 g, 0.31 m 1)-partly to sodium hydride (13.9 g, 60% dispersion in mineral oil, 0.348 mol) of tetrahydrofuran ( 40.5 ml) solution, the solution was stirred for 45 minutes. Next, n-propyl bromide (31.2 m, 0.344 mol) was added in portions, followed by 18-crown-6 (150 mg), and the mixture was heated under reflux for 18 hours. An aqueous ammonium chloride solution was added to the cooled solution, and the mixture was extracted with ethyl acetate (2X) and dichloromethane (2X). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on a silica gel with ethyl acetate: pentane (40:60) to give the title compound (20.2 g, 47%). , 400MHz) 5: 0.80 (t, 3H), 1.76 (m, 2H), 3.98 (t, 2H), 7.84 (s, 1H), 8.04 (s, 1H), 9.70 (s, 1H). LRMS: m / z (TSP +) 277.3 [2M + H] + Preparation Example 2 1-n-butyl-1H-imidazole-4-carbaldehyde

Following a procedure similar to that described in Preparation Example 1, the title compound was obtained from π-π-4--4-carboxaldehyde and n-butyl bromide (yield 28%). NMR (CDC1: ,, 300MHz) 5: 0.97 (t, 3H), 1.37 (m, 2H), (78) (78) 200302094 1.80 (m, 2H), 4.00 (t, 2H), 7.55 (s, 1H), 7.62 (s, 1H), 9.88 (s, 1H). LRMS: m / z (TSP +) 153.3 [MH +]. Preparation Example 3 (2 · cyclohexylethyl) -1 H-imidazole-4-carbaldehyde

Imidazole-4-carbaldehyde (4.8 g, 50 mmol) was added in portions to a suspension of sodium hydride (2.20 g, 60% dispersion in mineral oil, 55 mmol) in tetrahydrofuran (150 ml), followed by The mixture was stirred at room temperature for 1 hour. 2-Cyclohexylethyl bromide (8.6 ml, 55 mmol) was added, and the mixture was heated under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure, and the residue was partitioned between water (500 ml) and dichloromethane (500 ml). The layers were separated, dried over an organic phase of magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography using toluene: ethyl acetate (100: 0 to 96: 4) on a silica gel step by step to obtain the title compound (1.78 g). 'H-NMRiCDCh ^ 400MHz) 5: 0.98 (m, 2H), 1.20 (m, 4H), 1.68 (m, 7H), 4.00 (t, 2H), 7.4 (s, 1H), 7.60 (s, 1H), 9.80 (s, 1H). LRMS: m / z (TSP +) 207.2 [MH +]. Preparation Example 1 1-(2 -Phenethyl) -1 hydrazone -imidazole-4 -formaldehyde -83- 200302094

Add imidazole-4-carbaldehyde (6.73 g, 70 mmol)-partly to a suspension of sodium hydride (1.68 g, 60% dispersion in mineral oil, 70 mmol) in tetrahydrofuran (280 ml), then in the chamber The mixture was stirred at warm for 30 minutes. (2-Bromoethyl) benzene (9.56 ml, 70 mmol) was stirred at room temperature for 72 hours. The mixture was evaporated under reduced pressure, the residue was partitioned between water (300 ml) and dichloromethane (500 ml), and the layers were separated. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The crude φ-product was adsorbed with silica gel in advance, and purified by column chromatography using ethyl acetate: pentane (50:50 to 100: 0) on silica gel to obtain the title compound (1.44g) . j-NMR (CDCl3, 400MHz) 5: 3.16 (t, 2H), 4.23 (t, 2H), 7.02 ((1, 2Η), 7.28 (m, 3Η), 7.36 (s, 1Η), 7.50 (s, 1Η), 9.83 (s, 1H) o LRMS: m / z (ES +) 223 [MNa +]. Preparation Example 5 J-trityl-1 Η-imidazole-1 2 · A1 ·

A solution of trityl chloride (9.5 g, 34.3 mmol) in N, N-dimethylformamide (50 ml) was added dropwise to ice-cooled imidazole · 4-formaldehyde (3 g, hour). The reaction was then allowed to warm to room temperature 84-1 1.21111]] 〇1) and triethylamine (17〗 111, 1251111]] 〇 1) in 1 ^, dimethylformamide 2 (30ml) solution, and The solution was stirred at 2 (80) 200302094 and stirred for 18 hours. Water (200 ml) was added, and the resulting pink solid was collected, dried, and then the solid was dissolved in dichloromethane (200 ml). The resulting solution was washed with water (2x100 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The product was precipitated from ethanol to give the title compound (7.8 g) as a solid. j-NMIUCDCh ^ OOMHz) ^: 7.06 (m, 6H), 7.32 (m, 9H), 7.48 (s, 1H), 7.58 (s, 1H), 9.82 (s, 1H). Measured 値 by microanalysis: C, 81.54; Η, 5.37; N, 8.24. C23Hi8N2〇 theory 値: C, 8 1 · 6 1; Η, 5 · 3 6; N, 8. 8% 0 Preparation Example 6 2-K4-_methoxybenzyl) amino 1 ethanol Η0

Acetic acid (about 150 ml) was added to a methanol (1 L) solution of p-methoxybenzaldehyde (58.2 g, 0.42 mol) and ethanolamine (152 ml, 2.52 mol) to bring the pH to 6. Sodium borohydride triacetate (100 g, 0.47 ml) was added in portions, and once it was completely added, the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, made alkaline with a 1N sodium hydroxide solution, and extracted with dichloromethane (10x300 ml). The combined extract was evaporated, and the crude product was purified by column chromatography on silica gel with dichloromethane · methanol (98: 2 to 90:10) to obtain the title compound (42 g ). ] Η- NMR (CDCh, 400MHz) 5 ·· 2.7 8 (t, 2H), 3.62 (t, 2H), 3.75 (m, 5H), 4.24 (s, 2H), 6.81 (d, 2H), 7.22 (d, 2H). L R M S: m / z (E S4) 1 8 2 [M H +]. -85- (81) 200302094 Preparation Example 7 (2R) Small K4-methoxymethyl) amino group 2 -propionyl g — 〇,

ch3 p-methoxybenzaldehyde (5.45g, 0.04mol) was added dropwise to a solution of (RM-)-branzyl-2-propanol (9.00g '0.12mol) in tetrahydrofuran (40ml) and acetic acid (5ml). In a solution of tetrahydrofuran (40 ml), once the solution was completely added, the solution was stirred at room temperature for 2 hours. The solution was cooled in an ice bath, and sodium borohydride triacetate (9.50 g, 0.045 mol) was added in portions, followed by stirring the mixture at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (150 ml) and a sodium hydroxide solution (150 ml, 0.5 N). The layers were separated, the aqueous phase was saturated with sodium chloride, and extracted with dichloromethane (3x30 ml). The combined organic solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on a silica gel using methylene chloride: methanol: 0.88 ammonia (9 8: 2: 0.2 to 97: 3: 0.3) by column column delamination to obtain an orange oil (4.9g). . j-NMI ^ CDCh, 400MHz) 5: 1.12 (d, 3H), 2.39 (dd, 1H), 2.70 (dd, 1H), 3.62-3.79 (m, 6H), 6.82 (d, 2H), 7.19 (d , 2H). LRMS · m / z (ES +) 196 [MH +]. Preparation Example 8 (28.1 _-_ 1M (4-methoxybenzyl) amino 1-propanol (82) 200302094

(S)-(+)-l-Amino-2-propanol (9g, 0.12mol), p-methoxybenzaldehyde (5.45g, 0.04mol), acetic acid (5ml) and triacetic acid at room temperature A mixture of a solution of sodium borohydride (9.5 g, 0.045 mol) in methanol (80 ml) was stirred for 72 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (150 ml) and 0.5 N sodium hydroxide solution (100 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (4 x 30 ml). The combined organic solution was dried over magnesium sulfate, and concentrated under reduced pressure. The residual yellow oil was purified by column chromatography on a silica gel with dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2 to 95: 5: 0.5) in steps to obtain the title compound (6.2 g). iH-NMR (CDCh, 400MHz) 5: 1 · 10 (d, 3H), 2.24-2.40 (m, 2H), 2.65 (dd, 1H), 3.62-3.80 (m, 6H), 6.82 (d, 2H) , 7.19 (d, 2H). LRMS: m / z (ES +) 218 [MNa +] Preparation Example 9 · (2R) -2-f (4-methoxybenzyl) amine 1-propanol

H3C,

(R) (-)-2-Amino-1-propanol (10.36 ml, 133 mmol) was added dropwise to a solution of p-methoxybenzaldehyde (5.85 g, 42.9 mmol) in methanol (90 ml), and the mixture was placed on ice. The solution was allowed to cool in the bath. Add acetic acid (2.5ml) and sodium borohydride triacetate (] 0.0 £, 47.211 ^ 〇 丨), and spend 1 hour to warm the reaction mixture to room temperature of -87- (83) (83) 200302094. The solution was warmed to 40 ° C, stirred for 48 hours, and then concentrated under reduced pressure. The residue was partitioned between a saturated sodium bicarbonate solution (50 ml) and dichloromethane (100 ml), and the layers were separated. The aqueous phase was extracted with dichloromethane (10 x 50 ml), and the combined organic solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified twice by silica gel methylene chloride: methanol: 0.88 ammonia (97: 3: 0.3 to 90: 10: 1) by column chromatography to obtain the title compound (6.0 g). W-NMIUCDCh, 400MHz) 5 ·· 1.0 (d, 3H), 2.80 (m, 1H), 322 (dd, 1H), 3.58 (dd, 1H), 3.62 (d, 1H), 3.78 (m , 4H), 6.82 (d, 2H), 7.20 (d, 2H) ° LRMS: m / z (ES +) 196 [MH +]. [a] D = -34.85 (c = 0.137, methanol). Production Example 1 0 (2S) -2-K4-oxybenzyl) amino 1-propanol

Following the procedure described in Preparation Example 9, the title compound was obtained from (S)-(+)-2-amino-propylpropanol and p-methoxybenzaldehyde (yield 67%). iH-NMR (CDCh, 400MHz) 5: 1.08 (d, 3H), 2.83 (m, 1Η), 3.30 (dd, 1Η), 3.59 (dd, 1Η), 3.66 (d, 1Η), 3.77 ( s, 3Η), 3.82 (d, 1H), 4.08 (bs, 2H), 6.82 (d, 2H), 7.22 (d, 2H). [a] D = + 39.19 (c = 0.146, methanol). Production Example] 1-88- (84) (84) 200302094 4- (4-methoxybenzyl) -3-morpholinone

A solution of sodium hydroxide (7.08 g, 0.177 mol) in water (150 ml) was added to the solution of the amino alcohol (32 g, (M77 mol) in dichloromethane (250 ml)) of Preparation Example 6, and the mixture was cooled to 0 ° C. Over 30 minutes, add a solution of chloroacetamidine chloride (1 4 · 3 m 1, 0 · 1 7 7 m ο 1) in dichloromethane (50 m 1) dropwise, and stir the mixture at room temperature for 18 Hours. The layers were separated, and the organic layer was washed with sodium hydroxide (2N, 150 ml), 2N hydrochloric acid (150 ml), and a saline solution (50 ml), then dried over magnesium sulfate, and concentrated under reduced pressure. The oily body of the residue was It was dissolved in ethanol (200 ml), a solution of potassium hydroxide (9.93 g, 0.177 mol) in ethanol (200 ml) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was triturated with ether / pentane to give the title compound (26 g) as a white powder. W-NMRiCDCh, 400 MHz) δ: 3.20 (t, 2 ，), 3.78 (m, 5Η), 4.19 (s, 2Η), 4.54 (s, 2H), 6.82 (d, 2H), 7.18 (d, 2H). LRMS: m / z (ES +) 244 [MNa +]. Production Example 1 2 (6R) -4- (4-methoxybenzyl) V6 -methyl-3-morpholinone (85) (85) 200302094 Follow a procedure similar to that described in Production Example 11 The title compound was prepared from the alcohol of Preparation 7 and chloroacetamidine (yield 76%), with the following exceptions: In addition, the silica gel was washed with dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2) Purification of the compound by column column delamination. ΙΗ NMR (CDCh, 400MHz) δ: 1 · 1 8 (d, 3 Η), 2.99-3 · 1 4 (m, 2Η), 3.79 (m, 4H) , 4.17 (d, 1H), 4.25 (d, 1H), 4.38 (d, 1H), 4.61 (d, 1H), 6.82 (d, 2H), 7.17 (d, 2H). LRMS: m / z (ES, +) 25 8 [MNa +] Preparation Example 1 3 (6S) -4- (4-methoxybenzyl) -6-methyl-3-morpholinone

Following the procedure described in Preparation Example 11, the title compound was obtained as a yellow oily body from the amine alcohol in Preparation Example 8 (yield 61%). iH-NMR (CDCh, 400MHz) 5: 1.18 (d, 3H), 2.98 · 3 · 10 (ιτι, 2H), 3.78 (m, 4H), 4.18 (d, 1H), 4.25 (d, 1H) , 4.38 (d, 1H), 4.60 (d, 1H), 6.61 (d, 2H), 7.17 (d, 2H) o LRMS: m / z (ES +) 2 5 8 [MNa +] Cabinet example] 4 -90- (86) 200302094 (5S) -4- (4-methoxybenzyl) -5-methyl-3-morpholinone

CH.

It took 10 minutes to dropwise add a solution of chloroacetylacetonyl chloride (2.34ml, 29m mol) in dichloromethane (25ml) to the stirred amine alcohol (5.6g, 28.7mmol) of Preparation Example 10 which was cooled with ice. Sodium hydroxide solution (1.16 g, 29 mmol, using 20 ml of water as a solvent) and a mixture of dichloromethane (50 ml). The mixture was stirred at room temperature for 18 hours, and then the layers were separated. The organic phase was washed with a 1N sodium hydroxide solution (25 ml), 2M hydrochloric acid (20 ml) and a salt solution (20 ml), then dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol (40 ml), the solution was cooled in an ice bath, and a solution of potassium hydroxide (1.63 g, 29 mm) in ethanol (40 ml) was added dropwise over 5 minutes. The mixture was then allowed to warm to room temperature and stirred for 18 hours. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (150 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by stepwise purification on silica gel with dichloromethane: methanol: 0.88 ammonia (97: 3: 0.3 to 95: 5: 0.5) to give the title compound (4g). W-NMIUCDCh, 400MHz) 5: 1.26 (d, 3H), 3.37 (m, 1H), 3.62 (dd, 1H), 3.70 (dd, 1H), 3.80 (s, 3H), 3.90 (d, 1H), 4.20 (d, 1H), 4.24 (d, 1H), 5.33 (d, 1H), 6.83 (d, 2H), 7.19 (d, 2H). [a] D-109.66 (c = 0.139, methanol). Preparation Example) 5 -91-(87) 200302094 (5 R)-4-(j_-methyl ^ benzyl v 5 -methyl-3 -morpholinone

CH3 followed a similar procedure to that described in Preparation 14 to prepare the title compound from the alcohol of Preparation 9 (yield 49%). j-NMRiCDCh,

400MHz) 5 ·· 1.24 (d, 3H), 3.30 (m, l Η), 3.60 (dd, 1H), 3.70 (dd, 1H), 3.78 (s, 3H), 3.85 (d, 1H), 4.18 ( d, 1H), 4.22 (d, 1H), 5.28 (d, 1H), 6.81 (d, 2H), 7.18 (d, 2H). Preparation Example 1 6 4 -Methyl-3 -morpholinone

Over 30 minutes, a solution of chloroacetamidine chloride (3.81ml, 50mmol) in dichloromethane (100ml) was added dropwise to 2- (methylamino) ethanol (4ml, 50mmol) and sodium hydroxide (2§, 5 In a suspension of methylene chloride (501111) and water (501111), the mixture was stirred at room temperature for 72 hours, and then evaporated under reduced pressure. The residue was dissolved in ethanol (100 ml), potassium hydroxide (2.8 g, 50 mmol) was added, and the mixture was stirred at 40 ° C for 18 hours, followed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified on a silica gel using pentane: ethyl acetate (100: 50 to 50:50 to 0: 1 00) by column chromatography to obtain the title compound (3.42 g). iH-NMR iCDCh, 400 MHz) 5: -92 · (88) 200302094 2.98 (s, 3H), 3.34 (t, 2H), 3.84 (t, 2H), 4.14 (s, 2H). Measured radon: C, 51.55; radon, 8.20; N, 12.10. C5H9N02; 0. 1 H2O theory 値: C, 51.36; Η, 7.93; N, 11.98%. ΜΛΜΛ2_

LIjL; methylamine) 1 ethyl tert-butyl acetate JI

N, N-dimethylethanolamine (5.02ml, 50mmol) was added dropwise to ice-cooled sodium hydride (2.2g, 60% dispersion in mineral oil, 55mmol) in tetrahydrofuran (100ml) over 5 minutes. In the body, the solution was stirred for 30 minutes. Tert-butyl bromoacetate (7.38 m to 50 mmol) was added dropwise over 5 minutes, and then the mixture was warmed to room temperature and stirred for 18 hours. The mixture was pre-adsorbed on silica gel, and column-type delamination was performed on the silica gel with pentane ·· ethyl acetate: methanol (50: 50: 0 to 0: 1 00: 0 to 0:80:20). Purification by method gave the title compound (1.46 g) as a yellow oil. W-NMIUCDCh, 400MHz) 5: 1.50 (s, 9H), 2.30 (s, 6H), 2.59 (t, 2H), 3.64 (t, 2H), 4.00 (s, 2H "LRMS: m / z (ES + ) 204 [MH +] Preparation Example 1 8 L3R) -3- (2-tert-butoxy-2-oxoethoxy)

(89) (89) 200302094 Sodium hydride (704 mg, 60% dispersion in mineral oil, 17.6 mmol) was added to ice-cooled (3R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl alcohol (J · Med. Cliem. 1998, 41 (25), 4983) (5 g, 26.7 mmol) in a solution of tetrahydrofuran (100 ml). The mixture was warmed to room temperature and stirred for 20 minutes. Tert-butyl bromoacetate (5.2 g, 26.7 mmol) was added, and the mixture was heated under reflux for 18 hours, then cooled, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the layers were separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate: pentane (0: 100 to 20:80) on silica gel to obtain the title compound (1.95 g). iH-NMIUCDCh, 400MHz) 5: 1.42 (s, 9H), 1.44 (s, 9H), 1.85-2.05 (m, 2H), 3.40 (m, 4H), 3.94 (m, 2H), 4.10 (m, 1H). LRMS: m / z (ES +) 324 [MNa +] Preparation Example 1 9

3-Ringyl-3 -methylbutanoic acid H

Trimethylmethsalyl chloride (1.3 ml, 10.2 mm), cuprous chloride (30 mg, 0.3 mmol) and cyclohexyl magnesium chloride (461111, using ether as a solvent, 2N '9.2 mm). 1) Slowly add ice-cooled 3,4-diethyl methacrylate (1, 8.51 1101) in tetrahydrofuran (1 (^ 1 丨)) solution. Stir the solution for 10-94- (90) (90) 200302094 minutes', followed by warming to room temperature and stirring for 1 hour. A saturated aqueous ammonium chloride solution (10 ml) was added, and the mixture was partitioned between water (10 mi) and ether (20 ml). The layers were Separate and extract the aqueous phase with diethyl ether (2 X 100 ml). Dry the combined organic extracts with magnesium sulfate and concentrate under reduced pressure. Wash on silica gel with ethyl acetate: pentane (5:95) The crude product was purified by column column delamination to obtain the title compound (1.2 g). W-NMI ^ CDCh, 40 MHz) accounted for 0.75 (m, 8H), 1.05-1.28 (m, 7H), 1.62 (m, 1H), 1.78 (m, 4H), 2.20 (s, 2H), 4.10U, 2H). Preparation Example 20 i-Cyclohexane-3 -methyl-1 -butanol

Lithium borohydride (1.23 g, 56.6 mm) was added to a tetrahydrofuran (30 ml) solution of the ester (4 g '18.9 mmol) in Preparation Example 19, and the mixture was stirred at 50 ° C for 18 hours. Aqueous ammonium chloride solution (15 ml) was carefully added to the cooled solution, and the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic extracts were extracted with a salt solution, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography on a silica gel with ethyl acetate: pentane (20:80) to give the title compound (lg). W-NMIUCDCh '400MHz) 5 · 0.80 (s, 6H), 0.88-1 · 18 (ιη, 6H), 1.50 (1, 2H), 1.60 (m, 1H)' 1.70 (m, 4H , 3.64 (m, 2H) 0 -95- (91) (91) 200302094 Preparation Example 2 1 (3-Bromo-1J-dimethylpropyl) cyclohexane

Add triphenylphosphine (1.8g, 7.1 mmol)-partly to ice-cooled alcohol (lg, 5.9 mmol) of Preparation Example 20 and dichloro chloride (2.9 g, 8.8 m mol) of dichloromethane In the solution of Jiayuan (15ml), once it was completely added, the mixture was stirred at room temperature for 72 hours. The solution was concentrated under reduced pressure, and the residue was suspended in a mixture of pentane: ethyl acetate (5: 1 by volume). The resulting precipitate was filtered through a silica gel pad, washed with pentane; ethyl acetate (volume ratio 5: 1, 300 ml). The combined mash was concentrated under reduced pressure, and the product was purified by column chromatography on a silica gel with pentane elution to obtain the title compound (1.1 g). ] H-NMR (CDCl3, 400MHz) 5: 0.80 (2; cs, 6H), 0.90-1.20 (m, 6H), 1.62 (ιη, 3Η), 1.75 (m, 2H), 1.81 (m , 2H), 3.36 (m, 2H). Production Example 22 Zhu (2-bromoethyl) -1,1-dimethylcyclohexane

At 90 X: 2 · (4,4-dimethylcyclohexyl) ethanol (WO 9 9/5997 1) (2 g, 12.8 mmol), concentrated sulfuric acid (7 50 #L) and 48% hydrobromine The mixture of acid (3) is stirred for 7 hours. Water (25 m) was then carefully added to passivate the -96- (92) 200302094 cooled mixture, and the mixture was extracted with dichloromethane (3 x 30 ml). The complex organic extract was washed with a 2M sodium carbonate solution and a saline solution (30 ml) and then dried over magnesium sulfate, and concentrated under reduced pressure. The residual black colloid was purified by distillation to obtain the title compound (3 to 30 mg). t NMR (CDCh, 400MHz) 5 ·· 0 · 82 (2sx, 6H), 1 · 02-1 · 20 (m, 4H), 1.35 (η, 3H), 1.50 (m, 2H), 1.79 ( m, 2H), 3.40 (t, 2H).

Preparation Example 23

2- "Hydroxy- (1-propane-1H-imidazole-4-some) methyl 1-4- (4-methylchlorosome benzyl certain W morpholinone

OH Ο 0, ch3

At -78 ° C, a tetrahydrofuran (100 ml) solution of the compound of Preparation 11 (13 g, 58.7 mmol) was added dropwise to a lithium diisopropylamidamine solution (35.3 ml, using tetrahydrofuran / heptane / ethylbenzene as a solvent). , 2M, 70.5 mmol) ', the solution was stirred at -78 ° C for 20 minutes. The aldehyde (9.7 5 g, 7 0.5 mm 1) of Preparation Example 1 was added dropwise, and the mixture was warmed to room temperature, followed by stirring for 1.5 hours. An ammonium chloride solution (100 ml) was added, and the mixture was diluted with water (100 ml) and tetrahydrofuran (300 ml). The layers were separated, the aqueous phase was extracted with tetrahydrofuran (250 ml), and the combined organic solution was dried over magnesium sulfate and evaporated under reduced pressure. Ethyl Acetate: Dichloromethane: Methanol: 0.88 Ammonia (100: 0: 0: 0 to 0: 95: 5: 0.5) on a silica gel stepwise stripping tube -97- (93) 200302094 column delamination The crude product was purified by the method to obtain the title compound (14 g). 1 H-NMR (CDCl3, 400 MHz) (mixture of diastereomers) 5: 0.90 (t, 3H), 1.76 (m, 2H), 3.00 (m, 1H), 3.32-3.43 (m, 1H) , 3 · 61-3 · 81 (ηι, 6Η), 3.98 (m, 1Η), 4 · 42-4 · 58 (ιη, 3Η), 4.75 (m, 0.5Η), 5.03 (m, 0.5 ·) , 6.81 (m, 3Η), 7.15 (ιη, 2H), 7.38 (s, 1H). LRMS: m / z (ES +) 360 · 0 [ΜΗ +]

Production Example 24

IrJ hydroxy (1-propyl-1H-imidazol-4-yl) methyl1-4-methyl-3-morpholinone

Take 10 minutes to add lithium diisopropylamidamine solution (17.4ml, using heptane / tetrahydrofuran / ethylbenzene as a solvent, 2 M, 3 4 · 8 mm ο 1) to the cooled (· 7 8 ° C) In a solution of the compound (3.42 g, 29 mmol) in Preparation Example 10 in tetrahydrofuran (100 mi), the obtained solution was stirred for 20 minutes. The aldehyde (4 · 81 g, 3 4.8 mm 1) of Preparation Example 1 was added, and the mixture was slowly warmed to room temperature, followed by stirring for 18 hours. Aqueous ammonium chloride solution (20 ml) was added, and the mixture was extracted under reduced pressure. Ethyl acetate: methanol: diethylamine (50: 5 0: 0: 0 to 0: 1 0: 00: 0: 0 to 0: 90: 5: 5) was eluted on silica gel step by step The residue was purified by column chromatography to obtain the title compound (5.47 g) as a yellow colloid. iH-NMR (CDCh, 400 MHz) (mixture of diastereomers) 5: 0.90 (t, 3H), 1.78 (m, 2H), 2.98 (2sx, 3H), 3.10 (m, 1H), 3.57 ( nl, 2H), 3.80 (m, 3H), 3.98 · 04 · 08 (ιώ, 1H), 4.39, -98- (94) 200302094 4.49, 4.86, 4.98, 5.22 (5xm, 2H), 6.88 (s , 1H), 7.38 (s, 1H). LRMS: m / z (TSP +) 254.2 [MH +] Preparation Example 25 2-"(1-butyl-1H-imidazole-4-some hydroxy) methyl-1-4- (4-methylargon; some ) -3-morpholinone

OH OH A solution of the compound of Preparation 11 (3.63 g, 0, ch3 16.4 mmol) in tetrahydrofuran (40 ml) was added dropwise to a lithium diisopropylamidamine solution (9.8 ml, Using tetrahydrofuran / heptane / ethylbenzene as a solvent, 2M, 19.7 mmol), the solution was stirred at −78 ° C. for 30 minutes. The aldehyde (3.0 g, 19.7 mm) of Preparation Example 2 was added dropwise, and the mixture was warmed to room temperature and stirred for 18 hours. The mixture was partitioned between an ammonium chloride solution and ethyl acetate (300 ml). The layers were separated, the organic solution was dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate: methanol (100: 0 to 9 0: 1 0) on silica gel to obtain the title compound (4.35 g). W-NMIUCDCh '400MHz) (mixture of diastereomers) 5: 0.96 (t, 3H), 1.35 (m, 2H), 1.78 (m, 2H), 3.03 (m, 1H), 3.42 (m, 1H), 3.66-3.80 (m, 5H), 3.87 (m, 2H), 4.00 (m, 1H), 4.50 (m, 0.5H), 4.57 (m, 2.5H), 4.83 (m, 0.5H), 5.06 (m, 0.5H), 6.90 (m, 3H), 7.20 (m, 2 H), 7. 4 1 (s, 1 H) o LRMS: m / z (TS P +) 3 7 4. 〇 [Μ H +] -99- (95) (95) 200302094 Production Example 26 2-_f "1-(2-cyclohexylethyl) -1 η -imid-4 -yl 1 (hydroxy) methyl 1 · 4-( 4 -methoxycarbyl) -3 -morphine

Following a procedure similar to that described in Preparation Example 25, the title compound was obtained as a viscous product from the compound of Preparation Example 11 and the aldehyde of Preparation Example 3 (yield 66%). W-NMIUCDCh, 400MΗζ) (mixture of diastereomers) 5: 0.98 (η, 2Η), 1.22 (m, 4Η), 1.5 8-1.7 8 (m, 7Η), 3.03 (m, 1H ), 3.3 8-3.5 0 (m, 1H), 3.70-3.82 (m, 4H), 3.90 (m, 2H), 4.01 (m, 1H), 4.50 (d, 0.5H), 4.58 (ιη, 2.5H), 4.87 (m 0.5 μ), 5.08 (m, 0.5H), 6.82, 6.95 (m, 3H), 7.19 (m, 2H), 7.41 (s, 1H). LRMS: m / z (TSP +) 428.1 [MH +] Preparation Example 27 2-{Essential group _ (_ 2 -stem ethyl) -1 H -imidazole-4 -yl 1methyl bu 4- (4- Methoxybenzyl) -3 -morpholinone

Following a procedure similar to that described in Preparation 25, the title compound was obtained from the compound of Preparation 11 and the aldehyde of Preparation 4 (yield 54%) -100- (96) (96) 200302094, In addition to the following differences: Ethanol: ethyl acetate: methanol (50:50: 0 to 0: 100: 0 to 0: 87: 13) elution. lH-NMR (CDCh '400MHz) (mixture of diastereomers) 5: 3.02 (m, 3H)' 3.42 (m '! H), 3.74 (m, 4H)' 3.95-4.05 (m '1H) '4.12 (m' 2H) '4.45 (m, 0.5H) 5 4.58 (m 5 2.5H), 4.81 (m, 0.5H), 5.06 (d, 0.5H), 6.84 (m, 3H), 7-〇 7 (d '2H)' 7.l9 (m '2H)' 7.27 (m '4H). LRMS: m / z (ES +) 422 [MH +] Preparation Example 28 "Hydroxy (1-diphenylmethyl-1H-imidazol-4-yl) methyl 1-4- (4-methylbenzyl ) -3 -morpholinone

The solution of lithium diisopropylamidamine (88.5m in cyclohexane, 1.5M, 133mmol) and tetrahydrofuran (100ml) was cooled to -78 ° C. A tetrahydrofuran (100 ml) solution of the compound of Preparation 11 (26 g, 118 mmol) was added dropwise, and the solution was stirred for 30 minutes. The tetrahydrofuran (350 ml) solution of imidazole (39.9 g, 118 mmol) in Preparation Example 5 was added dropwise over 1 hour, and the solution was completely added, and the reaction was gradually heated to room temperature with stirring for 3 hours. A saturated ammonium chloride solution (200 m 1) and water (100 m 1) were added, each 1 罾 was separated, and the aqueous layer was extracted with ethyl acetate (100 m 1). The organic solution compounded with -101-(97) (97) 200302094 was dried with magnesium sulfate, and evaporated under reduced pressure. The residual orange oil was dissolved in ethyl acetate / methanol, and the solution was subjected to ultrasound. The resulting white precipitate was filtered off, washed with ether, and dried to give the title compound (21 g). The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography on a silica gel with ethyl acetate: methanol (96: 4) to obtain an additional product (28 g). W-NMRiCDCh, 400MHz) (mixture of non-corresponding isomers) 5 · 2.98 (m, 1H), 3.35 (m, 1H), 3.66 (m, 1H), 3.73 (s, 3H), 3.96 (m, 1H), 4.40 (d, 1H), 4.54 (s, 1H), 4.60 (d, 1H), 5.21 (m, 1H), 6.79 (m, 3H), 7.08 (m, 6H), 7.15 (m, 2H ), 7.26 (m, 9H), 7.37 (s, 1H). LRMS: m / z (TSP +) 5 60.2 [MH +] Preparation Example 29 (6R) -2- "Hydroxy (tritrimethyl-1H-imidazole-4-some) methyl1-4- (4- Methoxybenzyl) -6-methyl-3-morpholinone

Following a procedure similar to that described in Preparation 28, the title compound was obtained from the morpholinone of Preparation 12 and the imidazole of Preparation 5 (yield 62%). W-NMRiCDCh, 400 MHz) (mixture of non-corresponding isomers) 5: 1.00, i.〇6 (2xm, 3H), 2.87-3.04 (m, 2H), 3.76 (m, -102- (98) ( 98) 200302094 3H) '3.80-4.74 (m, 4H), 4_98-5.21 (m, 1H), 6.78 (m, 3H)' 7.05-7 · 20 (πί, 8H), 7.23 -7.40 (m , 10H). LRMS: m / z (ES +) 574 [MH +] Preparation of 彳 〇_ "Hydroxy (1-trityl-1H-imidazole-4-some) methyl l 4- (4-methoxy-yttrium,. 棊1 ^ 6-methyl-3-morpholinone

Following a procedure similar to that described in Preparation 28, the title compound was obtained as a yellow bubble (yield 53%) from the morpholinone of Preparation 1 3 and the imidazole of Preparation 5. j-NMI ^ CDCh, 400MHz) (mixture of non-corresponding isomers) 5 ·· 1.00, 1.05 (2xm, 3H), 2.85-3.04 (m, 2H), 3.76 (m, 3H), 3.80-3.96 (m , 1H), 4.39-4.70 (m, 3H) '4.9 8-5.20 (m, 1H), 6.78 (m, 3H), 7.05 -7.20 (m, 8H), 7.25 (m, 9H), 7.39 (m, 1H). LRMS: m / z (ES +) 574 [MH +] Preparation Example 3 1 (5SV2- [hydroxy (1-trityl-1H-imidazol-4-yl) methyl 1-4- (4-methyl Benzyl) -5-methyl-3-morpholinone-103- (99) (99) 200302094

Following a procedure similar to that described in Preparation 28, the title compound was obtained from the morpholinone in Preparation 14 and the imidazole in Preparation 5 (yield 57%). m-NMIUCDCh, 400MHz) (mixture of non-corresponding isomers) 5: 1.03-1.19 (m, 3H), 2.99-4.83 (m, 8H), 5.02-5 · 38 (ιη, 2Η), 6.78 -6.8 8 (m, 3Η), 7.1 (M.21 (m, 8Η), 7.22 · 7 · 42 (ιη, 10H). Preparation Example 32 (510-2- " -111-imidazole-4-some) methyl1-4- (4-methoxybenzyl-methylsome-3-morpholinone

Following a similar procedure to that described in Preparation 28, the title compound was obtained as yellow bubbles (yield 80%) from the morpholinone of Preparation 15 and the imidazole of Preparation 5. 1: H-NMR (CDCl3, 400MHz) (non-corresponding iso-104- (100) (100) 200302094 structure mixture: 1.00-1 · 16 (Π1, 3H), 3.16-4.94 (m, 8H) , 5.00- 5.37 (m, 2H), 6.72-6.83 (m, 3H), 7.04-7.19 (m, 8H), 7.21-7.40 (m, 10H). Preparation Example 3 3 2- "2- (dimethyl Amine) ethoxy i-3_hydroxy-1-propane-m-imidazol-4-yl) tert-butyl propionate

Take 5 minutes to add a solution of lithium diisopropylamidamine (4.3 ml, using heptane / tetrahydrofuran / ethylbenzene as a solvent, 2M, 8.6 mmol) dropwise to the tetrahydrofuran of the amine (1.46 g, 7.2 mmol) of Preparation Example 17 (20 ml) of the solution, stirred at -78 ° C for 20 minutes. The aldehyde (1.18 g, 8.6 mm) of Preparation Example 1 was added, and the mixture was stirred for 3 hours, and then heated to -20 ° C. Add water and pre-adsorb the mixture on silicone. The product was purified by silica gel column chromatography with ethyl acetate: methanol: diethylamine (100: 0: 0: 0 to 96: 2: 2) to obtain the title compound (1.36g). j-NMi ^ CDCh, 400MHz) (mixture of non-corresponding isomers) 5: 0.88 (m, 3H), 1.35 (2xs, 9H), 1.75 (m, 2H), 2.22 (s, 6H), 2.42 (m , 1H), 2.58 (m, 1H), 3 · 5 5 (m, 1 Η), 3 · 8 0 (m, 2 Η), 3 · 9 〇 (m '1 Η)' 4 · 1 7 (m '1 Η)' 4.82, 5.00 (m, 1 Η), 6.90 (2xs, 1 Η), 7.35 (2xs, 1 Η). -105- (101) 200302094 LRMS: m / z (TSP +) 342.2 [MH +] Preparation Example 34 (3S) -3- {l-tert-butoxycarbonyl-2-hydroxy-1-2- (1-propyl -1H-imidazole-4-a certain ethoxy 丨 pyrrolidine-1 -carboxylic acid tert-butyl ester

OH O CH. A solution of the compound of Preparation 18 (5.67 g, 18.8 mmol) in tetrahydrofuran (20 ml) was added dropwise to a solution of lithium diisopropylamidamine (11.3 ml in heptane / tetrahydrofuran) at -78 ° C. / Ethylbenzene as a solvent, 2M, 22.6 mmol), the solution was stirred at -7 8 ° C for 20 minutes. The aldehyde (3.12 g, 22.6 mm) of Preparation Example 1 was added in portions, and the mixture was warmed to room temperature, followed by stirring for 18 hours. Carefully add ammonium chloride solution (50 ml) and extract the mixture with tetrahydrofuran (2 X 200 ml). The combined organic solution was dried over magnesium sulfate and evaporated under reduced pressure. Purify the remaining orange oil body by column chromatography on silica gel with dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) step by step to obtain the title compound (3.7g) . 1H-NMR (CDCl3, 400MHz) (mixture of diastereomers) 5: 0.92 (t, 3H), 1.42 (s, 18H), l-79 (m, 2H), 1.94-2.14 (m, 1H), 2 · 75-3 · 50 (τη, 5H), 3.84 (ιτι, 2H), 4.0 · 3-4 · 35 (ιώ, 2H), 4.81-5 · 08 (ιι, 2H), 6.88 (m, 1H), 7.39 (s, 1H). LRMS: -106- (102) (102) 200 302 094 m / z (ES +) 440 [MH +] Preparation Example 35 (2EZ) di i: (4-methoxymethoxybenzyl) _2-"(l-propyl -1H-imid-4-yl) methylidene 1-3-morpholinone

Diethylamine (9.19 ml, 65.9 ml) was added to a dichloromethane (300 ml) solution of the alcohol (15.8 g, 44.0 mm) in Preparation Example 23. The solution was cooled in ice, methanesulfonyl chloride (5 · 1 m 1,6 5 · 9 m m ο 1) was added, and the solution was stirred at room temperature for 2 hours. Triethylamine (3.06 ml, 22 mm) was added, and the mixture was stirred at 40 ° C for 18 hours, followed by cooling. The mixture was diluted with dichloromethane (1,000 ml) and washed with sodium bicarbonate solution (200 ml). The aqueous washing solution was extracted with dichloromethane (400 ml), and the combined organic solution was dried with magnesium sulfate, and evaporated under reduced pressure. The column layer was stripped on silica gel with ethyl acetate: dichloromethane: methanol: 0.88 ammonia (100: 0: 0: 0 to 0: 95: 5: 0.5 to 0: 90: 10: 1) step by step. The residue was purified by isolation to obtain the title compound (8.3 g). iH-NMIUCDCh, 400MHz) (mixture of geometric isomers) 5: 0.9 (1, 3H), 1.78 (m, 2H), 3.39 (t, 2H), 3.77 (s, 3H), 3.83 (t , 2H), 4.15 (t, 2H), 4.61 (s, 2H), 6.81 (d, 2H), 7.00 (s, 1H), 7.19 (d, 2H), 7.28 (s, 1H), 7.41 (s, 1H). LRMS: m / z (ES +) 342 [MH +] -107- (103) (103) 200302094 Preparation Example 36

Fork 1-3-morpholinone

Following the procedure described in Preparation Example 3 to 5, the title compound was obtained as a yellow bubble from the alcohol in Preparation Example 28 (yield 77%). NMR (CDCh, 400 MHz) (mixture of geometric isomers) 5: 3.34 (t, 2H), 3.78 (s, 3H), 4.00 (t, 2H), 4.59 (s, 2H), 6.80 (d, 2H) , 6.98 (s, 1H), 7.10 (m, 6H), 7.17 (d, 2H), 7.28 (m, 10H), 7.39 (s, 1H). LRMS: m / z (ES +) 542 [MH +] Preparation Example 3 7 · (? Name: 6RM ^ L_4-methoxybenzyl) -6-methyl-2-m-tribenzazole -4 -yl) Carboxyl j _ 3 -morpholinone

By following the procedure described in Preparation Example 3 to 5, prepared from the alcohol of Preparation Example 9 -108- (104) (104) 200302094, the title compound was obtained as a pale yellow bubble (yield 57%). ] Η-NMR (CDCh, 400MΗζ) (mixture of geometric isomers) 6 ·· 1.02 (d '3H), 3.08 (dd, 1H), 3.20 (dd, 1H), 3.77 (s' 3H), 4 · 10 (ιη, 1H), 4.50 (d, 1H), 4.60 (d, 1H), 6.80 (d, 2H), 6.99 (s, 1H), 7.14 (ηι, 8H), 7.28 (ιη, 10H), 7.38 (s, 1H) 0 LRMS: m / z (ES +) 5 5 6 [MH +] Preparation Example 38 (2EZ, 6S) -4- (4-methoxybenzyl) -6-formaldehyde 2-f (l-trityl-1H · imidazol-4-yl) methylidene 1-3-morpholinone

Methanesulfonyl chloride (911 //11.78mmol) was added dropwise to the ice-cooled alcohol (4.5g, 7.85mmol) of Preparation Example 30 in dichloromethane (40ml) and triethylamine (1.64ml, 11.78). mmol) solution, the solution was stirred at room temperature for 1 hour. Triethylamine (546 # 1, 3.93 mmol) was added, and the mixture was stirred at 40 t for 18 hours. The cooled mixture was partitioned between dichloromethane (50 m 1) and water (50 m 1), and the layers were separated. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Residual orange oil was purified on a silica gel using methylene chloride ·· methanol: 0.88 ammonia (99: 1 ·· 0.:! To 98: 2: 0.2) by column-type delamination to obtain The title compound (2.5g) -109- (105) (105) 200302094 as a yellow bubble. j-NMI ^ CDCh, 400MHz) (mixture of geometric isomers) 5: 1.02 (d, 3H), 3.05 (m, 1H), 3.20 (m, 1H), 3.78 (s, 3H), 4.06 (m, 1H), 4.47-4.63 (m, 2H), 6.80 (d, 2H), 6.98 (s, 1H), 7.12 (m, 8H), 7.27 (m, 10H), 7.38 (s, 1H). LRMS: m / z (ES +) 5 5 6 [MH +] Preparation Example 39 (2EZ, 5S) -4- (4-Cyclobenzyl) -5-methyl-trityl-1H-imid

Azole-4 -yl) methylidene 1-3 -imomaline jS

Following a procedure similar to that described in Preparation Example 38, the title compound was prepared from the alcohol of Preparation Example 31 (yield 28%). , 400MΗζ) (mixture of geometric isomers) 5] .22 (d, 3Η), 3.38 (m, 1H), 3.78 (s, 3H), 3.81 (d, 1H), 3.95 (m, 2H), 5.28 (d, 1H), 6.80 (d, 2H), 69 5 (s, 1H), 7.10-7.19 (m, 9H), 7.28 (m, 9H), 7.40 (s, 1H) ° Preparation Example 40 L2EZ '51 ^) -_ ^ bis (1, methoxybenzyl) _5-methyl-2-"(1-tribenzyl-11 imidazole-4 · some) methylidene 3 -morpholine -110- (106 ) (106) 200302094

Following a procedure similar to that described in Preparation 38, the title compound was obtained from the alcohol in Preparation 32 (yield 27%). j-NMI ^ CDCh, 400MHz) (mixture of geometric isomers: 1.25 (d, 3H), 3.41 (m, 1Η), 3.78 (s, 3Η), 3.83 (dd, 1Η), 3.98 (m, 2Η) , 5.30 (d, 1H), 6.82 (d, 2H), 6.98 (s, 1H), 7.18 (m, 9H), 7.32 (m, 9H), 7.41 (s, 1H). Preparation Example 4 1 (2EZ) -2-Kl-butyl-1H-imidazol-4-yl) methylidene 1-4-M-methoxybenzyl) -3-morpholinone

Triethylamine (1.78 ml, 12.8 mmol) was added to a dichloromethane (50 ml) solution of the alcohol (4.34 g, 11.6 mmol) in Preparation Example 25. The solution was cooled in ice, and methanesulfonium chloride (990 " 1, 12.8 mm) was added. The solution was stirred for 30 minutes, triethylamine (1.78 n], 12.8 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and was eluted on a silica gel with dichloromethane ·· ethyl acetate: methanol (100: 0: 0 to 0:90:10) in a stepwise manner -111-(107) 200302094 column The residue was purified by delamination to give the title compound (1.22 g) as a viscous product. j-NMI ^ CDCh, 400MHz) (mixture of geometric isomers) 3. · 0.95 (t, 3H), 1.34 (πί, 2H), 1.78 (m, 2H), 3.42 (t, 2H), 3.80 (s, 3H), 3.94 (t, 2H), 4.19 (t, 2H), 4.63 (s, 2H), 6.84 (d, 2H), 7.02 (s, 1H), 7.22 (d, 2H), 7.32 ( s, 1H), 7.44 (s, 1H). LRMS: m / z (TSP +) 356.2 [MH +] Preparation Example 42 (2 EZ) -2-"(1- (2-cyclohexyl-ethyl) -1Η-imidazol-4-yl) methylidene 1- 4- (4-methylaminobenzyl) -3-morpholinone

Following the procedure described in Preparation Example 41, the title compound was obtained as a viscous product from the alcohol in Preparation Example 26 (yield 57%). lH-NMR (CDCh, ^ (^ is a mixture of eight geometric isomers) 5: 0.94 ^ 1, 21 ^), 1.1% !!, 4H), 1.64 (m, 7H), 3.40 (t'2H) ' 3.78 (s, 3H), 3.90 (t, 2H), 4.17 (t, 2H), 4.61 (s, 2H) '6.81 (d, 2H), 6.99 (s, 1H), 7.20 (d, 2H), 7.25 (s, 1H) '7.40 (s, 1H). LRMS: m / z (TSP +) 410.1 [MH +] Preparation Example 43 (2EZ) -4- (4-methoxybenzylbenzene 1 H bis. -112- (108) (108) 200302094

Triethylamine (0.98 m: 1, 7.03 mmol) was added to a solution of the alcohol (1.41 g, 3.35 mmol) in dichloromethane (15 ml) of Preparation Example 27. The solution was cooled in ice, and sulfanesulfonyl chloride (311 // 1, 4.02 mmol) was added, the mixture was warmed to 40 t, stirred for 18 hours, and then concentrated under reduced pressure. The residue was purified on a silica gel using pentane: ethyl acetate: methanol (75: 25: 0 to 0: 100: 0 to 0: 95: 5) in a stepwise column separation method to obtain an orange oil. The title compound (449 mg). NMR (CDC13, 400 MHz) (mixture of geometric isomers) 5: 3.03 (t, 2H), 3.42 (t, 2H), 3.80 (s, 3H), 4.18 (ιή, 4Η), 4.63 (s , 2Η), 6.85 (d, 2Η), 7.02 (s, 1Η), 7.06 (d, 2H), 7.25 (m, 7H) 0 LRMS: m / z (ES +) 404 [MH +] Preparation Example 44 L2EZ ) -2- "2- (dimethylamine) ethoxy1-3- (1-propyl-1H-imidazine) ^ 2-tert-butyl acrylate

Methanesulfonyl chloride (3 0 0 V 1 ′ 4 · 4 mm ο 1) was added dropwise to the cooled alcohol (1.36 g, 4.0 mmol) and triethylamine (61 6 β 1 J 4 · 4η · 1) in a solution of dichloromethane (20m). The solution was stirred at room temperature for 1 -113- (109) 200302094 hours, triethylamine (6 1 6 // 1, 4 · 4 mm 4) was added, and the solution was stirred at room temperature for 18 hours. Thin layer delamination analysis showed that starting material remained, so the solution was heated to reflux and stirred for 3 hours. The cooled mixture was pre-adsorbed on silica gel, and purified by column chromatography using ethyl acetate: diethylamine: methanol (100: 0: 0 to 96: 2: 2) on silica gel. The mixture gave the title compound (650 mg). W-NMIKCDCh, 400MHz) (mixture of geometric isomers) 5: 0.98 (t, 3H), 1.56 (s, 9H), 1.84 (m, 2H), 2.34 (s, 6H), 2.65 (t, 2H) , 3.94 (t, 2H), 4.04 (t, 2H), 7.08 (s, 1H), 7.44 (s, 1H), 7.98 (s, 1H). LRMS: m / z (TSP +) 324.2 [MH +] Preparation Example 45 (35) -3- 丨 "(£ 2) -1- (tert-butoxycarbonyl) -2- (1-propane-1:» -Imidazol-4-yl) vinyl 1oxy) pyrrolidone-1 -tert-butyl carboxylic acid

〇 ch3. The title compound was obtained as an orange oily body from the alcohol of Preparation 34 by following the procedure described in Preparation 44 (yield 36%). 1 Η-NMR (CD C13, 4 0 0 ¥ 112) (mixture of geometric isomers) 5: 0.93 (1, 3} 1), 1.35 · 1 · 5 6 (m, 1 8 Η), 1 · 8 0 (m, 2 Η), 1 · 9 8 (in, 1 Η), 2 · 1 7 (m, 1 Η), 3.2 6-3 · 6 6 (m, 4 Η), 3. 8 6 (m , 2 Η), 5 · 1 5 (m, 1 Η), 7 · 0 6, (110) (110) 200302094 7.15 (2xs, 1H), 7.35, 7.39 (2xs, 1H), 7.41 (s, 1H) LRMS: m / z (ES +) 422 [MH +] Preparation Example 46 (2EZ) -4 -methyl-2- 2-"(l-propyl-1H-imidazol-4-yl) methylene

Triethylamine (3.32111 to 23.8111111101) was added to a dichloromethane (80 ml) solution of the alcohol (5.472, 21.6 mmol) in Preparation Example 24, and the solution was cooled in ice. Take 5 minutes to add a solution of methanesulfonyl chloride (1.84 ml, 23.8 mmol) in dichloromethane (3 ml), and stir the solution at room temperature for 1 hour. The mixture was evaporated under reduced pressure, the residue was dissolved in N, N-dimethylformamide (15 ml), triethylamine (3.32 ml, 23.8 mmol) was added, and the solution was heated under reflux and stirred for 20 minutes. minute. The cooled solution was concentrated under reduced pressure, and the residue was dissolved in methanol (100 ml). The solution was then adsorbed on silica gel, and ethyl acetate · methanol · · diethylamine (100: 0: 0 to 95: 5: 0.5). Purification was carried out by column-type delamination to obtain the title compound (2.5 g). 1H-NMR (CDCh, 400 MHz) (mixture of geometric isomers) 5: 0.98 (t, 3H), 1.82 (m, 2H), 3.14 (s' 3H), 3.59 (t, 2H), 3.90 ( t, 2H), 4.2 6 (t, 2 H), 7 · 00 (s, 1 H), 7 · 3 5 (s, 1 H), 7 · 45 (s, 1H). LRMS: m / z (TSP +) 23 6.2 [MH +] Preparation Example 47 -115- (111) (111) 200302094 (-W2S) -4- (4-methoxybenzyl) -2-"(l -Propan-1H -imidazole-4-some) methylbu 3-morpholinone

A mixture of the olefin (8.3 g, 24.3 mmol) and 10% palladium / carbon catalyst (Degussa® 1 0 1) (800 mg) in ethanol (240 ml) was hydrogenated at 100 psi (690 kPa) and 50 ° C for 18 hours. , Then cooled and filtered through Arbocel®. The filtrate was evaporated under reduced pressure to give an orange oil. This product was purified on a Chiraicel® 0J column with hexane ·· isopropanol: diethylamine (70: 30: 0.5) and purified by column chromatography to obtain the palmar isomers. 1 (1.65 g), followed by p isomer 2 (title compound, i.54 g). j-NMI ^ CDCh, 400MHz) δ: 〇92 (t, 3H), 178 (m, 2h), 〇7 (m, 2H), 3.38 (m '2H), 3.74 (m, 1H), 3.79 ( m, 5H), 3.98 (ι, 1H), 4.52 (m '3H)' 6.72 (s, ih), 6.82 (d, 2H), 7.18 (d, 2H), 7.38 (s' 1H). [RMS: m / z (ES +) 344 [MH +]. [a] D = -66.10, (c = 0.368 'methanol). Preparation Example 4 8 LIB—yl_1H-imidazol · 4 • yl) methyl μ4 · (4_methyl benzyl) _3_ morpholine

-116- (112) (112) 200302094 The ene (2.5g, 6.96111111〇1) and 10% carbon catalyst (〇6 £ 11532 @ 101) of Preparation Example 41 were prepared at 50 ° C and 60psi (410kPa). A mixture of (2101) ethanol (100ml) was hydrogenated for 18 hours. The cooled mixture was filtered through Arbocel®, and the filtrate was evaporated under reduced pressure to obtain the title compound (2.44 g) as an oily body. W-NMIUCDCh, 400MHz) 6: 0.95 (t, 3H), 1.32 (m, 2H), 1.73 (m, 2H), 3.04 (m, 2H), 3.34-3 · 42 (ιη, 2H), 3.73 (m, 1H), 3.78 (s, 3H), 3.82 (t, 2H), 3.98 (m, 1H), 4.45-4.60 (m, 3H), 6.74 (s, 1H), 6.82 (d, 2H), 7.18 (d, 2H), 7.38 (s, 1H) 〇LRMS: m / z (TSP +) 3 5 8.2 [MH +] mmm. 4 9_s, -5 The compounds of the following general formula are followed and prepared in The procedure described in Example 48 is similar to the procedure described above, and was made from suitable olefins (Preparation Examples 4 2 and 43).

-117 (113) 200302094 Production example number R Yield (%) Data 491 0 ^ 75, viscous j-NMIUCDCh, 400 MHz) 5: 0.96 (m, 2H), 1.20 (m, 4H), 1.68 (m, 7H) ), 3.04 (m, 2H), 3.40 (m, 2H), 3.74 (m, 1H), 3.80 (s, 3H), 3.86 (s, 3H), 3.98 (m, 1H), 4.55 (m, 2H) , 6.74 (s, lH), 6.84 (d, 2H), 7.18 (d, 2H), 7.38 (s, lH) · LRMS: m / z (TSP +) 412.2 [MH +] 50 0 ^ — 91 Orange oil Volume ^ -NMRiCDCh ^ OOMHz) 5: 3.00-3.10 (m, 4H), 3.35 (dd, lH), 3.40 (dd, lH), 3.70 (m, lH), 3.79 (s, 3H), 3.98 (m, lH), 4.08 (t, 2H), 4.45 (m, lH), 4.55 (m, 2H), 6.69 (s, lH), 6.68 (d, 2H), 7.06 (d, 2H) > 7.18 (d, 2H), 7.25 (m, 4H) · LRMS: m / z (ES +) 406 [MH +] 1 on a silica gel with ethyl acetate: methanol (100: 0 to 90:10) stepwise stripping the tube Purification by column delamination -118- (114) (114) 200302094 (2RS) -4-methyl-2-"(1-propyl-1H-imidazol-4-yl) methyl 1-3-morpholine

A mixture of the ene (2.5 g, 1.061111111) and 10% absolute / carbon catalyst (〇621185 & © 101) (25〇1112) in ethanol (50ml) was mixed at 50 ° C and 60psi (410kPa). Hydrogenated for 18 hours. The cooled mixture was filtered through Arbocel® and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate: methanol: diethylamine (100: 0: 0: 0 to 96.5: 1.75: 1.7 5) to obtain the title compound as a colorless oil ( 2.08g). iH-NMR (CDCh, 400MHz) 5: 0.95 (t, 3H), 1.80 (m, 2H), 3.00 (m, 4H), 3.18 (m, 1H), 3.37 (ιη, 1H), 3.57 (m , 1H), 3.82 (m, 3H), 4.03 (m, 1H), 4.46 (dd, 1H), 6_78 (s, 1H), 7.39 (s, 1H). LRMS: m / z (ES +) 23 8 [MH +] Preparation Example 52 (21 ^)-2-"(1:»-imidazol-4-yl) methyl 1-heart (4-methoxybenzyl- ) -3-Morpholinone

The protected microphone mouthpiece of Preparation Example 3 (25 £ '46111111〇1) and ki / carbon 0 € 118 $ & © were prepared at 50 ° C and 60 psi (4 10 kPa). A mixture of acetic acid (500 g 1) with a catalyst (2.5 g) was hydrogenated for 18 hours. Thin layer delamination analysis showed residues of starting materials, so the mixture was filtered through Arbocel® at 50 ° C and 60 -119- (115) (115) 200302094 psi (410kPa) with a new catalyst (2.5g). A mixture of ethanol (500 ml) allowed the filtrate to hydrogenate for 18 hours. The mixture was filtered through Arbocel® and the filtrate was evaporated under reduced pressure. The product was purified on a silica gel using methylene chloride: methanol: 0.88 ammonia (98: 2: 0.2 to 95: 5: 0.5) in a stepwise column separation method to obtain the title compound (9 g ). W-NMIUCDCh, 400MHz) δ: 3.01 (m, 1Η), 3.18 (ιη, 2Η), 3.38 (m, 1Η), 3.70 (dd, 1H), 3.78 (s, 3H), 3.97 (dd, 1H) ), 4.32 (m, 1H), 4.50 (dd, 2H), 6.81 (d, 2H), 6.86 (s, 1H), 7.02 (d, 2H), 7.46 (s, 1H). LRMS: m / z (ES +) 3 02 [MH +] Preparation Example 5 3 (-)-(2S) -2-"(1H-imidazol-4-yl) methyl 1-4- (4-methylargon Certain benzyl) -3-morpholinone and Preparation Example 54 (+)-(2R) -2-KlH-imidazol-4-yl) methyl 1-4- (4-methoxybenzyl V3-morpholine The ketone was purified on a Chiralpak® OD column with hexane: isopropanol (80:20) to purify the racemic compound of Preparation Example 5 2 to obtain the title compound (> 99% ee) of Preparation Example 53. j-NMI ^ CDCh, 400MHz) 5: 3.01 (m, 1H), 3.18 (m, 2H), 3.38 (m, 1H), 3.70 (dd, 1H), 3.78 (s, 3H), 3.97 (dd, 1H) ), 4.32 (m, 1H), 4.50 (dd, 2H), 6.81 (d, 2H), 6.86 (s, 1H), 7.02 (d, 2H), 7.46 (s, 1H). LRMS: rn / z ( ES +) 3 24 [MNa4]. [A] D =-5 29.3 (c = 0.05, methanol). -120- (116) (116) 200302094 Further elution gave the title compound of Preparation 54 (& gt 99% ee :). Ill · NMR (CDC13, 400MHz) 5: 3.01 (m, 1H), 3.18 (m, 2H), 3.38 (m, 1H), 3.66-3 · 79 (ιη, 4H) , 3.97 (dd, 1H), 4.32 (t, 1H0, 4.50 (dd, 2H), 6.81 (d, 2H), 6.86 (s, 1H), 7.02 (d, 2H), 7.46 (s, 1H ). LRMS: m / z (ES +) 324 [MNa +] Preparation Example 5 5 a (2S, 6R) -2-f (lH-imidazole-4-some) methyl-1-4-(4-methylbenzylmethyl) and its 3-morpholinone and Preparation Example 5 5 b (21 ^ 6 &)-2- "(11 ~ 1-imidazole-4-some) a certain 1-4- (4-methanine; some) -6-methyl even-3 -morpholinone ch3 ch3

A mixture of ene (41 g, 132 minol) of Preparation Example 154 and 10% palladium / carbon catalyst (Degussa 101 type) (8 g) in ethanol (500 ml) was hydrogenated at 50 psi (345 kPa) and 60 ° C for 24 hours. The mixture was filtered through Arbocel®, the filtrate was concentrated under reduced pressure, and the residue was azeotroped with dichloromethane. The crude product was purified by column chromatography on silica gel (using a Biotage column) with methylene chloride: methanol · 0.88 ammonia (97 · 5ϋ0.1 to 90: 1 0: 1). On silica gel, dichloromethane: methanol: 0.88 ammonia (95: 5: 0.25) was used to elute the column -121-(117) (117) 200302094. The main product that ran faster was purified again to obtain The title compound of Preparation 55 &1; «屮] \ ^ (€ 0 (: 13,4001 \ 1 to 5) 1.19 (d, 3H), 2.97-3 · 22 (π, 4H), 3.78 (s, 3H), 3.84 (m, 1H), 4.32 (t, 1H), 4.40 (d, 1H), 4.50 (d, 1H), 6.80 (d, 2H), 6.86 (s, 1H), 7.00 (d, 2H), 7.46 (s, 1H ). LRMS: m / z (ES ') 314 [MH] · Ethyl ether: methanol: 0.88 ammonia (90: 10: 1) on silica gel, column column delamination purification, running slower, secondary The product was azeotroped with dichloromethane to give the title compound (220 mg) of Preparation Example 55b as a white bubble. W-NMIUCDCh, 400 MHz) 5: 1.19 (d, 3H), 2.97-3.22 (m, 4H ), 3.78 (s, 3H), 3.84 (ιη, 1H), 4.32 (t, 1H), 4.40 (d, 1H), 4.50 (d, 1H), 6.80 (d, 2H), 6.86 (s, 1H), 7.00 (d, 2H), 7.46 (s, 1H). Preparation Example 56 (2R, 6S) -2-"(lH-imidazol-4-yl) methyl-1-4- (4-methoxy certain benzyl) -6-methyl-3 -morpholinone

Following the procedure described in Preparation 52, the title compound was prepared from the protected olefin of Preparation 38 (yield 20%). i-NMR iCDCh, 400MHz) 5: 1 · 19 (d, 3H), 2.99 (m, 2H), 3.17 (m, 2H), -122- (118) (118) 200302094 3.78 (s, 3H), 3.83 ( m, 1H), 4.30 (m, 1H), 4.44 (dd, 2H), 6.80 (d, 2H), 6.85 (s, 1H), 7.00 (d, 2H), 7.45 (s, 1H). LRMS: m / z (ES +) 316 [MH +] Preparation Example 57 (2S, 5S) -2-"(lH-imidazol-4-yl) methyloxan (4-methylargonyl) -5 -Methyl-3-morpholinone

Following a procedure similar to that described in Preparation 52, the title compound was obtained from the protected olefin of Preparation 39 (yield:%). 1 !!-NMR (CDC13, 400MHz) (about 3: 1 mixture of C-2 stereoisomers described) 5: 1.15 (d, 3H), 3.22 (m, 3H), 3.48, 3.70- 4.00 ( 2xm '6H), 4.38 (m, 1H), 5.18-5.37 (m, 1H), 6.83 (d, 2H), 6.98 (m, 1H), 7.18 (d, 2H), 7.62 (s, 1H). LRMS: m / z (ES ') 314 [MH *] Preparation Example 5 8 (jR, 5R) -2-"(lH-imidazole-4-some 1methyl1-4- (4-methoxysome benzyl) ) -5 -methyl-3 -morpholinone

• 123- (119) (119) 200302094 The title compound was prepared from the protected imidazole of Preparation 40 by following a procedure similar to that described in Preparation 52 (yield 67%). 4-NMR (CDCh, 400 MHz) (about 3: 1 mixture of the described C-2 stereoisomers) 5: 1.16 (d, 3H), 3.22 (m, 3H), 3.46, 3.70-3.98 (2xm, 6H), 4.35, 4.39 (2xm, 1H), 5.20, 5.30 (2xd, 1H), 6.82, 6.94 (2xm, 3H), 7.18 (d, 2H), 7.53 (2xs, 1H). LRMS: m / z (ES.) 314 [MH ·] Preparation Example 59 (2RSMil-f2- (4-bromophenyl) ethyl-1H-imidazol-4-yl] methyl) -4- (4- Methoxybenzyl) -3-morpholinone

Sodium hydride (86 mg, 60% dispersion in mineral oil, 20.9 mm) was added in portions to tetrahydrofuran (100 ml) of imidazole (5 g, 19.9 mol) of Preparation Example 52 which was cooled with ice. ) In the solution, the solution was stirred for 15 minutes. Next, 4-bromophenylethyl methanesulfonate (Bioorg. Med. Chem. 1 996; 4 (5) 3645) (6.1 g, 21.9 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction was deactivated with water (50 ml), and the mixture was extracted with ethyl acetate (2 X 100 ml). The combined organic extract was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified on a silica gel with methylene chloride: methanol: 0.88 ammonia (99: 1: 0.1 to 95: 5: 0.5) by column chromatography to obtain the title compound (4.4 g). j-NMIUCDCh, -124- (120) (120) 200302094 400MHz) 5 2.97 (t, 2H), 3.04 (m, 2H), 3.36 (m, 2H), 3.70 (m, 1H), 3.78 (s , 3H), 3.97 (m, 1H), 4.03 (t, 2H), 4.45 (m, 1H), 4.54 (dd, 2H), 6.62 (s, 1H), 6.82 (d, 2H), 6.90 (d, 2H), 7.18 (d, 2H), 7.20 (s, 1H), 7.39 (d, 2H). Preparation Example 60 cyclohexylethyl) -11 ^ imidazol-4-yl1methyl 丨 -4- (4-methoxy certain; certain) -3-morpholinone

The compound of Preparation 53 (400 mg, 1.32 mmol), carbonate shavings (472 mg, 1.45 mmol), and 2-cyclohexylethyl bromide (227 // 1, 1.45 mmol) of N, N-di The methylformamide (4 ml) mixture was stirred for 18 hours. The cooled mixture was partitioned between ethyl acetate (250 ml) and water (100 ml), and the layers were separated. The organic phase was washed with water (3 x 100 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The column was first eluted with dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) on silica gel, then ethyl acetate: diethylamine (100: 0 to 95: 5). The crude product was purified twice by a delamination method to obtain the title compound (191 mg) as a colorless colloid. j-NMIUCDCh, 400MΗζ) ά: 0.90 (m, 2Η), 1.04-1 · 24 (ιώ, 4Η), 1.60 (m, 7Η), 3.02 (m, 2H), 3.26- 3.40 (m, 2H) , 3.70 (m, 1H), 3.78 (s, 3H), 3.81 (t, 2H), 3.97 (m, 1H), 4.42-4.5 8 (m, 3H), 6.68 (s, 1H), 6.80 (d, 2H), 7.14 (d, 2H), 7.35 (s, 1H). LRMS: -125- (121) (121) 200 302 094 m / z (ES +) 412 [MH +]. [a] D = -50.37, (c = 0_112, using methanol as a solvent) Preparation Example 6 1 (! R, 6S) -2-{"l- (2-Cycloylethyl) -1H-imidazole-4 -A 1 1-1-4- (4-methylblackylfluorenyl) -6-methyl · 3-3MALIN

The compound of Preparation Example 56 (200 mg, 0.635 mmol), carbonate shavings (248 mg, 0.762 mmol) and 2-cyclohexylethyl bromide (109 β 1, 0.70 mmol) of Ν, Ν-dimethylformate at 70 ° C. The methylformamide (8 ml) mixture was stirred for 18 hours. The cooled mixture was partitioned between ethyl acetate (10 ml) and water (10 ml), and the layers were separated. The organic phase was washed with water (2 x 20 ml) and a saline solution (20 ml), then dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified on a silica gel with methylene chloride: methanol: 0.88 ammonia (99: 1: 0.1 to 98: 2: 0.2) by column chromatography to obtain the title compound as a colorless colloid (120 mg ). ] H-NMR (CDCl3, 400MHz) 5: 0.90 (m, 2H), 1.18 (m, 7H), 1.62 (m, 7H), 2.94-3.08 (m, 3H), 3.32 (dd, 1H), 3.78 ( s, 3H), 3.80 (m, 3H), 4.43 (m, 3H), 6.66 (s, 1H), 6.80 (d, 2H), 7.14 (d, 2H), 7.32 (s, 1H) 0 LRMS: m / z (ES +) 426 [MH +] -126 · (122) 200302094 Preparation Example 62 [23,6men-2-{"1- (2-cyclohexylethyl) -1:»-imidazole-4- 11methyl-1_4- (4-methoxybenzyl) -6-methyl-3-morpholinone 9h3

Following the procedure described in Preparation 61, the title compound was obtained as a colorless oily body from the compound of Preparation 5 5 and 2-cyclohexylethyl bromide (yield 38%). W-NMFUCDCh, 400MHz) 5: 0.90 (m, 2H), 1.17 (m, 7H), 1.61 (m, 7H), 2.94-3.08 (m, 3H) '3.32 (dd, 1H), 3.78 (s, 3H), 3.81 (m, 3H), 4.43 (m, 3H), 6.66 (s, 1H), 6.80 (d, 2H), 7.12 (d, 2H), 7.32 (s, 1H). LRMS: m / z (ES +) 448 [MNa +] Preparation Example 63 (2S, 5S) -K Cyclohexylethyl) -iH-imidazol-4-one 1methylboxybenzyl) -6- Methyl-3-morpholinone

〇Following a procedure similar to that described in Preparation 61, the title compound (yield 21%) was prepared from the gel of Preparation 57 except for the following: 'Ethyl acetate · methanol: two Ethylamine (98: 1: 1) was eluted. !! & -127- (123) (123) 200302094 NMR (CDCh, 400MHz) (mixture of C-2 non-corresponding stereoisomers) 5: 0.98 (m, 2H), 1.20 (m, 7H), 1.68 (m , 7H), 3.05-3.98 (m, 11H), 4.50 (ιή, 1H), 5.22-5 · 40 (ιη, 1H), 6.76, 6.84 (s and m, 3H), 7.14, 7. · 20 (2xd, 2H), 7.39 (m, 1 H). LRMS: m / z (ES +) 426 [MH +] Preparation Example 64 (2R, 5 R) -2- 丨 「1- (2-cyclohexylethyloxazol-4-yl-1methyl 丨 -4- (4-methoxycarbyl) -5 -methyl-3 -morphine

Following a procedure similar to that described in Preparation Example 61, the title compound was prepared from the imidazole of Preparation Example 58 (yield 40%). W-NMI ^ CDCh '400MHz) (C-2 diastereoisomeric mixture) 5: 0.90 (m, 2H), 1.18 (m, 7H), 1.63 (m, 7H), 3.01-3.33 (m , 3H), 3.6 " · 90 (πι, 8Η), 4.42 (ιη, 1Η), 5.22 (ιη, 1Η), 6.72 (5, 1H), 6.80 (d, 2H), 7.16 (d , 2H), 7.35 (s, 1H). LRMS: m / z (ES +) 426 [MH +] Preparation Example 65

Llg, 6R) -2- 丨 Cyclohexyl-3-methylbutyl-imidazol-4-yl 1methyl 1.4- (4-methoxycarbamate) -6-methyl-3-morpholine_ -128- (124) 200302094

The bromide (420 mg, 1.8 mmol) of Preparation Example 21, imidazole (470 mg, 1.5 mmol) of Preparation Example 55, and N, N-dimethylformamide (5 86 mg, 1.8 mm) were prepared at 70 ° C. The methylformamide (5 ml) mixture was stirred for 18 hours. The cooled mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml), and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 15 ml), and the combined organic solution was washed with a salt solution (15 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography on a BioUge® silica gel column with toluene: diethylamine (99: 1 to 85:15) to give the title compound (60 mg). iH-NMI ^ CDCh, 400MHz) 5 ·· 0.82 (s, 6H), 0.90-1 · 10 (ιη, 8H), 1.63 (m, 3Η), 1.78 (m, 5Η), 2.94-3.06 (m , 3Η), 3.30 (dd, 1Η), 3.79 (m, 6H), 4.40-4.55 (m, 3H), 6.68 (s, 1H), 6.80 (d, 2H), 7.10 (d, 2H), 7.32 (s, 1H). LRMS: m / z (ES +) 468 [MH +] Preparation Example 66 L2S, 6R) -2-({l "2- (4.4-dimethylcyclohexyl) ethylimidazol-4-yl1 ridyl) 4- (4-Methoxybenzyl) -6-methyl-3-morpholinone

The title compound was prepared from the bromide of Preparation 22 and the imidazole of Preparation 55 by following a procedure similar to that described in Preparation 65. 1H-NMR (CDCh, 400 MHz) 6: 0.84 (2xs, 6H), 1.16 (m, 8H), 1.37 (m, 2H), 1.50 (η, 2H), 1.63 (m, 2H), 2.97 -3 · 10 (η, 3H), 3.35 (dd, 1H), 3.79 (s, 3H), 3.85 (m, 3H), 4.48 (m, 3H), 6.70 (s, 1H), 6.82 (d, 2H ), 7.16 (d, 2H), 7.35 (s'1H). LRMS: m / z (ES +) 454 [MH +] Preparation Example 67 (2 feet 5) -2-((1-"(2 £ 2) -3-bromo-2-propene-1-11-imidazole -4-yl 丨 methyl) -4- (4-methylaminocarbyl) -3 -morphine

Sodium hydride (133 mg, 60% dispersion in mineral oil, 3.32 mmol) was added to a solution of morpholinone (lg, 3.32 mmol) in tetrahydrofuran (10 ml), which was ice-cooled. Over a period of 5 minutes, 1,3-dibromo-1-propene (a mixture of cis and trans) (3 3 2 // 1, 3.32 mmol) was added dropwise, and then the mixture was warmed to room temperature and stirred 2 hours. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml), and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml), and the combined organic solution was dried over magnesium sulfate and evaporated under reduced pressure. The crude product -130- (126) 200302094 was purified by column chromatography on silica gel with dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2) to obtain the title compound as a colorless oil ( l.lg). j-NMIUCDCh, 400MHz) (mixture of geometric isomers) 5: 3.02 (m, 2H), 3.26 · 3.40 (m, 2H), 3 · 6 8 (m, 1 Η), 3 · 7 8 (s, 3Η), 3.96 (m, 1Η), 4.40 (d, 1 (), 4.42-4.55 (m, 3Η), 4.60 (m, 1Η), 6.22 (ιη, 1H), 6.70 (2Xs , 1H), 6-80 (m, 3H), 7.15 (m, 2H), 7.38 (2xs, 1H). LRMS: m / z (ES +) 420, 422 [MH +]

Preparation Example 68 (2RS) -4- (4-methylaminobenzyl) -2-"(buphenyl-1H-imidazole-4-some) methyl1-3-morpholinone

〇 4 human molecular sieves, copper acetate (452mg, 2.49mmol) and phenylboronic acid (405nig, 3.32ιηιηο1) were introduced into imidazole (500mg, 1.66mmol) and pyridine (269 // 1, 3.3 ) In a methylene chloride (20 ml) solution, the solution was stirred at room temperature for 18 hours. The pressurized air was bubbled into the solution for 10 hours. Use "cold fingers" to keep the solvent warm. The solution was then stirred under a nitrogen atmosphere for 18 hours. A saturated sodium bicarbonate (35 ml) solution of ethylenediaminetetraacetic acid (800 mg) was added, and the mixture was stirred for 20 minutes, followed by extraction with dichloromethane (70 ml). The aqueous phase was extracted with dichloromethane (20 ml), and the combined organic solution was washed with water (10 ml), dried over magnesium sulfate, and concentrated under reduced pressure. Residual -131-(127) (127) 200302094 was purified on a silica gel using methylene chloride: methanol: 0.88 ammonia (9 8: 2: 0.2 to 97: 3: 0.3) in a stepwise column column delamination method. Black solid to give the title compound (175 mg) as a pale yellow oil. ] H-NMR (CDCh, 400MHz) 5: 3 · 02 (m, 1 Η), 3 · 1 8 (m, 1 Η), 3.38 (m, 2H), 3.70-3.79 (m, 4H), 3.99 ( m, 1H), 4.42 (d, 1H), 4.50 (m, 1H), 4.60 (d, 1H), 6.77 (m, 2H), 7.10 (ιη, 3H), 7.32 (π, 3H) , 7.41 (m, 2H), 7.78 (bs, 1H). LRM S: m / z (ES +) 400 [MNa +] Preparation Example 69 (2RS) -2- (H- (2-methylbenzene) V1H-imidazol-4-yl 1methyl 4- (4- Methoxybenzyl) -3 -morpholinone

Following the procedure described in Preparation 68, the title compound was obtained from the imidazole and 2-methylphenylboronic acid of Preparation 52 (yield 16%). NMR (CDCh, 400MHz) ά: 2.15 (s, 3H), 3.02 (m, 1H), 3.18 (m, 1H), 3.38 (m, 2H), 3.77 (ιη, 4H) '3.98 (m, 1H ), 4.54 (m, 3H), 6.78 (d, 2H), 6.85 (bs, 1H), 7.15 (m, 3H), 7.21 (s, 1H), 7.25 (m, 2H) '7.45 (bs, 1H) . LRMS: m / z (TSP +) 470.2 [MH +] Preparation Example 7 0 (2RS) -2-{[l “3_phenoxy-Ping VlH-imidose-4_yl 1 methyl) -4 -(4-Methoxybenzyl) V 3 -morpholinone-132- (128) (128) 200302094

4 A molecular sieve (50 mg), copper acetate (174 mg, 0.9 6 mm ο 1) and 3-phenoxyphenylboronic acid (J. Chem. Soc. 1 970; 488) (350 mg, 1.6 mmol) Add the solution of Preparation 2 (2 0 mg, 0.8 mg, 0.8 mm) and chlordine (1 3 0 // 1, 1.6 mmol) in dichloromethane (2 ml). Then, pressurized air was passed into the solution to generate bubbles for 7 hours (incubate at 20-25 ° C with a water bath), and the solvent was insulated with "cold fingers". The solution was stirred under a nitrogen atmosphere for 18 hours. The mixture was partitioned between dichloromethane (80 ml) and a saturated sodium bicarbonate solution (30 ml) of ethylenediaminetetraacetic acid tetrasodium salt (lg), and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using ethyl acetate: diethylamine (100: 0 to 95: 5) on silica gel. The product was then purified on a Biotage® silica gel column with toluene: diethylamine (100: 0 to 88:12) by column chromatography to obtain the title compound (120 mg) as a pale yellow colloid. ). ] H-NMR (CDCh, 400MHz) 5: 3.01 (m, 1H), 3.15 (dd, 1H), 3.38 (m, 2H), 3.72 (m, 4H), 3.97 (m, 1H), 4.45 (d, 1H), 4.50 (m, 1H), 4.58 (d, 1H), 6.77 (d, 2H), 6.90 (m, 1H), 6.97 (ι, 1H), 7.00-7 · 18 (ηι, 7H), 7.37 (m, 3H), 7.75 (s, 1H). LRMS: m / z (TSP +) 470.2 [MH +] Preparation Example urn Compound of the following general formula -133- (129) 200302094

A procedure similar to that described in Preparation Example 70 was followed, and was prepared from morpholine S of Preparation 52 and a suitable boric acid. Preparation, Example R Yield (%) Data 71 ^ — 0 σ 8] H-NMR (CDCh, 400 MHz) 5: 3.00 (m, 2H), 3.26 (m, 2H), 3.62 (m, 1H), 3.75 ( s, 3H), 3.90 (m, 1H), 4.38 (m, 1H), 4.48 (s, 2H), 6.61 (s, 1H), 6.78 (d, 2H), 7.02 (m, 2H), 7.14 ( d, 2H), 7.22 (m, 4H), 7.30 (m, 1H), 7.40 (m, 3H) · LRMS: m / z (ES +) 454 [MH +] Ί1 1-19 Orange oil body 'H- NMRiCDCb ^ 400MHz) 5: 3.06 (m, 1H), 3.22 (m, 1H), 3.41 (m, 2H), 3.62 (s, 3H), 3.79 (m, 1H), 4.01 (m, 1H), 4.46 ( d, lH), 4.59 (m, lH), 4.62 (d, lH), 6.78 (d, 2H), 7.15 (d, 2H), 7.24 (m, lH), 7.50 (m, 3H), 7.79 (s, lH), 7.84 (dd, lH), 7.95 (m, 2H). LRMS: m / z (ES +) 450 [Mna +] -134- (130) 200302094 Production Example R Yield (%) Data 73 20 Colorless oil body 1 Η-NMR (CD C13, 4 0 0 Μ Η ζ) 5: 3.05 (m, 1H), 3.18 (dd, 1H), 3.40 (m, 2H), 3.77 (m, 4H) , 4.00 (m, 1H), 4.48 (d, 1H), 4.55 (m, 1H), 4.62 (d, 1H), 6.80 (d, 2H), 7.14 (d, 2H), 7.21-7.37 (m, 3H ), 7.45 (m, lH), 7.54 (s, lH), 7.78 (s, lH). LRMS: m / z (TSP + 457_7 [MH +] Preparation Examples 74 to 76 Compounds of the following general formula

〇 Followed a procedure similar to that described in Preparation Example 70 and was prepared from morpholinone of Preparation Example 53 and suitable boric acids. -135- (131) 200302094 Preparation Example R Yield (%) Data 74 (X 30 solid ^ -NMRiCDCh ^ 400MHz) 5: 3.02 (m, lH), 3.18 (dd, lH), 3.39 (m, 2H), 3.72 (m, 4H), 3.98 (m, lH), 4.43 (d, lH), 4.52 (m, lH), 4.60 (d, lH), 6.75 (d, 2H), 7.10 (m, 3H), 7.31 (m, 3H), 7.42 (dd, 2H), 7.78 (s, lH) · LRMS: m / z (TSP +) 37 8.1 [MH +]. [a] D = -34.8, (c = 0.10, methanol ) 7 5 Φ h3c ^ ch3 9 oil body j-NMIUCDCh, 400MHz) 5: 1.37 (s, 9H), 3.04 (m, lH), 3.19 (dd, lH), 3.40 (m, 2H), 3.76 (m, 4H), 4.00 (m, 1H), 4.46 (d, 1H), 4.58 (m, 1H), 4.62 (d, 1H), 6.78 (d, 2H), 7.14 (m, 3H), 7.26 (d, 2H) ), 7.44 (d, 2H), 7.77 (s, lH). LRMS: m / z (TSP +) 434.2 [MH +]

-136- (132) 200302094 Preparation Example R Yield (%) Data 76 12 1H-NMR (CDCh ^ 400MHz) 5: XX Colloid 3.10 (m, lH), 3.19 (dd, lH), 3.41 (m, Y CF0 2H), 3.78 (m, 4H), 4.00 (m, 1H), 4.58 (3 m, 3H), 6.80 (d, 2H), 7.17 (d, 2H), 7.20 (s, 1H), 7.80 (s, 2H), 7.83 (d, 2H). LRMS: m / z (TSP +) 514.0 [MH +]. [A] D =-28.96, (c = 0.096, methanol)

Production Examples 77 to 81 Compounds of the general formula CH0

, CH.

Following a procedure similar to that described in Preparation 70, it was prepared from morpholinone of Preparation 5 and appropriate nitric acid. -137- (133) 200302094 Preparation Example R Yield (%) Data 77 Brxy 33 Viscous j-NMIUCDCh, 400MHz) 5: 1.18 (d, 3H), 2.98-3.18 (m, 3H), 3.35, 3.38 (2xd , LH), 3.70 (m, 3H), 3.85 (m, lH), 4.41 (d, lH), 4.52 (m, lH), 4.58 (d, lH), 6.77 (d, 2H), 7.05 (m, 4H), 7.20-7.34 (m, 1H), 7.42 (d, 1H), 7.47 (s, 1H), 7.75 (s, 1H). LRMS: m / z (TSP +) 470.1, 472.0 [MH +] 78 σ '28 ^ -NMRiCDCh ^ 400MHz) 5: 1.19 (d, 3H), 3.00 (dd, 1H), 3.05-3.22 (m, 2H), 3.40 (dd, 1H), 3.75 (s, 3H), 3.92 ( m, lH), 4.42 (d, lH), 4.57 (m, lH), 4.60 (d, lH), 6.78 (d, 2H), 7.10 (m, 3H), 7.34 (m, 3H), 7.43 (m , 2H), 7.78 (s, 1H) · LRMS: m / z (ES +) 392 [MH +] -138- (134) 200302094 Preparation Example R Yield (%) Data 791 9 11 ^ -NMRCCDCb ^ 400MHz) 5: 1.18 (d, 3H), 3.00 (dd, 1H), 3.04-3.19 (m, 2H), 3.38 (dd, 1H), 3.76 (s, 3H), 3.87 (m, 1H), 4.42 (d, 1H), 4.55 (m, 1H), 4.58 (d, 1H), 6.78 (d, 2H), 6.96 (m, 2H), 7.02-7.1 8 (m, 7H), 7.38 (m, 3H), 7.76 ( s, lH) .LRMS: m / z (ES +) 484 [MH +] 80 41 White bubble ^ -NMRCCDCh ^ 400MHz) 5: 1.19 (d, 3H), 3.00 (dd, 1H), 3.07-3.20 (m, 2H), 3.40 (dd, 1H), 3.77 (s, 3H), 3.90 ( m, lH), 4.42 (d, 1H), 4.55 (m, lH), 4.60 (dd, lH), 6.78 (d, 2H), 7.01-7. 18 (m, 8H), 7.26 (d, 2H) , 7.38 (dd, 2H), 7.72 (s, 1H). LRMS: m / z (ES +) 384 [MH +] 1 = 3-phenoxyphenylboronic acid (J. Chem. Soc., 1 970; 48 8) Preparation Example 8 1 (28,610-2-{"1- (4-cyclohexylphenyl) -111-imidazol-4-yl 1methylbu 4- (4-methoxybenzyl) -6 -Methyl-3-morpholinone ch3

Γ ο. CH3 -139- ° (135) 200302094 At room temperature, copper acetate (39 8 mg, 2.2 mmol), 4-cyclohexylphenylboronic acid (980 mg, 4.8 mmol), and imidazole (790 mg, A mixture of 2.4 mmol) and pyridine (390 // 1, 4.8 mmol) in dichloromethane (20 ml) was stirred for 8 hours, during which air was bubbled with pressurized air, and the solvent was kept warm with "cold fingers". The solution was stirred under a nitrogen atmosphere for 18 hours. The mixture was partitioned between dichloromethane (200 ml) and water (200 ml) containing ethylenediamine tetraacetic acid tetrasodium salt (lg) and aqueous sodium bicarbonate solution (35 ml), and the layers were separated. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on a Biotage® silica gel column with toluene: diethylamine (95: 5 to 92: 8) to obtain the title compound (140 mg). W-NMIUCDCh, 400MHz): 1.15-1.47 (m, 9Η), 1.72-l_94 (m, 4Η), 2.55 (m, 1Η), 2.99 (dd, 1H), 3.03_3.20 (m, 2H), 3.39 (dd, 1H), 3.73 (s, 3H), 3.90 (ιη, 1H), 4.42 (d, 1H), 4.56 (ιη, 2H), 6.78 (d, 2H), 7.02-7.19 ( m, 5H), 7.20 (m, 2H), 7.74 (s, 1H). LRMS: m / z (ES4) 474 [MH +] Preparation Example 82 4- (cyclohexyloxy) phenylboronic acid

B (〇H) 2 Degassed a solution of 4- (cyclohexyloxy) phenyl bromide (J. Am. Chem. Soc. 1 97 8; 3 5 5 9) in tetrahydrofuran (40 ml) and then cooled to -78 t. Butyl-140- (136) 200302094 lithium lithium (1 3 · 4 7 m 1, with Kojima as the solvent, 1. 4 5 M, 1 9.5 mm ο 1) was added dropwise, and the mixture was stirred for 30 minutes . Take 10 minutes to add triisopropyl borate (5 · 0 1 m 1, 2 6 · 6 mm ο 1) dropwise, slowly warm the mixture (with stirring) to room temperature, and then pour in the hydroxide Sodium solution (0.25M, 300ml). This mixture was stirred for 15 minutes and then extracted with ether (2 X 150 ml). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid, and extracted with dichloromethane (2 × 150 ml). The combined organic extract was dried over magnesium sulfate and evaporated under reduced pressure to give the title compound (3.1 g) as a white solid. iH-NMR (CDCh, 400 MHz) 5: 0.888-1.62 (m, 7H), 1.80 (m, 2H) '2.00 (m, 2H), 4.39 (m, 1H), 6.98 (d, 2H), 8.17 (d, 2H) Preparation Example 8 3 (^ .§ .. "6 only) -_2bis ({1-" 4-bis (cyclohexyl) phenyl) phenyl: | 1 imidazol-4-yl } 甲某） -4-ί_4 -methoxybenzyl) -6 -methyl certain -3 -morpholinone

〇 Following a procedure similar to that described in Preparation 81, the title compound was obtained from the imidazole of Preparation 55 and the boronic acid of Preparation 82 (yield 41%). H-NfMR (CDCh, 400MΗζ) δ: i.i9 (d, 3Η) '1.38 (m, 3H), 1.57 (m, 3H), 1.80 (m, 2H), 1.99 (ηι, 2H), 2.99 (dd, 1H), 3.04-3.20 (m, 2H), 3.39 (cid, 1H), 3.77 (s, -141-(137) (137) 200302094 3H), 3.88 (m, 1H), 4.22 (m, 1H), 4.42 (d, 1H), 4.56 (m, 1H), 4.60 (d, 1H), 6.79 (d, 2H), 6.96 (d, 2H), 7.02 (s, 1H), 7 〇-7.28 (m, 4H), 7.65 (s, 1H) o LRMS: m / z (ES +) 490 [MH +] Preparation Example 84 (2RS) 2 2 (Π- (4'_ chloro " 1,1'-biphenyl1-3-yl) -1 Η · imidazol-4-yl 1 methyl-1) -4- (4-methoxybenzyl) -3-morpholinone

At 75 ° C, the bromide (200 mg, 0.44 inmol), 4-chlorophenylboronic acid (207 mg, 1.32 mmol), lithium chloride (56 mg, 1.3 mm 2 ο 1), carbonate shaving ( A mixture of 4 3 3 mg, 1.3 mm, 1) and tetrakis (triphenylphosphine) IE (51 mg, 0.044 mmol) in water (2 ml) and tetrahydrofuran (5 ml) was stirred for 18 hours. The cooled mixture was partitioned between dichloromethane and a 2M sodium carbonate solution containing 6% v / v of 0.88 ammonia. The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using silica: toluene: diethylamine (95: 5 to 93 ·· 7) to obtain the title compound (150 mg) as a pale yellow oil. j-NMIUCDCh, 400MHz) 5 · 3.05 (m, 1H), 3.20 (dd, 1H), 3.42 (m, 2H), 3.72 (s, 3H), 3.78 (m, 1H), 4.00 (m, 1H) , 4.48 (d, 1H), 4.58 (dd, -142- (138) 200302094 1H), 4.62 (d, 1H), 6.78 (d, 2H), 7.14 (d, 2H), 7.20 (s, 1H), 7.35-7.59 (m, 8H), 7.82 (s, 1H). Preparation Example 85 L2—S, 6_R) -2-{Π-(3 '-Chloroη, 1, -biphenyl 1-3 -some 1 H -imidazol-4 · yl1 ridyl 丨 -m hanging oxygen Moto-Methyl-3-?

CI

? H3

Following a procedure similar to that described in Preparation Example 84, the title compound was obtained as the white solid from the bromide and 3-chlorophenylboronic acid of Preparation Example 77 (yield 63%). UMRiCDCh, 400MHz) 5: 1.20 (d, 3H), 3.00 (dd, 1H), 3.07-3.21 (m, 2H), 3.41 (dd, 1H), 3.72 (s, 3H), 3.90 (m, 1H), 4.44 (d, 1H), 4.58 (m, 2H), 6.78 (d, 2H), 7.13 (d, 2H), 7.20-7.5 8 (m, 9H), 7.82 (s, 1H). LRMS: m / z (ES +) 502,504 [MH +] Preparation Example 8 6 (21 ^)-2- 丨 "1- (3 ', 4'-dichloro" 1_1'-biphenylphenyl 3 -Yl) -111-imidazol-4-yl 1methyl) -4- (4-methoxybenzyl) -3-morpholinone-143- (139) 200302094

The bromide (200 mg, 0.44 mmol), 3,4-dichloro-phenylboronic acid (102111 £, 0.531] 1111〇1), lithium chloride (56111 氯化, 1.32mmol) were prepared at 75 ° C. A mixture of carbonic acid shavings (433 mg, 1.32 mmol) and tetrakis (triphenylphosphine) IG (26 mg, 0.022 mmol) in water (2 ml) and tetrahydrofuran (5 ml) was stirred for 2.5 hours. Thin-layer delamination (TLC) analysis showed residual starting materials, so 3,4-dichlorophenylboronic acid (204 mg, 1.06 mmol) and tetrakis (triphenylphosphine) palladium (26 mg, 0.022 mmol) were added. The mixture was heated for 18 hours. The cooled mixture was partitioned between dichloromethane and 2M sodium carbonate solution (containing 0.88 ammonia at 6% v / v). The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by stepwise column chromatography on silica gel with toluene: diethylamine (95: 5 to 93: 7) to obtain the title compound (165 mg) as a crystalline solid. W-NMIUCDCh, 400MHz) 5: 3.06 (m, 1H), 3.20 (dd, 1H), 3.41 (m, 2H), 3.75 (m, 4H), 4.00 (m, 1H), 4.48 (d, 1H), 4.58 (m, 1H), 4.62 (d, 1H), 6.58 (2xs, 2H), 7.18 (m, 3H), 7.40 (m, 2H), 7.52 (m, 4H), 7.65 (s, 1H), 7.82 (s, 1H). LRMS: m / z (ES +) 522, 5 24 [MH +] Preparation Example 87 -144- (140) 200302094 (23,6 only) -2- 丨 "1- (3 ', 4'-dichloro "1,1'-biphenyl1-3-yl) -111-imidazol-4-yl 1methyl 丨 -4- (4-methoxybenzyl) -6-methyl-3-morpholinone

The bromide (200 mg, 0.425 mmol), 3,4-dichlorobenzeneboronic acid (243 mg, 1.27 mmol), lithium chloride (54 mg, 1.27 mmol), and carbonic acid planer (416 mg, 1.32 mmol) and a mixture of tetrakis (triphenylphosphine) palladium (23 mg, 0.02 mm) in water (2 ml) and tetrahydrofuran (5 ml) were stirred for 3 hours. The cooled mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure. Purify the residue on a Biotage® silica gel column with pentane: ethyl acetate: methanol (50: 50: 0 to 0: 100: 0 to 0: 95: 5) by stepwise column purification. A white bubble was obtained. The white bubbles were purified by column chromatography on a Biotage® silica gel column with ethyl acetate: methanol (100: 93 to 9: 7) to obtain the title compound as a white bubble ( 140mg). j-NMR (CDCl3, 400MHz) 5: 1 · 20 (d, 3Η), 3 · 00- 3.2 1 (m, 3Η), 3.40 (m, 1H), 3.75 (s, 3H), 3.90 (m, 1H ), 4.42 (m, 1H), 4.59 (m, 2H), 6.78 (d, 2H), 7.13 (d, 2H), 7.19 (s, 1H), 7.38 (m, 1H), 7.40 (m, 1H) , 7.50 (m, 4H), 7.65 (s, 1H), 7.81 (s, 1H). LRMS: m / z (ES +) 5 3 6, 5 3 8 [MH +] -145- (141) 200302094 Preparation Example S 8 (2S) -2- "n-propyl-1H-imidazol-4-yl ) A certain morpholinone

Ammonium osmium nitrate (4.55 g, 8.30 mmol) was added to a solution of the compound (1.43 g, 4.15 mmol) in Preparation Example 47 in acetonitrile (9 ml) and water (9 ml), and the mixture was stirred at room temperature for 18 hours, then at The organic layer was concentrated under reduced pressure, and the residue was dissolved in methanol. The solution was purified on a silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) by column chromatography to obtain an orange oil. The orange oil was purified by column delamination on a Dowex® 50WX8-200 ion exchange resin with water: 0.88 ammonia (100: 0 to 98: 2) to obtain the title compound (522 mg). ] H-NMR (CDCh, 400MHz): 0.88 (t, 3H), 1.75 (m, 2H), 3.00 (dd, 1H), 3.23 (m, 2H), 3.50 (m, 1H), 3.74 ( m, 1H), 3.79 (t, 2H), 4.00 (m, 1H) '4.43 (dd, 1H), 5.94 (bs, 1H), 6.73 (s, 1H), 7.36 (s, 1H). LRMS: m / z (ES +) 224 [MH +] l Preparation Example 89 llRS) -2-"(l-Ding-1H-Mib-4_yl) methyl 1-3-Π Malin _

h3c 〇 Ammonium nitrate (5.7g, 10.4mmol) was added to a solution of the compound -146- (142) (142) 200302094 (1.87g, 5.2mmol) in acetonitrile (50ml) and water (50ml) in Preparation Example 48, in The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue was purified on a DoweX® 50WX8-200 ion exchange resin column with 5% 0.88 ammonia. This product was purified by stepwise purification on silica gel with dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to give the title compound (300 mg). 1H-NMR (CDCl3, 400MHz) 5: 0.96 (t, 3H), 1.34 (m, 2H), 1.75 (m, 2H), 3.02 (dd, 1H), 3.28 (m, 2H), 3.56 (m, 1H ), 3.78 (m, 1H), 3.82 (t, 2H), 4.02 (m, 1H), 4.48 (dd, 1H), 5.98 (bs, 1H), 6.77 (s, 1H), 7.38 (s, 1H) . LRMS: m / z (ES +) 238 [MH +] Preparation Example 90 (2RS) -2-{"1- (2-cyclohexylethyl) -1 H-Misozino-4 -yl 1methyl 丨-3-Morinda

Ammonium ammonium nitrate (1.1 g, 2.0 mmol) was added to a solution of the compound (41 1 mg, 1.0 mm ο 1) in acetonitrile (5 m 1) and water (5 m 1) in Preparation Example 49. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was pre-adsorbed on silica gel, and washed on the silica gel with ethyl acetate: dichloromethane: methanol: 0.88 ammonia (100: 0: 0: 0 to 75: 0: 25: 0 to 0: 90: 10: 1) The residual column was purified by lifting column delamination. The δ-Hai product 'was purified and purified on a reverse-phase polystyrene gel with water: methanol (100: 0 to 0: 100) to obtain the title compound (52 2 m g). j-NMRiCDsOD, 400MΗζ) δ ·· l (m, 2H), 1.24 (m), -147- (143) (143) 200302094 4H), 1.76 (m, 7H), 3.22 (m, 3H ), 3.40 (η, 1H), 3.80 (m, 1H), 4.02 (m, 1H), 4.22 (m, 2H), 4.38 (m, 1H), 7.43 (s, 1H), 8.85 (s, 1H). LRMS: m / z (TSP +) 292.2 [MH +] Preparation Example 9 1 (2R, 6S) -2- (`` l- (2-cyclohexylethyl) -1Η-imidazol-4-yl 1methylbenzene 6-methyl-3 _ morpholinone

Cerium ammonium nitrate (3 87 mg, 0.758 mmol) was added to a solution of the compound (120 mg, 0.28 3 mmol) in Preparation Example 61 in acetonitrile (8 ml) and water (5 ml), and the mixture was stirred at 40 ° C for 18 hours. Concentrated under reduced pressure. The residue was pre-adsorbed on silica gel, and the residue was purified by dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2 to 95: 5: 0.5) on silica gel to obtain the title compound (66 mg) as a colorless oil. . W-NMIUCDCh, 400MHz) 5: 0.92 (m, 2H), 1.18 (m, 7H), 1.62 (m, 7H), 2.98 (dd, 1H), 3.18 (m, 2H), 3.23 (dd, 1H), 3.83 (m, 3H), 4.41 (m, 1H), 6.19 (bs, 1H), 6.70 (s, 1H), 7.30 (s, 1H). LRMS: m / z (ES +) 328 [MNa +] Preparation Example 92 (23,610-2-("1- (2-Cyclohexylethyl) -111-imidazol-4-yl 1-methyl 6-methyl -3 -morpholinone-148- (144) 200302094

CH

Following the procedure described in Preparation 91, the titled compound was obtained as the pale yellow solid from the protected morpholinone of Preparation 62 (yield 63%). ^ -NMRCCDCh ^ 400MHz) 5: 0.92 (m, 2H), 1.18 (m, 7H)

, 1.62 (m, 7H), 2.98 (dd, 1H), 3.19 (m, 2H), 3.23 (dd, 1H), 3.83 (m, 3H), 4.41 (m, 1H), 6.03 (bs, 1H), 6.70 (s, 1H), 7.34 (s, 1H). LRMS: m / z (ES +) 3 28 [MNa +] Preparation Example 93 (23, 610-2-((1- "2- (4.4-dimethylcyclohexyl) ethyl 1-111-imidazole-4 -Yl 1 methyl) -6-methyl-3-morpholinone

Following a procedure similar to that described in Preparation 91, the title compound was obtained from the protected morpholinone of Preparation 66 (53% yield), except for the following: with ethyl acetate: methanol: Diethylamine (99: 0.5: 0.5 to 95: 2.5: 2.5) was eluted. j-NMIUCDCh, 400MHz) 5: 0.82 (2xs, 6H), 1.10 (d, 3H), 1.18-1.38 (m, 8H), 1.48 (m, 1H), 1.63 (η, 2H), 2.98 (m , 1H), 3.19 (m, 2H), 3.23 (dd, 1H) -149- (145) (145) 200302094, 3.84 (m, 3H), 4.41 (m, 1H), 6.97 (bs, 1H), 7.21 (s, 1H), 7.34 (s, 1H). LRMS: m / z (ES +) 334 [MH +] Preparation Example 94 (2S.6R) -2- 丨 Π “3-cyclohexyl-3 · methylbutyl) -1Η-imidazol-4-yl 1 Methyl 1_6-methyl-3-morpholinone

Following a procedure similar to that described in Preparation 91, the title compound was obtained from the protected morpholinone of Preparation 65 (52% yield), except for the following: with dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 93: 7: 0.7) elution. W-NMRiCDsOD, 400MHz) 6 ·· 0.86 (s, 6H), 1.00 (m, 2H), 1.03-1 · 28 (ιή, 7H), 1.70 (m, 7H), 2.90 (m, 1H), 3.03 (m, 1H), 3.18 (m, 2H), 3.82 (m, 1H), 3.95 (m, 2H), 4.36 (m, 1H), 5.42 (s, 1H), 6.86 (s, 1H), 7.50 (s, 1H). LRMS: m / z (ES +) 348 [MH +] Preparation Example 95 (23,58) -2-("1- (2-cyclohexyl) -111-imidazol-4-yl 1methyl 5-methyl-3 -morpholinone

-150-(146) (146) 200302094 The protected morpholinone (170 mg, 0 · 4 mm ο 1) and nitrate nitrate (5 50 mg, 1 · 0 mm) were prepared at 40 ° C at 40 ° C. ο 1) A mixture of water (1 ml 1) and acetonitrile (1 ml) was stirred for 18 hours, and then concentrated under reduced pressure. The residue was purified on a Biotage® silica gel column with ethyl acetate: diethylamine (95: 4 to 80: 2) to obtain the title compound (18 mg). j-NMI ^ CDCh, 400MHz) 5: 0.97 (m, 2H), 1.20 (m, 7H), 1.66 (m, 7H), 3.06 (dd, 1H), 3.25 (dd, 1H), 3.58 (m , 1H), 3.65 (dd, 1H), 3.83 (m, 3H), 4.43 (dd, 1H), 6.15 (bs, 1H), 6.78 (s, 1H), 7.38 (s, 1H). Preparation Example 9 6 (2-foot_510-2- 丨 "1- (9, -Ninhexylethyl) -111-imidazole-4-some 1 methyl certain 5-methyl-3 -morpholinone

Following the procedure described in Preparation 95, the title compound was obtained from the protected morpholinone of Preparation 64 (yield 34%). j-NMIUCDCh, 400 MHz) 5: 0.78-0.9 8 (m, 2H), 1.03-1.22 (ι, 7H), 1.62 (m, 7Η), 3.02 (m, 1Η), 3.18 ( dd, 1Η), 3.55 (m, 1Η), 3.61 (dd, 1H), 3.77 (dd, 1H), 3.82 (t, 2H), 4.38 (m, 1H), 6.24 (bs, 1H), 6.73 (s 1H), 7.37 (s, 1H). m m m 97, -151-(147) (147) 200302094 (2RS) -2-{"l- (2-phenethyl) -1Η · imidazol-4-yl 1methylb-morpholinone

Ammonium nitrate (8 8 3 mg, 1.6 mmol) was added to a solution of the compound (3 26111 £, 0.81111111〇1) in acetonitrile (2.41111) and water (2.41111) in Preparation Example 50, and the mixture was stirred at room temperature for 5 And then concentrated under reduced pressure. The residue was dissolved in methanol, adsorbed on silica gel, and then purified by dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) on silica gel to obtain the title compound as an orange oil. (97mg). W-NMIUCDCh, 400MHz) 5: 3.02 (m, 3H), 3.26 (m, 2H), 3.52 (m, 1H), 3.77 (m, 1H), 4.00 (m, 1H), 4.10 (t, 2H), 4.43 (dd, 1H), 5.99 (bs, 1H), 6.70 (s, 1H), 7.05 (d, 2H), 7.24 (m, 4H). LRMS: m / z (ES +) 286 [MH +] Preparation Example 98 (2RS) -2- (丨 [[2- (4-Bromophenyl) ethene 1-1H-imidazol-4-yl] A ) -3-morpholinone

A solution of ammonium nitrate (1.35 £, 2.4811 〇1) in water (51111) was added to the bromide (600 mg, 1.2 4 mm ο 1) of acetonitrile (100 m 1) 制备 in Preparation Example 5 The mixture was stirred at 40 ° C for 18 hours. Thin layer delamination analysis showed -152- (148) 200302094 starting material residue, so ammonium nitrate (308 mg, 0.56 mmol) was added, and the mixture was stirred at 40 ° C for 2 hours. The cooled mixture was concentrated under reduced pressure, and the residue was purified by purification on silica gel with dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2 to 95: 5: 0.5) to obtain the title compound (250 mg). NMR (CDCh, 400MHz) 5: 2.98 (t, 2H), 3.03 (m, 1 Η), 3.25 (m, 2H), 3.52 (m, 1H), 3.77 (m, 1H), 4.00 (m, 1H), 4.05 (t, 2H), 4.42 (m, 1H), 5.99 (bs, 1H), 6.65 (s, 1H), 6.93 (d, 2H), 7.22 (s, 1H), 7.40 ( d, 2H). Preparation Examples 99 to 1__01 Compounds of the following general formula

The procedures similar to those described in Preparation 98 were made from the corresponding protected ketones. Preparation Example R Yield (%) Data 99 (X 58 iH-NMR (CDCh, 400 MHz) 5: 3.1 (dd, 1H), 3.25 (m, 1H), 3.37 (m, 1H), 3.58 (m, 1H) ), 3.78 (m, lH), 4.02 (m, lH), 4.54 (m, lH), 5.83 (bs, lH), 7.15 (s, lH), 7.33 (m, 3H), 7.42 (m, 2H) , 7.78 (s, lH) · LRMS: m / z (ES +) 280 [MNa +] -153- (149) 200302094 Preparation Example R Yield (%) Data 100 〇; 74 ^ -NMRCCDCh ^ 400MHz) 5: 2.20 (s, 3H), 3.16 (dd, lH), 3.30 (m, lH), 3.38 (dd, lH), 3.58 (m, lH), 3.80 (m, lH), 4.04 (m, lH), 4.56 (dd, lH), 6.18 (bs, lH), 6.90 (s, lH), 7.20-7.35 (m, 4H), 7.50 (s, lH) · HRMS: m / z272.1 394 [MH +] 1011 ^ -NMRiCDsOD ^ 400MHz) 5: 2.92 (dd, lH), 3.05 (m, lH), 3.19 (m, lH), 3.63 (m, lH), 3.86 (m, lH), 4.22 (m, lH), 6.82 (s, lH), 7.10 (m, 2H), 7.30 (m, 3H), 7.40 (m, 1H), 7.50 (m, 4H). LRMS: m / z (ES +) 356 [MNa +] 1 2 Ethyl acetate: methanol: diethylamine (100: 0: 0 to 90: 5: 5)

Preparation Example 102 (2RS) -2- (Π- (3-phenoxyphenyl) -1H-imidazol-4-yl 1methylb-morpholinone

〇 Add a solution of ammonium nitrate (350 mg, 0.63 mm 1) in water (1 m 1) to -154- (150) (150) 200302094 The protected morpholinone (120 mg, 0.256 mmol) The mixture was stirred in an acetonitrile (2 ml) solution at 40 ° C for 18 hours. TLC analysis showed that the starting material remained. Therefore, europium nitrate (500 mg, 0.91 mmol) was added, and the mixture was stirred at 40 ° C for 8 hours. The mixture was evaporated under reduced pressure, and the residue was partitioned between dichloromethane (50 ml) and a saturated sodium bicarbonate solution (50 ml) of ethylenediaminetetraacetic acid (lg). The phases were separated and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified and purified on silica gel with ethyl acetate: methanol: diethylamine (100: 0: 0 to 96 ... 2 ... 2) to obtain the title compound (25 mg). W-NMIUCDCh, 400MHz) 5: 3.05 (dd, 1H), 3.21-3.18 (m, 2H), 3.57 (m, 1H), 3.77 (m, 1H), 4.00 (m, 1H), 4.48 (dd, 1H) ), 6.15 (bs, 1H), 6.90 (d, 1H), 6.98 (s, 1H), 7.02 (m, 3H), 7.14 (m, 2H), 7.37 (m, 3H), 7.74 (s, 1H) . LRMS: m / z (TSP +) 3 50.0 [MH +] Preparation Example 103 (2RS) -2- 丨 Π- (2- 棻 a) -1Η-imidazole · 4-a certain 1-methyl 3-morpholinone

Following a procedure similar to that described in Preparation Example 02, the title compound was obtained as yellow colloid from the protected morpholinone in Preparation Example 72 (yield 56%), except for the following differences: Chloromethane · methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) elution. 'H-NMIUCDCh, 400MHz) 5: 3.15 (dd, 1H), 3.23 (ι, 1H), 3.38 (dd, 1H), 3.58 (ι -155- (151) (151) 200302094, 1H) , 3.78 (m, 1H), 4.02 (m, 1H), 4.53 (dd, 1H), 6.01 (bs, 1H), 7.22 (d, 2H), 7.48 (m, 3H), 7.75 -7.94 (m, 4H ). LRMS: m / z (ES +) 3 0 8 [MH +] Preparation Example 104 Π-phenyl-1H-imidazole-4-some 1methyl certain 3-morphone

Ammonium nitrate (1.43 g, 2.61 mm) was added to a solution of the protected morpholinone (330 mg, 0.87 mmol) in water (2 ml) and acetonitrile (2 ml) in Preparation Example 74, and the mixture was stirred at 40 t. Stir for 4 hours. TLC analysis showed residual starting material, so ammonium nitrate (1.43 g, 2.61 mmol) was added, and the mixture was stirred at 40 ° C for 2 hours. The mixture was partitioned between dichloromethane (200 ml) and a saturated sodium bicarbonate solution (50 ml) of ethylenediaminetetraacetic acid (lg). The layers were separated and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was eluted on silica gel with ethyl acetate: methanol: diethylamine (100: 0: 0: 0 to 96: 2: 2). This product was azeotroped with toluene and dichloromethane to obtain the title compound (173 mg) as an oily substance. ] H-NMR (CDCh, 400 MHz) 5: 3.14 (dd, 1H), 3.28 (m, 1H), 3.38 (dd, 1H), 3.58 (η, 1H), 3.80 (m, 1H), 4.05 ( m, 1H), 4.56 (dd, 1H), 5.98 (bs, 1H), 7.17 (s, 1H), 7.37 (m, 3H), 7.45 (m, 2H), 7.79 (s, 1H). LRMS: m / z (TSP +) 25 8.1 [MH +] [a] 〇 = -70.59, (c = 0.104, methanol). (152) (152) 200302094 Preparation Example 105 (2 S)-2-(Π-(4-tert-butylphenyl) -1 fluorene-imidazole-4 -yl 1-methyl-1,3-morpholinone

Ammonium ammonium nitrate (297 mg, 0.55 mmol) was added to the protected morpholinone (94 mg, 0.2 2 mm ο 1) in water (2 m 1) and acetonitrile (2 m 1) solution of Preparation Example 75, in The mixture was stirred at 40 ° C for 15 hours. A solution of ethylenediaminetetraacetic acid (0.5 g) in a saturated sodium bicarbonate solution (5 ml) was added, and the mixture was extracted with dichloromethane (2 x 50 ml). The combined organic extract was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified and purified on silica gel with ethyl acetate: methanol: diethylamine (98: 1: 1 to 94: 3: 3) to obtain the title compound (22 mg) as an oily body. W-NMI ^ CDCh, 400MHz) 5 ·· 1.37 (s, 9H), 3.12 (dd, 1H), 3.26 (m, 1H), 3.38 (dd, 1H), 3.58 (m, 1H), 3.79 (m, 1H), 4.04 (m, 1H), 4.55 (m, 1H), 6.22 (bs, 1H), 7.10 (s, 1H), 7.25 (d, 2H), 7.42 (d, 2H), 7.77 (s, 1H ). LRMS: m / z (TSP +) 314.1 [MH +] Preparation Example 106 _ (-)-(2S) -2- (i l- "3,5-bis (trifluoromethyl) phenylphenyl 1H-imid Wow-4-a) Jiamou

0 -157- (153) 200302094

Following the procedure described in Preparation Example 105, the title compound was obtained as a solid from the protected morpholinone of Preparation Example 76 (yield 81%). iH-NMR (CDCh, 400 MHz) 5: 3.18 (dd, 1 Η), 3.30 (m, 1 Η), 3.39 (dd, 1H), 3.60 (m, 1H), 3.80 (m, 1H), 4.06 (m, 1H), 4.55 (m, 1H), 5.88 (bs, 1H), 7.20 (s, 1H), 7.81 (s, 2H), 7.84 (s, 1H), 7.87 (s, 1H) . LRMS: m / z (TSP +) 394.0 [MH +]. [a] D = -40.35, (c = 0.116, methanol). Preparation Example 107 (2RS) -2- {Π- (4, chloro Π J′-biphenylbu 3-yl) -1H-imidazol-4-yl 1methyl

Gib 3 · morpholinone I

Following the procedure described in Preparation Example 05, the title compound was obtained as a solid from the protected morpholinone of Preparation Example 84 (yield 91%). 1 H-NMR (CDCh, 400 MHz) 5: 3 · 10 (dd, 1 Η), 3 · 25 (m, 1 Η), 3.38 (dd, 1 Η), 3.57 (m, 1 Η), 3.78 (m, 1Η), 4.02 (m, 1Η), 4.52 (dd, 1H), 5.96 (bs, 1H), 7.17 (s, 1H), 7.37 (m, 3H), 7.42 (m, 1H), 7.50 (ηι , 3H), 7.57 (s, 1H), 7.80 (s, 1H). LRMS: m / z (ES-) 3 66 (MH-) -158- (154) 200302094 Preparation Example 108 ^ 21 ^)-2- 丨 `` 1- (3'.4'-dichloro''1.1'- Biphenyl 1-3-yl) -1: »-imidazol-4-yl 1-methyl 3-methyl tf ketone

Following the procedure described in Preparation Example 105, the title compound was obtained from the protected morpholinone of Preparation Example 86 (yield: 49%). W-NMIUCDCh, 400MHz) 5: 3.10 (dd, 1H), 3.25 (m, 1H), 3.38 (dd, 1H), 3.57 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 4.02 (m, 1H), 4.52 (dd, 1H), 5.86 (bs, 1H), 7.18 (s, 1H), 7.37 (m, 2H), 7.50 (m, 4H), 7.62 (s, 1H), 7.80 (s, 1H). LRMS: m / z (ES +) 402, 402 (MH +) Preparation Examples 109 to 114 Compounds of the following general formula

Following a procedure similar to that described in Preparation 1 05, -159 * (155) 200302094 was prepared from a suitable protected morpholinone. Preparation Example R Yield (%) Data 109 σ 50 j-NMRCCDCh, 400MHz) 5: 1.22 (d, 3H), 3.08 (dd, 1H), 3.22 (m, 2H), 3.38 (dd, 1H), 3.92 ( m, lH), 4.50 (m, lH), 6.62 (bs, lH), 7.16 (s, lH), 7.37 (m, 3H), 7.42 (m, 2H), 7.78 (s, 1H). 110 σ ° 25 j-NMIUCDCh, 400MHz) 5: 1.20 (d, 3H), 3.02 (dd, 1H), 3.20 (m, 2H), 3.34 (dd, 1H), 3.88 (m, lH), 4.44 (m, lH) , 6.05 (bs, lH), 6.90 (d, lH), 6.98 (s, lH), 7.02 (m, 4H), 7.14 (m, lH), 7.36 (m, 3H), 7.70 (s, lH). LRMS: m / z (ES +) 3 64 [MH +] 111 44 W-NMIUCDCh, 400MHz) 5: V 1 viscose 1.24 (d, 3H), 3.09 (dd, lH), 3.22 (m, XX body 2H ), 3.39 (dd, lH), 3.95 (m, lH), 4.50 (m, lH), 5.86 (bs, lH), 7.03 (m, 4H), 7.18 (m, 2H), 7.36 (m, 4H) , 7.70 (s, 1H). LRMS: m / z (ES +) 3 64 [MH +] -160- (156) 200302094 Preparation Example R Yield (%) Data 1 121 α C, X): 44 1H-NMR (CDCh ^ 400MHz) 5: 1.23 (d, 3H), 3.10 (dd, lH), 3.22 (m, 2H), 3.39 (dd, lH), 3.94 (m, lH), 4.55 (m, lH), 5.84 (bs, lH), 7.20 (s, lH), 7.39 (m, 3H), 7.42-7.60 (m, 5H), 7.80 (s, lH) · 1 131? 40 solid ^ -NMRCCDCh »400MHz) 5: 1.22 (m, 5H), 1.40 (m, 4H), 1.70-1.90 (m, 4H), 2.55 (m, lH), 3.09 (dd, lH), 3.21 (m, 2H), 3.38 (dd, lH), 3.92 (m, lH), 4.50 (m, lH), 6.00 (bs, lH), 7.10 (s, lH), 7.27 (m54H), 7.74 (s, lH). LRMS: m / z (ES +) 3 54 [MH +] 1 142 9: 1 34! H> NMR (CDCl3 ^ 400MHz) 5: 0.88-1.15 (m, 2H), 1.22 (d, 3H), 1.38 (m, 3H), 1-5 (m, 1H), 1.80 (m, 2H ), 1.99 (m, 2H), 3.06 (dd, lH), 3.22 (m, 2H), 3.39 (dd, lH), 3.92 (m, lH), 4.22 (m, lH), 4.50 (m, lH) , 5.84 (bs, lH), 6.97 (d, 2H), 7.05 (s, lH), 7.22 (d, 2H), 7.64 (s, lH). -161-(157) (157) 200302094 Acetonitrile: Water ( 3: 1, volume) was used as the reaction solvent. Acetonitrile: water (2: 1, volume) ) Used as a reaction solvent Preparation Example 1 1 5

^ 6 趵-?.] "1- (3'.4'-dichloro" 1,1'-biphenylbu 3-yl) -111-imidazole

Following a procedure similar to that described in Preparation 105, the title compound was obtained as a white foam from the protected morpholinone of Preparation 87 (yield 63%). 'H-NMRiCDCh, 400MHz) 5 ·· 1.24 (d, 3H), 3.14 (dd, 1H), 3.23 (m, 2H), 3.40 (dd, 1H), 3.97 (ιη, 1H), 4.56 (dd '1H), 5.80 (bs, 1H), 7.10 (s, 1H), 7.40 (m, 2H), 7.55 (m, 4H), 7.68 (s, 1H), 7.81 (s, 1H). LRMS: m / z (TSP +) 416.1, 420.1 [MH +] Preparation Example 1 1 6 (2 S)-2-(1 H -imidazol-4-ylmethyl) -3 -morpholine_

-162- (158) (158) 200302094 Prepare the protected morpholinone (500 mg, 1.66 mm) and ammonium nitrate (2.5 g, 4.5 mmol) in water at 40 ° C. (6 ml) and acetonitrile (6 ml) were stirred for 18 hours. Carbonic acid (1.5 S) was added, and the mixture was stirred for 10 minutes, followed by adsorption on silica gel. The product was isolated with ethyl acetate, methanol, and diethylamine (96: 2: 2 to 80:10:10) on silica gel, and further dichloromethane: methanol (90 : 10 to 85:15), and purified to obtain the title compound (240 mg). ^ -NMI ^ CDsOD, 400MHz) 5: 3.02-3.42 (m, 4H), 3.78 (m, 1H), 4.00 (m, 1H), 4.38 (m, 1H), 6.75 (s, 1H), 7.78 (s , 1H). HRMS: m / z (ES +) 1 82.0924 [MH +] Preparation Example 11 7 (-)-(2S, 6R) -2- (lH-imidazol-4-ylmethyl) -6-Tianmou-3- Morpholinone

A mixture of the protected morpholinone (U, 3.2 mmol) and ammonium ammonium nitrate (5.2 g, 9.6 mmol) in water (20 ml) and acetonitrile (30 ml) was stirred at 40 ° C for 18 hours. The solvent was evaporated under reduced pressure. The residue was suspended in a dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 by volume) mixture on a silica gel with dichloromethane: methanol: 0.88 ammonia (9 0: 1 0: 1) Elution and purification twice. The obtained oily body was azeotroped with diethyl ether to give the title compound (3 80 mg) as colorless bubbles. j-NMIUCD ^ OD, 400MHz) 5 -163- (159) 200302094: 1.21 (d, 3H), 3.02 (m, 2H), 3.19 (m, 2H), 3.90 (m, 1H), 4.36 (m, 1H) ), 6.81 (s, 1H), 7.54 (s, 1H). LRMS: m / z (ES +) 196 [MH +]. [a] D =-1 04.56 (c = 0.19, methanol). Preparation Example 1 1 8 LIS) -2-i''l- (tert-Butyl argonylcarbonyl H-midol-4-some 1-methyl 3- 3-chloro chloride. 4-morpholine carboxylic acid tert-butyl ester

〇 Ο CH, stir the solution of morpholinone (70 mg, 0.39 mmol), dimethylamine pyridine (3 mg), and di-tert-butyl dicarbonate (354 mg, 1.62 mmol) in acetonitrile (5 ml) at room temperature. 42 hours. The mixture was concentrated under reduced pressure, and the residue was purified by purification on silica gel with dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 95: 5; 0.5) to obtain the title compound (96 mg). W-NMI ^ CDCh, 400MHz): 1.58 (s, 9Η), 1.61 (s, 9Η), 3.04 (dd, 1Η), 3.35 (dd, 1H), 3.78 (m, 3H), 4.05 (m, 1H ), 4.50 (m, 1H), 7.20 (s, 1H), 8.00 (s, 1H). HRMS: m / z (ES +) 3 82.1 972 [MH +] Preparation Example 11 9 (2S, 6R) -2-({l-F4- (cyclohexyloxy) phenyl 1-1H 4-Methyl 1-methyl) -6-methyl-3-oxomorpholine-4-tert-butyl carboxylate-164- (160) (160) 200302094

Add 4-dimethylaminopyridine (49 mg, 0.4 mm ο 1) and di-tert-butyl dicarbonate (174 mg, 0.8 mm ο 1) to the morpholinone (1 3 in Preparation Example 114) 5 mg '0.37 mmol) of acetonitrile (5 ml)' was stirred at room temperature for 5 hours. TLC analysis showed that there was a residue of the starting material 'so di-tert-butyl dicarbonate (87 mg g' 0 · 4 in m ο 1) 'was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure 'and the residue was purified by washing with silica gel with ethyl acetate to obtain the title compound (95 mg). LRMS ·· mh (ES +) 470 [MH +] Preparation Example 120 (23) -2-(((1old-2-"(tert-butoxycarbonyl)) amine-1-1-methylethyl-1oxy丨 -3- (1- "4-Cyclopyrene-1phenyl" -1H-imidazole-4-some) lithium propionate

A mixture of the protected morpholinone (87 mg, 0.19 mmol) and lithium hydroxide (24 mg, 0.56 mmol) in tetrahydrofuran (0.5 ml) and water (1 ml) was prepared at room temperature for 18 hours at room temperature. . The reaction mixture was evaporated under reduced pressure to obtain the title compound. 1H-NMR (D20, 400MHz) 5: 0.60 (m -165- (161) 200302094, 2H), 1.00-1.3 8 (m, 16H), 1.50 (m, 2H), 1.70 (m, 2H), 2.58 (m, 1H), 2.80 (m, 2H), 2.94 (m, 1H), 3.30 (m, 1H), 3.82 (m, 1H), 4.00 (m, 1H), 6.63 (d, 2H ), 6.82 (s, 1H), 7.00 (d, 2H), 7.56 (s, 1H). LRMS: m / z (ES-) 486 [MH]-Preparation Example 1 2 1 (2RS) -2-((1- "2- (4, ethyl Π, Γ-biphenyl 1.4-yl) Ethyl 1H-imidazol-4-yl 丨 a) -3-morpholinone

0 The bromide (250 mg, 0.69 mmol), 4-ethylphenylboronic acid (154 mg, 1.03 mmol), tetrakis (triphenylphosphine) IG (78 mg, 0.06 8 mmol) and sodium carbonate solution (100 mg) were prepared at 100 ° C. 41 // 1, 2M, 0.823 mmol) in water (1 ml) and dioxane (5 ml) was heated for 3 hours. The cooled reaction mixture was diluted with water (10 ml), and the mixture was extracted with ethyl acetate (3 × 15 ml). The combined organic extract was dried with magnesium sulfate, and evaporated under reduced pressure. The crude product was eluted on silica gel with dichloromethane: methanol: 0.88 ammonia (99: 10: 0.1 to 95: 5: 0.5) to give the title compound (170 mg). 4-NMR (CDCh, 400MHz) 5: 1.22 (t, 3 Η), 2.64 (q, 2Η), 3.02 (m, 3H), 3.22 (m, 2H), 3.44 (ιώ, 1H ), 3.72 (m, 1H), 3.98 (m, 1H), 4.10 (t, 2H), 4.42 (m, 1H), 5.90 (bs, 1H), 6.70 (s, 1H), 7.08 (d, 2H) , 7.22 (m, 3H), 7.44 (m, 4H). -166- (162) (162) 200302094 Preparation Examples 122 to 131

Arylboronic acid (RB (OH) 2) (0.74 mm) was added to the bromide (180 mg, 0.49 mm) of Preparation Example 98, tetrakis (diphenylphosphine) period (56 mg, 0.51ηπηο1) and sodium carbonate. Solution (295 // 1, 2M, 0.593 mmol) in a solution of water (1 ml) and dioxane (5 ml). The reaction mixture was heated to 100 ° C for 4 hours and then cooled. Water (15 ml) was added and the mixture was extracted with ethyl acetate (3 X 15 ml). The combined organic extract was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was eluted on silica gel with dichloromethane: methanol: 0.88 ammonia (97: 3: 0.3 to 9 5: 5: 0 · 5) to obtain the desired product as shown in the table below. Production Example R Yield J%) Data 122 H, C {63 iH-NMR (CDCh, 400 MHz) 5: 1.28 (d, 6H), 2.95 (m, 1H), 3.02 (m, 3H), 3.24 (m, 2H), 3.52 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H), 4.12 (t, 2H), 4,44 (m, 1H), 5.92 (bs, 1H), 6.75 (bs , 1Η), 7.14 (d, 2H), 7.28 (m, 3H), 7.50 (m, 4H). LRMS: m / z (ES +) 404 [MH +] -167- (163) 200302094 Preparation Example R Yield (%) Data 123 cXl. 78 1H-NMR (CDCl3, 400 MHz) 5: 3.04 (m, 3H), 3.26 (m, 2H), 3.54 (m, lH), 3.76 (m, lH), 4.00 (m, lH), 4.15 (t, 2H), 4.44 (m, lH), 6.06 (bs, lH), 6.75 (s, lH), 7.14 (d, 2H), 7.19 (dd, lH), 7.24 ( s, lH), 7.40 (m, 3H), 7.59 (d, lH). 124 FsCxx 61 [H-NMR (CDCl3, 400MHz) 5: 3.06 (m, 3H), 3.25 (m, 2H), 3.54 (m , LH), 3.77 (m, lH), 4.01 (m, lH), 4.15 (t, 2H), 4.44 (m, lH), 5.83 (bs, lH), 6.77 (s, lH), 7.17 (d, 2H), 7.24 (s, 1H), 7.55 (d, 2H), 7.66 (m, 4H). LRMS: m / z (ES +) 45 2 [Mna4]

-168- (164) 200302094 Preparation Example R Yield (%) Data 125 Cc ^ CF3 66 ^ -NMRCCDCh ^ OOMHz) 5: 3.05 (m, 3H), 3.26 (m, 2H), 3.55 (m, 1H), 3.7 (m, lH), 4.00 (m, lH), 4.17 (t, 2H), 4.45 (m, lH), 5.96 (bs, lH), 6.74 (s, lH), 7.09 (d, 2H), 7.20 -7.34 (m, 4H), 7.42 (dd, lH), 7.57 (dd, lH), 7.75 (d, lH). Microanalysis and actual measurement: C, 62.77; H, 5.21; N, 9.46. C23H22N3. 2F3: 0.5H2O theory 値 C, 63 · 01; Η, 5.29; N, 9.58%. 126 Cl 56] H-NMR (CDCl 3, 400 MHz) 5: 3.02 (m, 3H), 3.22 (m, 2H), 3.5 (m, lH), 3.74 (m, lH), 4.00 (m, lH), 4.14 (t, 2H), 4.41 (dd, lH), 5.95 (s, lH), 6.74 (s, lH), 7.08 (d, 2H), 7.19-7.35 (m, 5 H), 7.4 2 (s, 1 H) · LRMS: m / z (ES +) 430,432 [MH4] -169- (165) 200302094 Preparation Example R Yield (%) Data 127 h3c, 0σ h3c ^ ch3 70 1H-NMR (CDCh, 400MHz) 5: 1.25 ((1,6Η), 2.90 (ιη, 1Η), 3.05 (ιη, 3H), 3.22 (m, 2H), 3.44 (m, 1H), 3.75 (m, 4H), 4.00 (m, lH), 4.15 (t, 2H), 4.44 (m, lH), 5.86 (s, lH), 6.78 (s, lH), 6.92 (d, lH), 7.15 (m, 4H), 7.35 ( s, lH), 7.44 (d, 2H) · LRMS: m / z (ES +) 456 [MNa +] 128 ^ -NMRiCDCh ^ OOMHz) 5: 3.02 (m, 3H), 3.22 (m, 2H), 3.47 (m, lH), 3.70 (m, lH), 3.98 (m, lH), 4.09 (t, 2H), 4.42 (dd, lH), 5.82 (s, lH), 6.74 (s, lH), 7.10 ( d, 2H), 7.22 (s, 1H), 7.38 (d, 2H), 7.44 (m, 4H). HRMS: m / z (ES +) 396.147 [MH +]

-170- (166) 200302094 Preparation R Yield Data

(%) 129

130

36 ^ -NMRiCDCh ^ OOMHz) 5: 2.35 (2xs, 6H), 3.06 (m, 3H), 3.30 (m, 2H), 3.55 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H) , 4.17 (t, 2H), 4.46 (dd, 1H), 5.83 (bs, 1H), 6.78 (s, 1H), 7.15 (d, 2H), 7.21 (d, 1H), 7.30 (m, 3H), 7.53 (_d? 2H) .LRMS: m / z (ES4) 3 91 [MH +] 62 ^ -NMRiCDCh ^ OOMHz) 5: 2.20 (s, 3H), 3.02 (m, 3H), 3.22 (m, 2H) , 3.50 (m, lH), 3.75 (m, lH), 4.00 (ni, lH), 4.10 (m, 2H), 4.42 (m, lH), 5.81 (s, lH), 6.72 (m, 2H) , 7.02-7.25 (m, 7H). LRMS: m / z (ES +) 3 9 5 [MH +] (167) 200302094 Preparation Example R Yield (%) Data 131 ^ CH3 σ 52 ^ -NMRCCDCh, 400MHz) ^: 1.04 (t, 3H), 2.55 U, 2H), 3.01 (m, 3H), 3.22 (m, 2H), 3.48 (m, lH), 3.72 (m, lH), 3.98 (m, lH), 4.10 (t, 2H), 4.4 2 (dd, lH), 6.10 (s, lH), 6.74 (s, lH), 7.06 (d, 2H), 7.10 (d, lH), 7.19 (m, 3H), 7.25 (m, 3H). Micro Analyzed and measured 値 C, 70.93; H, 7.15; N, 10.39. C24H27N3O2; H2O theoretical 値 C, 70.74; Η, 7.17; N, 10.31%.

Preparation Example 132

[21 ^)-2- (1-1 .- [(25 2): 11-generation-2-propenylbu 1: ^-imidazol-4-yl 丨 methyl) -3 -morpholinone

Stir ammonium nitrate (2.6 g, 4.75 nimol) and the compound of Preparation 67 (1 g, 2.38 mm ο 1) in acetonitrile (10 m 1) and water (5 m 1) at 40 ° C. 18 hours. TLC analysis showed residual starting material, so ammonium nitrate (650 mg, 1.19 mmol) was added, and the mixture was stirred at 40 ° C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was azeotroped with methanol. The crude -172- (168) (168) 200302094 product was pre-adsorbed on silica gel, and purified on silica gel by dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 95: 5: 0.5) to obtain The title compound (370 mg). ^ -NMRiCDCh 400MHz) (mixture of geometric isomers) 5: 3.00 (ι (, 1Η), 3.23 (πί, 2Η), 3.50 (m, 1Η), 3.74 (η, 1Η), 4.0〇 (m, 1Η), 4.42 (m, 2H), 4.62 (d, 1 H), 5.98 (bs, 1 H), 6.26 (m, 1.5H), 6.42 (d, 0.5H ), 6.75 (2xs, 1H), 7.40 (2xs, 1H). LRMS: m / z (ES +) 300, 302 [MH +] Preparation Example 1 3 3 (-)-(28) -2- 丨 "1- (2-cyclohexyl-ethyl) -111-imidazole-4 -Yl-1methyl} -3-morphone

Ammonium nitrate (482 mg, 0.88 mmol) and water (1 ml) were added to a solution of the compound of Preparation Example 60 (181 mg, 0.44 mmol) in acetonitrile (1 ml), and the mixture was stirred at 40 ° C for 18 hours . TLC analysis showed that the starting material remained, so ammonium nitrate (250 mg, 0.46 mmol) was added, and the mixture was stirred at 40 ° C for 5 hours. The mixture was partitioned between dichloromethane (75 ml) and a solution of ethylenediaminetetraacetic acid (lg) in a sodium bicarbonate aqueous solution (30 ml), and the phases were separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by purification on silica gel with dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 94: 6: 6) to give the title compound (80 mg) as a viscous body. 1H-NMR (CDCh, 400MHz) 5: 0.97 (m, 2H), 1.20 (m, 4H), (169) (169) 200302094 1.63 (m, 7H), 3.02 (dd, 1H), 3.26 (m, 2H), 3.56 (m, 1H), 3.78 (m, 1H), 3.86 (t, 2H), 4.02 (m, 1H), 4.45 (m, 1H), 5.83 (bs, 1H), 6.76 ( s, 1H), 7.38 (s, 1H). LRMS: m / z (TSP +) 292.1 [MH +]. [a] D =-60 · 1 0, (c = 0 · 0 5, methanol). Preparation Example 134 (2RS) -2- (i 1-"(2 £ 2) -3 41,1'-biphenyl1-4-yl-2-propenylbu1:»-imidazol-4-yl 丨Methyl) -3-morpholinone

The bromide (185 mg, 0.62 mmol), 4-biphenylboronic acid (183 mg, 0.925 mmol), tetrakis (triphenylphosphine) palladium (72 mg, 0.06 2 mmol) and sodium carbonate (78 mg, A mixture of 0.74 mmol) of water (3 ml) and dioxane (6 ml) was heated for 3 hours, then cooled, and the mixture was partitioned between water (20 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic extract was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified on silica gel by dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 98: 2: 0.2) to obtain the title compound (100 mg) as a white bubble. l-NMIUCDCh, 400 MHz) (mixture of geometric isomers) δ: 3.00 (m, 1H), 3.22 (m, 2H), 3.54 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H) , 4.44 (m, 1H), 4.62 (m, 1H), 4.78 (m, 1H), 5.80, 6.26 (2xm, 1H), -174- (170) (170) 200302094 5.93 (bs' 1H) '6.54' 6.66-6 · 80 (2 × 2η, 2H), 7.23-7.60 (m, cis). LRMS: m / z (ES +) 374 [MH +] Agricultural production 1 3 5 to 1 3 7 Compounds of the following formula

Following a procedure similar to that described in Preparation Example 1 34, it was prepared from the bromide of Preparation Example 132 and a suitable boric acid. Preparation Example R Yield (%) Data 135 36 W-NMR iCDCh ^ OOMHzH A mixture of geometric hetero white structures) 5: 3.00 (m, 1H),-u; bubble 3.20-3.35 (m, 2H), 3.50 ( m, lH), 3.62 (m, lH), 3.98 (m, lH), 4.42 (m, lH), 4.62 (m, lH), 4.78 (m, lH), 5.75 (bs, 1Η), 5.82 , 6.30 (2 × ιη, 1Η), 6.57, 6.78 (2xm, 2H), 7.18-7.58 (m, 10H). LRMS: m / z (ES +) 374 [MH +] -175- ( 171) (171) 200302094 Preparation Example R Yield (%) Data 1361 〇r? 41 White bubble W-NMIUCDCh / OOMHzK mixture of geometric isomers) 5: 2.98 (dd, 1H), 3.22 (m, 2H) , 3.50 (m, lH), 3.74 (m, 1 Η), 4 · 0 0 (m, 1 Η), 4 · 4 2 (m, 1 Η), 4 · 5 4 (m, 2H)? 5.66, 6.18 (2xm, lH)? 5.82 (bs, lH), 6.50_6.72 (m, 2H), 7.22-7.42 (m, 10H). LRMS: m / z (ES +) 39 6 [MNa +] 137 OOk 51 white bubbles W-NMIUCDChJOOMHzM mixture of geometric isomers) 5: 3.00 (m, lH), 3.20-3.35 (m, 2H), 3.50 (m, lH), 3.75 (m, lH), 4.00 (m, lH), 4.44 (m, lH), 4.64 (m, lH), 4.80 (m, lH), 5.78 (bs, lH), 5.84, 6.38 (2xm, lH), 6.62-6.85 (m, 2 H), 7.30-7.82 (m, 8H). LRMS: m / z (ES +) 34 8 [MH +] 1 = Preparation without column separation method 1 3 8 (2RS) -2- ( (l- (2EZ) -3- (4-bromophenyl) -2-propenyl-1H-imidazol-4-yl) methyl) -3 -morpholinone-176- (172) 200302094

Following the procedure described in Preparation Example 1 34, the title compound was obtained from the compound of Preparation Example 67 and 4-bromophenylboronic acid (yield 42%). !! h_

NMR (CDCh, 400 MHz) (mixture of geometric isomers) 5: 3.00 (m, 1H) '3.25 (m, 2H), 3.54 (m, 1H), 3.76 (m, 1H), 4.00 (ιη, 1H), 4.43 (m, 1H), 4.59-4.79 (m, 2H), 5_80, 6.22 (2xm, 2H), 6.40 5 6.62 (2xm, 1 H), 6.72, 6 · 7 8 (2xs , 1 H), 7.06 (d, 1H), 7.19 (d, 1H), 7.3 8-7.5 8 (m, 3H). LRMS: m / z (TSP +) 376.1, 378.1 [MH +] Preparation Example 139 (2RS) -2- (i lf (2EZ) -3- (4, methyl Π, Γ-biphenylphenyl 4-yl ) -2-propenyl 1 1 -imidazol-4-yl) methyl) -3 -morpholinone_

At 100 ° C, the bromide (1 32 m § 0.3 5 mm ο 1), 4-tolueneboronic acid (72 mg, 0.52 mmol) 'tetrakis (triphenylphosphine) (50 mg) , 0 · 0 4 m ο 1) and sodium carbonate (2 7 0 / z 1 '2 Μ' 0 · 5 3 mm ο 1), and the mixture in the evil house (6ml) was heated for 1.5 hours. The cooled reaction mixture was partitioned between -177- (173) (173) 200302094 water (20 ml) and ethyl acetate (20 ml), and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The remaining yellow oil was purified by purification on silica gel with dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 98: 2: 0.2) to obtain the title compound (77 mg) as a white bubble. W-NMIUCDCh, 400MHz) (mixture of geometric isomers) 5: 2.38 (2xs, 3H), 3.00 (ιη, 1H), 3.25 (m, 2H), 3.54 (m, 1H), 3.75 (m, 1H), 4.00 (ιη, 1H), 4.43 (m, 1H), 4.62 (m, 1H), 4.78 (m, 1H), 5.78, 6.28 (2Xm, 2H), 6.55, 6.68-6.80 (2; cm, 2H), 7.22 (m, 3H), 7.3 8 -7.63 (m, 6H) LRMS: m / z (ES +) 3 8 8 [MH +] Preparation Example 140 (2RS) -2-({l- "(2EZ) -3- (4'-fluorenyl [1,1,1-phenyl of biphenyl) -2-propylbut 1H-imidazol-4-yl 丨 methyl) -3-morpholinone

The bromide (100 mg, 0.27 mmol), cardiochlorophenylboronic acid (63 mg, 0.4 mmol), tetrakis (triphenylphosphine) palladium (31 mg, 0.027 mmol) and sodium carbonate solution ( A 400 // 1,2M, 0.79mmol) mixture of ethanol (1ml) and toluene (4ml) was heated for 3 hours. TLC analysis showed residual starting materials, so dioxane (3 ml), 4-chlorophenylboronic acid (21 mg, 0 · 13 mm ο 1) and tetrakis (diphosphine) absolute (1 5 mg, 0 · 0 1 3 mm ο 1), -178- (174) 200302094 at 100 ° C. The mixture was stirred for 6 hours. The cooled reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml), and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified on silica gel by dichloromethane: methanol: 0.88 ammonia (9 8: 2: 0.2) to give the title compound (60 mg) as a white solid. W-NMR iCDCh, 400 MHz) (mixture of geometric isomers) 5: 3.02 (ιη, 1H), 3.27 (m, 2H), 3.57 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 4.47 (m, 1H), 4.65, 4.79 (2xd, 2H), 5.82, 6.32 (m, 1H), 6.18 (bs, 1H), 6.57, 6.82 (2xm, 2H), 7.30 ( d, 1H), 7.39-7.79 (m, 8H). LRMS: m / z (ES +) 430 [MNa +] Preparation Example 1 4 1 (21 ^)-2- (丨 1- [~ (2 £ 2) -3- (2 ', 5'-difluoro "1,1'-Biphenyl molybdenum 4-Ethenyl-? .- propenyl1-1H-imidyl-4-methyl 丨 methyl) -3-morpholinone

The title compound was prepared from the compound of Preparation Example 138 and 2,5-difluorophenylboronic acid by following the procedure described in Preparation Example 140. 1H-NMR (CDCl3, 4 0 0 Μ Η z) (mixture of geometric isomers) δ: 3 · 0 2 (m, 1 Η), 3.28 (m, 2H), 3.57 (m, 1H), 3.78 (m, 1H), 4.00 (ι, 1H), 4.45 (m, 1H), 4.63 (d, 1H), 4.79 (d, 1H), 5.82, 6.36 (m, 1H), -179 · ( 175) 200302094 6.14 (bs, 1H), 6.58, 6.79 (2xm, 2H), 7.00 (m, 1H), 7.14 (m, 2H), 7.32 (d, 1H), 7.40-7.70 (m, 4H) o LRMS : m / z (ES +) 432 [MNa +] Preparation Example 1 4 2 (2RS) -2- "2- (dimethylamino) ethoxybenzene 3- (1-propyl-1H-imidazole- 4-yl) tert-butyl propionate

ch3

A mixture of the olefin (650 mg, 2.01 mmol) and 10% iG / Carbon Catalyst (Degussa® 101) (60 mg) in ethanol (2 0 m 1) was hydrogenated at 50 t: and 60 psi (410 kPa) for 1 8 hour. The cooled mixture was filtered through ArboCe1®, and the filtrate was evaporated under reduced pressure. The residue was purified on a silica gel with ethyl acetate: diethylamine: methanol (100: 00: 97 to 97: 1.5: 1.5) to obtain the title compound (502 mg). W-NMIUCDCh, 400 MHz) 6: 0.92 (t, 3H), 1.42 (s, 9H), 1.77 (m, 2H), 2.21 (s, 6H), 2.48 (t, 2H), 2.90- 3.03 (m, 2H), 3.42 (m, 1H), 3.70 (m, 1H), 3.80 (t, 2H), 4.08 (m, 1H), 6.79 (s, 1H), 7.37 (s, 1H). LRMS: m / z (TSP +) 3 26.2 [MH +] Preparation Example 1 4 3 (3S) -3-HlRSV2-tert-butoxy-2-hexyloxy-1-Π-propyl-1H-imidazole- 4-_ -180- (176) 200302094 group) 1 group 1 ethoxybupyrrolidine carboxylic acid tert-butyl ester V-0 CH;

O CK \ Ί 一 > h3c A mixture of the ene of Preparation 45 (1.19 g '2.83 mmol) and Degussa® 101 catalyst (120 mg) in ethanol (12 ml) was hydrogenated at 50 ° C and 60 psi (410 kPa). 18 hours. TLC analysis showed residual starting material, so a catalyst (120 mg) was added, and the mixture was hydrogenated at 50 ° C and 60 psi (410 kPa) for 18 hours. The mixture was filtered through Arbocel®, the catalyst was washed with ethanol, and the combined filtrate was evaporated under reduced pressure. The remaining oil was purified by washing with silicone acetate on ethyl acetate to give the title compound (227 mg) as a colorless oil. H-NMR (CDCl3, 400 MHz) 5: 0.92 (t, 3H), 1.42 (m, 18H) '1.79 (ι, 2H), 2.00-2.30 (m, 2H)' 2.80-2.95 (m, 1H ), 3.00-3.48 (ι, 5H), 3.84 (t, 2H), 4.05-4.20 (ι, 2H), 6.75 (m, 1H), 7.50 (m, 1H). LRMS ·· m / z (ES +) 424 [MH +] Preparation Example 144 C2RS) -2-in- (3- "l, l, -fluorenyl-4-ylpropyl) · 1fluorene-imidazole-4 -Some 1

Gib 3 -morpholinone (177) (177) 200302094 At 50 ° C and 60 psi (410 kPa), ene (100 mg, 0.268 mmol) and Degussa® 101 catalyst (15 mg) in ethanol (12 ml) The mixture was hydrogenated for 6 hours. TLC analysis showed residual starting material, so Degussa® 101 catalyst (20 mg) was added and the mixture was hydrogenated for 18 hours. The reaction mixture was filtered through Arbocel®, the catalyst was washed with ethanol, and the combined filtrate was evaporated under reduced pressure. The residue was purified by dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 98: 2: 0.2) on silica gel to obtain the title compound (70 mg) as a colorless oil. j-NMI ^ CDCh, 400MHz) 6 2.10 (m, 2H), 2.61 (t, 2H), 3.02 (dd, 1H), 3.23 (m, 2H), 3.49 (m, 1H), 3.74 (m, 1 H), 3 · 8 6 (t, 2H), 4 · 0 0 (m, 1H), 4.42 (m, 1H), 6 · 2 0 (bs, 1 H), 7 · 20 (d, 2 H ), 7. 2 9 (m, 1 H), 7.39 (m, 4H), 7.50 (d, 2H), 7.54 (d, 2H). LRMS: m / z (ES +) 398 [MNa +]

Production Example 1 4 5 to 〖W compound of the following general formula

The procedures similar to those described in Preparation Example 1 44 were followed, and were prepared from suitable olefins. -182- (178) 200302094 Preparation Example R Yield (%) Data 1451 (T 0 70 1H-NMR (CDCl3, 400MHz) 5: 2.17 (m, 2H), 2.68 (t, 2H), 3.02 (m, lH ), 3.24 (m, 2H), 3.50 (m, lH), 3.74 (m, lH), 3.90 (t, 2H), 4.00 (m, lH), 4.43 (m, lH), 6.50 (bs, lH) , 6.78 (s, 1H), 7.16 (d, 1H), 7.32-7.48 (m, 7H), 7.58 (d, 2H) · LRMS: m / z (ES +) 377 [MH +] 146 71 ^ -NMRiCDCh ^ OOMHz) 5: 1.82 (m, 2H), 2.58 (t, 2H), 2.97 (dd, lH), 3.22 (m, 2H), 3.50 (m, lH), 3.60 -3.77 (m, 3H), 3.99 (m, lH), 4.40 (m, lH), 5.82 (bs, lH), 6.55 (s, lH), 7.20 (m, 7H), 7.38 (m, 3H). LRMS: m / z (ES +) 3 9 8 [MH4] -183- (179) 200302094 Production Example R Yield (%) Data 147 f) h3c 65 ^ -NMRCCDCh ^ OOMHz) 5: 2.10 (m, 2H), 2.38 (s, 3H), 2.61 (t, 2H), 3.02 (dd, 1H), 3.23 (m, 2H), 3.50 (m, 1H), 3.75 (ni, 1H), 3.83 (t, 2H), 4 · 0 0 (m, 1 Η) ), 4.4 2 (m, 1 Η), 5. 8 2 (bs, 1H), 6.77 (s, 1H), 7. 19 (m, 4H), 7.38 (s, 1H), 7.45 (m, 4H) LRMS: m / z (ES +) 412 [MNa +] 148 / Cl 57】 H-NMR (CDCl3,400MHz) 5: 2.10 ( m, 2H), 2.60 (t, 2H), 3.02 (dd, 1H), 3.25 (m, 2H), 3.50 (m, 1H), 3.74 (m, 1H), 3.85 (t, 2H), 4.00 (m , LH), 4.42 (m, lH), 6.05 (bs, lH), 6.77 (s, lH), 7.19 (d, 2H), 7.38 (ni, 3H), 7.45 (m, 4H). LRMS: m / z (ES +) 43 2 [MNa +] -184- (180) (180) 200302094 Preparation Example R Yield (%) Data 149 F \ r F 76 1H-NMR (CDCl3, 400MHz) 5: 2.08 (m, 2H), 2.60 (t, 2H), 3.02 (dd, lH), 3.23 (m, 2H), 3.50 (m, lH), 3.74 (m, lH), 3.85 (t, 2H), 4.00 (m, lH ), 4.42 (m, lH), 6.00 (bs, lH), 6.75 (s, lH), 6.96 (m, lH), 7.05 (m, 2H), 7.20 (d, 2H), 7.38 (s, lH) , 7.42 (d, 2H). LRMS: m / z (ES +) 434 [MNa +] 150 70 1H-NMR (CDCh5400MHz) 5: 2.20 (m, 2H), 2.78 (t, 2H), 3.06 (dd, lH), 3.30 (m, 2H), 3.54 (m, lH), 3.75 (m, lH), 3.90 (t, 2H), 4.03 (m, lH), 4.48 (m, lH), 5.89 (bs, lH) ), 6.78 (s, lH), 7.28 (d, lH), 7.39 (s, lH), 7.45 (m, 2H), 7.59 (s, lH), 7.80 (m, 3H). LRMS: m / z ( ES +) 372 [MNa +] 1 = Preparation example without column separation method 1 5 1 (2S, 6R) -4- (4-methoxybenzyl) -6- Methyl-2-II1- (2-pyridyl) -1H-imidazol-4-yl 1methyl 丨 -3-morpholinone -185- (181) (181) 200302094

A mixture of imidazole (566 mg, 1.8 mmol), cuprous oxide (20 mg, 0.14 mmol) and potassium carbonate (372 mg, 2.7 mmol) in 2-bromopyridine (1 ml) was heated at 100 ° C for 18 hours. . The cooled mixture was purified by purification on a Biotage® silica gel column with toluene: diethylamine (93: 7 to 86:14) to obtain the title compound (482 mg) as a bubble. iH-NMi ^ CDCh, 400MHz) (5: 1 mixture of local isomers) 5: 0.94, 1.20 (2; cd, 3H), 2.83-3.23 (m, 4H), 3.63, 3.78 (2xs, 3H ), 3.97 (m, 1H), 4.16, 4.22 (2xd, 1H), 4.50-4.82 (m, 2H), 6.64, 6.82 (2xd, 2H), 7.00, 7.18 (2xd, 2H), 7.35, 7.44 (2xm, 1H), 7.59 (m, 2H), 7.96 (il, 1H), 8.40-8.57 (m, 2H). HRMS: m / z (ES +) 3 93.1 926 [MH +] Preparation Example 1 5 2 (2S, 6R) -6-methyl-2- 丨 Π- (2-pyridyl) -1Η-imidazole-4- 1methyl} -3-morpholinone

Protected morpholinone (454 mg, 1 · 16 mm ο 1) and europium nitrate (1 · 5 8 5 g, 2 · 9 mm ο 1) in water (8 at 40 ° C) (8 m 1) and acetonitrile-186- (182) (182) 200302094 (16 ml) were heated for 6 hours. The cooled mixture was diluted with methanol (100 ml), and the solution was adsorbed on silica gel. The product was isolated on silica gel with dichloromethane: methanol: 0.88 ammonia (95: 5: 1), and the product was further isolated on a Biotage® silica gel column with toluene: diethylamine (92: 8) followed by dichloro Methane: methanol: 0.88 ammonia (95: 5: 1) was eluted to give the title compound (204 mg). NMR (CD3OD, 400MHz) (7: 1 mixture of local isomers) 5: 1.01, 1.21 (2xd, 3H), 2.92-336 (m, 4H), 3.78, 3.93 (2xm, 1H), 4.27, 4.46 (2xm, 1H), 7.37, 7.45 (2xm, 1H, 7.58-7.70 (m, 2H), 7.96, 8.00 (2xm, 1H), 8.40-8 · 18 (m, 2H). Preparation Example 1 5 3 ( 6R) -2- "Hydroxy (1-propyl-1H-imidazol-4-yl) methyl-1-4- (4-methoxybenzyl) -6-methyl-3-morpholinone

A tetrahydrofuran solution of the compound of Preparation Example 12 (6.81 g, 29.0 mmol) was added dropwise at -78 ° C to a lithium diisopropylamidamine solution (23.2 ml, using cyclohexane as a solvent, 1.5 M, 34.8 mmol), the solution was stirred at -78 ° C for 20 minutes. Next, a solution of the aldehyde (4 g, 29.0 mmOU of tetrahydrofuran (80 m 1)) in Preparation Example 1 was added dropwise, and the mixture was slowly warmed to room temperature. A saturated ammonium chloride aqueous solution (50 ml), water ( 100 ml), and the mixture was extracted with ethyl acetate. The combined organic extract -187- (183) (183) 200302094 was dried with magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was used on a silica gel. : Methanol (98: 2 to 95: 5) was used to elute and purify the orange oil body of the residue to obtain the title compound (5.71 g) as an orange oil body. 5: 0.92 (ιH, 3H), 1.14 (m, 3H), 1.58 (m, 2H), 2.96-3 · 18 (η, 2H), 3.78-4 · 00 (π, 6H), 4.22 -4.76 (m, 3Η), 5.06-5.30 (m, 1Η), 6.81-6.95 (m, 3Η), 7.18 (m, 2H), 7.42 (d, 1H). LRMS: m / z (ES +) 374 [MH +] Preparation Example 154 (2EZ, 6R) -4- (4-methylbenzyl) -6-methyl-2-f (lH-imidazole-4- A) Formamidine 1-3-morpholinone

A mixture of the compound of Preparation Example 37 (91 g, 164 mm 1) and water (90 ml) in glacial acetic acid (900 ml) was heated at 40 ° C for 1 hour. The cooled mixture was concentrated under reduced pressure, diluted with water (400 ml), and the precipitate was filtered off. The filtrate was washed with diethyl ether (2 x 400 ml), then neutralized with sodium bicarbonate, and extracted with ethyl acetate (1000 ml). The orange solution was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to give the title compound (46.4 g) as a colloid. 1H-NMR (CDCh, 400MHz) 5: 1 · 4 1 (d, 3Η), 3.24 (dd, 1Η), 3.38 (dd, 1H), 3.80 (s, 3H), 4.34 (m, 1H), 4.58 (d, 1H), 4.68 (d, 1H), 6.84 (d, 2H), 6.97 (s, 1H), 7.20 (d, 2H), (184) (184) 200302094 7.30 (s, 1H) 1 5 5 (2 £ /, 6-Hex-4- (4-methoxybenzyl) -6-methyl-2-"(bupropyl-111-imidazol-4-yl) methylidene 1-3-morpholine ketone

Triethylamine (3 m2, 21.75 mmol) was added dropwise to a solution of the alcohol (5.41 g, 14.50 mmol) in Preparation Example 153 in dichloromethane (60 ml), and the solution was cooled to zero. Formic acid was added with chlorine (1.68 m 1, 2 1.7 5 m m 1), and the mixture was allowed to warm to room temperature, followed by stirring for 2 hours. Triethylamine (2 ml, 14.50 mm 1) was added and the mixture was warmed to 35 t: and stirred for 18 hours. The solution was washed with water (100 ml), sodium bicarbonate solution (100 ml) and saline solution (50 ml), then dried over magnesium sulfate, and concentrated under reduced pressure. 8 g was purified by purification on silica gel with dichloromethane ·· methanol: 0.88 ammonia (99: 1: 0.1 to 98: 2: 0.2) to obtain an isomer of the title compound (1.8 g ), And the second isomer (260 mg). j-NMI ^ CDCh, 400MHz, major isomer) 5: 0 · 9 6 (t, 3 Η), 1 · 3 8 (d, 3 Η), 1 · 8 0 (m, 2 Η), 3.20 (dd, 1H), 3.32 (dd, 1H), 3.78 (s, 3H), 3.86 (t, 2H), 4.25 (m, • 1H), 4.57 (d, 1H), 4.65 (d, 1H), 6.84 (d, 2H), 7.02 (s, 1H), 7.20 (d, 2H), 7.35 (s, 1H), 7.46 (s, 1H). LRMS: m / z (ES +) 3 5 6 [MH +]. Measured by microanalysis: C, 63.99; Η -189- (185) (185) 200302094, 6.88; N, 1 1.00 C2OH25N303; H2O theoretical 値: C, 64.3 2; Η, 7 · 29; N, 1 1.25% ο Preparation Example 156 (2S, 6R) -4- (4-methylgas benzyl) -6-methyl-2- 2-((l-propyl-1H-imidazole-4-some Methyl 1-3-morpholinone? H3

A mixture of the ene (1.8 g, 5.07 mmol) and 10% palladium / carbon catalyst (Degussa 101) (200 mg) in ethanol (50 ml) was hydrogenated at 50 ° C and 60 psi (410 kPa) for 18 hours. TLC analysis showed residual starting material. The mixture was filtered, and the filtrate was evaporated under reduced pressure, and the residue was dissolved in ethanol (50 ml). A 10% palladium / carbon catalyst (Degussa 1 0 1) (200 mg) was forced in, and the mixture was hydrogenated at 50 ° C & 60 psi (410 kPa) for 18 hours, followed by filtration. The filtrate was evaporated under reduced pressure, and the residue was purified by dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2) on silica gel to obtain the title compound (1.35 g) as a colorless oil. 1H-NMR (CDCh, 400MHz) 5: 0.92 (t, 3H), 1.19 (d, 3H), 1.78 (m, 2H), 2.98-3.16 (m, 3H), 3.58 (dd, 1H), 3.82 (m , 6H), 4.50 (m, 3H), 6.75 (s, 1H), 6.82 (d, 2H), 7.18 (d, 2H), 7.58 (s, 1H). LRMS: m / z (ES +) 3 5 8 [MH +]. Measured by microanalysis: C, 62.12; H, 7.58; N, 10.89 C20H27N3O3; 1.5 H2O Theoretical: C, 62.48; H, 7.86; N, -190- (186) (186) 200302094 10.93 % 〇 Preparation Example 1 5 7 (2S, 6R) -6 -methyl-2-[(1-propyl-1H -weiwa-4-yl) methyl] -3-?

A solution of the compound of Preparation Example 156 (1.2 g, 3.36 mmol) in methanesulfonic acid (5 ml) was stirred at 70 ° C for 2 hours. The cooled mixture was washed with diethyl ether (2 x 20 ml) by decantation. Water (20 ml) was added, and the mixture was basified with 0.88 ammonia, followed by washing with ethyl acetate (20 ml). The aqueous phase was evaporated under reduced pressure, the residue was suspended in acetonitrile, and the mixture was heated to 50 ° C. The acetonitrile solution was separated by decantation and evaporated under reduced pressure to obtain an oily body. This oil was purified by dichloromethane: methanol: 0.88 ammonia (98: 2: 0 · 2 to 96: 4: 0.4) on silica gel to obtain the title compound (5 60 mg) as a colorless oil. j-NMRiCDCh, 400MHz) 5: 0.94 (t, 3H), 1.22 (d, 3H), 1.59 (m, 2H), 3.04 (dd, 1H), 3.18-3.37 (m, 3H), 3 85 (ιή, 3H), 4.42 (m, 1H), 6.50 (s, 1H), 6.79 (s, 1H), 7.68 (s, 1H) o LRMS: m / z (ES +) 23 8 [MH + ] Preparation Example 1 5 8 (2R, 6R) -2-"(lH-imidazol-4-yl) methyl 1-6-methyl-3-morpholine-191 (187) (187) 200302094? Ha

Ammonium ammonium nitrate (1.1 g, 2 mmol) was added to a solution of the protected lactamamine (200 mg, 0.63 mmol) in water (4 ml) and acetonitrile (4 ml) in Preparation Example 55b, and the mixture was stirred at room temperature. Stir for 3 hours. The solution was diluted with acetonitrile (5 ml) and 0.88 ammonia (4 ml), the mixture was filtered through Arbocel®, and washed with acetonitrile: water (50:50, 10 ml). The filtrate was evaporated under reduced pressure, and the aqueous residue was washed with diethyl ether, followed by evaporation under reduced pressure. The crude product was purified on silica gel by dichloromethane: methanol: 0.88 ammonia (95: 5: 0.25 to 92: 8: 0.4) to obtain the title compound (88 mg) as a bubble. j-NMRiDaO, 400MHz) 5: 1.20 (d, 3H), 3.02-3.30 (m, 6H), 4.01 (m, 1H), 4.40 (dd, 1H), 6.86 (s, 1H), 7.58 (s, 1H ). The compounds of the present invention can be tested using the following analysis based on the analysis disclosed in Boffa et al., J. Biol. Chem. 1998, 273, 2127. The compounds of the invention were incubated with activated TAFI and a standard substrate for TAFIa. The substrate's hydrolysis rate was determined and compared to the hydrolysis rate in the absence of the compound. The inhibitory amount is expressed as Ki . TAFIa inhibition analysis i) The activation of human TAFI (recombinant or purified) by AFI is stimulated by -192- (188) (188) 200302094 Live: at 22 ° C with 10 // 1 human coagulation Enzyme (10NIH units / ml), 10 // 1 rabbit thrombomodulin (30 // g / ml), 6 // 1 calcium chloride (50mM), 50 // 1, 20mM HEPES (N- [2-hydroxyl Ethyl] piperazine-N- [2-ethanesulfonic acid]) buffer (containing 150 mM sodium chloride and 0.01% TWEEN 80 (polyoxyethylene-sorbitan monooleate)) at pH 7.6 Incubate 20 // 1 original solution (360 // g / ml) for 20 minutes. At the end of the incubation, 10 // L PPACK (D-Phe-Pro-Arg chloromethanone) (100 nM) was added to neutralize thrombin. The resulting TAFIa solution was stored on ice for 5 minutes and finally diluted with 175 // 1 HEPES buffer. ii) Ki determination (TAFIa) K i calculation Many different dilutions of test compound water were made. Add 1 50 // 1 HEPES buffer and 10 # 1 TAFIa to each 20 // 1 dilution, followed by pre-incubation at 24 ° C for 15 minutes. Then, at the standard concentration, 20 // 1 furylpropenyl-propionamidine-lysine (FAAL) was added to each dilution. The conversion of the substrate was measured by reading the absorbance of the reaction mixture at 330 nm for a total of 30 minutes every 15 seconds. The reaction was performed at 24 ° C, and the samples were mixed for 3 seconds before each absorbance reading. A plot of percent inhibition versus test compound concentration is then drawn out; IC5 can be calculated from this plot. value. The Cheng-Prusoff equation was then used to calculate Ki 値 〇 Two control groups (positive control and negative control) were used to check the accuracy of the results in each case -193- (189) 200302094. For the first control group, the analysis was performed as described above, but using 20 // ml of water without diluting the test compound. This analysis showed minimal inhibition. For the second control group, the analysis was performed as described above, but an effective amount of a non-specific carboxypeptidase inhibitor was used instead of a diluent of the test compound. This analysis shows the greatest inhibitory effect. When the two control groups cannot indicate the minimum and maximum inhibitory effects, respectively, the results are discounted and the test compounds are analyzed again.

Using the analysis described above, the compounds of the examples were found to be potent and selected inhibitors of TAFIa. All compounds tested had Ki 値 less than 20 // Μ. The specific Kis of several compounds are detailed below: Compounds of the Examples: Ki (TAFIa)

4 10 nM 5 10 ηΜ 40 14 nM 49 9 nM 51 26nM

In the case of TAFIa to CPN, the selectivity of the compound of the present invention is determined by calculating the ratio of Ki 値 of the compound of the present invention for CPN to Ki 値 for TAFIa. Ki 値 was calculated using an analysis for the calculation of TAFIa Ki, but replaced 10 // L TAFIa with 10 // 1 person CPN. The compounds of the invention tested exhibited a strong selectivity of TAFIa for CPN greater than 50: 1. The calculated selectivity of specific Ki and several compounds are detailed below: -194-(190) 200302094 Example compounds: Ki (CPN) selectivity 5 > 10 β Μ > 1000 5 1 > 10 // Μ > 380

-195-

Claims (1)

(1) 200302094 Patent application scope 1. A compound such as formula (I) R9 (I) wherein: η is 0, 1, 2 or 3; R 1 is selected from the group consisting of: (a) — Ci.6, optionally substituted linear or branched (b) — optionally substituted Straight or branched C2.6 (c) an optionally substituted straight or branched C2.6 (d) aryl, (e) aromatic heterocyclic ring, (f) heterocyclic ring, (g) Hydrogen; oxo group OR10, OR ", OR10 where any of the above groups (a), (b) and (c) are selected from: C3_7 cycloalkyl, aryl, aromatic hetero Ring, heterocyclic ring, NR ^ R11, S (O) pR] 0, 0C (0) Rn, CO2R10, C〇NR S〇2NR10Rn ^ halogen and NHS〇2R1 (), where p is 0, 1 or 2; R2 , R3, R4, R6, R7 and R9 are each independently selected from hydrogen and -196- (2) (2) 200302094 or halogen optionally substituted straight or branched Cm alkyl groups; R5 and R8 are each independently Is selected from: hydrogen and a linear or branched (Cl_6) group optionally substituted by OR1 () or halogen, or both are C2 · 6 alkylene bonds R1Q and R11 are each independently selected from : Hydrogen and straight or branched C! .6 alkyl; aryl is a 6-14-membered aromatic monocyclic or fused polycyclic carbocyclic group, May be optionally substituted with one or more substituents selected from the group consisting of: R12, halogen, OR13, NR13R ", NR13CO2R12, CO2R13, NR13SO2R12, CN, haloalkyl, 〇 (haloalkyl ), SR13, S (〇) R12, S〇2R12, OC (〇) R13, S〇2NR13R14 'C (〇) NR13R14, C3-7 cycloalkyl, 〇 (C3-7 ring courtyard), R15 Hekou 〇R15, where R12 is a straight or branched Cw alkyl group, R13 and R14 are each independently selected from: hydrogen and straight or branched CV6 alkyl group, and R15 is R12, OR13, halogen or haloalkane The aryl group is an optionally substituted phenyl group; the aromatic heterocyclic ring is a 5- to 7-membered aromatic ring containing 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, and the ring may be selected by more than one member selected from The following groups are arbitrarily substituted: OR13, NR13R14, CO2R13, NR13CO2R12 > R12 > halogen, CN, haloalkyl, o (haloalkyl), SR13, S (〇) R12, S 〇2R12, 〇C (〇) R13, NRi3SChR12, S〇2NR13R14fP C (〇) NR13R14; and the heterocyclic ring is a 3 to 8-membered ring, which contains 1 to 3 heteroatoms independently selected from the following: oxygen Sulfur and nitrogen, the ring is a saturated or partially saturated ring, and the ring may be further optionally substituted with one or more substituents selected from the group consisting of 〇R13, NR13R14, Co2R13, NR13C〇2R14, R12 , Halogen, -197- (3) 200302094 CN, haloalkyl '〇 (haloalkyl), SR13, S (〇) R12, S〇2R12, 〇C (〇) R13, NR13S〇2R12, S〇2NR13R14 Wo C (0) NR13R14, or a tautomer of a compound such as formula (I), or a pharmaceutically acceptable salt of a compound of formula (I) or a tautomer thereof. 2. The compound according to item 1 of the scope of patent application, wherein the substitution type of imi is represented by the following formula dD1) R9 (ID1). 3 · If the compound in the scope of patent application No. 1, its stereochemical form is shown by the following formula (IA) R -198- (4) (4) 200302094 4. If the compound in the scope of patent application No. 2 has a stereochemical form as shown in the following formula (ΙΑ) R9 R7 I 丨 (ΙΑ) 〇 5. The compound according to item 1 of the scope of patent application, wherein η is 〇 or work. 6. If the compound in the scope of patent application No. 4 is applied, among them. 7. The compound as claimed in claim 5 in which n; ^ 〇. 8 · As claimed in the § 靑 patent scope of the first compound, wherein only 1 is a | $ group, Cm alkenyl or a Cl. 6 焼 group which can be optionally substituted by one or more substituents selected from the following C3. 7 cycloalkyl, aryl, aromatic heterocycle, OR1. , CChR10, halogen, and NHS〇2R] °. 9. The compound as claimed in item 6 of the scope of patent application, wherein R1 is hydrogen, aryl, C2 · 6 alkenyl or a Cw alkyl group which may be optionally substituted by more than one of the following substituents: C3.7 cycloalkane Group, aryl group, aromatic heterocyclic ring, OR1. , CChR1. , Halogen, and NHSChR ". 10. The compound according to item 8 of the application, wherein R1 is hydrogen, aryl, or Cu j which can be optionally substituted by a substituent selected from the group consisting of cyclohexyl and aryl. 1 1. The compound according to item 10 of the scope of patent application, wherein R1 is hydrogen or -199- (5) (5) 200302094 C! -3 alkyl. 12. The compound according to item 11 of the application, wherein R1 is hydrogen. 13. The compound as claimed in claim 1 wherein R2 and R3 are each independently hydrogen or C! .6 alkyl. 14. The compound as claimed in claim 9 wherein R2 and R3 are each independently hydrogen or Cl.6 alkyl. 15. For the compound in the thirteenth patent application, wherein R2 and R3 are both hydrogen. 16. The compound according to item 1 of the patent application, wherein R4 is hydrogen or CV6 alkyl. 17. The compound as claimed in claim 14, wherein R4 is hydrogen or Cu alkyl. 18. A compound as claimed in item 16 in which R4 is hydrogen. 19. The compound according to item 1 of the scope of patent application, wherein R6, R7 and R9 are each independently hydrogen or Cu alkyl. 20. The compound as claimed in claim 17 wherein R6, R7 and R9 are each independently hydrogen or Cm alkyl. 21. The compound as claimed in claim 19, wherein R6, R7 and R9 are each independently hydrogen or methyl. 22. For the compound in the scope of application for item 21, wherein R6, R7 and R9 are all hydrogen. 2 3. The compound according to item 1 of the scope of patent application, wherein R5 is hydrogen or Cm alkyl. 2 4. The compound as claimed in claim 20, wherein R5 is hydrogen or -200- (6) (6) 200302094 alkyl. 25. The compound as claimed in item 23, wherein R5 is hydrogen or methyl. 26. For example, the compound in the scope of application for item 25, where R5 is methyl. 27. For example, in the compound, the scope of application for item 23, wherein R8 is hydrogen or methyl. 28. The compound as claimed in item 27, wherein R5 is hydrogen. Zhao 29. The compound according to item 1 of the scope of patent application, which is selected from the following (2S)-(-)-2- (2-aminoethoxy) -3- (1-phenyl-1H-imidazole- 4-yl) propionic acid; (2S) -2-{[((lR) -2-amino-p-methylethyl] oxy} -3- [1- (2-cyclohexylethyl) -1Η-imidazole- 4-yl] -propionic acid; (2S) -2-{[(lR) -2 -amino-1-methylethyl] oxy 丨 -3- (1-phenyl-1 Η -imid-- 4 -yl) propanoic acid; (2S) -2-{[(2S) -2-aminopropyl] oxy} -3- [1- (2-cyclohexylethyl) -1 fluorene-imidazole- 4-yl] propanoic acid; (2S) -2- (2-aminoethoxy) -3- (1fluoren-imidazol-4-yl) propanoic acid; (2S) -2-{[((R))-2 -Amino-1-methylethyl] oxybutyrate 3- (1'-imidazol-4-yl) propanoic acid; and (2S) -2-{[((R))-2-amino-1-methyl Ethyl] oxy} -3- [1- (2-pyridyl) -1Η-imidazol-4-yl] -propionic acid, and pharmaceutically acceptable salts of the above compounds. -201-(7) 200302094 30. If the scope of application for items 1 to 29 is applied, it is used as a medicine. 3 1 · If items 1 to 29 of the scope of patent application are applied, it is used for the treatment of atherosclerosis, adhesions, skin scarring, cancer, and diseases that can benefit from the body selected from the following diseases. Maintenance of bradykinin levels 3 2. A kind of thrombosis, atherosclerosis, adhesions, skin scarring, inflammation, and bradykinin water which can be used in the treatment of a disease selected from the following Disorders, the pharmaceutical composition comprises a compound as in any of the applications | item 29. 3 3. A compound such as the scope of application of the patent claims No. 1 to No. 1 for the manufacture of a medicinal disease, atherosclerosis, adhesion, skin scarring, inflammation, and bradykines that can benefit from the body selected from the following conditions Peptide level disorders. 34. Use according to the scope of application for item 33 for the treatment of thrombosis. 3 5-A method for producing a compound such as formula (I) The compound of any one of R9 The compound of any one of: a thrombosis, an animal fibrosis, an inflammation or an elevated condition. Pharmaceutical composition: maintenance or promotion of blood formation, cancer, and fibrosis. Use of the product in any one of items 1 to 29. Use: maintenance or promotion of thrombus, cancer, and fibrosis. R7 I (8) 200302094 wherein: η is 0, 1, 2 or 3; R1 is selected from the following groups: (a) — an optionally substituted straight or branched Cl_0 alkyl group, (b) — an optionally substituted group Substituted straight or branched C2.6 alkenyl, (c) An optionally substituted straight or branched C2-6 block, fluorenyl, · (e) aromatic heterocyclic ring, (f) heterocyclic ring (G) hydrogen; wherein any of the substituents in the above groups (a), (b) and (c) is selected from the group consisting of: Ch cycloalkyl, aryl, aromatic heterocyclic ring, heterocyclic ring, r10, NR10Rn, S (0) PR10, OC (〇) Rn, Co2R10, CONR ^ Rn, S02NR10Rn > halogen and NHSChR1. , Where p is 0 ,; 1 or 2; R2, R3, R4, R6, R7, and R9 are each independently selected from: hydrogen and a linear or branched C 1 · 6 alkane optionally substituted with qrU · or halogen R5 and R8 are each independently selected from the group consisting of: hydrogen and a linear or branched (Ci_6) alkyl group arbitrarily substituted by OR1 ° or halogen, or both are C2.6 and the radical bonds R1Q and R11 Each is independently selected from the group consisting of hydrogen and straight or branched chain (1 ~ 6, its aryl group is a 6-14 section aromatic monocyclic or fused polycyclic fire blocker, each group can be affected by more than one Arbitrarily selected from the following groups, U-substituted-203- (9) (9) 200302094: R12 'halogen, 〇13, NR13r14 > NR13C〇2R12' CQ2R13, NR " S〇2R12, CN, haloalkyl, 〇 (haloalkyl), SR13, S (〇) R12, S02R12, OC (〇) R13, S02NR13R14, C (〇) NR13R14, C3.7 cycloalkyl, 〇 (C ^ 7 ring i: end group), R15 and OH15, where R12 is a straight or branched Cm alkyl group, and Chi and 13 are each independently selected from: hydrogen and straight or branched Ci. 6 alkyl, and R15 is R12, OR13, halogen or haloalkyl Arbitrarily substituted phenyl; Aromatic heterocycle is an aromatic ring of 5 to 7 sections, which contains 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, and the ring may be selected by more than one The following groups are arbitrarily substituted: 〇r13, nr13r14, 〇2r13, NR13C02R12, R12, halogen 'CN, halogen group, 0 (halogen group), SR ", S (〇) R12, SO2R12 > 〇C (〇) R13, nr13s〇2r12, S〇2NR13R14 and C (〇) NR13R14; and the heterocyclic ring is a 3 to 8-membered ring, which contains i to 3 heteroatoms independently selected from the following: oxygen, Sulfur and nitrogen, the ring is a saturated or partially saturated ring, and the ring may be further optionally substituted with one or more substituents selected from the group consisting of 〇R13, NR13R14, Co2R13, NR13C〇2R14, R12 , Halogen, CN, halofluorenyl, 〇 (halogeno), SR ", S (〇) R12, SChR12, 〇C (〇) Ri3, NR13S〇2R12, S〇2NR13R14 and c (〇) nr] 3r14, Or a tautomer of a compound of formula (I), the method comprises the steps of: (i) preparing a compound of formula (II) -204- (10) 200302094 R8 where: P1 is an optionally substituted C 1.6 alkyl group, C4-7 cycloalkyl group, an optionally substituted benzyl sylalkyl group; as defined by Ri, R2, R, R4, R5, R6, R7, And any optionally substituted or tris (Ci_6 alkyl) methyl R8, P9 R and η are treated as in the formula (I) (i.e., a reagent suitable for removing the ρ1 group or a general formula (II) Compound 3 6 ·-A method for producing a compound such as formula (I) wherein ο is Π or 2 8 R \ 1 / / | \ R 1 is selected from the following groups: -205- (11) (11) 200302094 (a) —an optionally substituted straight or branched C〃6 alkyl group, (b ) — An optionally substituted straight or branched (2 · 6 alkenyl, (c) an optionally substituted straight or branched C2.6 alkynyl, (d) aryl, (e) Aromatic heterocyclic ring, (f) heterocyclic ring, (g) hydrogen; wherein any substitution in the above groups (a), (b) and (c) is _ < is selected from: C3-7 cycloalkane Group, aryl group, aromatic heterocyclic ring, heterocyclic ring, 〇 〖〇, NR10R1], S (O) pR] 0, 〇C (〇) Rn, CO2R10, CONR10R ^, SO2NR10R ", halogen and NHS〇2R10, wherein p is 0, 1 or 2; R2, R3, R4, R6, and R7 are each independently selected from: hydrogen and a linear or branched Cw alkyl group optionally substituted by 〇Ri. Or halogen; R5 and R8 are each independently selected from the group consisting of: hydrogen and a linear or branched (Cl · -6) alkyl group optionally substituted by OR1 ^ or halogen, or both are a C2 · 6 alkylene chain; R9 Is hydrogen; R1Q and R11 are each independently selected from: hydrogen and linear or branched Ci alkyl; aryl is a 6-14 section aromatic mono Or a fused polycyclic carbocyclic group, which may be optionally substituted with one or more substituents selected from the group: R12, halogen, OR13, NR] 3R14, NR13C02R12, CChRu, NR13S02R12, CN , Haloalkyl, 〇 (haloalkyl), SR ", S (〇) R ", S〇2R] 2, 0C (〇) R13, S〇2NR13R14, C (〇) NR13R14, C3-7 , 〇 (C3-7 ring base), R15 and 〇R15, where R12 is a straight or branched Cw alkyl group, R13 and R14 are independently selected -206- (12) 200302094 From: hydrogen and straight or branched C! .6 alkyl of the chain, and R15 is phenyl optionally substituted by R12, OR13, halogen or haloalkyl; aromatic heterocyclic ring is a 5- to 7-membered aromatic ring, which contains 1 to 3 Heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, the ring may be arbitrarily substituted with more than one group selected from: OR13, NR13R14, Co2R13, NR13CChR12, R12, halogen, CN, haloyl , 〇 (halogenated radical), SR13, S (〇) R12, S〇2R12, 〇 (〇) R13, NR13S〇2R12, S〇2NR13R14, and C (〇) NR13R14; and the heterocyclic ring is a kind of 3 to 8 Nodal ring He contains 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. The ring is a saturated or partially saturated ring. The ring may be further arbitrarily selected by one or more substituents selected from the following groups. Substitution: 〇R13, NR13R14, Co2R13, NR13C02R14, R12, halogen, CN, haloalkyl, 〇 (haloalkyl), SR13, S (〇) R12, SChR12, 〇C (〇) R13, NR13S 〇2R12, S〇2NR13R14 and C (〇) NR13R14, or a tautomer of a compound of formula (I), the method comprises the following steps: (i) preparing a compound of formula (XIV) wherein : R1 , R3, R4, R5, R6, R7 ^ and n have the same meanings as defined in formula (I) -207 · (13) 200302094; (ii) a reagent or a combination of reagents suitable for hydrolyzing the amidine bond of the lactam ring Physical treatment of a compound of formula (II). -208- 200302094 Figure Lu, (a), the designated representative of this case is: (b), a brief description of the element representative symbols of this representative map 柒, the chemical formula that can best show the characteristics of the invention in this case: -4-