JP2011505341A - Biaryl PDE4 inhibitors to treat inflammatory, cardiovascular and CNS disorders - Google Patents

Abstract

  The present invention relates to a genus of biaryl compounds containing at least one further ring. The compound is a PDE4 inhibitor useful for the treatment and prevention of stroke, myocardial infarction and cardiovascular inflammatory diseases and disorders. The compound has the general formula I: Specific embodiments are as follows.

Description

Detailed Description of the Invention

<< Field of Invention >>
The present invention relates to a chemical genus of phosphodiesterase 4 (PDE4) biaryl inhibitors useful for the treatment and prevention of stroke, myocardial infarction, cardiovascular inflammatory disease and central nervous system disease.

《Background Technology》
PDE4 is an enzyme that metabolizes the major cAMP found in inflammatory and immune cells. PDE4 inhibitors may have been proven as anti-inflammatory agents COPD and rhinitis, especially in inflammatory lung diseases such as asthma. They inhibit the release of cytokines and other inflammatory signals and prohibit the production of reactive oxygen species. Numerous PDE4 inhibitors are available in various clinical indications (Torphy and Page. 2000. TIPS 21, 157-159; Burneuf and Pruniaux. 2002. Curr. Pharmaceutical Design 8, 1255-1296; Lipworth. 2005. Lancet 365 ( 167-175)). To quote from a recent article in the Pharmacology Journal in the UK, “PDE4 inhibitors have been developed as a new anti-inflammatory treatment from the 1980s with asthma and the main indication is chronic obstructive pulmonary disease (COPD) Despite the initial optimism, none of them has yet reached the market: most cases (including various structural classes of PDE4 inhibitors, including silomilast, filaminast, irimimilast, picramilast, tofimilast .. Is suspended due to lack of efficacy, a major challenge is the low therapeutic ratio of these compounds, which strictly limits the doses that can be done. Because of the large number of these compounds, the maximum tolerated dose is sub-therapeutic or effective dose response curves Sashiku to the underlying top is situated is likely. Thus, the challenge is to overcome this limitation. ", [Giembycz, Brit. J. et al. Pharmacol. 155, 288-290 (2008)]. Many of the prior art PDE4 inhibitors did not reach the market due to the adverse side effects of vomiting (Giembycz 2005. Curr. Opin. Pharmaceutical 5 (238-244)). Analysis of all known PDE4 inhibitors suggests that they compete with cAMP and bind within the active site (Housley et al. 2005. DDT 10 (1503-1519)); The therapeutic ratio can be explained. Based on the gene-specific inhibitor (PDE4D) and target justification and in vitro efficacy, it is known to be a person of skill in the prior art that the compound is inflammatory disease and is arising from Alzheimer's disease ( Effective as an anti-inflammatory agent for the treatment, improvement or prevention of complications effective as a CNS drug for the treatment of Parkinson's disease, schizophrenia and depression and the neuroprotective of Huntington's chorea) And the compounds of the present invention are non-competitive inhibitors of cAMP.

ＰＤＥ４酵素阻害を呈している化合物に関する。 << Summary of Invention >>
The present invention then has the general formula I:

It relates to compounds exhibiting PDE4 enzyme inhibition.

ここで、

五つまたは６会員を有する環は、メチルによって任意に置換される；
ｎは、ゼロ（１または２）である；
そして、Ｒ２０、Ｒ２１およびＲ２２は、各発生においてＨおよび（Ｃ１―Ｃ４）アルキルと独立して選択される。 In these compounds,
R1 is an optionally substituted carbon cycle or optionally substituted with 3 or fewer ring heterocycles;
R2 is an optionally substituted carbon cycle or optionally substituted with 2 or fewer ring heterocycles;
R3 is -C (= O) NH2- (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkyl-R30, (C2-C6) alkyl-R31 and methyl selected from H A saturated 4- or 5-membered heterocycle optionally substituted by
R30 is selected —C (═O) NH 2 and a 4- or 5-membered heterocycle optionally substituted by methyl;
R31 is selected from an alkoxyl group (C1-C4), amino, hydroxy, (C1-C6) alkylamino, di (C1-C6) alkylamino;
R4 is selected from H and F;
R6 is selected from H, (C1-C6) alkyl and halogen;
X is N, N → O or C—R5;
R5 is selected from H (halogen) to OH ((C1-C6) alkyl (alkoxy (C1-C6)) CF3, CN, NH2, CH2OH, CH2NH2 and C≡CH);
M is selected from a direct bond and -C (R20) (R21)-O-NR22-S (O) n-C (= O) -C (R20) (R21) C (R20) (R21 ) -C (R20) = C (R21) -C (R20) (R21) -OC (R20) (R21) -NR22-C (R20) (R21) -S (O) n-C (R20) ) (R21) -C (= O) -OC (R20) (R21) -NR22-C (R20) (R21) -S (O) nC (R20) (R21)-C (= O)- C (R20) (R21)-and;

here,

Rings with 5 or 6 members are optionally substituted by methyl;
n is zero (1 or 2);
R20, R21 and R22 are then independently selected for H and (C1-C4) alkyl at each occurrence.

The present invention also relates to the first formula (where X is N or N → O). Represented by the formulas associated with the two subgenus of

The second, X is CR5 is represented by the formula:

  The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the general formula I above. If the synthetic is or appears as a salt, the salt must be a pharmaceutically acceptable salt.

  In a third aspect, the present invention relates to a method for the treatment or prevention of disease or a condition transmitted by phosphodiesterase 4. The method is the formula I. Or the condition may be allergic, acute, or related to chronic inflammation. The disease may be, for example, atherosclerosis, thrombosis, stroke, acute coronary syndrome, stable angina, peripheral vascular disease, significant leg ischemia, intermittent claudication, abdominal aortic aneurysm or myocardial infarction.

  The selective PDE4 inhibitors of the present invention are likely to help improve cognition and thus treat learning disorders, memory loss and other cognitive dysfunctions. The selective PDE4 inhibitors of the present invention are also useful in treating asthma and chronic obstructive pulmonary disease (COPD). The compounds of the present invention (inhibiting tumor growth and metastasis) also find utility in the treatment and prevention of cancer. And esophageal cancer, brain cancer, pancreatic cancer and colon cancer are included.

  These and other embodiments of the invention will become apparent in the context of the following description and claims.

<< Detailed Description of the Invention >>
When deriving and maintaining their definitions, substitutions are defined throughout this specification.

  Unless otherwise specified, alkyl is intended to include linear, branched, or periodic hydrocarbon structures and combinations thereof. A combination is, for example, cyclopropylmethyl. Lower alkyl refers to alkyl groups of 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sand t-butyl and the like. Preferred alkyl groups are those of C20 or below; C1 for C8 is more preferred. Cycloalkyl is a subset of alkyl containing ˜8 carbon atoms including 3 cyclic hydrocarbon groups. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.

  C1 for C20 hydrocarbon includes alkyl, cycloalkyl, poly-cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbons are associated with any substitution of hydrogen and carbon as the only basic voter.

  Unless otherwise stated, the term “carbon cycle” is intended to include systems in which the ring atoms are also all carbons other than in the oxidized state. The Thus (C3-C10) carbon cycle is associated with unpleasant and pleasing systems, including systems such as cyclopropane, benzene, cyclopentene and cyclohexene; the carbon polycycle (C8-C12) is associated with norbornane, deca, And related to systems like naphthalene. Unless otherwise limited, carbocycles relate to monocycles, bicycles, and polycycles.

  Related to groups of eight carbon atoms of an alkoxyl group or of an alkoxyl, 1 to a straight, branched or periodic configuration and combinations thereof attached to the parent structure by oxygen. Examples include ethoxy, methoxypropoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower alkoxy relates to groups containing 1 to 4 carbons. For purposes within this application, ethylenedioxy wherein the alkoxyl group and the alkoxyl of the lower alkoxyl group are related to ether groups from 3 to 8 atoms in a straight, branched, periodic configuration. And combinations thereof attached to the parent structure with alkyl and include methylenedioxy. Examples include methoxy methyl, methoxy ethyl, ethoxy propyl, and the like. Alkoxyaryl refers to an alkoxy substituent attached to an aryl. There, the aryl is attached to the parent structure. Arylalkoxy refers to an aryl substituent attached to oxygen. There, oxygen is attached to the parent structure. Substituted arylalkoxy is related to substituted aryl with attached substituents

  Oxaalkyl refers to an alkyl remainder in which one or more carbons (and their associated hydrogens) are replaced with oxygen. Examples include 3,6,9-tri oxa decyl, 2,6,7-trioxabicyclo [2.2.2] octane, including methoxy propoxy. That is, it relates to a compound in which oxygen is bonded to its adjacent atom (which forms an ether bond) via a single bond, which is understood in the prior art [Chemical Abstracts (127 (a) unrestricted) The term oxa-alkyl is intended, as it is not related to the oxygen of adhesion twice, (see the Chemical Substrates Naming and Indexing) (as published by the American Chemical Society (196)). And that is found in the carbonyl group. Similarly, thia-alkyl and aza-alkyl relate to the rest of the alkyl, respectively, which one or more carbons have been replaced with sulfur or nitrogen. Examples include ethylaminoethyl and methyl thiopropyl.

  Unless otherwise specified, acyl relates to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms in a straight, branched, periodic configuration (saturated). And the combination of them attached to the parent structure due to carbonyl functionality and not saturated is good. As long as the position of attachment to the parent remains with the carbonyl, one or more carbons of the acyl residue can be replaced with nitrogen, oxygen or sulfur. Examples include acetyl, benzoyl, propionyl, iso-butyryl, t-butoxycarbonyl, carbonyl containing benzyl groups, and the like. Lower-acyl relates to groups containing 1 to 4 carbons. Oxygen with double adhesion, called "oxo", called substitution itself.

Aryl and heteroaryl average (i) phenyl group (or benzene) or monocyclic 5- or 6-membered heteroaromatic compound has 1 to 4 heteroatoms selected from O, N or S Including ringing,
(ii) the bicyclic 9- or 10-membered aromatic or heterocyclic aromatic ring rings 0-4 heteroatoms containing a system selected from O, N or S, or (iii) Tricyclic 13- or 14-membered aromatic or heterocyclic aromatic compounds ring 0-5 heteroatoms containing a system selected from O, N or S. As understood herein, aryl includes not only the need for all but one or more rings with a pleasing remainder. Thus, an aromatic heterocycle consisting of 5 to 10 several parts is, for example, imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole. And cyclic carbons comprising 6 to 14 aromatic moieties, including and pyrazole, include, for example, benzene, naphthalene, indane, tetralin and fluorene.

  Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure by alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to a parent structure with an alkyl. In embodiments, an alkyl in which the arylalkyl or heteroarylalkyl group is an alkyl group of 1 to 6 carbons. Examples include, for example, pyridinylmethyl, pyrimidinylethyl and the like.

  Heterocycle means the remainder of the cycloalkyl or aryl carbon cycle in which 1 to 3 carbons are replaced with a heteroatom selected from the group consisting of N, O and S. Nitrogen and sulfur heteroatoms can optionally be oxidized. Nitrogen heteroatoms can optionally be quaternized. Unless stated otherwise, the heterocycle may be non-flavored or savory. It should be noted that heteroaryl is a subset of heterocycles where heterocycles are plentiful. Examples of remaining heterocyclic rings within the scope of the present invention include pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydro-isoquinoline, benzofuran, benzo-dioxane, benzodioxole (when generated as a substituent, Commonly referred to as oxy-phenyl), morpholine, thiazole, pyridine (including 2-oxo-pyridine), pyridine N-oxide, pyrimidine, thiophene (ie thien), furan, oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane , Azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, imidazolopyridine, pyrazine, fully unsaturated tet Hydro allophone system among the above and thiazole idine, iso thiazole, 1,2-thiazine-1, 1-dioxide, quinuclidine, iso thiazole idine, benzimidazole, thia diazole, benzopyran, benzo Thiazole, benzo-triazole, benzoxazole, tetrahydrofuran, tetrahydropyran, benzothien, thia morpholine, thia morpholine sulfoxide, thia morpholine sulfone, oxa diazole, triazole, tetrazole, isatin (di-oxo-indole) , Phthalimide (di-oxo-iso-indole), pyrrolopyridine, triazolopyridine and dihydro.

An oxygen heterocycle is a heterocycle containing at least one oxygen of the ring,
It can contain added oxygen (as well as other heteroatoms). The oxygen heterocycles found in the examples of the present invention include tetrahydrofuran, benzodioxole, morpholine, isoxazole and 2,6,7-trioxabicyclo [2.2.2] octane. A sulfur heterocycle is a heterocycle containing at least one sulfur of the ring, which can contain added sulfur (as well as other heteroatoms). A nitrogen heterocycle is a heterocycle containing at least one nitrogen of the ring, which can contain added nitrogen (as well as other heteroatoms).

  As used herein, the term “optionally substituted” can be used interchangeably with what is “unsubstituted or substituted”. The term “substituted” refers to the replacement of one or more hydrogen atoms of a specified group with a specified group. Examples, substituted alkyl, aryl, cycloalkyl, heterocycle etc. are alkyl, aryl, cycloalkyl or each remaining up to 3 hydrogen atoms are halogen, haloalkyl, alkyl, acyl, alkoxy alkyl, hydroxy alkyl, carbonyl (Ie, oxo), phenyl, heteroaryl, hydroxy, alkoxy, halo-alkoxy, oxa-alkyl, carboxy, alkoxycarbonyl [—C (═O) O-alkyl to relate to a heterocycle replaced by benzene-sulfonyl ], Alkoxycarbonylamino [-NHC (= O) O-alkyl], alkoxycarbonylaminoalkyl [-alkyl-NHC (= O) O-alkyl], carboxyalkylcarbonylamino [-NHC (= O) -alkyl-CO H], carboxamide [—C (═O) NH 2], aminocarbonyloxy [—OC (═O) NH 2], alkylaminocarbonyl [—C (═O) NHalkyl], dialkylaminocarbonyl [—C (= O) N (alkyl) 2], aminocarbonylalkyl [-alkyl-C (= O) NH2], cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl) (aryl) aminoalkyl , Alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, alkyl (hydroxyalkyl) amino, heterocyclic alkoxy, monovalent SH group, alkylthio, alkylsulfonyl, alkylsulfonyl Amino, alkylsulfur Ynyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocycle, heterocyclealkyl, phenoxy, benzyl Oxy, heteroaryloxy, heterocyclic amino, hydroxyimino, alkoxyimino, oxa-alkyl, amino-sulfonyl, trityl, amidino, guanidino, ureido-NHC (= O) NHalkyl-NHC (= O) NH-heterocyclic- Alkyl—NHC (═O) N (alkyl) 2, heterocyclic alkylcarbonylamino, phenyl and benzyloxy containing benzyl groups. Oxo that is included in the substitutions described in the “optionally substituted”, as recognized by those skilled in the art in the prior art. -The reason is as follows. Oxo is a divalent group where there are situations where it is not suitable as a substituent (eg to phenyl). Particularly for R1, the remaining of the additional substitution amino acids considered to be within the term, the amino acid amide, the amino acid and the protected amide of those amides, and N methylated (mono or -As appropriate-di) amine acids and amino acid amides.

用語「アミノ酸性、アミノ酸性アミドの残り」、その他はアミノ酸その他に関連する引く、考慮される官能基は親構造体に結合の中で分かれる。例えば、分子で、Ｐ―１４３は、下記を例示した：

１つが（ＢＯＣ）糖イナーム糖をフェニル環に接続する水素を減算したあと、残るＡの構造は以下の通りである：

これは、意味ｓｔｒｉｃｔｏでないそれがＣ末端アミド上の水素を欠いているので被保護アミノ酸アミド。取付け（例えばＣＯＯＨのＯＨまたはＮＨ２のＨ）の位置で原子を欠いているこれおよび類似の構造は、本明細書において、それらのそれぞれの両親の「残り」と称される。 R1, substituent alkyl, acyl, alkoxy alkyl, hydroxy lower alkyl, phenyl, heteroaryl, benzene sulfonyl, lower alkoxy, haloalkoxy, oxa alkyl, alkoxycarbonyl, alkoxycarbonylamino, carboxamide, alkyl aminocarbonyl, amino For alkylamino, (alkyl) (aryl) aminoalkyl, alkylaminoalkyl, heterocyclylalkoxy, alkylthio, sulfonylamino, alkylsulfinyl, alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino for amidino, aryl, benzyl, Heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, phenoxy, benzyloxy, hetero Reyloxy, heterocyclylamino, oxa-alkyl, amino-sulfonyl, amidino, guanidino, ureido, benzyloxy can be further substituted by 1, 2 substituents from the above list of substituents and contain benzyl groups Phenyl. Especially for R1, the remainder of the substitution amino acids considered to be within the scope of the term, the amino acid amides, and the protected residue of the amino acids and their amides (as well as the specific remainder below): -CH2CF3-CF3-CHO-COOH-CN, halogen-OH-OEt-C (= O) NH2-C (= O) NHEt-C (= O) NMe2-COOCH3-COOEt-CH2NHC (= O) NH2-CH (CH3) NHC (= O) NH2-CH2NHC (= O) H-CH2NHC (= O) CH3-CH2C (= O) NH2-CH2COOH-CH2COOEt-CH2NHC (= O) OEt-CH2NHC (= O) O-C6H5 -CH2NHC (= O) C (= O) NH2-CH2NHC (= O) NHEt-C (CH3) 2OH-CH2 HC (= O) N (CH3) 2-CH2NHC (= O) NHCH3-CH2NH2-CH (CH3) NH2-C (CH3) 2NH2-CH2OH-CH2CH2OH-CH2NHSO2CH3-CH2OC (= O) NHEt-OCH3-OC (= O) NH 2 —OCH 2 CH 2 N (CH 3) 2 —OCH 2 CH 2 OCH 3 —NHC (═O) NH 2 —NHC (═O) NHEt—NHCH 3 —NHEt—NH (tBoc) —NHCH 2 COOH (“Remaining Glycine”) — N (CH 3) CH 2 COOH ( “Remaining N-methyl glycine”)-NHC (= O) NHCH2CH2Cl-NHSO2NH2-NHEt-N (CH3) 2-NH2-NH (CH3) C (= O) NH2-NHSO2CH3-N (SO2CH3) 2-NHC (= O) OCH3-NHC = O) OtBu-NHC (= O) CH3-SO2NH2-NHC (= O) CH2CH2COOH-NHC (= O) NHCH2COOH-CH2NHCHO-NHC (= O) NHCH2COOEt-NHC (= O) NH (CH2) 3COOEt-NHC ( = O) NH (CH2) 2COOEt-N (CH3) CH2CH2OH-NHC (= O) OEt-N (Et) C (= O) OEt-NHC (= O) NH (CH2) 2COOH-NHC (= O) CH2N (CH3) 2-NHC (= O) NH (CH2) 3COOH-NHC (= O) CH2NH2-NHC (= O) CH2CH2NH2-NHC (= O) CH2NH (tBoc),

The term “amino acid, the remainder of the amino acid amide”, etc., relates to the amino acid and the like, the functional groups considered, which are separated in the bond to the parent structure. For example, in the molecule P-143 exemplified the following:

After one subtracts the hydrogen connecting the (BOC) sugar inert sugar to the phenyl ring, the structure of A remaining is as follows:

This is not a strictto meaning protected amino acid amide because it lacks a hydrogen on the C-terminal amide. This and similar structures lacking an atom at the position of attachment (eg OH in COOH or H in NH 2) are referred to herein as the “residues” of their respective parents.

  The terms “haloalkyl” and “haloalkoxyl group” inferior alkyl, or alkoxyl group, each substituted by one or more halogen atoms. The terms “alkylcarbonyl” and “alkoxycarbonyl” mean —C (═O), alkyl, or —alkoxy C (O), respectively.

  The term “halogen” means fluorine, chlorine, bromine or iodine. In one example, the halogen may be fluorine or chlorine.

  The substituent Rn is usually defined when derived and retains its definition throughout the specification and in all independent claims.

  In some characterizations of the substituents, it is detailed that certain substituents can be attached to form a ring. Unless otherwise stated, this type of ring can exhibit varying degrees of unsaturation (from fully saturated to fully unsaturated), can contain heteroatoms, and can be It is contemplated that it may be substituted or an alkoxyl group.

That is, the compound of the present invention can contain one or more atoms containing an atomic mass or mass number different from the atomic mass, or a mass number normally found in nature, wherein the compound of the invention is identified in a radioisotope It is recognized that it can exist. Each particular contain trivalent phosphorus, radioisotopes fluorine and chlorine hydrogen (carbon) ^{include 2H, 3H, 13 C, 14} C, 15 N, 35 S, 18 F and 36Cl. Those radioisotopes of other atoms and / or compounds containing other radioisotopes are within the scope of the invention. ¹⁴ C, a radioisotope is particularly preferred for those ready and detectable, Tritiated (ie 3H) and carbon-14. Isotopes ^11C, 13 N, compounds containing 15O and ¹⁸ F are well suited for positron emission tomography. Compounds identified with the radioisotope of formula I of the present invention and its prodrugs can usually be prepared by methods well known to those skilled in the art. Conveniently, this type of radioisotope-identified compound can be obtained in the Examples and Schemes by replacing readily available radioisotope-identified reagents with non-radioisotope-identified reagents. It can be prepared by performing the disclosed procedure.

  As used herein, in the prior art, as understood by those skilled in the art, the description of “compound” includes salts (solvates, cocrystals and any stereoisomeric forms of the compound as well as The inclusion complex) or any kind of hybrid form of the compound is intended to be included in any ratio (especially in the claims). Thus, in accordance with some embodiments of the present invention, the compounds described herein include, as such, salt forms, including the context of pharmaceutical compositions, methods of treatment and compounds in themselves. Is provided. Thus, for example, as described above, the recitation “compound of formula I”, wherein R1 is imidazolyl, includes imidazolium salts. In certain embodiments, the term “a compound of formula I” relates to a compound or a pharmaceutically acceptable salt thereof.

  The compounds described herein can contain asymmetric centers and thus can give rise to enantiomers, mixtures of diastereomers and other stereoisomeric forms. As (R), with respect to absolute stereochemistry, each enantiomeric center can be defined—or in any ratio from (S)-. Racemic to optically pure form. Should contain all such possible isomers of this kind. Optically active (R)-and (S) -isomers can be prepared using enantiomers or enantiomers, or can be resolved using conventional techniques. it can. The prefix “rac” relates to the racemate. As used herein, when a compound described contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, the compound has the E and Z geometric isomers. It is intended to include. Unless explicitly stated, the expression that any double bond described for any carbon-carbon configuration is only selected for convenience is not intended to indicate a particular configuration. Thus, a carbon-carbon double bond, optionally depicted as E, can be Z, E, or any combination of the two. Likewise, all tautomeric forms are also intended to be included.

  The term “solvate” relates to compounds of the formula I in the solid state, in which molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent for therapeutic management is physiologically acceptable at the controlled dosage. Examples of suitable solvents for therapeutic management are ethanol and water. When water is the solvent, the solvate is called a hydrate. In general, a solvate is formed by: dissolving a compound in a suitable solvent and separating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotroped at ambient conditions. Inclusion complexes are described in Remington: Science and 19th, Pharmacopoeia Execution Editing (1995) Volume 1 (pages 176-177). And it shall be referred to in this specification. The most commonly used inclusion complexes are those with cyclodextrin. And all cyclodextrin complexes (natural and synthetic) are specifically included within the scope of the claims.

The term “pharmaceutically acceptable salts” relates to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Amino salicylate, n-hydromethylene citrate, ascorbate, aspartate, calcium edetate, camphorate, cansylate, caprate, caprate, caprylate, cinnamate , Tichroic, dichloroacetic acid, edetate (EDTA), edicylic acid, embonate, estrate, esylate, fluoride, formate, gentisic acid is glucuronic acid, glycerophosphoric acid, glycolate, glycolylarsanylate, Glucose hexyl resorcinate, hyperic acid, hydroxynaphthoic acid, iodide, lactobionic acid, malonic acid, mesylate, napadisylic acid, napsylic acid, nicotinate, oleate, orotic acid, oxalate, oxoglutarate, palmitate Septate, suitable pharmaceutically acceptable for the compounds of the present invention Anions are acetate, benzene sulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonic acid, citrate, ethanesulfonate, fumaric acid ester, gluconic acid Salt, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelic acid, methanesulfonate, mucate, nitrate, pamonate, pantothenate, phosphate , Succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetoamide benzoate, adipate, alginate, etc. comb-like, comb-like polymer, phenylethyl Barbituric acid, Picrate, Pidroic acid, Propionate, Rodanid, Salicylate, Sebacic acid, Stearate, Ta Nin salt, teoclate, tosylate. The desired salt can be obtained by ion exchange of any antiions obtained in the synthesis of quat. These methods are well known to those skilled in the art. Although pharmaceutically acceptable anions are preferred for preparing pharmaceutical compositions, other anions are quite acceptable as synthetic intermediates. When the compound contains an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention are lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine , Metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from meglumine (N-methyl sugar amine) and procaine.

  As used herein, the schematic representation of racemic, ambiscale and scalaric or enantiomerically pure compounds used is Maehr J. Taken from the chemical Ed. 62, 114-120 (1985): solid and broken wedges are used to mean the absolute configuration of antipodal elements, the wavy line and one thin line can produce the bond it represents Solid and broken bold lines indicate the relative composition shown, but are geometric descriptions that mean a racemic character, and are points, indicating the negation of any stereochemical meaning The broken line means an enantiomerically pure compound of undefined absolute composition and is outlined.

  Terminology related to “protecting”, “deprotecting” and “protected” functions occurs throughout this application. This type of terminology is used in the prior art in the context of processes that are well understood by those of skill in the art and require treatment over time with a series of reagents. In that context, protection groups are related to groups. It is then used to mask functionality during process steps where it would otherwise react, but reaction is not desirable. The protection group prevents reaction at that step, but can then be removed to expose the first function. Removal or “deprotection” occurs after a reaction or reaction completion that interferes with function. Thus, when a series of reagents are identified, in the process of the present invention, those of ordinary skill immediately envisage those groups that are appropriate, as “protect the group”, as they are. Can do. Appropriate groups are therefore mentioned in standard textbooks in the field of chemistry (for example, Organic Synthesis by TW, Protective Groups). Green [John Wiley, New York, 1991]. And it shall be referred to in this specification.

  A comprehensive list of abbreviations used by organic chemists is displayed in the first question for each Organic Chemistry journal quantity. The list, which is typically shown in a table entitled “Abbreviations Standard List”, is hereby incorporated by reference.

  In general, the compounds of the invention can be prepared by the methods illustrated in the general reaction scheme, for example under or as described therein. It then uses readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to utilize variants which are known in themselves but which are not mentioned here. The starting materials are commercially available, can be synthesized as described in the examples, or can be obtained by methods well known in the art in the prior art.

PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, management of cilomilast and roflumilast (PDE4 inhibitor) for patients suffering from asthma and COPD initially showed excellent results. However, the effect of Shiromilast disappeared in the long-term referee [Lipworth, Lancet 365, 167-175 (2005)]. Genetic studies have clearly shown an association between PDE4D and ischemic stroke (Gretarsdottil et al. 2003. Natural genetics. 35, 1-8). L-454,560, a selective PDE4 inhibitor, has been shown to improve learning of the murine model in vivo [Houwan et al., Biochemical Pharmacology 73, 1971-1981, 2007]. This suggests that selective PDE4 inhibitors are useful for treating learning disorders, memory loss (eg, Alzheimer's disease) and other cognitive dysfunctions. Rolipram (another selective PDE4 inhibitor) has been used in several rodent models [Blokland et al., Current Pharmaceutical Design 12 as well as in primates [Ruttan et al., 2008, Psychopharmacology 196, 643-648 (2008)]. , 2511-2523, 2006]. Rolipram also improves the results of two separate studies of mice in vivo in a model that is recognized in the prior art by a person skilled in the art to predict the usefulness of schizophrenia [Kanes et al., Neuroscience 144, 239. -246 (2007), Davis and Gould (Behav. Neurosci.) 119, 595-602 (2005)] Rolipram also showed neuroprotective effects in a murine model of Huntington's chorea [DeMarch et al. Neurobiol. . Dis. 25, 266-273 (2007)] This suggests that PDE4 modulators are useful in treating many CNS diseases. Selective PDE4 inhibitors (eg rolipram) are also helpful in treating bone loss [Yao et al . Musculoskelet. Neuronal Interact. 7, 119-130 (2007)].

  In addition, a PDE4 inhibitor (YM976) has been shown to ameliorate the effects of murine experimentally induced interstitial cystitis. And decrease in frequency of urination and urination [Kita et al., BJU Int. 102, 1472-1476, 2008], resulting in an increase in urine volume each hour. Another PDE4 inhibitor (IC485) is a tartrate-blocking bladder [Kaiho et al. BJU Int. 101, 615-20, 2008] was shown to be equally effective as a tolteradine (a drug marketed to treat hypersensitive bladder). These findings suggest that PDE4 inhibitors are useful in treating signs of bladder overreaction, inflammation and pain.

  In addition to the above studies showing the usefulness of in vivo models, many authors have proposed a connection between PDE4 inhibition and putative utilities as antidepressants [Houslay et al., Drug Discov Today 10, 1503-1519. (2005), Poleskaya et al., Biol. Psychiatr. 61, 56-64 (2007), soon. Current Opin. Invetig. Drugs 5, 34-39 (2004)] and as anxiolytic agents [Chan et al., Neurosychopharmacology August 15, 2007, Pub, Cherry et al., Biochim. Biophys. Acta 1518, 27-35, 2001] Rolipram has been shown in human clinical trials to improve the reduction [Hebenstrite et al., Pharmacopsychiat. 22, 156-160 (1989)] Other possible utilities may include Pick's disease and epilepsy.

  Furthermore, the compounds, compositions and methods of the present invention may be useful for treating cancer. Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., Biochem. J. 393, 21-41 (2006), Ogawa et al., Blood 99, 3390-3397, 2002] Compounds are only one or more of the following drugs, alcohol, amphetamines, antipsychotic drugs, antiretroviral therapy, MDMA Can also be managed to overcome the cognitive impairment induced (3,4-methylenedioxy-N-methylamphetamine, cannabis, cocaine, δ-9 tetrahydrocannabinol, dextroamphetamine, haloperidol, heroin and Other opiates (ketamine and methamphemine).

  Furthermore, the compounds, compositions and methods of the present invention may be used as imaging agents, particularly when identified by radioisotopes as described above or labeled by flowering and rotating labels by methods known in the art. Can be used and can be in other directions for diagnosis or treatment. Furthermore, modified embodiments of the compounds of the present invention having chemically active groups can be used for protein labeling, and immobilization of the compounds of the present invention on a solid support is for affinity purification. It could have been useful.

  As many of the utilities have outlined the above, it may be advantageous to administer general Formula I compounds with cholinesterase inhibitors (eg, tacrine, huperzine, donepezil), NMDA antagonists (eg, ranisemin, remasemide, neramexane, memantine) Calpain inhibitors (eg CEP-3122), antioxidants (eg vitvitamin E, coenzyme Q10) and drugs that have shown clinical efficacy, but whose mechanism is unknown (eg dimbon). Compounds of formula I can also be administered with one or more of the following drugs to improve recognition: amisulpiride, atomoxetine, bromocriptine, buspirone, caffeine, chlorpromazine, clonidine, clozapine, diazepam, flumazenil, Fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan, modafinil, olanzapine, paroxetine, pergolide, phenol-serine, quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.

  The condition “how to treat or prevent” means the elimination of symptoms and / or effects associated with improvement, prevention or disability. The term “preventing” as used herein relates to administering a drug in advance to cope with or blunt the acute onset. Those of ordinary skill in medicine (and the current method claims aim) recognize that the term “prevent” is not an absolute term. It will be appreciated that in medical practice it relates to the prophylactic administration of a drug to substantially reduce the likelihood or severity of the condition. And this is the intended sensation in the applicant's claims. As used herein, reference to “treatment” of a patient is intended to include prophylaxis.

  The term “mammal” is used in the dictionary sense. Humans are included in the mammal group. And humans are the preferred subject of the method.

  The cognitive impairment to be treated results from one or more of the following disorders, which are unable to do so by itself, and are necessarily associated with PDE4 abnormalities: acute pain, AD / HD-attention deficit hyperactivity disorder , AIDS dementia complex, alcoholism, amphetamine poisoning, amygdaloid hippocampal resection, anorexia nervosa, anterior body wall damage, antisocial behavior, antisocial personality disorder, anxiety, autism, basal ganglion lesion Bipolar disorder, borderline personality disorder, anteflexia, capgra syndrome, carcinoid syndrome, carotid endarterectomy, chronic drug misuse, chronic fatigue syndrome, chronic occupational lytic encephalopathy, chronic pain, Cerebral ischemia, coronary artery bypass surgery, intensive care requiring critical disease, dementia Alzheimer type (DAT), Lewy body dementia type, front type dementia, ischemia Dementia, tooth pain, developmental dyslexia, diabetes, dorsolateral frontal cortical compression, Down syndrome, drug abuse, abnormal execution syndrome, fibromyalgia, frontal lobe injury, frontal lobe resection, frontal atypical frontal Skull dementia, gluten ataxia, hallucination, head injury, hearing loss, heart disease, heart failure, heavy social drinking, hepatic encephalopathy, heroin addiction, herpes encephalitis, hippocampal atrophy, HIV / AIDS, Huntington's chorea, hydrocephalus , Hypercortisolemia, bone hyperplastic frontal muscle interna, hypertension, unexplained pain, insomnia, Korsakov syndrome, slow parafreni, lead exposure, left ventricular systolic dysfunction, orbital frontal cortical lesions, liver failure Long term health diving, Machado-Joseph disease, crazy hatter disease, mania depression effects, depression, mercury poisoning, mild cognitive impairment (MCI), aging mild cognitive impairment (M I), motor neuron disease, multiple sclerosis, multiple system atrophy, narcolepsy, neuronal migration disorder, standard pressure hydrocephalus, obsessive-compulsive disorder, organophosphorus insecticide exposure, panic disorder, parafreni, Parkinson's disease, periventricular brain Injury, personality disorder, nasal gasoline, phenylketonuria, post-cerebral symptom syndrome, need of premature birth, intensive care, premenstrual discomfort disorder, progressive supranuclear palsy, psychosis, psychosis, suspected dementia , Kidney cancer, Roifman syndrome, schizophrenia disorder, schizophrenia, seasonal emotional disorder, self-harm, semantic dementia, dyslexia, social withdrawal of schizophrenia, lytic encephalopathy, spina bifida , Steel-Richardson-Olzsewski syndrome, solid human syndrome, stratocapsular infarction, subarachnoid hemorrhage, substance abuse, delayed Facial paralysis, temporal lobe resection, temporal lobe lesions, tinnitus, Tourette syndrome, transient cerebral ischemia, traumatic brain injury, hair loss, tuberous sclerosis and white matter lesions.

  While it may be possible for the compounds of formula I to be managed as biochemicals, it is often preferred to present them as part of a pharmaceutical composition. According to present embodiments, the invention there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with or more pharmaceutically its carrier and optionally one or more Other therapeutic ingredients. The carrier must be “acceptable” and not harmful to its recipients in the sense of being compatible with the other elements of the formulation. Furthermore, when a reference is made in its independent claim to its synthetic or pharmaceutically acceptable salt, it also relates to this type of compound, even if no explicit reference is made to the dependent claim salts. It will be understood that claims dependent on the independent claims include pharmaceutically acceptable salts of the compounds.

  The formulation contains oral, parenteral (subcutaneous, intradermal, intramuscular, including venous and intraarticular), rectal and localized (dermal (buccal) sublingual glands and Including those suitable for intraocular) management. The most appropriate route may depend on the recipient's condition and failure. The formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods known in pharmacy. This type of method involves the step of bringing the compound of its (“active ingredient”) formula (I) or a pharmaceutically acceptable salt or solvate with a carrier. It then constitutes one or more accessory components. In general, the formulations are uniformly and intimately brought with the active ingredient in association with a liquid carrier or a finely divided solid carrier or both, and if necessary, the product is shaped into the desired formulation It is prepared by.

  Formulations suitable for oral administration are aqueous liquids or as powders or granules, which can be presented as separate units (eg capsules, cachets or tablets each containing a predetermined amount of the active ingredient) As dissolution or termination of a non-aqueous solution, or as an oil-liquid emulsion of water or an aqueous liquid emulsion of oil. The active ingredient can also be presented as a bolus, electuary or paste.

  For optionally one or more accessory ingredients, tablets can be made by compression or molding. Compressed tablets should flow like powders or granules (optionally combined with binders, lubricants, inert diluents, oiling, active surfaces or dispersion aids) in a suitable machine It can be prepared by compressing the mobile form of the active ingredient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or recorded and can be prepared to provide continued, delayed or controlled release of the active ingredient therein. . The pharmaceutical composition can include the following: This expression is intended to include one or more inert excipients, which include starch, and a “pharmaceutically acceptable inert carrier”. Monohydric alcohol, granulated chemicals, microcrystalline cellulose, diluents, lubricants, binders, disintegrants, etc. If desired, tablet dosages of the disclosed compositions, including “pharmaceutically acceptable carrier” also including controlled release means, can be standard aqueous or coated by non-aqueous techniques.

  The pharmaceutical composition can also optionally include other therapeutic ingredients, anti-hardening drugs, preservatives, sweeteners, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any kind of optional ingredient must be compatible with the compound of formula I to ensure the stability of the formulation. For example, artificial products include, for example, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melizitol, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myo-inositol, etc. , Albumins that may contain other additives and their hydrates (and amino acids such as alanine, glycine and betaine and peptides and proteins).

  Examples of excipients as pharmaceutically acceptable carriers and pharmaceutically acceptable inert carriers and added ingredients as described above include binders, fillers, disintegrants, lubricants, antibacterial agents and coating chemicals However, the present invention is not limited to this.

  The dose range for adult humans is usually 0.005 mg to 10 g / day orally. Other forms of presentation provided in tablets or separate units are multiples of this type of dose or the same thing usually around 10 mg to 200 mg (eg units containing 5 mg to 500 mg) An amount of a compound of formula I that is effective as can be conveniently included. The exact amount of compound given to the patient is the responsibility of the attending physician. However, the dose used depends on many factors. And the age and intercourse of the patient (the exact disorder being treated) and its severity.

  A dose unit (e.g. oral dose unit), e.g. from 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, In the present specification, 5 to 100 mg (for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 4 0mg, 500mg).

  For additional information about pharmaceutical compositions and their formulations, see, for example, Remington: Pharmacy, 20th edition, 2000 Science and Practice. The drug can be administered, for example, by intravenous injection, intramuscular injection, subcutaneous injection, or intraperitoneal injection. And locally, sublingual. And within the joint (at the joint). And within the skin. And on the cheek side, it is an eye (including an intraocular thing). And, alternatively, intranasally (including using a cannula). A microcellular formulation via a liposomal formulation (see EP 736299, WO 99/59550 and WO 97/13500, for example) as an aqueous liquid or non-aqueous solution, an oil-in-water emulsion of water or an oil-in-water emulsion of oil (For example, via WO 97/11682), via the formulation described in WO 03/094886, or as some other form of solution or stop, the drug may be, for example, active ingredients, gels, pellets, pastes, It can be administered orally as a tablet or standing containing a predetermined amount of syrup, bolus, electuary, slurry, capsule, powder, granule. The drug can also be administered transdermally (ie reservoir-type or matrix-type patches, microneedles, heat-poration, hypodermic needles, iontophoresis, electroporation, ultrasound or sonophoresis, jet injection or (Via other forms of any combination of the previous method, Prausnitz et al. 2004, Nature Reviews Drug Discovery 3: 115). The drug can be administered topically, for example, at the site of improper handling of damaged blood vessels. The drug can be coated on the stent. The drug can be administered using a high rate transdermal particle injection technique using the hydrogel particle formulation described in US20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160 and WO 02/19989. Examples of gypsum containing transdermal preparations and the absorption promoter dimethyl isosorbide can be found in WO 89/04179. WO 96/11705 provides formulations suitable for transdermal management. The agent can be administered suppositories in the form or can be by other vaginal or rectal means. The drug can be administered in transmembrane formulations as described in WO 90/07923. The drug can be administered non-invasively via dehydrated particles as described in US 6,485,706. The drug can be administered in enteric drug formulations as described in WO 02/49621. The drug can be administered intranasally using formulations described in US 5,179,079. Formulations suitable for parenteral injection are described in WO 00/62759. The drug can be administered using the casein formulations described in US 20030206939 and WO 00/06108. The drug can be administered using a particulate formulation described in US 20020034536.

  Drug alone or in combination with other suitable components, intratracheal instillation (delivery of solution to the lung by syringe), intratracheal delivery of liposomes, inhalation (administration of powder formulation by syringe or to the lung) Any other similar device) and aerosol inhalation can be administered by the pulmonary route utilizing several techniques. Aerosols (eg, jet or ultrasonic nebulizers, metered dose inhalers, MDIs) and dry Powder inhalers, DPIs can also be used in intranasal applications. Aerosol formulations are stable dispersions or suspensions of solid materials and liquid droplets in a gaseous medium, and propellants (eg, hydrofluoroalkanes (HFAs (ie, HFA-134a and HFA-227)) that are pressure-accepted. Or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a hybrid of Propellants 11, 12, and / or 114), propane, nitrogen, etc.). Pulmonary formulations can include osmotic enhancers (eg, fatty acids and sugars). And chemicals, enzyme inhibitors (eg, protease inhibitors), adjuvants (eg, glycocholic acid (surfactin) width 85 and nafamostat), preservatives (eg, benzalkonium chloride or chlorobutanol) and ethanol ( Chelate (typically 5%, but perhaps up to 20% by weight). Ethanol is commonly included in aerosol compositions as it can enhance the function of the metering valve and possibly improve dispersion stability. The pulmonary formulation can also include surfactants including, but not limited to, bile salts described in US 6,524,557 and references. Some of them are also described in US 6,524,557 (eg C8-C16 fatty acid salts, bile salts, phospholipids) or alkyl sugars in the report to enhance the absorption of the compound of the formulation. Surfactants are advantageous. Also suitable in the present invention is a dry powder formulation comprising a therapeutically effective amount of an active compound mixed with a suitable carrier and configured for connection with a dry Powder inhaler. Absorption enhancers that can be added to dry powder formulations of the present invention include those described in US 6,632,456. WO 02/080884 describes a new method for surface modification of powders. Aerosol formulations can include US 5,230,884, US 5,292,499, WO 017/8694, WO 01/78696, US 2003019437, US 20030165436 and WO 96/40089 (which includes vegetable oils). . Sustained release formulations suitable for inhalation are described in WO 01/13891, WO 02/067902, WO 03/072080 and WO 03/079885, as well as in US 20010036481A1, 200302201919A1 and US 20040018243A1. . Pulmonary formulations containing microparticles are described in WO 03/015750, USA 20030008013 and WO 00/00176. Pulmonary formulations containing stable glassy state powder are described in US20020141945 and US6,309,671. US 6,290,987 describes liposome-based formulations that can be administered via aerosol or other means, and other aerosol formulations are described in EP 1338272A1 WO 90/09781, US 5,348,730, US 6,436,367, WO 91/04011 and US 6,294,153. Powder formulations for inhalation are described in US 20030053960 and WO 01/60341. The drug can be administered intranasally as described in US 20010038824.

  Buffered salt and similar solvent drug solutions are commonly used to produce nebulizer aerosols. A simple nebulizer operates on Bernoulli's principle and uses a stream of air or oxygen to produce spray particles. More complex nebulizers use ultrasound to create spray particles. Remington is Pharmacy's Science and Practice, and both types are known in the art and are described in standard textbooks of pharmacy such as Sprawl's American Pharmacy. Other devices that produce aerosols use compressed gases, usually hydrofluorocarbons and chlorofluorocarbons. And these devices are likewise described in standard textbooks (eg Sprawl and Remington), which are mixed with any necessary excipients in the drug and pressurized containers.

  Drugs can be incorporated into the liposomes to improve half-life. The drug can also be joined to a polyethylene glycol (PEG) chain. Additional formulations containing methods for pegylation and PEG-conjugates (ie PEG-based hydrogels, PEG-modified liposomes) are found in Harris and Chess (Nature Reviews Drug Discovery 2): 214-221 and Reference in it. The drug can be administered via a nanocochrate or a cochleate delivery vehicle (BioDelivery Sciences International). The drug can be delivered trans mucus sarcasm (ie, across the mucosal surface (eg, vagina, eyes or nose)) described in US 5,204,108 and using formulations such as that. The drug can be prepared in microcapsules as described in WO 88/01165. The drug can be administered internally orally using the formulations described in US 20020055496, WO 00/47203 and US 6,495,120. The drug can be delivered using the nano-emulsion formulation described in WO 01 / 91728A2.

  In general, compounds of formula I can be prepared by the methods illustrated in the general reaction scheme, for example under or as described therein. It then uses readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to utilize variants which are known in themselves but which are not mentioned here.

The present invention relates to compounds exhibiting PDE4 enzyme inhibition. And has the general formula I.

In one example, R3 is other than H and R2 is pyrazolyl or substituted with phenyl, X is CR5. In another embodiment, M is selected from a direct bond -CH2-CH (OH)-C [] (CH3) (OH)-C [] (CH3) (NH2)-C ( = O)-O--NH--N (CH3) --- S (O) n--CH2NH--CH2CH2 --- CH = CH--CH2S (O) n--CH2O--

There are two subgenera of compounds of formula I. First, where X is represented by the formula N or N → O:

Second, where X is represented by a formula that is CR5:

  In one example, R1 is substituted phenyl. In other embodiments, R2 is pyrazolyl or substituted with phenyl and R1 is phenyl. In other embodiments, R2 is pyrazolyl or substituted phenyl and R1 is substituted phenyl.

  In other embodiments, R 1 is an unsubstituted heterocycle. In other embodiments, R 1 is a substituted heterocycle. In both heterocyclic embodiments, the heterocycle is pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydro-isoquinoline, benzofuran, benzo-dioxane, benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine , Thiene, furan, oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, purine, imidazolopyridine, pyrazine, thiazole idine Iso-thiazole (1,2-thiazine-1,1-dioxide, 2,6,7-trioxabicyclo [2.2 2] Octane) quinuclidine (iso-thiazole-idine) benzimidazole (thia-diazole) benzopyran (benzothiazole) benzo-triazole (benzoxazole) benzoxadiazole (tetrahydrofuran) tetrahydro-pyran (benzothien) thia morpholine (thia • Morpholine sulfoxide) thia morpholine sulfone (oxa diazole) triazole (tetrazole) iso indole (pyrrolopyridine) triazolopyridine, and dihydro, and whether specifically named, tetrahydro and the like. For example, the dihydro congener of indole is indoline or dihydro indole, and the tetrahydro congener of pyridine is piperidine. In a further embodiment, R1 is an optionally substituted heterocycle selected from pyrazole (benzodioxole) morpholine (thiazole) pyridine (pyridine N-oxide) pyrimidine (thien) oxazolidine (isoxazole) azetidine (piperazine) Pyrrolidine (imidazole) imidazolidine (imidazolopyridine) pyrazine (1,2-thiazine-1,1-dioxide) benzimidazole (thia diazole) benzo triazole (benzoxazole) oxa diazole (triazole) tetrazole (iso Indole) pyrrolopyridine, triazolopyridine and their dihydro and tetrahydro congeners.

  In examples, substituted phenyl or substituted heterocycle is substituted by a substituent selected from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzene-sulfonyl. Hydroxy, alkoxy, halo-alkoxy, oxa-alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxy-alkyl, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamide, aminocarbonyloxy, alkyl- Aminocarbonyl, dialkylaminocarbonyl, cyano, aminocarbonylalkyl, acetoxy, nitro, amino, alkylamino, Alkylamino, aminoalkyl, (alkyl) (aryl) aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl (hydroxyalkyl) amino, heterocyclic alkoxy, monovalent SH groups, including alkylthio, Alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocycle , Heterocyclic alkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclic amino, hydroxyimino, alkoxyimino, oxa Rualkyl, amino-sulfonyl, trityl, amidino, guanidino, ureido-NHC (= O) NHalkyl-NHC (= O) NH-heterocyclic-alkyl-NHC (= O) N (alkyl) 2, heterocyclic alkylcarbonylamino , Phenyl containing benzyl group, benzyloxy, amino acid residue, amino acid amide, amino acid protected residue, amino acid amide protected residue, N methylated amino acid and N methylated amino acid amide. Typical amino acids are glycine, alanine and proline.

第１の属の化合物の１つの実施態様は、Ｒ３がメチルまたはフルオロ・メチルであるそれらである、Ｒ６は、Ｈである、そして、Ｍは、そうである―ＣＨ２―または―ＣＨ２Ｏ。 In other embodiments, a substituted phenyl or substituted heterocycle is substituted with a selected substituent —CH 3 —CH 2 CF 3 —CF 3 —CHO—COOH—CN, halogen—OH—OEt—C (═O ) NH2-C (= O) NHEt-C (= O) NMe2-COOCH3-COOEt-CH2NHC (= O) NH2-CH (CH3) NHC (= O) NH2-CH2NHC (= O) H-CH2NHC (= O) ) CH3-CH2C (= O) NH2-CH2COOH-CH2COOEt-CH2NHC (= O) OEt-CH2NHC (= O) O-C6H5-CH2NHC (= O) C (= O) NH2-CH2NHC (= O) NHEt-C (CH3) 2OH-CH2NHC (= O) N (CH3) 2-CH2NHC (= O) NHCH3-CH NH2-CH (CH3) NH2-C (CH3) 2NH2-CH2OH-CH2CH2OH-CH2NHSO2CH3-CH2OC (= O) NHEt-OCH3-OC (= O) NH2-OCH2CH2N (CH3) 2-OCH2CH2OCH3-NHC (= O) NH2 —NHC (═O) NHEt—NHCH 3 —NHEt—NH (tBoc) —NHCH 2 COOH—N (CH 3) CH 2 COOH—NHC (═O) NHCH 2 CH 2 Cl—NHSO 2 NH 2 —NHEt—N (CH 3) 2 —NH 2 —NH (CH 3) C ( = O) NH2-NHSO2CH3-N (SO2CH3) 2-NHC (= O) OCH3-NHC (= O) OtBu-NHC (= O) CH3-SO2NH2-NHC (= O) CH2CH2COOH-NHC (= O) NHCH2COOH CH2NHCHO-NHC (= O) NHCH2COOEt-NHC (= O) NH (CH2) 3COOEt-NHC (= O) NH (CH2) 2COOEt-N (CH3) CH2CH2OH-NHC (= O) OEt-N (Et) C ( = O) OEt-NHC (= O) NH (CH2) 2COOH-NHC (= O) CH2N (CH3) 2-NHC (= O) NH (CH2) 3COOH-NHC (= O) CH2NH2-NHC (= O) CH2CH2NH2-NHC (= O) CH2NH (tBoc),

One embodiment of compounds of the first genus are those where R3 is methyl or fluoromethyl, R6 is H, and M is —CH2— or —CH2O.

  In examples, R2 is from optionally substituted phenyl, optionally substituted monocyclic unsaturated heterocycle, unsubstituted bicyclic unsaturated heterocycle and fluoro substituted bicyclic unsaturated heterocycle. Selected. In a further embodiment, R2 is selected from optionally substituted phenyl, indole, benzodioxole, benzoxadiazole, benzo-dioxane, benzimidazole, oxa-diazole, pyrazole, pyridine and pyridine N-oxide. In a further embodiment, R2 is meta-substituted phenyl, indole, benzodioxole, 2,2-difluorobenzodioxole, benzo oxa diazole, benzimidazole, 5- (pyridin-4-yl) [1 , 2,4] Oxa-diazole, 5- (pyridin-4-yl) [1,3,4] oxa-diazole, benzo-dioxane, 4-chloro-pyrazole, 4- (pyridine-4- Yl) pyrazole, 6-chloro-pyridine, 3- (trifluoromethyl) pyrazole and pyridine N-oxide.

そこにおいて、Ｒ７は、水素（ハロゲン）から、ニトロ（シアノ）に選ばれるハロ（Ｃ１―Ｃ６）アルキル、アルコキシル基で（Ｃ１―Ｃ６）、ヒドロキシ（Ｃ１―Ｃ６）、オキサ・アルキル、カルボキシ、（Ｃ１―Ｃ６）アルコキシカルボニル、アミノカルボニル（―ＣＯＮＨ２）、（Ｃ１―Ｃ６）アルキル・アミノカルボニル、アシル、ヒドロキシ（Ｃ１―Ｃ６）アルキルは、（Ｃ１―Ｃ６）アルコキシ、アミノ（Ｃ１―Ｃ６）アルキル、アミノ、（Ｃ１―Ｃ６）アルキルアミノ、ジ［アルキル］（Ｃ１―Ｃ６）アミノにかさをかぶせる。そして、１価のＳＨ基を含む、（Ｃ１―Ｃ６）アルキルチオ、（Ｃ１―Ｃ６）アルキルスルフィニル、（Ｃ１―Ｃ６）アルキルスルホニル、（Ｃ１―Ｃ６）アルキルスルホンアミド、アシルアミノ，アミジノ、フェニル、ベンジル、異型シクロ・イル、フェノキシ、ベンジルオキシおよびヘテロアリールオキシ、及びＲ８およびＲ１３は、ＨおよびＦと独立して選択される。更なる実施態様（Ｒ７が水素から選択される及びＲ１３がＨである及びＲ８）において、フルオロ，クロロ、シアノで、ブローモ（ニトロ）アセチル、トリフルオロメチル（メトキシ）トリフルオロメトキシ、オキサジアゾリル、テトラゾリル、メチルチオ、メタンスルフィニル、メタンスルホニル、メタンスルホンアミド、アミノ、メトキシ・メチル、ヒドロキシエチルおよびモルホリニル。 In other embodiments, R2 is substituted phenyl:

R7 is a halo (C1-C6) alkyl selected from hydrogen (halogen) to nitro (cyano), an alkoxyl group (C1-C6), hydroxy (C1-C6), oxa-alkyl, carboxy, ( C1-C6) alkoxycarbonyl, aminocarbonyl (-CONH2), (C1-C6) alkyl aminocarbonyl, acyl, hydroxy (C1-C6) alkyl are (C1-C6) alkoxy, amino (C1-C6) alkyl, Cap the amino, (C1-C6) alkylamino, di [alkyl] (C1-C6) amino. And (C1-C6) alkylthio, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonamide, acylamino, amidino, phenyl, benzyl, which contain a monovalent SH group Atypical cyclo yl, phenoxy, benzyloxy and heteroaryloxy, and R8 and R13 are independently selected from H and F. In further embodiments (R7 is selected from hydrogen and R13 is H and R8), fluoro, chloro, cyano, bromo (nitro) acetyl, trifluoromethyl (methoxy) trifluoromethoxy, oxadiazolyl, tetrazolyl, Methylthio, methanesulfinyl, methanesulfonyl, methanesulfonamide, amino, methoxymethyl, hydroxyethyl and morpholinyl.

  In other embodiments, R1 is selected from optionally substituted phenyl, optionally substituted with 5 several heteroaryls, optionally substituted with 6-membered heteroaryls, Optionally, a non-aryl heterocycle consisting of several parts of 4-7 was substituted, optionally replacing a fused bicycle.

合成ものは、第一のふるい分けにおいて、作動中であるように見えない。Ｒ１がそうである及びＲ３がそうである，Ｒ５がＨである時―ＣＨ３、Ｒ２は、そうである―ＮＯ２

合成ものは、第一のふるい分けにおいて、作動中であるように見えない。そして、Ｒ３がそうである，Ｒ５がＨである時―ＣＨ３、Ｒ２は、そうである―ＯＣＨ３、または―ＣＯＣＨ３およびＲ１が、そうである

合成ものは、第一のふるい分けにおいて、作動中であるように見えない。 For example, R1 can be selected from optionally substituted phenyl, optionally substituted selected from thiazole, thiadiazole, pyrazole, oxa diazole, isoxazole, triazole, imidazole, thiophene, tetrazole and oxazole. A heteroaryl consisting of 5 parts, pyridine, pyrimidine, pyridazinone, pyrimidinone, pyridinone, pyraryl and diaryl optionally consisting of several parts heteroaryl, consisting of several parts A non-aryl heterocycle comprising an optionally substituted 5-and 6-piperazine, oxazolidinone, imidazolidinone, morpholine, piperidine, pyrrolidinone, pyrrolidinedione, pyrrolidine, Peridinone, piperidinedione and trioxabicyclo [2.2.2] octane, and benzoxazolone, indole, isoindolinedione, 2H-pyrrolopyridinedione, purine, indolinedione, triazolopyridinone, benzimidazole, benzoxazi Bicyclic ring with an optionally substituted fuse selected from azole, quinoline and quinolones, wherein the substituent is hydrogen, halogen, halo (C1-C6) alkyl, alkoxyl group (C1-C6), Independent of the hydroxyl group, it is selected from carboxy, (C1-C6) alkoxycarbonyl, aminocarbonyl (—CONH2), (C1-C6) alkylaminocarbonyl. Carbonyl (oxo), acyl, hydroxy (C1-C6) alkyl is (C1-C6) alkoxy, amino (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkyl, nitro, amino, ( C1-C6) alkylamino, di [alkyl] (C1-C6) cyano, which caps amino. And (C1-C6) alkylthio, sulfoxide, sulfone, sulfonate, sulfone-imide, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, amino containing monovalent SH group Carbonyl (C1-C6) alkyl, (C1-C6) alkoxycarbonyl (C1-C6) alkyl, carboxy (C1-C6) alkyl, formylamino (C1-C6) alkyl, carboxy (C1-C6) alkylamino- (CH2 ) P-NR12CO- (CH2) q-NR9R10-NHSO2R11-OCH2CH2NR9R10-NHSO2NR9R10-SO2NR9R10- (CH2) p-NHCOR9, OCONR9R10 and NR12COOR11,
R3 is selected -CH3-CH2CH3-CF3-CHF2 and -CH2F,
R5 is selected from H-F-OH-CH3-OCH3-CF3-CN-NH2 and -C≡CH,
R2 is
(a) Phenyl and R 7 are —NH 2 —SCH 3 selected from H, halogen, nitro, acetyl, hydroxyethyl, methoxy carbonyl —SOCH 3 —SO 2 CH 3 —OCH 3 —OCF 3 —CN—CF 3 —CH 2 OCH 3, or
(b) benzoxadiazole, benzodioxole, 2,2-difluorobenzodioxole, benzoxadiazole, benzo-dioxane, benzimidazole, oxa-diazole, pyrazole, pyridine and pyridine N-oxide,
R9 is H, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carboxy (C1-C6) alkyl, (C1-C6) alkoxy carboxy (C1-C6) alkyl Selected from the
R10 is alternatively taken together, H (C1-C6) alkyl), or
R9 and R10 together form a heterocycle optionally substituted with (C1-C6) alkyl;
p is 0 or 1;
q is 0, 1 or 2;
R11 is linear (C1-C6) alkyl;
R12 is H or (C1-C6) alkyl, or
Two adjacent substituents together form an optionally substituted fused heterocycle. When R5 is H, R3 is—the compounds that have been tested and found to be operational are those with R8, CH3 and R1 are substituted or unsubstituted pyrazoles—NO2 or R8 represents two adjacent substituents that form an optionally substituted fused heterocycle. R3 is, when R5 is H-CH3, R2 is-CF3 and R1 are

The composite does not appear to be in operation at the first screen. R1 is and R3 is, when R5 is H -CH3, R2 is -NO2

The composite does not appear to be in operation at the first screen. And when R3 is, when R5 is H -CH3, R2 is -OCH3, or -COCH3 and R1 are

The composite does not appear to be in operation at the first screen.

そこにおいて、Ｒ１ａは、フェニル、５会員を有するヘテロアリール、６会員を有するヘテロアリール、４―７の幾つかの部分から成る非アリール複素環またはヒューズのついた二環である、
Ｒ１４は、Ｈから選択される―ＣＨ２ＮＨＣ（＝Ｏ）ＮＨ２―ＮＨＣ（＝Ｏ）ＮＨ２―ＮＨＣ（＝Ｏ）ＮＨＥｔ―ＣＨ３―ＣＨ２ＣＦ３―ＣＨ２ＮＨＣ（＝Ｏ）ＣＨ３―ＮＨＣＨ３―ＮＨＥｔ―ＮＨ（ｔＢｏｃ）―ＣＨＯ―ＮＨＣ（＝Ｏ）ＮＨＣＨ２ＣＨ２Ｃｌ―ＮＨＳＯ２ＮＨ２―ＮＨＥｔ―Ｎ（ＣＨ３）２―ＮＨ２―ＣＯＯＨ―Ｃ（＝Ｏ）ＮＨ２―ＣＨ２Ｃ（＝Ｏ）ＮＨ２―ＣＨ２ＣＯＯＨ―ＣＨ２ＣＯＯＥｔ―ＣＮ―ＯＣＨ３―ＯＣ（＝Ｏ）ＮＨ２―ＮＨ（ＣＨ３）Ｃ（＝Ｏ）ＮＨ２、ハロゲン―ＣＨ２ＮＨＣ（＝Ｏ）ＯＥｔ―ＮＨＳＯ２ＣＨ３―Ｎ（ＳＯ２ＣＨ３）２―ＮＨＣ（＝Ｏ）ＯＣＨ３―ＯＨ―ＣＨ２ＮＨＣ（＝Ｏ）Ｎ（ＣＨ３）２―ＣＨ２ＮＨ２―ＣＨ２ＯＨ―ＣＨ２ＣＨ２ＯＨ―ＳＯ２ＮＨ２―ＮＨＣ（＝Ｏ）ＮＨＣＨ２ＣＯＯＨ―ＣＨ２ＮＨＣＨＯ―ＮＨＣ（＝Ｏ）ＮＨＣＨ２ＣＯＯＥｔ―ＣＯＯＣＨ３―ＣＯＯＥｔ―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）３ＣＯＯＥｔ―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）２ＣＯＯＥｔ―ＮＨ（Ｅｔ）Ｃ（＝Ｏ）ＯＥｔ―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）２ＣＯＯＨ―ＣＨ２ＮＨＳＯ２ＣＨ３―ＯＥｔ―ＮＨＣ（＝Ｏ）ＣＨ２Ｎ（ＣＨ３）２―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）３ＣＯＯＨ―ＮＨＣ（＝Ｏ）ＣＨ２ＮＨ２―ＮＨＣ（＝Ｏ）ＣＨ２ＣＨ２ＮＨ２―ＮＨＣ（＝Ｏ）ＣＨ２ＮＨ（ｔＢｏｃ）―ＯＣＨ２ＣＨ２Ｎ（ＣＨ３）２―ＯＣＨ２ＣＨ２ＯＣＨ３、3′―ニトロ―６―メトキシ・ビフェニル―３―イルメチル、テトラヒドロイミダゾール―２―１上のイル、３―メチルテトラヒドロイミダゾール―２―１―１―イル、ピラゾール―１―イル、

Ｒ１５は、Ｈ、ＮＯ２、ＯＨ、ＮＨ２から選択される、及び―ＮＨＳＯ２ＮＨ２、または、
Ｒ１４とＲ１５は、メチレン・ジオキシを形成する、
Ｒ２７は、水素（ハロゲン）から、ニトロ（シアノ）に選ばれるハロ（Ｃ１―Ｃ６）アルキル、アルコキシル基で（Ｃ１―Ｃ６）、ヒドロキシ（Ｃ１―Ｃ６）、オキサ・アルキル、カルボキシ、（Ｃ１―Ｃ６）アルコキシカルボニル、アミノカルボニル（―ＣＯＮＨ２）、（Ｃ１―Ｃ６）アルキル・アミノカルボニル、アシル、ヒドロキシ（Ｃ１―Ｃ６）アルキルは、（Ｃ１―Ｃ６）アルコキシ、アミノ（Ｃ１―Ｃ６）アルキル、アミノ、（Ｃ１―Ｃ６）アルキルアミノ、ジ［アルキル］（Ｃ１―Ｃ６）アミノにかさをかぶせる。そして、１価のＳＨ基を含む、（Ｃ１―Ｃ６）アルキルチオ、（Ｃ１―Ｃ６）アルキルスルフィニル、（Ｃ１―Ｃ６）アルキルスルホニル、（Ｃ１―Ｃ６）アルキルスルホンアミド、アシルアミノ，アミジノ、フェニル、ベンジル、異型シクロ・イル、フェノキシ、ベンジルオキシおよびヘテロアリールオキシ、
Ｒ２８は、ＨおよびＦから選択される、または、
Ｒ２８とＲ２７は、５会員を有する環を形成する。 One example of a compound of the second genus has the formula

Where R1a is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, non-aryl heterocycle consisting of several parts of 4-7, or a fused bicyclic ring,
R14 is selected from H —CH 2 NHC (═O) NH 2 —NHC (═O) NH 2 —NHC (═O) NHEt—CH 3 —CH 2 CF 3 —CH 2 NHC (═O) CH 3 —NHCH 3 —NHEt—NH (tBoc) — CHO-NHC (= O) NHCH2CH2Cl-NHSO2NH2-NHEt-N (CH3) 2-NH2-COOH-C (= O) NH2-CH2C (= O) NH2-CH2COOH-CH2COOEt-CN-OCH3-OC (= O) NH2-NH (CH3) C (= O) NH2, halogen-CH2NHC (= O) OEt-NHSO2CH3-N (SO2CH3) 2-NHC (= O) OCH3-OH-CH2NHC (= O) N (CH3) 2- CH2NH2-CH2OH-CH2CH2OH-SO2NH2-NHC (= O) NHCH COOH-CH2NHCHO-NHC (= O) NHCH2COOEt-COOCH3-COOEt-NHC (= O) NH (CH2) 3COOEt-NHC (= O) NH (CH2) 2COOEt-NH (Et) C (= O) OEt-NHC ( = O) NH (CH2) 2COOH-CH2NHSO2CH3-OEt-NHC (= O) CH2N (CH3) 2-NHC (= O) NH (CH2) 3COOH-NHC (= O) CH2NH2-NHC (= O) CH2CH2NH2-NHC (= O) CH2NH (tBoc) -OCH2CH2N (CH3) 2-OCH2CH2OCH3, 3'-nitro-6-methoxybiphenyl-3-ylmethyl, yl on tetrahydroimidazole-2-1, 3-methyltetrahydroimidazole-2- 1-1-Ile, pyrazo 1-yl,

R15 is selected from H, NO2, OH, NH2, and -NHSO2NH2, or
R14 and R15 form methylene dioxy,
R27 is selected from hydrogen (halogen) to nitro (cyano), halo (C1-C6) alkyl, alkoxyl group (C1-C6), hydroxy (C1-C6), oxa-alkyl, carboxy, (C1-C6) ) Alkoxycarbonyl, aminocarbonyl (—CONH2), (C1-C6) alkyl aminocarbonyl, acyl, hydroxy (C1-C6) alkyl are (C1-C6) alkoxy, amino (C1-C6) alkyl, amino, ( C1-C6) Alkylamino, di [alkyl] (C1-C6) amino is overlaid. And (C1-C6) alkylthio, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonamide, acylamino, amidino, phenyl, benzyl, which contain a monovalent SH group Atypical cyclo yl, phenoxy, benzyloxy and heteroaryloxy,
R28 is selected from H and F, or
R28 and R27 form a 5-membered ring.

In a further embodiment, R27 and R28 represent fused heterocycles at the 3 and 4 positions such that the phenyl to which they are attached and R28 are selected from the following and the remainder is formed from R27:

  In another embodiment, R27 is selected from halogen and is a nitro group, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, trifluoromethoxy Cyano, 1,3,4-thiadiazol-2-yl, or R8 is methylenedioxy or difluoromethylenedioxy and is taken together with R7. In the foregoing embodiments, R1a can be selected from a benzene ring, triazole, pyridine or pyridine-N-oxide, pyrazole, tetrahydro-thiophene, imidazole, pyrimidine, thiadiazole, and imidazopyridine.

  In an embodiment of the present invention R5 is fluoro, H, CN or OH. In other embodiments, R3 is methyl or fluoromethyl.

Another embodiment of the compounds of the invention has the formula.

そこにおいて、

４―７の員環は、その窒素によって、取り付けられる複素環である、Ｒ１７およびＲ１８は、Ｈ、（Ｃ１―Ｃ６）アルキルおよびハロ（Ｃ１―Ｃ６）アルキルからそれぞれに選択される、Ｒ１９は、Ｈ、（Ｃ１―Ｃ６）アルキル、ハロ（Ｃ１―Ｃ６）アルキルから選択される−［（Ｃ１―Ｃ６）アルキル］ＣＯＯＨおよび−［（Ｃ１―Ｃ６）アルキル］ＣＯＯ（Ｃ１―Ｃ６）アルキル、そして、Ｒ２０は、カルボン酸、カルボキサミド、カルボン酸エステル、主要な、第２であるか、第三期のアルコールおよび主要な、第２であるか、第三期のアミンから選択される。カルボン酸の実施例、カルボキサミド、カルボン酸エステル、主要な、第２であるか、第三期のアルコールおよび主要な、第２であるか、第三期のアミンは、含む―ＣＯＯＨ―ＣＯＮＨ２―ＣＯＮＨＣＨ３―ＣＯＮ（ＣＨ３）２―ＣＯＯＣＨ３―ＣＨ２ＯＨ―ＣＨ（ＣＨ３）ＯＨ―Ｃ（ＣＨ３）２ＯＨ―ＣＨ２ＮＨ２―ＣＨ（ＣＨ３）ＮＨ２及び―Ｃ（ＣＨ３）２ＮＨ２。さらなる態様において、Ｘは、ＣＨ、ＣＦまたはＮ→Ｏである、Ｍは、そうである―ＣＨ２―または―Ｓ、Ｒ２７ａは、クロロ（シアノ）アセチルおよびメチルチオから選択される、Ｒ１６が選択される及び―ＮＲ１７Ｃ（＝Ｏ）ＮＲ１８Ｒ１９、

さらなる態様において、Ｙは、ＣＨである、Ｍは、そうである―ＣＨ２、Ｒ２７ａは、そうであるクロロ、そして、Ｒ１６は、そうである―ＮＲ１７Ｃ（＝Ｏ）ＮＲ１８Ｒ１９。更に更なる実施態様において、Ｒ１６は、そうである―ＮＲ１７Ｃ（＝Ｏ）ＮＲ１８Ｒ１９およびＲ１７（Ｒ１９がすべての水素である及びＲ１８）。 In these compounds, R3 is methyl or methyl fluoride, Y is CH or N, R27a is selected from halogen (cyano) acetyl, methylthio, nitro and trifluoromethyl, R16 is selected And -NR17C (= O), NR18R19 and

Where

The 4-7 membered ring is a heterocycle attached by its nitrogen, R17 and R18 are each selected from H, (C1-C6) alkyl and halo (C1-C6) alkyl, R19 is -[(C1-C6) alkyl] COOH and-[(C1-C6) alkyl] COO (C1-C6) alkyl selected from H, (C1-C6) alkyl, halo (C1-C6) alkyl, and R20 is selected from carboxylic acids, carboxamides, carboxylic esters, primary, secondary or tertiary alcohols and primary, secondary or tertiary amines. Examples of carboxylic acids, carboxamides, carboxylic esters, primary, secondary or tertiary alcohols and primary, secondary or tertiary amines include -COOH-CONH2-CONHCH3 -CON (CH3) 2-COOCH3-CH2OH-CH (CH3) OH-C (CH3) 2OH-CH2NH2-CH (CH3) NH2 and -C (CH3) 2NH2. In a further embodiment, X is CH, CF or N → O, M is —CH 2 — or —S, R 27a is selected from chloro (cyano) acetyl and methylthio, R 16 is selected And -NR17C (= O) NR18R19,

In a further embodiment, Y is CH, M is —CH2, R27a is chloro, and R16 is —NR17C (═O) NR18R19. In yet a further embodiment, R16 is -NR17C (= O) NR18R19 and R17 (R19 is all hydrogen and R18).

ＶＩ
いずれで
Ｒ１４は、Ｈから選択される―ＣＨ２ＮＨＣ（＝Ｏ）ＮＨ２―ＮＨＣ（＝Ｏ）ＮＨ２―ＮＨＣ（＝Ｏ）ＮＨＥｔ―ＣＨ３―ＣＨ２ＣＦ３―ＣＨ２ＮＨＣ（＝Ｏ）ＣＨ３―ＮＨＣＨ３―ＮＨＥｔ―ＮＨ（ｔＢｏｃ）―ＣＨＯ―ＮＨＣ（＝Ｏ）ＮＨＣＨ２ＣＨ２Ｃｌ―ＮＨＳＯ２ＮＨ２―ＮＨＥｔ―Ｎ（ＣＨ３）２―ＮＨ２―ＣＯＯＨ―Ｃ（＝Ｏ）ＮＨ２―ＣＨ２Ｃ（＝Ｏ）ＮＨ２―ＣＨ２ＣＯＯＨ―ＣＨ２ＣＯＯＥｔ―ＣＮ―ＯＣＨ３―ＯＣ（＝Ｏ）ＮＨ２―ＮＨ（ＣＨ３）Ｃ（＝Ｏ）ＮＨ２、ハロゲン―ＣＨ２ＮＨＣ（＝Ｏ）ＯＥｔ―ＮＨＳＯ２ＣＨ３―Ｎ（ＳＯ２ＣＨ３）２―ＮＨＣ（＝Ｏ）ＯＣＨ３―ＯＨ―ＣＨ２ＮＨＣ（＝Ｏ）Ｎ（ＣＨ３）２―ＣＨ２ＮＨ２―ＣＨ２ＯＨ―ＣＨ２ＣＨ２ＯＨ―ＳＯ２ＮＨ２―ＮＨＣ（＝Ｏ）ＮＨＣＨ２ＣＯＯＨ―ＣＨ２ＮＨＣＨＯ―ＮＨＣ（＝Ｏ）ＮＨＣＨ２ＣＯＯＥｔ―ＣＯＯＣＨ３―ＣＯＯＥｔ―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）３ＣＯＯＥｔ―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）２ＣＯＯＥｔ―ＮＨ（Ｅｔ）Ｃ（＝Ｏ）ＯＥｔ―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）２ＣＯＯＨ―ＣＨ２ＮＨＳＯ２ＣＨ３―ＯＥｔ―ＮＨＣ（＝Ｏ）ＣＨ２Ｎ（ＣＨ３）２―ＮＨＣ（＝Ｏ）ＮＨ（ＣＨ２）３ＣＯＯＨ―ＮＨＣ（＝Ｏ）ＣＨ２ＮＨ２―ＮＨＣ（＝Ｏ）ＣＨ２ＣＨ２ＮＨ２―ＮＨＣ（＝Ｏ）ＣＨ２ＮＨ（ｔＢｏｃ）―ＯＣＨ２ＣＨ２Ｎ（ＣＨ３）２―ＯＣＨ２ＣＨ２ＯＣＨ３、3′―ニトロ―６―メトキシ・ビフェニル―３―イルメチル、テトラヒドロイミダゾール―２―１上のイル、３―メチルテトラヒドロイミダゾール―２―１―１―イル、ピラゾール―１―イル、

Ｒ１５は、Ｈ、ＮＯ２、ＯＨ、ＮＨ２から選択される、及び―ＮＨＳＯ２ＮＨ２、または、
Ｒ１４とＲ１５は、メチレン・ジオキシを形成する。 Examples of such substituents on phenyl, 5-membered heteroaryl, 6-membered heteroaryl, non-aryl heterocycles composed of several parts of 4-7 or fused bicycles (R1a) are: Can be described by the formula VI:

VI
In any case, R14 is selected from H-CH2NHC (= O) NH2-NHC (= O) NH2-NHC (= O) NHEt-CH3-CH2-CF3-CH2NHC (= O) CH3-NHCH3-NHEt-NH (tBoc ) -CHO-NHC (= O) NHCH2CH2Cl-NHSO2NH2-NHEt-N (CH3) 2-NH2-COOH-C (= O) NH2-CH2C (= O) NH2-CH2COOH-CH2COOEt-CN-OCH3-OC (= O) NH2-NH (CH3) C (= O) NH2, halogen-CH2NHC (= O) OEt-NHSO2CH3-N (SO2CH3) 2-NHC (= O) OCH3-OH-CH2NHC (= O) N (CH3) 2-CH2NH2-CH2OH-CH2CH2OH-SO2NH2-NHC (= O) HCH2COOH-CH2NHCHO-NHC (= O) NHCH2COOEt-COOCH3-COOEt-NHC (= O) NH (CH2) 3COOEt-NHC (= O) NH (CH2) 2COOEt-NH (Et) C (= O) OEt-NHC ( = O) NH (CH2) 2COOH-CH2NHSO2CH3-OEt-NHC (= O) CH2N (CH3) 2-NHC (= O) NH (CH2) 3COOH-NHC (= O) CH2NH2-NHC (= O) CH2CH2NH2-NHC (= O) CH2NH (tBoc) -OCH2CH2N (CH3) 2-OCH2CH2OCH3, 3'-nitro-6-methoxybiphenyl-3-ylmethyl, yl on tetrahydroimidazole-2-1, 3-methyltetrahydroimidazole-2- 1-1-Ile, Razoru-1-yl,

R15 is selected from H, NO2, OH, NH2, and -NHSO2NH2, or
R14 and R15 form methylene dioxy.

  In certain embodiments, R 3 is selected —CH 3 —CH 2 CH 3 —CF 3 —CHF 2 and —CH 2 F. In certain embodiments, R 5 is —F—OH—CH 3 —OCH 3 —CF 3 —CN—NH 2 and —C≡CH selected from H. In certain embodiments, R 7 is —NH 2 —SCH 3, methoxy carbonyl —SOCH 3 —SO 2 CH 3 —OCH 3 —OCF 3 —CN—CF 3 —3 and 4 selected from H, halogen, nitro, acetyl, hydroxyethyl CH2OCH3 and oxa diazole and fused heterocycles in position.

  In certain embodiments of compound I, R5 may be fluoro, H, CN or OH. In certain embodiments of compound I, R3 may be methyl or fluoromethyl. (Fluoromethyl is intended to include CHF2, CH2F and CF3.)

  Except those identified in paragraph [0069], all of the compounds belonging to the parent genus I and its subgenera are effective as PDE4 inhibitors, but not all compounds are new. . In particular, certain well-known species belong to the genus I. However, no usefulness in inhibiting PDE4 was suggested for these species. Upon examination, it can be found that the compound excluded from the claim is patentable to the inventor of this application, which can also find its additional species and genera The inventor is not patentable. In any case, the genus of species exclusion and applicant's claims are to be considered artifacts of patent prosecution and are not intended to reflect the inventor's concept or explanation of those inventions. The present invention, in a constitutional embodiment, is all active compounds of formula I other than those in civilian possession. In particular, literature searches have shown that specific compounds in which R2 is a 5-membered ring heterocycle, M is CH2, R3 is methyl, and X is N, with R1 substituted tetralin. There are known. It is known that R1 is a five-membered ring heterocycle, M is CH2, R3 is methyl, X is N as well as certain compounds, and R2-substituted tetralin.

  In general, the compounds of the invention can be prepared by the methods illustrated in the general reaction scheme, for example under or as described therein. It then uses readily available starting materials, reagents and conventional synthesis procedures.

  Usually a compound of formula I, wherein two biaryl groups are linked by a C—C bond and R2 is a substituted aryl / heteroaryl, suitably functionalized containing the desired function W W may be, for example, CH, N, COH, CF, etc. (Route A, Scheme A1). Generally, via a Suzuki or Stille bond (G1 → G2), the biaryl moiety can be made first. In such cases, Y = halogen or OSO2R (OTf, ONf) and other reagents are R2-B (OR) 2 or R2-SnR3 or vise versa, where R2-halogen is boronate as Y Link to G1 containing / boronic acid or trialkyl tin. When A is a substituent derived from carbon (eg, CH3, CH2OH, CO2R), "CN and the like. These groups change to provide an intermediate G3 in which D is halogen or OTf, ONf or OCOOR ", as the transition metal is guided by the use of the substituent (R1). Catalyzed (for example, Suzuki, Stille or Leek reaction) (carbonates). An alternative route to type G4 compounds is necessary to essentially reverse the order of incorporation of the R1 and R2 fragments. In Scheme A1, as emphasized, route B allows the formation of G6, where the R2 fragment is in the sequence used for the example Suzuki (Stille coupling) (chemistry used for G1-G2). (Similar) led to the later stage.

<< Reaction Process Formula A1 >>

  One can attach R1. And it may be aryl (heterocyclic (aperiodic) aliphatic or any other desired type of function) to the central aromatic ring (Ar) due to the wide anger of class M. The central aromatic ring (Ar) can be a biaryl ring system with an R2 group already attached, or the R2 group can be attached following that of R1. The linker group M may be a linear chain of one or more atoms consisting of C, N, O or S. Linker group M can also consist of functions including but not limited to amides, sulfonamides, sulfones or ketones. It will be apparent to those skilled in the art that many of these illustrated functional groups can be attached in multiple ways (eg, Ar—CH 2 —O—R 1 or Ar—O—CH 2 —R 1). Considering those compounds with M group (eg S or O), the heteroatoms may be initially in the Ar or R1 group. Some examples of how the two groups can be added are nucleophilic substitutions, metal activated joints and nucleophilic substitutions (formula A2). The chemical reactivity of the Ar and R1 groups must of course be taken into account when determining which partners contain linker heteroatoms and which serve as reaction partners. For example, in aromatic ring systems, it is well known that electron-pulling classifies paragraphs, or ortho-leaving groups (eg, halogens) allow the sensitivity of aromatic halogens for nucleophilic substitution. Thus, the Ar1 group containing NO2, CO2R, ketone, CN and others allows the formation of aryl-M-aryl (heteroaryl) intermediates. Linker group M may be subject to further finishing. For example, sulfides can be oxidized to sulfoxides as sulfones and amines can be subject to alkylation or reduced amination. Well known synthetic transformations can be used to create class M (eg, ether amide, sulfonamide, etc.). The functional group positions of the precursors Ar and R1 groups can be used to dictate the nature and type of bond (eg, alternative ether), as described above.

<< Reaction process formula A2 >>

  The key fragments Ar and R1 can also be connected using a non-transition metal catalyzed CC bond forming a coupling reaction. When A = H, Fridle-Crafts acylation or alkylation can be used to combine Ar and R1 groups. Given the chemical reactivity of the aromatic para-methoxy group of the Ar ring, Friedel-Crafts acylation generally includes the following: optimally refined R1-COCl (chlorinated acid to form compound G10 )group. In this case J = CO. And it can be reduced to a second alcohol (generally by a hydride reducing agent). If R′MgX or other such organometallic compound chemicals are used, the J═CO group can be converted to a tertiary alcohol with the simultaneous addition of the R ′ group. In other variations, the addition of R′MgX-type reagents results in tertiary amine derivatives, and the J═CO group can be changed to standard methods using imines or oximes. If necessary, the CH = group (M), the J = CO group can be reduced using a number of established methods. In other variations (where A = H), the aldehyde group uses any Vilsmeier reaction or uses a Lewis acid (TiCl4, BF3.OEt2, etc.) transferred reaction with dichloromethyl methyl. Can be guided. The aldehyde functionality can then be changed to a suitable transition metal catalyzed binding reaction partner. Alternatively, aldehye can be used for the Wittig reaction forming an olefin or CH2CH2 bond to incorporate R1. In yet another variation, the substituent “A” can is various forms of carbonyl (aldehyde or ketone) or imine group. In one example, the optimally refined organometallic compound R1 group (eg R1-MgX) addition to aldehyde G9 (= CHO) results in G10 with J = C (H) OH. This reduction in alcohol causes G11 with M = CH2. When G9 contains A = ketone or imine, similar types of transformations can be used by those skilled in the art.

<< Reaction process formula A3 >>

  Alternatively, the C—C bond forming a reaction between Ar and the R1 group is achieved by substitution of the leaving group on R1 by a nucleophilic atom present in the class region M of G12 (formula G4). Can do. Activated groups can also be removed to provide Z = H (Z = CO2R-decarboxylation, or Z = CN (decyano), or they can be other functional groups (eg, Z = CH2 ) H or CH2NH2. When MZ is CH2-halide or CH2-O-sulfonate, the R1 fragment can be led through the formation of an ether bond. This allows attachment of R1 to the central aromatic ring by spacers (M) that vary in length and composition. (Method A4)

<< Reaction process formula A4 >>

  The R1 group could also be an assembled form of ringing acyclic intermediates or heteroaromatic compounds that form heterocylic. Examples of these chemistries arise from 2-halo-ketones or olefins, including the formation of acyl hydrazides in the form of 5-membered heteroaryls (eg, oxa-diazoles, thia-diazoles, triazoles, G17), G16 Thiazoles from dipolar cycloaddition reactions or groups of acetyls forming 5-membered heterocycles or 5-membered heteroaryls (G18) [Formula A5]. Alternatively, a 6-membered heteroaryl or heterocycle is a Diels-Alder variant using an appropriately substituted alkyl aryl ether functionalized with dienophile or diene—Diels-Alder chemistry Can be formed using. The required aperiodic precursors can be synthesized by standard methods according to the previously described intermediate (eg, aldehyde, alkyl halide) schemes.

<< Reaction process formula A5 >>

  When the R2 group is linked to the Ar group by a heteroatom (N), these biaryl systems can be converted to organometallic mediated aza coupling reactions or other nucleophilic aromatic substitution-based procedures (formula G6 ) Can be prepared. Ar- (N) R2 biaryls can be formed from an intermediate G6 where the R1 group is already suitable. Alternatively, the (N) R2 ring can be first added to the central Ar ring, R1 can be attached by methods using various means described in previous schemes. . Examples of (HN) R2 heteroaryl or heterocycle include, but are not limited to, imidazole, pyrrole, pyrazole, pyrrolidine or triazole. The R2 functional group can be synthesized completely before addition of (N) R2 to Ar, or can be optimally synthesized after formation of the key CN bond.

<< Reaction process formula A6 >>

  The diverse selection of substituents that R1 and R2 can be today has, well-known, formed what standard functional group transformations know in the prior art. Some of these include amide, sulfonamide, urea formation. And oxazolone (carbamate from R2) R3 or Ar is an imido azo alone that rings a fragment carrying the appropriate amine, carboxylic acid, alcohol or phenol group. A particularly useful aromatic ring functionalization technique in which the R2 or R1 ring can be used and is a nucleophilic substitution of an ortho-halo N-containing aromatic ring (G20, Formula A7). Examples of ring substrates useful for this type of transformation include 2-halo-pyridine, 2-halo-pyrimidine and 2-halo-imidazole. In addition, other leaving groups of halogen (X) can be used such as sulfonate esters (OTf, ONf). These substitution reactions can be carried out using alkali or tertiary amine bases, or can be communicated by using organometallic compound reagents (eg, palladium or aluminum reagents). Examples of nucleophilic atoms (R ') useful for this type of transformation can perform amines (primary, secondary, acyclic or periodic), alcohols, phenols, nucleophilic substitutions Including a heterocyclic group (imidazole or pyrrazole) group containing NH.

<< Reaction process formula A7 >>

  The R1 group contains added functional groups (eg amines), in which ester / acid / alcohols can be masked or protected during pre-mass chemistry, these are further Can be used for functional group manipulation. A wide variety of modifications of R1 function can be achieved using established synthetic procedures including, but not limited to, alkylation, reducing amination, nucleophilic substitution, cyclization, saponification and oxidation / reduction. it can. In addition, like these functional group manipulations, the monocyclic Ar1 can be further transformed into a bicyclic ring. Examples of this type of ring transformation can be represented by the finishing of pyridine derivatives to imidazo [1,2-a] pyridine and imidazo [1,5-a] pyridine. These functional group manipulations and bicyclic ring finishes can be achieved at any chemically suitable position in the synthesis or its post incorporation prior to R2 or other synthetic transformations.

  These above transformations can be performed from alkylated phenols containing or lacking a central Ar ring fluoro substituent. Some of these methods can also be applied to 3 alkoxy pyridines as Ar ring starting materials. The non-limiting examples described in later schemes should serve as a wide range of examples of possible reactions. Similarly, these functional groups can be derived and W = CH2OH, COOH, CN, CONH2 etc. (or optimally protected precursors) followed by a similar chemistry (formula A1-A7) Analogs that can be withdrawn form starting materials derived from esters or amides.

The following examples of compounds of the invention were prepared.

  In another embodiment, the present invention forms a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound as described above.

  The methods of the invention correspond to compositions and formulations. The method includes giving a patient in need of treatment a therapeutically effective amount consistent with the synthesis to the present invention. The present invention also provides a method for inhibiting phosphodiesterase 4.

In vitro testing method for PDE4 enzyme. The in vitro activity of the PDE4 enzyme and the in vitro efficacy of the therapeutic agents described in this invention were measured using real time, enzyme linked spectrophotometric analysis. Using three different conjugating enzymes, the product of the PDE4 reaction is a β-nicotinamide adenine dinucleotide (NADH) linked to a shortened form of oxidation, whose dissipation is 340 nM. Can be monitored spectrophotometrically.
Test the explanation. Buffer A containing 50 mM Tris, pH 8.0, 16 mM MgCl 2 and 80 mM KCl is prepared and stored at room temperature. Buffer 8.0 contains 50 mM Tris, pH 8.0 is prepared and stored at toom temperature. Stock solutions of the following reagents are prepared at Buffer B and stored at −20 degrees C: adenosine-5′-triphosphate (ATP), periodic adenosine-5′-monophosphate (cAMP) , Phosphoenolpyruvate (PEP) and NADH. Analytical mixture is prepared by mixing Buffer A, trifluoroethylphosphine (TCEP), ATP, PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate dehydroganese (LDH) and PDE4 in a final 20 mL volume. Is done. And that's enough for a single 96-well assay plate. The test article (10 μL) of 1: 1 DMSO / H 2 O mixture is pre-warmed at room temperature for 10 minutes and the mixture (180 μL) is assayed. The enzyme reaction is initiated by the addition of cAMP (10 μL). All final concentrations with the following components of the analysis (200 μL / well) follow: 10 mM MgCl 2, 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, Appropriate amounts of 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH and PDE4. The reaction progress curve is monitored in a plate reader that can measure low absorbance at 340 nM. The low absorbance decrease of 340 nanometers is due to the oxidation of NADH. Explicit regulations that do not include the test article and negative regulations that do not include the test article and cAMP are included in every assay plate. The reaction rate is determined from the slope of the linear part of the evolution curve. All data are percentages normalized to regulation and shown as percentage suppression.

  Results of testing representative species are shown below in Tables 9 and 10. Operation is A = <5 μM, B = 5-20 μM, C = 20-40 μM.

  In the present invention, the activity of the PDE4 inhibitor that was deprived was also measured using E4 (LTE4) of human whole blood in leukotrienes measuring proactive analysis after Sephadex stimulation. The anti-inflammatory activity of the therapeutic agents of the present invention is demonstrated by inhibition of eosinophil activation as measured by a sephadex bead for stimulated LTE4 production in all human blood. For each sample, 356 microliters of heparinized human whole blood (Vactainer tube # 6480) is added to the wells of a 96-well plate. Then 4 microliters of a series of synthetic diluents (in DMSO) are added in one of the triplicates. The stop can then be mixed and hatched to 37 ° C for 15 minutes with a gentle shake. The blood sample is then stimulated by adding 40 μL Sephadex G-15 beads (Sigma Aldrich, Sweden). Beads are predissolved in PBS (0.16 g / mL PBS). After mixing, the stop is warmed at 37 ° C for 90 minutes. Then 8 μL of 15% EDTA / PBS is added to each sample (centrifuged and mixed for 5 min at 21 x C and 115 x in the supernatant and 115 x in the supernatant). In each plate, 10 clear regulations and 10 negative regulations are used. And DMSO is included instead of the synthesis solution. As described for the sample, clear regulation is stimulated by Sephadex. And with negative regulation (unstimulated), the Sephadex solution is replaced with PBS. The resulting plasma sample's LTE4 level is determined using a commercial enzyme-linked immunoassay (Cayman Chemical, Ann Arbor, MI) according to the manufacturer's instructions. Examples P-050, P-075, P-107, P-113, P-136, P-139, P-140, P-156, P-163, P-168, P-175, P-181, P-187, P-200, P-221, P-222, P-227, P-237, P-239, P-242, P-243, P-250, P-269, P-287, P- 312, P-315, P-318, P-325, P-328, P-330, P-332, P-336, P-337, P-338, P-339, P-342, P-356, P-378, P-382, P-403, P-405, P-409, P-415, P-420 and P-439 all showed an IC50 <1 μM of the previous active analysis, but Example P -358 had> 1 μM, IC50. Those skilled in the art recognize in the prior art that the positive results of the PDE4 model are predictive of therapeutic utility as described above.

  The following specific, non-limiting examples illustrate the synthesis of the compounds of the present invention.

<< General reaction process formula 1 >>

Example 1. Preparation for P-065

  Synthesis of 2-bromo-6-methyl-pyridine-3-ol (I-2, X = Br, Y = CH3): 6-methyl-pyridine-3-ol (I-1, Y = Y of pyridine (15 mL)) To CH3, 5.0 g, 45.82 mmol) bromine (3.66 g, 22.91 mmol) was added. The reaction was stirred at room temperature under N2 for 20 h. The natural reaction mixture was poured into crushed ice water (300 mL). And stirred for 3 h. The combined organic extract was washed with brine and the mixture was extracted with ethyl acetate (5 × 100 mL), dried over Na 2 SO 4, filtered and 2-bromo-6-methyl- as a light yellow solid. Concentrated to yield 6.3 g (73%) of pyridine-3-ol (I-2, X = Br, Y = CH3).

  Synthesis of 2-bromo-3-methoxy-6-methyl-pyridine (I-3, X = Br, Y = R1 = CH3): 2-bromo-6-methyl-pyridine-3-ol (I-2), 6.0 g, 31.91 mmol), and K2CO3 (8.82 g, 63.82 mmol) in acetone (100 mL) was additional MeI (6.79 g, 479.87 mmol). The reaction was stirred at 45 ° C. under N 2 for 20 h. The reaction was cooled to room temperature, passed through a filter and concentrated. The rest as an eluent yielding 2.34 g (36%) of 2-bromo-3-methoxy-6-methyl-pyridine (I-3, X = Br, Y = R1 = CH3) as an off-white solid Purified by silica gel column chromatography with 1: 1 dichloromethane-hexane.

  Synthesis of 3-methoxy-6-methyl-2- (3-trifluoromethyl-phenyl) -pyridine (I-4, Y = R1 = CH3, R2 = CF3): above (1.2 g, 5.94 mmol) To the synthesized 2-bromo-3-methoxy-6-methyl-pyridine, 3trifluoromethylphenylboronic acid (1.69 g, 8.91 mmol), PPh3 (0.31 g, 1.19 mmol), K2CO3 (2.46 g, 17. 82 mmol) and Pd (OAc) 2 (0.13 g, 0.59 mmol) were additional DME (15 mL) and EtOH—H 2 O (1: 1, 6 mL). Ar gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 80 ° C. under Ar for 20 h. H2O and dichloromethane (40 mL each) were added and the reaction was cooled to room temperature and concentrated. The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder is 1.36 g (86 of 3-methoxy-6-methyl-2- (3-trifluoromethyl-phenyl) -pyridine (I-4, Y = R1 = CH3, R2 = CF3) as a light yellow solid. %) Was purified by silica gel column chromatography with 1: 1 dichloromethane-hexane and then dichloromethane.

Synthesis of 6-bromomethyl-3-methoxy-2- (3-trifluoromethyl-phenyl) -pyridine (I-5, R1 = CH3 _, R2 = CF3 _, Y = CH2Br). To the synthesized 3-methoxy-6-methyl-2- (3-trifluoromethyl-phenyl) -pyridine, the above (1.3 g, 4.86 mmol) and CCl4 (25 mL) NBS (1.04 g, 5. 83 mmol) was benzoyl with peroxide (0.12 g, 0.49 mmol) added. The reaction was stirred at 80 ° C. under N 2 for 20 h. The reaction was cooled to room temperature and concentrated. The remainder is dissolved in a mixture of dichloromethane and hexane (1: 1, 8 mL) to produce 0-bromomethyl-3-methoxy-2- (3-trifluoromethyl-phenyl) -pyridine as an off-white solid. Purified by silica gel column chromatography with 1: 1 dichloromethane-hexane to yield .74 g (44%).

Synthesis of 6- (4-fluoro-benzyl) -3-methoxy-2- (3-trifluoromethyl-phenyl) -pyridine (P-065): synthesized above (0.2 g, 0.58 mmol) 6 -Bromomethyl-3-methoxy-2- (3-trifluoromethyl-phenyl) -pyridine and 4-fluorophenylboronic acid (0.12 g, 0.87 mmol), PPh3 (0.03 g, 0.12 mmol), K3PO4 (0. 37 g, 1.73 mmol) and Pd (OAc) 2 (0.013 g, 0.058 mmol) were additional DME (4.0 mL) and EtOH—H 2 O (1: 1, 1.0 mL). The reaction was stirred at 80 ° C. for 20 h. The reaction was cooled to room temperature (concentrated). The remainder yields 0.056 g (22%) of 6- (4-fluoro-benzyl) -3-methoxy-2- (3-trifluoromethyl-phenyl) -pyridine (P-065) as a clear mucus. For this purpose, it was purified by silica gel column chromatography using 1: 1 dichloromethane-hexane and then dichloromethane. ¹ H NMR (CDCl ₃ , 400 MHz): 8.24 (s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.6-7.64 (m, 1 H), 7.52-7.65 (m, 1 H ), 7.2-7.34 (m, 4 H), 6.96-7.05 (m, 2 H), 4.14 (s, 2 H), 3.85 (s, 3 H); MS (APCI +): 362.1 (M + 1), LC-MS: 97.2%

The following compounds were prepared as per general reaction scheme 1. And it was similar to the preparation of P-065.

実施例２。Ｐ―１７６の準備。

<< General reaction process formula 2 >>

Example 2. Preparation for P-176.

Synthesis of 2-bromo-3-nitrophenol (I-8, X = Br): (provided by a modification of the reported procedure (J. Org). Chemistry 1988, 53, pp 1170-1176). At reflux, 13 mL of HBr (48% water) was added to 2-amino-3-nitrophenol (24.9 mmol, formula of 1.0) with 24 mL of water and 12 mL of 1,4-dioxane. 10 minutes or more. The resulting solution was refluxed for an additional 15 minutes to cool 0-5 ° C. In a solution of sodium nitrite (24.4 mmol, 0.98 formula), 20 mL of water was added over 10 minutes and stirred for 15 minutes. The reaction mixture was then heated to 60 ° C. for 15 minutes, allowed to cool naturally to room temperature and stirred for 16 hours. The reaction mixture was then extracted with two portions of diethyl ether, and the composite ether layer was washed with brine, dried over magnesium sulfate, and the celite layer was filtered and concentrated. The remainder is diluted with dichloromethane (by 0.1% MeOH) to produce 2-bromo-3-nitrophenol (I-8, X = Br) as a pale orange-brown solid. Purified via silica gel plug filtration with dichloromethane. Yield: 50% ^{. 1} H NMR (400 MHz; CDCl ₃ ): 6.07 (s, 1H), 7.25 (dd, J = 8.4, 1.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.0, 1.6 Hz, 1H) ppm.

Synthesis of 2-bromo-3-nitro-anisole (I-9, X = Br, R1 = CH3): of 2-bromo-3-nitrophenol synthesized above (11.5 mmol, 1.0 formula) In solution, the resulting mixture was stirred at room temperature for 16 hours and DMF was added at room temperature with added cesium carbonate (13.8 mmol, formula of 1.2) (iodo methane (33.7 mmol, 2 .9 formula) followed). The cake was washed with two parts of water, the reaction mixture was filtered and poured into water (stirred for 2 hours), and the resulting solid was 2-bromo-3- Dry to yield nitro-anisole (I-9, X = Br, R1 = CH3). Yield: 97%; ¹ H NMR (400 MHz; CDCl ₃ ): 3.97 (s, 3H), 7.07 (dd, J = 8.4, 1.2 Hz, 1H), 7.32 (dd, J = 8.0, 1.6 Hz, 1H ), 7.40 (t, J = 8.0 Hz, 1H) ppm.

Synthesis of 2-bromo-3 methoxy aniline (I-10, X = Br, R1 = CH3): (provided by a modification of the reported procedure WO Patent: WO 2006/7700). Glacial acetic acid was added to the solution of 2-bromo-3-nitro-anisole synthesized above (10.3 mmol, 1.0 formula) at room temperature and powdered (42.1 mmol, 4 .1eq) is covered with iron. The resulting mixture was heated to reflux for 1.5 hours and cooled to room temperature. The reaction mixture was diluted with water and solid sodium carbonate was added until the pH was 6-7. Dichloromethane was added and the mixture was filtered through celite. The dry (sodium sulfate) organic fertilizer was concentrated because there was room to have 2-bromo-3 methoxy aniline (I-10, X = Br, R1 = CH3) as an oil. Yield: 90%; ¹ H NMR (400 MHz; CDCl ₃ ): 3.87 (s, 3H), 4.16 (br s, 2H), 6.31 (dd, J = 8.0, 1.2 Hz, 1H), 6.42 (dt, J = 8.0, 0.8, 0.4 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H) ppm.

Synthesis of 2-amino-3-bromo-4methoxyphenyl)-(4-fluoro-phenyl) -methanone (I-11, X = Br, Y = NH2, R1 = CH3, R2 = 4-fluorophenyl) : To a solution of boron trichloride (1.0 M of heptane, 10.0 mmol, 1.1 formula) a solution of 2-bromo-3 methoxy aniline synthesized above at 0 ° C. of tetrachloroethane was added (9 .09 mmol, one formula) in tetrachloroethane over 1 min. The resulting mixture was stirred at the same temperature for 10 minutes and to it was added a solution of 4-fluorobenzonitrile (18.2 mmol, 2 formulas) tetrachloroethane and aluminum chloride (10.0 mmol). 1.1 formula). The reaction was heated to 110 ° C. for 5 hours, cooled to room temperature and allowed to stir for 16 hours. The reaction mixture was added 10 mL of 3N HCl and the resulting mixture was heated to 90 ° C. for 1 hour and cooled to room temperature. The pH was adjusted with 6N NaOH to 11-12 and extracted with dichloromethane. The organic fertilizer was washed with brine solution, dried over magnesium sulfate and filtered. The filtered water was concentrated and the remaining 65% yield. 2-amino-3-bromo-4methoxyphenyl)-(4-fluoro-phenyl) -methanone (I-11, X = Br, Y = NH2, R1 = CH3, R2 = 4-fluorophenyl) Purified via silica gel chromatography using 10% hexane in dichloromethane as the eluent produced: ¹ H NMR (400 MHz; CDCl ₃ ): 3.95 (s, 3H), 6.25 (d, J = 8.8 Hz, 1H), 6.85 (br s, 2H), 7.11-7.16 (M, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.60-7.64 (m, 2H) ppm.

Synthesis of 2-bromo-6- (4-fluoro-benzyl) -3methoxyaniline (I-12, X = Br, Y = NH2, R1 = CH3, R2 = 4-fluorophenyl): tri-fluoroacetic acid To the solution of (21.6 mmol, formula of 10) -15 degree dichloromethane, C was added in partial sodium borohydride (8.06 mmol, formula 3.7)
While maintaining the internal bath temperature between -15 ° C and -20 ° C, the reaction mixture was able to heat to 0-5 ° C and the above ketone solution (caution, strong gas evolution) ( 2.16 mmol, 1.0 eq), dichloromethane was added over approximately 5 minutes. The resulting mixture could be stirred for 16 hours at room temperature and quenched with 5% water. Extracted with ethyl acetate and NaHCO3. The composite organic fertilizer was washed with water (brine), dried over magnesium sulfate and concentrated. The rest was taken up in THF and treated with BH3 * THF (15 mmol) at room temperature for 1 hour (TLC analysis showed a hybrid of starting ketone and the desired methylene product). Excess borane was quenched with methanol and mixing was concentrated. Three more portions of methanol were added and mixing was concentrated. The rest is 40% yield. As an eluent to give 2-bromo-6- (4-fluoro-benzyl) -3methoxyaniline (I-12, X = Br, Y = NH2, R1 = CH3, R2 = 4-fluorophenyl) Purified via flash chromatography on silica gel using 1: 1 dichloromethane-hexane: ¹ H NMR (400 MHz; CDCl ₃ ): 3.86 (s, 2H), 3.87 (s, 3H), 4.07 ( br s, 2H), 6.33 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.98 (ddd, J = 8.8, 8.4, 2.0 Hz, 2H), 7.12 (ddd, J = 8.0, 6.4, 1.0 Hz, 2H) ppm.

Synthesis of 3- (4-fluoro-benzyl) -6-methoxy-3'-nitro-biphenyl-2-ylamine (P-176): 2-bromo-6- (4-fluoro-benzyl) -3 methoxy aniline Hybridization of the above synthesized (0.403 mmol, formula 1.0), 4 fluorophenylboronic acid (0.605 mmol, 1.5 eq), and dioxane K2CO3 (650 mL, 3.2 eq) and tetrakis (triphenylphosphine). ) Palladium added, 10 minutes, 2M degassed with nitrogen and resulting mixture degassed for an additional 5 minutes. The reaction was stirred at 70 ° C. for 16 hours and cooled to room temperature. The reaction was diluted with water and extracted with two portions of ethyl acetate. The composite organic fertilizer was dried over magnesium sulfate and washed with three parts of water (brine) to filter celite. The rest is 46% yield. Flash on silica gel using 20% acetone in hexane as eluent to give 3- (4-fluoro-benzyl) -6-methoxy-3'-nitro-biphenyl-2-ylamine (P-176) Purified via chromatography; ¹ H NMR (400 MHz; CDCl ₃ ): 3.70 (s, 3H), 3.86 (s, 2H), 6.42 (d, J = 8.4 Hz, 1H), 6.97-7.02 (m , 2H), 7.04 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 5.2, 3.2 Hz, 2H), 7.60-7.67 (m, 2H), 8.18-8.20 (m, 2H) ppm; LC / MS (86.9%); (ESI +): Found 353.6 (M + 1), Calcd 352.4 m / z.

実施例３。Ｐ―４０４の準備。

<< General reaction process formula 3 >>

Example 3. Preparation for P-404.

  Integration of three '-chloro-6-fluoro-2 methoxy biphenyls (I-16, R1 = CH3, R2 = Cl, Y = F): 2-bromo-3-fluoroanisole (1.0 g, 4. 88 mmol), 3 chlorophenyl bromic acid (0.91 g, 5.88 mmol), PPh3 (0.64 g, 2.44 mmol), K2CO3 (0.27 g, 1.95 mmol) and Pd (OAc) to 2 (0.13 g 0.58 mmol) was added dioxane (8 mL) and EtOH—H 2 O (1: 1, 4 mL). Ar gas was bubbled by the stirred reaction for 5 minutes. The reaction was heated in a microwave oven (Biotage Initiator II) using 180 oC for 20 minutes. The reaction was cooled to room temperature (moved and combined with an additional 0.5 g scale concentrated). The remainder is 1 to give 1.33 g (77%) as mucus three '-chloro-6-fluoro-2methoxy biphenyls (I-16, R1 = CH3, R2 = Cl, Y = F). Purified by silica gel column chromatography using 1: dichloromethane-hexane.

  N- [4- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl) -phenyl] -acetamide (I-19, R1 = CH3, R2 = Cl, Y = F, R3 = 4 Synthesis of —acetylamino phenyl): To a stirred suspension of 4-acetylaminobenzoic acid (old rich, 1.32 g, 5.58 mmol) in anhydrous THF (20 mL) was added SOCl 2 (1.19 g, 10 .04 mmol) and DMF (4 drops) were added. The reaction mixture was stirred at room temperature for 3 h. It was concentrated under vacuum because there was room to have chloride (I-18, R3 = 4-acetylamino phenyl) 4-acetylamino benzoyl as a light yellow solid.

  To a stirred solution of nitrobenzene (12 mL) was added wise AlCl3 (2.23 g, 16.73 mmol) over 10 minutes and the solution was stirred at room temperature for 20 minutes. The solution of 4-acetylamino benzoyl chloride synthesized above (1.32 g, 5.58 mmol) in dichloromethane (4 mL) was an additional part up to the reaction mixture. And it stirred for 72 hours. The reaction mixture was poured into crushed ice water (250 mL) (Extracted with dichloromethane (2 × 60 mL)). The combined organic layer was washed with brine (60 mL), dried (Na 2 SO 4), passed through a filter and then 1.97 g (89%) of N- [4- (3 as a light brown solid. '-Chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl) -phenyl] -acetamide (I-19, R1 = CH3, R2 = Cl, Y = F, R3 = 4-acetylamino phenyl) To yield, it was purified by silica gel column chromatography using dichloromethane and then 3% methanol-dichloromethane.

  Synthesis of hydrochloric acid (I-19, R3 = 4-aminophenyl) (4-amino-phenyl)-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanone. To the stirred suspension of the synthesized N- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl) -phenyl] -acetamide, ethanol (40 mL) above (1.75 g) was added. 4.44 mmol) was an additional con. HCl (40 mL). The reaction was filtered and 0.82 g of hydrochloric acid (4-amino-phenyl)-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanone as a light yellow solid ( 48%) was washed with water from hexane and refluxed for 2 h (cooled to room temperature).

  Synthesis of (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl) -methanone: glacial acetic acid (10 mL) in sodium azide (0.2 g , 3.06 mmol) was added trimethyl orthoformate (0.32 g, 3.06 mmol) and (4-amino-phenyl)-(3′-chloro-2-fluoro-6-methoxy-biphenyl) To the stirred suspension of -3-yl) -methanone, the hydrochloride was synthesized above (0.4 g, 1.02 mmol). Rather than being basified by ammonium hydroxide solution (28%), the reaction was stirred at room temperature for 3 h (diluted with cold water (60 mL)). Extracted with dichloromethane (2 × 40 mL), the combined dichloromethane solution was washed with brine (40 ml), dried over Na 2 SO 4, filtered and (3′-chloro-2- Concentrated to yield 0.38 g (90%) of fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl) -methanone.

Synthesis of 1- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -1H-tetrazole (P-404): synthesized (3′-chloro-2 To -fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl) -methanone, the above (0.1 g, 0.24 mmol) of TFA (1.5 mL) was added Triethylsilane (0.28 g, 2.4 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was basified with ammonium hydroxide solution (28%), filtered and 1- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-] as an off-white solid. ylmethyl) -phenyl] -1H-tetrazole (P-404) was washed with dry water to yield 0.08 g (81%) and cooled to 0 ° C. (diluted with water (3 mL)). ¹ H NMR (DMSO-d ₆ , 400 MHz): 7.2- 7.4 (m, 6 H), 7.04-7.12 (s, 3 H), 6.7 (d, J = 8.4 Hz, 1 H), 3.95 (s, 2 H), 3.77 (s, 3 H) ppm; MS (APCI +): 365.1 (M-28), LC-MS: 95.9%.

The following compounds were prepared by incorporation of various R3 groups similar to the preparation of P-404.

<< General reaction process formula 4 >>

実施例４。Ｐ―４４３の準備。 << General reaction process formula 5 >>

Example 4. Preparation for P-443.

  Synthesis of 3-bromo-2-fluoro-4methoxybenzaldehyde (I-30). In a three-necked 250 mL round bottom flask equipped with nitrogen lines and agitation, the rod was placed 2-bromo-1-fluoro-3-methoxybenzene (I-29, 2.0 g, 9.75 mmol) and dichloromethane (48 mL). The solution was cooled in an ice-water bath for 15 minutes and the reaction mixture was allowed to react for 2 hours with heating to room temperature and titanium tetrachloride (5.02 mL, 45.8 mmol) and dichloro • Methyl methyl ether (1.32 mL, 14.6 mmol) was added. The reaction mixture was slowly added to ice water (250 mL) and extracted with dichloromethane (2 × 100 mL). Washed with saturated sodium bicarbonate solution (75 mL), water (75 mL) and brine (75 mL), dried (MgSO4), concentrated and the organic portion combined. The crude material was powdered with hexane (15 mL) to produce 1.67 g of 3-bromo-2-fluoro-4methoxybenzaldehyde (I-30) as a 74% off-white solid. It was. MS (ESI +): 233.2 (M +)

  Synthesis of (3-bromo-2-fluoro-4methoxyphenyl) -methanol (I-31). In a 100 mL round bottomed flask equipped with agitation, the rod is placed in 3-bromo-2-fluoro-4 methoxybenzaldehyde (I-30, 1.67 g, 7.17 mmol), methanol ( 12 mL), dichloromethane (12 mL) and sodium borohydride. The reaction mixture could be stirred at room temperature for 17 hours, quenched with water (10 mL) and 1M HCl (5 mL) and extracted with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was triturated with hexane (15 mL) to yield 955 mg (57%) of (3-bromo-2-fluoro-4methoxyphenyl) -methanol (I-31) as a white solid.

  Synthesis of (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanol (I-32). To a 100 mL round bottom flask was added additional (3-bromo-2-fluoro-4methoxyphenyl) -methanol (I-31, 1.04 g, 4.0 mmol) (3-chlorophenylboronic acid (0.76 g, 4.8 mmol) was Pd (PPh3) 4 (0.45 g, 0.41 mmol) (Na2CO3 (6 mL, 2 M aq) (toluene), 32 mL) and EtOH, 11 mL. And then stirred for 24 hours at 80 ° C. The product was extracted with ethyl acetate and water was added.The combined organic fertilizer was concentrated and 50% ethyl acetate / hexane was added. Filtered to an eluting SiO2 plug, the solid was triturated with ether and passed through a filter. The filtered water was concentrated, triturated with ether and filtered, and the filter cake was obtained as a white solid (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl). ) -Combined and purified by flash column chromatography eluting with acetone / hexanes by 20% to give methanol (I-32, 0.79 g, 67%).

  Integration of 3-bromomethyl-3'-chloro-2-fluoro-6 methoxy biphenyl (I-33). In a 250 mL circle, the bottom flask is synthesized above (1.21 g, 4.54 mmol) and additional (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanol, dichloromethane (20 mL), PPh3 (1.19 g, 4.54 mmol) and the solution was cooled to 0 ° C. The reaction was stirred at 0 ° C. for 2 h and NBS (0.81 g, 4.54 mmol) was added. The organic fertilizer was washed and concentrated with H2O. The remainder is eluted with ethyl acetate / hexane by 8% to give 3-bromomethyl-3'-chloro-2-fluoro-6methoxybiphenyl (I-33, 956 mg, 64%) as an off-white solid. Purified by flash column chromatography.

  Synthesis of 3'-chloro-2-fluoro-6-methoxy-3- (4-nitro-benzyl) -biphenyl (I-34). In a 40 mL vial equipped with a stir bar, 3-bromomethyl-3′-chloro-2-fluoro-6 methoxy biphenyl (I-33, 400 mg, 1.21 mmol) (exposed phenyl bromic acid (420 mg, 1 .45 mmol), potassium phosphate (tribasic) (514 mg, 2.42 mmol), dimethoxyethane, 3.5 mL) and 50% aqueous ethanol, 3.5 mL were deployed. After removing gas from the minutes by nitrogen for 15, tetrakis (tri-phenyl-phosphine) palladium (0) (140 mg, 0.121 mmol) was added. The mixture was heated to 60 ° C. for 18 hours and the palladium catalyst was removed by filtering the celite. To the filtered water, water (50 mL) and saturated ammonium chloride solution (50 mL) were added. After extracting acetate (3 × 50 mL) with ethyl, the organic portions were combined, washed with brine (75 mL), dried (MgSO 4) and concentrated. The crude material was 20% as eluent to yield 342 mg (76%) of 3′-chloro-2-fluoro-6-methoxy-3- (4-nitro-benzyl) -biphenyl (I-34) as a yellow solid. Of silica gel using ethyl acetate / hexane. MS (APCI): 370.1 (M-1).

  Synthesis of 4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenylamine (I-35): In an 18 mL vial with stirring, the rod was placed Iron powder (179 mg, 3.20 mmol), ethanol (5.0 mL) and water (1.2 mL). The mixture was heated to 85 ° C in an oil bath and the reaction was continued at 85 ° C for 2 hours and the product 3'-chloro-2-fluoro-6-methoxy-3- (4- Nitro-benzyl) -biphenyl (6) (340 mg, 0.914 mmol) was added. The reaction mixture was cooled to room temperature and filtered through celite. Extraction was performed with ethyl acetate (2 × 60 mL) and to the filtered water was added water (50 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and 245 mg of 4- (3'-chloro-2 as a yellow, viscous oil in 79% yield. Concentrated to yield -fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenylamine (I-35). MS (APCI +): 342.0 (M + 1).

Synthesis of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -thiazol-2-yl-amine. (P-443): In an 8 mL vial with agitation, the stick is placed 4- (3′-chloro-2-fluoro-6-methoxy-) synthesized above (100 mg, 0.293 mmol) Biphenyl-3-ylmethyl) -phenylamine (I-35), 2-bromothiazole (52.1 μL, 0.585 mmol), 10% aqueous ethanol (1.5 mL) and concentrated hydrochloric acid (48.8 μL, 0 .585 mmol). The mixture was heated to 90 ° C. for 18 hours and cooled to room temperature. After water (30 mL) and 5% aqueous potassium carbonate (30 mL) were added, the water-like portion was withdrawn with ethyl acetate (2 × 35 mL) and the organic portions were combined to give brine (30 mL ) Washed, dried (magnesium sulfate) and concentrated. The crude material is 3% acetone / as eluent to yield 57 mg of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -thiazol-2-yl-amine. Purified by column chromatography using dichloromethane. As a white solid, 45% yield in (P-443). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.75 (s, 3 H), 3.94 (s, 2 H), 6.62 (d, J = 4 Hz, 1 H), 6.70 (dd, J = 8, 1 Hz , 1 H), 7.10 (t, J = 9 Hz, 1 H), 7.20-7.22 (m, 2 H), 7.26-7.40 (m, 8 H) ppm; MS (APCI +): 425.0 (M + 1) , LC-MS: 89%
Example 5. Preparation for P-238.

Synthesis of N- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -2-dimethylamino-acetamide (P-238). In an 8 ml vial, 4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenylamine (I-35) (70 mg, 0.2 mmol, HCl salt) ( EDCI (80 mg, 0.4 mmol, two formulas), HOBt (41 mg, 0.3 mmol, 1 formula, N, N-dimethyl glycine / HCl salt (31 mg, 0.3 mmol, 1.5 formula) .5 formula), Et3N (0.2 ml, 1.43 mmol, 5.3 formula), N, N-dimethyl foraminifera sugar (2 ml) The resulting mixture was stirred at rt overnight. Was poured into water and extracted with EtOAc, evaporation of the solvent gave a residue, which used silica gel in methanol (33: 1) as the eluent to convey the free base product Was purified by chromatography on dichloromethane, which was converted to the HCl salt by treating etheric HCl with 2N, 65 mg of N- [4- (3′-chloro-) as 75% HCl salt. 2-Fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -2-dimethylamino-acetamide (P-238) yields ¹ H NMR (CDCl ₃ , 400 MHz): 9.04 (br s, 1 H), 7.46-7.52 (m, 2 H), 7.37-7.43 (m, 1 H), 7.24-7.36 (m, 3 H), 7.14-7.23 (m, 2 H), 7.01-7.12 (m, 1 H), 6.64-6.74 (m, 1 H), 3.86-3.98 (m, 2 H), 3.73 (s, 3 H), 3.05 (s, 2 H), 2.36 (s, 6 H) ppm; LCMS : 96%.
Example 6. Preparation for P-243.

Synthesis of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-243). 4- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenylamine (I-35) (100 mg, 0.26 mmol, one formula) (cyanic acid (74 mg, 0. 52 mmol, 2 formulas) sodium) mixed water (1 ml) was sonicated and with HOAc (1 ml), rt was then shaken at rt for 20 min overnight. The mixture was diluted with water. The precipitate was collected by filtration and washed with water. After drying, the product (probably the corresponding acetamide) gave 71 mg of crude product containing fewer polar lines. Trituration of the crude product with acetone / hexanes yielded 56 mg of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] as a white solid in 56% yield. -Urea (P-243) was given. 1H of ^{NMR (DMSO-d6,400MHz): 1} H NMR (DMSO-d 6, 400 MHz): 8.42 (s, 1 H), 7.40 - 7.47 (m, 2 H), 7.36 (m, 1H), 7.23 -7.32 (m, 4 H), 7.07 (m, 2 H), 6.92 (m, 1 H), 5.76 (s, 2 H), 3.83 (s, 2 H), 3.72 (s, 3 H) ppm.

実施例７。Ｐ―２５２の準備 << Reaction process formula 6 >>

Example 7. Preparation for P-252

Integration of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-ylamine P-252. A solution of N, N-dimethylformamide (8 mL) of I-145 (1.20 g, 3.70 mmol) and 2-aminopyridine-5 boronic acidic pinacol ester (894 mg, 4.06 mmol) uses a 10 minute stream of nitrogen. The gas was removed. The stop was stirred at 65 ° C. under nitrogen for 15 h and the solution was potassium carbonate (1.54 g, 11.1 mmol), allyl palladium (II) chloride dimer under nitrogen. (203 mg, 0.555 mmol) and bis (phenylphosphino) pentane (489 mg, 1.11 mmol) were added. To the reaction was added ethyl acetate (50 mL) and water (50 mL) and biphasic filtration were filtered through celite (˜15 g). Celite was washed with ethyl acetate (2 × 20 mL) and water (2 × 20 mL) and filtered water were cut off. The organic extracts were combined and the aqueous layer was extracted with ethyl acetate (100 mL). Brine (200 mL) (dried over sodium sulfate) was filtered and the organic solution was washed with water (200 mL) and the solvent was removed under vacuum. The remainder was filtered and washed with hexane (5 mL) and diethyl ether (2 mL) to give P-252 as a beige powder (190 mg, 15% yield) and flash silica gel column chromatography (dichloromethane Of 10-33% acetone (powdered in diethyl ether (5 mL)). ¹ H NMR (400 MHz, CDCl ₃ ): 7.97 (d, J = 2.4 Hz, 1H), 7.39-7.27 (m, 5H), 7.07 (t, J = 8.6 Hz, 1H), 6.69 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 4.32 (s, 2H), 3.82 (s, 2H), 3.75 (s, 3H) ppm. LCMS = 96.6% purity. MS (APCI +) = 343.0 (M + 1).
Example 8. Preparation for P-258.

Synthesis of N- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methanesulfonamide (P-258). To a solution of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylamine (P-252) to be synthesized, pyridine (2 ml) above (70 mg, 0 .18 mmol) was stirred with methanesulfonyl chloride (23 mg, 0.20 mmol) at 0 C under nitrogen at room temperature for 20 h. The reaction mixture was diluted with water, neutralized with 6N HCl, extracted with ethyl acetate, washed with water and brine, and dried over Na 2 SO 4. After it was concentrated in vacuo, the rest was N- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methanesulfoamide (P— 258) (25 mg, 32%) was purified by chromatography on silica gel. ¹ H NMR (400 MHz, CDCl ₃ ) 8.15 (s, 1 H), 7.58 (dd, J = 8.8, 2.1 Hz, 1 H), 7.38 (s, 1 H), 7.34 (t, J = 6.6 Hz, 3 H), 7.24-7.31 (m, 2 H), 7.11 (t, J = 8.5 Hz, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 3.89 (s, 2 H), 3.77 ( s, 3 H), 3.09 (s, 3 H) ppm.
Example 9. Preparation for P-429.

  Synthesis of 6- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester (I-37). To a 20 mL vial with agitation, a stick is added with additional 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-ylamine (P-252, 565 mg, 1 .65 mmol), ethyl bromopyruvate (0.52 mL, 4.12 mmol) and 5 mL DME. The reaction was stirred at room temperature for 18 hours and basified with NaHCO3 (water sat). The product was extracted with ethyl acetate and concentrated. Purification by flash column chromatography (5% acetone / dichloromethane) was obtained as an off-white solid with 6- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,2- a] Pyridine-2-carboxylic acid ethyl ester (I-37) (198 mg, 27%) provided a tan solid that was triturated with ether.

Synthesis of 6- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,2-a] pyridine-2-carboxylic acid amide (P-429). In an 8 mL vial, 6- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo synthesized with ethyl ester (I-37) above (37 mg, 0.084 mmol) [ 1,2-a] pyridine-2-carboxylic acid and 2 mL of 7N NH3 / MeOH were added. After stirring at 60 ° C for 20 hours, the reaction was concentrated. Grinding with ether yields 6- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,2-a] pyridine-2-carboxylic acid amide (P- 429) (24.5 mg, 71%) was formed. 1H-NMR (400 MHz, DMSO-d6): ¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.42 (s, 1H), 8.30 (s, 1H), 7.64 (br s, 1H), 7.53 (d , J = 4.6 Hz, 1H), 7.42 (m, 5H), 7.30 (m, 1H), 7.23 (dd, 1H, J = 9.6, 1.6 Hz), 6.97 (d, 1H), 8.4 Hz), 3.95 ( s, 2H), 3.74 (s, 3H) ppm. LC / MS = 83.4%, 410.0 (APCI +).
Example 10. Preparation for P-456.

Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456). The flask was made of 3-bromomethyl-3′-chloro-2-fluoro-6methoxybiphenyl (I-32, 3.3 g, 10 mmol), 2-fluoro-pyridine-5 boronic acid (1.4 g, 10 mmol), toluene (40 mL) 2 M water was entrusted. Na2CO3 (10 mL, 20 mmol), ethanol (10 mL) and Pd (PPh3) ₄ (577 mg, 0.5 mmol). The reaction mixture was bubbled with nitrogen gas for 5 minutes. The yellow reaction mixture was then stirred at 80 ° C. After stirring overnight, the reaction mixture was cooled to room temperature and concentrated in vacuo. The remainder was diluted in EtOAc (20 mL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo. Crude oil was purified by silica gel column chromatography. And 3.23 g (93% yield) of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456) as a colorless solid Was extracted with hexane / EtOAc (9: 1) to yield ¹ H NMR (400 MHz, DMSO-d ₆ ) 3.73 (s, 3 H), 3.98 (s, 2 H), 6.95 (d, J = 8.6 Hz, 1 H), 7.11 (dd, J = 8.4, 2.8 Hz, 1 H), 7.25-7.51 (m, 5 H), 7.82 (td, J = 8.2, 2.4 Hz, 1 H), 8.14 (s, 1 H), 8.32 (s, 1 H) ppm.
Example 11. Preparation for P-446.

Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid (P-446). The vial was entrusted with D, L-azetidine-2-carboxylic acid (56 mg, 0.56 mmol) and DMF (1 mL). Then NaH (mineral oil, 33 mg, 0.84 mmol of 60% dispersion) was added slowly (gas evolution). After stirring for 2 minutes at room temperature, 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456) was added. The heterogeneous white reaction mixture was stirred at 120 ° C. and heated. After stirring overnight, the reaction mixture was cooled to rt and diluted in EtOAc (5 mL). The mixture was injected into a separatory chimney with 0.5M HCl (1 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine (15 mL), dried over Na 2 SO 4 and concentrated in vacuo. Crude oil was purified by silica gel column chromatography. As a cream solid, 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid (P-446) Withdrawn with methanol (9: 1) in dichloromethane to yield 7.7 mg (6% yield).
Example 12. Preparation for P-445.

  Synthesis of N- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -oxalamic acid ethyl ester (I-40). To 20 mL, the vial was added [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid ethyl ester (P-367) (152 mg 0.43 mmol), dichloromethane (4 mL), TEA (0.11 mL, 0.85 mmol). Ethyl chloro oxoacetate (71 uL, 0.64 mmol) was added and the solution was cooled to 0 ° C. After 20 minutes at room temperature, the organic solution was washed with H2O and brine and concentrated. Ethyl acetate was added to the rest. And it gave a solid and was filtered. The solid is triturated with ether to give N- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -oxalamic as a gray blue solid The acid was dried to give the ethyl ester (I-40) (69 mg, 35%).

  Synthesis of 6- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,5-a] pyridine-3-carboxylic acid ethyl ester (I-41). To a 4 mL vial was added the above compound (12) (44 mg, 0.096 mmol) (dichloromethane (1 mL), pyridine (31 uL, 0.48 mmol) and POCl3 (13 uL, 0.14 mmol). Stirred for 18 hours and H 2 O was added The product was extracted with dichloromethane and concentrated using 20% acetone / hexane purifying extraction. FCC is a 6- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,5-a] pyridine-3-carboxylic acid as an tan solid. I-41) A yellow semi-solid powdered with hexane to give (8.2 mg, 19%) It was.

Synthesis of 6- (3′-chloro-2fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,5-a] pyridine-3-carboxylic acid amide (P-445). To a 4 mL vial, I-41 (7 mg, 0.016 mmol) and 2 mL of 7N NH3 / MeOH were added. The reaction was stirred at 60 ° C. for 18 hours and 6- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -imidazo [1,5-a] as a tan solid Concentrated to give amide (P-445) (6.6 mg, 99%) to pyridine-3-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.29 (s, 1 H), 7.82 (br s, 1 H), 7.71 (d, J = 9.3 Hz, 1 H), 7.52 (s, 1 H), 7.49-7.33 (m, 5 H), 7.33-7.26 (m, 1 H), 6.95 (s, 2 H), 3.97 (s, 2 H), 3.74 (s, 3 H) ppm. LC / MS = 88.6 %, 410.0 (APCI +).

実施例１３。Ｐ―３７８の準備 << Reaction process formula 7 >>

Example 13. Preparation for P-378

  Synthesis of [4- (3-Bromo-4methoxybenzyl) -phenyl] -urea (I-44). Up to 40 mL vials equipped with Teflon screw caps and magnetic stir bar were added 2-bromo-4-bromomethyl-1-methoxybenzene (649 mg, 2.32 mmol), [4- (4,4,5,5 -Tetramethyl- [1,3,2] dioxabolan-2-yl) -phenyl] -urea (577 mg, 2.20 mmol) and potassium phosphate (933 mg, 4.40 mmol). Dimethoxyethane (15 mL) (ethanol, 3.7 mL) and water, 3.7 mL were then added to the vial. The solution was degassed by bubbling N2 gas with a 20 minute solution, and to this the active solution was added tetrakis (triphenylphosphine) palladium (127 mg, 0.11 mmol). The vial was capped and placed in an oil bath for stirring at 65 ° C. for 12.5 h. The cooled reaction mixture was concentrated under a flow of N2 gas to a total volume of 5 mL, then diluted with ethyl acetate (20 mL) and water (10 mL). Upon shaking, a white solid precipitates immediately. The solid is passed through a filter and dried to yield 272 mg (34%) of [4- (3-bromo-4methoxybenzyl) -phenyl] -urea (I-44) as a white solid.

Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-378). In a 20 mL vial with a screw cap added and equipped with a magnetic stir bar, [4- (3-Bromo-4methoxybenzyl) -phenyl] -urea (I-44) was added to the above compound (250 mg, 0.746 mmol), dimethoxyethane (5 mL), ethanol (1 mL) and water (1 mL) were combined. To this mixture was added 3 chlorophenyl bromate (140 mg, 0.895 mmol), potassium phosphate (316 mg, 1.49 mmol) and tetrakis (triphenylphosphine) palladium (30 mg, 0.0254 mmol). The active reaction mixture was degassed by bubbling N2 gas with a 10 minute solution. The vial was covered and placed in an oil bath for stirring at 80 ° C. for 16 h. The cooled reaction mixture was concentrated on drying. It was then diluted with water (5 mL) and ethyl acetate (15 mL). The combined organic extract was dried under a stream of N 2 gas (Na 2 SO 4), filtered and concentrated and the aqueous layer was extracted with ethyl acetate (2 × 5 mL). The remainder was purified by flash chromatography on silica gel (35 g) utilizing 9: 1 dichloromethane / acetone as eluent. By TLC, the pure fragments were combined to give 139 mg (51 of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-378) as an off-white solid. %) Concentrated to give. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.74 (s, 3H), 3.83 (s, 2H), 5.75 (br s, 2H), 7.03 (d, J = 8.4 Hz, 1H), 7.08 (m , 2H), 7.15 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.28 (m, 2H), 7.36-7.41 (m, 3H), 7.48 (m, 1H), 8.40 (br s, 1H) ppm.

The following compounds were prepared analogous to the above examples.

実施例１４。Ｐ―２６８の準備

<< General reaction process formula 8 >>

Example 14. Preparation for P-268

  Synthesis of 3-iodo-4 methoxyphenylamine (I-45, X = I, Y = H, Z = NH2, R1 = CH3): 3-in the neck, equipped with stir bar, condenser and N2 wire The flask reached the round bottom of 250 mL was placed iron powder (3.50 g, 62.7 mmol), ammonium chloride (4.88 g, 91.3 mmol), ethanol (72 mL) and water (23 mL). It was. The mixture was heated to 85 ° C. and 2-iodo-1-methoxy-4-nitrobenzene (5.0 g, 17.9 mmol) was a wise additional part over about 2 minutes. The mixture could be stirred at 85 ° C. for 2 hours and the celite was filtered. The filtrate was concentrated and the celite was washed with EtOH (100 mL). The concentrated material was additional water (100 mL) and ethyl acetate (150 mL). The watery portion was re-drawn with ethyl acetate (150 mL) and the organic portion was removed. The organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The crude material was 3.92 g of 3-iodo-4methoxyphenylamine (I-45, X = I, Y = H, Z = NH2, R1 = CH3) as a brown semi-solid in 88% yield. Was purified by column chromatography utilizing 50% EtOAc / hexanes as the eluent. MS (ESI +): 250.1 (M + 1)

  Synthesis of 1- (5'-amino-2'-methoxy-biphenyl-3-yl) -ethanone (I-47, Y = H, Z = NH2, R1 = CH3, R2 = COCH3): A 100 mL round bottomed flask equipped with a condenser, stir bar and N2 wire was placed above (2.92 g, 11.7 mmol) arranged 3-iodo-4 methoxyphenyl amine, 3-acetylphenyl bromic acid (2.11 g, 12.9 mmol), potassium carbonate (4.85 g, 35.1 mmol), triphenylphosphine (921 mg, 3.51 mmol), 1,4-dioxane (23 mL), palladium (II) Acetate (263 mg, 1.17 mmol) followed by 50% aqueous ethanol (23 mL). The mixture was heated to 90 ° C. for 16 hours and cooled to room temperature. The palladium catalyst was removed via filtration and added to filtered water 1M HCl (50 mL) and water (50 mL). The organic portions were combined, washed with brine (75 mL), dried (MgSO 4) and the concentrated, water-like portion was Extracted with ethyl acetate (2 × 75 mL). The crude material was 1.18 g of (5'-amino-2'-methoxy-biphenyl-3-yl) -ethanone (I-47, Y = H, Z = 42%) as a pale orange oil with a yield of 42%. Purified by column chromatography utilizing 50% EtOAc / hexane as eluent to yield NH2, R1 = CH3, R2 = COCH3). MS (APCI +): 242.0 (M + 1).

  1- [2′-Methoxy-5 ′-(4-nitro-phenylamine) -biphenyl-3-yl] -ethanone (I-49, Y = H, Q = NH, R1 = CH3, R2 = COCH3 , R3 = NO2): In a 40 mL vial equipped with a stir bar, 1-iodo-4-nitrobenzene (1.26 g, 5.07 mmol) (cesium carbonate (2.20 g, 6.76 mmol) (± ) Are arranged -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (316 mg, 0.507 mmol) and (5'-amino-2'-methoxy-biphenyl-3-yl) A solution of ethanone (I-47, Y = H, Z = NH2, R1 = CH3, R2 = COCH3) synthesized the above (816 mg, 3.38 mmol) of toluene (13.5 mL). Stirred for 0 minutes, and tris (dibenzylideneacetone) di-palladium (0) (310 mg, 0.338 mmol) and the mixture was heated to 110 ° C. for 16 hours The reaction was cooled to room temperature. The filtered water was treated with Extracted with water (40 mL), 1 M HCl (40 mL) and then ethyl acetate (2 × 75 mL) .The organic portions were combined and washed with brine ( 75 mL), dried (MgSO 4) and concentrated The crude material was 277 mg of 1- [2′-methoxy-5 ′-(4-nitro as a 23% yield dark orange solid. -Biphenyl-3-yl] -ethanone (I-49, Y = H, Q = NH, R1 = CH3, R2 = COCH3, R3 = NO2) It was purified by column chromatography using 35% EtOAc / hexanes and as eluent to produce.

  Synthesis of hydrochloric acid 1- [5 '-(4-amino-phenylamine) -2,' -methoxy-biphenyl-3-yl] -ethanone: In an 18 mL vial equipped with stirring, the rod was placed Iron powder (148 mg, 2.66 mmol), ammonium chloride (207 mg, 3.87 mmol), absolute EtOH (3.1 mL) and water (1.0 mL). The mixture is heated to 85 ° C and the additional-[2'-methoxy-5 '-(4-nitro-phenylamine) -biphenyl synthesized above (275 mg, 0.759 mmol) A mixture that was -3-yl] -ethanone (I-49, Y = H, Q = NH, R1 = CH3, R2 = COCH3, R3 = NO2) was heated for 2 hours and added. The reaction was cooled to room temperature. It was then filtered into Extracted with Celite and ethyl acetate (2 × 40 mL). The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The crude material was purified by column chromatography utilizing 75% EtOAc / hexane as eluent to produce 207 mg free base as a 82% yield dark orange oil. The free base was treated with 4.0 M HCl in 1,4-dioxane (1.0 mL) and stirred at room temperature for 3 hours. The solid was collected via suction filtration and the reaction mixture was treated with diethyl ether (4 mL). After washing the solid with diethyl ether (3 × 2 mL), 100 mg of hydrochloric acid 1- [5 ′-(4-amino-phenylamine) -2, ′-methoxy-biphenyl-3-yl] -ethanone is , 44% yield as a brown solid. MS (APCI): 366.9 (M-2), LC-MS: 85%

  Synthesis of [4- (3′-acetyl-6-methoxy-biphenyl-3-ylamino) -phenyl] -urea (P-268): In an 8 mL vial equipped with stirring, the stick is above (free base ) (60.0 mg, 0.180 mmol) 1- [5 ′-(4-amino-phenylamine) -2, ′-methoxy-biphenyl-3-yl] -ethanolone, water ( 600 μL), acetic acid (300 μL) and cyanic acid (46.8 mg, 0.720 mmol) sodium. Mixing was stirred at room temperature for 4 hours, and water (20 mL) was added alongside the P-traction (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material is an eluent that yields 32 mg of [4- (3′-acetyl-6-methoxy-biphenyl-3-ylamino) -phenyl] -urea (P-268) as a light brown solid in 47% yield. As purified by a column utilizing 75% acetone / DCM. MS (APCI +): 376.1 (M + 1), LC-MS: 94%.

実施例１５。Ｐ―４４７の準備。 << Reaction process formula 9 >>

Example 15. Preparation for P-447.

  1-Methoxy-4-phenylsulfanyl- (4'-nitrobenzene) (I-51). A solution of 4-methoxybenzenethiol (500 mg, 3.57 mmol) and 4-iodo nitrobenzene (1.07 g, 4.28 mmol) in dimethylformamide (10 mL) was stirred at room temperature. In orange, the solution was added solid cesium carbonate (3.48 g, 10.7 mmol). The resulting purple solution was stirred overnight at room temperature. The solution was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The aqueous wash was extracted with ethyl acetate (50 mL). Washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL), combined organic laundry. And the solvent was removed under vacuum and dried over sodium sulfate and transferred. The resulting solid was purified by flash silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give product I-51 (933 mg, 99% yield).

  2-Bromo-methoxy-4- (4'-nitro-phenyl-sulfanyl) -benzene (I-52). A 10% v / v solution of glacial vinegar (9 mL) acid in bromine (1 mL) was prepared. A solution of I-51 (780 mg, 2.99 mmol) in glacial acetic acid (7.8 mL) was stirred at room temperature. To this solution was added 10% bromine in acetic acid solution (3.53 mL total solution, 6.87 mmol bromine). The reaction could be stirred at room temperature for 2 h. The reaction was combined with a previous pilot running in this reaction (100 mg 0.383 mmol). TLC showed similar results and the previous run reacted under the same conditions. The combined reaction was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic extract was then washed with saturated aqueous sodium bicarbonate (2 × 100 mL), water (100 mL) and brine (100 mL), dried over sodium sulfate, transferred and removed under vacuum. The resulting yellow residue was obtained by flash silica gel column chromatography (10% of hexane as eluent) to give I-52 (550 mg, 48% overall yield) and a 1 second impure yield (420 mg). % Ethyl acetate).

  3'-Chloro-2-methoxy-5- (4-nitro-phenyl-sulfonyl) -biphenyl (I-53). A solution of the above synthesis I-52 (550 mg, 1.62 mmol) and 3-chlorobenzenebromate (278 mg, 1.78 mmol) in toluene (6 mL) was degassed with a 15 minute stream of nitrogen. The reaction was degassed under a stream of nitrogen and To was the reaction was added ethanol (800 uL) and 2M aqueous sodium carbonate solution (1.6 mL). The reaction was heated to 100 ° C. under nitrogen for 5 h and to the reaction was added tetrakis (triphenylphosphine) palladium (0) (93.4 mg, 8.08 × 10 −2 mmol). The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic stop was washed with water (50 mL). The aqueous wash was extracted into ethyl acetate (50 mL). The organic extracts were then combined, washed with water (2 × 30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and the solvent was removed under vacuum. The resulting crude red oil is purified by flash silica gel column chromatography (10% ethyl acetate in hexanes) to give I-53 (329.9 mg, 55% yield) as a yellow powder. It was.

Chloride (P-447) 4- (3'-chloro-6-methoxy-biphenyl-3-ylsulfanyl) -phenylammonium. Synthesis of ethanol (5 mL) and water (1.5 mL) I-53 (315 mg, 0.847 mmol), iron powder (166 mg, 2.97 mmol) and solid ammonium chloride (231 mg, 4.32 mmol) suspension , Heated to 80 degrees C for 21h. The dark residue was dissolved in ethyl acetate (30 mL) and water (30 mL) and the solvent was removed under vacuum. The layers were separated and the aqueous layer was extracted with ethyl acetate (30 mL). The organic extract was combined. Brine (50 mL) (dried over sodium sulfate) was then filtered and washed with water (50 mL) and the solvent was removed under vacuum. The rest was dried under high vacuum overnight. Dioxane (1 mL) 4N hydrogen chloride was added and the orange oil was dissolved in dioxane (2 mL) (stirring). The reaction was stirred at room temperature for 3 h and the solvent was removed under vacuum to convey the product (P-447) (257.8 mg, 81% yielded) as a brown powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.95-7.49 (m, 1H), 7.46-7.37 (m, 3H), 7.34 (dd, J = 8.6, 2.2 Hz, 1H), 7.26-7.23 (m, 3H), 7.16 (d, J = 8.8 Hz, 1H), 6.96-6.95 (m, 2H), 3.78 (s, 3H) ppm.LCMS = 97.5% purity. MS (APCI +) = 342.0 (M + 1).
Example 16. Preparation for P-448.

1- [4- (3′-Chloro-6-methoxy-biphenyl-3-ylsulfanyl) -phenyl] -3-ethylurea (P-448). A solution of the above compound (P-447) (195 mg, 0.520 mmol) in pyridine (3 mL) was stirred at room temperature. To the reaction, ethyl isocyanate (110 mg, 1.56 mmol) was added. The solution was stirred at room temperature for 22.5 h. The reaction was diluted in ethyl acetate (50 mL) and washed with water (50 mL). The aqueous laundry was extracted into ethyl acetate (50 mL) and the organic extracts combined. The ethyl acetate solution was washed with 1N aqueous hydrochloric acid (50 mL), water (2 × 50 mL) and brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. The resulting solid was triturated with diethyl ether (5 mL), passed through a filter, washed with diethyl ether (2 × 3 mL) and washed with product (P-448) (109.2 mg, 51% Dried to tell the surrender). ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.49-7.48 (m, 1H), 7.39-7.29 (m, 5H), 7.26-7.19 (m, 4H), 6.94 (d, J = 8.8 Hz, 1H) , 6.19 (s, 1H), 4.60 (m, 1H), 3.82 (s, 3H), 3.32-3.25 (m, 2H), 1.15 (t, J = 7.4 Hz, 3H) ppm. LCMS = 97.3% purity. MS (APCI +) = 413.0 (M + 1).
Example 17. Preparation for P-449.

1- [4- (3′-Chloro-6-methoxy-biphenyl-3-sulfinyl) -phenyl] -3-ethylurea (P-449). Glacial acetic acid (9 mL) 30% aqueous hydrogen peroxide (w / w) (1 mL) made 10% v / v solution. To a slurry of the above compound (P-448) (41.3 mg, 0.100 mmol) in acetic acid (300 uL) was added a hydrogen peroxide solution (96.7 uL, 0.100 mmol hydrogen peroxide). The solution was stirred for 1 hour at room temperature. The solvent was removed under vacuum and the remainder purified by silica gel thin layer chromatography (pulled with 10% acetone in dichloromethane) (powdered with diethyl ether (5 mL)) was filtered off. The product (P-449) (29.3 mg, 68% yield) was dried to convey as brown gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.55-7.44 (m, 5H), 7.36-7.32 (m, 5H), 7.20 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.27 (m, 1H), 3.84 (s, 3H), 3.29-3.22 (m, 2H), 1.12 (t, J = 7.4 Hz, 1H) ppm. LCMS = 97.6% purity. MS (APCI +) = 429.1 (M + 1).
Example 18. Preparation of P-450.

1- [4- (3′-Chloro-6-methoxy-biphenyl-3-sulfonyl) -phenyl] -3-ethyl-urea (P-450). 1- [4- (3′-Chloro-6-methoxy-biphenyl-3-ylsulfanyl) -phenyl] -3-ethylurea (P-448) (41.3 mg, 0.100 mmol) in glacial acetic acid (300 uL) The solution of was stirred at room temperature. To the solution, 290 uL of acetic acid 10% v / v (30% w / w hydrogen peroxide in water) was added. The resulting solution was stirred for 1.5 h at room temperature. The solvent was removed under vacuum, and the remainder was purified by silica gel thin layer chromatography (withdrawing with 25% acetone in dichloromethane) to give product (P-450) (20.2 mg, 45% Dried to convey a yellow oil). ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.55-7.44 (m, 5H), 7.35-7.31 (m, 4H), 7.28 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.32 (t, J = 5.6 Hz, 1H), 3.84 (s, 3H), 3.28-3.21 (m, 2H), 1.11 (t, J = 7.4 Hz, 1H) ppm. LCMS = 97.9% purity. MS (APCI +) = 473.1 (M +28), 443.0 (M + 1).
Example 19. Preparation for P-540.

P-540 synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylsulfanyl) -phenyl] -urea. A solution of PR195 (200 mg, 0.585 mmol) and water (10 mL) and glacial acetic acid (5 mL) in sodium cyanate (76 mg, 1.17 mmol) was stirred overnight at room temperature. Water (20 mL) was added to the gum stop and the reaction was extracted into ethyl acetate (2 × 20 mL). The organic extract was combined. The solvent was then removed under vacuum to give crude PR199 as a yellow eucalyptus of the bark and 1N aqueous hydrochloric acid (2 × 20 mL), saturated aqueous sodium bicarbonate (2 × 20 mL), water (20 mL) and brine (20 mL) ) (Dried over sodium sulfate). The crude oil material was purified as a white powder, purified by preliminary thin layer chromatography (silicon dioxide) with dichloromethane. ¹ H NMR (400 MHz, CDCl ₃ ) 7.49-7.48 (m, 1H), 7.41-7.28 (m, 5H), 7.23 (s, 4H), 6.95 (d, J = 8.0 Hz, 1H), 6.31 (s , 1H), 4.57 (s, 2H), 3.83 (s, 3H) ppm. LCMS = 95.3% purity. MS = 385.1 (M + 1).

The following compounds were prepared analogous to the above examples.

実施例２０。Ｐ―３８０の準備

<< General reaction process formula 10 >>

Example 20. Preparation for P-380

  2-Bromo-4- (4-fluoro-benzyl) -1 methoxybenzene: In a 250 mL round bottomed flask equipped with stirring, the rod is placed 3-bromo-4-methoxybenzyl Bromide (5.0 g, 17.9 mmol), 4 fluorophenylboronic acid (2.76 g, 19.7 mmol), potassium phosphate (tribasic) (7.60 g, 35.8 mmol), dimethoxyethane (30 mL) and 50 % Aqueous ethanol (30 mL). Mixing was degassed with nitrogen for 30 minutes and tetrakis (triphenylphosphine) palladium (0) (5.17 g, 4.48 mmol) was added. Mixing was heated to 60 ° C. for 4 hours and the palladium catalyst was filtered off. To the filtered water, water (100 mL) and saturated ammonium chloride solution (150 mL) were added. After extracting the acetate salt (3 × 100 mL) with ethyl, the organic portions were combined, washed with brine (150 mL), dried (MgSO 4) and concentrated. The crude material utilized 5% EtOAc / hexane as eluent to yield 2.12 g of 2-bromo-4- (4-fluoro-benzyl) -1 methoxybenzene as a 40% yield colorless oil. It was refined by the pillar.

4-Chloro-1- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -1H-pyrazole (P-380): In a 2-5 mL microwave vial equipped with a stir bar, the above product (250 mg, 0.847 mmol) (4-chloro-1H-pyrazole (172 mg, 1.69 mmol), potassium carbonate (234 mg, 1.69 mmol), CuI (48.4 mg, 0.254 mmol) and N-methyl-2-pyrrolidone (2.8 mL) was placed and the mixture was heated to 190 ° C. in a Biotage Initiator microwave reactor for 1 hour Saturated ammonium chloride solution (30 mL) with P with ethyl acetate (2 × 30 mL) -Following traction and mixing was quenched with water (30 mL) 35% organic fraction Viscous, in products (P-380) as a yellow oil, to ^{surrender. 1 H NMR (400 MHz,} CDCl 3) δ 3.87 (s, 3 H), 3.93 (s, 2 H), 6.94 -6.98 (m, 3 H), 7.08 (dd, J = 8, 2 Hz, 1 H), 7.12-7.16 (m, 2 H), 7.55 (d, J = 2 Hz, 1 H), 7.60 (s , 1 H), 8.04 (s, 1 H) ppm. MS (APCI +): 317.0 (M + 1); LC-MS: 97%.
Example 21. Preparation for P-389.

Synthesis of 4- {1- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -1H-pyrazol-4-yl} -pyridine (P-389). In a 2-5 mL microwave vial with stirring, the bars are placed I-185 (250 mg, 0.847 mmol), 4- (1H-pyrazol-4-yl) -pyridine (245 mg, 1.69 mmol) ), Potassium carbonate (234 mg, 1.69 mmol) and N-methyl-2-pyrrolidone (2.8 mL). Mixing was degassed with nitrogen for 10 minutes and CuI (48.4 mg, 0.254 mmol) was added. The mix was heated to 190 degrees C in a 1 hour Biotage Initiator microwave reactor. Saturated ammonium chloride solution (50 mL) was followed by extraction with ethyl acetate (2 × 100 mL) and the mixture was quenched with water (50 mL). The organic portions were combined, dried (MgSO4) and concentrated. The remainder was clarified via column chromatography utilizing 15% acetone / dichloromethane as eluent. After a failed recrystallization attempt with dichloromethane / hexane, 41 mg of P-389 as a 13% viscous, yellow oil yields. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.91 (s, 3 H), 3.96 (s, 2 H), 6.95-7.02 (m, 3 H), 7.10-7.18 (m, 3 H), 7.42-7.45 (m, 2 H), 7.62 (d, J = 2 Hz, 1 H), 8.04 (s, 1 H), 8.41 (s, 1 H), 8.57-8.59 (m, 2 H) ppm. MS (APCI + ): 360.1 (M + 1); LC-MS: 90%.
Example 22. Preparation for P-396.

Synthesis of 1- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -3-trifluoromethyl-1H-pyrazole (P-396). In a 2-5 mL microwave vial with agitation, the bars are placed I-185 (250 mg, 0.847 mmol), 3-trifluoromethyl-1H-pyrazole (230 mg, 1.69 mmol), potassium carbonate (234 mg, 1.69 mmol) and N-methyl-2-pyrrolidone (2.8 mL). Mixing was degassed with nitrogen for 10 minutes and CuI (48.4 mg, 0.254 mmol) was added. The mix was heated to 190 degrees C in a 1 hour Biotage Initiator microwave reactor. Saturated ammonium chloride solution (30 mL) was followed by extraction with ethyl acetate (2 × 60 mL) and the mixture was quenched with water (30 mL). The organic portions were combined, dried (MgSO4) and concentrated. The remainder was purified via column chromatography using 7% yield of viscous, 20% ethyl acetate / hexane as eluent to yield 20 mg P-396 as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.86 (s, 3 H), 3.94 (s, 2 H), 6.65 (d, J = 2 Hz, 1 H), 6.95-6.99 (m, 3 H), 7.10-7.16 (m, 3 H), 7.57 (d, J = 2 Hz, 1 H), 8.03 (m, 1 H) ppm. MS (APCI +): 351.0 (M + 1); LC-MS: 92% .

実施例２３。Ｐ―１１７の準備。

<< General Reaction Process Formula 11 >>

Example 23. Preparation for P-117.

  2- (3-iodo-phenyl)-[1,3,4] oxa-diazole: containing 3-iodobenzoyl hydrazide (4.5 g, 17.17 mmol) and 85.6 ml triethylorthoformate (30 equivalents) The mixing was refluxed for 16 hours. The reaction mixture was concentrated to a solid residue and triturated by mixing 15 ml of diethyl ether / heptane = 1: 1. After filtration and drying, 3.9 g of a white solid was obtained. The mother liquor was agglomerated and recrystallized 1: 3 from a methanol / water = mix to deliver an additional 200 mg of product (total 4.1 g).

  6-Methoxy-3 '-[1,3,4] oxadiazol-2-yl-biphenyl3-carbaldehyde. 5-formyl-2-methoxyphenyl boronic acid (414 mg, 2.29 mmol), the above product, a mixture of 2- (3-iodo-phenyl)-[1,3,4] oxa-diazole, (626 mg, 2 .29 mmol), aqueous 2N K 2 CO 3 (3.4 mL, 3 equivalents), DME (15 mL) of 2Cl 2 (50 mg, 0.068 mmol), Pd (PPh 3) stirred at 80 ° C. for 7 h. The reaction mixture is r. t. And was diluted with ethyl acetate (45 mL) and washed with water, brine, dried over Na 2 SO 4. After removal of the solvent, 700 mg of crude oil was obtained. Purification by column chromatography delivered 350 mg of product (yield: 55%).

(4-Fluoro-phenyl)-(6-methoxy-3 '-[1,3,4] oxadiazol-2-yl-biphenyl-3-yl) -methanol (P-117). To the above aldehyde solution in anhydrous THF (1 mL), 6-methoxy-3 ′-[1,3,4] oxadiazol-2-yl-biphenyl3-carbaldehyde (86 mg, 0.307 mmol) THF (0.46 ml, 1M), a solution of 4-fluoro-phenyl-magnesium bromide was added dropwise -78 (C. After the addition was complete, the resulting mixture could heat to room temperature, Stirred for 40 minutes, then saturated aqueous NH 4 Cl was added and the mixture was extracted with EtOAc (2 × 10 ml) The combined organic layers were washed with water and dried over Na 2 SO 4. Removal gave a rest, which was on silica gel to deliver 112 mg of product (P-117) Purified by chromatography ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.82 (s, 3H), 5.85 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.98- 7.05 (m, 2H), 7.31- 7.39 (m, 4H), 7.54 (t, 1H), 7.67- 7.7 (m, 1H), 8.01- 8.04 (m, 1H), 8.23 (s, 1H), 8.46 (s, 1H) ppm; LCMS (ESI +): 377 (M + 1).

The following compounds were prepared analogous to the above examples.
Example 24. Preparation for P-118.

2- [5 ′-(4-Fluoro-benzyl) -2, ′-methoxy-biphenyl-3-yl]-[1,3,4] oxa-diazole (P-118). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.80 (s, 3H), 3.95 (s, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.97-6.99 (m, 2H), 7.13- 7.17 ( m, 4H), 7.54 (t, 1H), 7.68- 7.7 (m, 1H), 8.01- 8.03 (m, 1H), 8.23 (s, 1H), 8.46 (s, 1H) ppm; MS (APCI +): 361 (M + 1), LCMS: 96.7%.
Example 25. Preparation for P-093.

(4-Fluoro-6-methoxy-3'-nitro-biphenyl-3-yl)-(4-fluoro-phenyl) -methanol (P-093). 1H NMR (400 MHz, CDCl3): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (t, J = 2.0 Hz, 1 H), 8.15-8.19 (m, 1 H), 7.75-7.79 (m, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.38-7.41 (m, 2 H), 7.01-7.06 (m, 2 H), 6.72 (d, J = 12 Hz , 1 H), 6.13 (br s, 1 H), 3.82 (s, 3 H) ppm Calc.373.36; APCI - (M-2):. 371.0;> 85%.
Example 26. Preparation for P-094.

4-Fluoro-5- (4-fluoro-benzyl) -2-methoxy-3'-nitro-biphenyl (P-094). 1H NMR (400 MHz, CDCl3): ¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.33 (br s, 1 H), 8.15-8.17 (m, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.12-7.18 (m, 2 H), .7.10 (d, J = 8.4 Hz, 1 H), .6.97 (t, J = 8.4 Hz , 2 H), 6.74 (d , J = 11.6 Hz, 1 H), 3.95 (s, 2 H), 3.81 (s, 3 H) ppm Calc.357.36; APCI - (M-1):. 356.1, - (M-2): 355.2, 93%.
Example 27. Preparation for P-079.

(4-Fluoro-phenyl)-(3'-nitro-6-trifluoromethoxy-biphenyl-3-yl) -methanol (P-079). ¹ H NMR (400 MHz, CDCl ₃ ) δ2.29 (1H, d, J = 3.2 Hz), 5.91 (1H, d, J = 3.2 Hz), 7.06 (2H, m), 7.37 (3H, m), 7.44 (1H, dd, J = 8.4, 2.4 Hz), 7.49 (1H, d, J = 2 Hz), 7.61 (1H, dd, J = 8 and 8 Hz), 7.78 (1H, m), 8.25 (1H , m), 8.32 (1H, m) ppm.
Example 28. Preparation for P-080.

5- (4-Fluoro-benzyl) -3, '-nitro-2-trifluoromethoxy-biphenyl (P-080). ¹ H NMR (400 MHz, CDCl ₃ ) δ4.02 (2H, s), 7.01 (2H, m), 7.16 (2H, m), 7.24 (2H, m), 7.31 (1H, m), 7.60 (1H , dd, J = 8, 8 Hz), 7.77 (1H, m), 8.24 (1H, m), 8.30 (1H, m) ppm.

実施例２９。Ｐ―００９の準備。

<< General Reaction Process Formula 12 >>

Example 29. Preparation for P-009.

  (3-Bromo-4-methoxyphenyl) -acetonitrile, synthetic 4-methoxyphenyl-acetonitrile (5.88 g, 40 mmol) was mixed with KBr (9.52 g, 80 mmol) (dichloroethane chloride (80 mL) in tetrabutylammonium chloride. (332 mg, 1.2 mmol) was added 21% w / w nitric acid (48 g, 160 mmol) The reaction mixture was stirred at rt for 20 h, diluted with dichloromethane (80 mL) and sat. NaHCO3 water, dried with water (2 x 50 mL), brine, Na2SO4 (2 x 50 mL) After removal of the solvent under vacuum, the rest is to convey 6.32 g of product Yield, powdered with Et 2 O (10 ml) / hexane (40 ml): 70 %.

  (6-Methoxy-3′-nitro-biphenyl-3-yl) -acetonitrile, the above product (2.26 g, 10 mmol), 3-nitrophenyl boronic acid (1.67 g, 10 mmol), tri-phenyl phosphine (262 mg, 1 mmol), K2CO3 (4.14 g, 30 mmol), 1,2-dimethoxyethane (80 mL) Pd (OAc) 2 (112 mg, 0.5 mmol), ethanol (10 mL) and water (10 mL) reaction mixture Was stirred at 80 ° C for 20 hours under Ar. After removal of the solvent under vacuum, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with water (2 × 40 mL), brine and dried over Na 2 SO 4. After removal of the solvent, the remainder is powdered with Et2O (20 mL) to deliver 2.18 g of product, yield: 81%.

  (6-Chloro-pyridazin-3-yl)-(6-methoxy-3'-nitro-biphenyl-3-yl) -acetonitrile, DMF (15 mL) product (1072 mg, 4 mmol) 3,6-dichloropyridazine To a hybrid of (1311 mg, 8.8 mmol) was added 0 ° C. partial NaH (400 mg, 60% of oil, 10 mmol) under Ar. The reaction mixture was stirred at 0 ° C. for 1 hour, allowed to slowly heat up to rt and then stirred at rt for 16 hours. The reaction mixture was cooled to 0 ° C. and added sitting. NH4Cl water. (50 mL) / water (150 mL) and the resulting solid stirred at rt for 10 min is passed through a filter, decomposed in ethyl acetate (80 mL) and water (2 × 40 mL) Washed with (brine) and dried over Na2SO4. After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane as eluent to deliver 1.4 g of product, yielding: 92%.

6- (6-Methoxy-3′-nitro-biphenyl-3-ylmethyl) -2H-pyridazin-3-1 (P-009). A reaction mixture of the above product (600 mg, 1.58 mmol) in acetic acid (10 mL), concentrated HCl (20 mL) and water (10 mL) was refluxed for 18 hours. r. t. After cooling to rt, water (200 mL) was added to the reaction mixture and rt for 20 min. I was agitated. The resulting solid was r. t. And passed through a filter and dried. The solid decomposed in dichloromethane (50 ml) and the solid removed by filtration. After removal of the dichloromethane, the solid was washed with diethyl ether (20 mL) to yield 310 mg of product (P-009), yielding: ¹ H NMR (400 MHz, CDCl ₃ ) δ3.83 ( 3H, s), 3.92 (2H, s), 6.88 (1H, d, J = 9.6 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.13 (1H, d, J = 9.6 Hz), 7.18 ( 1H, m), 7.22 (1H, dd, J = 8.4. 2 Hz), 7.56 (1H, dd, J = 8, 8 Hz), 7.82 (1H, m), 8.18 (1H, m) ppm; MS ( ESI +): 338.6 (M + 1); LC-MS: 96%.

The following compounds were prepared analogous to the above examples.
Example 30. Preparation for P-012.

6- (3-Benz [1,2,5] oxadiazol-5-yl-4methoxybenzyl) -2H-pyridazine-3-1 (P-012). ¹ H NMR (400 MHz, CDCl ₃ ) δ3.85 (3H, s), 3.92 (2H, s), 6.89 (1H, d, J = 9.6 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.23 (1H, d, J = 2 Hz), 7.27 (1H, m), 7.60 (1H, m), 7.81 (1H, m), 7.85 (1H, m ), 10.42 (1H, br s).
Example 30. Preparation for P-018.

6- [6- (2-methoxyethoxy) -3, '-nitro-biphenyl-3-ylmethyl] -2- (2 methoxyethyl) -2H-pyridazine-3-1 (P-018). ¹ H NMR (400 MHz, CDCl ₃ ) δ3.34 (3H, s), 3.36 (3H, s), 3.68 (2H, m), 3.80 (2H, t, J = 5.5 Hz), 3.92 (2H, s ), 4.14 (2H, m), 4.36 (2H, t, J = 5.5 Hz), 6.84 (1H, d, J = 9.5 Hz), 6.98 (1H, d, J = 8 Hz), 7.05 (1H, d , J = 9.5 Hz), 7.19-7.22 (2H, m), 7.55 (1H, dd, J = 8 and 8 Hz), 7.87 (1H, m), 8.17 (1H, m), 8.49 (1H, m) .
Example 31. Preparation for P-020.

Carbamic acid 3′-nitro-5- (6-oxo-1,6-dihydro-pyridazin-3-ylmethyl) -biphenyl-2-yl ester (P-020). ¹ H NMR (400 MHz, DMSO-d6) δ3.92 (2H, s), 6.82 (1H, dd, J = 9.6 and 2.4 Hz), 6.82 (1H, br s), 7.15 (1H, br s), 7.18 (1H, J = 8.4 Hz), 7.32 (1H, dd, J = 8 and 2 Hz), 7.41 (1H, d, J = 10 Hz), 7.44 (1H, d, J = 2Hz), 7.75 (1H , dd, J = 8 and 8 Hz), 7.88 (1H, m).

実施例３２。Ｐ―２２４の準備。

<< General Reaction Process Formula 13 >>

Example 32. Preparation for P-224.

Synthesis of 2- (6-methoxy-3′-nitro-biphenyl-3-ylmethoxy) -pyridine (P-224). In a 20 mL vial with agitation, the bars were summed I-70 (230 mg, 0.71 mg), 2-hydroxypyridine (91 mg, 0.59 mmol), Ag2CO3 (236 mg, 0.89 mmol) and 4 mL benzene. . The reaction was stirred at 80 ° C. protected from light for 18 hours. The reaction was stirred at 80 ° C. for a further 3 days and an additional 204 mg of 2-hydroxypyridine and 515 mg of Ag 2 CO 3 was added. The filtered water was concentrated and the reaction was passed through the filter. The remainder was purified by flash column chromatography eluting with ethyl acetate / hexanes by 20% to give 63 mg (32%) of P-224 as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 8.42 (s, 1 H), 8.22-8.13 (m, 2 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.63-7.53 (m, 2 H) , 7.52-7.44 (m, 2 H), 7.02 (d, J = 8.3 Hz, 1 H), 6.89 (dd, J = 5.4, 6.2 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H ), 5.37 (s, 2 H), 3.85 (s, 3 H) ppm. LC / MS = 90.0%, 337.1 (APCI +).
Example 33. Preparation for P-479.

3- [1- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-imidazol-4-yl] -pyridine (P-479). The flask was charged with 3- (1H-Imidazol-4-yl) -pyridine (165 mg, 0.75 mmol) and THF (5 mL). Then NaH (mineral oil, 60 mg, 60% dispersion of 1.5 mmol) was added slowly (gas evolution). After 2 minutes of stirring at room temperature, 3-Bromomethyl-3′-chloro-2-fluoro-6methoxybiphenyl (165 mg, 0.5 mmol) was added. The reaction mixture was rt. Was stirred at. After stirring overnight, the reaction mixture was quenched with water (20 mL). The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo. Crude oil was purified by silica gel column chromatography. It was then extracted with dichloromethane / MeOH (200: 5) to produce 77.1 mg (39% yield) of the product (P-479) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.75 (s, 3 H), 5.26 (s, 2 H), 7.02 (d, J =, 8.59 Hz, 1 H), 7.28-7.50 (m, 6 H), 7.78-7.88 (m, 2 H), 8.04-8.11 (m, 1 H), 8.38 (dd, J = 4.7, 1.2 Hz, 1 H), 8.96 (d, J = 1.5 Hz, 1 H) ppm.

実施例３４。Ｐ―１２０の準備。 << Reaction process formula 14 >>

Example 34. Preparation for P-120.

  A 100 mL round bottom flask with a stir bar was (6-methoxy-3'-nitro-biphenyl-3-yl) -acetic acid (I-71) Into was 5-bromomethyl-2-methoxy-3 '-Nitro-biphenyl (I-70) (0.60 g, 1.86 mmol), NaCN (0.18 g, 3.72 mmol) and dried DMF (20 mL) were added. The reaction was stirred at room temperature for 20 hours with 20 mL water and 20 mL dichloromethane added. The watery one was extracted with 20 mL dichloromethane and the layers were separated. The composite organic fertilizer was washed with water (3 × 20 mL) and concentrated to afford the corresponding nitrile used as it was in the next reaction. To a 100 mL round bottom flask with a stir bar, natural nitrile (10 mL ethanol and 5 mL 2N KOH) was added. The solution was stirred at reflux for 18 hours and the stop dissolved in response to heating. Ethanol was removed under reduced pressure and the reaction was cooled to room temperature. The remaining watery portion was then washed with 2 × 10 mL of dichloromethane acidified to pH = 1 using 6N HCl. The resulting precipitate was filtered and washed with water (2 × 10 mL). After drying in a 4 hour 40 ° C vacuum oven, 0.32 g (60%) of I-71 was obtained as a yellow solid.

  (6-Methoxy-3′-nitro-biphenyl-3-yl) -acetic acid 3-methyl-oxane-3-ylmethyl ester (I-73). In a 20 mL vial with a stir bar, the above acid (I-71) (0.12 g, 1.15 mmol), 2 mL dichloromethane, 3-hydroxymethyl-3-methyl-oxane (0.30 g, 1.04 mmol) , DMAP (38 mg, 0.31 mmol), DCC (0.24 g, 1.15 mmol) and 2 mL of dichloromethane were added. After the reaction was stirred, 10 mL of hexane was added, the chamber and reaction temperature for 30 was noted, and an additional 10 minutes was stirred. The celite pad was washed with 5: 1 hexane and the stop was filtered to celite: dichloromethane (3 × 10 mL). The filtered water was concentrated and purified by flash column chromatography using 30% ethyl acetate / hexane to give 0.33 g (85%) of I-73 as a colorless semi-solid.

1- (6-Methoxy-3'-nitro-biphenyl-3-ylmethyl) -4-methyl-2,6,7-tri-oxabicyclo [2.2.2] octane (P-120), stir To a 100 mL round bottom flask with the bars were addition I-73 (0.32 g, 0.86 mmol) and 10 mL dry dichloromethane. BF3-OEt2 (270 uL, 2.2 mmol) was added and the solution was cooled to −15 ° C. The reaction was able to achieve room temperature over 4 hours, which was then slowly cooled back to 0 ° C. The reaction was concentrated and triethylamine (0.48 mL, 3.45 mmol) was added. The product was purified by flash column chromatography using 50% ethyl acetate / hexane 2% ethyl acetate to yield 9.8 mg (3%) of product (P-120) as a colorless oil. It was. ¹ H NMR (400 MHz, CDCl ₃ ) 2.99 (s, 3 H), 3.81 (s, 3 H), 3.90 (s, 6 H), 6.93 (d, J = 8.3 Hz, 1 H), 7.27-7.35 (m, 2 H), 7.54 (t, J = 8.0 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 2 H), 8.15 (dd, J = 8.3, 1.3 Hz, 2 H), 8.43 ( t, J = 1.8 Hz, 1 H) ppm. MS (APCI +) 372.1.

実施例３５。Ｐ―３４１の準備

<< General Reaction Process Formula 15 >>

Example 35. Preparation for P-341

  1-Bromo-3- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -propan-2-1, stir the solution in a 20 mL vial with stir bar at 80 ° C for 1 hour And additional (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -acetic acid (I-74, R1 = Me, Y = F) (306 mg, 1.04 mmol), Dichloroethane, 4 mL was thionyl chloride (151 uL, 2.08 mmol). The reaction was stirred for 16 hours at room temperature and a solution of (trimethylsilyl) diazomethane (1.56 mL, 3.11 mmol, 2.0 M of ether) was added and 4 mL of dichloromethane was added, the solution was cooled to 0 ° C. It was done. 0.5 mL of HBr (48% of H 2 O) was added and the reaction was cooled to 0 ° C. After 30 minutes at 0 ° C., Na 2 CO 3 was added until the reaction finished drying and bubbling with the addition of Na 2 SO 4. The suspension was filtered and concentrated to produce the product (390 mg, 99%) as a brown oil. And as it was, it was used.

4- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -thiazole-2-ylamine (P-341). To a 20 mL vial, the above compound (390 mg, 1.05 mmol), ethanol (4 mL) and thiourea (160 mg, 2.10 mmol) were added. The reaction was stirred at 75 ° C. for 2 hours and cooled to room temperature. The product was extracted with ethyl acetate and water (10 mL) and 10 mL brine were added. The organic fertilizer was dried over Na2SO4, filtered and concentrated. The remainder was purified by flash column chromatography eluting with methanol / dichloromethane by 3% to allow room for the crude product as a yellow solid. The solid was triturated with 1: 5 ether: hexane conveying the pure product (135 mg, 37%) as a tan solid. A 2.0 M HCl / ether solution was added and the solid decomposed in ether: THF. The stop was concentrated to give the title compound (P-341). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (br s, 1 H), 7.52-7.42 (m, 2 H), 7.38 (s, 1 H), 7.37-7.27 (m, 2 H), 6.98 (d, J = 8.6 Hz, 1 H), 6.42 (s, 1 H), 4.00-3.55 (br s, 2H), 3.87 (s, 2 H), 3.75 (s, 3 H). MS: 349.0 (APCI +).
Example 36. Preparation for P-346.

1- [4- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -thiazol-2-yl] -3-ethyl-urea (P-346). To 8 mL, the vial was addition P-341 (40 mg, 0.11 mmol), pyridine (2 mL) and ethyl isocyanate (24 mg, 0.34 mmol). The solution was stirred at 50 ° C. for 3 days and the reaction was stirred at 80 ° C. for 2 hours and 40 mg of ethyl isocyanate added was added. After cooling to room temperature, the product was extracted with ethyl acetate and water was added. The organic fertilizer was agglomerated and the remaining extract was purified by flash column chromatography by purifying 15-product (P-346) (31 mg, 64%) as an off-white solid with 20% acetone / Hexane. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.42 (br s, 1H), 7.45-7.42 (m, 2H), 7.37 (s, 1H), 7.30-7.25 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.57 (s, 2H), 3.86 (s, 2H), 3.73 (s, 3H), 3.14-3.11 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H). LC / MS = 95.4%, 420.0 (APCI +).

実施例３７。Ｐ―３６９の準備。 << Reaction Process Formula 16 >>

Example 37. Preparation for P-369.

[5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -thiazol-2-yl] -carbamic acid tert-butyl ester (I-78). To 8 mL, the vial was added I-33 (70 mg, 0.21 mmol), (5-tributylstannyl-thiazol-2-yl) -carbamic acid tert-butyl ester (I-77, 104 mg, 0.21 mmol), 4A Molecular sieve (100 mg) and THF (2 mL). Mixing was degassed with N 2 for 10 minutes and Pd (PPh 3) ₄ (25 mg, 0.021 mmol) was added. After stirring at 80 ° C. for 18 hours, the filter cake was washed with EtOAc and the suspension was filtered. The filtered water was washed with water and concentrated. Purification by flash column chromatography (15% acetone / hexane) provided I-78 (11 mg, 12%) as a white semi-solid.

5- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -thiazol-2-ylamine (P-369). To a 4 mL vial, I-78 (10 mg, 0.022 mmol) and 1 mL of 4N HCl / dioxane were added. After stirring for 8.5 hours, the reaction was reacted with P-369 (6.8 mg, 77%) ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.69 (br s, 2 H), 7.52-7.45 (m, 2 H), 7.43-7.36 (m, 2 H), 7.32 (d, J = 4.6 Hz, 1 H), 7.29 (d, J = 6.3 Hz, 1 H), 7.08-7.01 (m, 2 H), 5.29 (s, 2 H), 3.77 (s, 3 H) ppm. LC / MS = 94.4%, 349.0 (APCI +).

実施例３８。Ｐ―３３３の準備。

<< General Reaction Process Formula 17 >>

Example 38. Preparation for P-333.

  5- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4] thiadiazol-2-ylamine (P-333). Hybridization of (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -acetic acid (I-79) (0.998 mmol, 1.0 formula) and thio-half carbazide, (2.99 mmol Three formulas) Acid chlorides containing excessively, especially trivalent phosphorus, could be heated to 120 ° C. for 45 minutes and allowed to cool to room temperature. The resulting mixture was added to water and extracted with two portions of ethyl acetate. The organic fertilizer was washed with brine and dried over magnesium sulfate. The remainder is purified via flash chromatography on silica gel using 5% of dichloromethane (1N NH3 in MeOH) as the eluent with a margin of 39% yield of the desired product (P-333). It was.

¹ HNMR (DMSO-d ₆ , 400 MHz): 3.75 (s, 3H), 4.17 (s, 2H), 6.98 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.37-7.41 (m, 2H), 7.43-7.49 (m, 2H), 7.58-7.76 (br s, 2H)
Example 39. Preparation for P-342.

  Synthesis of methyl [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4] thiadiazol-2-yl] -carbamate (P-342). In methyl chloroformate (0.388 mmol, 1.4 formula) benzene with a solution of P-333 (0.286 mmol, 1.0 formula). The mixture was heated to reflux for 10 h and could be cooled to room temperature. The resulting mixture was diluted with ethyl ether, filtered and washed with ethyl ether. The solid was dried at 30-35 ° C. under vacuum because the four hs can afford a 41% yield of the title compound (P-342).

¹ H NMR (400 MHz, DMSO-d ₆ ): 3.73 (s, 3H), 3.75 (s, 3H), 4.32 (s, 2H), 4.74 (br s, 1H), 6.99 (d, J = 8.8 Hz , 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.38 (s, 1H) 7.42-7.47 (m, 3H) ppm. LC / MS (94.0%) APCI ⁺ found: 408.0; calc'd: 407.9 m / z
Example 40. Preparation for P-343

1- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4] thiadiazol-2-yl] -3-ethyl-urea (P-343) Synthesis of. In the solution of P-333 (0.214 mmol, 1.0 formula), pyridine was the added ethyl isocyanate (0.643 mmol, 3 formulas) and as a result stirred at room temperature for 4 days. The resulting solution. The reaction was diluted with water and stirred for 1 h. The solid was passed through a filter, washed with water, and dried under high vacuum to afford a 47% yield of the title compound (P-343). 1H NMR (400 MHz, DMSO-d6): 1.04 (t, J = 7.2 Hz, 3H), 3.12 (q, J = 5.6 Hz, 2H), 3.75 (s, 3H), 4.26 (s, 2H), 6.53 (br s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 6.4, 1.2 Hz, 1H), 7.38 (s, 1H), 7.40-7.48 (M, 3H), 10.71 (s, 1H) ppm. LC / MS = 94.8% purity APCI + found: 421.0; calc'd: 420.9 m / z
Example 41. Preparation for P-352.

Synthesis of [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4] thiadiazol-2-yl] -urea (P-352). In solution of P-333 (0.177 mmol, 1 eq), THF was added trimethylsilyl isocyanate at room temperature (0.886 mmol, 5 eq), and the resulting solution was stirred overnight and . The reaction was then heated to 60 degrees C for 5 h (trimethylsilyl isocyanate added) (0.460 mmol, 2.6 eq), allowed to proceed overnight at 60 ° C. and added It was. The reaction was cooled and drained into excess aqueous 5% sodium bicarbonate. The resulting suspension was stirred at room temperature for 1 h, filtered and washed with water. The solid was dried in vacuo to give the title compound (P-352) as a white solid in 46% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): 3.75 (s, 3H), 4.26 (s, 2H), 6.30 (br s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.29 (d , J = 6.4 Hz, 1H), 7.38 (s, 1H), 7.40-7.48 (m, 4H), 10.72 (s, 2H) ppm. LC / MS = 91.1% purity. APCI ⁺ found: 393.0; calc'd : 392.8 m / z.

実施例４２。Ｐ―０１５の準備。

<< General reaction process formula 18 >>

Example 42. Preparation for P-015.

  Acetic acid 4-methoxyphenyl ester (I-85, R1 = Me, Y = H), 4-methoxyphenol (6.2 g, 50 mmol), K2CO3 (10 g, 72 mmol) and acetone (150 ml) in acetic anhydride (6 .12 g, 60 mmol) was stirred at RT. until morning. The solid was filtered off and washed with acetone (50 ml). After removal of acetone, 8.6 g of product was obtained. Surrender: 100%.

  Rt to a mixture of the above product (4.15 g, 25 mmol) of acetic acid 3-bromo-4 methoxyphenyl ester (I-86, R1 = Me, Y = Br), acetonitrile (100 ml). Of NBS (5.34 g, 30 mmol) was added. The reaction mixture was stirred at 75 ° C. until morning and more NBS (5.34 g, 30 mmol) was added and the reaction mixture was rt until morning. Was stirred at. After removal of the solvent, the crude product went directly to the next step.

  3-Bromo-4methoxyphenol (I-87, R1 = Me, Y = Br): mixed in crude product of the above MeOH (100 mL) (25 mmol) and 2N aqueous NaOH, 40 min. t. The pH of the reaction mixture stirred at (30 mL) was extracted with dichloromethane (4 × 60 mL) to match the acidic one by adding 2N aqueous HCl. The dichloromethane layer was dried over Na2SO4. After removal of the solvent, the remainder was purified by silica gel column chromatography with dichloromethane as eluent to give 2.9 g of product Yield: 57% (for two steps)

  To a mixture of 3- (3-bromo-4methoxyphenoxy) -6-chloro-pyridazine, DMSO (15 ml) above product (1420 mg, 7 mmol) 3,6-dichloropyridazine (1252 mg, 8.4 mmol), rt . Of K2CO3 (1159 mg, 8.4 mmol) was added. The reaction mixture was stirred at 110 ° C. for 3 hours under Ar. After cooling to rt, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 50 mL). The combined ethyl acetate layer was washed with water (3 × 50 mL) and dried over Na 2 SO 4 with brine. After removal of the solvent, the solid was washed with diether (20 mL) to give 1650 mg of product Yield: 75%

  A reaction mixture of 6- (3-bromo-4methoxyphenoxy) -2H-pyridazine-3-1, acetic acid (10 mL) above product (455 mg, 1.4 mmol) was stirred at 110 ° C. for 7 hours. . After removal of the solvent, the solid was washed with ethyl acetate (10 mL) to deliver 340 mg of product. Yield: 82%, MS (ESI +): 297.3 (M + 1), LC-MS: 94%.

6- (6-Methoxy-3′-nitro-biphenyl-3-yloxy) -2H-pyridazine-3-1 (P-015), the above product (85 mg, 0.29 mmol), 3-nitrophenyl bromic acid ( 72 mg, 0.43 mmol), tri-phenylphosphine (16 mg, 0.06 mmol), K2CO3 (124 mg, 0.9 mmol), 1,2-dimethoxyethane (6 ml) Pd (OAc) 2 (7 mg, 0.03 mmol) ), Ethanol (0.5 ml) and water (0.5 ml) were stirred at 80 ° C. for 20 hours under Ar. The reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (2 × 40 mL). The combined organic phase was washed with water (2 × 30 mL) and dried over Na 2 SO 4 with brine. After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane as the eluent giving 39 mg of product (P-015) Yield: 40%. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.85 (3H, s), 7.03 (1H, d, J = 10 Hz), 7.04 (1H, d, J = 8.8 Hz), 7.16-7.20 (2H, m), 7.22 (1H, d , J = 10 Hz), 7.57 (1H, dd, J = 8, 8 Hz), 7.86 (1H, m), 8.19 (1H, m), 8.41 (1H, m), 9.62 (1H, br s). MS (ESI +): 340.6 (M + 1); LC-MS: 92%.

実施例４３。Ｐ―４３９およびＰ―４４０の準備 << General reaction process formula 19 >>

Example 43. Preparation of P-439 and P-440

Integration of 2'-Fluoro-3'-hydroxy-6'-methoxy-biphenyl-3-carbonitrile (I-89, R1 = Me, R2 = 3-CN, R3 = H). Nitrogen flow for 15 minutes To that solution A was in I-88a (2.00 g, 8.22 mmol) and 3-cyanophenylboronic acid (1.45 g, 9.87 mmol) in toluene (30 mL) Removed, palladium (0) tetrakis (tri-phenyl phosphine) (475 mg, 0.411 mmol) was added and a stop formed ethanol (5 mL) and 2 M aqueous sodium carbonate (8. 2 mL) was added. The reaction was heated to 108 ° C. and stirred at this temperature overnight. The reaction was diluted with ethyl acetate (200 mL) and water (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (200 mL). The organic extract was combined. Brine (300 mL) (dried over sodium sulfate) was then filtered and washed with water (400 mL) and the solvent was removed under vacuum to give the crude product. The crude material was purified by flash silica gel column chromatography (0-5% methanol in dichloromethane) to give I-89a (1.53 g, 77% yield) as a beige powder. 1H NMR (400 MHz CDCl ₃ ) d: 7.74-7.73 (m, 1H), 7.67-7.64 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 9.4 Hz, 1H ), 6.691 (dd, J = 9.2, 2.0 Hz, 1H), 4.91 (br m, 1H), 3.77 (s, 3H) ppm. LCMS = 100% purity. MS (APCI-) = 224.0 (M-19) .

Synthesis of 2'-fluoro-6'-methoxy-3 '-(6-nitro-pyridin-3-yloxy) -biphenyl-3-carbonitrile (I-89b). A solution of n-methyl pyrrolidine (10 mL) of I-89a (500 mg, 2.06 mmol) and 5-bromo-2-nitro pyridine (379 mg, 1.87 mmol) was removed by a stream of nitrogen. To the solution was added cesium carbonate (1.22 g, 3.74 mmol) (chloride (92.4 mg, 0.934 mmol) copper (I) and 2,2,6,6-tetramethyl-3,5- Heptanedione (43.1 mg, 0.234 mmol) was added The reaction was heated to 60 ° C. overnight The reaction was diluted with ethyl acetate (75 mL) and water (75 mL) and the layers separated. The aqueous washes were extracted with ethyl acetate (75 mL) and the organic extracts combined, and the organic extracts were washed with 1N aqueous sodium hydroxide (100 mL), water (100 mL) and brine (100 mL). The solvent was removed under reduced pressure to give the crude product and dried over sodium sulfate and transferred. Te I-89b (541.8mg, 79% will yield to) to give, was purified by flash silica gel column chromatography (0-50% ethyl acetate in ^{hexane). 1 H NMR (400 MHz} , CDCl ₃ ) 8.34 (d, J = 2.8 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.74 (m, 1H), 7.69-7.64 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.8, 2.4 Hz, 1H), 7.26 (t, J = 9.0 Hz, 1H), 6.86 (dd, J = 9.2, 1.6 Hz, 1H), 3.85 (s, 3H ) ppm. LCMS = 74.2% purity. MS (APCI +) = (M-29).

Synthesis of 5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-yloxy) -pyridin-2-yl-ammonium chloride (P-439). Of tin of I-89b (R1 = Me, R2 = 3-CN, R3 = 2-N02-3-pyridyl) (250 mg, 0.684 mmol) and isopropyl alcohol (2.5 mL) and concentrated hydrochloric acid (1.25 mL) Discontinuation of (II), chloride (567 mg, 2.51 mmol) was stirred at reflux for 3 h. The reaction was added ethyl acetate (50 mL) and aqueous saturated sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). Brine (50 mL) (dried over sodium sulfate) was filtered and the combined organic extract was washed with water (50 mL) and the solvent was removed under vacuum. The remainder was purified by flash silica gel column chromatography (drawn with 50% ethyl acetate in toluene) to give a free base as an orange gum. Dioxane 4N hydrochloric acid was added (2 mL) and the gum was dissolved in dioxane (1 mL). The stop was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The remainder is triturated with diethyl ether (5 mL) and filtered to give P-439 (55.1 mg, 22% yield) as a pale yellow solid, diethyl ether (2 × 1 mL). ).
1H NMR (400 MHz d6-DMSO) d: 7.89-7.84 (m, 4H), 7.75 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 8.2 Hz, 1H), 7.32 (t, J = 9.4 Hz, 1H), 7.02-6.99 (m, 2H), 3.77 (s, 3H). LCMS = 96.2% purity. MS (APCI +) = 336.1 (M + 1).

Synthesis of 1- [5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-yloxy) -pyridin-2-yl] -3-ethyl-urea (P-440). A solution of P-439 (85.0 mg, 0.230 mmol) and ethyl isocyanate (49.0 mg, 0.690 mmol) in pyridine (1.5 mL) was stirred at room temperature until morning. The reaction was neutralized with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). Brine (50 mL) (dried over sodium sulfate) was filtered and the composite extract was washed with water (50 mL) and the solvent was removed under vacuum. The remainder was purified by preparative silica gel thin layer chromatography (5% acetone in dichloromethane), triturated with diethyl ether (3 mL), filtered and P-440 (32.0 mg, 3 mg, white powder) 34% was yielded) and was washed with diethyl ether (2 mL).
¹ H NMR (400 MHz, DMSO-d ₆ ) 9.10 (s, 1H), 7.99 (t, J = 1.8 Hz, 1H), 7.90 (s, 1H), 7.87 (dt, J = 7.5 Hz, 1.50 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69-7.65 (m, 2H), 7.46 (d, J = 2.00 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.99 ( dd, J = 9.2 Hz, 1.60 Hz, 1H), 3.76 (s, 2H), 3.31 (s, 3H), 3.15 (2H), 1.07 (t, J = 7.4 Hz, 3H).
LCMS = 97.9% purity. MS (APCI +) = 407.1 (M + 1).

実施例４４。Ｐ―２０３の準備。

<< General reaction process formula 20 >>

Example 44. Preparation for P-203.

  3-Bromo-2-fluoro-4methoxybenzaldehyde and N- {4-[(3 ′) was a hot (80 ° C.) solution of TFA (50 ml) in hexamethylenetetramine (13.7 g, 97.5 mmol). -Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -amino] -phenyl} -acetamido To was prepared by adding 1 hour of TFA (40 ml) of 3-bromo-2-fluoro-4methoxybenzene (10 g 48.8 mmol) was added. The resulting solution was continued to stir at 80 ° C. for 1 h. After it was cooled to room temperature, the reaction mixture was poured into water and stirred for 30 minutes. The product is collected in a filter and dried in vacuo (total amount: 11 g) as an inseparable mix to produce the desired aldehyde (I-91) and dimer amine impurities. 1H-NMR showed that the molar ratio of these two products was about 1: 1.

  3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-carbaldehyde (I-92), the above product (1.0 g, 4.3 mmol), 3 chlorophenyl bromic acid (1.34 g, 8.6 mmol) , K2CO3 (1.36 g, 12.9 mmol) and dioxane / H2O (5: 1, 40 ml) (Ph3P) 4Pd (1.49 g, 1.29 mmol) was mixed with 85C for 20 h under nitrogen. Until heated. After it was cooled to room temperature, the mixture was diluted with water, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. After it was concentrated in vacuo, the remainder was purified by column chromatography on silica gel to yield the title compound (I-92) (0.4 g).

  3-hydroxymethyl-6-methoxy-3'-nitro-biphenyl-2-ol To was a solution of the above product (I-92) (0.4 g, 1.5 mmol) in methanol (8 ml) 4′-Amino acetanilide (0.34 g, 2.3 mmol) and p-toluenesulfonic acid monohydrate (0.013 g, 0.08 mmol) were added. The resulting mixture was stirred at room temperature for 20 h. After the solvent was removed, the remainder was dissolved in acetic acid (4 ml) and 0C sodium cyanoborohydride (0.28 g, 4.5 mmol). The result was stirred at room temperature for 2 h. The mixture was poured into ice water, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. After it was vacuum concentrated, the remainder was purified by column chromatography on silica gel to produce the product (I-93, R1 = Me, Y = F) (0.4 g, 67%).

N- {4-[(3'-Chloro-2-fluoro-6-hydroxy-biphenyl-3-ylmethyl) -amino] -phenyl} -acetamide (P-203). To a solution of the above product (0.17 g, 0.43 mmol) in methylene chloride (20 mL) was added −78 ° C. BBr3 (0.32 g, 1.28 mmol) and it was stirred at −78 ° C. After that, the result was that the heat could reach room temperature and kept stirring for 3 h. The reaction disappeared with ice water and was basified with Na2CO3. The resulting mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. The solvent was removed in vacuo to obtain product P-203 (150 mg, 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 10.06 (br s, 1 H), 7.46-7.61 (m, 4 H), 7.40-7.47 (m, 2 H), 7.30 (s, 1 H), 7.25 (d, J = 6.3 Hz, 1 H), 7.07-7.16 (m, 2 H), 7.01 (d, J = 8.7 Hz, 1 H), 4.40 (s, 2 H), 2.03 (s, 3 H) ppm.

The following compounds were prepared by procedures similar to those described above.
Example 45. Preparation for P-251.

N- {4-[(3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -sulfamoyl] -phenyl} -acetamide (P-251) ¹ H NMR (400 MHz, CDCl ₃ ) 7.71 (d, J = 8.7 Hz, 2 H), 7.58 (d, J = 8.7 Hz, 2 H), 7.45 (br s, 1 H), 7.26-7.37 (m, 2H), 7.17-7.25 (m, 2 H), 7.12-7.19 (m, 1 H), 6.68 (d, J, =, 8.6 Hz, 1 H) 4.83 (t, J = 6.2 Hz, 1 H) 4.19 (d, J, =, 6.3 Hz, 2 H) 3.75 (s, 3 H) 2.21 (s, 3 H) ppm.

実施例４６。Ｐ―０２５の準備。

<< General reaction process formula 21 >>

Example 46. Preparation for P-025.

  2-Iodo-3-methoxy-6-methyl-pyridine (I-95): 2-iodo-6-methyl-pyridine-3-ol (I-94) (1.0 g, 4.25 mmol) and acetone (20 mL) ) To K2CO3 (1.18 g, 8.51 mmol) was added MeI (0.91 g, 6.38 mmol). The reaction was stirred at 45 ° C. under N 2 for 20 h. The reaction was cooled to room temperature and concentrated. The remainder was purified by silica gel column chromatography using dichloromethane to yield 1.04 g (98%) of the product (I-95, R1 = Me) as a light yellow solid.

  3-Methoxy-6-methyl-2- (3-nitrophenyl) -pyridine (I-96): the above product (I-95, R1 = Me) (0.5 g, 2.0 mmol), 3-nitrophenylboronic acid Of (2) (0.5 g, 3.06 mmol), PPh3 (0.11 g, 0.4 mmol), K2CO3 (0.83 g, 6.0 mmol) and Pd (OAc) to 2 (0.045 g, 0. 2 mmol) was additional DME (16 mL) and EtOH—H 2 O (1: 1, 4 mL). Ar gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 60 ° C. under Ar for 18 h. H2O and dichloromethane (40 mL each) were added and the reaction was cooled to room temperature and concentrated. The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The rest was obtained by silica gel column chromatography using 1: 1 dichloromethane-hexane and then dichloromethane to yield 0.22 g (44%) of the product (I-96, R1 = Me) as a light yellow solid. Purified.

  6-Bromomethyl-3-methoxy-2- (3-nitrophenyl) -pyridine (I-97): the above product (I-96, R1 = Me) (0.21 g, 0.86 mmol) and CCl4 (10 mL) To NBS (0.17 g, 0.95 mmol) was added benzoyl peroxide (0.02 g, 0.08 mmol). The reaction was stirred at 60 ° C. under N 2 for 18 h. The reaction was cooled to room temperature and concentrated. The remainder is dissolved in a mixture of dichloromethane and hexane (1: 1, 8 mL) to produce 0.15 g (55%) of the product as a light brown solid, 1: 1 dichloromethane / hexane, It was then purified by silica gel column chromatography using dichloromethane.

3-Methoxy-6-methoxymethyl-2- (3-nitrophenyl) -pyridine (P-025): the above product (0.08 g, 0.25 mmol), methanol (0.11 g, 2.5 mmol) and To CsCO3 (0.24 g, 0.74 mmol), DMF (2 mL) was added. The vial was capped and stirred at room temperature for 20 h. The reaction was diluted with 1: 1 ethyl acetate-H 2 O (60 mL). The watery one was extracted with ethyl acetate (2 × 20 mL) and the organic layer was separated. The combined organic extract was dried over Na 2 SO 4 and filtered to concentrate to yield 0.066 g (97%) of the product (P-025) as an off-white solid. ¹ H NMR (CDCl ₃ , 400 MHz): 8.88 (dd, J = 2.0, 1.6 Hz, 1 H), 8.3-8.35 (m, 1 H), 8.2-8.24 (m, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 3.61 (s, 2 H), 3.92 (s, 3 H), 3.50 (s, 3 H); MS (APCI +): 275.1 (M + 1), LC-MS: 96.1%.

実施例４７。Ｐ―０９１の準備。 << Reaction Process Formula 22 >>

Example 47. Preparation for P-091.

  2-methoxy 5-methylphenyl bromate (I-99) (5 g, 30.3 mmol), 3-iodo-benzene trifluoride (8.24 g, 30.3 mmol), K2CO3 (8.3 g, 60.6 mmol), 2-methoxy-5-methyl-3'-trifluoromethyl-biphenyl (I-100) A reaction mixture of methanol (200 ml) in palladium acetate (350 mg, 1.5 mmol) and water (40 ml) And stirred. The reaction mixture was concentrated to 1/3 and it was diluted with ethyl acetate (300 ml) and with 0.6N sodium hydrogen sulfate solution (300 ml) with water (150 ml double speed) and with brine. , Dried over Na2SO4 and washed. After removal of the solvent, 7.75 g of product (I-100) was obtained as an oil. Surrender: 100%.

  5-Bromomethyl-2-methoxy-3′-trifluoromethyl-biphenyl (I-101), 250 mL round bottom flask with stir bar added to I-100 (5 g, 18.79 mmol) And CCl4 (125 mL). To this solution was added 1 g NBS and 100 mg AIBN. Mixing was reflux under a 1 hour sunlamp and the flask was connected to a condenser. This was stirred at reflux under N2 for another 2 hours until 1 g of NBS reaction mixture and AIBN was 100 mg.

  And added. The mixture was refluxed for an additional 2 hours and after 2 hours, another portion of NBS (1.3 g) and 108 mg of AIBN were added. The reaction mixture was cooled to RT, concentrated in half and filtered off. The solid was washed with 100 mL CCl4. After removal of the solvent, 6.76 g of crude product (I-101) was obtained.

3- (6-Methoxy-3'-trifluoromethyl-biphenyl-3-ylmethoxy) -cyclopent-2-enone (P-091). To the 1,3-solution, 1.5 ml of anhydrous DMF in cyclopentanedione (110 mg, 1.11 mmol) was added at 0 ° C. NaH (mineral oil, 45 mg, 60% dispersion of 1.11 mmol). The stop was stirred for 30 min and a solution of 1.5 ml DMF I-101 (350 mg, 0.76 mmol) was added. Overnight, the reaction mixture was stirred at RT. The reaction mixture was quenched with saturated NH 4 Cl solution and extracted with methylene chloride. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 300 mg of crude oil. The cleanup was done using a silica gel plate (1500 um) prepared to produce 125 mg of product P-091. ¹ H NMR (CDCl ₃ , 400MHz): 2.45 (t, 2H), 2.66 (t, 2H), 3.05 (d, 1H), 3.84 (s, 3H), 5 (s, 2H), 5.43 (s, 1H ), 7.02 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2Hz, 1H), 7.38 (dd, J = 8.4, 2.4Hz, 1H), 7.53 (t, 1H), 7.6 (d, J = 8.4Hz, 1H), 7.7 (d, J = 8.4Hz, 1H), 7.77 (s, 1H). LCMS (APCI +): 363 (M + 1), 90%.
Example 48. Preparation for P-092.

Synthesis of 3- (6-methoxy-3'-nitro-biphenyl-3-ylmethoxy) -cyclopent-2-enone (P-092). To a 50 mL round bottom flask with stirring, the sticks were I-70 (284 mg, 0.83 mmol), 1,3-cyclopentadione (217 mg, 2.21 mmol), K2CO3 (305 mg, 2.21 mmol) and 5 mL. Of DMF was added. The reaction was stirred at room temperature for 18 hours. 5 mL dichloromethane and 5 mL water were added. The watery one was extracted with 10 mL of dichloromethane and the layers were separated. The complex organic fertilizer was washed with water (4 × 10 mL), dried over sodium sulfate and concentrated. The remainder was purified by flash column chromatography using 0-2% methanol / dichloromethane. 112 mg (37%) of P-092 obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 2.41-2.54 (m, 2 H) 2.60-2.71 (m, 2 H) 3.86 (s, 3 H) 5.01 (s, 2 H) 5.44 (s, 1 H) 7.04 (d, J = 8.5 Hz, 1 H) 7.37 (d, J = 2.2 Hz, 1 H) 7.41 (dd, J = 8.5, 2.2 Hz, 1 H) 7.58 (t, J = 8.0 Hz, 1 H) 7.86 (d, J = 7.8 Hz, 1 H) 8.20 (dd, J = 8.3, 1.3 Hz, 1 H) 8.41 (t, J = 1.7 Hz, 1 H). LC / MS = 92.0%, 340.1 (APCI +)

実施例４９。Ｐ―１２８の準備。 << Reaction Process Formula 23 >>

Example 49. Preparation for P-128.

  (2-Fluoro-6-methoxy-3'-nitro-biphenyl-3-yl) -thiophen-2-yl-methanone (I-103) Tonitrobenzene (0.5 mL) in thiophene-2-carbonyl chloride (90 mg , 0.6 mmol) in a 25 mL vial was -10 oC. After stirring at 0 ° C. for 2 h, which was an additional AlCl 3 (75 mg, 0.75 mmol), 6-fluoro-2-methoxy-3′-nitro-biphenyl (31) in nitrobenzene (0.5 mL) (31) ( 125 mg, 0.5 mmol) is rt. Added to. The reaction mixture could be stirred at rt for 24 hours. The reaction mixture was cooled to −10 ° C. and quenched with ice water (10 mL (extracted with ethyl acetate (10 mL)) washed with brine (30 mL) with water (2 × 10 mL), NaHCO 3, sat. After removal of the solvent, the crude oil was purified by crystallization from ether-hexane to give a 60% yield of 100 mg of I-103. Calc.357.4, APCI- (M): 356.9 (342 (M-16-1) 97.4%)

2- (2-Fluoro-6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -tetrahydro-thiophene (P-128). In a 25 mL vial containing the compound, triethylsilane (1 mL) I-103 (90 mg, 0.25 mmol) was −10 ° C. added TFA (1 mL). The reaction mixture was able to stir at rt for 72 h with heat at rt. The reaction mixture was poured onto 30 mL ice water. And extracted with ethyl acetate (3 × 30 mL). It was then washed with NaHCO3 (sitting. 30 mL), water (20 mL), dried over Na2SO4 and brine (30 mL). After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane as the eluent delivering 30% product (P-128) in 30% yield. 1H NMR (CDCl ₃ , 400 MHz): 8.33 (br s, 1 H), 8.22-8.26 (m, 1 H), 7.59-7.76 (m, 5 H), 7.15 (t, J = 4.0 Hz, 1 H ), 6.91 (d, J = 9.2 Hz, 1 H), 3.89 (s, 3 H) LCMS: Calc.347.4; APCI - (M) 347.0: 99%.
Example 50. Preparation for P-481

Synthesis of 5- (2-methoxy-5- [1,2,4] triazol-1-ylmethyl-phenyl) -benzo [1,2,5] oxa-diazole (P-481). Dimethylformamide (15 mL) and 1 M aqueous cesium carbonate (4.5 mL, 4.5 mmol) of 1- (3-bromo-4methoxybenzyl) -1H- [1,2,4] triazole (I-104, 402 mg, 1.50 mmol), benzo [1,2,5] oxadiazole-5-boronic acid (I-105, 246 mg, 1.50 mmol), palladium (0) bis (dibenzylideneacetone) (43 mg, 0 0.075 mmol) and triphenylphosphine (39.3 mg, 0.15 mmol) were heated to 85 ° C. for stirring overnight. The rest was suspended in ethyl acetate (15 mL) and the solvent was removed under vacuum. The organic stop is washed with water (3 × 15 mL) and brine (dried over sodium sulfate, decolorized through activated carbon, passed through filter) and solvent removed under vacuum to give the crude material. It was. The remainder was purified by recrystallization from dichloromethane (2 mL) and hexane (10 mL) to give P-481 (180 mg, 39% yield). 1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.88 (s, 4 H) 5.51 (s, 2 H) 7.06 (d, J = 7.8 Hz, 1 H) 7.41-7.54 (m, 3 H) 7.59 (d, J = 9.3 Hz, 1 H) 7.71-8.03 (m, 3 H) 8.25 (s, 1 H) 9.34 (br. S., 1 H), LCMS = 95.7% purity.
Example 51. Preparation for P-482

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-benzotriazole (P-482). Dimethylformamide (10 mL) and 1M aqueous sodium carbonate (4.5 mL, 4.5 mmol) 1- (3-bromo-4methoxybenzyl) -1H-benzotriazole (I-106) (477 mg, 1.50 mmol) ) Suspension of 3 nitrophenyl bromate (250 mg, 1.50 mmol), palladium (0) bis (dibenzylideneacetone) (43 mg, 0.075 mmol) and triphenylphosphine (39 mg, 0.15 mmol) , Heated to 85 ° C for stirring overnight. The rest was suspended in ethyl acetate (20 mL) and the solvent was removed under vacuum. The organic stop was washed with water (3 × 20 mL) and brine. And it dried over sodium sulfate. It was then decolorized through activated carbon and the solvent was removed under vacuum to give the crude material. The remainder was dissolved in ethyl acetate (5 mL) and purified by adding hexane (25 mL) until the solid formed. This was repeated three times to give P-482 (210 mg, 39% yield). ¹ H NMR (400 MHz, CDCl- ₃ ): 3.82 (s, 3H), 5.86 (s, 2H), 6.98 (d, J = 8.2 Hz, 1H), 7.30-7.37 (m, 2H), 7.37-7.52 (m, 3H), 7.52-7.59 (m, 1H), 7.75 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.18 (dd, J = 8.2, 1.2 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H) ppm. LCMS = 93.9% purity.

実施例５２。Ｐ―０１０、Ｐ―４８３、Ｐ―０１４の準備 << Reaction process formula 24 >>

Example 52. Preparation for P-010, P-483, and P-014

Synthesis of 2-Bromo-4-bromomethyl-1 methoxybenzene (I-42). Chloride (1.04 g, 3.73 mmol) tetrabutylammonium was followed by 4- (bromomethyl) anisol (25.0 g, 124 mmol) in dichloroethane (62 mL) and nitric acid (21% by volume, 149 g, 497 mmol). To a solution of potassium bromide (29.6 g, 248 mmol) was added dichloroethane (188 mL) and the reaction was stirred at room temperature for 5 h. The organic layer was separated. It was then washed with water (2 × 100 mL, 2 × 150 mL). 2% aqueous potassium carbonate (150 mL) (dried over sodium sulfate) and solvent were then removed under vacuum. The remainder was clarified by passing through a flash silica gel plug (10% ethyl acetate in hexane) to give the title compound (I-42) (9.22 g, 26% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.59 (d, 1 H), 7.30 (dd, J = 8.2, 2.2 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 4.44 ( s, 2 H), 4.44 (s, 3 H).

Synthesis of 1- (3-bromo-4methoxybenzyl) -1H-indole (I-107, X = CH). A solution of DMF (15 mL) indole (250 mg, 2.14 mmol) was chilled in an ice bath. To this solution was added 2-Bromo-4-bromomethyl-1 methoxybenzene (500 mg, 1.79 mmol) followed by sodium hydride (64.3 mg, 2.68 mmol). The reaction was warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride (75 mL) was added to the reaction as the layers were separated. The organic extract was washed with saturated aqueous ammonium chloride (2 × 75 mL), water (3 × 75 mL) and brine (50 mL). The extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The remaining was purified by flash silica gel column chromatography eluting with 1: 3: title compound (I-107, X═CH) taken in further reaction (490 mg, 87% is Dichloromethane to yield).
1H NMR (400 MHz CDCl3) d: 7.659-7.635 (m, 1H), 7.391 (dd, J = 1.60 Hz, 0.80 Hz, 1H), 7.215-7.092 (m, 4H), 6.996-6.969 (m, 1H) , 6.794 (d, J = 8.40 Hz, 1H), 6.549 (dd, J = 3.00 Hz, 1.00 Hz, 1H), 5.234 (s, 2H), 3.850 (s, 3H).

  Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-indole (P-010). Discontinuation of 1- (3-bromo-4methoxybenzyl) -1H-indole (150 mg, 0.474 mmol), dichloride (13.3 mg, 0.0190 mmol) palladium bis (tri phenylphosphine) and dioxane ( 10 mL) and 1M aqueous sodium carbonate (1.1 mL) of 3-nitrophenyl bromic acid (94.9 mg, 0.569 mmol) were stirred at 85 ° C. for 22 h. To the reaction, ethyl acetate (30 mL) was added. The organic stop was washed with water (4 × 30 mL). Brine (2 × 30 mL) (dried over sodium sulfate) and solvent were then removed under vacuum. The rest is a flash silica gel column to obtain 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-indole P-010 (23.6 mg, 17% yield). Purified by chromatography (10% ethyl acetate in hexane as eluant).

  1H NMR (400 MHz, CDCl3) d: 8.36 (t, J = 1.60, 1H), 8.16 (dt, J = 6.40, 0.90, 1H), 7.76 (dd, J = 6.40, 0.80, 1H), 7.65 (d , J = 6.40, 1H), 7.53 (t, J = 6.20, 1H), 7.326 (d, J = 6.40, 1H), 7.26-7.10 (m, 5H), 6.92 (d, J = 7.20, 1H), 6.55 (d, J = 2.40, 1H), 5.32 (s, 2H), 3.797 (s, 3H). LCMS = 87.7% purity. MS (APCI +) = 359.1 (M + 1).

  Synthesis of 1- (3-bromo-4methoxybenzyl) -1H-benzo imidazole (I-107, X = N). A suspension of DMF (10 mL) in 1H-benzo-imidazole (317 mg, 2.68 mmol) and potassium carbonate (495 mg, 3.58 mmol) was stirred at 45 ° C. for 1 h. The reaction was stirred at 45 ° C. for 4 h, cooled to room temperature, stirred overnight at room temperature, and heated to 2-Bromo-4-bromomethyl-1methoxybenzene (500 mg, 1 .79 mmol) was added. About half of the solvent was removed under vacuum and ethyl acetate (30 mL) was added. The organic solution was washed with saturated aqueous ammonium chloride (3 × 30 mL), water (2 × 15 mL) and brine (15 mL). The organic extract was dried over anhydrous sodium sulfate and solvent removed under vacuum to give the crude product as an orange oil. The product was purified by flash silica gel column chromatography eluting dichloromethane methanol with 5% to give the title compound (282.5 mg, 48% yield) and 50% pure A second crop of 2-Bromo-4-bromomethyl-1 methoxybenzene (207.1 mg).

  1H NMR (400 MHz CDCl3) 7.93 (s, 1H0 7.84-7.82 (m, 1H), 7.45 (d, J = 2.40 Hz, 1H), 7.30-7.26 (m, 3H) 7.07 (dd, J = 8.60 Hz, 2.20 Hz, 1H), 6.84 (d, J = 8.40 Hz, 1H), 5.28 (s, 2H), 3.87 (s, 3H).

  Synthesis of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -1H-benzo-imidazole (P-483). Palladium acetate (8.9 mg, 0.0394 mmol) was added and 1- (3-bromo-4 methoxybenzyl) -1H-benzo imidazole (I-107, X = N) (250 mg, 0. 788 mmol), 3 nitrophenyl bromic acid (132 mg, 0.788 mg), triphenylphosphine (20.6 mg, 0.0788 mmol), 1,2-dimethoxyethane (6 mL) in solid potassium carbonate (326 mg, 2.37 mmol). ), Water (1 mL) and ethanol (1 mL) suspension was flushed with argon gas. The reaction was heated to 80 degrees C until morning. Added palladium acetate (8.9 mg, 0.039 mmol) and triphenylphosphine (20.6 mg, 0.0788 mmol) were added and the mixture was stirred at 80 ° C. for an additional night. . The solvent was removed under vacuum and started in ethyl acetate (50 mL). The combined aqueous layer was extracted with ethyl acetate (50 mL) and the organic solution was washed with saturated aqueous ammonium chloride (2 × 75 mL) (water (3 × 75 mL) water). The combined organic extract was washed with brine (75 mL). Then it was decolorized using activated carbon. It was then dried over sodium sulfate and the solvent was removed under vacuum. The yellow powder was filtered to give raw P-483 and hexane (20 mL) was added, the remainder started in dichloromethane (5 mL). This was purified by flash silica gel column chromatography eluting with dichloromethane acetone by 10-20%, and excess boronic acid removed by: removing the remainder of dichloromethane (3 mL) Start and wash with 1N aqueous sodium hydroxide solution. The composite extract was dried over sodium sulfate, this wash was extracted into dichloromethane (5 mL), and P-483 (23.9 mg, 8.4% yields) as a sticky orange solvent powder Removed under vacuum to give.

1H NMR (400 MHz, DMSO-d ₆ ) d: 8.44 (s, 1H), 8.27 (t, J = 2.00 Hz, 1H), 8.21-8.178 (m, 1H), 7.924-7.898 (m, 1H), 7.711 (t, J = 8.00 Hz, 1H), 7.646-7.597 (m, 2H), 7.523 (d, J = 2.40 Hz, 1H), 7.398 (dd, J = 8.40 Hz, 2.00 Hz, 1H), 7.219- 7.127 (m, 3H), 5.485 (s, 2H), 3.764 (s, 3H). LCMS = 93.1% purity. MS (ESI +) = 360.9 (M + 1).

Synthesis 5- (5-Benzimidazol-1-ylmethyl-2-methoxyphenyl) -benzo [1,2,5] oxa-diazole (P-014). 1- (3-Bromo-4methoxybenzyl) -1H-benzo-imidazole (I-107, X = N) (250 mg, 0.778 mmol), 1N aqueous cesium carbonate (2.4 mL) in DMF (5 mL) And a suspension of triphenylphosphine (20.7 mg, 0.0788 mmol) was stirred. To the stop was added benzo [1,3] dioxol-5-yl-bromate (155 mg, 0.946 mmol) (reaction removed by nitrogen) and bis (dibenzylideneacetone) palladium (0) (22.7 mg, 0.0394 mmol) was added under nitrogen. The reaction was stirred overnight at 100 ° C. After cooling to room temperature, ethyl acetate (50 mL) was added. The organic suspension is washed with saturated aqueous ammonium chloride (2 × 50 mL), 1N aqueous sodium hydroxide (3 × 50 mL), water (50 mL) and brine (50 mL), decolorized through activated carbon and dried over sodium sulfate. Was removed under vacuum to give the crude product. The product was purified by flash silica gel column chromatography eluting with 1% dichloromethane to give P-014 (102.1 mg, 36% yield) as an off-white powder. ¹ H NMR (400 MHz, d6-DMSO) d: 8.446 (s, 1H), 8.054-8.020 (m, 2H), 7.715 (dd, J = 9.60 Hz, 1.60 Hz, 1H), 7.651-7.649 (m, 2H), 7.605 (d, J = 2.40 Hz, 1H), 7.440 (dd, J = 8.60 Hz, 2.20 Hz, 1H), 7.244-7.147 (m, 3H), 5.485 (s, 2H), 3.787 (s, 3H).
Example 53. Preparation for P-005

  Synthesis of 2-bromo-4-chloromethyl-1 methoxybenzene (I-109). I-109 was synthesized from 4-chloromethylanisole (25.0 g, 159.6 mmol) using the same conditions as I-42 to give I-109 (19.1 g, 51 % Was purified by dissolution of diethyl ether (50 mL) and hexane (50 mL) and crystallization by removing diethyl ether under vacuum to give yield.

  1H NMR (400 MHz CDCl3) d: 7.584 (d, J = 2.40 Hz, 1H), 7.296 (dd, J = 8.40 Hz, 2.00 Hz, 1H), 6.871 (d, J = 8.40 Hz, 1H), 4.520 ( s, 2H), 3.901 (s, 3H).

  Synthesis of 1- (3-bromo-4methoxybenzyl) -1H- [1,2,4] triazole (I-110). DMF (225 mL) 1,2,4-triazole (5.72 g, 82.8 mmol), 3-bromo-4-methoxybenzyl chloride (I-109) (13.0 g, 55.2 mmol) and solid cesium A suspension of carbonate (27.0 g, 82.8 mmol) was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (400 mL) Dilute with 400 ml EA and washed with water (300 mL). The aqueous laundry was extracted with ethyl acetate (2 × 150 mL) and all combined ethyl acetate extracts were saturated aqueous ammonium chloride (3 × 300 mL), water (2 × 300 mL) and brine (300 mL) Washed with sodium sulfate and solvent removed under vacuum to give I-110 as a yellow oil (11.39 g, 77% yields), which is an oily yellow solid Solidified.

¹ H NMR (400 MHz CDCl ₃ ) d: 8.060 (s, 1H), 7.969 (s, 1H), 7.492 (d, J = 2.00 Hz, 1H), 7.212 (dd, J = 8.60 Hz, 2.20 Hz, 1H ), 6.890 (d, J = 8.40 Hz, 1H).

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-1,2,4] triazole (P-005). A solution of DMF (250 mL) in I-110 (12.8 g, 47.6 mmol) and 3 nitrophenyl bromic acid (9.53 g, 57.1 mmol) was added at room temperature and 1 N aqueous sodium carbonate (143 mL) for 10 minutes. , Tri-phenyl-phosphine (2.49 g, 9.51 mmol) and bis (dibenzylideneacetone) palladium (0) removed (2.73 g, 4.75 mmol under nitrogen. Reaction was 80 degrees Heated to C and stirred overnight, as the reaction did not go to completion, it was heated to 100 ° C. for 2 h with vigorous stirring, diluted with ethyl acetate (1 L), and water (3 × 1 L ) And brine (500 mL), and the sodium sulfate solution removed under vacuum to give a brown oil. The oil was purified by silica gel column chromatography eluting with dichloromethane acetone with 0-5% and the residue gives a 30% hybrid of I-110 and P-005 To be dissolved in ethyl acetate (300 mL) (washed with water (2 × 300 mL)) and brine (300 mL), this mixture was dissolved in a solution of 3 nitrophenyl bromic acid (8.00 g, 47.9 mmol) and 1,2-dimethoxyethane (150 mL) was added to triphenylphosphine (2.24 g, 8.58 mmol), argon was bubbled for 10 min, and methanol (15 mL), water (15 mL), solid Potassium carbonate (17.8 g, 129 mmol) and palladium acetate (960 mg, 4.2 mmol) was added under argon gas and the argon flow was continued for 10 minutes The reaction was stirred overnight under nitrogen at 80 ° C. The solvent was removed under vacuum and The residue was dissolved in ethyl acetate (300 mL) and washed with water (300 mL), the water was extracted with ethyl acetate (2 × 300 mL), and the extracts were combined. (2 × 500 mL), washed with saturated aqueous sodium bicarbonate (2 × 500 mL) and brine (500 mL), dried over sodium sulfate and removed under vacuum to give the crude product as a brown oil. The product is a flash silica gel column chromatography eluting with dichloromethane acetone by 0-25% to give slightly dirty P-005. It was purified by Rafi. The material was triturated with hexane (300 mL), and dichloromethane (15 mL) and hexane (10 mL) in dichloromethane (30 mL), pure P-005 (5.26 g, 36% yielded as a white powder) Was washed with hexane (20 mL).
¹ H NMR (400 MHz, CDCl ₃ ): 3.84 (s, 3H), 5.34 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.28 (d, 1 H), 7.32 (dd , J = 8.5, 2.2 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.97 (s, 1 H), 8.09 (s, 1 H), 8.19 (dd, J = 8.3, 1.3 Hz, 1 H), 8.38 (t, J = 1.7 Hz, 1 H) ppm. LCMS = 100.0% purity. MS (APCI +) = 311.1 (M + 1) .
HPLC (220 nm); 99.95%. [Mobile Phase A and Mobile Phase B = Water and Acetonitrile, Symmetry C18, (250 x 4.6 mm, 5 um), Flow = 1.0 mL / min, Inj.Wash = ACN, Inj. Vol. = 10 uL. Retention time = 22.16 min]

  Elemental Analysis (Calc): C 61.93, H 4.55, N 18.05 (Found), C 61.92, H 4.62, N 17.88.

  Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-1,2,4] triazole hydrochloride (P-005). A solution of I-111 (200 mg, 0.645 mmol) in tetrahydrofuran (6 mL) was stirred at room temperature. To this, 2M hydrogen chloride in diethyl ether was added at room temperature. The reaction became cloudy after 10 seconds. The reaction could be stirred at room temperature for 45 minutes and the reaction was filtered and washed with diethyl ether to give P-005 (189.0 mg, 85% yield) as a white solid. .

1H NMR. (400 MHz d6-DMSO) d: 8.736 (s, 1H), 8.282 (t, J = 2.00 Hz, 1H), 8.219-8.192 (m, 1H), 8.026 (s, 1H), 7.941-7.922 (m, 1H), 7.724 (t, J = 8.00 Hz, 1H), 7.434 (d, J = 2.40 Hz, 1H), 7.389 (dd, J = 8.40 Hz, 2.40 Hz, 1H), 7.175 (d, J = 8.80 Hz, 1H), 5.417 (s, 2H), 3.797 (s, 3H).
LCMS = 100.0% purity. MS (APCI +) = 311.1 (M + 1).
Elemental Analysis (Calc): C, 55.42 H 4.36, N 16.16, Cl 10.22 (Found): C 55.23, H 4.39, N 16.00, Cl 11.06
Example 54. Preparation for P-486

  Synthesis of 5- (2-methoxy-5- [1,2,4] triazol-1-ylmethyl-phenyl) -1H-indole (P-486). P-486 is derived from 1H-indole-3 bromic acid (240 mg, 1.49 mmol) and I-110 (200 mg, 0.746 mmol) using conditions similar to those used for I-111. It was synthesized. The reaction was excited by diluting the reaction with ethyl acetate (50 mL). It was then washed with 1N aqueous sodium hydroxide (3 × 30 mL), water (2 × 30 mL) and brine (30 mL). The remainder was purified by flash silica gel column chromatography eluting with 2% methanol in dichloromethane (followed by flash silica gel column chromatography eluting with 20-% ethyl acetate in hexane) and The organic portion was concentrated and separated on a silica gel pre-plate eluting ethyl acetate in hexane by 50% to give P-486 (51.6 mg, 23% yield).

1H NMR (400 MHz, CDCl3) δ ppm 3.82 (s, 3 H) 5.33 (s, 2 H) 6.58 (br. S., 1 H) 6.98 (d, J = 8.33 Hz, 1 H) 7.18-7.25 ( m, 2 H) 7.29-7.35 (m, 2 H) 7.38-7.44 (m, 1 H) 7.73 (s, 1 H) 7.96 (s, 1 H) 8.06 (s, 1 H) 8.17 (br. s. , 1 H)
LCMS = 100.0% purity. MS (APCI +) = 305.1 (M + 1).
Example 55. Preparation for P-488

  Synthesis of 6- (6-hydroxy-3'-nitro-biphenyl-3-ylmethyl) -2H-pyridazin-3-1 (P-488). Synthesis of dichloroethane (15 ml) To a hybrid of P-009 (260 mg, 0.77 mmol), boron tribromide (dichloromethane, 2.3 ml, 2.3 mmol of 1 M) was added at -70 ° C. The reaction mixture was allowed to warm slowly to rt and was then stirred at rt for 2 hours. I was watered (100ml) and sat down. NaHCO3 water. The resulting solid was stirred at rt for 1 hour and added to the reaction mixture (20 ml) and the resulting solid was filtered with water (50 ml) to give 236 mg (95%) of P-488. Passed through and washed.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 3.83 (2H, s), 6.79 (1H, dd, J = 9.6 and 2 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.10 (1H, dd, J = 8.4 and 2 Hz), 7.29 (1H, d, J = 2.4 Hz), 7.33 (1H, d, J = 9.6 Hz), 7.70 (1H, dd, J = 8 and 8 Hz), 8.00 ( 1H, m), 8.16 (1H, m), 8.40 (1H, m), 9.83 (1H, s), 12.80 (1H, br). MS (ESI-): 322.5 (M-1) LC-MS: 97 %.
Example 56. Preparation of P-487 and P-018

  6- [6- (2-Methoxyethoxy) -3, '-nitro-biphenyl-3-ylmethyl] -2H-pyrazine-3-1 P-018 and 6- [6- (2-methoxyethoxy)- 3. Integration of '-nitro-biphenyl-3-ylmethyl] -2- (2 methoxyethyl) -2H-pyridazin-3-1 P-487. A reaction mixture of complex P-488 (97 mg, 0.3 mmol), bromoethyl methyl ether (63 mg, 0.45 mg) and 2-butanone (15 ml) of K2CO3 (124 mg, 0.9 mmol) was added to argon for 18 hours. And stirred at 80 ° C. After cooling to rt, the pH was adjusted to acidic by addition of 2N aqueous HCl, then extracted with ethyl acetate (40 ml) and water (10 ml) was added to the reaction mixture. The organic layer was washed with water (20 ml) (brine) and dried over Na2SO4. After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate. Hexane as eluent to give 30 mg product P-487 (3a) and 20 mg product P-018 (3b).

P-487: ¹ H-NMR (400 MHz, DMSO-d ₆ ) 3.24 (3H, s), 3.61 (2H, m), 3.89 (2H, s), 4.15 (2H, m), 6.81 (1H, d , J = 9.6 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.26 (1H, dd, J = 8.8 and 2 Hz), 7.35 (2H, m), 7.71 (1H, dd, J = 8 and 8 Hz), 8.00 (1H, m), 8.18 (1H, m), 8.43 (1H, m) ppm. MS (ESI-): 380.6 (M-1) LC-MS: 98%.

P-018: ¹ H-NMR (400 MHz, CDCl ₃ ) 3.34 (3H, s), 3.36 (3H, s), 3.68 (2H, m), 3.80 (2H, t, J = 5.5 Hz), 3.92 ( 2H, s), 4.14 (2H, m), 4.36 (2H, t, J = 5.5 Hz), 6.84 (1H, d, J = 9.5 Hz), 6.98 (1H, d, J = 8 Hz), 7.05 ( 1H, d, J = 9.5 Hz), 7.19-7.22 (2H, m), 7.55 (1H, dd, J = 8 and 8 Hz), 7.87 (1H, m), 8.17 (1H, m), 8.49 (1H , m) ppm. MS (APCI +): 440.1 (M + 1)

実施例５７。Ｐ―０１７の準備 << Reaction Process Formula 25 >>

Example 57. Preparation for P-017

  Synthesis of 2,6-dimethoxy-3'-nitro-biphenyl (I-81). 1-bromo-3-nitrobenzene (2.02 g, 10.0 mmol), 2,6-dimethoxyphenyl bromic acid (2.70 g, 15.0 mmol), triphenylphosphine (0.52 g, 2.0 mmol), To K2CO3 (4.14 g, 30.0 mmol) and palladium, (II) acetate (0.009 g, 0.04 mmol) was additional DME (80 mL) and EtOH / H2O (1: 1, 20 mL). It was. Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 80 ° C. under argon for 20 h. H2O (60 mL) and dichloromethane (80 mL) were added and the reaction was cooled to room temperature and concentrated. The watery one was extracted with dichloromethane (2 × 40 mL) and the layers were separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 10% ethyl acetate / hexane as the eluent to yield 1.69 g (65%) of I-81 as a white solid.

Synthesis of (2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl) -pyridin-4-yl-methanone (I-112). I-81 (0.26 g, 1.0 mmol), 4-nicotinyl chloride (0.18 g, 1.0 mmol) and dichloromethane (2 mL) were stirred at room temperature for 5 minutes. AlCl3 (0.33 g, 2.47 mmol) was added in portions over 30 minutes under argon and argon gas was bubbled through the reaction mixture for an additional 2 minutes. The vial was covered and stirred at 50 ° C. for 4 h at room temperature for 30 minutes. The reaction was cooled to room temperature and poured onto chilled concentrated HCl (3 mL). The aqueous layer was separated and basified by the addition of 50% aqueous NaOH and extracted with ethyl acetate (2 × 30 mL), and the resulting aqueous mixture was extracted with dichloromethane (2 × 30 mL). It was. The complex organic fertilizer was dried, filtered and concentrated with Na2SO4. The remainder was purified by silica gel column chromatography using 2% MeOH / dichloromethane as the eluent to yield 0.02 g (6%) of I-112 as an off-white solid. 1H NMR (CDCl ₃ , 400 MHz): 12.53 (s, 1H), 8.84 (dd, J = 4.4, 1.6 Hz, 2 H), 8.3-8.32 (m, 1 H), 8.21-8.25 (m, 1 H ), 7.74-7.78 (m, 1 H), 7.48-7.63 (m, 4 H), 6.61 (d, J = 8.8 Hz, 1 H), 3.87 (s, 3 H); MS (ESI-): 349.3 (M-1), LC-MS: 94.3%.

Integration of 6-methoxy-3'-nitro-3-pyridin-4-ylmethyl-biphenyl-2-ol (P-017). To a cooled and (0 ° C) stirred solution of TFA (2.5 ml) under N2, a portion of NaBH4 (0.12 g, 3.09 mmol) over 20 minutes was added and the reaction mixture was warmed to 15 ° C. And a solution of I-112 (0.055 g, 0.15 mmol) in dichloromethane (2.5 mL) was added over 30 minutes. The reaction was stirred at room temperature for 20 h, poured onto ice water (10 mL), essentially (pH 8-10) with the addition of 50% aqueous NaOH, and ethyl acetate (3 × 40 mL). ). The combined organic extract was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 2% MeOH / dichloromethane as eluent to yield 0.039 g (74%) of P-017 as a foam solid. 1H NMR (CDCl3, 400MHz): 8.41 (d, J = 4.4 Hz, 1 H), 8.2-8.26 (m, 2 H), 7.6-7.74 (m, 2 H), 7.1-7.18 (m, 3 H) , 6.57 (d, J = 8.0 Hz, 1 H), 5.3 9s, 1 H), 3.96 (s, 2 H), 3.73 (s, 3 H); MS (ESI-): 335.1 (M-1), LC-MS: 92.5%.
Example 58. Preparation for P-019.

<< Reaction process formula 26 >>

  Synthesis of 2-iodo-3-methoxy-6-methyl-pyridine (I-95). 2-Iodo-6-methyl-pyridine-3-ol (1.0 g, 4.25 mmol) and acetone (20 mL) in K2CO3 (1.18 g, 8.51 mmol) to MeI (0.91 g, 6.38 mmol). Was added. The reaction was stirred at 45 ° C. under N 2 for 20 h. The reaction was cooled to room temperature and concentrated. The remainder was purified by silica gel column chromatography with dichloromethane to yield 1.04 g (98%) of I-95 as a light yellow solid.

  Synthesis of 3-methoxy-6-methyl-2- (3-nitrophenyl) -pyridine (I-113). I-95 (0.5 g, 2.0 mmol), 3 nitrophenylboronic acid (0.5 g, 3.06 mmol), triphenylphosphine (0.11 g, 0.4 mmol), K2CO3 (0.83 g, 6.0 mmol) ) And palladium, (II) acetate (0.045 g, 0.2 mmol) was additional DME (16 mL) and EtOH—H 2 O (1: 1, 4 mL). Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 60 ° C. under argon for 18 h. H2O and dichloromethane (40 mL each) were added and the reaction was cooled to room temperature and concentrated. The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 1: 1 dichloromethane-hexane and then dichloromethane to yield 0.22 g (44%) of I-113 as a light yellow solid.

  Synthesis of 6-bromomethyl-3-methoxy-2- (3-nitrophenyl) -pyridine (I-114). To N-113 (0.17 g, 0.95 mmol) in I-113 (0.21 g, 0.86 mmol) and CCl4 (10 mL) was added benzoyl peroxide (0.02 g, 0.08 mmol). The reaction was stirred at 60 ° C. under N 2 for 18 h. The reaction was cooled to room temperature and concentrated. The remainder was dissolved in a mixture of dichloromethane and hexane (1: 1, 8 mL) and purified by silica gel column chromatography with 1: 1 dichloromethane: Hexane yielding 15 g (55%), then dichloromethane.

Synthesis of 3-methoxy-2- (3-nitrophenyl) -6-pyridin-4-ylmethyl-pyridine (P-019). I-114 (0.1 g, 0.31 mmol), 4 cyclic boronic acid (0.057 g, 0.46 mmol), Triphenylphosphine (0.008 g, 0.031 mmol), K3PO4 (0.13 g, 0.62 mmol) and palladium , (II) acetate (0.004 g, 0.015 mmol) was additional DME (4 mL) and EtOH—H 2 O (1: 1, 1 mL). Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 80 ° C. under argon for 18 h. The reaction was cooled to room temperature, concentrated and diluted with H 2 O and dichloromethane (40 mL each). The watery one was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by preparative TLC using 3% MeOH in dichloromethane to yield 0.051 g (51%) of P-019 as light brown mucus. 1H NMR (CDCl3, 400MHz): 8.89 (dd, J = 2.0, 1.6 Hz, 1 H), 8.52-8.55 (m, 1 H), 8.31-8.34 (m, 1 H), 8.2-8.24 (m, 1 H), 7.64-7.7 (m, 1 H), 7.58 (t, J = 8.0 Hz, 1 H), 7.44-7.49 (m, 1 H), 7.2-7.3 (m, 2 H), 7.12 (d, J = 8.4 Hz, 1 H), 4.16 (s, 2 H), 3.9 (s, 3 H); MS (APCI +): 322.1 (M + 1), LC-MS: 95.6%.
Example 59. Preparation for P-020.

  Synthesis of carbamic acid 3′-nitro-5- (6-oxo-1,6-dihydro-pyridazin-3-ylmethyl) -biphenyl-2-yl ester (P-020). A reaction mixture of combined P-488 (97 mg, 0.3 mmol) and dichloromethane (15 ml) in chlorosulfonyl group isocyanate (64 mg, 0.45 mg) was stirred at rt under argon for 3 days. The reaction mixture was diluted with water (40 ml) and washed with dichloromethane (40 mL) and ethyl acetate (40 mL). The water was removed under vacuum, the rest was stirred with acetone (40 mL), and the resulting solid was filtered with water (30 mL) to give 20 mg of product P-020, Washed. The resulting solid was passed through a filter to give an additional 40 mg of product P-020 and the acetone mother liquor was concentrated to 5 ml.

Yield: 55% ¹ H-NMR (400 MHz, DMSO-d ₆ ) 3.92 (2H, s), 6.82 (1H, dd, J = 9.6 and 2.4 Hz), 6.82 (1H, br), 7.15 (1H, br ), 7.18 (1H, J = 8.4 Hz), 7.32 (1H, dd, J = 8 and 2 Hz), 7.41 (1H, d, J = 10 Hz), 7.44 (1H, d, J = 2 Hz), 7.75 (1H, dd, J = 8 and 8 Hz), 7.88 (1H, m). MS (ESI +): 367.5 (M + 1) LC-MS: 92%.
Example 60. Preparation for P-021.

Synthesis of 6-benzo [1,3] dioxol-5-ylmethyl-3-methoxy-2- (3-nitrophenyl) -pyridine (P-021). I-114 (0.1 g, 0.31 mmol), 3,4-methylenedioxyphenyl bromic acid (0.077 g, 0.46 mmol), triphenylphosphine (0.008 g, 0.031 mmol), K3PO4 (0. 13g, 0.62mmol) and palladium, (II) acetate (0.004g, 0.015mmol) was additional DME (4mL) and EtOH-H2O (1: 1, 1mL). Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 80 ° C. under argon for 18 h. The reaction was cooled to room temperature, concentrated and diluted with H 2 O and dichloromethane (40 mL each). The watery one was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 1: 1 dichloromethane-hexane and then dichloromethane to yield 0.08 g (71%) of P-021 as a light brown mucus. 1H NMR (CDCl ₃ , 400 MHz): 8.89 (dd, J = 2.0, 1.6 Hz, 1 H), 8.34-8.37 (m, 1 H), 8.2-8.24 (m, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.22-7.28 (m, 2 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.78-6.8 (m, 2 H), 5.93 (s, 2 H), 4.09 (s, 2 H), 3.88 (s, 3 H) ppm. MS (APCI +): 365.1 (M + 1), LC-MS: 94.3%.
Example 61. Preparation for P-491.

Synthesis of [5-methoxy-6- (3-nitrophenyl) -pyridin-2-yl] -methanol (P-491). To I-114 (0.06 g, 0.19 mmol), cyclopentanol (0.032 g, 0.37 mmol) and CsCO3 (0.18 g, 0.56 mmol), DMF (2.5 mL) was added. . The vial was capped and stirred at room temperature for 20 h. The reaction was diluted with 1: 1 ethyl acetate-H 2 O (60 mL). The watery one was extracted with ethyl acetate (2 × 20 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by preparative TLC using 2% MeOH in dichloromethane to yield 0.015 g (31%) of P-491 as mucus. 1H NMR (CDCl ₃ , 400 MHz): 8.88 (dd, J = 2.0, 1.6 Hz, 1 H), 8.32-8.36 (m, 1 H), 8.22-8.26 (m, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.78 (d, J = 4.8 Hz, 2 H), 3.94 (s , 3 H), 3.37 (t, J = 9.2 Hz, 1 H); MS (APCI +): 261.1 (M + 1), LC-MS: 100%.
Example 62. Preparation for P-023.

Synthesis of 6- (4-fluoro-benzyl) -3-methoxy-2- (3-nitrophenyl) -pyridine (P-023). Up to I-114 (0.05 g, 0.15 mmol) 4-fluorophenylbrominated acidic (1) (0.032 g, 0.23 mmol), triphenyl phosphine (0.004 g, 0.015 mmol), K3PO4 (0.066 g, 0.31 mmol) and palladium (II) acetate (0.002 g, 0.008 mmol) with additional DME (1.8 mL) and EtOH-H2O (1: 1, 0.6 mL). there were. The reaction was stirred using a Biotage-60 Microwave Synthesizer for 5 minutes at 160 ° C. The reaction was cooled to room temperature and concentrated. The remainder was purified by silica gel column chromatography using 1: 1 dichloromethane-hexane and then dichloromethane to yield 0.024 g (46%) of P-023 as a light brown mucus. 1H NMR (CDCl ₃ , 400 MHz): 8.89 (dd, J = 2.0, 1.6 Hz, 1 H), 8.32-8.36 (m, 1 H), 8.2-8.24 (m, 1 H), 7.59 (t, J = 8.4 Hz, 1 H), 7.22-7.3 (m, 3 H), 7.07 (d, J = 8.4 Hz, 1 H), 6.96-7.04 (m, 2 H), 4.14 (s, 2 H), 3.88 (s, 3 H); MS (APCI +): 339.1 (M + 1), LC-MS: 100%.
Example 63. Preparation for P-024.

Synthesis of 3-methoxy-2- (3-nitrophenyl) -6- [1,2,4] triazol-1-ylmethyl-pyridine (P-024). I-114 (0.055 g, 0.17 mmol), 1H- [1,2,4] triazole (0.018 g, 0.26 mmol) and CsCO3 (0.17 g, 0.51 mmol) to DMF (2 mL). Was added. The vial was capped and stirred at room temperature for 20 h. The reaction was diluted with 1: 1 ethyl acetate-H 2 O (60 mL). The watery one was extracted with ethyl acetate (2 × 20 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by preparative TLC using 3% MeOH in dichloromethane to yield 0.043 g (81%) of P-024 as an off-white solid. 1H NMR (CDCl ₃ , 400 MHz): 8.87 (dd, J = 2.0, 1.6 Hz, 1 H), 8.22-8.3 (m, 3 H), 7.99 (s, 1 H), 7.6 (t, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 5.5 (s, 2 H), 3.92 (s, 3 H); MS ( (APCI +): 312.1 (M + 1), LC-MS: 100%.
Example 64. Preparation for P-026.

Synthesis of 4- [5-methoxy-6- (3-nitrophenyl) -pyridin-2-ylmethyl] -morpholine (P-026). To I-114 (0.06 g, 0.19 mmol), morpholine (0.032 g, 0.37 mmol) and Cs2CO3 (0.18 g, 0.56 mmol), DMF (2.5 mL) was added. The vial was capped and stirred at room temperature for 20 h. The reaction was diluted with 1: 1 ethyl acetate-H 2 O (60 mL). The watery one was extracted with ethyl acetate (2 × 20 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 5% methanol in dichloromethane to yield 0.051 g (80%) of P-026 as a mucus. 1H NMR (CDCl ₃ , 400 MHz): 8.86 (dd, J = 2.4, 1.6 Hz, 1 H), 8.3-8.34 (m, 1 H), 8.2-8.24 (m, 1 H), 7.59 (t, J = 8.4 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 3.91 (s, 3 H), 3.75 (t, J = 4.4 Hz , 4 H), 3.71 (s, 2 H), 2.56 (t, J = 4.4 Hz, 4 H); MS (APCI +): 330.9 (M + 1), LC-MS: 97%.
Example 65. Preparation for P-030.

Synthesis of 6-iso-propoxy-methyl-3-methoxy-2- (3-nitrophenyl) -pyridine (P-030). DMF (2.0 mL) in NaH (0.016 g, 0.39 mmol) in chilled and (0 ° C) stirred suspension with DMF (0.5 ml) in isopropanol (0.033 g, 0.56 mmol) Was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. After cooling to 0 ° C., a solution of DMF (1.0 mL) of I-114 (0.06 g, 0.19 mmol) was added over 5 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 20 h. The reaction was poured into crushed ice water and extracted with ethyl acetate (2 × 40 mL). The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using dichloromethane to yield 0.027 g (47%) of P-030 as a mucus. 1H NMR (CDCl ₃ , 400 MHz): 8.86 (dd, J = 2.0, 1.6 Hz, 1 H), 8.33 (dt, J = 8.0, 1.2 Hz, 1 H), 8.2-8.25 (m, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 4.66 (s, 2 H), 3.91 (s , 3 H), 3.72-3.81 (m, 1 H), 1.27 (d, J = 6.0 Hz, 6 H); MS (APCI +): 303.1 (M + 1), LC-MS: 100%.
Example 66. Preparation for P-031.

Integration of 1- [5-methoxy-6- (3-nitrophenyl) -pyridin-2-ylmethyl] -pyrrolidine-2-1 (P-031). To I-114 (0.08 g, 0.25 mmol), pyrrolidone (0.042 g, 0.5 mmol) and Cs2CO3 (0.24 g, 0.74 mmol), DMF (3 mL) was added. The vial was capped and stirred at room temperature for 20 h. The reaction was diluted with 1: 1 ethyl acetate-H 2 O (60 mL). The watery one was extracted with ethyl acetate (2 × 20 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by a follow-up TLC using 5% methanol in dichloromethane to yield 0.054 g (78%) of P-031 as mucus. 1H NMR (CDCl ₃ , 400 MHz): 8.88-8.9 (m, 1 H), 8.36 (dt, J = 8.0, 1.2 Hz, 1 H), 8.2-8.25 (m, 1 H), 7.6 (t, J = 8.0 Hz, 1 H), 7.26-7.34 (m, 2 H), 4.61 (s, 2 H), 3.92 (s, 3 H), 3.49 (t, J = 7.2 Hz, 2 H), 2.47 (t , J = 8.02 Hz, 2 H), 2.0-2.2 (m, 2 H); MS (APCI +): 328.8 (M + 1), LC-MS: 94.0%.
Example 67. Preparation for P-033.

Integration of 1- [5-methoxy-6- (3-nitrophenyl) -pyridin-2-ylmethyl] -imidazolidine-2-1 (P-033). To I-114 (0.08 g, 0.25 mmol), imidazol-2-one (0.053 g, 0.62 mmol) and K2CO3 (0.086 g, 0.62 mmol), DMF (3 mL) was added. The vial was capped at 80 ° C. for 20 h and heated. The reaction was diluted with 1: 1 ethyl acetate-H 2 O (60 mL). The watery one was extracted with ethyl acetate (2 × 20 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by a preparatory TLC using 5% methanol in dichloromethane to yield 0.015 g (18%) of P-033 as an off-white foam solid. 1H NMR (CDCl ₃ , 400 MHz): 8.88-8.95 (m, 1 H), 8.36 (dt, J = 7.6, 1.6 Hz, 1 H), 8.2-8.24 (m, 1 H), 7.6 (t, J = 8.4 Hz, 1 H), 7.35 (s, 2 H), 4.55 (s, 1 H), 4.53 (s, 2 H), 3.92 (s, 3 H), 3.44-3.58 (m, 4 H); MS (APCI +): 329.0 (M + 1), LC-MS: 90.7%.
Example 68. Preparation for P-038.

Synthesis of 6-cyclopentyloxymethyl-3-methoxy-2- (3-nitrophenyl) -pyridine (P-038). DMF (2.0 mL) NaH (0.016 g, 0.39 mmol) in a chilled and (0 ° C.) stirred stop was taken to DMF (0.5 ml) in cyclopentanol (0.048 g, 0.56 mmol). ) Solution was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. After cooling to 0 ° C., a solution of DMF (1.0 mL) of I-114 (0.06 g, 0.19 mmol) was added over 5 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 20 h. The reaction was poured into crushed ice water and extracted with ethyl acetate (2 × 40 mL). The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using dichloromethane to yield 0.047 g (77%) of P-038 as a mucus. 1H NMR (CDCl ₃ , 400 MHz): 8.86 (dd, J = 2.4, 1.6 Hz, 1 H), 8.3-8.34 (m, 1 H), 8.2-8.24 (m, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 4.63 (s, 2 H), 4.07-4.12 (m, 1 H ), 3.91 (s, 3 H), 1.7-1.84 (m, 8 H); MS (APCI +): 329.7 (M + 1), LC-MS: 96.1%.
Example 69. Preparation for P-064.

<< Reaction process formula 27 >>

  Synthesis of 2-bromo-6-methyl-pyridine-3-ol (I-115). Bromine (3.66 g, 22.91 mmol) was added to 6-methyl-pyridine-3-ol (5.0 g, 45.82 mmol) in pyridine (15 mL). The reaction was stirred at room temperature under N2 for 20 h. The natural reaction mixture was poured into crushed ice water (300 mL) and stirred for 3 h. The reaction was extracted with ethyl acetate (5 × 100 mL), washed with brine, dried over Na 2 SO 4 and filtered to yield 6.3 g (738%) of I-115 as a light yellow solid. Concentrated to do.

  Synthesis of 2-bromo-3-methoxy-6-methyl-pyridine (I-116). To raw I-115 (6.0 g, 31.91 mmol) and acetone (100 mL) in K2CO3 (8.82 g, 63.82 mmol), methyl iodide (6.79 g, 479.87 mmol) was added. The reaction was stirred at 45 ° C. under N 2 for 20 h. The reaction was cooled to room temperature, passed through a filter and concentrated. The remainder was purified by silica gel column chromatography using 1: 1 dichloromethane-hexane to yield 2.34 g (36%) of I-116 as an off-white solid.

  Synthesis of 3-methoxy-6-methyl-2- (3-trifluoromethyl-phenyl) -pyridine (I-117). I-116 (1.2 g, 5.94 mmol), 3 trifluoromethylphenyl bromic acid (1.69 g, 8.91 mmol), triphenylphosphine (0.31 g, 1.19 mmol), K2CO3 (2.46 g, 17 .82 mmol) and palladium, (II) acetate (0.13 g, 0.59 mmol) was additional DME (15 mL) and EtOH—H 2 O (1: 1, 6 mL). Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 80 ° C. under argon for 20 h. H2O and dichloromethane (40 mL each) were added and the reaction was cooled to room temperature and concentrated. The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography with 1: 1 dichloromethane-hexane and then dichloromethane to yield 1.36 g (86%) of I-117 as a light yellow solid.

  Synthesis of 6-bromomethyl-3-methoxy-2- (3-trifluoromethyl-phenyl) -pyridine (I-118). To N-117 (1.04 g, 5.83 mmol) in I-117 (1.3 g, 4.86 mmol) and CCl4 (25 mL) was added peroxide (0.12 g, 0.49 mmol) benzoyl. The reaction was stirred at 80 ° C. under N 2 for 20 h. The reaction was cooled to room temperature and concentrated. The remainder is dissolved in a mixture of dichloromethane and hexane (1: 1, 8 mL) to yield 0.74 g (44%) of I-118 as an off-white solid, 1: 1 dichloromethane— It was purified by silica gel column chromatography using hexane.

  3-Methoxy-6- [1,2,4], triazol-1-ylmethyl-2- (3-trifluoromethyl-phenyl) -pyridine (synthesis of P-064). I-118 (0.2 g, 0.58 mmol), 1H- [1,2,4] triazole (0.048 g, 0.26 mmol) and Cs2CO3 (0.56 g, 1.73 mmol) to DMF (4 mL). Was added. The vial was capped and stirred at room temperature for 20 h. The reaction was diluted with crushed ice—H 2 O (60 mL), stirred for 5 h, passed through a filter and dried to yield 0.14 g (73%) of P-064 as an off-white solid. 1H NMR (CDCl3, 400MHz): 8.28 (s, 1 H), 8.21 9s, 1 H), 8.09 (d, J = 7.6 Hz, 1 H), 7.99 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.52-7.59 (m, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 5.49 (s, 2 H) , 3.89 (s, 3 H) ppm. MS (APCI +): 335.1 (M + 1), LC-MS: 91.4%.

実施例７０。Ｐ―４９２の準備 << Reaction process formula 28 >>

Example 70. Preparation for P-492

Synthesis of 1- (3-bromo-4methoxybenzyl) -piperidine-2,6-dione (I-119). Discontinuation of anhydrous DMF (12 mL) in sodium hydride (56.0 mg, 2.34 mmol) was stirred under nitrogen for 5 minutes. The reaction was stirred for an additional 5 minutes under nitrogen and To was stopped, piperidine-2,6-dione (264 mg, 2.34 mmol) was added. After gas evolution was over, the reaction was stirred under nitrogen at ambient temperature for 24 h and I-109 (500 mg, 2.12 mmol) was added. The suspension was extracted with ethyl acetate (100 mL) and the reaction was diluted with saturated aqueous ammonium chloride (100 mL). Saturated aqueous ammonium chloride (3 × 50 mL), brine dried over anhydrous sodium sulfate (50 mL) and the solvent removed under vacuum yields to yield 476.1 mg of I-119 as 72% purple powder The purple organic extract was washed with water (3 × 50 mL) water. ¹ H NMR (400 MHz, CDCl ₃ ) 7.59 (d, J = 2.40 Hz, 1H), 7.33 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.80 (d, J = 8.40 Hz, 1H), 4.85 (s, 2H), 3.86 (s, 3H), 2.67 (t, J = 6.6 Hz, 4H), 1.95-1.92 (m, 2H).

Synthesis of 1- (3-benzo [1,3] dioxol-5-yl-4methoxybenzyl) -piperidine-2,6-dione (P-492). The solution of I-119 (200 mg, 0641 mmol) and 1,4-dioxane benzo [1,3] dioxol-5-yl-boronic acid (117 mg, 0.705 mmol) was added to a 10 minute subsequence, triphenylphosphine ( 33.5 mg, 0.128 mmol), degassed by a stream of nitrogen for the mixing of solid potassium carbonate (265 mg, 1.92 mmol) and ethanol, and water (1: 1, 1 mL) was added. The reaction was stirred under nitrogen for 10 minutes To and the reaction was added palladium (II) acetate and the reaction was heated to 80 ° C. for stirring overnight. The rest was suspended in saturated aqueous ammonium chloride (50 mL) and the solvent was removed under vacuum and the aqueous slurry was extracted with ethyl acetate (2 × 50 mL). Brine (30 mL) (dried over sodium sulfate) was decolorized using activated carbon and the composite extract was washed with water (3 × 50 mL) and the solvent was removed under vacuum. The remainder elutes acetone in dichloromethane followed by trituration with diethyl ether (10 mL) to yield 50.9 mg P-492 as a 22% off-white solid by 0-10%. Purified by chromatography on flash silica gel).
¹ H NMR (CDCl ₃ 400 MHz). 7.29 (m, 2H), 7.03 (d, J = 1.6 Hz, 1H), 6.95 (dd, J = 8.1 Hz, J = 1.7 Hz, 1H), 6.86 (t, J = 8.2 Hz, 2H), 5.98 (s, 2H), 4.92 (s, 2H), 3.78 (s, 3H), 2.66 (t, J = 6.6 Hz, 4H), 1.93 (m, 2H). LCMS = 100.0% purity.MS (APCI-) 350.0 (MH).
Example 71. Preparation for P-070.

Synthesis of (S) -1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidin-3-ol (P-070). In a 20 mL vial with stirring, the stick was I-114 (0.30 g, 0.93 mmol), (S) -pyrrolidin-3-ol (54 mg, 0.62 mmol), Cs2CO3 (0.20 g) 0.62 mmol) and DMF (2 mL). The reaction was stirred at room temperature for 4 days and 10 mL of water was added. Organic fertilizer was combined and concentrated and the product was extracted with ethyl acetate (3 × 10 mL). The remainder was purified by flash column chromatography using 0-5% methanol / dichloromethane to 27.7 mg (14%) of P-070 aford as a yellow oil. 1H NMR (400 MHz, CDCl3). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.75 (m, 1 H) 2.14-2.27 (m, 1 H) 2.29-2.41 (m, 1 H) 2.56 (dd, J = 10.1, 5.1 Hz, 1 H) 2.68 (d, J = 9.8 Hz, 1 H) 2.88 (td, J = 8.6, 5.3 Hz, 1 H) 3.63 (s, 2 H) 3.83 (s, 3 H) 4.29-4.43 (m, 1 H) 6.96 (d, J = 8.3 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.56 (t, J = 8.0 Hz, 1 H) 7.86 (d, J = 7.7 Hz, 1 H) 8.17 (dd, J = 8.2, 1.9 Hz, 1 H) 8.42 (s, 1 H) ppm. LC / MS = 98.5%, 329.1 (APCI +)
Example 72. Preparation for P-071.

Synthesis of (R) -1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidin-3-ol (P-071). The same procedure was used as described for P-070 except that (R) -Pyrrolidin-3-ol was used. P-071 was obtained as a yellow oil, 44.2 mg (22%). ¹ H NMR (400 MHz, CDCl ₃ ) 1.75 (m, 1 H) 2.13-2.28 (m, 1 H) 2.29-2.41 (m, 1 H) 2.56 (dd, J = 10.0, 5.0 Hz, 1 H) 2.69 (d, J = 9.8 Hz, 1 H) 2.88 (td, J = 8.6, 5.2 Hz, 1 H) 3.63 (s, 2 H) 3.83 (s, 3 H) 4.29-4.41 (m, 1 H) 6.96 ( d, J = 8.3 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.56 (t, J = 8.0 Hz, 1 H) 7.86 (d, J = 7.8 Hz, 1 H) 8.17 (dd, J = 8.2 , 1.3 Hz, 1 H) 8.42 (t, J = 1.7 Hz, 1 H) ppm. LC / MS = 99.0%, 329.1 (APCI +)
Example 73. Preparation for P-493.

Synthesis of [(R) -1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidin-2-yl] -methanol (P-493). The same procedure was used as described for P-070 except that (R) -1-pyrrolidin-2-yl-methanol was used to obtain P-493 (110 mg, 52%). It was.
Example 74. Preparation for P-072.

Synthesis of [(S) -1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidin-2-yl] -methanol (P-072). The same procedure was used as described for P-070 except that (R) -1-pyrrolidin-2-yl-methanol was used to obtain P-072 (68 mg, 32%). It was.
Example 75. Preparation for P-076.

Integration of 3- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -oxazoline-2-1 (P-076). To a dry 100 mL round bottom flask with stirring, the bar was additional oxazolidinone (0.15 g, 1.74 mmol) and dry THF (8 mL). NaH (83 mg, 2.09 mmol) was added and the solution was cooled to 0 ° C. The stop was stirred at room temperature for 10 minutes at 0 ° C. and cooled to 0 ° C. The reaction was stirred at room temperature for 16 hours and 2 mL of dry THF I-114 (0.56 g, 1.74 mmol) was added to the above mixture. THF was removed under reduced pressure and 10 mL of aqueous saturated NH 4 Cl was added. The product was extracted with ethyl acetate (3 × 10 mL) and an additional 10 mL of water was added. The combined organic fertilizer is dried over sodium sulfate and concentrated by flash column chromatography using 35% -75% ethyl acetate / hexanes to obtain 94 mg (16%) of P-076 as an oil. Purified. ¹ H NMR (400 MHz, CDCl ₃ ) 3.47 (t, J = 8.1 Hz, 2 H) 3.84 (s, 3 H) 4.32 (t, J = 7.8 Hz, 2 H) 4.44 (s, 2 H) 7.00 ( d, J = 8.4 Hz, 1 H) 7.26 (s, 1 H) 7.33 (dd, J = 8.5, 2.2 Hz, 1 H) 7.57 (t, J = 8.0 Hz, 1 H) 7.83 (d, J = 7.7 Hz, 1 H) 8.19 (dd, J = 8.2, 1.3 Hz, 1 H) 8.40 (t, J = 1.8 Hz, 1 H) ppm. LC / MS = 98.0%, 328.1 (APCI-)
Example 76. Preparation for P-001.

<< Reaction process formula 29 >>

  Integration of 2-methoxy-5-methyl-3'-nitro-biphenyl (I-69): 2-methoxy-5-methylphenylbromate (1.65 g, 10 mmol), 3-nitro-iodo-benzene (2.49 g, The reaction mixture of 10 mmol), K 2 CO 3 (2.76 g, 20 mmol), palladium (II) acetate (112 mg, 0.5 mmol) in methanol (75 ml) and water (15 ml) was stirred at rt overnight. The reaction mixture was diluted with diluted Na2S2O7 water, water, brine with washed ethyl acetate (300 ml) and dried over Na2SO4. After removal of the solvent, 2.5 g (100%) of I-69 was obtained.

  Integration of 5-bromomethyl-2-methoxy-3'-nitro-biphenyl (I-70): synthesis of carbon tetrachloride (150 mL) to a hybrid of I-69 (2.43 g, 10 mmol) at rt. Of bromine (1.76 g, 11 mmol) was added. The reaction mixture was stirred at 80 ° C. under a 1 hour sunlamp. After removal of the solvent, the remainder was washed with diethyl ether (15 mL) / Hexane (15 mL) to give 2.1 g (65%) of Synthesis I-70.

Synthesis of 5- (4-fluoro-benzyl) -2-methoxy-3′-nitro-biphenyl (P-001): I-70 (300 mg, 0.93 mmol), 4-fluorophenyl boronic acid (196 mg, 1.4 mmol), triphenylphosphine (52 mg, 0.2 mmol), K3PO4 (394 mg, 1.86 mmol), DME (5 ml) palladium (II) acetate (22 mg, 0.1 mmol), ethanol (0. The reaction mixture of 5 ml) and water (0.5 ml) was stirred at 80 ° C. overnight under argon. The reaction mixture was diluted with diethyl ether (40 ml) (washed with water (brine) and dried over Na 2 SO 4). After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / Hexane as eluent to give 200 mg (60%) of P-001. ¹ H NMR (400 MHz, DMSO-d ₆ ): 3.77 (s, 3H), 3.94 (s, 2H), 7.05-7.14 (m, 3H), 7.22-7.34 (m, 4H), 7.65-7.78 (m , 1H), 7.92 (d, J = 7.8 Hz, 1 H), 8.18 (dd, J = 8.2, 1.34 Hz, 1 H), 8.28 (t, J = 1.8 Hz, 1 H) ppm. LCMS = 97.4% purity TSI (+) = 308.6 (M-29).
Example 77. Preparation for P-494.

Synthesis of 5- (4-fluoro-benzyl) -3, '-nitro-biphenyl-2-ol (P-494): P-001 (200 mg, 0.59 mmol) in dichloromethane (15 ml) -78oC additional BBr3 (dichloromethane, 1.78ml, 1.78mmol of 1M) under N2. The reaction mixture was stirred at −78 ° C. overnight at rt. The reaction mixture was diluted with water and extracted with dichloromethane (2 × 20 ml). The dichloromethane layer was washed with water (2 × 40 ml) (brine) and dried over Na 2 SO 4. After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / Hexane as eluent to give 180 mg (94%) of P-494. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.94 (2H, s), 4.83 (1H, s), 6.87 (1H, d, J = 8 Hz), 6.99 (2H, m), 7.07-7.17 (4H, m), 7.60 (1H, dd, J = 8 and 8 Hz), 7.85 (1H, m), 8.21 (1H, m), 8.40 (1H, m). MS (APCI-): 322.1 (M-1) LC-MS: 97%.
Example 78. Preparation for P-067.

(7) Synthesis of 2-difluoromethoxy-5- (4-fluoro-benzyl) -3, '-nitro-biphenyl (P-067): Hybridization of synthesis P-494 (100 mg, 0.3 mmol) and DMF (6 ml ) To NaOH (40 mg, 1 mmol) was added sodium chlorodifluoroacetate (228 mg, 1.5 mmol). The reaction mixture was stirred overnight at 50 ° C. After removal of the solvent, the residue was diluted with water (40 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic extract was washed with water (4 × 30 ml) (brine) and dried over Na 2 SO 4. After removal of the solvent, the remainder was purified by silica gel column chromatography with dichloromethane / Hexane as eluent giving 45 mg (40%) of P-067. ¹ H-NMR (400 MHz, CDCl ₃ ) 4.00 (2H, s), 6.37 (1H, t, J = 7,3 Hz), 7.00 (2H, m), 7.15 (2H, m), 7.22 (1H, m), 7.59 (1H, dd, J = 8 and 8 Hz), 7.80 (1H, m), 8.22 (1H, m), 8.32 (1H, m) ppm. MS (APCI-): 373.1 (M-1 LC-MS: 98%.

Example 79. Preparation for P-022.

  Synthesis of 2'-methoxy-5 '-[1,2,4] triazol-1-ylmethyl-biphenyl-3-carboxylic acid methyl ester (P-022). 1,4-Dioxane (50 mL) of 3-methoxycarbonylphenyl bromate (816 mg, 4.53 mmol) for 45 min To this solution was bis (triphenylphosphine) under nitrogen Palladium (II) dichloride (106 mg, 0.151 mmol) and 1M aqueous sodium carbonate (9 mL) were added and the nitrogen stream bubbled by resolution of I-110 (810 mg, 3.02 mmol). The reaction was heated to 85 ° C. overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (150 mL). The organic solution was washed with water (5 × 100 mL). Brine (100 mL) (dried over sodium sulfate) and solvent were then removed under vacuum. The remainder was purified by flash silica gel column chromatography eluting with dichloromethane of methanol followed by flash silica gel column chromatography with 50% ethyl acetate in hexane followed by 0-2% and the remaining laundry was acetic acid Dissolved in ethyl (10 mL). The organic solution was washed with water (2 × 10 mL) extracted with ethyl acetate (2 × 10 mL) and washing. The combined ethyl acetate extract was washed with water (3 × 10 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. The product is recrystallized by dissolving in hot diethyl ether (2 mL) to remove diethyl ether under added hexane (3 mL) under a stream of nitrogen. The product was filtered and washed with hexane (3 × 3 mL) to give P-022 (233.6 mg, 23.9% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) d: 8.15 (t, J = 1.60 Hz, 1H), 8.066 (s, 1H), 8.019-7.999 (m, 1H), 7.97 (s, 1H), 7.69-7.67 (m, 1H), 7.47 (t, J = 7.60 Hz, 1H), 7.29-7.26 (m, 2H), 6.989 (d, J = 9.20, 1H), 5.33 (s, 2H), 3.93 (s, 3H ), 3.82 (s, 3H) ppm.

LCMS = 99.0% purity. MS (APCI +) = 324.1 (M + 1).
Example 80. Preparation for P-044.

Synthesis of 1- (3-benzo [1,3] dioxol-5-yl-4methoxybenzyl) -1H- [1,2,4] triazole (P-044). DMF (40 mL) of benzo [1,3] dioxol-5-yl-bromate (345 mg, 2.08 mmol) for To 10 minutes To was bis (dibenzylideneacetone) under nitrogen Palladium (0) (120 mg, 0.208 mmol), triphenyl phosphine (109 mg, 0.416 mmol) and 1M aqueous sodium carbonate (6.25 mL) were added and the nitrogen flow was I-110 (500 mg, 1 .87 mmol) resulted in bubbling. The reaction was heated to 80 ° C. under a nitrogen atmosphere and stirred for 16 h. The remaining stop was diluted with ethyl acetate (50 mL) and approximately 3/4 of the solvent was removed under vacuum. The organic solution was washed with water (3 × 50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under reduced pressure. The product was purified twice by 0-1% by flash silica gel column chromatography eluting with dichloromethane methanol. And followed by 0-25% acetone in dichloromethane to give P-044 (296.1 mg, 51% yield) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) 8.05 (s, 1H), 7.96 (s, 1H), 7.24-7.21 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.98-6.89 (2H) , 6.85 (d, J = 8.0 Hz, 1H), 5.99 (s, 2H), 5.31 (s, 2H), 3.82 (s, 3H) ppm. LCMS = 100.0% purity. MS (APCI +) = 310.1 (M + 1). HPLC (220 nm); 97.7%. [Water and acetonitrile with 0.05% trifluroacetic acid, Column: Symmetry C18 (250 x 4.6 mm, 5 um), Gradient, Flow = 1.0 ml / min, Wash = CAN, Inj vol. = 10ul, Retention time = 21.2 min]

Example 81. Preparation for P-058.

Synthesis of 1- (3′-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H- [1,2,4] triazole (P-058). 1,2-dimethoxyethane (5 mL) of 3 fluorophenyl bromic acid (172 mg, 1.23 mmol) for 10 min To this solution was triphenyl phosphine (58.8 mg) under nitrogen. 0.112 mmol), solid potassium carbonate (463 mg, 3.36 mmol), ethanol (1 mL), water (1 mL) and palladium (II) acetate (25.1 mg, 0.112 mmol) were added and the nitrogen stream was Foamed upon resolution of I-110 (300 mg, 1.12 mmol). The reaction was stirred at 100 ° C. for 18 h. The solvent was removed under vacuum and the remainder was started in ethyl acetate (50 mL). Residual palladium was washed with water (2 × 50 mL), brine, 50 mL, and filtered and the organic extract was dried over sodium sulfate and removed under vacuum. The organic solution was saturated aqueous ammonium chloride (50 mL). ). The crude product was purified by 5% by flash silica gel column chromatography eluting with dichloromethane methanol. This was followed by a second flash silica gel column eluting with 5% acetone in dichloromethane. The solid thus obtained was recrystallized in diethyl ether (5 mL) and hexane (10 mL) and passed through a filter and washed with hexane (5 mL) to give P-058 ( 65 mg, 21% yield) as white powder. ¹ H NMR (400 MHz CDCl ₃ ): δ 8.07 (s, 1H), 7.97 (s, 1H), 7.36 (dt, J = 8.0 Hz, J = 6.0 Hz, 1H), 7.25 (m, 2H), 7.03 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.32 (s, 2H), 3.83 (s, 3H) ppm. LCMS = 100.0% purity. MS: (APCI +) = 284.1 (M + 1 ).
Example 82. Preparation for P-081.

  Synthesis of 2'-methoxy-5 '-[1,2,4] triazol-1-ylmethyl-biphenyl-3-carbonitrile (P-081). Nitrogen flow was continued for 5 minutes to remove gas and 1,2-dimethoxyethane (5 mL) of 3-cyanophenylbromate (121 mg, 0.821 mmol) for 15 minutes To solution was ) Bubbled with the solution of ethanol (0.5 mL) and water (0.5 mL) and I-110 (200 mg, 0.746 mmol). To was the solution was under nitrogen simultaneously with solid potassium carbonate (309 mg, 2.24 mmol), triphenylphosphine (39.1 mg, 0.149 mmol) and palladium (II) acetate (16.7 mg, 0.0746 mmol) was added. The reaction was heated to 80 ° C. and stirred with heating overnight. The reaction was cooled to room temperature and solvent removed under vacuum. The remainder was diluted with ethyl acetate (30 mL). The spent catalyst was then filtered off, washed with water (2 × 30 mL), and the combined aqueous layer was extracted with ethyl acetate (30 mL). The combined organic extract was washed with saturated aqueous ammonium chloride (50 mL), water (2 × 50 mL), brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. The remainder was purified by flash silica gel column chromatography eluting with acetone of dichloromethane by 3-15% to give a white solid. It was then triturated with diethyl ether (10 mL), filtered and with diethyl ether (2 × 5 mL) to give P-081 (112.8 mg, 52% yield) as a white solid. Washed.

1 H NMR (400 MHz CDCl ₃ ) 8.08 (s, 1H), 7.97 (s, 1H), 7.81 (t, J = 1.8 Hz, 1H), 7.69 (dt, J = 8.0 Hz, 1.5, 1H), 7.61 (dt, J = 8.0 Hz, 1.3, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 8.6, 2.2 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H) , 7.00 (d, J = 8.4 Hz, 1H), 5.33 (s, 2H), 3.83 (s, 3H) ppm. MS (ESI +) = 291.4 (M + 1).

Example 83. Preparation for P-082.

Synthesis of 1- (2′-methoxy-5 ′-[1,2,4] triazol-1-ylmethyl-biphenyl-3-yl) -ethanone (P-082). Nitrogen flow was continued for 5 minutes to remove gas and 1,2-dimethoxyethane (5 mL) of 3-acetylphenylbromate (135 mg, 0.821 mmol) for 20 minutes To solution ) Bubbled with the solution of ethanol (0.5 mL) and water (0.5 mL) and I-110 (200 mg, 0.746 mmol). To was the solution was under nitrogen simultaneously with solid potassium carbonate (309 mg, 2.24 mmol), triphenylphosphine (39.1 mg, 0.149 mmol) and palladium (II) acetate (16.7 mg, 0.0746 mmol) was added. The reaction was heated to 80 ° C. and stirred with heating overnight. The reaction was cooled to room temperature and solvent removed under vacuum. The remainder was diluted with ethyl acetate (50 mL). The organic solution was washed with water (3 × 50 mL). Saturated aqueous ammonium chloride (50 mL), brine, 50 mL are then dried over sodium sulfate and decolorized on activated carbon. The solvent is then removed under vacuum. The rest is a silica gel spare plate eluting with acetone of dichloromethane by 10% to give P-082 (109.1 mg, 48% yield) as a sticky rubber by 3-15%. Purified by subsequent flash silica gel column chromatography eluting with dichloromethane acetone. 1H NMR (400 MHz, CDCl ₃ ) 8.08-8.07 (m, 2H), 7.97 (s, 1H), 7.94-7.92 (m, 1 H), 7.70-7.68 (m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.30-7.26 (m, 2H), 67.00 (d, J = 8.0 Hz, 1H), 5.33 (s, 2H), 3.83 (s, 3H), 2.63 (s, 3H) ppm. LCMS = 99.5% purity. MS (APCI +) = 308.1 (M + 1).
Example 84. Preparation for P-084.

Synthesis of 1- (6-methoxy-3′-trifluoromethoxy-biphenyl-3-ylmethyl) -1H- [1,2,4] triazole (P-084). P-084 was synthesized from I-110 (200 mg, 0.746 mmol) and 3 trifluoromethoxyphenyl bromic acid (169 mg, 0.821 mmol) by the same reaction conditions used for P-081. After removal of the solvent under vacuum, the remainder was diluted with ethyl acetate (30 mL) and washed with water (30 mL). The aqueous wash was extracted with ethyl acetate (30 mL) and the combined organic extract was washed with water (2 × 50 mL). Then saturated aqueous ammonium chloride (50 mL), brine, 50 mL are dried over sodium sulfate and decolorized through activated carbon. The solvent is then removed under vacuum. The remainder was purified by flash silica gel column chromatography eluting with dichloromethane acetone by 5% to give P-084 as a yellow oil (187.3 mg, 54% yields). 1H NMR (400 MHz, DMSO-d ₆ ) 8.45 (s, 1H), 7.87 (s, 1H), 7.57-7.53 (m, 2H), 7.48-7.48 (brm, 1H), 7.43-7.39 (m, 2H ), 7.31-7.29 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.45 (s, 2H), 3.84 (s, 3H) ppm.LCMS = 100.0% purity. MS (APCI +) = 350.1 (M + 1). Example 85. Preparation P-085.

Synthesis of 1- (6-methoxy-3′-methylsulfanyl-biphenyl-3-ylmethyl) -1H- [1,2,4] triazole (P-085). P-085 was synthesized from I-110 (200 mg, 0.746 mmol) and 3 methylsulfanylphenyl bromic acid (138 mg, 0.821 mmol) using the same conditions as P-081. The reaction was excited by: diluting with ethyl acetate (30 mL) and washing with water (30 mL). The aqueous wash was extracted with ethyl acetate (30 mL) and the organic extracts combined. It was then washed with water (2 × 50 mL). Saturated aqueous ammonium chloride (50 mL), brine, and 50 mL are then decolorized with activated carbon and dried over sodium sulfate. The solvent is then removed under vacuum. The remainder was purified by flash silica gel column chromatography eluting with acetone of dichloromethane by 5% to give P-085 (117.1 mg, 50% yield) as a yellow eucalyptus of the bark. 1H NMR (400 MHz, CDCl ₃ ) 8.06 (s, 1H), 7.97 (s, 1H), 7.37 (t, J = 1.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.26-7.23 (m, 4H), 6.97 (d, J = 8.4 Hz, 1H), 5.32 (s, 2H), 3.81 (s, 3H), 2.50 (s, 3H) ppm.

LCMS = 100.0% purity. MS (APCI +) = 312.1 (M + 1).
Example 86. Preparation for P-086.

Synthesis of 1- (6,3′-Dimethoxy-biphenyl-3-ylmethyl) -1H- [1,2,4] triazole (P-086). P-086 was synthesized from I-110 (200 mg, 0.746 mmol) and 3 methoxyphenylbronic acid (125 mg, 0.821 mmol) using the same conditions as P-081. The reaction was cooled to room temperature and solvent removed under vacuum. The rest was suspended in ethyl acetate (30 mL). The organic extracts were combined and washed with water (30 mL) (a watery wash extracted with ethyl acetate (30 mL)). The organic extract was washed with water (3 × 30 mL). Then saturated aqueous ammonium chloride (30 mL), brine, and 30 mL are decolorized with activated carbon and dried over sodium sulfate. The solvent is then removed under vacuum. The product was purified by flash silica gel column chromatography eluting with dichloromethane acetone by 5% to obtain P-086 (148.9 mg, 68% yield) as a yellow oil. ¹ H NMR (400 MHz, acetone-d ₆ ) 8.45 (s, 1H), 7.86 (s, 1H), 7.36-7.28 (m, 3H), 7.10-7.03 (m, 3H), 6.91-6.88 (m, 1H), 5.43 (s, 2H), 3.82 (s, 6H) ppm. LCMS = 100% purity MS (APCI +) = 296.1 (M + 1).
Example 87. Preparation for P-102.

Synthesis of 3- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -phenol (P-102). To a 20 mL vial with agitation, the stick was added I-70 (0.30 g, 0.93 mmol), 3 hydroxyphenyl bromic acid (0.19 g, 1.40 mmol), tri-phenyl phosphine (49 mg, .0. 19 mmol), K3PO4 (0.40 g, 1.86 mmol), DME (5 mL), water (0.5 mL) and ethanol (0.5 mL). N2 gas was bubbled by the stirred reaction for 10 minutes. N2 was bubbled for an additional 5 minutes and palladium (II) acetate (21 mg, 0.09 mmol) was added. The reaction was stirred at 80 ° C. under N 2 for 18 hours. 20 mL water and 20 mL ethyl acetate were added and the reaction was cooled to room temperature. The watery one was extracted with ethyl acetate (3 × 15 mL) and the layers were separated. Organic fertilizer was combined, dried and concentrated with sodium sulfate. The remainder was purified by flash column chromatography using 15% ethyl acetate / Hexanes to obtain 177 mg (57%) of P-102 as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 3.81 (s, 3 H) 3.93 (s, 2 H) 4.72 (s, 1 H) 6.62-6.72 (m, 2 H) 6.79 (d, J = 7.7 Hz, 1 H) 6.94 (d, J = 8.3 Hz, 1 H) 7.11-7.23 (m, 3 H) 7.54 (t, J = 8.0 Hz, 1 H) 7.82 (d, J = 7.8 Hz, 1 H) 8.16 (dd , J = 8.2, 1.34 Hz, 1 H) 8.39 (t, J = 1.8 Hz, 1 H) ppm. MS: (APCI-) 335.1
Example 88. Preparation for P-103.

Synthesis of [3- (6-Methoxy-3′-nitro-biphenyl-3-ylmethyl) -phenyl] -methanol (P-103). The same procedure used for P-102 was used except that 3 hydroxybenzyl bromic acid was used. The title compound P-103 was obtained as a yellow oil (209 mg, 64%). ¹ H NMR (400 MHz, CDCl ₃ ) 1.62 (t, J = 5.8 Hz, 1 H) 3.81 (s, 3 H) 3.99 (s, 2 H) 4.67 (d, J = 5.6 Hz, 2 H) 6.94 ( d, J = 8.3 Hz, 1 H) 7.10-7.24 (m, 5 H) 7.27-7.34 (m, 1 H) 7.54 (t, J = 8.0 Hz, 1 H) 7.83 (d, J = 7.7 Hz, 1 H) 8.16 (dd, J = 8.3, 1.0 Hz, 1 H) 8.38 (s, 1 H) ppm.LC/MS = 96.8%, (APCI-) 349.1
Example 89. Preparation for P-104.

Integration of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-pyridine-2-1 (P-104). To a 20 mL vial with agitation, the sticks added 2-hydroxypyridine (74 mg, 0.78 mmol), K 2 CO 3 (0.24 g, 1.71 mmol), I-70 (0.30 g, 0.94 mmol) and 3 mL of DME. Mixing was stirred at 80 ° C for 18 hours and cooled to room temperature (filtered to remove solids) and concentrated. The remainder was purified by flash column chromatography using 30% -75% ethyl acetate / hexanes to obtain 124 mg (40%) of P-104 as a tan solid. 1H NMR (500 MHz, CDCl3) 8.38 (t, J = 1.9 Hz, 1 H), 8.17 (dd, J = 1.3, 8.2 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.9 Hz, 1 H), 7.40-7.27 (m, 5 H), 6.99 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 8.9 Hz, 1 H), 6.17 ( td, J = 1.2, 6.7 Hz, 1 H), 5.14 (s, 2 H), 3.82 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3) δ 162.8, 156.4, 148.3, 139.8, 139.6, 137.3 , 135.8, 130.9, 130.1, 129.3, 129.1, 128.7, 124.7, 122.2, 121.6, 111.9, 106.5, 55.9, 51.7 ppm. LC / MS = 96.7%, 337.1 (APCI +).
Example 90. Preparation for P-105.

Into was synthesized in 2- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -phenol (P-105), a 20 mL vial with a stir bar was I-70 (0 .30 g, 0.93 mmol), 2-hydroxyphenyl bromic acid (GS39) (0.19 g, 1.40 mmol), triphenylphosphine (49 mg, 0.19 mmol), K3PO4 (0.40 g, 1.86 mmol) , DME (5 mL), water (0.5 mL) and ethanol (0.5 mL) were added. N2 gas was bubbled by the stirred reaction for 10 minutes. N2 was bubbled for an additional 5 minutes and palladium (II) acetate (21 mg, 0.09 mmol) was added. The reaction was stirred at 80 ° C. for 18 hours and the vial was capped. 5 mL water and 5 mL ethyl acetate were added and the reaction was cooled to room temperature. The watery one was extracted with ethyl acetate (3 × 10 mL) and the layers were separated. Organic fertilizer was combined, dried and concentrated with sodium sulfate. The remainder was purified by flash column chromatography using 15% ethyl acetate / hexane to yield 120 mg (38%) of P-105 as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 3.80 (s, 3 H) 3.99 (s, 2 H) 4.74 (s, 1 H) 6.78 (d, J = 7.8 Hz, 1 H) 6.90 (t, J = 7.5 Hz, 1 H) 6.94 (d, J = 8.2 Hz, 1 H) 7.09-7.17 (m, 2 H) 7.19-7.25 (m, 2 H) 7.53 (t, J = 8.0 Hz, 1 H) 7.82 (d , J = 7.8 Hz, 1 H) 8.15 (dd, J = 8.2, 1.2 Hz, 1 H) 8.38 (t, J = 1.8 Hz, 1 H) ppm. MS: 334.1 (APCI-)
Example 91. Preparation for P-119.

Synthesis of 5-fluoro-2- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -phenol (P-119). To a 20 mL vial with agitation, the stick was added I-70 (0.30 g, 0.93 mmol), 4-fluoro-2hydroxyphenyl bromic acid (0.22 g, 1.40 mmol), tri-phenyl phosphine ( 49 mg, 0.19 mmol), K3PO4 (0.40 g, 1.86 mmol), DME (5 mL), water (0.5 mL) and ethanol (0.5 mL). N2 gas was bubbled by the stirred reaction for 10 minutes. N2 was bubbled for an additional 5 minutes and palladium (II) acetate (21 mg, 0.09 mmol) was added. The reaction was stirred at 80 ° C. for 18 hours and the vial was capped. 5 mL water and 5 mL ethyl acetate were added and the reaction was cooled to room temperature. The watery one was extracted with ethyl acetate (3 × 10 mL) and the layers were separated. Organic fertilizer was combined, dried and concentrated with sodium sulfate. The remainder is a flush with 15% ethyl acetate / hexane followed by a preparative TLC using 1: 1 dichloromethane / Hexanes to obtain 24.3 mg (7%) of P-119 as a pale yellow oil. -Purified by column chromatography. ¹ H NMR (400 MHz, CDCl3) 3.81 (s, 3 H) 3.94 (s, 2 H) 5.07 (br s, 1 H) 6.55 (dd, J = 9.8, 2.6 Hz, 1 H) 6.61 (td, J = 8.4, 2.55 Hz, 1 H) 6.94 (d, J = 8.3 Hz, 1 H) 7.07 (dd, J = 8.3, 6.7 Hz, 1 H) 7.17-7.24 (m, 2 H) 7.54 (t, J = 8.0 Hz, 1 H) 7.81 (d, J = 7.7 Hz, 1 H) 8.16 (dd, J = 8.3, 1.3 Hz, 1 H) 8.38 (t, J = 1.8 Hz, 1 H) ppm. LC / MS = 97.2%, 352.1 (APCI-)
Example 92. Preparation for P-134

Synthesis of 2- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -benzoic acid methyl ester (I-121). To a 20 mL vial with agitation, the stick was added I-70 (0.30 g, 0.93 mmol), 2 methoxycarbonylphenylbornic acid (0.18 g, 1.02 mmol), triphenylphosphine (49 mg, 0. 19 mmol), K3PO4 (0.40 g, 1.86 mmol), DME (5 mL), water (0.5 mL) and ethanol (0.5 mL). N2 gas was bubbled by the stirred reaction for 10 minutes. N2 was bubbled for an additional 5 minutes and palladium (II) acetate (21 mg, 0.09 mmol) was added. The reaction was stirred at 80 ° C. for 18 hours and the vial was capped. 5 mL water and 5 mL ethyl acetate were added and the reaction was cooled to room temperature. The watery one was extracted with ethyl acetate (3 × 10 mL) and the layers were separated. Organic fertilizer was combined, dried and concentrated with sodium sulfate. The remainder was purified by flash column chromatography using 10% acetone / hexanes to yield 241.0 mg (69%) of I-121 as a colorless oil.

[2- (6-Methoxy-3′-nitro-biphenyl-3-ylmethyl) -phenyl] -methanol (P-134). In a 20 mL vial with 4 mL dry THF and agitation, the stick was I-121 (126.5 mg, 0.34 mmol). DIBAL-H (0.84 mL, 0.84 mmol, 1.0 M in hexane) was added and the solution was cooled to 0 ° C. The reaction was stirred at 0 ° C. for 30 minutes. Aqueous 1N HCl (1 mL) was added followed by 5 mL of water. The aqueous solution was extracted with ethyl acetate (3 × 10 mL). The organics were combined, dried over sodium sulfate and concentrated. The product was purified by flash column chromatography using 12% acetone / hexanes to yield 71 mg (66%) of P-134 as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 1.44 (t, J = 5.9 Hz, 1 H), 3.80 (s, 3 H), 4.10 (s, 2 H), 4.70 (d, J = 5.8 Hz, 2 H ), 6.92 (d, J = 8.9 Hz, 1 H), 7.10-7.16 (m, 2 H), 7.16-7.22 (m, 1 H), 7.27-7.30 (m, 2 H), 7.39-7.45 (m , 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.80 (d, J = 7.7 Hz, 1 H), 8.15 (dd, J = 8.2, 1.3 Hz, 1 H), 8.38 (t, J = 1.7 Hz, 1 H). LC / MS = 99.9%, 349.1 (APCI-).
Example 93. Preparation for P-108

  Synthesis of 1- (6-methoxy-3′-methoxymethyl-biphenyl-3-ylmethyl) -1H- [1,2,4] triazole (P-108). P-108 was synthesized from I-110 (200 mg, 0.746 mmol) and 3 methoxymethylphenyl bromic acid (136 mg, 0.821 mmol) using the same conditions as P-081. The reaction was cooled to room temperature and solvent removed under vacuum. The rest was suspended in ethyl acetate (30 mL). The organic extracts were combined and washed with water (30 mL) (a watery wash extracted with ethyl acetate (30 mL)). The organic extract was washed with water (3 × 30 mL). Then saturated aqueous ammonium chloride (2 × 30 mL), brine, 30 mL are decolorized with activated carbon and dried over sodium sulfate. The solvent is then removed under vacuum. The product is purified by flash silica gel column chromatography eluting with 0-25% dichloromethane acetone to obtain P-108 (49.0 mg, 19% yield) as a yellow oil. The silica gel pre-plate eluting with 3% dichloromethane acetone for the three developments.

¹ H NMR (CDCl ₃ ) d: 8.444 (s, 1H), 7.849 (s, 1H), 7.44-7.354 (m, 4H), 7.295-7.280 (m, 2H), 7.104-7.086 (m 1H), 5.435 (s, 2H), 4.472 (s, 2H), 3.805 (s, 3H), 3.350 (s, 3H).

LCMS = 100.0% purity. MS (APCI +) = 310.1 (M + 1). Example 94. Preparation for P-495

Synthesis of 1- (3′-methanesulfonyl-6-methoxy-biphenyl-3-ylmethyl) -1H- [1,2,4] triazole (P-495). P-495 was synthesized from I-110 (200 mg, 0.746 mmol) and 3 methanesulfonylphenyl bromate (136 mg, 0.821 mmol) by a similar process up to P-081. Upon completion, a watery laundry was extracted with ethyl acetate (2 × 30 mL) and the remainder was washed with ethyl acetate (20 mL), washed in 20 mL. The organic extract was combined and washed with water (3 × 50 mL), saturated aqueous ammonium chloride (2 × 50 mL) and brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. The impure product was washed with 5-15% acetone in dichloromethane and 5% to give P-495 (145.0 mg, 57% yield) by separation on silica gel with dichloromethane acetone. It was purified by flash silica gel column chromatography eluting a pre-eluting metal plate. ¹ H NMR (400 MHz, CDCl ₃ ) d: 8.09-8.08 (m, 2H), 7.97 (s, 1H), 7.97-7.90 (m, 1H), 7.79-7.77 (m, 1H), 7.60 (t, J = 6.4 Hz, 1H), 7.32-7.26 (m, 2H), 7.01 (d, J = 6.8 Hz, 1H), 5.34 (s, 2H), 3.83 (s, 3H), 3.09 (s, 3H).

LCMS = 100.0% purity. MS (APCI +) = 344.0 (M + 1).
Example 95. Preparation for P-163.

<< Reaction Process Formula 30 >>

  Synthesis of 2-bromo-6- (4-fluoro-benzoyl) -3methoxybenzonitrile (I-123). To a cooled (0 ° C) solution of con (2-amino-3-bromo-4methoxyphenyl)-(4-fluoro-phenyl) -methanone (I-122, 0.32 g, 1.0 mmol). NaNO2 (0.065 g, 0.95 mmol) with a solution of HCl (1.5 mL). The reaction mixture was stirred at 0 ° C. for 10 minutes. It was then added at 0 ° C. to a suspension of water (0.5 mL) in Cu (I) CN (0.031 g, 1.2 mmol) and toluene (1 mL) over 5 minutes. The reaction mixture was slowly warmed to room temperature. And stirred at room temperature for 2 h and then at 50 ° C. for 30 min, the reaction was extracted with dichloromethane (3 × 5 mL) and the combined organic extracts were washed with brine and dried over Na 2 SO 4 Filtered and concentrated under vacuum. The remainder was purified by silica gel column chromatography with 1: 1 dichloromethane-hexane and then dichloromethane to yield I-123 (0.201 g, 61% yield) as a white solid.

  Synthesis of 2-bromo-6- (4-fluoro-benzyl) -3methoxybenzonitrile (I-124): Tri-fluoroacetic acid (1.0 mL) of I-123 (0.15 g, 0.45 mmol) To the solution, triethylsilane (0.55 g, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. It agglomerated under vacuum to yield I-124 (0.14 g, 94% yield) as a white solid.

Synthesis of 3- (4-fluoro-benzyl) -6-methoxy-3'-nitro-biphenyl-2-carbonitrile (P-163): up to I-124 (0.14 g, 0.42 mmol), 3-nitrophenyl Bromic acid (0.07 g, 0.44 mmol), PPh3 (0.05 g, 0.21 mmol), K2CO3 (0.02 g, 0.16 mmol) and Pd (OAc) 2 (0.01 g, 0.06 mmol) are Added dioxane (10 mL) and EtOH—H 2 O (1: 1, 5 mL). The reaction was degassed by an Argon flow for 5 minutes. The reaction was then stirred at 85 ° C. under Ar for 18 h. H2O (40 mL) and dichloromethane (40 mL) were added and the reaction was cooled to room temperature (concentrated under vacuum). The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated under vacuum. The remainder was purified by silica gel column chromatography with dichloromethane to yield P-163 (0.07 g, 46% yield) as an off-white solid. 1H NMR (CDCl3, 400MHz): 8.12-8.26 (m, 2 H), 7.54-7.62 (m, 2 H), 7.1-7.2 (m, 3 H), 6.9-7.04 (m, 2 H), 6.86 ( d, J = 8.4 Hz, 1 H), 4.07 (s, 2 H), 3.71 (s, 3 H); MS (APCI +): 383.1 (M + 1).
Example 96. Preparation for P-169

  Synthesis of 1- (3′-methanesulfinyl-6-methoxy-biphenyl-3-ylmethyl) -1H- [1,2,4] triazole (P-169). 30% hydrogen peroxide by weight of aqueous solution (1 mL) was diluted with glacial acetic acid (9 mL). The solution of glacial acetic acid (300 uL) in P-085 (38.1 mg, 0.111 mmol) was stirred at room temperature and the hydrogen peroxide solution was added dropwise (107 uL total solution, 3.78 mg of 3.78 mg Hydrogen peroxide, 0.111 mmol). The reaction was stirred at room temperature for 1 h. After completion, solid sodium carbonate was added to the mix (˜100 mg). The reaction was diluted with water (500 uL) and extracted with ethyl acetate (3 × 1 mL). The organic extract was combined. It was then dried over sodium sulfate and the solvent was removed under vacuum. The rest was dried under high vacuum overnight to give P-169 (25.6 mg, 70% yield).

1H NMR (400 MHz, CDCl ₃ ) 8.08 (s, 1H), 7.97 (s, 1H), 7.79-7.78 (m, 1H), 7.64-7.54 (m, 3H), 7.31-7.28 (m, 2H), 7.00 (d, J = 8.40 Hz, 1H), 5.33 (s, 2H), 3.83 (s, 3H), 2.76 (s, 3H) ppm. LCMS = 96.4% purity. MS (APCI +) = 328.1 (M + 1 ).
Example 97. Preparation for P-530

Synthesis of (4-amino-phenyl)-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanone (I-127). Discontinuation of I-126 (108 mg, 0.28 mmol), Fe powder, 55 mg, 0.98 mmol, NH 4 Cl (75 mg, 1.40 mmol) (water (1 mL) was stirred at 80 ° C. for 2 hours and ethanol (3 mL) ). Upon completion, the reaction was filtered through celite, washed with ethyl acetate and concentrated under vacuum. The remainder was washed with saturated aqueous NaHCO3, starting in ethyl acetate. The composite excerpt was concentrated under vacuum to give the compound I-127 (90 mg, 90% yield) as a yellow eucalyptus of the bark.

Synthesis of N- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl) -phenyl] -acetamide (I-128). A solution of I-127 (88 mg, 0.25 mmol) in pyridine (2 mL) and acetic anhydride (35 uL, 0.37 mmol) was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate and washed with 1N aqueous HCl. The composite extract was dried over Na2SO4 and concentrated to a solid that was triturated with diethyl ether to give I-128 (21 mg, 21% yield) as a white solid.

Synthesis of N- {4- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -1-hydroxyethyl] -phenyl} -acetamide (P-530). The reaction disappeared by the addition of saturated aqueous NH 4 Cl, a mixture of I-128 (18.4 mg, 0.046 mmol) in THF (1 mL) and methyl magnesium bromide (46 uL, 0.14 mmol, 3.0 M ether) was Stir at room temperature for 10 minutes. . The reaction was extracted with ethyl acetate and the combined extract was detersive with brine, dried over Na2SO4 and concentrated under vacuum. The remainder was filtered into SiO2 to remove any remaining inorganic impurities to give P-530 (4.6 mg, 24% yield) as a white solid. ¹ H NMR (400 MHz,, DMSO-d ₆ ) 9.85 (s, 1 H), 7.70 (t, J = 9.1 Hz, 1 H), 7.50-7.34 (m, 4 H), 7.29-7.21 (m, 3 H), 7.21-7.12 (m, 1 H), 6.97 (d, J = 8.9 Hz, 1 H), 3.74 (s, 3 H), 2.00 (s, 3 H), 1.82 (s, 3 H)

Purification of P-560 and P-561

  The enantiomers of P-530 were separated by semi-preparative HPLC. Samples for injection were dissolved in warm EtOH. The column used was Chiralpack AD (250 X 20 mm, 10 um). The mobile phase was with 15% EtOH, 85% hexane, 0.2% DEA. And the fraction was isocratic to 9.9 mL / min, the fraction was collected by manually changing the fraction and the injection volume was 385 uL. UV detection was set at 254 nanometers and run time was 60 minutes. The retention time of the first enantiomer collected was 33.2 minutes, which is P-560, and the second enantiomer was 41.5 minutes, which was P-561.

  The enantiomeric purity of each fragment was then measured by analytical scale enantiomeric HPLC using a Chiralpack AD column (250 x 4.6 mm, 5 um). The mobile phase was with 15% EtOH, 85% hexane, 0.2% DEA. And it was isocratic to 1.0 mL / min, the injection volume was 10 uL, the run time was 30 min, and the UV detection was set at 254 nanometers. Retention times were 12.3 and 14.9 minutes, respectively, and the first racemic mixed sample was injected. The enantiomeric excess was determined to be 100.0% and the retention time of P-560 was 12.3 minutes. The enantiomeric excess was determined to be 99.2% and the retention time of P-561 was 15.0 minutes.

  The absolute stereochemistry of P-560 and P-561 is unknown. The stereochemistry of the structure was arbitrarily derived.

  N- {4-[(R) -1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -1-hydroxyethyl] -phenyl} -acetamide (P-560).

¹ H NMR (400 MHz, DMSO-d ₆ ) 9.85 (s, 1 H), 7.70 (t, J = 9.1 Hz, 1 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.41-7.37 ( m, 2 H), 7.29-7.22 (m, 3 H), 7.19-7.14 (m, 1 H), 6.97 (d, J = 8.9 Hz, 1 H), 5.67 (br. s., 1 H), 3.74 (s, 3 H), 2.00 (s, 3 H), 1.82 (s, 3 H)

  N- {4-[(S) -1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -1-hydroxyethyl] -phenyl} -acetamide (P-561).

¹ H NMR (400 MHz, DMSO-d ₆ ) 9.85 (s, 1 H), 7.70 (t, J = 9.1 Hz, 1 H), 7.44 (d, J = 8.6 Hz, 2 H), 7.41-7.36 ( m, 2 H), 7.29-7.21 (m, 3 H), 7.20-7.15 (m, 1 H), 6.97 (d, J = 8.9 Hz, 1 H), 5.67 (br s, 1 H), 3.74 ( s, 3 H), 2.00 (s, 3 H), 1.82 (s, 3 H)
Example 98. Preparation for P-547

<< Reaction Process Formula 31 >>

  Integration of three '-Chloro-2 methoxy biphenyls (I-16). Of 2-iodoanisol (3.00 g, 12.8 mmol) in water (10 mL) and methanol (50 mL), 3-chlorophenyl bromic acid (2.41 g, 15.4 mmol) and potassium carbonate (3.54 g, 25.6 mmol). The discontinuation was removed by a 20 minute nitrogen flow. The solution was stirred overnight at room temperature (18 h) and To was stopped To was added palladium (II) acetate (57.6 mg, 0.2564 mmol). To the reaction was added ethyl acetate (100 mL) and water (100 mL). The layer was cut off. The aqueous layer was then extracted with ethyl acetate (100 mL) and combined with the organic extract. Brine (150 mL) (decolorized with activated carbon) was dried over sodium sulfate and the organic solution was washed with water (2 × 150 mL) and the solvent was removed under reduced pressure. The resulting residue is flash silica gel column chromatography eluting ethyl acetate in hexane by 10-30% to give I-16 (2.50 g, 89% yield) as a colorless oil. It was purified by. 1H NMR (400 MHz CDCl3) 7.53 (t, J = 1.8 Hz, 1H), 7.40 (dt, J = 7.2 Hz, 1.6 Hz, 1H), 7.38-7.28 (m, 4H), 7.05-6.97 (m, 2H ), 3.82 (s, 3H).

  Synthesis of (3′-chloro-6-methoxy-biphenyl-3-yl)-(4-nitrophenyl) -methanone (I-129). A solution of I-16a (1.50 g, 6.86 mmol) in nitrobenzene (6 mL) was cooled to 0 ° C. in an ice-water bath. Trichloride (1.10 g, 8.23 mmol) aluminum was an additional portionwise and the solution was stirred at 0 ° C. for 1 h. To the solution was added 4-nitro-benzoyl chloride (1.53 g, 8.23 mmol) and the reaction was allowed to warm to room temperature and stirred for 20 h. The solution was poured into 100 mL ice water mix and stirred for 2 h. The yellow oil was extracted into ethyl acetate (2 × 100 mL) and the organic extracts were combined. The solvent removed under vacuum to give the raw I-129 to the resulting oil was flash silica gel column chromatography (hexanes) to give I-129 (1.66 g, 66% yield). 10-33% ethyl acetate) and the extract was washed with saturated aqueous sodium bicarbonate (100 mL), water (2 × 150 mL) and brine (150 mL) (dried over sodium sulfate).

1H NMR (400 MHz CDCl3) d: 8.35-8.34 (m, 2H), 7.92-7.91 (m, 2H), 7.84-7.81 (m, 2H), 7.51-7.51 (m, 1H), 7.37-7.34 (m , 3H), 7.08 (d, J = 6.8 Hz, 1H), 3.94 (s, 3H).
MS (APCI +) = 304.1 (M-63.0)

  Synthesis of 3'-chloro-2-methoxy-5- [bis-secondary- (4-nitrophenyl) -methyl] -biphenyl (I-130). The solution of I-129 (500 mg, 1.36 mmol) in dichloromethane (10 mL) was removed with nitrogen. The resulting orange solution was cooled to 0 ° C. in an ice water bath and to the solution was added duetro-trifluoroacetic acid (3.91 g, 34.0 mmol). A wise sodium-boron-containing deuteride (569 mg, 13.6 mmol) portion over 45 minutes is slowly added to the solution, and the reaction is allowed to stir overnight at room temperature. It was. The reaction was basified to pH 9 with saturated aqueous sodium bicarbonate and extracted into ethyl acetate (75 mL). The excerpt was washed with water (2 × 50 mL) and brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. The crude material was purified by flash silica gel column chromatography (10% ethyl acetate in hexanes) to give I-130 (500 mg, quantitative yield).

  1H NMR (400 MHz CDCl3) 8.16-8.14 (m, 2H), 7.489-7.48 (m, 1H), 7.37-7..26 (m, 5H), 7.13 (dd, J = 8.4 Hz, 2.4 Hz, 1H ), 7.10 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H).

  Synthesis of 4- [Bisdeutero- (3′-chloro-6-methoxy-biphenyl-3-yl) -methyl] -phenylamine (I-131). A suspension of I-130 (440 mg, 1.24 mmol), iron powder (241 mg, 4.33 mmol) and ammonium chloride (337 mg, 6.31 mmol) in ethanol (5 mL) and water (1.6 mL) is 1 h At room temperature for 30 minutes and at 100 ° C for 30 minutes. Ethanol was removed under reduced pressure (reaction diluted with water (50 mL)) and extracted with ethyl acetate (2 × 50 mL). The composite extract was washed with water (2 × 50 mL) and brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum to give I-131 (279 mg, 70% yield) as an orange oil.

  1H NMR (400 MHz CDCl3) d: 7.43 (m, 1H), 7.31-7.19 (m, 3H), 7.07-7.04 (m, 2H), 6.93-6.910 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.57-6.55 (m, 2H), 3.72 (s, 2H), 3.50 (s, 2H).

  Synthesis of {4- [Bisdutero- (3'-chloro-6-methoxy-biphenyl-3-yl) -methyl] -phenyl} -urea (P-547). A suspension of I-131 (270 mg, 0.829 mmol) and sodium cyanate (107.7 mg, 1.66 mmol) in water (15 mL) and glacial acetic acid (7.5 mL) was stirred at room temperature until morning. It was done. To the solution was added aqueous saturated sodium bicarbonate (10 mL) and the reaction was extracted with ethyl acetate (50 mL, 25 mL). The extracts combined. It was then washed with water (50 mL) and brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum to give P-547 as an orange gum. The material is purified by flash silica gel column chromatography (withdrawn with 10-25% ethyl acetate in dichloromethane) to give P-547 (111 mg, 36% yield) as a white powder Were recrystallized in water (10 mL) and isopropanol (8 mL).

1H NMR (400 MHz, d6-DMSO): 8.40 (s, 1H), 7.48-7.36 (m, 4H), 7.29-7.27 (m, 2H), 7.20-7.10 (m, 2H0, 7.09-7.08 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 5.75 (s, 2H), 3.74 (s, 3H).
LCMS = 96.9% purity. MS (APCI +) = 369.1 (M + 1), 326.1 (M-42.0).
HPLC (254 nm); 96.6%. [Mobile Phase A and Mobile Phase B = Water and Acetonitrile, Symmetry C18, (250 x 4.6 mm, 5 um), Flow = 1.0 mL / min, Inj. Wash = ACN, Inj. Vol. = 10 uL. Retention time = 28.37 min]

  Example 99. Preparation of P-537, P-538, and P-539.

<< Reaction Process Formula 32 >>

  Synthesis of (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-nitrophenyl) -methanone (I-133). To the solution of 4-nitro-benzoyl chloride of nitrobenzene (6 mL) (1900 mg, 10.2 mmol) was aluminum trichloride (1360 mg, 10.2 mmol) added at 0 ° C. Three '-chloro-6-fluoro-2methoxy biphenyls (2.01 g, 8.5 mmol) of nitrobenzene (1 mL) were added at 0 ° C and the mixture could be heated to room temperature and 1 h Stir at room temperature for (cooled to 0 ° C). The reaction mixture was allowed to heat to room temperature and stirred for 24 h. The reaction mixture was cooled to −10 ° C., washed with water (2 × 10 mL), saturated aqueous sodium bicarbonate (10 mL), brine (30 mL) and extracted with ice water (50 mL) (ethyl acetate (2 × 25 mL)). And dried over Na2SO4. . After filtration and removal of the solvent, the crude oil was purified by crystallization from ether-hexane to give I-133 (3.00 g, 91% yield).

  Synthesis of secondary- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-nitrophenyl) -methanol (P-537). To a mixture of THF-D 2 O (1: 1, 20 mL) I-133 (500 mg, 1.25 mmol) was added 0 ° C NaBD 4 (190 mg, 3.1 mmol). The reaction mixture was allowed to heat to room temperature and was stirred for 24 h. The mixture is poured into ice water (100 mL), neutralized with aqueous saturated NH 4 Cl (5 mL), extracted with ethyl acetate (3 × 30 mL), washed with water (20 mL) and brine (30 mL). And dried over Na2SO4. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate-hexane as eluent to give P-537 (350 mg, 70% yield).

1H NMR (CDCl ₃ , 400 MHz) 8.21 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.23-7.37 (m, 5 H), 6.78 (dd, J = 8.8, 1.2 Hz, 1 H), 3.77 (s, 3 H), 2.39 (s, 1 H) .Calc.388.8; APCI ⁺ (M-OH): 371.1, 100%.

  Synthesis of secondary- (4-amino-phenyl)-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanol (P-538). To a mixture of P-537 (300 mg, 0.7 mmol) in ethyl acetate (10 mL), Pd / C (10%, 450 mg, 4 mmol) was added at room temperature. Mixing was shaken under Hydrogen Air (30 psi) for 60 minutes and the reaction vessel was sealed. The solid was passed through a filter and filtered water was concentrated to give the crude product. The crude oil was purified by silica gel column chromatography with ethyl acetate-hexane as eluent and further purified by preparative TLC to obtain P-538 (45 mg, 16% yield).

1H NMR (CDCl ₃ , 400 MHz) 7.46 (t, J = 8.4 Hz, 1 H), 7.23-7.37 (m, 4 H), 7.18 (d, J = 8.4 Hz, 2 H), 6.77 (dd, J = 8.8, 1.2 Hz, 1 H), 6.55 (d, J = 8.4 Hz, 2 H), 3.77 (s, 3 H), 2.10 (s, 1 H) .Calc.358.8; APCI ⁺ (M-OH) : 341.1, 91%.

  Synthesis of (4-amino-phenyl)-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanone (I-134). In solution of I-133 (500 mg, 1.2 mmol) in EtOH-H 2 O (1: 1, 15 mL) was additional solid NH 4 Cl (200 mg, 4 mmol) and iron powder (150 mg, 3 mmol) And the reaction was stirred at room temperature for 72 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (3 × 30 mL), washed with water (20 mL) and brine (30 mL), dried over Na 2 SO 4 and filtered. The solvent was removed under vacuum to obtain I-134 (380 mg, 82% yield).

  Synthesis of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl) -phenyl] -urea (P-434). To the solution of I-134 (220 mg, 0.7 mmol) in pyridine (1 mL) was added THF (4 mL) and the reaction was stirred at room temperature for 36 h and trimethylsilylicyanate (1 mL, excess). The mixture was poured into 25 mL of aqueous ice. To stop, saturated aqueous sodium bicarbonate (5 mL) was added and the resulting mixture was stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (3 × 30 mL) (washed with water (20 mL)) and brine (30 mL), dried over Na 2 SO 4 and filtered. The solvent was removed under vacuum and the crude product was purified by silica gel column chromatography with ethyl acetate-hexane as eluent to obtain P-434 (50 mg, 20% yield).

Synthesis of {4-[(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -hydroxy-secondary-methyl] -phenyl} -urea (P-539). To a mixture of THF (5 mL) and D 2 O (2 mL) P-434 (50 mg, 0.13 mmol) was added 0 ° C NaBD4 (50 mg, 0.25 mmol). The reaction mixture was allowed to heat to room temperature and was stirred for 24 h. The reaction mixture was poured into 20 mL ice water. It was then neutralized with NH 4 Cl (sitting. 2 mL), extracted with ethyl acetate (3 × 10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 (passed through a filter) and solvent removed under vacuum. After removal of the solvent, the remainder was purified by preparative TLC to give P-539 (12 mg, 26% yield). 1H NMR (DMSO-d6, 400 MHz) d: 8.45 (s, 1 H), 7.49 (t, J = 8.8 Hz, 1 H), 7.41-7.44 (m, 2 H), 7.24-7.34 (m, 4 H), 7.17 (d, J = 8.8 Hz, 1 H), 6.97 (d, J = 9.2 Hz, 1 H) 5.79 (s, 1 H), 3.73 (s, 3 H) ppm.Calc.401.85; APCI ⁺ (M-OH): 384.1, 98.6%.
Example 100. Preparation for P-541

[4- (3′-Chloro-6-ethoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-541). Discontinuation of Et-I (23 uL, 0.28 mmol) in P-421 (66 mg, 0.19 mmol), K 2 CO 3 (39 mg, 0.28 mmol) and acetone (2 mL) was stirred at 50 ° C. for 16 h. An additional 50 uL of EtI and 80 mg of K 2 CO 3 were additional amd where the reaction was stirred at 50 ° C. for 4 h. The reaction was stirred at 60 ° C. for 2 h, to the reaction was added 80 mg Cs 2 CO 3 and 50 uL EtI and the reaction was concentrated. The crude product was 20%, purified by flash column chromatography, -30% Acetone / DCM, which was purified to give the title compound as a white solid, P-541 (37 mg, 51%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.40 (s, 1 H), 7.53 (s, 1 H), 7.45-7.39 (m, 2 H), 7.39-7.34 (m, 1 H), 7.28 (d, J = 8.3 Hz, 2 H), 7.19-7.13 (m, 2 H), 7.09 (d, J = 8.5 Hz, 2 H), 7.01 (d, J = 8.1 Hz, 1 H), 5.75 (s, 2 H), 4.01 (q, J = 7.0 Hz, 2 H), 3.82 (s, 2 H), 1.31-1.18 (m, 3 H). LC / MS = 96.5%, 381.1 (APCI +).
Example 101. Preparation for P-542

  {4- [6- (2-amino-ethoxy) -3, '-chloro-biphenyl-3-ylmethyl] -phenyl} -urea (P-542). A suspension of sodium iodide (20 mg) in P-421 (100 mg, 0.28 mmol), 2-bromoethylamine hydrobromide (204 mg, 8.8 mmol), Cs2CO3 (600 mg, 18.4 mmol) and acetone (10 mL). The liquid was stirred at reflux for 20 h. The reaction mixture was then a portion between dichloromethane and water, and the organic layer was extracted with 1N NaOH followed by 1N HCl. The acidic extract was adjusted to pH 10 by addition of NaOH followed by extraction with dichloromethane. The residue was color layer analyzed with dichloromethane: methanol (9: 1) to obtain P-542 (9 mg, 8.1% yield) as a solid and the solvent was removed in vacuo.

¹ H NMR (CDCl ₃ ) 7.50-7.52 (m, 1H), 7.28-7.32 (m, 2H), 7.17-7.23 (m, 3H), 7.11-7.13 (m, 2H), 7.09-7.11 (m, 1H ), 6.89-6.92 (m, 2H), 3.96 (t, J = 5 Hz, 2H), 3.93 (s, 2H), 2.99 (t, J = 5 Hz, 2H), APCI (M + 1; 396.1) LCMS 95%.
Example 102. Preparation for P-543

  {4- [3'-Chloro-6- (tetrahydro-furan-2-ylmethoxy) -biphenyl-3-ylmethyl] -phenyl} -urea (P-543). Phenol P-421 (mg mixed in 100, 0.28 mmol), DMF (2 mL) in K 2 CO 3 (78 mg, 0.56 mmol) was heated at 80 ° C. for 24 h and brominated (50 mg, 0 .28 mmol) Tetrahydrofurfuryl. To this mixture the reaction was run at 100 ° C. for 6 h and K 2 CO 3 (78 mg), NaI (10 mg) and bromide (50 mg) tetrahydrofurfuryl were added. The dichloromethane layer was washed with brine, the mixture was cooled to room temperature, partitioned between dichloromethane and water, dried over Na2SO4, filtered and concentrated. The remainder was cleaned by a preparatory plate with dichloromethane: methanol (95: 5) to obtain P-543 (55 mg, 45% yield).

¹ H NMR (400 MHz, DMSO-d6) 8.39 (s, 1H), 7.58 (s, 1H), 7.37-7.43 (m, 3H), 7.28 (d, J = 7.2Hz, 1H), 7.14-7.17 ( m, 2H), 7.08 (d, J = 7.2 Hz, 2H), 7.02 (d, J = 7.2 Hz, 1H), 4.07 (m, 1H), 3.94 (t, J = 5 Hz, 2H), 3.82 ( s, 2H), 3.6- 3.69 (m, 2H), 1.88- 1.93 (m, 1H), 1.73- 1.77 (m, 2H), 1.62- 1.69 (m, 1H).
APCI (M + 1; 437) LCMS 93.5%;
Example 103. Preparation of P-548 and P-557

<< Reaction Process Formula 33 >>

  Synthesis of {4- [3′-chloro-6- (2-dimethylamino ethoxy) -biphenyl-3-ylmethyl] -phenyl} -urea (P-548). A suspension of P-421 (100 mg, 0.283 mmol), dimethylaminoethyl bromide hydrobromide (198 mg, 0.850 mmol) and cesium carbonate (600 mg, 1.84 mmol) in acetone (10 mL) for 17 h At reflux. The stop was diluted with dichloromethane (50 mL). It was then washed with 0.5N aqueous hydrochloric acid (100 mL) and the solvent was removed under vacuum. Natural orange oil elutes dichloromethane acetone followed by 10% to elute dichloromethane methanol by 10% to give P-548 (13.4 mg, 11% yield) as a colorless gum. Purified by preparative thin layer chromatography (silica gel).

1H NMR (400 MHz CDCl3) d: 7.54 (m, 1H), 7.39-7.36 (m, 1H), 7.31-7.08 (m, 8H), 6.90-6.89 (m, 1H), 6.23 (s, 1H), 4.57 (s, 2H), 4.05 (t, J = 5.8 Hz, 2H), 3.92 (s, 2H), 2.68 (t, J = 5.60 Hz, 2H), 2.27 (s, 6H).
LCMS = 97.3% purity. MS (APCI +) = 424.2 (M + 1)

  Synthesis of 2- [3′-chloro-5- (4-ureido-benzyl) -biphenyl-2-yloxy] -acetamide (P-557). A suspension of acetone (15 mL) in P-421 (150 mg, 0.425 mmol), 2-bromoacetamide (175 mg, 1.28 mmol) and cesium carbonate (900 mg, 2.76 mmol) was stirred at reflux overnight. It was. The solvent was removed under a stream of nitrogen and the dried residue was suspended in ethyl acetate (50 mL). The organic solution was washed with water (50 mL) and brine (15 mL). The solvent was then removed under vacuum to give the crude product and dried over sodium sulfate and transferred. The solid was triturated in a mixture of dichloromethane (5 mL), methanol (5 mL) and acetone (2 mL) to give P-557 (58.9 mg, 34% yield) as a white powder.

３―［３´―クロロ―５―（４―ウレイド―ベンジル）―ビフェニル―２―ｙｌｏｘｙ］―アゼチジン―１―カルボン酸ｔｅｒｔ―ブチル・エステル（Ｉ―１３６）。フェノールＰ―４２１（１５０ｍｇ、０．４２ｍｍｏｌ）、３―ｍｅｔｈａｎｅｓｕｌｆｏｎｙｌｏｘｙ―アゼチジン―１カルボン酸酸性ｔ―ブチル・エステル（２００ｍｇ、０．７９ｍｍｏｌ）およびＤＭＦ（２ｍＬ）のＣｓ２ＣＯ３（２７７ｍｇ、０．８５ｍｍｏｌ）の混成は、１８ｈのための１００度Ｃで加熱された。混合は、室温に冷やされて、ジクロロメタンと水の間に分割された。水層は、ジクロロメタンによって、二回抽出された。複合有機層は、塩水によって、洗われて、Ｎａ２ＳＯ４を通じて乾燥して、濾過されて、集中した。残りは、油としてＩ―１３６（２００ｍｇ、定量的収率）を得るために、ジクロロメタン：メタノール（９５：５）を有する準備のプレートにより浄化された。 1H NMR (400 MHz, DMSO-d ₆ ) 8.40 (s, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.52-7.50 (m, 1H), 7.41 (t, J = 7.2 Hz, 1H) , 7.43-7.37 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.20-7.15 (m, 3H), 7.09 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.75 (s, 2H), 4.42 (s, 2H), 3.83 (s, 2H). LCMS = 93.63% purity. MS (APCI +) = 410.1 (M + 1).
Example 104. Preparation for P-554

3- [3'-Chloro-5- (4-ureido-benzyl) -biphenyl-2-yloxy] -azetidine-1-carboxylic acid tert-butyl ester (I-136). Phenol P-421 (150 mg, 0.42 mmol), 3-methanesulfonoxy-azetidine-1 carboxylic acid t-butyl ester (200 mg, 0.79 mmol) and DMF (2 mL) in a mixture of Cs2CO3 (277 mg, 0.85 mmol) Was heated at 100 degrees C for 18 h. The mixture was cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane. The composite organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The remainder was clarified by a prepared plate with dichloromethane: methanol (95: 5) to obtain I-136 (200 mg, quantitative yield) as an oil.

  {4- [6- (Azetidin-3-yloxy) -3, '-chloro-biphenyl-3-ylmethyl] -phenyl} -urea (P-554). I-136 (200 mg, 0.393 mmol) in a solution of dichloromethane (2 mL) at 0 degrees, C was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The mixture was then extracted with dichloromethane (3 × 5 mL) and diluted with water, saturated aqueous NaHCO 3 (0.5 mL) was added. The combined organic layer is purified by dish-thin layer chromatography ready to be drawn off by dichloromethane concentrated under vacuum dried and passed through Na 2 SO 4 (filtered): P—as a solid Methanol (95: 5) to give 554 (20 mg, 12% yield).

¹ H NMR (400 MHz, CDCl ₃ ) 7.51 (t, 1H), 7.38-7.41 (m, 1H), 7.27-7.33 (m, 2H), 7.12-7.22 (m, 5H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.22 (br s, 1H), 4.97 (m, 1H), 4.56 (br s, 1H), 3.91 (s, 2H), 3.85- 3.89 (t, 2H), 3.73- 3.75 (m, 2H), 3.48- 3.52 (m, 1H) ppm.
APCI (M + 1; 408) LCMS 97%;
Example 105. Preparation for P-553

  {4- [3′-Chloro-6- (thietan-3-yloxy) -biphenyl-3-ylmethyl] -phenyl} -urea P-553). Synthesis P-553 was reported for P-554 (Example 104) and synthesized by a similar route.

1H NMR (CDCl3) δ: 7.48 (t, 1H), 7.34-7.38 (m, 1H), 7.27-7.33 (m, 2H), 7.12-7.22 (m, 5H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.28 (bs, 1H), 5.19 (m, 1H), 4.59 (bs, 1H), 3.92 (s, 2H), 3.46- 3.53 (t , 2H), 3.23- 3.31 (m, 2H).
APCI (M + 1; 425)
Example 106. Preparation for P-555

{4- [3'-Chloro-6- (oxetan-3-yloxy) -biphenyl-3-ylmethyl] -phenyl} -urea (P-555). Synthesis P-555 was reported for P-554 and synthesized by a similar route. 1H NMR (DMSO-d ₆ ) δ 8.39 (s, 1H), 7.57 (t, 1H), 7.38-7.48 (m, 3H), 7.28 (d, J = 8.4Hz, 2H), 7.22 (d, J = 2.4 Hz, 1H), 7.09-7.14 (m, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 1H), 5.75 (s, 2H), 5.25 (m, 1H), 4.87 (t, J = 5 Hz, 2H), 4.46 (m, 2H), 3.82 (s, 2H).
APCI (M + 1; 409) LCMS 97%.
Example 107. Preparation for P-556

4- [3'-Chloro-6- (S) -1-methyl-ppyrrolidin-3-yloxy) -biphenyl-3-ylmethyl] -phenyl} -urea (P-556). Synthesis P-556 was reported for P-554 (Example 104) and synthesized by a similar route.
1H NMR (400 MHz, CDCl ₃ ) 7.51 (t, 1H), 7.37-7.39 (m, 1H), 7.27-7.33 (m, 2H), 7.12-7.22 (m, 5H), 7.06 (dd, J = 8.4 , 2.4 Hz, 1H), 6.8 (d, J = 8.4 Hz, 1H), 6.29 (br s, 1H), 4.76 (m, 1H), 4.59 (br s, 1H), 3.91 (s, 2H), 3.02 (m, 1H), 2.6 (t, 2H), 2.35 (s, 3H), 2.17- 2.24 (m, 2H). APCI (M + 1; 436)
Example 108. Preparation for P-562

  4- [3′-Chloro-6- (oxetane-3-yloxy) -biphenyl-3-ylmethyl] -phenylamine (P-562). Synthesis P-562 was reported for P-554 (Example 104) and synthesized by a similar route.

1H NMR (400 MHz, DMSO-d ₆ ) 7.56 (t, 1H), 7.57 (t, 1H), 7.37-7.48 (m, 3H), 7.18 (d, J = 2 Hz, 1H), 7.01 (dd, J = 8.4, 2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 5.75 (s, 2H), 5.25 (m, 1H), 4.93 (br s, 2H), 4.87 (t, J = 5 Hz, 2H), 4.46 (m, 2H), 3.72 (s, 2H) ppm. APCI (M + 1 ; 366) LCMS 97%;
Example 109. Preparation for P-563

  {4- [3′-Chloro-6- (S) -1-pyrrolidin-2-ylmethoxy) -biphenyl-3-ylmethyl] -phenyl} -urea (P-563). Synthesis P-562 was reported for P-554 (Example 104) and synthesized by a similar route.

1H NMR (400 MHz, DMSO-d ₆ ) 9.25 (br s, 1H), 8.77 (br s, 1H), 8.49 (s, 1H), 7.57 (s, 1H), 7.37-7.46 (m, 3H), 7.28 (d, J = 8.4 Hz, 1H), 7.19 (overlap, 2H), 7.08 (d, overlap, J = 8.4 Hz, 3H), 4.09- 4.22 (m, 2H), 3.84 (overlap, 1H), 3.13 (m, 1H), 2.97 (m, 1H), 2.05 (m, 1H), 1.71- 1.83 (m, 3H) ppm.
Example 110. Preparation for P-565

  {4- [3'-Chloro-6- (R) -1-methyl-pyrrolidin-3-yloxy) -biphenyl-3-ylmethyl] -phenyl} -urea (P-565). Synthesis P-562 was reported for P-554 (Example 104) and synthesized by a similar route.

1H NMR (400 MHz, CDCl ₃ ) 7.51 (t, 1H), 7.35-7.38 (m, 1H), 7.23- 7.31 (m, 4H), 7.13 (d, J = 8.4 Hz), 7.11 (s, 1H) , 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 6.95 (br s, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.8 (br s, 2H), 4.75 (m, 1H), 3.89 (s, 2H), 3.06 (t, 2H), 2.62 (m, 2H), 2.36 (s, 3H), 2.17-2.24 (m, 1H), 1.93- 1.98 (m, 1H) ppm. APCI (M +1; 436) LCMS 98%.
Example 111. Preparation for P-550

<< Reaction Process Formula 34 >>

  Synthesis of 1-bromo-5-bromomethyl-3-fluoro-2methoxybenzene (I-137). A solution of acetic acid (4 mL) in 4-bromomethyl-2-fluoro-1methoxybenzene (1.0 g, 4.57 mmol) heated and stirred at (80 ° C.) was stirred for 30 min in acetic acid (2 mL) bromine (1 Solution, 0.09 g, 6.85 mmol) was added and the reaction mixture was stirred at 80 ° C. for 18 h, cooled to room temperature and drained into crushed ice water (50 mL). Ammonium hydroxide solution (28%) was added to pH 8 and extracted with dichloromethane (2 × 40 mL), washed with water, dried over Na 2 SO 4, filtered and concentrated under vacuum. It was. The remainder was purified by silica gel column chromatography using 5% ethyl acetate in hexane to yield I-137 (0.43 g, 31% yield) as a mucus.

  Synthesis of 4- (3-bromo-5-fluoro-4methoxybenzyl) -phenyl] urea (I-138): up to I-137 (0.2 g, 0.67 mmol), [4- (4, 4, 5,5-tetramethyl- [1,3,2] dioxabolan-2-yl) -phenyl] -urea (0.19 g, 0.74 mmol) and Pd (Ph-3P) 4 (0.04 g, 0.04 mmol) ) Was added toluene (8 mL), EtOH (2 mL) and 2M aqueous Na-2CO3 solution (0.7 mL, 1.4 mmol). The stop was degassed by 15 minutes of bubbled argon gas. The reaction was stirred at 60 ° C. under argon air for 24 h. The reaction was cooled to room temperature and H2O (20 mL) and ethyl acetate (30 mL) were added. The layers were separated and a watery wash was extracted with ethyl acetate (2 × 20 mL). The combined organic extract was dried through Na2SO4 (passed through a filter) and a concentratedunder vacuum. The remainder was triturated with dichloromethane to yield I-138 (0.18 g, 77% yield) as a yellow solid.

Synthesis of [4- (3′-chloro-5-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-550): discontinuation of I-138 (0.11 g, 0.31 mmol) In addition, 3 chlorophenyl bromic acid (0.05 g, 0.34 mmol) and Pd (Ph-3P) 4 (0.02 g, 0.02 mmol) were added to toluene (6 mL), EtOH (1.5 mL) and 2 M aqueous Na-CO3 solution (0.31 mL, 0.62 mmol). The reaction was degassed by a 15 minute stream of argon. The reaction was stirred at 80 ° C. under argon air for 18 h. Ethyl acetate (20 mL) was added and the reaction was cooled to room temperature, and H2O (20 mL). The watery laundry was extracted with ethyl acetate (2 × 10 mL) and the layers were separated. The combined organic extract was dried over Na2SO4, filtered and concentrated under vacuum. The remainder was purified by thin layer chromatography in preparation with 8% methanol in dichloromethane to yield P-550 (0.064 g, 53% yield) as an off-white solid. 1H NMR (DMSO-d ₆ , 400 MHz): 8.42 (s, 1 H), 7.41-7.54 (m, 4 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.1-7.17 (m, 3 H), 7.08 (s, 1 H), 5.77 (s, 2 H), 3.85 (s, 2 H), 3.64 (s, 3 H); MS (APCI +): 485.1 (M + 1), LC-MS : 99.1%; HPLC 96.8% pure.
Example 112. Preparation for P-558

Synthesis of (4-amino-phenyl)-(3′-chloro-6-methoxy-biphenyl-3-yl) -methanone (P-558). To resolve I-129 (500 mg, 1.3 mmol) in EtOH—H 2 O (1: 1, 15 mL) was additional NH 4 Cl (200 mg, 4 mmol) and iron powder (150 mg, 3 mmol). The reaction mixture was stirred at room temperature for 72 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (3 × 30 mL), washed with water (20 mL) and brine (30 mL), dried over Na 2 SO 4 and filtered. The solvent was removed under vacuum to obtain P-558 (420 mg, 85% yield). 1H NMR (DMSO- d ₆ , 400MHz) 7.70 (dd, J = 8.4, 2.4 Hz, 1 H), 7.40-7.57 (m, 7 H), 7.25 (d, J = 8.8 Hz, 1 H), 6.61 (d, J = 8.8 Hz, 2 H), 6.09 (s, 2 H), 3.88 (s, 3 H) ppm. Calc. 337.8; APCI ⁺ (M + 1): 338, 98%. P-566

1- [4- (3′-Chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -3- (tetrahydro-furan-2-yl) -urea (P-566). 1H NMR (DMSO-d ₆ , 400 MHz): 8.27 (s, 1 H), 7.47-7.50 (m, 1 H), 7.34-7.45 (m, 3 H), 7.27-7.32 (m, 2 H), 7.09-7.21 (m, 4 H), 7.03 (d, J = 8.4 Hz, 1 H), 6.71 (d, J = 9.3 Hz, 1 H), 5.52-5.48 (m, 1 H), 3.84 (s, 2 H), 3.73 (s, 3 H), 3.70-3.79 (m, 1 H), 3.62-3.69 (m, 1 H), 1.99-2.11 (m, 1 H), 1.79-1.91 (m, 2 H ), 1.57-1.69 (m, 1 H) ppm.
Example 114. Preparation of P-523 and P-533

<< Reaction process formula 35 >>

  (R) -2- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yloxymethyl] -pyrrolidine-1-carboxylic acid tert-butyl ester Synthesis of (I-139). The mixture of N-boc-D-prolinol (225 mg, 1.12 mmol) and sodium hydride (60% weight dispersion, 66 mg, 1.68 mmol) in dimethylformamide (2 mL) was stirred until gas evolution was complete. After 2 minutes of stirring, P-456 (194 mg, 0.56 mmol) was added and the reaction became hot at 120 ° C. overnight. The reaction was cooled to room temperature. Diluted ethyl acetate (10 mL) (washed with water (10 mL)) and watery laundry were then extracted with ethyl acetate (25 mL). The composite extract was dried through sodium sulfate (filtered) and solvent removed under vacuum. The remainder was purified by silica gel column chromatography (9: 1 hexane / ethyl acetate) to give I-139 (60.4 mg, 25% yield) as a thick colorless oil.

  Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2- (R) -1-pyrrolidine-2-ylmethoxy) -pyridine (P-523). A biphasic solution of I-139 (60 mg, 0.11 mmol) and trifluoroacetic acid (851 mg, 0.75 mmol) in dichloromethane (2 mL) and water (0.5 mL) was heated to 80 ° C. for 4 h. Mixing was concentrated under vacuum and the remainder was purified by silica gel column chromatography (9: 1 dichloromethane / methanol) to give P-523 (32.4 mg, 69% yield). LCMS = 100% purity.

(R) -2- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yloxymethyl] -pyrrolidine-1-carboxylic acid ethylamide (P-533) ) Synthesis. A solution of P-523 (235 mg, 0.55 mmol) and ethyl isocyanate (0.2 mL, 2.8 mmol) in pyridine (1 mL) was stirred overnight at room temperature. The extracts were combined and the reaction was diluted with water (5 mL) (extracted with ethyl acetate (2 × 3 mL)). The organic solution was dried through sodium sulfate (filtered) and solvent removed under vacuum. The remainder was purified by silica gel column chromatography (19: 1 dichloromethane / methanol) to give P-533 (92.1 mg, 34% yield). Some P-533 (19.0 mg) was futer cleaned by sodium bicarbonate wash and spare silica gel tells (14.1 mg) thin layer chromatography (9: 1 dichloromethane / methanol) To do. ¹ H NMR (400 MHz, DMSO-d ₆ ) 1.03 (t, J = 7.2 Hz, 3 H), 1.80-1.95 (m, 4 H), 3.07 (m, 2 H), 3.18 (m, 1H), 3.30 (m, 1H), 3.72 (s, 3H), 3.87 (s, 2H), 3.97 (m, 1H), 4.05 (m, 1H), 4.28 (m, 1H), 6.22 (t, J = 5.2 Hz , 1H), 6.76 (d, J = 8.4 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 7.26-7.32 (m, 2 H), 7.36 (s, 1 H), 7.39- 7.50 (m, 2H), 7.55 (dd, J = 8.4, 2.2 Hz, 1 H), 8.03 (d, J = 2.01 Hz, 1 H) ppm. MS (APCI +): 498.2 (M + 1), LC- MS: 92.2%.
Example 115. Preparation for P-568

Synthesis of 2-azetidine-1-yl-5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridine (P-568): I-140 (0.15 g, 0.46 mmol) and azetidine To the hybrid of (0.09 g, 0.92 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (0.35 g, 2.29 mmol) was added. The reaction mixture was stirred and 85 ° C for 15 minutes. The reaction was then cooled to room temperature, diluted with dichloromethane (6 mL), washed with 0.5 N aqueous HCl (2 × 4 mL), dried over Na 2 SO 4, filtered and concentrated. . The rest was used 3% methanol in dichloromethane followed by thin layer chromatography in preparation with 5% methanol in dichloromethane to yield P-568 (0.05 g, 30% yield) as mucus. Purified by silica gel column chromatography. 1H NMR (DMSO-d ₆ , 400 MHz): 7.99 (d, J = 1.6 Hz, 1 H), 7.34-7.49 (m, 5 H), 7.14-7.2 (m, 2 H), 7.04 (d, J = 8.8 Hz, 1 H), 6.28 (dd, J = 8.4, 0.8 Hz, 1 H), 3.86 (t, J = 7.2 Hz, 4 H), 3.77 (s, 2 H), 3.74 (s, 3 H ), 2.22-2.32 (m, 2 H); MS (APCI +): 365.1 (M + 1), LC-MS: 100%.
Example 116. Preparation for P-571

Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid amide (P-571): THF ( N-methylmorpholine (0.05 g, 0.54 mmol) was added to a cooled (0 ° C.) solution of 10 mL) of I-141 (0.23 g, 0.54 mmol). The reaction mixture was stirred for 5 minutes and isobutyl chloroformate (0.07 g, 0.54 mmol) was added. The reaction was stirred at 0 ° C. for 45 minutes and ammonium hydroxide (28%, 4.0 mL) was added. The reaction was warmed to room temperature, stirred for 1.5 h and diluted with water (5 mL). The organic layer was separated. The aqueous layer was then extracted with ethyl acetate (2 × 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The rest is silica gel column chromatography using 5% methanol in dichloromethane and 5% methanol in dichloromethane to yield P-571 (0.03 g, 13% yield) as an off-white solid. Was purified by thin layer chromatography in preparation. 1H NMR (DMSO-d ₆ , 400 MHz): 7.99 (d, J = 2.0 Hz, 1 H), 7.51 (br s, 1 H), 7.4-7.48 (m, 3 H), 7.36 (s, 1 H ), 7.24-7.3 (m, 2 H), 7.14 (br s, 1 H), 6.92 (d, J = 8.8 Hz, 1 H), 6.34 (d, J = 8.4 Hz, 1 H), 4.39 (dd , J = 9.2, 6.4 Hz, 1 H), 3.7-3.9 (m, 2 H), 3.8 (s, 2 H), 3.72 (s, 3 H), 2.26-2.46 (m, 2 H); MS ( (APCI +): 426.1 (M + 1), LC-MS: 94.3%.
Example 117. Preparation for P-572

Synthesis of 4- [5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -morpholine (P-572). I-140 (0.15 g, 0.46 mmol) and morpholine (0.08 g, 0.92 mmol) were combined with 1,8-diazabicyclo [5.4.0], undec-7-ene (0.35 g (2 .29 mmol) was added). The reaction mixture was stirred at 160 ° C. for 6 h. The reaction was cooled to room temperature, diluted with dichloromethane (6 mL), washed with 0.5 N aqueous HCl (2 × 4 mL), dried over Na 2 SO 4, filtered and concentrated under vacuum. It was done. The remainder was purified by silica gel column chromatography using 3% methanol in dichloromethane to yield P-572 (0.042 g, 23% yield) as mucus. 1H NMR (DMSO-d ₆ , 400 MHz): 8.07 (d, J = 2.8 Hz, 1 H), 7.38-7.45 (m, 5 H), 7.16-7.24 (m, 2 H), 7.04 (d, J = 8.4 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 1 H), 3.8 (s, 2 H), 3.74 (s, 3 H), 3.67 (t, J = 4.8 Hz, 4 H), 3.36 (t, J = 4.8 Hz, 4H); MS (APCI +): 395.1 (M + 1), LC-MS: 95.1%.
Example 118. Preparation for P-581

2-{(S) -1- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -pyrrolidin-2-yl} -propane-2 -Synthesis of ol (P-581). Solution of I-142 (0.05 g, 0.11 mmol) in chilled (0 ° C.) and THF (8.0 mL) was added with brominated (3M sol, 0.26 mL, 0.88 mmol) added methyl It was magnesium. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction was then cooled to 0 ° C. and saturated aqueous ammonium chloride solution (5 mL) was added. The aqueous suspension was extracted with diethyl ether (2 × 30 mL), washed with brine (10 mL), dried over Na 2 SO 4, filtered and P-581 (0.046 g, 0.046 g, 88% concentrated under vacuum to yield). 1H NMR (DMSO-d ₆ , 400 MHz): 7.90 (d, J = 2.4 Hz, 1 H), 7.75 (br s, 1 H), 7.36-7.48 (m, 4 H), 7.26-7.32 (m, 2 H), 6.92 (d, J = 8.8 Hz, 1 H), 6.61 (d, J = 8.8 Hz, 1 H), 6.33 (br s, 1 H), 4.0-4.08 (m, 1 H), 3.79 (s, 2 H), 3.72 (s, 3 H), 3.3-3.45 (m, 2 H), 1.7-2.0 (m, 4 H), 1.11 (s, 3 H), 0.98 (s, 3 H) ; MS (APCI +): 455.1 (M + 1), LC-MS: 97.5%.
Example 119. Preparation for P-601

Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -pyrrolidin-3-ol (P-601). To 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456, 0.3 g, 0.87 mmol) and 3-pyrrolidine ol, (2 ) (0.15 g, 1.74 mmol) was additional 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.66 g, 4.34 mmol). The reaction mixture was stirred and heated at 100 ° C. for 2.5 h, cooled to room temperature, diluted with dichloromethane (8 mL) and washed with 0.5 N HCl (2 × 4 mL). Dried over Na 2 SO 4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 5% methanol in dichloromethane to yield 0.27 g (75%) of P-601 as a white solid.
1H NMR (DMSO-d ₆ , 400 MHz): 7.95 (s, 1 H), 7.2-7.46 (m, 6 H), 6.91 (d, J = 8.4 Hz, 1 H), 6.35 (d, J = 8.4 Hz, 1 H), 4.9 (d, J = 3.6 Hz, 1 H), 4.32-4.4 (m, 1 H), 3.76 (s, 2 H), 3.71 (s, 3 H), 3.12-3.45 (m , 4 H), 1.8-2.05 (m, 2 H) ppm; MS (APCI +): 413.1 (M + 1), LC-MS: 91.6%.
Example 120. Preparation for P-602

Synthesis of 1- [5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -pyrrolidin-3-ol (P-602): 5- (3′-chloro- In 6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (I-140, 0.22 g, 0.67 mmol) and 3-pyrrolidine ol, (2) (0.12 g, 1.34 mmol) is Additional 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.51 g, 3.36 mmol). The reaction mixture was stirred and heated at 100 ° C. for 1.5 h, cooled to room temperature, diluted with dichloromethane (8 mL) and washed with 0.5 N HCl (2 × 4 mL). Dried over Na 2 SO 4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 5% methanol in dichloromethane to yield 0.13 g (49%) of P-602 as a white solid. 1H NMR (DMSO-d ₆ , 400 MHz): 7.9 (d, J = 2.4 Hz, 1 H), 7.3-7.49 (m, 5 H), 7.12-7.2 (m, 2 H), 7.03 (d, J = 8.4 Hz, 1 H), 6.34 (d, J = 8.8 Hz, 1 H), 4.89 (d, J = 3.6 Hz, 1 H), 4.35 (br s, 1 H), 3.76 (s, 2 H) , 3.73 (s, 3 H), 3.2-3.45 (m, 4 H), 1.8-2.05 (m, 2 H) ppm; MS (APCI +): 395.1 (M + 1), LC-MS: 99.1%.
Example 121. Preparation for P-612

(S) -1- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -pyrrolidin-2-carboxylic acid amide (P-612) Synthesis: (S) -1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -pyrrolidine-2-carboxylic acid in THF (2 mL) To a cooled and (0-5 oC) stirred solution of (I-143, 0.15 g, 0.34 mmol), diisopropylethylamine (0.05 g, 0.37 mmol) was added. Reaction stirred at 0-5 ° C for 45 minutes, isobutyl chloroformate (0.05 g, 0.37 mmol) was added, and the mixture was stirred for 5 minutes. The reaction was heated to ambient temperature and hydroxylated (28%, 4.0 mL) Ammonium was added. And it stirred for 1.5 hours. The reaction mixture was diluted with water (5 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL), the organic layer was separated. The combined organic layer was dried over Na2SO4, filtered and concentrated. The rest is silica gel with 5% methanol in dichloromethane followed by thin layer chromatography prepared with 5% methanol in dichloromethane to yield 0.074 g (49%) of P-612 as an off-white solid. -Purified by column chromatography. 1H NMR (DMSO-d ₆ , 400 MHz): 8.27 (d, J = 2.4 Hz, 1 H), 7.34-7.46 (m, 4 H), 8.2 (d, J = 8.8 Hz, 1 H), 7.65 ( dd, J = 8.8, 2.4 Hz, 1 H), 7.4-7.46 (m, 2 H), 7.37 (br s, 1 H), 7.26-7.38 (m, 2 H), 6.94 (d, J = 8.0 Hz , 1 H), 3.92-3.98 (m 3 H), 3.93 (s, 2 H), 3.73 (s, 3 H), 2.55 (t, J = 8.4 Hz, 2 H), 1.98-2.06 (m, 2 H) ppm; MS (APCI +): 441.1 (M + 1), LC-MS: 97.0%; HPLC 97.1% pure.
Example 122. Preparation for P-615

Synthesis of (S) -1- [5- (3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid amide (P-615) . (S) -1- [5- (3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid in THF (2.5 mL) ( To a cooled and (0-5 oC) stirred solution of I-143, 0.22 g, 0.54 mmol), N, N-diisopropylethylamine (0.07 g, 0.57 mmol) was added. Reaction stirred at 0-5 ° C for 45 minutes, isobutyl chloroformate (0.08 g, 0.57 mmol) was added, and the mixture was stirred for 5 minutes. The reaction was heated to room temperature, methanol (7M sol, 1.0 mL, 7.0 mmol) in ammonia was added and stirred for 0.5 h. The reaction mixture was diluted with water (5 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL), the organic layer was separated. The combined organic layer was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 5% methanol in dichloromethane. This was followed by a thin layer chromatography ready with 5% methanol in dichloromethane to yield 0.06 g (27%) of P-615 as an off-white solid. 1H NMR (DMSO-d ₆ , 400MHz): 7.99 (d, J = 2.8 Hz, 1 H), 7.51 (br s, 1 H), 7.34-7.46 (m, 4 H), 7.24-7.3 (m, 2 H), 7.14 (br s, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.35 (d, J = 8.4 Hz, 1 H), 4.39 (dd, J = 9.6, 6.8 Hz, 1 H), 3.7-3.9 (m, 2 H), 3.8 (s, 2 H), 3.72 (s, 3 H), 2.26-2.48 (m, 2 H) ppm; MS (APCI +): 426.6 (M + 1 ), LC-MS: 98.0%.
Example 123. Preparation for P-617

Synthesis of (R) -1- [5- (3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid amide (P-617) . (R) -1- [5- (3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid in THF (2.5 mL) ( To the cooled 0-5 oC and stirred solution of I-144, 0.14 g, 0.33 mmol), N, N-diisopropylethylamine (0.09 g, 0.69 mmol) was added. Isobutyl chloroformate (0.05 g, 0.36 mmol) is 0-5 ° C for 30 minutes of Ammonium hydroxide solution (28%, 1.0 mL, 8.0 mmol) with the reaction heated to room temperature. The reaction stirred at was added and added and stirred for 0.5 h, the reaction mixture was stirred for 5 min. The reaction mixture was diluted with water (5 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL), the organic layer was separated. The combined organic layer was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 5% methanol in dichloromethane. This was followed by a thin layer chromatographic preparation using 5% methanol in dichloromethane to yield 0.07 g (47%) of P-617 as an off-white solid. 1H NMR (DMSO-d ₆ , 400 MHz): 7.99 (d, J = 2.8 Hz, 1 H), 7.51 (br s, 1 H), 7.38-7.46 (m, 3 H), 7.4 (br s, 1 H), 7.24-7.3 (m, 2 H), 7.14 (br s, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.34 (d, J = 8.0 Hz, 1 H), 4.39 ( dd, J = 9.6, 6.8 Hz, 1 H), 3.7-3.9 (m, 2 H), 3.84 (s, 2 H), 3.72 (s, 3 H), 2.26-2.48 (m, 2 H) ppm; MS (APCI +): 426.9 (M + 1), LC-MS: 100%.
Example 124. Preparation of P-615-HCl

Hydrochloric acid (P-615-HCl) (S) -1- [5- (3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid Synthesis of amides. (S) -1- [5- (3′-Chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carboxylic acid was cooled and (0- To the stirred solution, ether (2 mL) amide (P-615, 0.04 g, 0.1 mmol) was ether (0.5 ml, 1.0 mmol) and reaction added 2 M HCl. And it was stirred for 1 h. The ether layer was removed. It was then triturated again with ether (2.0 mL). It was then concentrated to yield 0.045 g (98%) of P-615-HCl as a white solid. 1H NMR (DMSO-d6, 400 MHz): 7.92 (d, J = 2.0 Hz, 1 H), 7.78 (d, J = 7.6 Hz ,, 1 H), 7.69 (br s, 1 H), 7.26-7.48 (m, 6 H), 6.95 (d, J = 8.8 Hz, 1 H), 6.72 (d, J = 9.2 Hz, 1 H), 4.8-4.9 (m, 1 H), 4.0-4.18 (m, 2 H), 3.89 (s, 2 H), 3.73 (s, 3 H), 2.64-2.74 (m 1 H), 2.26-2.34 (m, 1 H) ppm; MS (APCI +): 426.16 (M + 1) , LC-MS: 98.8%; HPLC 98.3% pure.
Example 125. Preparation of P-617-HCl

Hydrochloric acid (P-617-HCl) (R) -1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-2-carvone Synthesis of acid amide: The reaction was stirred for 1 h and ether (2 mL) of (R) -1- [5- (3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl) -pyridine-2- Yl] -azetidine-2-carboxylic acid (P-617, 0.057 g, 0.13 mmol) in a cooled and (0-5 oC) stirred solution of ether (0.65 ml, 1.3 mmol) in 2M. Of HCl was added. The ether layer was removed. It was then triturated again with ether (2.0 mL). It was then concentrated to yield 0.059 g (98%) of P-617-HCl as a white solid. 1H NMR (DMSO-d ₆ , 400 MHz): 7.92 (d, J = 2.0 Hz, 1 H), 7.78 (d, J = 7.6 Hz ,, 1 H), 7.69 (br s, 1 H), 7.26- 7.48 (m, 6 H), 6.95 (d, J = 8.8 Hz, 1 H), 6.72 (d, J = 7.62 Hz, 1 H), 4.8-4.9 (m, 1 H), 4.0-4.16 (m, 2 H), 3.89 (s, 2 H), 3.73 (s, 3 H), 2.64-2.74 (m 1 H), 2.26-2.36 (m, 1 H) ppm; MS (APCI +): 426.16 (M + 1 ), LC-MS: 95.8%; HPLC 97.3% pure.

実施例１２６。Ｐ―５６９の準備 << Reaction Process Formula 36 >>

Example 126. Preparation for P-569

  5- (3′chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (synthesis of P-456). In a 250 mL round bottomed flask equipped with a condenser, the nitrogen line and stir bar are placed on the arranged carbon acid 3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethylmethyl Carbonate (I-145, 3.61 g, 11.1 mmol), 2-fluoropyridine bromate (1.72 g, 12.2 mmol), potassium carbonate (4.60 g, 33.3 mmol), 1,5-bis (diphenyl) Phosphino) pentane (1.47 g, 3.33 mmol) and DMF (56 mL). The reaction mixture was degassed with bubbling nitrogen for 15 minutes and allyl palladium (II) chloride dimer (609 mg, 1.67 mmol) was added. The reaction mixture was heated to 85 ° C. for 18 hours. To the reaction, the mixture was additional water (80 mL) and saturated ammonium chloride (150 mL). The watery portion was withdrawn with ethyl acetate (3 × 125 mL). The organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The crude material was purified by column chromatography utilizing 10% hexane / dichloromethane as the eluent to yield 2.45 g P-456 as a 64% yield light yellow solid.

  Synthesis of 2-azetidin-1-yl-5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine (P-569). In an 8 mL vial with agitation, the rod is placed 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456, 150 mg) 0.434 mmol), azetidine (88.0 uL, 1.30 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (306 uL, 2.17 mmol). The mixture was heated to 160 ° C for 1 hour and cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The organic portion was combined, washed with brine (15 mL) and concentrated to yield 156 mg of P-569 as a white solid in 94% yield (MgSO4) and dried (MgSO4). Was withdrawn with dichloromethane (2 × 30 mL).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.37-2.44 (m, 2 H), 3.73 (s, 3 H), 3.87 (s, 2 H), 4.19 (t, J = 8 Hz, 4 H ), 6.76 (bd, J = 9 Hz, 1 H), 6.95 (d, J = 9 Hz, 1 H), 7.28 (bd, J = 7 Hz, 1 H), 7.33 (d, J = 8 Hz, 1 H), 7.36 (bs, 1 H), 7.42-7.48 (m, 2 H), 7.76 (bd, J = 9 Hz, 1 H), 7.86 (s, 1 H) ppm. MS (APCI +): 383.1 (M + 1) LC-MS: 96%
Example 127. Preparation for P-577

5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2- (2S, 5S) -2,5-dimethyl-pyrrolidin-1-yl) -pyridine (P-577) Synthesis: In an 8 mL vial with agitation, the rod is placed in 5- (3′Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456) , 100 mg, 0.289 mmol), (2S, 5S) -2,5-dimethyl-pyrrolidine (176 mg, 1.30 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (367 uL, 2 .60 mmol). The mixture was heated to 160 ° C for 3 hours and cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The organic portions were combined, washed with brine (15 mL), dried (MgSO4), and the concentrated, watery portion was withdrawn with dichloromethane (2 × 30 mL). The crude material was purified by silica gel column chromatography utilizing 5% acetone / dichloromethane as eluent to yield 10 mg P-577 as a pale colored viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J = 6 Hz, 6 H), 1.56-1.61 (m, 4 H), 3.72 (s, 3 H), 3.75 (s, 2 H), 4.07-4.12 (m, 2 H), 6.38 (d, J = 9 Hz, 1 H), 6.92 (d, J = 8 Hz, 1 H), 7.27-7.32 (m, 3 H), 7.37 (s, 1 H), 7.41-7.47 (m, 2 H), 7.95 (d, J = 2 Hz, 1 H) ppm. MS (APCI +): 425.1 (M + 1) LC-MS: 92%
Example 128. Preparation for P-582

Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-pyrrolidin-1-yl-pyridine (P-582). In an 8 mL vial with agitation, the rod is placed 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456, 100 mg) 0.289 mmol), pyrrolidine (60.3 uL, 0.723 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (204 uL, 1.45 mmol). The mixture was heated to 160 ° C. for 30 minutes and cooled to room temperature. The reaction mixture was diluted with dichloromethane (25 mL) and washed with 0.5 M HCl (3 × 10 mL). The organic portions were combined, washed with brine (15 mL), dried (MgSO4) and the concentrated, combined water-like portion was withdrawn with dichloromethane (15 mL). The crude material was purified by silica gel column chromatography utilizing 10% acetone / dichloromethane as the eluent to yield 79 mg P-582 as a light orange semi-solid in 69% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.89-1.93 (m, 4 H), 3.31-3.34 (m, 4 H), 3.71 (s, 3 H), 3.77 (s, 2 H), 6.37 (d, J = 9 Hz, 1 H), 6.91 (d, J = 9 Hz, 1 H), 7.23-7.28 (m, 2 H), 7.32 (dd, J = 9, 2 Hz, 1 H), 7.36 (s, 1 H), 7.41-7.47 (m, 2 H), 7.95 (d, J = 2 Hz, 1 H) ppm. MS (APCI +): 397.1 (M + 1) LC-MS: 98%

実施例１２９。Ｐ―５８７の準備 << Reaction process formula 37 >>

Example 129. Preparation for P-587

  Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I-146). In a 250 mL round bottomed flask equipped with a condenser, the nitrogen line and stir bar were placed on the arranged carbon acid 3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethylmethyl Carbonate (I-145, 3.60 g, 11.1 mmol), 5- (4,4,5,5-Tetramethyl- [1,3,2] dioxabolan-2-yl) -methyl pyridine-2-carboxylate Ester (3.21 g, 12.2 mmol), potassium carbonate (4.60 g, 33.3 mmol), 1,5-bis (diphenylphosphino) pentane (1.47 g, 3.33 mmol) and DMF (56 mL) . The reaction mixture was degassed with bubbling nitrogen for 15 minutes and allyl palladium (II) chloride dimer (609 mg, 1.67 mmol) was added. The reaction mixture was heated to 85 ° C. for 8 hours. After the addition of water (50 mL) and dichloromethane (100 mL), the mixture was filtered through celite. The watery part was withdrawn by dichloromethane (75 mL) and the layers were separated. The organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The crude material is 1%, 5%, 10% acetone / eluent as eluent, yielding 3.13 g of I-146 as an orange yellow viscous oil with solids in shape in 73% yield. Purified by column chromatography using gradient elution of dichloromethane.

Synthesis of hydrochloric acid (P-587) 2- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -propan-2-ol. In a 100 mL circle, the flask reached the bottom was placed 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I -146, 2.0 g, 5.18 mmol) and tetrahydrofuran (26 ml). The solution was cooled to 0 ° C. and a solution of methyl bromide (3M in diethyl ether) (8.6 mL, 25.9 mmol) methyl magnesium was added over 10 minutes. Mixing was stirred at 0 ° C. for 5 minutes and at room temperature for 3 hours. The reaction mixture was concentrated by a stream of nitrogen, cooled to 0 ° C., and then slowly quenched with saturated ammonium chloride (20 mL). The organic portions were combined, washed with brine (25 mL), (MgSO4) and concentrated, the watery portion was withdrawn with ethyl acetate (3 × 40 mL). The crude material was purified by column chromatography utilizing 7% acetone / DCM as the eluent to produce a colorless viscous oil. This product was compounded by separating the material from exactly the same reaction conditions and purification (442 mg as a white semi-solid separated from a 1.04 gram run) of 1.04 g progression (MCLS 1546-106). The complex was purified by silica gel column chromatography utilizing 50% gradient elution and 60% as eluent yielding 1.33 g P-587 as 44% colorless, viscous oil. Of ethyl acetate / hexane yield. In an 18 mL vial with agitation, the bar was placed P-587 (325 mg, 0.842 mmol). Then diethyl ether (3.5 mL) was followed by diethyl ether (1.5 mL, 3.00 mmol) of 2M HCl. The mixing is stirred for 45 minutes, concentrated by a stream of nitrogen, and set in a high vacuum oven set at 40 degrees C for 18 hours to produce 355 mg of P-587 HCl salt as an off-white solid. And dried. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.53 (s, 6 H), 3.74 (s, 3 H), 4.13 (s, 2 H), 6.98 (d, J = 8 Hz, 1 H), 7.29 (bd, J = 7 Hz, 1 H), 7.38 (s, 1 H), 7.40-7.48 (m, 3 H), 7.95 (bd, J = 8 Hz, 1 H), 8.18 (bs, 1 H ), 8.56 (s, 1 H) ppm.MS (APCI +): 386.1 (M + 1). HPLC purity: 98.8%.
Example 130. Preparation for P-599

  Synthesis of [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methanol (P-599). In an 8 mL vial with agitation, the rod is placed 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I -146, 100 mg, 0.259 mmol) and tetrahydrofuran (1.3 mL). The solution was cooled to 0 degrees C and lithium aluminum hydride (39.3 mg, 1.04 mmol) was added resulting in strong gas evolution. The mixing was then stirred at 0 ° C. for 1 hour and concentrated by a stream of nitrogen. The solid was diluted with dichloromethane (2 mL) and slowly quenched with water (7 mL). The organic portions were combined, filtered through celite, dried (MgSO4), and the concentrated, watery portion was withdrawn with DCM (3 x 6 mL). The crude material was purified by silica gel column chromatography utilizing 30% acetone / dichloromethane to yield 22 mg P-599 as a pale orange viscous oil in 24% yield.

1H NMR (400 MHz, DMSO-d6) δ 3.72 (s, 3 H), 3.95 (s, 2 H), 4.51 (s, 2 H), 5.33 (bs, 1 H), 6.94 (d, J = 9 Hz, 1 H), 7.27-7.46 (m, 6 H), 7.61 (bd, J = 8 Hz, 1 H), 8.38 (s, 1 H) ppm. MS (APCI +): 358.1 (M + 1) LC -MS: 96%
Example 131. Preparation for P-588

  Synthesis of {2- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-yloxy] -ethyl} -dimethylamine (P-588). In an 8 mL vial with stirring, the bars were sodium hydride (34.7 mg, 0.867 mmol), THF (1.1 mL) and 2-dimethylamino-ethanol (87.2 uL, 0.867 mmol). The mixture was stirred for 5 minutes and 5- (3′Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456, 100 mg, 0.289 mmol) and A solution of THF (1.1 mL) was added.After stirring for 2 hours at 60 ° C., the reaction was combined with previous run (30 mg scale) and quench with water (20 mL). After extraction with ethyl acetate (2 × 30 mL)), the organic portions are combined, dried (MgSO 4), concentrated, It was dried in a high vacuum oven at 60 ° C. for 18 hours to yield 136 mg of P-588 as a turbid, pale yellow viscous oil in 87% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.18 (s, 6 H), 2.57 (t, J = 6 Hz, 2 H), 3.72 (s, 3 H), 3.87 (s, 2 H), 4.28 (t, J = 6 Hz, 2 H), 6.73 (d, J = 8 Hz, 1 H), 6.93 (d, J = 8 Hz, 1 H), 7.27-7.29 (m, 1 H), 7.32 (d, J = 9 Hz, 1 H), 7.37 (s, 1 H), 7.41-7.47 (m, 2 H), 7.53 (dd, J = 8, 2 Hz, 1 H), 8.03 (br s, 1 H). MS (APCI +): 415.1 (M + 1) LC-MS:> 99%.
Example 132. Preparation for P-595

Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -1-methyl-ethylamine (P-595). In an 18 mL vial equipped with a stir bar, cerium (III) chloride (315 mg, 1.28 mmol) was placed. It was then placed and cleaned with a vacuum cleaner and heated with a heat gun to remove residual moisture. The mixture was then cooled to 0 ° C. and stirred for 1 hour and at room temperature for 25 minutes and THF (2 mL) was added. After cooling to −78 ° C. for 15 minutes, the mixture was stirred at −78 ° C. for an additional 15 minutes and methyl lithium (1.6 M in diethyl ether) (800 uL, 1.28 mmol) was added. . After this time, the mixture was stirred at -78 degrees C for 1 hour and reacted at room temperature for 2 hours and 5- (3'-Chloro-2-fluoro-6-difluoromethoxy-biphenyl-3-ylmethyl) A solution of) -pyridine-2-carbonitrile (P-355, 150 mg, 0.425 mmol) and THF (800 uL) was added. Mixing was allowed to react at room temperature for 1 hour and added methyl lithium (1.6 M in diethyl ether) (530 uL, 0.850 mmol) was introduced after cooling to 0 ° C. The reaction was then cooled to 0 ° C. and quenched with isopropanol (2 mL). After filtration through Celite, the filtered water was concentrated and combined with the material from the previous run (30 mg scale). The composite was purified by silica gel column chromatography utilizing gradient elution of 10% 1M NH3 in MeOH / dichloromethane and yielded 20% yielding 17 mg P-595 as 8% dark orange oil . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.35 (s, 6 H), 3.72 (s, 3 H), 3.93 (s, 2 H), 6.95 (d, J = 8 Hz, 1 H), 7.27-7.47 (m, 6 H), 7.55 (s, 1 H), 8.40 (s, 1 H) ppm.
MS (APCI +): 385.1 (M + 1).

実施例１３３。Ｐ―５９６の準備 << Reaction process formula 38 >>

Example 133. Preparation for P-596

  5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridine-2-carbonitrile (synthesis of I-148). In a 40 mL vial with stirring, the bar is placed I-147 (1.0 g, 2.88 mmol), 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaboran-2-yl) -pyridine-2-carbonitrile (729 mg, 3.17 mmol), tetrakis (triphenylphosphine) palladium (166 mg, 0.144 mmol), ethanol (4.4 mL) and toluene (17.6 mL) )Met. After stirring for 5 minutes, the reaction mixture was degassed by bubbling nitrogen from mixing and a 2M aqueous solution of sodium carbonate (2.88 mL) was added. After heating at 80 ° C. for 2.5 hours, the filtered water was diluted with water (40 mL) and extracted with ethyl acetate (2 × 60 mL) and the reaction was filtered through Celite. The organic portion was combined by silica gel column chromatography utilizing 40% ethyl acetate / hexane as eluent to yield 859 mg of I-148 as a yellow viscous oil in 80% yield and dried. (MgSO4), concentrated and purified.

  Synthesis of C- [5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methylamine (P-596). In a 40 mL vial with stirring, methanol (20 mL) concentrated in HCl (967 uL, 11.6 mmol) and 10% Pd / C, the rod was placed 5- (3'-chloro-6-difluoro Methoxy-biphenyl-3-ylmethyl) -pyridine-2-carbonitrile (I-148, 860 mg, 2.32 mmol). The reaction can be stirred at ambient temperature for 6 hours under hydrogen air. After the mixture is filtered through celite, the filtered water is concentrated. Then water (20 mL) is followed by extraction with ethyl acetate (2 × 50 mL) and diluted with 0.5 M HCl (20 mL). The organic portion was combined by silica gel column chromatography utilizing 10% 1M NH3 in MeOH / dichloromethane as eluent to yield 121 mg P-596 as a 14% yield pale yellow solid and dried. (MgSO4), concentrated and purified.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.12 (bs, 2 H), 3.74 (s, 2 H), 3.99 (s, 2 H), 7.11 (t, J = 74 Hz, 1 H), 7.23 (d, J = 8 Hz, 1 H), 7.32-7.35 (m, 2 H), 7.40-7.51 (m, 5 H), 7.64 (dd, J = 10, 2 Hz, 1 H), 8.45 ( s, 1 H) ppm. MS (APCI +): 375.1 (M + 1), LC-MS: 99%.
Example 134. Preparation for P-598

  Synthesis of [5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid phenyl ester (I-149). In an 8 mL vial with agitation, the stick is placed C- [5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methylamine (P -596, 115 mg, 0.307 mmol), dichloromethane (1.5 mL) and triethylamine (85.6 uL, 0.614 mmol). The solution was cooled to 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes and phenyl chloroformate (57.8 uL, 0.461 mmol) was added. The reaction was quenched by water (3 mL) and the organic portion was removed. Eluent with organic portion combined, washed with brine (3 mL), dried (MgSO4) and concentrated to yield 78 mg of I-149 as a 51% yield of yellow viscous oil. Purified by silica gel column chromatography using 70% ethyl acetate / hexane as the water-like portion was extracted with dichloromethane (2 mL).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.01 (s, 2 H), 4.32 (d, J = 6 Hz, 2 H), 6.92-7.39 (m, 9 H), 7.41-7.48 (m, 4 H), 7.51 (s, 1 H), 7.71 (dd, J = 8, 2 Hz, 1 H), 8.292 (t, J = 6 Hz, 1 H), 8.51 (d, J = 2 Hz, 1 H). MS (APCI +): 495.1 (M + 1). LC-MS:> 99%.

  Synthesis of hydrochloric acid (P-598) 1- [5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -3-methyl-urea. In an 8 mL vial with agitation, the rod is placed 5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid phenyl ester (I -149, 74 mg, 0.150 mmol), tetrahydrofuran (300 uL) and methylamine (40 parts by weight of water) (116 uL, 1.50 mmol). The solution was stirred at room temperature for 2 hours and concentrated by a stream of nitrogen. The solid was triturated with diethyl ether (2 mL) and collected to wash with diethyl ether (2 mL) to yield 48 mg of P-598 as a white solid. To P-598 (41 mg, 0.0949) was added diethyl ether (700 uL) diethyl ether (2 mL) and 2M HCl. The mixture was stirred at ambient temperature for 2 hours. The solid was then collected and washed with diethyl ether (1 mL) and dried in a high vacuum oven to produce 35 mg of P-598 HCl salt as a white solid in 50% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.55 (s, 3 H), 4.18 (s, 2 H), 4.46 (s, 2 H), 6.29 (bs, 1 H), 6.78 (bs, 1 H), 7.13 (t, J = 74 Hz, 1 H), 7.27 (d, J = 8 Hz, 1 H), 7.42-7.49 (m, 5 H), 7.52 (s, 1 H), 7.76 (d , J = 8 Hz, 1 H), 8.39 (d, J = 8 Hz, 1 H), 8.79 (s, 1 H).
MS (APCI +): 432.1 (M + 1-HCl). LC-MS:> 99%.

実施例１３５。Ｐ―６０６の準備 << Reaction process formula 39 >>

Example 135. Preparation for P-606

Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -ethylamine (P-606). In a 40 mL vial where the nitrogen was cooled to 0-5 ° C. and the line was lined in / out and equipped with stirring, the rod was brominated (3 M of diethyl ether) (1.32 mL, 3.96 mmol) arranged methyl magnesium. After addition of a solution of 5- (3′-Chloro-2-fluoro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridine-2-carbonitrile (P-355, 700 mg, 1.98 mmol) in tetrahydrofuran (10 mL) The reaction was warmed to ambient temperature and stirred for 40 minutes. The reaction was heated to 60 ° C. for 3 hours and methyl magnesium bromide (3M in diethyl ether) (660 uL, 1.98 mmol) was added. A slurry of lithium aluminum hydride (150 mg, 3.96 mmol) in tetrahydrofuran (1 mL) was added and the reaction was cooled to 0-5 degrees C. The reaction was heated to 60 ° C. for 1 hour and partially concentrated, cooled to 0-5 ° C. and quenched with water (5 mL) and 1M NaOH (3 mL). After the addition of ethyl acetate (10 mL), the filtered water layer was separated and the reaction was filtered through celite. A 50 gram silica gel SNAP cartridge (Biotage SP4 with an organic portion utilizing gradient elution of 5-40% MeOH / dichloromethane to yield 124 mg P-606 as a 17% yield of yellow viscous oil. Combined with a Flash Chromatography instrument), dried (MgSO4), concentrated and purified, the watery portion was withdrawn with ethyl acetate (30 mL). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.26 (d, J = 7 Hz, 3 H), 3.72 (s, 3 H), 3.94 (s, 2 H), 3.99 (q, J = 6 Hz , 1 H), 6.94 (d, J = 8 Hz, 1 H), 7.27-7.29 (m, 1 H), 7.32-7.38 (m, 3 H), 7.41-7.47 (m, 2 H), 7.57 ( dd, J = 8, 2 Hz, 1 H), 8.39 (s, 1 H). MS (APCI +): 372.3 (M + 2). LC-MS: 95%
Example 136. Preparation of P-606-diHCl

  Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -ethylamine dihydrochloride (P-606-diHCl): stirring In the 8 mL vial provided, the rod is 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-] arranged in diethyl ether (600 uL). Yl] -ethylamine (P-606, 115 mg, 0.311 mmol), diethyl ether (3 mL), 1,4-dioxane (300 uL) and 2M HCl. The solid was collected and washed with diethyl ether (3 mL) and dried to yield 98 mg of P-606-diHCl as a light tan solid in 71% yield, mixing at ambient temperature for 15 minutes Was stirred at.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.47 (d, J = 7 Hz, 3 H), 3.73 (s, 3 H), 4.01 (s, 2 H), 4.46-4.51 (m, 1 H ), 6.96 (d, J = 8 Hz, 1 H), 7.27 (d, J = 6 Hz, 1 H), 7.36 (s, 1 H), 7.38-7.48 (m, 4 H), 7.72 (dd, J = 8, 2 Hz, 1 H), 8.33 (bs, 3 H), 8.55 (d, J = 2 Hz, 1 H).
MS (APCI +): 371.5 (M + 1-2HCl)
LC-MS: 92%
Example 137. Preparation for P-613

Hydrochloric acid (P-613) {1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -ethyl} -urea synthesis: with stirring In the 8 mL vial, the rod is placed 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -ethylamine dihydrochloride Compound (P-606, 55 mg, 0.124 mmol), water (800 uL), sodium cyanate (32.2 mg, 0.496 mmol) followed by glacial acetic acid (400 uL). The mixture was stirred at room temperature for 18 hours, then quenched slowly with a saturated solution of sodium bicarbonate (3 mL) and extracted with dichloromethane (3 × 4 mL). The organic portion is a 10 gram silica gel SNAP cartridge utilizing a gradient elution of 2-20% MeOH / dichloromethane to yield 13 mg P-613 (free base) as a 25% yield off-white solid. Combined (Biotage SP4 Flash Chromatography Instrument), dried (MgSO4), concentrated and purified. To P-613 (free base) (13 mg, 0.0314 mmol) was added diethyl ether (300 uL) with diethyl ether (1 mL) and 2M HCl. The mixture could be stirred for 10 minutes at room temperature and concentrated to dry to produce 14 mg of P-613 HCl salt as a quantitative yield of an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.36 (d, J = 7 Hz, 3 H), 3.73 (s, 3 H), 4.06 (s, 2 H), 4.82 (m, 1 H), 5.53 (br s, 2 H), 6.69 (br s, 1 H), 6.97 (d, J = 9 Hz, 1 H), 7.29 (br d, J = 6 Hz, 1 H), 7.38-7.47 (m , 4 H), 7.60 (br d, J = 8 Hz, 1 H), 8.02 (br d, J = 8 Hz, 1 H), 8.58 (s, 1 H) ppm.

実施例１３８。Ｐ―６１０の準備 << Reaction process formula 40 >>

Example 138. Preparation for P-610

  Synthesis of acidic 3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl ester (I-151) of carbon. Synthesis I-151 was synthesized after the same procedure as that for the generation of I-223.

  Synthesis of 5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I-152). In a 40 mL vial with agitation, the stick is placed on the arranged acidic 3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl ester (I-151, 700 mg, 2.04 mmol) ), 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaboloran-2-yl) -pyridine-2-carboxylic acid methyl ester (590 mg, 2.24 mmol), potassium carbonate (846 mg) 6.12 mmol), 1,5-bis (diphenylphosphino) pentane (270 mg, 0.612 mmol) and DMF (10 mL). The reaction mixture was degassed with bubbling nitrogen for 15 minutes and allyl palladium (II) chloride dimer (112 mg, 0.306 mmol) was added. The reaction mixture was heated to 85 ° C. for 4 hours. To the reaction mixture was added water (40 mL), and ethyl acetate (40 mL) and the mixture was filtered through celite. The watery portion was withdrawn with ethyl acetate (40 mL) and the filtered water layer was separated. The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The crude material was collected on a 50 gram silica gel SNAP cartridge (Biotage) utilizing a gradient elution of 12-100% ethyl acetate / hexane to yield 458 mg of I-152 as a sticky yellow solid in 56% yield. It was purified by SP4 Flash Chromatography instrument.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.86 (s, 3 H), 4.12 (s, 2 H), 7.13 (t, J = 74 Hz, 1 H), 7.25 (d, J = 8 Hz , 1 H), 7.37 (dd, J = 8, 2 Hz, 1 H), 7.57 (dt, J = 7, 2 Hz, 1 H), 7.44-7.52 (m, 4 H), 7.88 (dd, J = 8, 2 Hz, 1 H), 7.99 (d, J = 8 Hz, 1 H), 8.71 (s, 1 H) ppm.
MS (APCI +): 404.5 (M + 1). LC / MS: 98%.

Synthesis of hydrochloric acid (P-610) 2- [5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -propan-2-ol. In a 40 mL vial with agitation, the rod is placed 5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I-152, 385 mg, 0.953 mmol) and tetrahydrofuran (8 mL). The solution was cooled to 0 ° C. and the reaction was warmed to ambient temperature and could be stirred for 2 h and brominated (3M in diethyl ether) (3.2 mL, 9.53 mmol) methyl. Magnesium was added. The reaction was concentrated and placed in an ice bath and slowly disappeared with a saturated solution of ammonium chloride (5 mL). After adding dichloromethane (15 mL), the watery portion was withdrawn with dichloromethane (15 mL) and the filtered water layer was separated, and the mixture was filtered through Celite. The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The crude material was a 10 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography utilizing a gradient elution of 2-20% acetone / dichloromethane to yield 183 mg P-610 as a 48% yield colorless oil. Purified by a measuring instrument). To P-610 (175 mg, 0.433 mmol) was added diethyl ether (700 uL) with diethyl ether (1 mL) and 2M HCl. The mixture could be stirred at room temperature for 20 minutes and concentrated to dry to produce 139 mg of P-610-HCl as a 73% yield off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.53 (s, 6 H), 3.82 (bs, 1 H), 4.17 (s, 2 H), 7.14 (t, J = 74 Hz, 1 H), 7.27 (d, J = 9 Hz, 1 H), 7.43-7.54 (m, 6 H), 7.97 (bs, 1 H), 8.32 (bs, 1 H), 8.67 (s, 1 H) ppm. MS ( ESI +): 405.6 (M + 1-HCl. LC / MS: 92%.

実施例１３９。Ｐ―６１１の準備 << Reaction process formula 41 >>

Example 139. Preparation for P-611

Synthesis of hydrochloric acid (P-611) 5- (3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridine-2-ylamine. In a 40 mL vial with agitation, the sticks are placed in synthetic I-151 (1.0 g, 2.92 mmol), 5- (4,4,5,5-tetramethyl- [1,3,2]. Dioxaboralan-2-yl) -pyridine-2-ylamine (707 mg, 3.21 mmol), potassium carbonate (1.21 g, 8.76 mmol), 1,5-bis (diphenylphosphino) pentane (386 mg, 0.876 mmol) and DMF (15 mL). The reaction mixture was degassed with bubbling nitrogen for 15 minutes and allyl palladium (II) chloride dimer (160 mg, 0.438 mmol) was added. The reaction mixture was heated to 85 ° C. for 4 hours. To the reaction mixture was added water (40 mL), and ethyl acetate (40 mL) and the mixture was filtered through celite. The watery portion was withdrawn with ethyl acetate (40 mL) and the filtered water layer was separated. The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The crude material was a 50 gram silica gel SNAP cartridge (using a gradient elution of 1-10% methanol / dichloromethane to yield 841 mg P-611 as a viscous dark yellow oil in 80% yield ( Purified with a Biotage SP4 Flash Chromatography instrument. To P-611 (840 mg, 2.33 mmol) was added 1,4-dioxane (2 mL) 1,4-dioxane (8 mL) and 4M HCl. The mixture could be stirred for 20 minutes at room temperature and concentrated to dry to produce 643 mg of P-611-HCl as a yellow orange solid in 70% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.39 (bs, 2 H), 3.89 (s, 2 H), 6.932 (s, 1 H), 7.14 (t, J = 74 Hz, 1 H), 7.26 (d, J = 8 Hz, 1 H), 7.36 (dd, J = 9, 2 Hz, 1 H), 7.42-7.52 (m, 4 H), 7.85 (dd, J = 9, 2 Hz, 1 H), 7.91 (br s, 1 H), 7.94 (br s, 1 H), 13.71 (br s, 1 H) ppm. LC / MS: 94%.
Example 140. Preparation for P-616

[5- (3'-chloro-6-difluoromethoxy - biphenyl-3-ylmethyl) - pyridin-2-yl] - -urea (P-616). In an 18 mL vial equipped with agitation, the stick is P-611 (80 mg, 0.222 mmol) arranged with cyanic acid (57.7 mg, 0.888 mmol), glacial acetic acid (1.5 mL), water (750 uL) And sodium. The mixture was heated to 80 ° C. for 3 hours, cooled to room temperature, diluted with dichloromethane (4 mL), and quenched slowly with a saturated solution of sodium bicarbonate (20 mL) to pH 8. The watery portion was withdrawn with dichloromethane (2 × 15 mL) and the layers were separated. The organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 5% methanol / dichloromethane as eluent to produce a brown oil. To this, the material was diethyl ether (500 uL) added diethyl ether (1 mL) and 2M HCl. After steering at room temperature for 30 minutes, mixing is concentrated and dried to produce a P-616-HCl of 39mg of 40% of the yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.89 (s, 2 H), 6.93 (d, J = 9.0 Hz, 1 H), 7.13 (t, J = 74 Hz, 1 H), 7.35 (dd , J = 8, 2 Hz, 1 H), 7.41-7.52 (m, 4 H), 7.84 (d, J = 2 Hz, 1 H), 7.86-7.90 (m, 2 H), 13.55 (s, 1 H) ppm. MS (ESI +): 404.5 (M + 1-HCl).

実施例１４１。Ｐ―６２１の準備 << Reaction process formula 42 >>

Example 141. Preparation for P-621

  Synthesis of 5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (I-153). Synthesis I-153 was prepared in a manner similar to 70% yield of P-611 (Example 138). MS (ESI +): 364.4 (M + 1). LC / MS: 96%.

Synthesis of 2-{[5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methyl-amino} -acetamide (P-621). In an 8 mL vial with agitation, the rod is placed 5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (I-153, 210 mg, 0. 1). 577 mmol), 2-methylamino-acetamide hydrochloride (216 mg, 1.73 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (488 uL, 3.46 mmol). The mixture was heated to 160 ° C. for 3 hours and then diluted with dichloromethane (5 mL). The aqueous wash was combined with dichloromethane (2 × 3 mL), extracted and the organic portion was washed with 0.5 M HCl (3 mL). The organic portions were combined, washed with brine (4 mL), dried (MgSO4) and concentrated. The crude material was purified by a Teledyne CombiFlash system utilizing a 12 g RediSepRf silica gel cartridge and a gradient elution of 0-30% methanol / dichloromethane. And followed by a preparatory TLC (20 × 20 cm, 1000 microns) using 5% methanol / dichloromethane as the eluent yielding 8 mg of P-621? ? Yield as a 3% dark brown semi-solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.98 (s, 3 H), 3.83 (s, 2 H), 4.03 (s, 2 H), 6.53 (d, J = 9 Hz, 1 H), 7.10 (t, J = 74 Hz, 1 H), 7.21 (d, J = 8 Hz, 1 H), 7.30 (dd, J = 8, 2 Hz, 1 H), 7.36 (d, J = 2 Hz, 1 H), 7.40-7.50 (m, 5 H), 8.01 (d, J = 2 Hz, 1 H) ppm. MS (APCI +): 432.1 (M + 1). LC / MS: 86%.
Example 142. Preparation for P-618

Synthesis of hydrochloric acid (P-618) N- [5- (3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -2-dimethylamino-acetamide. In an 18 mL vial with agitation, the bars were placed dimethyl glycine (58.5 mg, 0.567 mmol), dichloromethane (2.8 mL) and thionyl chloride (82.5 uL, 1.13 mmol). . The solution was stirred at room temperature for 4 hours and concentrated. To the reaction mixture was added a solution of P-611 (150 mg, 0.378 mmol), tetrahydrofuran (2.8 mL) and diisopropylethylamine (263 uL, 1.51 mmol). The mixture was stirred at ambient temperature for 2 hours and then heated to 45 degrees C for 60 hours. The reaction was concentrated, diluted with ethyl acetate (3 mL) and washed with water (5 mL). The watery portion was withdrawn with ethyl acetate (3 × 3 mL) and the layers were separated. The organic portions were combined, washed with brine (5 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 5% methanol / dichloromethane (with 1% AcOH) as eluent. This was followed by a preparative TLC (20 × 20 cm, 1500 microns) using 10% methanol / dichloromethane as the eluent to yield 27 mg P-618 as a 16% yield orange semi-solid. To P-618 (45 mg, 0.0561 mmol) was added diethyl ether (500 uL) with diethyl ether (1 mL) and 2M HCl. The mixture could be stirred at room temperature for 20 minutes and concentrated to dry to produce 8 mg P-618-HCl as a pale orange solid in 30% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.86 (d, J = 4 Hz, 6 H), 4.00 (s, 2 H), 4.16 (m, 2 H), 7.17 (t, J = 74 Hz , 1 H), 7.25 (d, J = 8 Hz, 1 H), 7.34 (dd, J = 8, 2 Hz, 1 H), 7.41-7.51 (m, 5 H), 7.77 (dd, J = 8 , 2 Hz, 1 H), 7.97-7.99 (m, 1 H), 8.34 (d, J = 2 Hz, 1 H), 9.82 (bs, 1 H), 11.14 (s, 1 H) ppm. MS ( (APCI +): 446.1 (M + 1).
LC / MS: 96%
Example 143. Preparation for P-622

Synthesis of 2-{[5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methyl-amino} -acetamide (P-622). In an 8 mL vial with agitation, the sticks were placed P-456 (210 mg, 0.607 mmol), 2-methylaminoacetamide hydrochloride (227 mg, 1.82 mmol) and 1,8-diazabicyclo [ 5.4.0] Undec-7-ene (513 uL, 3.64 mmol). The mixture was heated to 160 ° C. for 2.5 hours and then diluted with dichloromethane (5 mL). An aqueous wash was combined with dichloromethane (3 × 3 mL), extracted and the organic portion was washed with 0.5 M HCl (3 × 3 mL). The organic portions were combined, washed with brine (4 mL), dried (MgSO4) and concentrated. The crude material was purified by a Teledyne CombiFlash system utilizing a RediSepRf 12 g silica gel cartridge and a gradient elution of 0-30% isopropanol / dichloromethane to produce material still containing impurities. The dirty material was purified by preparative TLC (20 × 20 cm, 1000 microns) using 10% isopropanol / dichloromethane as eluent to yield 89 mg P-622 as a 35% yield yellow solid. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.99 (s, 3 H), 3.71 (s, 3 H), 3.78 (s, 2 H), 4.03 (s, 2 H), 6.53 (d, J = 9 Hz, 1 H), 6.90-6.92 (m, 2 H), 7.23-7.25 (m, 1 H), 7.28 (d, J = 8 Hz, 2 H), 7.34-7.37 (m, 2 H) , 7.40-7.47 (m, 2 H), 7.95 (d, J = 2 Hz, 1 H) ppm. MS (APCI +): 414.1 (M + 1).
Example 144. Preparation of P-573

  5- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-imidazol-1-yl-pyridine (synthesis of P-573). To a 20 mL vial containing P-456 (200 mg, 0.55 mmol) and 1H-imidazole-2-carboxylic acid (202 mg, 1.8 mmol), rt. DBU (0.5 mL, excess) was added. The mix was heated to 160 ° C and could be stirred at 160 ° C for 2.5h and the vial was sealed. The mixture was cooled to rt and extracted with 20 mL ice water solution (2N HCl until pH = 1-2, acidified, ethyl acetate (3 × 15 mL) and water (3 × 15 mL). Brine (20 mL) was poured over and dried over Na2SO4. After removal of the solvent, the remainder was separated by chromatography on silica gel with dichloromethane / iPA as eluent to obtain a 26% yield of P-573 (60 mg).

1H NMR (DMSO-d ₆ , 400 MHz): 8.48 (s, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 7.91 (br s, 1 H), 7.85 (dd, J = 8.2, 2.4 Hz, 1 H), 7.74 (d, J = 9.2 Hz, 1 H), 7.27-7.47 (m, 5 H), 7.11 (s, 1 H), 6.86 (d, J = 7.6 Hz, 1 H) , 4.01 (s, 2 H), 3.73 (s, 3 H) ppm.
LC / MS: 393.84 Calc.393.8; APCI + (M + 1): 394.1, 99%

実施例１４５。Ｐ―５９０の準備 << Reaction process formula 43 >>

Example 145. Preparation for P-590

Synthesis of 5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carbonitrile (P-590). To 100 mL, I-154 (1324 mg, 4 mmol) mixed and toluene / EtOH / H 2 O (4/1/1, 25 mL) 5- (4,4,5,5-tetramethyl- [1,3,2] A flask containing dioxaboran-2-yl) -pyridine-2-carbonitrile (1.1 g, 4.4 mmol) was added with potassium phosphate (1 .7 g, 8 mmol) and tetrakis (1 .7 g, under nitrogen). Triphenylphosphine) palladium (0) (400 mg, 0.3 mmol). The reaction mixture was stirred at 60 ° C. for 4 h. The reaction mixture was cooled to ambient temperature, poured onto an aqueous ice solution (100 mL) and extracted with ethyl acetate (3 × 30 mL). Mixed organic layer water (30 mL), brine, 25 mL were dried over Na2SO4, washed and concentrated in vacuo. The remainder was separated by chromatography on silica gel with ethyl acetate-hexane as the eluent yielding P-590 (380 mg, 27%). 1H NMR (CDCl3, 400 MHz): 8.61 (s, 1 H), 7.61 (d, J = 1.2 Hz, 2 H), 7.46-7.48 (m, 1 H), 7.29-7.37 (m, 3 H), 7.11 (dd, J = 8.4, 2.4 Hz, 1 H), 7.08 (d, J = 2.4 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 4.03 (s, 2 H), 3.81 (s, 3 H) ppm.
Calc. 338.84; APCI + (M + 1): 339.1, 100%.
Example 146. Preparation for P-591

Synthesis of hydrochloric acid (P-591) C- [5- (3′-halo-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methylamine. To a 50 mL flask containing P-590 (220 mg, 0.66 mmol) in, EtOH (14 mL) was added 12 N HCl (1 mL) and then rt. Of Pd / C (10%, 200 mg). The system could be stirred at ambient temperature under hydrogen air (15 psi) for 3 h. The filtered water was concentrated and the solid was removed by filtration. The remainder was purified via chromatography on silica gel with ethyl acetate as eluent to obtain a 70% yield of P-591 (160 mg). P-591 (25 mg) was treated with 2N HCl in diethyl ether (2 mL) because it could afford a 60% yield of P-591 HCl salt (16 mg). ¹ H NMR (DMSO-d ₆ , 400 MHz): 8.54 (s, 1 H), 8.26 (br.s, 2 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.39-7.47 (m, 4 H), 7.22-7.27 (m, 2 H), 7.06 (d, J = 8.4 Hz, 1 H), 4.14 (br s, 2 H), 3.99 (s, 2 H), 3.74 (s, 3 H ) ppm.Calc.338.84; APCI ⁺ (M + 1): 339.1, 100%.
Example 147. Preparation for P-592

Synthesis of [5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid phenyl ester (P-592). In a 20 mL vial containing P-591 (140 mg, 0.4 mmol) in dichloromethane (3 mL) and triethylamine (85 mg, 0.8 mmol), 0-5 oC phenyl chloroformate (95 mg, 0.6 mmol) was Added. The reaction mixture was allowed to stir for 1 h with heat at ambient temperature. The mixture was poured onto 30 mL of aqueous ice. And extracted with dichloromethane (3 × 15 mL). The combined organic layer was dried through Na2SO4 and vacuum concentration and washed with water (20 mL), brine, 15 mL. The remainder was purified via chromatography on silica gel with ethyl acetate-hexane as eluent to obtain 150 mg (79%) of P-592.
1H NMR (CDCl ₃ , 400 MHz): 8.46 (s, 1 H), 7.48-7.52 (m, 2 H), 7.11-7.37 (m, 10 H), 6.92 (d, J = 8.4 Hz, 1 H) , 6.13 (br.s, 1 H), 4.55 (d, J = 4.8 Hz, 2 H), 3.97 (s, 2 H), 3.80 (s, 3 H) ppm.
Calc. 458.9; APCI ⁺ (M + 1): 459.1, 100%.
Example 148. Preparation for P-597

Synthesis of hydrochloric acid (P-597) 1- [5- (3'-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -3-ethyl-urea. To a 20 mL vial containing P-591 (66 mg, 0.2 mmol) of pyridine (2 mL) was added ambient temperature isocyanato-ethane (0.2 mL, excess) and the resulting mixing was 48 h. Stirred. The solid was passed through a filter, washed with water (2 × 20 mL), air dried to yield 55 mg of P-597, and the mixture was poured onto 20 mL of aqueous ice. The free base was treated with dioxane 4N HCl at ambient temperature to afford a 63% yield of 55 mf of P-597 HCl salt. 1H NMR (DMSO-d ₆ , 400 MHz). 8.72 (s, 1 H), 8.29 (d, J = 7.6 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.50 (br s , 1 H), 7.37-7.41 (m, 3 H), 7.29-7.31 (m, 2 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.67 (s, 1 H), 6.36 (s, 1 H), 4.44 (s, 2 H), 4.09 (s, 2 H), 3.75 (s, 3 H), 3.00 (d, J = 7.2 Hz, 2 H), 0.98 (t, J = 7.2 Hz, 3 H) ppm.
Example 149. Preparation for P-593

Synthesis of hydrochloric acid (P-593) 1- [5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -3-methyl-urea: P-592 (92 mg, 0 .2 mmol) in a 20 mL vial in which THF (3 mL) was excess methylamine (40% of H 2 O (1 mL)) and the resulting mixing was ambient temperature for 4 h in could be stirring. Diethyl ether (10 mL) was added and the solvent was removed. The solid was passed through a filter, washed with diethyl ether (2 × 5 mL) and air dried to yield 50 mg of P-593. The free base was treated with 4N HCl in dioxane (0.5 mL) to afford a 52% yield of 45 mg P-593 HCl salt. 1H NMR (DMSO-d6, 400 MHz): 8.77 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.51 (s, 1 H), 7.31-7.44 (m, 5 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.90 (s, 1 H), 4.49 (s, 1 H), 4.12 (s, 3 H), 3.75 (s, 3 H), 2.54 (s, 2 H) ppm. Calc. 395.88; APCI + (M + 1): 396.1, 100%.
Example 150. Preparation of P-600

  1- [5- (3′-Chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methylamine hydrochloride (synthesis of P-600). A 50 mL flask containing CeCl3 (370 mg (1). Mmol) was dried with a heat gun for 0.5 h. After cooling to ambient temeratre, the mixture could be stirred for 2 h and THF (5 mL) was added and cooled to −78 ° C. Methyl lithium (1M of ether (1 mL)) was added at −78 ° C. and stirred at −78 ° C. for 1 h, and P-590 (170 mg, 0.5 mmol) in THF (0.5 mL) was Added. The mixture could be stirred at −78 ° C. for 0.5 h, allowed to heat to ambient temperature and stirred for 16 h. The reaction disappeared with the addition of isopropanol (1 mL). The solid was removed by filtration and the filtered water was concentrated. The remainder is ethyl acetate-EtOH as an eluent to obtain 30 mg of P-600 treated with 2N HCl in diethyl ether (2 mL) to afford an 8% yield of 15 mg of P-600 HCl salt. Purified via chromatography on silica gel with

  1H NMR (DMSO-d6, 400 MHz): 8.59 (d, J = 2.0 Hz, 1 H), 8.39 (br s, 2 H), 7.80 (dd, J = 8.0, 2.0 Hz, 1 H), 7.54 ( d, J = 8.4 Hz, 1 H), 7.48 (br s, 1 H), 7.36-7.45 (m, 3 H), 7.25-7.28 (m, 2 H), 7.06 (d, J = 9.2 Hz, 1 H), 3.99 (s, 2 H), 3.74 (s, 3 H), 1.57 ppm (s, 6 H) ppm. LC / MS: Calc. 409.9; APCI + (M + 1): 410.1, 100%

実施例１５１。Ｐ―６０５の準備 << Reaction process formula 44 >>

Example 151. Preparation for P-605

Synthesis of 5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2 carboxylic acid methyl ester (I-156). Hybridization of I-155 (2.0 g, 6.6 mmol) and 5- (4,4,5,5-tetramethyl- [1,3,2] dioxabolan-2-yl) -pyridine-2-carboxylic acid To the 250 mL flask that was in, DME (30 mL) methyl ester (1.6 g, 6 mmol) was added with additional K2CO3 (2.5 g, 18 mmol), ₂ [Pd (y3C3H5Cl)] (300 mg, 0.8 mmol). ) And rt DPPPent (800 mg, 1.9 mmol) under nitrogen. The reaction mixture was heated to 85 ° C. and stirred at 85 ° C. for 16 h. The reaction mixture was cooled to rt. The resulting semi-solid was then separated from the aqueous layer to form a crude oil purified by chromatography on silica gel with dichloromethane-acetone as eluent to obtain I-156 (1200 mg, 50%), ice water (200 mL ) Was injected on top. 1H NMR (CDCl3, 400 MHz): 8.64 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.47 (s, 1 H) , 7.29-7.36 (m, 2 H), 7.11 (d, J = 8.0 Hz, 1 H), 7.09 (d, J = 2.0 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.04 (s, 2 H), 3.99 (s, 3 H), 3.80 (s, 3 H) ppm. LC / MS: Calc. 367.84; APCI + (M + 1): 368.1, 99%.

2- [5- (3′-Chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -propan-2-ol HCl salt (P-605) and 1- [5- (3 ′ Synthesis of -chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -ethaneone (I-157). To a 50 mL dry flask containing I-156 (350 mg, 1 mmol) in THF (5 mL) and methyl magnesium bromide (ether, 3 mL, 9 mmol of 3M) was cooled to 0 ° C. The reaction mixture was allowed to heat to ambient temperature, stirred for 16 h, and drained onto 50 mL ice water. The mixture was neutralized with NH4Cl (sitting. 10 mL), and the organic fertilizer was with water (20 mL), brine (20 mL), Na2SO4. After removal of solvent extracted with ethyl acetate (3 × 20 mL), which was dried and washed through, 15% of 60 mg of I-157 yielded and the rest was 100% of P-605 in 28% yield. Was purified by silica gel column chromatography with dichloromethane-acetone as the eluent. 50 mg of P-605 was treated with diethyl ether (1 mL) of 2N HCl due to the margin of a 99% yield of 55 mg of P-605 HCl salt. 1H NMR (DMSO-d6, 400 MHz): 8.60 (br s, 1 H), 7.85-8.24 (m, 2 H), 7.30-7.52 (m, 6 H), 7.08 (d, J = 6.8 Hz, 1 H), 4.08 (s, 2 H), 3.75 (s, 3 H), 1.51 ppm (s, 6 H) ppm. LC / MS: Calc. 367.88; APCI + (M + 1): 368.1, 96%.
Example 152. Preparation for P-609

  Synthesis of 2- (1-azetidin-1-yl-ethyl) -5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridine (P-609). To a 25 mL vial containing I-157 (52 mg, 0.15 mmol) and azetidine was added HCl salt of MeOH (2 mL) (30 mg, 0.3 mmol) with 0 ° C. added sodium cyanoborohydride (16 mg, 22 mmol). there were. The reaction mixture was allowed to stir for 72 h with heat at ambient temperature. The mixture was poured onto 5 mL 0.5N aqueous sodium hydroxide solution and extracted with ethyl acetate (3 × 10 mL). The composite organic fertilizer was washed with water (10 mL) and dried over Na2SO4 with brine (10 mL). After removal of the solvent, the remainder was purified by chromatography on silica gel with dichloromethane-acetone as the eluent to yield a 54% yield of 30 mg P-609.

1H NMR (CDCl3, 400 MHz): 8.41 (d, J = 2.0 Hz, 1 H), 7.27-7.48 (m, 6 H), 7.10-7.15 (m, 2 H), 6.91 (d, J = 8.0 Hz , 1 H), 3.92 (s, 2 H), 3.79 (s, 3 H), 3.41-3.46 (m, 1 H), 3.10-3.25 (m, 4 H), 2.00-2.07 (m, 2 H) , 1.21 (d, J = 6.4 Hz, 3 H) ppm.
Example 153. Preparation for P-567

Synthesis of 5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I-158). The flask that reached the round bottom to 250 mL was added I-154 (4.89 g, 15.69 mmol), 5- (4,4,5,5-Tetramethyl- [1,3,2] dioxabolan-2- Yl) -pyridine-2-carboxylic acid methyl ester (4.52 g, 17.26 mmol), toluene (120 mL), EtOH (20 mL), water (20 mL) and K3PO4 (6.66 g, 31.38 mmol). . The outage was degassed by N2 for 15 minutes and the reaction was stirred at 80 ° C. for 1 hour and Pd (PPh 3) 4 (1.81 g, 1.57 mmol) was added. The watery one was extracted with 50 mL EtOAc and the layers were separated. The organic fertilizer was combined, washed with 50 mL brine, dried over Na 2 SO 4, filtered and concentrated. The remainder was purified by flash column chromatography eluting with acetone / hexanes by 10% to yield 890 mg of I-158 as a pale yellow oil produced in 15%.

[5- (3′-Chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methanol (P-567). To a 100 mL round bottom flask was added I-158 (0.71 g, 1.93 mmol), THF, 20 mL, and the solution was cooled to 0 ° C. The reaction was stirred at 0 ° C. for 1 hour and LiAlH 4 (0.29 g, 7.72 mmol) was added. The product was extracted with EtOAc (3 × 20 mL) and 20 mL of water was added slowly. Organic fertilizers were combined, filtered and concentrated celite. The remainder was purified by flash column chromatography eluting with acetone / hexanes by 20% to provide 352 mg of P-567 as a 54% yield of light yellow oil. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J = 1.6 Hz, 1 H), 7.64 (dd, J = 2.0, 7.9 Hz, 1 H), 7.49 (s, 1 H), 7.45-7.34 ( m, 4 H), 7.25-7.20 (m, 2 H), 7.05 (d, J = 8.6 Hz, 1 H), 5.31 (t, J = 5.8 Hz, 1 H), 4.50 (d, J = 5.9 Hz , 2 H), 3.93 (s, 2 H), 3.74 (s, 3 H) ppm. LC / MS = 92.1%, 340.1 (APCI +).
Example 154. Preparation for P-570

Hydrochloric acid (P-570) ethyl-carbamic acid 5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl ester. To 18 mL, the vial was summed P-567 (98 mg, 0.29 mmol), toluene (2 mL) and ethyl isocyanate (57 uL, 0.72 mmol). The reaction was stirred at 60 ° C. for 6 hours and concentrated. The solid was triturated with ether to obtain 79 mg of P-570 as a white solid. Of this material, 68 mg was decomposed and concentrated in 4N HCl / Dioxane. This solid was triturated with ether and passed through a filter and washed with ether to afford 50 mg of P-570 HCl salt as a 45% yield tan solid. . 1H NMR (400 MHz, DMSO-d6) 8.48 (d, J = 1.5 Hz, 1 H), 7.71-7.64 (m, 1 H), 7.49 (s, 1 H), 7.45-7.34 (m, 3 H) , 7.32-7.19 (m, 3 H), 7.05 (d, J = 9.1 Hz, 1 H), 5.01 (s, 2 H), 3.94 (s, 2 H), 3.74 (s, 3 H), 3.07- 2.95 (m, 2 H), 1.01 (t, J = 7.2 Hz, 3 H) ppm. LC / MS = 100.0%, 411.0 (APCI +).
Example 155. Preparation for P-534

1- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-imidazole-4-carboxylic acid methyl ester (I-159) and 3- (3'-chloro-2- Fluoro-6-methoxy-biphenyl-3-ylmethyl) -3H-imidazole-4-carboxylic acid methyl ester (I-160). To 18 mL, the vial was added methyl 4-imidazole carboxylate (113 mg, 0.90 mmol), DMF (3 mL) and NaH (43 mg, 1.08 mmol). After 20 minutes at room temperature, I-33 (295 mg, 0.90 mmol) was added. The reaction was stirred at room temperature for 2 hours and water was added. The organic fertilizer was concentrated and the product was extracted with EtOAc. The remainder was purified to be removed by 6% -10% acetone / dichloromethane-flash column chromatography that cleaves regioisomers. The 4-substituted ester I-159 (67 mg, 20%) and the 2-substituted ester I-160 (79 mg, 23%) were obtained as colorless oils.

1- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-imidazole-4-carboxylic acid amide (P-534). To an 8 mL vial, I-159 (30 mg, 0.08 mmol) and 2 mL of 7N NH3 / MeOH were added. The reaction was stirred at 60 ° C for 6 days it was concentrated. Ether was filtered to form 8 mg of P-534 as a tan solid with a 28% yield, filtered to form a washed solid. 1H NMR (400 MHz, DMSO-d6) 7.77 (s, 1 H), 7.63 (s, 1 H), 7.48-7.36 (m, 4 H), 7.29 (d, J = 6.4 Hz, 1 H), 7.26 (br s, 1 H), 7.05 (br s, 1 H), 7.02 (d, J = 8.7 Hz, 1 H), 5.25 (s, 2 H), 3.75 (s, 3 H) ppm.
Example 156. Preparation for P-535

3- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -3H-imidazole-4-carboxylic acid amide (P-535). To an 8 mL vial, I-160 (36 mg, 0.096 mmol) and 2 mL of 7N NH3 / MeOH were added. The reaction was stirred at 60 ° C for 6 days it was concentrated. Filtered to be washed with ether to yield 7 mg of P-535 as a 20% white solid, and yielded, the solid was triturated with eth. 1H NMR (400 MHz, DMSO-d6) 7.83 (s, 1 H), 7.75 (br s, 1 H), 7.63 (s, 1 H), 7.51-7.41 (m, 2 H), 7.38 (s, 1 H), 7.29 (d, J = 6.6 Hz, 1 H), 7.19 (br s, 1 H), 7.10-7.00 (m, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 5.59 ( s, 2 H), 3.72 (s, 3 H) ppm. LC / MS = 92.2%, 359.1 (APCI-).
Example 157. Preparation for P-536

1- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -4-nitro-1H-imidazole (P-536). The solution was cooled to 0 ° C. and in a 100 mL circle, the bottom flask was summed with I-33 (1.0 g, 3.03 mmol), DMF, 25 mL. Hydrogenated (145 mg, 3.64 mmol) Ssodium was added followed by 4-nitro-1H-imidazole (377 mg, 3.34 mmol). The reaction was stirred at 0 ° C. for 2 hours and 10 mL of water was added. The complex organic fertilizer was concentrated and the product was extracted with 3 x 15 mL EtOAc. The product was purified by flash column chromatography eluting with acetone / hexanes by 20% to yield 625 mg of P-536 as a 57% yield of straw oil. 1H NMR (400 MHz, DMSO-d6) 8.41 (d, J = 0.9 Hz, 1 H), 7.94 (s, 1 H), 7.56-7.37 (m, 4 H), 7.30 (d, J = 6.4 Hz, 1 H), 7.03 (d, J = 8.6 Hz, 1 H), 5.34 (s, 2 H), 3.76 (s, 3 H) ppm
Example 158. Preparation for P-531

C- [5- (4,4,5,5-Tetramethyl- [1,3,2] dioxabolan-2-yl) -pyridin-2-yl] -methylamine (I-161), 100 ml round bottom Into the flask was 5- (4,4,5,5-tetramethyl- [1,3,2] dioxabolan-2-yl) -pyridine-2-carbonitrile (1.0 g, 0.43 mmol). ), 20 mL MeOH, conc. Was added. HCl (1.8 mL, 2.17 mmol) and 10% Pd / C (0.2 g). The reaction was stirred under hydrogen air for 18 hours. The reaction was filtered through celite (washed with MeOH) and concentrated to a yellow solid. As was the case, materials were used.

1-ethyl-3- [5- (4,4,5,5-tetramethyl- [1,3,2] dioxabolan-2-yl) -pyridin-2-ylmethyl] -urea (I-162). In a 50 mL circle, the bottom flask is loaded with additional C- [5- (4,4,5,5-tetramethyl- [1,3,2] dioxabolan-2-yl) -pyridin-2-yl]- Methylamine (I-161,1 g, crude), pyridine (10 mL) and ethyl isocyanate (0.5 mL, 6.5 mmol). The reaction was stirred for 30 minutes at room temperature and NaHCO3 (sitting) was added. The complex organic fertilizer was dried over Na 2 SO 4 and the product was extracted with 3 × 10 mL EtOAc and concentrated. The remainder is 50% yielding 100% MeOH yielding 289 mg of I-162 as a -22% brown oil purified by flash column chromatography eluting with acetone / dichloromethane.

1- [4- (3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethoxy) -pyridin-2-ylmethyl] -3-ethyl-urea (P-531). To 8 mL, the vial was added I-163 (125 mg, 0.39 mmol), 1-ethyl-3- [5- (4,4,5,5-tetramethyl- [1,3,2] dioxabolan-2- Yl) -pyridin-2-ylmethyl] -urea (I-162, 119 mg, 0.39 mmol), K3PO4 (248 mg, 1.17 mmol), DME (2.5 mL), EtOH (0.5 mL) and water (0. 5 mL). The stop was degassed by N2, and Pd (PPh3) 4 was added. The reaction was stirred at 80 ° C for 1 hour. The product was extracted with EtOAc (3 × 2 mL) and water (2 mL) was added. The organic extracts were combined and concentrated. The remainder was purified by extraction with 25%-then 50% acetone / dichloromethane-flash column chromatography giving a brownish gray solid powdered with ether. The resulting solid was recrystallized from EtOH to provide 7 mg P-531 as a 4% yield white solid. 1H NMR (400 MHz, DMSO-d6) 8.26 (d, J = 2.8 Hz, 1 H), 7.89-7.82 (m, 2 H), 7.75-7.53 (m, 3 H), 7.47 (dd, J = 3.0 , 8.6 Hz, 1 H), 7.22 (d, J = 8.6 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 1 H), 6.33 (t, J = 5.8 Hz, 1 H), 6.01 (t , J = 5.4 Hz, 1 H), 5.16 (s, 2 H), 4.22 (d, J = 5.9 Hz, 2 H), 3.78 (s, 3 H), 3.09-2.95 (m, 2 H), 0.99 (t, J = 7.1 Hz, 3 H) ppm. LC / MS = 90.7%, 435.2 (APCI +).
Example 159. Preparation for P-244

2- (3-Bromo-4methoxyphenyl) -ethanol (I-164). The mixture was cooled to 0 ° C. and in a 100 mL circle, the bottom flask was additional (3-bromo-4 methoxyphenyl) -acetic acid (0.58 g, 2.37 mmol), THF, 10 mL. The reaction was stirred for 20 hours at room temperature and BH3-THF (10.6 mL, 10.6 mmol, 1.0 M in THF) was added. The solvent was removed on the rotary evaporator and 20 mL of MeOH was added. This was repeated for another 5 hours. The remainder was purified by flash column chromatography eluting 20% acetone / hexanes with 10- to yield 457 mg of I-164 as a 83% yield of light yellow oil.

2-Bromo-4- (2-bromoethyl) -1 methoxybenzene (I-165). In a 100 mL circle, the bottom flask was loaded with additional 2- (3-bromo-4 methoxyphenyl) -ethanol (I-164, 418 mg, 1.81 mmol), dichloromethane (15 mL), carbon tetrabromide (1. 50 g, 4.52 mmol) and tri-phenylphosphine (1.19 g, 4.52 mmol). After stirring for 1 hour at room temperature, the reaction was concentrated. The remainder yielded 1.91 g of I-165 as a colorless oil that was purified by flash column chromatography and extracted with hexane, which was used without further purification.

1- [2- (3-Bromo-4methoxyphenyl) -ethyl] -1H-pyridine-2-1 (I-166). In a 100 mL circle, the bottom flask was loaded with additional 2-bromo-4- (2-bromoethyl) -1 methoxybenzene (I-165, 1.82 g, crude), 2-hydroxypyridine (258 mg, 2. 72 mmol), K2CO3 (625 mg, 4.53 mmol) and DME (20 mL). After stirring for 18 hours at 80 ° C, the filtrate was concentrated and the suspension was filtered. The remainder is 50% acetone / hexane yielding 221 mg of I-166 as a brown oil in 25-40% yield (2 steps) purified by flash column chromatography.

1- [2- (6-Methoxy-3′-nitro-biphenyl-3-yl) -ethyl] -1H-pyridine-2-1 (P-244). In a 40 mL vial, 1- [2- (3-bromo-4methoxyphenyl) -ethyl] -1H-pyridine-2-1 (I-166, 210 mg, 0.68 mmol), 3nitrophenyl bromic acid (125 mg 0.75 mmol), PPh3 (36 mg, 0.014 mmol), potassium carbonate (283 mg, 2.04 mmol), dimethoxyethane (10 mL), ethanol (1 mL) and water (1 mL) were added. The stop was degassed with N2 for 5 min and then palladium (II) acetate (15 mg, 0.068 mmol). After removing the gas from the reaction for an additional 2 minutes, stirring at 80 ° C for 18 hours. To the reaction, 5 mL water and 10 mL ethyl acetate were added. The watery one was extracted with ethyl acetate (3 x 10 mL) and the layers were separated. Organic fertilizers were combined and concentrated. The remainder is 10-20% acetone / dichloromethane purified by flash column chromatography. The resulting (136 mg) yellow oil was dissolved in 1 mL ether and allowed to stand at room temperature for 3 days. The formed tan solid was filtered, washed with ether and dried to yield a 31% yield of 74 mg of P-244. 1H NMR (400 MHz, CDCl3) δ 8.30-8.29 (m, 1H), 8.18-8.15 (m, 1H), 7.81-7.79 (m, 1H), 7.54 (t, J = 8.0 Hz), 7.37-7.33 ( m, 1H), 7.19 (dd, J = 8.2, 2.2 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.95-6.93 (m, 2H), 6.61 (d, J = 9.2 Hz, 1H ), 6.06 (td, J = 6.6, 1.2 Hz, 1H), 4.15 (t, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.07 (t, J = 7.0 Hz, 2H) ppm. LC / MS = 99.4%, 351.6 (ESI +).
Example 160. Preparation for P-003

5- [5- (4-Fluoro-benzyl) -2-methoxyphenyl] -benzo [1,3] dioxole (P-003). P-003 was prepared by following the method described for P-001. 1H NMR (400 MHz, CDCl3) 3.80 (s, 3 H) 3.93 (s, 2 H) 5.98 (s, 2 H) 6.83-6.92 (m, 2 H) 6.92-7.05 (m, 4 H) 7.05-7.12 (m, 2 H) 7.16 (dd, J = 8.4, 5.6 Hz, 2 H) ppm. LCMS = 94.4% purity. TSI (+) = 365.4 (M + 29).
Example 161. Preparation for P-004

5- [5- (4-Fluoro-benzyl) -2-methoxyphenyl] -benzo [1,2,5] oxa-diazole (P-004). P-004 was prepared by following the method described for P-001. 1H NMR (400 MHz, CDCl3) 3.84 (s, 3 H), 3.97 (s, 2 H), 6.91-7.05 (m, 3 H), 7.13-7.24 (m, 4 H), 7.62 (dd, J = (9.3, 1.3 Hz, 1 H) 7.75-7.87 (m, 2 H) ppm. LCMS = 96.2% purity. TSI (+) = 365.4 (M + 31).
Example 162. Preparation for P-006

  Synthesis of 5- (5-imidazol-1-ylmethyl-2-methoxyphenyl) -benzo [1,2,5] oxadiazole (P-006). 1- (3-bromo-4methoxybenzyl) -1H-imidazole (I-167, 267 mg, 1.00 mmol) of dimethylformamide (20 mL) and 1 M aqueous cesium carbonate (3.0 mL, 3.0 mmol), Benzo [1,2,5] oxadiazole-5-bromate (I-105, 164 mg, 1.00 mmol), palladium (0) bis (di-benzylideneacetone) (28.7 mg, 0.050 mmol) and tri A suspension of phenyl phosphine (26.2 mg, 0.10 mmol) was heated to 85 ° C. for stirring overnight. The rest was suspended in ethyl acetate (25 mL) and the solvent was removed under vacuum. The organic suspension was washed with water (3 × 20 mL) and brine, dried over sodium sulfate, decolorized through activated carbon, filtered and concentrated. The remainder yields 9.1% to submit layer chromatography (ethyl acetate: dichloromethane 3: 1), 10.4 mg P-006, which was cleaned with a thin spare silica gel. 1H NMR (400 MHz, CDCl3) 3.86 (s, 3 H) 5.13 (s, 2 H) 6.93 (s, 1 H) 7.01 (d, J = 8.32 Hz, 1H) 7.10 (s, 1 H) 7.17-7.25 (m, 2 H) 7.52-7.62 (m, 2 H) 7.78-7.85 (m, 2 H) ppm. LCMS = 100% purity. APCI (+) = 307.1 (M + 1).

実施例１６３。Ｐ―４７４の準備 << Reaction process formula 45 >>

Example 163. Preparation for P-474

Synthesis of 3- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -pyridine (P-474). Dimethylformamide (5 mL) and 1 M aqueous sodium carbonate (1.5 mL, 1.5 mmol) I-168 (158 mg, 0.53 mmol), 3 pyridine bromic acid (61.5 mg, 0.50 mmol), palladium (0) A suspension of bis (dibenzylideneacetone) (14.4 mg, 0.025 mmol) and triphenylphosphine (13.1 mg, 0.050 mmol) was heated to 85 ° C. for stirring overnight. The rest was suspended in ethyl acetate (15 mL) and the solvent was removed under vacuum. The organic stop was washed with water (3 × 15 mL) and brine. It was then dried over sodium sulfate and solvent removed under vacuum to give the crude material. The remainder yields 69.1 mg (47%) of P-474 purified by preparative thin layer chromatography on silica gel.
LCMS = 94.6% purity.
Example 164. Preparation for P-475

Synthesis of 3- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -pyridine 1-oxide (P-475). The vial is charged with P-474 (60 mg, 0.20 mmol), methyl ruthenium oxide (2.5 mg, 0.010 mmol), 30% aqueous hydrogen peroxide (0.5 mL) and dichloromethane (1.0 mL). It had been. The reaction could be stirred at room temperature for 3 days. The biphasic mixture was treated with a catalytic amount of manganese dioxide (1.7 mg, 0.02 mmol) and stirred carefully until the end of oxygen evolution (1 h). The phase was cut off. The aqueous layer was then extracted into dichloromethane (2 × 1 mL). The organic layers are then combined and dried over sodium sulfate. The solvent is then removed under vacuum to yield a 34% yield of 20.9 mg of P-475. 1H NMR (400 MHz, CDCl3) 3.82 (s, 3 H) 3.94 (s, 2 H) 6.89-7.24 (m, 8 H) 7.41 (d, J = 8.1 Hz, 1 H) 8.16 (d, J = 6.3 Hz, 1 H) 8.44 (s, 1 H) ppm. LCMS = 92.0% purity.
Example 165. Preparation for P-007

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-benzotriazole (P-007). Dimethylformamide (10 mL) and 1 M aqueous sodium carbonate (4.5 mL, 4.5 mmol) I-169 (477 mg, 1.50 mmol), 3 nitrophenyl bromic acid (250 mg, 1.50 mmol), palladium (0) bis A suspension of (dibenzylideneacetone) (43 mg, 0.075 mmol) and triphenylphosphine (39 mg, 0.15 mmol) was heated to 85 ° C for stirring overnight. The rest was suspended in ethyl acetate (20 mL) and the solvent was removed under vacuum. The solvent was removed under vacuum to give a residue and brine (dried over sodium sulfate) was decolorized through activated carbon, filtered and the organic stop was washed with water (3 × 20 mL). The remainder was dissolved in ethyl acetate (5 mL) and purified by adding hexane (25 mL) until the solid formed. This was repeated three times to yield a 39% yield of 210 mg of P-007. 1H NMR (400 MHz, CDCl3) 3.83 (s, 3 H), 5.87 (s, 2 H), 6.99 (d, J = 8.2 Hz, 1 H), 7.31-7.52 (m, 4 H), 7.56 (t , J = 7.9 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1 H), 8.13 (d, J = 8.3 Hz, 1 H), 8.19 (dd, J = 8.2, 1.2 Hz, 1 H), 8.36 (d, J = 1.6 Hz, 1 H) ppm. LCMS = 93.9% purity. APCI (+) = 361.10 (M + 1).
Example 166. Preparation for P-037

Synthesis of 1- (3-Benz [1,3] dioxol-5-yl-4methoxybenzyl) -1H-imidazole (P-037). To a solution of I-167 (484 mg, 1.80 mmol) and benzo [1,3] dioxol-5-bromic acid (332 mg, 2.00 mmol) was added palladium (0) bis (dibenzylideneacetone) (57.5 mg, 0.100 mmol) was added, and dimethylformamide (40 mL) and 1 M aqueous sodium carbonate (6.0 mL, 6.0 mmol) triphenylphosphine (52.4 mg, 0.200 mmol) were stirred overnight. Was heated to 80 ° C. The rest was suspended in ethyl acetate (30 mL) and the solvent was removed under vacuum. The organic stop was washed with water (3 × 30 mL) and brine (dried through sodium sulfate, decolorized through activated charcoal, passed through filter) and solvent removed under vacuum to give the rest . The remainder was extracted with reverse phase purified (water: acetonitrile 3: 1 to 1: 1) dichloromethane and reduced pressure to yield 69.6 mg P-037 as a 13% yield clear viscous oil. Continue by removal of the solvent under. 1H NMR (400 MHz, CDCl3) 3.81 (s, 3 H), 5.08 (s, 2 H), 5.99 (s, 2 H), 6.82-6.96 (m, 4 H), 7.00 (d, J = 1.5 Hz , 1 H), 7.09 (d, J = 10.2 Hz, 3 H), 7.55 (s, 1 H) ppm. LCMS = 100% purity. APCI (+) = 309.10 (M + 1).
Example 167. Preparation for P-040

Synthesis of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -piperidine-2,6-dione (P-040). To a solution of I-70 (161 mg, 0.500 mmol) and dimethyl glutarimide (113 mg, 1.00 mmol), formamide (1.5 mL) was hydrogenated (60% weight dispersion, 40 mg, 1.00 mmol) sodium. Added -78oC. After the evolution of hydrogen gas was over, the reaction was stirred overnight at 120 ° C. The reaction mixture was filtered and the filtered water was concentrated under reduced pressure. The remainder was diluted with ethyl acetate (15 mL). The brine (dried over sodium sulfate) was then filtered, washed with water, and the solvent was removed under vacuum. Dichloromethane (2 mL) was followed by silica gel column chromatography (50% ethyl acetate in hexane) to afford 45% yield of 79.8 mg P-040 and the product was hexane (50 mL) And purified by grinding.
¹ H NMR (400 MHz, CDCl ₃ ) 1.94 (quintet, J = 6.4 Hz, 2H), 2.67 (t, J = 6.4 Hz, 4H), 3.81 (s, 3H), 4.94 (s, 2H), 6.92 ( d, J = 8.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.81 ( ddd, J = 8.0, 1.6, 1.2 Hz, 1H), 8.16 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 8.39 (t, J = 2.0 Hz, 1H) ppm. LCMS = 92% purity.
Example 168. Preparation for P-041

Synthesis of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -1H-indole-2,3-dione (P-041). To the solution of I-70 (98 mg, 0.300 mmol) and dimethyl isatin (88 mg, 0.60 mmol), formamide (1.0 mL) was hydrogenated (60% weight dispersion, 24 mg, 0.6 mmol) sodium. Added -78oC. After the evolution of hydrogen gas was over, the reaction was stirred overnight at room temperature. The reaction mixture was filtered and the filtered water was concentrated under reduced pressure. The remainder was diluted with ethyl acetate (15 mL). The brine (dried over sodium sulfate) was then filtered, washed with water, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (4: 1 ethyl acetate: hexanes) to yield 39.1% yield of 45.5 mg P-041). 1H NMR (400 MHz, CDCl3) 3.82 (s, 3 H), 4.93 (s, 2 H), 6.85 (d, J = 7.9 Hz, 1 H), 6.98 (d, J = 8.6 Hz, 1 H), 7.07-7.14 (m, 1 H), 7.29-7.40 (m, 2 H), 7.49-7.65 (m, 4 H), 7.79 (d, J = 7.8 Hz, 1 H), 8.18 (s, 1 H) , 8.37 (t, J = 1.74 Hz, 1 H) ppm. Turb. Spray (+) = 389.60 (M + 1)
Example 169. Preparation for P-042

Synthesis of 2- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -iso-indole-1,3-dione (P-042). To a solution of I-70 (161 mg, 0.500 mmol) and dimethyl phthalimide (147 mg, 1.00 mmol), formamide (1.5 mL) was hydrogenated (60% weight dispersion, 40 mg, 1.0 mmol) sodium. Added -78oC. After hydrogen gas evolution was over, the reaction was stirred overnight at 80 ° C. The reaction mixture was filtered and the filtered water was concentrated under reduced pressure. The remainder was diluted with ethyl acetate (15 mL). The brine (dried over sodium sulfate) was then filtered, washed with water, and the solvent was removed under vacuum. The crude product was purified by trituration several times in hexane (100 mL) and ethyl acetate (5 mL) to yield 43.8 mg of P-042 as a gray white solid in 26% yield. 1H NMR (400 MHz, CDCl3) 3.80 (s, 3 H), 4.84 (s, 2 H), 6.95 (d, J =, 8.5 Hz, 1 H), 7.43 (d, J = 2.2 Hz, 1 H) , 7.49 (dd, J = 8.5, 2.2 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.65-7.76 (m, 2 H), 7.77-7.87 (m, 3 H), 8.17 (dd, J = 8.2, 1.3 Hz, 1 H), 8.39 (t, J = 1.8 Hz, 1 H) ppm. LCMS = 97.1% purity. APCI (+) = 359.1 (M-29).
Example 170. Preparation for P-043

Synthesis of 2- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolo [3,4-c] pyridine-1,3-dione (P-043). To a solution of I-70 (161 mg, 0.500 mmol) and dimethyl pyridinecarboxide (148 mg, 1.00 mmol), formamide (1.5 mL) was hydrogenated (60% weight dispersion, 40 mg, 1.0 mmol) sodium. Added -78oC. After hydrogen gas evolution was over, the reaction was stirred overnight at 80 ° C. The reaction was diluted with ethyl acetate (15 mL). And it was washed with water. The brine (decolorized with activated carbon) is then dried over sodium sulfate and filtered. The solvent is then removed under vacuum. The crude product was purified by trituration several times in hexane (100 mL) and ethyl acetate (5 mL) to yield 20.9 mg of P-043 as an 11% yield of gray white solid. 1H NMR (400 MHz, CDCl3) 3.81 (s, 3 H), 4.86 (s, 2 H), 6.96 (d, J = 8.5 Hz, 1 H), 7.43 (d, J = 2.2 Hz, 1 H), 7.45-7.52 (m, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.71-7.83 (m, 3 H), 8.18 (d, J = 8.3 Hz, 1 H), 8.38 (s, 1 H), 9.06 (d, J = 4.70 Hz, 1 H), 9.08-9.17 (m, 2 H), 9.20 (s, 1 H) ppm. LCMS = 95.2% purity. APCI (-) = 389.1 (M ).
Example 171. Preparation for P-047

Synthesis of 2- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -2H- [1,2,4] triazolo [4,3-a] pyridine-3-1 (P-047. I- To a solution of 70 (161 mg, 0.500 mmol) and dimethyl triazolepyridine (135 mg, 1.00 mmol), formamide (1.5 mL) was added hydrogenated (60% weight dispersion, 40 mg, 1.0 mmol) sodium. -78 ° C. After the evolution of hydrogen gas was over, the reaction was stirred at 75 ° C. for 4 h, the reaction was diluted water (15 mL), and the resulting precipitate separated. Decomposed in ethyl acetate (10 mL), decolorized with activated carbon, dried over sodium sulfate, filter It swiped, then the solvent was removed under vacuum to afford 43.2 mg P-047 as a 23% yield of a cream colored solid). 1H NMR (400 MHz, CDCl3) 3.82 (s, 3 H), 5.16 (s, 2 H), 6.48 (ddd, J = 7.1, 4.0, 3.2 Hz, 1 H), 6.99 (d, J = 8.5 Hz, 1 H), 7.04-7.13 (m, 2 H), 7.41 (d, J = 2.2 Hz, 1 H), 7.47 (dd, J = 8.5, 2.2 Hz, 1 H), 7.55 (t, J = 8.0 Hz , 1 H), 7.73-7.86 (m, 2 H), 8.17 (dd, J = 8.2, 1.2 Hz, 1 H), 8.39 (t, J = 1.8 Hz, 1 H) ppm. LCMS = 98.0% purity.
APCI (+) = 377.1 (M + 1).
Example 172. Preparation for P-052

Synthesis of 2- (3-Benz [1,3] dioxol-5-yl-4methoxybenzyl) -iso-indole-1,3-dione (P-052). A suspension of phthalimide (147 mg, 1.00 mmol), I-168 (138 mg, 0.500 mmol) and solid potassium carbonate (138 mg, 1.00 mmol) was stirred for over 72 h. Water was added and a precipitate formed. The stop was stirred for 10 minutes and the solid collected and dissolved in ethyl acetate (20 mL). The organic solution was dried over sodium sulfate (filtered) and solvent removed under vacuum to yield a 93% yield of 173 mg of P-052. 1H NMR (400 MHz, CDCl3) 3.78 (s, 3 H), 4.82 (s, 2 H), 5.91-6.00 (m, 2 H), 6.80-6.98 (m, 3 H), 7.02 (d, J = 1.3 Hz, 1 H), 7.35-7.43 (m, 2 H), 7.70 (dd, J = 5.4, 3.0 Hz, 2 H), 7.80-7.88 (m, 2 H) ppm. LCMS = 95.6% purity.
Example 173. Preparation for P-055

Synthesis of 6- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -pyrrolo [3,4-b] pyridine-5,7-dione (P-055). A suspension of dimethylformamide (20 mL) in I-70 (322 mg, 1.00 mmol), quinoline imide (148 mg, 1.00 mmol) and solid potassium carbonate (276 mg, 2.00 mmol) was stirred overnight at room temperature. It was done. The resulting precipitate was separated and the reaction was diluted water (stirred for 10 minutes). The solid was decomposed in ethyl acetate (20 mL). The solvent was then removed under vacuum to yield 145 mg of P-055 as a 37% yield light yellow solid and dried over sodium sulfate and passed through a filter. 1H NMR (400 MHz, CDCl3) 3.81 (s, 3 H), 4.91 (s, 2 H), 6.96 (d, J = 8.5 Hz, 1 H), 7.45 (d, J = 2.2 Hz, 1 H), 7.48-7.66 (m, 3 H), 7.80 (d, J = 7.8 Hz, 1 H), 8.10-8.22 (m, 2 H), 8.39 (t, J = 1.8 Hz, 1 H), 8.96 (dd, J = 4.9, 1.4 Hz, 1 H) ppm. LCMS = 95% purity. TSI (+) = 390.40 (M + 1).
Example 174. Preparation for P-062

Integration of 2-methoxy-3'-nitro-biphenyl (I-169). Methanol (25 mL) and water (5 mL) 2-methoxyphenyl bromate (911 mg, 6.00 mmol) (3-nitro-iobenzone (1.24 g, 5.00 mmol), palladium (II) acetate (22 mg, 0.10 mmol) ) And solid potassium carbonate (1.38 g (10). Mmol) was stirred overnight at room temperature, the reaction was diluted with ethyl acetate (50 mL), and brine (dried over sodium sulfate). ) Was filtered and washed with water (2 × 50 mL) and the solvent was removed under vacuum to give the crude product The product was 940 mg as a white solid in 82% yield. Was purified by silica gel column chromatography (hexane / ethyl acetate 9: 1) to yield I-169. 1H NMR (400 MHz, CDCl3) 3.84 (s, 3 H), 6.96-7.14 (m, 2 H), 7.30-7.44 (m, 2 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.86 (d, J = 7.7 Hz, 1 H), 8.17 (dd, J = 8.2, 1.2 Hz, 1 H), 8.42 (s, 1 H) ppm.

Synthesis of 4- (3-Benz [1,3] dioxol-5-yl-4methoxybenzyl) -3,5-dimethyl-isoxazole (P-062). To a solution of I-168 (138 mg, 0.500 mmol) and dimethylformamide (5 mL) of 3,5-dimethyl-isoxazole-4 boronic acid (70 mg, 0.500 mmol) palladium (0) was added bis (Dibenzylideneacetone, 14 mg, 0.025 mmol, tri-phenyl phosphine (13 mg, 0.0500 mmol) and 1 M aqueous sodium carbonate (1.5 mL, 1.5 mmol). The resulting stop was for 72 h. Stirred at 85 ° C. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), and brine (dried over sodium sulfate) was filtered and water (3 × 10 mL) And the solvent was removed under reduced pressure. The crude oil was purified by silica gel preparative thin layer chromatography eluting with hexane and dichloromethane by 1: 1 to yield 16.2 mg (10%) of P-062. NMR (400 MHz, CDCl3) 2.11 (s, 3 H), 2.31 (s, 3 H), 3.64 (s, 2 H), 3.79 (s, 3 H), 5.98 (s, 2 H), 6.80-6.94 (m, 3 H), 6.94-7.05 (m, 3 H) ppm. LCMS = 100% purity. APCI (+) = 338.10 (M + 1).
Example 175. Preparation for P-066

Synthesis of C- (6-methoxy-3′-nitro-biphenyl-3-yl) -methylamine (I-170): suspension of P-052 (700 mg, 1.80 mmol) and hydrazine hydrate (0 In .35 mL. (7.2 mmol), ethanol (60 mL) was stirred at reflux for 6 h. As the solvent evaporated, the reaction was cooled to room temperature (passed through a filter). The remainder was dissolved in ethanol (15 mL), precipitated with water (50 mL) and filtered to yield 97.9 mg as a 21% yield white solid.

  Synthesis of 4- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -4H- [1,2,4] triazole (P-066). A solution of hydrazine formate (25 mg, 0.41 mmol) and N, N-dimethylformamide dimethyl acetal (0.050 mL, 0.41 mmol) in acetonitrile (0.5 mL) was stirred at 50 ° C. for 30 minutes. To the solution was I-170 (98 mg, 0.38 mmol) and acetic acid (0.5 mL) were added. The reaction was then stirred at 160 ° C. for 6 h. The reaction was cooled to room temperature and agglomerated under vacuum. The combined extract was washed with brine, the reaction was diluted with water (30 mL) and extracted with dichloromethane (2 × 30 mL). The solvent was then removed under vacuum and dried over sodium sulfate and passed through a filter. Crude oil material was purified preparative thin layer chromatography (9: 1 dichloromethane: methanol) on silica gel to yield a 17% yield of 19.4 mg P-066. 1H NMR (400 MHz, CDCl3): 3.86 (s, 3H), 5.19 (s, 2H), 7.03 (d, J = 8.5 Hz, 1H), 7.17-7.25 (m, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 8.16-8.24 (m, 3H), 8.37 (t, J = 1.9 Hz, 1H) ppm. LCMS = 94.0% purity. APCI (+) = 311.1 (M + 1).

実施例１７６。Ｐ―０７３の準備 << Reaction process formula 46 >>

Example 176. Preparation for P-073

Synthesis of (3-Benz [1,3] dioxol-5-yl-4-methoxyphenyl)-(2-methyl-2H-pyrazol-3-yl) -methanol (P-073). A solution of 1-methylpyrazole (123 mg, 1.50 mmol) in tetrahydrofuran (10 mL) was cooled to 0 ° C. in an ice bath and n-butyl lithium (hexane, 0.80 mL, 2.0 mmol of 2.5 M). ) Was added. The yellow solution was stirred at 0 ° C. for 30 minutes followed by the addition of I-170 (256 mg, 1.00 mmol) and the resulting light green solution was stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined extract was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (1: 1 hexane: dichloromethane) to yield 259.1 mg P-073 as a pale yellow solid in 77% yield. 1H NMR (400 MHz, CDCl3): 3.81 (s, 3H), 3.83 (s, 3H), 5.90 (s, 1H), 5.98 (s, 2H), 6.12 (d, J = 1.6 Hz, 1H), 6.82 -6.89 (m, 1H), 6.91-6.98 (m, 2H), 7.03 (d, J = 1.5 Hz, 1H), 7.29 (s, 2 H), 7.40 (d, 1 H) ppm. LCMS = 98.9% ; APCI (+) = 339.1 (M +1).
Example 177. Preparation for P-075

Synthesis of 5- (3-Benz [1,3] dioxol-5-yl-4methoxybenzyl) -1-methyl-1H-pyrazole (P-075). To a solution of trifluoroacetic acid (2.0 mL) P-073 (169 mg, 0.500 mmol), triethylsilane (0.50 mL, 3.0 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic extract was washed with brine, dried over sodium sulfate, filtered and the solvent removed under vacuum. The crude product was purified by silica gel column chromatography (20% methanol in dichloromethane) to yield 39.1 mg (24%) of P-075. ¹ H NMR (400 MHz, CDCl ₃ ) 7.40 (d, J = 1.7 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 7.02-7.06 (m, J = 2.4 Hz, 1H), 7.02 ( d, J = 1.7 Hz, 1H), 6.91-6.94 (m, 1H), 6.90 (s, 1H), 6.86 (t, J = 8.5 Hz, 2H), 5.98 (s, 2H), 3.95 (s, 2H ), 3.80 (s, 3H), 3.74 (s, 3H) ppm.
Example 178. Preparation for P-074

Synthesis of 1- (3-Benz [1,3] dioxol-5-yl-4methoxybenzyl) -1H-pyrazole (P-074). A suspension of pyrazole (136 mg, 2.00 mmol), I-168 (108 mg, 1.00 mmol) and solid potassium carbonate (276 mg, 2.00 mmol) was stirred overnight at room temperature. Water (30 mL) was added and the suspending agent was extracted with ethyl acetate (2 × 30 mL). The composite organic layer was washed with brine, dried over sodium sulfate, passed through a filter, and the solvent was removed under vacuum. The product was purified by silica gel column chromatography (10% ethyl acetate in hexanes) to yield 44.4 mg P-074 as a 14% yield light yellow oil. 1H NMR (400 MHz, CDCl3) 7.54 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 4.4, 2.2 Hz, 2H), 7.01 (d, J = 1.7 Hz, 1H), 6.91-6.94 (m, 2H), 6.82-6.87 (m, 1H), 6.26 (t, J = 2.1 Hz, 1H), 5.98 (s, 2H), 5.28 (s, 2H ), 3.80 (s, 3H)
Example 179. Preparation for P-077

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-pyrazole (P-077). A suspension of dimethylformamide (10 mL) in I-70 (322 mg, 1.00 mmol), pyrazole (136 mg, 2.00 mmol) and solid potassium carbonate (276 mg, 2.00 mmol) was stirred overnight at room temperature. . The reaction was extracted with ethyl acetate (2 × 30 mL) with diluted water (30 mL). The combined extract was washed with brine, dried over sodium sulfate, filtered and the solvent removed under vacuum. The remainder was purified by silica gel column chromatography (15% ethyl acetate in hexanes) to give P-077 (148 mg, 48% yield) as a white solid.
1H NMR (400 MHz, DMSO-d6): 8.27 (s, 1H), 8.17-8.22 (m, 1H), 7.89-7.94 (m, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.72 ( t, J = 8.0 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.28-7.33 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.19-6.30 (m, 1H), 5.32 (s, 2H), 3.79 (s, 3H) ppm.
LCMS = 99.7% purity. APCI (+) = 310.1 (M + 1)
Example 180. Preparation for P-087

Synthesis of [4- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -acetic acid ethyl ester (P-087). To the solution of I-171 (102 mg, 0.300 mmol) of 1,2-dimethoxyethane (5 mL) was added ethyl hydrazinoacetate hydrochloride (93 mg, 0.60 mmol) and 4 angstrom molecular sieves (200 mg). And the reaction was stirred at reflux for 3 h. The hot suspension was filtered and the solvent was removed under vacuum. The remainder was dissolved in dichloromethane (10 mL) and washed with water (30 mL). The aqueous wash was extracted with dichloromethane (2 × 30 mL) and the extracts combined. The organic solution was washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo. The remainder was purified by silica gel column chromatography (2: 1 hexane: ethyl acetate) to give P-087 (97.1 mg, 76% yield). 1H NMR (400 MHz, CDCl¬3): 8.38 (t, J = 1.9 Hz, 1H), 8.15 (dd, J = 8.2, 2.3 Hz, 1H), 7.79-7.82 (m, 1H), 7.53-7.56 ( m, 1H), 7.07-7.10 (m, 2H), 6.90 (d, J = 9.1 Hz, 1H), 4.79 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H ), 3.74 (s, 2H), 2.13 (s, 3H), 2.13 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm. LCMS: 98.7% purity. APCI (+) = 310.1 (M -29)
Example 181. Preparation for P-088

Synthesis of 2- [4- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -ethanol (P-088). To the solution of I-171 (102 mg, 0.300 mmol) in 1,2-dimethoxyethane (5 mL) was added 2-hydroxyethyl hydrazine (0.037 mL, 0.60 mmol) and four angstrom molecular sieves (200 mg). And the reaction was stirred at reflux for 3 h. The hot suspension was filtered and the solvent was removed under vacuum. The remainder was dissolved in dichloromethane (10 mL) and washed with water (30 mL). The aqueous wash was extracted with dichloromethane (2 × 30 mL) and the extracts combined. The organic solution was washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography (2: 1: 0.3 hexane: ethyl acetate: methanol) to give P-088 (61.0 mg, 53% yield) as a yellow solid. It was. 1H NMR (400 MHz, CDCl3): 8.37 (t, J = 2.0 Hz, 1H), 8.16 (dt, J = 8.2, 1.1 Hz, 1H), 7.81 (dt, J = 7.7, 0.8 Hz, 1H), 7.54 -7.57 (m, 1H), 7.06-7.10 (m, 2H), 6.91 (d, J = 9.1 Hz, 1H), 4.05-4.09 (m, 2H), 3.95-4.02 (m, 2H), 3.80 (s , 3H), 3.73 (s, 2H), 2.14 (s, 3H), 2.16 (s, 3H) ppm. LCMS: 98.2% purity. APCI (+) = 382.1 (M + 1)
Example 182. Preparation for P-089

Synthesis of 4- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -3,5-dimethyl-1H-pyrazole (P-089). To a solution of I-171 (102 mg, 0.300 mmol) in 1,2-dimethoxyethane (5 mL) was added hydrazine (0.029 mL, 0.60 mmol) and four angstrom molecular sieves (200 mg) and the reaction Was stirred at reflux for 3 h. The hot suspension was filtered and the solvent was removed under vacuum. The remainder was dissolved in dichloromethane (10 mL) and washed with water (30 mL). The aqueous wash was extracted with dichloromethane (2 × 30 mL) and the extracts combined. The organic solution was washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography (1: 1 hexane: ethyl acetate) to give P-089 (67.8 mg, 67% yield) (400 MHz, CDCl-3). 1H NMR (400 MHz, CDCl¬¬¬3): 8.38 (s, 1H), 8.13-8.20 (m, 1H), 7.75-7.83 (m, 1H), 7.50-7.58 (m, 1H), 7.05- 7.13, (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 2H), 2.18 (s, 6H) ppm. LCMS = 97.2% purity. APCI ( +) = 338.1 (M + 1).
Example 183. Preparation for P-090

4- (6-Methoxy-3'-nitro-biphenyl-3-ylmethyl) -3,5-dimethyl-1- (2,2,2-tri-fluoro-ethyl) -1H-pyrazole (P-090) Synthesis. Solution of I-171 (102 mg, 0.300 mmol) in 1,2-dimethoxyethane (5 mL) was combined with 2,2,2-trifluoroethyl hydrazine (0.098 mL, 0.60 mmol) and 4 angstroms Molecular sieves (200 mg) were added and the reaction was stirred at reflux for 3 h. The hot suspension was filtered and the solvent was removed under vacuum. The remainder was dissolved in dichloromethane (10 mL) and washed with water (30 mL). The aqueous wash was extracted with dichloromethane (2 × 30 mL) and the extracts combined. The organic solution was washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography (5: 1 hexane: ethyl acetate) to give P-090 (64.5 mg, 51% yield) as a yellow red oil. 1H NMR (400 MHz, CDCl¬3): 8.38 (t, J = 2.0 Hz, 1H), 8.16 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.78-7.81 (m, 1H), 7.52- 7.55 (m, 1H), 7.04-7.07 (m, 2H), 6.91 (d, J = 9.1 Hz, 1H), 4.58 (q, J = 8.4 Hz, 2H), 3.78-3.81 (m, 3H), 3.73 (s, 2H), 2.20 (s, 3H), 2.14 (s, 3H) ppm. LCMS = 97.6% purity. APCI (+) = 420.1 (M + 1).
Example 184. Preparation for P-101

実施例１８５。Ｐ―１１５の準備実施例１８５。Ｐ―１１５の準備 Synthesis of 2- [4- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -acetamide (P-101). The solution was stirred overnight at room temperature and to the solution of methanol (5 mL) P-087 (212 mg, 0.500 mmol) was added ammonia (methanol, 0.5 mL, 3.5 mmol 7M). The resulting stop was agglomerated under vacuum and dissolved in ethyl acetate (10 mL). Brine (10 mL) (dried over sodium sulfate) was filtered and the reaction was washed with water (10 mL) and the solvent was removed under vacuum. The resulting solid was triturated in hexane (10 mL) in dichloromethane (1 mL) to give P-101 (85.8 mg, 44% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 8.31-8.37 (m, 1H), 8.14-8.20 (m, 1H), 7.77-7.84 (m, 1H), 7.51-7.59 (m, 1H), 7.01- 7.10 (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.05 (br s, 1H), 5.39 (br s, 1H), 4.68 (s, 2H), 3.80 (s, 3H), 3.73 (s, 2H ), 2.17 (s, 3H), 2.16 (s, 3H) ppm. LCMS = 98.2% purity. APCI (+) = 395.1 (M + 1).

Example 185. Preparation Example 185 for P-115. Preparation for P-115

  Synthesis of 3- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -4-methoxy-benzaldehyde (I-172). To a solution of 5-formyl-2 methoxyphenyl, boronic acid (1.0 g, 5.5 mmol) in water (6 mL) and methanol (30 mL) was added with additional 5-bromo-2,2-difluoro-1 , 3-benzodioxole e (0.97 mL, 7.2 mmol), solid potassium carbonate (1.5 g, 11 mmol) and palladium (II) acetate (25 mg, 0.11 mmol). The reaction was stirred at room temperature for 16 h. The black mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined extract was decolorized with activated carbon, dried over sodium sulfate, filtered and concentrated to 20 mL under vacuum. The solution was purified by silica gel column chromatography eluting acetate (11: 1) with hexane / ethyl to give I-172 (620 mg, 39% yield) as a white solid. .

  [3- (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -4-methoxyphenyl]-(2-methyl-2H-pyrazol-3-yl) -methanol (I-173) Synthesis. A solution of 1-methylpyrazole (123 mg, 1.5 mmol) under a positive nitrogen atmosphere was cooled to 0 ° C. in an ice-water bath. To the active solution was added 0-C stirred n-butyl lithium (hexane, 0.80 mL, 2.0 mmol of 2.5 M) for 30 minutes, and I-172 (292 mg, 1 .0 mmol) was added in one portion. The reaction was stirred for an additional 2 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 × 30 mL). The composite excerpt was washed with salt water. The solvent was then removed under reduced pressure to give I-173 (220 mg, 59% yield) as a yellow solid and dried over sodium sulfate and passed through a filter.

Synthesis of 5- [3- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -4-methoxy-benzyl] -1-methyl-1H-pyrazole (P-115). To a solution of tri-fluoroacetic acid (2.0 mL) of I-173 (187 mg, 0.500 mmol), triethyl silane (0.50 mL, 3.0 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined extract was washed with brine, dried over sodium sulfate, filtered and the solvent removed under vacuum. The remainder was P-115 (29.9 mg, 17% was purified by preliminary thin layer chromatography (20: 1 dichloromethane / methanol) by silica gel column chromatography (5: 2 hexane / ethyl acetate) and silica gel. Give, surrender). 1H NMR (400 MHz, CDCl3): 3.74 (s, 3 H), 3.81 (s, 3 H), 3.96 (s, 2 H), 6.02 (d, J = 1.6 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1 H), 7.00-7.17 (m, 4 H), 7.24 (d, J = 1.5 Hz, 1 H), 7.40 (d, J = 1.6 Hz, 1 H) ppm. LCMS = 100% purity APCI (+) = 359.1 (M + 1).
Example 186. Preparation for P-201

  Synthesis of 5- (3-Benz [1,3] dioxol-5-yl-4-difluoromethoxy-benzyl) -1-methyl-1H-pyrazole (P-201). Benzo [1,3] dioxol-5-boronic acid (108 mg, 0.65 mmol), I-174 (158 mg, 0.500 mmol), palladium (II) triphenylphosphine chloride (35 mg, 0.050 mmol) and 1M in xylene (3 mL) Discontinuation of aqueous sodium carbonate (1.0 mL, 1.00 mmol) was stirred at 150 ° C. for 24 h. The reaction was diluted with ethyl acetate (10 mL). The brine (dried over sodium sulfate) was then filtered and washed with water (3 × 10 mL) and the solvent was removed under vacuum. The rest was purified by silica gel column chromatography (4: 1 hexane / ethyl acetate), and the layer was used to give P-201 (13.4 mg, 7% yield) with extra silica gel. Thin the chromatography (5: 1 dichloromethane / acetone).

1H NMR (400 MHz, CDCl¬3): 3.64 (s, 3 H), 4.05 (s, 2 H), 5.82 (s, 1 H), 5.95 (s, 2 H), 6.63 -6.94 (m, 7 H), 7.59 (s, 1 H) ppm. LCMS = 99% purity. APCI (-) = 321.1 (M-37).
Example 187. Preparation for P-306

Synthesis of 5- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4] oxadiazol-2-ylamine (P-306). A solution of hydrazine hydrate (0.5 mL) of I-176 (277 mg, 1.00 mmol) was stirred at 100 ° C. overnight. The reaction was concentrated under vacuum to obtain a rubbery white solid. Cyanogen bromide (212 mg, 2.00 mmol) was added and the crude material was dissolved in 1,2-dimethoxyethane (0.5 mL). The reaction was stirred at room temperature for 3 h. The reaction was diluted with dichloromethane (5 mL) and washed with 1M aqueous sodium hydroxide (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum. The remainder gives P-306 (64.2 mg, 30% yield) purified by preparative thin layer chromatography (hexane / ethyl acetate) by silica gel. 1H NMR (400 MHz, DMSO-d6): 3.77 (s, 3 H), 4.01 (s, 2 H), 6.87 (s, 2 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.21- 7.29 (m, 2 H), 7.36-7.47 (m, 3 H), 7.50 (s, 1 H) ppm. LCMS = 97.1% purity. APCI (+) = 316 (M).
Example 188. Preparation for P-393

Synthesis 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrimidin-2-yl] -azetidine-3-ol (P-393). A suspension of dimethylformamide (1.5 mL) in I-177 (72 mg, 0.20 mmol), azetidine-3-ol hydrochloride (44 mg, 0.40 mmol) and potassium carbonate (55 mg, 0.40 mmol) was Stir at 80 ° C overnight. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with diethyl ether (3 × 5 mL). The composite excerpt was concentrated and by silica gel column chromatography (2: 1 hexane / ethyl acetate) to give P-393 (73.3 mg, 92% yield) the crude material as a cream white solid. Purified. 1H NMR (400 MHz, CDCl3): 3.75 (s, 3 H), 3.77 (s, 2 H), 3.98 (dd, J = 10.3, 4.3 Hz, 2 H), 4.34-4.43 (m, 2 H), 4.77 (br s, 1 H), 6.70 (d, J = 8.3 Hz, 1 H), 7.08 (t, J = 8.6 Hz, 1 H), 7.26-7.40 (m, 4 H), 8.21 (s, 2 H) ppm.
LCMS = 100% purity. APCI (+) = 400 (M).
Example 189. Preparation for P-397

  Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1-oxy-pyridin-2-yl] -3-ethyl-urea (P-397). A solution of diethyl ether (5 mL) of P-356 (82.7 mg, 0.200 mmol) was stirred with peracetic acid (32% wt. 0.06 mL, 0.300 mmol) for 3 h at room temperature. Mixing was concentrated and the remainder was purified by silica gel column chromatography (19: 1 dichloromethane / methanol) to give P-397 (27.6 mg, 32% yield).

1H NMR (400 MHz, CDCl¬3): 1.12 (t, 3 H) 3.17-3.35 (m, 2 H), 3.72-3.80 (m, 3 H), 3.87 (s, 2 H), 6.64-6.78 ( m, 1 H), 6.86 (br s, 1 H), 7.02-7.17 (m, 1 H), 7.22 (s, 1 H), 7.29-7.43 (m, 3 H), 7.93 (s, 1 H) , 8.36 (d, J = 8.9 Hz, 1 H), 9.73 (s, 1 H) ppm.
LCMS = 100% purity. APCI (-) = 428.1 (M-2).
Example 190. Preparation for P-398

Synthesis of [5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -carbamic acid ethyl ester (P-398). A solution of tetrahydrofuran I-178 (166 mg, 0.500 mmol) was cooled to 0 ° C. To the reaction, pyridine (0.08 mL, 1 mmol) was added, and the reaction stirred for 10 minutes To the solution was slowly added ethyl chloroformate (0.09 mmol, 1 mmol). And the yellow stop was stirred overnight at room temperature. The reaction could sit behind the addition of water (10 mL) and the bottom solids were collected by filtration. The solid was suspended in dimethyl sulfoxide (5 mL) and water (5 mL) and filtered to give P-398 (14.6 mg, 7.2% yield) as a white solid. 1H NMR (400 MHz, CDCl¬3): 1.31 (t, J = 7.1 Hz, 3 H), 3.76 (s, 3 H), 3.91 (s, 2 H), 4.23 (q, J = 7.1 Hz, 2 H), 6.73 (d, J = 8.6 Hz, 1 H), 7.12 (t, J = 8.5 Hz, 1 H), 7.32-7.41 (m, 1 H), 7.44-7.56 (m, 2 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.70 (s, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 8.12 (s, 1 H) ppm. LCMS = 94.0% purity. APCI (+) = 406.1 (M + 1).
Example 191. Preparation of P-405-HCl

  Synthesis of 1- [5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -3-ethyl-urea hydrochloride (P-405-HCl) . A solution of I-178 (166 mg, 0.500 mmol) and ethyl isocyanate (0.2 mL, 2.5 mmol) in pyridine (0.5 mL) was stirred overnight at room temperature. To the solution, water (5 mL) was added and the reaction was stirred for 1 h. The formed solid was passed through a filter. It was then triturated with tetrahydrofuran and water to give the rest. The remainder was purified by silica gel column chromatography (100: 1 dichloromethane / methanol) to give dirty P-405 (131 mg, 65% yield). Dioxane (0.75 mL, 3.0 mmol) 4N hydrogen chloride was added and the entire material was suspended in diethyl ether (1.5 mL). The added hydrogen chloride solution was added (2.25 mL, 9 mmol). The reaction mixture could be stirred overnight at room temperature. The precipitate was filtered and dried to give P-405-HCl (52.5 mg, 24% yield).

1H NMR (400 MHz, DMSO-d6): 1.09 (t, J = 7.2 Hz, 3 H), 3.12-3.25 (m, 2 H), 3.74 (s, 3 H), 3.94 (s, 2 H), 6.97 (d, J = 8.7 Hz, 1 H), 7.25-7.47 (m, 2 H), 7.53-7.92 (m, 5 H), 8.10 (s, 1 H) ppm. LCMS = 100% purity. APCI ( +) = 405.1 (M + 1).
Example 192. Preparation for P-406

  Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2- (R) -1-methyl-pyrrolidine-3-yloxy) -pyrimidine (P-406). To the solution of I-177 (65 mg, 0.18 mmol) and (R) tetrahydrofuran (1 mL) of-(-)-methyl-3-pyrrolidine ol (0.039 mL, 0.36 mmol) was slowly added NaH ( 60% weight dispersion, 29 mg, 0.72 mmol). Once the gas evolution was over, the reaction was stirred at 80 ° C. for 4 h. The reaction was cooled to room temperature and diluted with water (10 mL). The pH of the aqueous layer was adjusted to pH 7 by addition of 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate (3 × 2 mL), and the aqueous mixture was extracted again with ethyl acetate (2 × 2 mL). It was. The composite extract was dried over sodium sulfate, filtered and solvent removed under vacuum. The remainder was purified by silica gel column chromatography (9: 1 dichloromethane / methanol) to give P-406 (46.8 mg, 61% yield) as a dark pale yellow oil.

1H NMR (400 MHz, CDCl3): 2.03-2.48 (m, 2 H), 2.54 (s, 3 H), 2.72-2.93 (m, 2 H), 3.00 (br s, 1 H), 3.47 (dd, J = 11.4, 5.9 Hz, 1 H), 3.77 (s, 3 H), 3.87 (s, 2 H), 5.45 (t, J = 6.4 Hz, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 7.12 (t, J = 8.5 Hz, 1 H), 7.29-7.41 (m, 3 H), 8.37 (s, 2 H) ppm. LCMS = 100% purity. MS (ESI +) 428.1 (M + H ).
Example 193. Preparation for P-417

Synthesis of 2'-fluoro-3 '-[2- (3-hydroxy-azetidin-1-yl) -pyrimidin-5-ylmethyl] -6,' -methoxy-biphenyl-3-carbonitrile (P-417). To a stirred solution of I-177 (61 mg, 0.17 mmol) and azetidine-3-ol, dimethylformamide (0.5 mL) hydrochloride (40 mg, 0.34 mmol) was added solid potassium carbonate (48 mg, 0.34 mmol) And the pale yellow solution was then stirred at 80 ° C. overnight. The reaction was cooled to room temperature. The resulting precipitate was then collected by filtration and diluted with water (15 mL) and stirred at room temperature for 30 minutes. The crude oil was purified by trituration with dichloromethane / diethyl ether / hexane to give P-417 (26 mg, 39% yield) as a white cream solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 3.68-3.74 (m, 5 H), 3.77 (s, 2 H), 4.08-4.26 (m, 2 H), 4.52 (br s, 1 H), 5.63 (d, J = 6.4 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 7.32 (t, J = 8.7 Hz, 1 H), 7.54-7.74 (m, 2 H), 7.74 -7.91 (m, 2 H), 8.24 (s, 2 H) ppm.
LCMS = 100% purity. APCI (+) = 391.1 (M + 1).
Example 194. Preparation for P-513

1-ethyl-3- {5- [2-fluoro-6-methoxy-3 '-(1H-tetrazol-5-yl) -biphenyl-3-ylmethyl] -pyridin-2-yl} -urea (P-513 ) Synthesis. A mixture of P-405 (405 mg, 1.00 mmol), dimethylformamide (10 mL), sodium azide (325 mg, 5.00 mmol) and ammonium chloride (374 mg, 7.00 mmol) was stirred at 80 ° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (50 mL). The aqueous wash was extracted with ethyl acetate (2 × 30 mL). The extracts are then combined and dried over sodium sulfate. The solvent is then removed under vacuum. The remainder was purified by silica gel column chromatography (19: 1 to 4: 1 dichloromethane / methanol) to give P-513 (11.5 mg, 2.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 1.05-1.10 (m, 3 H), 3.11-3.21 (m, 2 H), 3.72 (s, 3 H), 3.88 (s, 2 H), 6.93 (d , J = 8.6 Hz, 1 H), 7.10-7.37 (m, 3 H), 7.42 (s, 1 H), 7.54 (s, 1 H), 7.90 (br s, 2 H), 8.07 (s, 2 H), 9.09 (s, 1 H) ppm. LCMS = 95.9% yield.APCI (+) = 448.1
Example 195. Preparation for P-456

Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (P-456). Toluene (10 mL) and ethanol (2.5 mL) I-33 (824 mg, 2.50 mmol), 2-fluoropyridine-5 boronic acid (352 mg, 2.50 mmol), 2M aqueous sodium carbonate (2.5 mL, Discontinuation of 5.00 mmol) and palladium (0) tetrakis (triphenylphosphine) (144 mg, 0.125 mmol) was stirred at 80 ° C. overnight under a high pressure nitrogen atmosphere. The reaction was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined extract was dried over sodium sulfate, filtered and concentrated under vacuum. The remainder was purified by silica gel column chromatography (4: 1 hexane / ethyl acetate) to give P-456 (695 mg, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 3.73 (s, 3 H), 3.98 (s, 2 H), 6.95 (d, J = 8.6 Hz, 1 H), 7.11 (dd, J = 8.4, 2.7 Hz , 1 H), 7.25-7.51 (m, 5 H), 7.82 (td, J = 8.2, 2.4 Hz, 1 H), 8.14 (s, 1 H), 8.32 (s 1H) ppm. LCMS = 97.4% purity APCI (+) = 346 (M)
Example 196. Preparation for P-457

  Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -azetidine-3-ol (P-457). Mixture of dimethylformamide (1 mL) azetidine-3-ol (56 mg, 0.56 mmol) and sodium hydride (60% weight dispersion, 33 mg, 0.84 mmol) was stirred under discontinued gas evolution . After 2 minutes of stirring, P-456 (97 mg, 0.28 mmol) was added and the reaction became hot at 140 ° C. overnight. The reaction was cooled to room temperature, diluted with water (5 mL) and extracted with ethyl acetate (2 × 5 mL). The composite extract was dried through sodium sulfate (filtered) and solvent removed under vacuum. The remainder is a silica gel column chromatography of ethyl acetate and hexane (9: 1 followed by dichloromethane / methanol 1) to give P-457 (22.2 mg, 19.9% yield) as a cream solid. : 2 hexane / ethyl acetate) and trituration.

  1H NMR (400 MHz, DMSO-d6): 3.61 (dd, 2 H), 3.68-3.74 (m, 3 H), 3.78 (s, 2 H), 4.09 (t, J = 7.5 Hz, 2H), 4.47 -4.60 (m, 1 H), 5.59 (d, J = 6.6 Hz, 1 H), 6.33 (d, J = 8.5 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 7.20- 7.32 (m, 2 H), 7.32-7.39 (m, 2 H), 7.39-7.50 (m, 2 H), 7.96 (d, J = 1.6 Hz, 1 H) ppm. LCMS = 98.5% purity. APCI ( +) = 399 (M).

実施例１９７。Ｐ―５２２の準備 << Reaction process formula 47 >>

Example 197. Preparation for P-522

Synthesis of 1- (3′-chloro-6-methoxy-biphenyl-3-yl) -6-nitro-1H-benzo-imidazole (P-522). Ethanol (1 mL), water (1 mL) and 1,2-dimethoxyethane (2 mL) I-179 (328 mg, 1.00 mmol), potassium phosphate (424 mg, 2.00 mmol) and 3-chlorophenylboronic acid (313 mg, 1 mL) .30 mmol) was degassed by a 15 minute stream of nitrogen. To was mixed, palladium (0) tetrakis (tri-phenyl-phosphine) was added and the reaction was stirred at 80 ° C. overnight. The reaction was cooled to room temperature, basified with 1M aqueous sodium hydroxide (2 mL), diluted with water (15 mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by silica gel column chromatography (4: 1 to 1: 1 hexane / ethyl acetate) to give P-522 (310 mg, 82% yield) as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) 3.90 (s, 3 H), 7.36-7.51 (m, 3 H), 7.60 (d, J = 7.4 Hz, 1 H), 7.64-7.77 (m, 3 H) , 7.81 (d, J = 9.1 Hz, 1 H), 8.23 (dd, J = 9.1, 2.2 Hz, 1 H), 8.67 (d, J = 2.0 Hz, 1 H), 8.88 (s, 1 H) ppm .
LCMS = 96.1% purity. APCI (+) = 380 (M).
Example 198. Preparation for P-524

  Synthesis of 3- (3′-chloro-6-methoxy-biphenyl-3-yl) -3H-benzimidazol-5-ylamine (P-524). A solution of P-522 (310 mg, 0.811 mmol) in ethanol (577 mg) and tetrahydrofuran (5 mL) was stirred at room temperature. The reaction was stirred at 80 ° C. for 3 h and to the solution was added tin (II) chloride hydrate (900 mg, 4.00 mmol). The reaction was then cooled to room temperature and concentrated in vacuo. The remainder was diluted with chloroform (10 mL). The brine (dried over sodium sulfate) was then filtered and washed with 1N aqueous sodium hydroxide (4 mL) (water) and the solvent was removed under vacuum. The remainder was purified by silica gel column chromatography (9: 1 dichloromethane / methanol) to give P-524 (55.3 mg, 19% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d6): 3.86 (s, 3 H), 4.87 (s, 2 H), 6.66 (dd, J = 8.6, 1.9 Hz, 1 H), 6.86 (d, J = 1.9 Hz , 1 H), 7.25-7.35 (m, 2 H), 7.38-7.65 (m, 4 H), 7.66 (s, 1 H), 8.30 (s, 1 H) ppm. LCMS = 93.9% purity. APCI ( +) = 380 (M).
Example 199. Preparation for P-529

Synthesis of 1- [3- (3′-chloro-6-methoxy-biphenyl-3-yl) -3H-benzimidazol-5-yl] -3-ethyl-urea (P-529). A solution of P-524 (35 mg, 0.10 mmol) and ethyl isocyanate (0.04 mL, 0.5 mmol) in pyridine (0.2 mL) was stirred overnight at room temperature. The extracts were combined and the reaction was diluted with water (2 mL) (extracted with ethyl acetate (2 × 2 mL)). The extract was dried through sodium sulfate (filtered) and solvent removed under vacuum. The remainder was purified by trituration with ethyl acetate and diethyl ether to give P-529 (19.0 mg, 45% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 1.07 (t, J = 7.2 Hz, 3 H), 3.02-3.20 (m, 2 H), 3.88 (s, 3 H), 5.96-6.09 (m, 1 H ), 7.23 (dd, J = 8.7, 1.9 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 1 H), 7.40-7.54 (m, 3 H), 7.54-7.62 (m, 2 H), 7.62-7.73 (m, 2 H), 7.89 (d, J = 1.7 Hz, 1 H), 8.42 (s, 1 H), 8.46 (s, 1 H) ppm.
LCMS = 94.17% purity. APCI (+) = 421.1 (M).
Example 200. Preparation for P-473

Synthesis of [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -dimethylamine (P-473). To a solution of pyrrolidine-3-carboxylic acid methyl ester (185 mg, 1.12 mmol), sodium hydride (60% weight dispersion, 66 mg, 1.68 mmol) was added. After 2 minutes of stirring, P456 (194 mg, 0.56 mmol) was added and the reaction was stirred for 10 minutes in a microwave reactor at 240 ° C. and 15 bars. The aqueous layer was extracted with ethyl acetate (3 × 5 mL) and the reaction was diluted with ethyl acetate (5 mL) (washed with 0.1 N aqueous hydrochloric acid (5 mL)). The combined extract was washed with brine, dried over sodium sulfate, filtered and the solvent removed under vacuum. The crude material was purified by silica gel column chromatography (9: 1 ethyl acetate / hexanes) to give P-473 (80.7 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6): 2.96 (s, 6 H), 3.71 (s, 3 H), 3.77 (s, 2 H), 6.57 (d, J = 8.6 Hz, 1 H), 6.91 ( d, J = 8.6 Hz, 1 H), 7.18-7.50 (m, 6 H), 7.98 (d, J = 2.0 Hz, 1 H) ppm.
LCMS = 96.9% purity. APCI (+) = 371.1 (M).
Example 201. Preparation for P-029

Integration of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-029). DMF (10 mL) hydride (15.6 mg, 0.652 mmol) was able to stir under nitrogen for 15 minutes to stop the sodium suspension under nitrogen. Add 2-pyrrolidone (55.5 mg, 0.652 mmol) and reaction which can be stirred at room temperature for 15 min. The reaction was stirred under nitrogen at ambient temperature for 16 h and to the reaction I-70 (200 mg, 0.621 mmol) was added. The layers were separated and the reaction was diluted with saturated aqueous ammonium chloride (50 mL) (extracted with ethyl acetate (50 mL)). The organic extract was washed with saturated aqueous ammonium chloride (2 × 50 mL), water (3 × 50 mL), brine (50 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. The product was purified by separation on a silica gel pre-plate eluting with dichloromethane methanol by 10% to give P-029 (108 mg, 53% yield) as a yellow eucalyptus of the bark.
1H NMR (400 MHz, CDCl3): 8.40 (t, J = 2.2 Hz, 1H), 8.20-8.17 (m, 1H), 7.82 (dt, J = 7.6 Hz, 1.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.45 (s, 2H), 3.83 (s, 3H), 3.30 (t, J = 7.0 Hz, 2H), 2.44 (t, J = 8.2 Hz, 2H), 2.03-1.99 (m, 2 H) ppm.
LCMS = 93.9% purity. MS (ESI +) = 327.7 (M + 1).
Example 202. Preparation for P-034

Integration of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -imidazolidine-2-1 (P-034). Discontinuation of DMF (10 mL) in potassium carbonate (160 mg, 1.16 mmol), 2-imidazolidone (104 mg, 1.21 mmol) and I-70 (150 mg, 0.466 mmol) was heated to 80 ° C. overnight. The reaction was cooled to room temperature, ethyl acetate (30 mL) and saturated aqueous ammonium chloride (30 mL) were added, and the layers were separated. The excerpt was washed with saturated aqueous ammonium chloride (2 × 30 mL), water (2 × 30 mL), brine (30 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. The crude product was purified by silica gel preparatory TLC to give P-034 (30.2 mg, 20% yield) as a white powder. 1H NMR (400 MHz, CDCl3): 8.41 (t, J = 2.0 Hz, 1H), 8.19-8.16 (m, 1H), 7.84 (dt, J = 7.9 Hz, 1.5 Hz, H), 7.56 (t, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.37 (s, 2H), 4.32 (brs, 1H), 3.84 (s, 3H), 3.41-3.33 (m, 4H) ppm.
LCMS = 86.3% purity. MS (ESI +) = 328.3 (M + 1).
Example 203. Preparation for P-035

Synthesis of 2- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-[1,2] thiazine 1,1-dioxide (P-035). Discontinuation of DMF (8 mL) sodium hydride (11.7 mg, 0.489 mmol) was stirred under nitrogen for 5 minutes. To was stopped, 1,4-butanesultam (66.1 mg, 0.489 mnmol) was added under nitrogen, the reaction was stirred at room temperature for 30 minutes To and the reaction was Addition I-70 (150 mg, 0.466 mmol) and the reaction was stirred overnight at room temperature under nitrogen. The reaction was diluted with ethyl acetate (40 mL). And water (2 × 50 mL), brine, 40 mL was washed with saturated aqueous ammonium chloride (2 × 50 mL) dried over sodium sulfate and the solvent was removed in vacuo. The remainder was purified by silica gel preparative TLC eluting to give P-035 with dichloromethane (99.4 mg, 57% yield) as an off-white powder. 1H NMR (400 MHz, CDCl3): 8.41 (t, J = 1.8 Hz, 1H), 8.20-8.17 (m, 1H), 7.85-7.83 (m, 1H), 7.57 (t, J = 8.0 Hz, 1H) , 7.37 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.30 (s, 2H), 3.84 (s , 3H), 3.27-3.24 (m, 2H), 2.11-3.08 (m, 2H), 2.24-2.21 (m, 2H), 1.66-1.570 (m, 2H) ppm. LCMS = 98.9% purity. MS (APCI -) = 376.1 (M).
Example 204. Preparation for P-036

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2,5-dione (P-036). The reaction was stirred under nitrogen for 15 minutes until gas evolution ceased and hydrogenated (16.6) into a solution of pyrrolidine-2,5-dione (67.2 mg, 0.679 mmol) in DMF (10 mL). 3 mg, 0.679 mmol) sodium was added. The reaction was stirred under nitrogen at room temperature for 16 h and to the reaction I-70 (100 mg, 0.310 mmol) was added. The reaction was diluted with ethyl acetate, the organic layer was washed with water (2 × 50 mL), saturated with aqueous ammonium chloride (2 × 50 mL), and an aqueous wash was combined. The organic extracts were combined and the aqueous wash was extracted with ethyl acetate (50 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, the solvent was removed under vacuum and filtered. The resulting yellow oil was purified by silica dioxide preparative TLC eluting to give P-036 with dichloromethane (68.6 mg, 65% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): 8.39 (t, J = 2.0 Hz, 1H), 8.18 (ddd, J = 8.2, 2.2, 2.0 Hz, 1H), 7.80 (dt, J = 8.0, 1.3 Hz, 1H) , 7.56 (t, J = 8.0 Hz, 1H) 7.45 (dd, J = 7.2, 2.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.66 (s, 2H), 3.82 (s, 3H), 2.71 (s, 4H) ppm. MS (ESI +) = 341.4 (M + 1). LCMS = 97.5% purity.
Example 205. Preparation for P-045

  Integration of 1- (3-bromo-4 methoxy benzyl) -pyrrolidine-2-1 (I-181). Discontinuation of anhydrous DMF (15 mL) in sodium hydride (28.8 mg, 1.20 mmol) was stirred at room temperature under nitrogen for 5 minutes. The reaction was stirred overnight at room temperature and a stirred reaction for 10 minutes Subsequential I-42 (320 mg, 1.14 mmol) was added, and To the reaction was under nitrogen. -Pyrrolidone (102 mg, 1.20 mmol) was added. The reaction was diluted with ethyl acetate (50 mL). The organic material was washed with saturated aqueous ammonium chloride (2 × 30 mL), water (2 × 30 mL), brine (2 × 30 mL). It was then dried over sodium sulfate and solvent removed under vacuum to give I-42 (243 mg) taken on without purification.

  Integration of 1- (3-Benz [1,3] dioxol-5-yl-4methoxybenzyl) -pyrrolidine-2-1 (P-045). A solution of 1,4-dioxane (15 mL) in I-42 (230 mg, 0.809 mmol) and benzo [1,3] dioxol-5-yl-boronic acid (201 mg, 1.21 mmol) was added by a 30 minute stream of nitrogen. The gas was removed, and then dichloride (28.4 mg, 0.0405 mmol) bis (triphenylphosphine) palladium (II) was added under nitrogen. Degassing continued for 5 minutes. This was followed by the addition of 1M aqueous sodium carbonate (2.5 mL). The reaction was heated to 80 ° C. with stirring overnight under nitrogen. The reaction did not go to completion so the reaction was stirred at 80 ° C. for 5 h and additional benzo [1,3] dioxol-5-yl-boronic acid (201 mg, 1.21 mmol) and dichloride (28.4 mg) , 0.0405 mmol) bis (tri-phenyl-phosphine) palladium (II) was added. The reaction was diluted with ethyl acetate (40 mL) (washed with brine (2 × 40 mL), water (4 × 40 mL) and brine (40 mL)). The solution was dried over sodium sulfate (the solvent was removed under vacuum to give the remainder and passed through a filter). This material was purified by 10% purified by thin multiple developed silica gel preplates to give dichloromethane (10% of dichloromethane to give P-045 (21.3 mg, 8.1% yield) as a yellow syrup). Layer chromatography eluting with methanol followed by acetone.

  1H NMR (400 MHz, CDCl3): 7.19-7.17 (m, 2H), 7.04 (d, J = 1.6 Hz, 1H), 6.96-6.85 (m, 3H), 5.99 (s, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 2.43 (t, J = 8.0 Hz, 1H), 2.00-1.97 (m, 2H) ppm. MS (ESI +) = 326.7 (M + 1).

実施例２０６。Ｐ―０５３の準備 << Reaction process formula 48 >>

Example 206. Preparation for P-053

  Synthesis of 1- (3-bromo-4methoxybenzyl) -pyrrolidine-2,5-dione (I-182): discontinuation of sodium hydride (56.2 mg, 2.34 mmol) in anhydrous DMF (20 mL) Stirred under nitrogen for 5 minutes. The resulting slurry was agitated for 5 minutes, and To, which was and was stopped, was stirred after adding pyrrolidine-2,5-dione (231 mg, 2.34 mmol). 109 (500 mg, 2.13 mmol) was allowed to stir at ambient temperature under nitrogen for 17.5 h and was added under nitrogen and diluted with ethyl acetate (50 mL). I-182 as 84% yellow powder yields, the organic solution is water removed under vacuum to yield 532.8 mg (4 × 50 mL), brine (2 × 50 mL), dry completely sulfuric anhydride Washed with sodium and solvent. 1H NMR (400 MHz CDCl3) d: 7.59 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.569 ( s, 2H), 3.870 (s, 3H), 2.710 (s, 4H).

  Synthesis of 1- (3-Benz [1,3] dioxol-5-yl-4methoxybenzyl) -pyrrolidine-2,5-dione (P-053). Solid potassium carbonate (417 mg, 3.02 mmol) and water mixture (1: 1, 1 mL) ethanol was added under nitrogen, solution of I-182 (300 mg, 1.01 mmol) and 1,4-dioxane ( 5 mL) of benzo [1,3] dioxol-5-yl-boronic acid (183 mg, 1.10 mmol) by a nitrogen stream for Subsequencely triphenylphosphine (52.7 mg, 0.201 mmol) for 10 min. The gas was removed. The reaction was stirred for 5 minutes under nitrogen, palladium (II) acetate (22.6 mg, 0.101 mmol) was added, and the reaction was heated to 80 ° C. under nitrogen for 19 h. It was. The layers were separated, the mixture was diluted with saturated aqueous ammonium chloride (50 mL) and ethyl acetate (50 mL) and the solvent was removed under vacuum, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extract was washed with sodium sulfate and the separated solvent thoroughly dried with water (3 × 30 mL) (brine (30 mL)). The remainder was color layer analyzed on flash silica gel eluting with dichloromethane acetone by 10% to yield 153.7 mg P-053 as a 45% yield yellow powder. 1H NMR (CDCl3, 400 MHz): δ 7.35 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.94 (ddd, J = 8.0 Hz, J = 1.6 Hz, J = 0.8 Hz, 1H) , 6.87 (m, 2H), 4.63 (s, 2H), 3.79 (s, 3H), 2.70 (s, 4H). LCMS = 91.2%. MS (ESI +) = 340.3 (M + 1).

実施例２０７。Ｉ―１８６の準備 << Reaction process formula 49 >>

Example 207. Preparation for I-186

  Integration of 4-fluoro-4'-methoxydiphenyl methane (I-184). 4-fluorophenyl bromate (6.70 g, 47.9 mmol), basic solid potassium phosphate (13.6 g, 63.9 mmol), tri-phenyl phosphine (168 mg, 0.639 mmol) and palladium (II) acetate A suspension of (72 mg, 0.319 mmol) was stirred under nitrogen in toluene (100 mL). Nitrogen was flowed with stirring for 15 minutes, and then 4- (chloromethyl) anisol (5.00 g, 31.9 mmol) was added under nitrogen and the reaction was heated to 80 ° C. overnight. It was done. The reaction was further stirred at 80 ° C. for 6 h and added palladium (II) acetate (72 mg, 0.319 mmol) was added. As the reaction was stirred overnight at 80 ° C. and a third portion of palladium (II) acetate (144 mg, 0.639 mmol) and more tri-phenylphosphine (336 mg, 1.28 mmol) was added The reaction was not complete. The reaction was diluted with ethyl acetate (300 mL) (washed with 1N aqueous sodium hydroxide (2 × 300 mL), water (3 × 300 mL) and brine (2 × 300 mL)). The organic extract was dried over sodium sulfate and decolorized through activated carbon (solvent removed and passed through filter). The remainder was purified by flash silica gel column chromatography (hexane Rf = 0.31 10% ethyl acetate) to yield 2.50 g of I-184 as a clear oil in 36% yield. And it was taken on without further purification. 1H NMR (400 MHz, CDCl3) 7.13-7.06 (m, 4H), 6.976-6.93 (m, 2H), 6.84-6.82 (m, 2H), 3.89 (s, 2H), 3.78 (s, 3H) ppm.

  Synthesis of 2-bromo-4- (4-fluoro-benzyl) -1 methoxybenzene (I-185). Biphasic solution bromide of 21% (w / v) aqueous nitric acid (8.32 g, 27.7 mmol) and 4-fluoro-4-methoxydiphenyl methane (I-184, 1.50 g, 6.94 mmol) In potassium (1.65 g, 13.9 mmol) and 1,2-dichloroethane (16 mL), chloride (57.7 mg, 0.208 mmol) tetrabutylammonium was stirred overnight at room temperature and the red stop was dichloromethane (30 mL). It became thinner. The organic layer was washed with aqueous potassium carbonate (2% with v (3 × 50 mL)), water (2 × 50 mL) and brine (50 mL) and the aqueous layer was removed. The reaction was dried over magnesium sulfate (filtered) and solvent removed under vacuum. The crude product was purified by flash silica gel column chromatography (hexane Rf = 0.39 10% ethyl acetate) as a yellow oil in 60% yield to 1.24 g I-185. 1H NMR (400 MHz, CDCl3) d: 7.34 (d, J = 1.6 Hz, 1H), 7.12-7.10 (m, 2H), 7.05 (dd, J = 6.6 Hz, 1.80 Hz, 1H), 6.99-6.96 ( m, 2H), 6.82 (d, J = 6.80 Hz, 1H), 3.867 (s, 5H) ppm.

Lanes containing 2- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -4,4,5,5-tetramethyl- [1,3,2] di-oxa-boron (I-186 ) Synthesis. Biscolate di-boron (516 mg, 2.03 mmol) was added under nitrogen and the nitrogen flow was 15 minutes Subsequential solid potassium acetate (499 mg, 5.08 mmol) ([1,1'- 2-bromo-4- (4-fluoro-benzyl) -1-methoxybenzene (I-185) in DMF (5 mL) for bis (diphenylphosphino) ferrocene] dichloropalladium (II) (138 mg, 0.169 mmol) The reaction was heated to 85 ° C. 16 h, the reaction was cooled to room temperature, and diluted with ethyl acetate (50 mL) and water (50 mL). The biphasic suspension is filtered twice over the spent spent catalyst. Brine (50 mL) (decolorized through activated charcoal) is removed under vacuum, dried over sodium sulfate (filtered) and solvent and the organic extract is washed with water (3 × 50 mL) The remainder was flash silica gel column chromatography (hexane (Rf = 0.10) 10% of 10%) to yield 419.8 mg of I-186 as a colorless oil in 72% yield. 1H NMR (400 MHz, CDCl3) d: 7.50 (d, J = 2.4 Hz, 1H), 7.14-7.09 (m, 3H), 6.97-6.92 (m, 2H), 6.78 (d , J = 8.4 Hz, 1H), 3.88 (s, 2H), 3.80 (s, 3H), 1.35 (s, 12H) ppm. MS (ESI +) = 341.3 (M-1), 500.7 (M + 159).
Example 208. Preparation for I-187

  Synthesis of 2,2-difluoro-benzo [1,3] dioxol-5-yl-bromate (I-187): anhydrous diethyl ether (5 mL) in tert-butyl lithium (1.15 mL, 1.95 mmol) The solution was cooled to -78 degrees. C under nitrogen. Diethyl ether (0.80 mL) of 5-bromo-2,2-difluoro-benzo [1,3] dioxole (180 mg, 0.760 mmol) was added and the reaction was stirred at −78 ° C. for 1 h. This was followed by the addition of tri-iso-propyl borate (0.37 mL, 1.60 mmol) under nitrogen. A reaction that allows for 1.5 h of stirring while allowing heat to enter the ambient temperature. The reaction was poured into 4N aqueous sodium hydroxide (5 mL), stirred, adjusted to pH 1 by the dropwise addition of concentrated aqueous hydrochloric acid, and the product was extracted with ethyl acetate (10 mL). The organic extract was dried over anhydrous sodium sulfate (filtered) and solvent removed under vacuum to yield 140.2 mg of I-187 as a brown solid. And it was taken on without further purification.

  1H NMR (400 MHz, DMSO-d6) 7.77-7.74 (m, 1H), 7.67-7.65 (m, 1H), 7.51 (s, 1H).

実施例２０９。Ｐ―１３１およびＰ―１３２の準備

<< Reaction process formula 50 >>

Example 209. Preparation of P-131 and P-132

Integration of (S) -5- (tert-butyl-dimethyl-silanyloxamethyl) -pyrrolidine-2-1 (I-188). Solution of (S) -5-hydroxymethyl-pyrrolidine-2-1 (1.0 g, 8.69 mmol), DMF (10 mL), chloride (1.57 g, 10.42 mmol) t-butyldimethylsilyl and imidazole (0 .89 g, 13.03 mmol) was stirred at ambient temperature for 4 hours with 4 mL of water added. The watery one was extracted with dichloromethane (10 mL) and the layers were separated. The combined organic fertilizer was washed with water (15 mL) and brine (15 mL), dried over sodium sulfate and filtered to give 1.91 g of I-188 as a 96% yield colorless oil. Concentrated to produce.

Integration of (R) -5- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidine-2-1 (I-189).
I-189 was prepared in a similar manner as that for I-188. And it started with (R) -5-hydroxymethyl-pyrrolidine-2-1. 1.91 I-189 g was obtained as a 96% colorless oil.

Integration of (S) -5- (tert-butyl-dimethyl-silanyloxymethyl) -1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (I-190) . To a 20 mL vial with the solution cooled to 0 ° C. and with stirring, the stick was summed I-188 (0.28 g, 1.24 mmol), dry THF, 4 mL. The suspension was stirred for 30 minutes at ambient temperature and sodium hydride (65 mg, 1.61 mmol) was added. After cooling to 0 ° C., I-70 (0.40 g, 1.24 mmol) was added and the reaction was stirred at ambient temperature for 18 hours with 5 mL of water added. The product was extracted with ethyl acetate (4 × 15 mL). The organic fertilizer was combined, dried with sodium sulfate, filtered and concentrated. Flash column chromatographic purification using 30% ethyl acetate / Hexanes yielded 476 mg of I-190 as a colorless oil in 83% yield.

(R) -5- (tert-Butyl-dimethyl-silanyloxymethyl) -1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (I-191). I-191 was prepared in a highly delayed manner as that for I-190. And started with I-189.
462 mg of I-191 was obtained as a colorless oil in 80% yield.

Integration of (S) -5-hydroxymethyl-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-131). To a 50 mL round bottom flask with the solution cooled to 0 ° C. and equipped with stirring, the stick was addition I-190 (0.45 g, 0.96 mmol), dry THF, 5 mL. The reaction was stirred at 0 ° C. for 30 minutes and TBAF (1.4 mL, 1.43 mmol, 1.0 M in THF) was added. The product was extracted with ethyl acetate (3 × 10 mL) and 2 mL saturated aqueous NH 4 Cl and 2 mL water were added. The complex organic fertilizer was washed with brine, dried over sodium sulfate, filtered and concentrated. The remainder was purified by flash column chromatography using 10-25% acetone / dichloromethane to yield 307 mg (90%) of P-131 as a colorless semi-solid. 1H NMR (400 MHz, CDCl3) 8.39 (s, 1 H), 8.18 (dd, J = 1.3, 8.3 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.9 Hz, 1 H), 7.32 (dd, J = 1.9, 8.4 Hz, 1 H), 7.25 (d, J = 2.0 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 4.81 ( d, J = 15.0 Hz, 1 H), 4.29 (d, J = 14.9 Hz, 1 H), 3.83 (s, 3 H), 3.78 (d, J = 2.5 Hz, 1 H), 3.68-3.50 (m , 2 H), 2.65-2.48 (m, 1 H), 2.46-2.31 (m, 1 H), 2.16-2.03 (m, 1 H), 2.02-1.91 (m, 1 H). LC / MS = 100.0 %, 357.1 (APCI +).

Integration of (R) -5-hydroxymethyl-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-132). Except starting with I-191, P-132 was prepared in a similar manner as that for P-131. 310 mg (91%) of P-132 was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) 8.39 (t, J = 1.7 Hz, 1 H), 8.18 (dd, J = 1.3, 8.3 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.32 (dd, J = 2.1, 8.5 Hz, 1 H), 7.25 (d, J = 2.1 Hz, 1 H), 6.97 (d, J = 8.5 Hz, 1 H), 4.80 (d, J = 14.9 Hz, 1 H), 4.30 (d, J = 15.0 Hz, 1 H), 3.83 (s, 3 H), 3.79 (dd, J = 2.8, 11.4 Hz, 1 H ), 3.68-3.53 (m, 2 H), 2.64-2.50 (m, 1 H), 2.46-2.32 (m, 1 H), 2.15-2.03 (m, 1 H), 2.02-1.90 (m, 1 H LC / MS = 100.0%, 357.1 (APCI +).
Example 210. Preparation of P-155 and P-156

Synthesis of toluene-4-sulfonic acid (S) -1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -5-oxo-pyrrolidin-2-ylmethyl ester (I-192). To a 20 mL vial with stirring, a 0 ° C. rod and dichloromethane (5 mL) were added P-131 (0.25 g, 0.70 mmol), TsCl (0.16 g, 0.84 mmol), triethylamine (0.15 mL, 1 .05 mmol) and DMAP (9 mg, 0.07 mmol). The reaction was stirred at room temperature for 18 hours and concentrated. The remainder was purified by flash column chromatography using 10% acetone / dichloromethane to yield 340 mg (95%) of I-192 as a colorless oil.

Synthesis of toluene-4-sulfonic acid (R) -1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -5-oxo-pyrrolidin-2-ylmethyl ester (I-193). Except starting with P-132, I-193 was prepared in a similar manner as that for I-192. 290 mg (92%) of I-193 was obtained as a colorless oil.

Integration of (S) -5-azidomethyl-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (I-194). In a 20 mL vial with stirring, the bars were summed I-192 (0.33 g, 0.65 mmol), DMF (4 mL) and NaN3 (63 mg, 0.97 mmol). The reaction was stirred at 60 ° C. for 1 hour and cooled to room temperature. The product was extracted with dichloromethane (2 × 5 mL) and 5 mL of water was added. The combined organic fertilizer was washed with water (4 × 5 mL), dried over sodium sulfate and filtered to concentrate to obtain 0.24 g (97%) of I-194 as a colorless oil.

Integration of (R) -5-azidomethyl-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (I-195). I-195 was prepared in a similar manner as that for I-194 except starting with I-193. I-195 (0.20 g, 96%) was obtained as a colorless oil.

Integration of (S) -5-aminomethyl-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-155). To a 50 mL round bottom flask with stirring, the bars were summed I-194 (0.24 g, 0.63 mmol), THF (4 mL) and PPh3 (0.50 g, 1.89 mmol). The reaction was stirred at room temperature for 18 hours with 1 mL of water added. After an additional 2 days of stirring at room temperature, the THF was removed under reduced pressure. 1N HCl was increased until the solution was washed with dichloromethane (3 × 3 mL) and the aqueous material was pH = 1. The product was extracted with dichloromethane (3 × 3 mL), concentrated and the aqueous phase was basified with 1 N NaOH at pH = 11. The remainder was purified by flash column chromatography using 5% methanol / dichloromethane to give 164 mg (73%) of P-155 as a pale yellow oil. 1H NMR (400 MHz, CDCl3) 8.39 (s, 1 H), 8.18 (dd, J = 1.3, 8.2 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.9 Hz, 1 H), 7.30 (dd, J = 1.9, 8.4 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 4.85 ( d, J = 14.9 Hz, 1 H), 4.15 (d, J = 14.9 Hz, 1 H), 3.83 (s, 3 H), 3.61-3.50 (m, 1 H), 2.93-2.84 (m, J = 4.8 Hz, 1 H), 2.80 (br. S., 1 H), 2.61-2.49 (m, 1 H), 2.47-2.35 (m, 1 H), 2.19-2.03 (m, 1 H), 1.95- 1.83 (m, 1 H). LC / MS = 100.0%, 356.1 (APCI +).

Integration of (R) -5-aminomethyl-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-156). Except starting with I-195, P-156 was prepared in a similar manner as that for P-155. P-156 (80 mg, 43%) was obtained as a pale yellow oil. 1H NMR (400 MHz, CDCl3) 8.39 (s, 1 H), 8.18 (dd, J = 1.1, 8.3 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.30 (dd, J = 1.8, 8.4 Hz, 1 H), 7.23 (d, J = 1.9 Hz, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 4.85 ( d, J = 14.9 Hz, 1 H), 4.15 (d, J = 14.9 Hz, 1 H), 3.83 (s, 3 H), 3.61-3.49 (m, 1 H), 2.93-2.84 (m, 1 H ), 2.83-2.74 (m, 1 H), 2.61-2.49 (m, 1 H), 2.46-2.35 (m, 1 H), 2.15-2.03 (m, 1 H), 1.95-1.83 (m, 1 H LC / MS = 100.0%, 356.1 (APCI +).
Example 211. Preparation for P-135

Synthesis of 2-fluoro-5- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -benzoic acid methyl ester (I-196). To a 20 mL vial with stirring, the stick was added I-70 (0.30 g, 0.93 mmol), 4-fluoro-3methoxycarbonylphenyl bromic acid (203 mg, 1.02 mmol), tri-phenyl phosphine (49 mg 0.19 mmol), K3PO4 (0.40 g, 1.86 mmol), DME (5 mL), water (0.5 mL) and ethanol (0.5 mL). N2 gas was bubbled by the stirred reaction for 10 minutes. N2 was bubbled for another 5 min and Pd (OAc) ₂ (21 mg, 0.09 mmol) was added. The reaction was stirred at 80 ° C. for 18 hours and the vial was capped. 5 mL water and 5 mL ethyl acetate were added and the reaction was cooled to room temperature. The watery one was extracted with ethyl acetate (3 × 10 mL) and the layers were separated. Organic fertilizer was combined, dried and concentrated with sodium sulfate. The remainder was purified by flash column chromatography using 10% acetone / Hexanes to give 207 mg (56%) of I-196 as a colorless oil.

Synthesis of fluoro-5- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -phenyl] -methanol (P-135). In a 20 mL vial with agitation, the stick was summed I-196 (112.3 mg, 0.28 mmol) and 4 mL dry THF. DIBAL-H (0.71 mL, 0.71 mmol, 1.0 M sol. In hexanes) was added and the solution was cooled to 0 ° C. The reaction was stirred at 0 ° C for 1 hour. Aqueous 1N HCl (1 mL) was added followed by water (5 mL). The aqueous solution was extracted with ethyl acetate (3 × 10 mL). Organic fertilizers were combined, dried and concentrated through sodium sulfate. 8.38 (s, 1 H) ppm. The product uses 10% acetone / hexane to obtain 53 mg (51%) of P-135 as NMR (400 MHz, CDCl3) 1.72 (t, J = 6.2 Hz, 1H) of colorless oil 1H Purified by flash column chromatography. 1H NMR (400 MHz, CDCl3) 1.72 (t, J = 6.2 Hz, 1 H) 3.81 (s, 3 H) 3.95 (s, 2 H) 4.73 (d, J = 6.2 Hz, 2 H) 6.91-7.02 ( m, 2 H) 7.06-7.21 (m, 3 H) 7.23-7.28 (m, 1 H) 7.54 (t, J = 8.0 Hz, 1 H) 7.82 (d, J = 7.7 Hz, 1 H) 8.16 (dd , J = 8.3, 1.3 Hz, 1 H) 8.38 (s, 1 H) ppm. LC / MS = 100.0%, 367.1 (APCI-).
Example 212. Preparation of P-153 and P-154

1- (6-Methoxy-3'-nitro-biphenyl-3-ylmethyl) -1H-imidazole-4-carboxylic acid methyl ester (I-197) and 1- (6-methoxy-3'-nitro-biphenyl- Synthesis of 3-ylmethyl) -1H-imidazole-5-carboxylic acid methyl ester (I-198). To a 20 mL vial with agitation, the stick was added I-70 (0.30 g, 0.92 mmol), 1H-imidazole-4-carboxylic acid methyl ester (0.12 g, 0.93 mmol), K 2 CO 3 (0. 15 g, 1.12 mmol) and DMF (3 mL). The reaction was stirred at room temperature for 20 hours. 10 mL of water and layers were separated and 10 mL of dichloromethane was added to the reaction. The complex organic fertilizer was washed with water (3 × 10 mL) and the watery one was extracted with 10 mL of dichloromethane. The dichloromethane portion was concentrated and first purified by flash column chromatography using 0-5% methanol / dichloromethane followed by preparative TLC using 10% acetone / dichloromethane. 72.4 I-197 mg (21%) and I-198 91.1 mg (27%) were obtained as a pale yellow oil.

Synthesis of [3- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -3H-imidazol-4-yl] -methanol (P-153). In a 20 mL vial with agitation, the stick was summed I-198 (85.5 mg, 0.23 mmol) and 5 mL dry THF. DIBAL-H (0.70 mL, 0.70 mmol, 1.0 M sol. In hexanes) was added and the solution was cooled to 0 ° C. The reaction was stirred for 16 hours at room temperature and cooled to 0 ° C. Aqueous 1N HCl (1 mL) was added followed by 3 mL of 1N NaOH and 5 mL of ethyl acetate. The watery one was extracted with ethyl acetate (3 × 10 mL) and the layers were separated. The organics were combined, dried over sodium sulfate and concentrated. The remainder was purified by flash column chromatography using 50% acetone / dichloromethane. This was followed by flash column chromatography using 5% methanol / dichloromethane to obtain 52.2 mg (66%) of P-153 as a tan solid. 1H NMR (400 MHz, DMSO-d6) 3.79 (s, 3 H) 4.38 (d, J = 5.2 Hz, 2 H) 5.13 (t, J = 5.3 Hz, 1 H) 5.21 (s, 2 H) 6.80 ( br. s., 1 H) 7.16 (d, J = 8.5 Hz, 1 H) 7.27 (dd, J = .5, 1.9 Hz, 1 H) 7.34 (d, J = 1.9 Hz, 1 H) 7.65-7.77 (m, 2 H) 7.92 (d, J = 7.8 Hz, 1 H) 8.20 (dd, J = 8.1, 1.7 Hz, 1 H) 8.28 (s, 1 H) ppm. LC / MS = 99.9%, 340.1 ( (APCI +)

  Synthesis of [1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-imidazol-4-yl] -methanol (P-154). P-154 was prepared in a similar manner as that for P-153 except starting with I-197. P-154 (45.0 mg, 71%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) 3.79 (s, 3 H) 4.28 (d, J = 5.5 Hz, 2 H) 4.75 (t, J = 5.6 Hz, 1 H) 5.12 (s, 2 H) 7.03 ( s, 1 H) 7.16 (d, J = 8.5 Hz, 1 H) 7.38 (dd, J = 8.5, 2.1 Hz, 1 H) 7.44 (d, J = 2.2 Hz, 1 H) 7.68 (d, J = 0.8 Hz, 1 H) 7.72 (t, J = 8.0 Hz, 1 H) 7.94 (d, J = 7.9 Hz, 1 H) 8.20 (dd, J = 8.2, 1.5 Hz, 1 H) 8.29 (t, J = 1.7 Hz, 1 H). LC / MS = 99.9%, 340.1 (APCI +).

実施例２１３。Ｐ―１４０の準備

<< General reaction process formula 51 >>

Example 213. Preparation for P-140

Synthesis of 1- [5 ′-(4-fluoro-benzyl) -2′-methoxy-biphenyl-3-yl] -ethanone (P-140). The nitrogen stream was adjusted to 1-185 (150 mg, 0.508 mmol) and 1,2-dimethoxyethane (4 mL) of 3 acetylphenyl bromic acid (91.7 mg, 0.18 mmol) for 15 min (followed by addition of ethanol). 559 mmol) bubbled: water (1: 1, 1 mL). The nitrogen flow was continued for 10 minutes, and solid potassium carbonate (210 mg, 1.52 mmol), triphenyl phosphine (26.8 mg, 0.102 mmol) and palladium (II) acetate (11.4 mg, .0. 0508 mmol) was added. The reaction was heated to 80 ° C. and stirred and heated overnight. The reaction was diluted with ethyl acetate (50 mL), saturated with aqueous ammonium chloride (50 mL), filtered twice and separated. Brine (50 mL) (dried over anhydrous sodium sulfate) was filtered, the organic extract was washed with water (3 × 50 mL), and the solvent was removed under vacuum. The reaction was performed by flash silica gel column chromatography (hexane (Rf = 0.10 of 10% ethyl acetate in hexane) to give P-140 (88.0 mg, 52% yield) as a colorless oil. Of 5% ethyl acetate). 1H NMR (400 MHz, DMSO-d6) d: 7.98 (t, J = 1.6 Hz, 1H), 7.91 (dt, J = 7.9 Hz, 1.4 Hz, 1H), 7.70 (dt, J = 8.0 Hz, 1.5 Hz , 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.30-7.30 (m, 2H), 7.23-7.21 (m, 2H), 7.12-7.05 (m, 3H), 3.93 (s, 2H), 3.74 (s, 3H), 2.60 (s, 3H) ppm.LCMS = 98.5% purity. MS (APCI +) = 335.1 (M + 1).
Example 214. Preparation for P-141

Synthesis of 2,2-difluoro-5- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -benzo [1,3] dioxole (P-141). Solution of I-185 (114 mg, 0.385 mmol) and I-187 (140 mg, 0.693 mmol) of 1,2-dimethoxyethane (3 mL) for 20 minutes bubbled and the reaction was heated to 80 ° C. Nitrogen flow was continued for 5 minutes To by addition of ethanol and aqueous solution (1: 1, 0.75 mL) and the reaction was added solid potassium carbonate (160 mg, 1.16 mmol), tritium under nitrogen. It was supposed to be phenyl Mitsumatsu (20.2 mg, 0.0770 mmol) and palladium (II) acetate (8.6 mg, 0.0385 mmol) and stirred at this temperature overnight. The biphasic solution was filtered, the residue was dissolved in ethyl acetate (20 mL) and water (20 mL), the solvent was removed under vacuum, and the two layers were separated. The aqueous laundry was extracted into ethyl acetate (20 mL) and the composite excerpt was washed with water (3 × 50 mL). Saturated aqueous ammonium chloride (50 mL) (dried over sodium sulfate) is then decolorized with activated carbon and filtered. The solvent is then removed under vacuum. The rest is flash silica gel column chromatography followed by preliminary silicon dioxide TLC (2.5% acetone in dichloromethane) to give P-141 (96.8 mg, 68% yield) (dichloromethane (dichloromethane 10% acetone Rf = 0.40) 5% acetone). 1H NMR (400 MHz, DMSO-d6) 7.48 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.30-7.179 (m, 5H), 7.11-7.03 (m, 3H ), 3.90 (s, 2H), 3.74 (s, 3H) ppm. MS (ESI +) = 371.8 (M-1), 353.0 (M-19).
Example 215. Preparation for P-151

Synthesis of 5- (4-fluoro-benzyl) -2-methoxy-3'-methylsulfanyl-biphenyl (P-151). P-151 was synthesized from I-185 (160 mg, 0.542 mmol) and 3-methylsulfanylphenyl bromic acid (100 mg, 0.596 mmol) using the same conditions as described for P-141. . For the reaction, the vial was added ethyl acetate (50 mL) and water (50 mL), the biphasic solution was filtered, and the layers were separated. The organic extract was washed with water (3 × 50 mL). Aqueous saturated ammonium chloride (50 mL), brine, 50 mL are then dried over sodium sulfate and filtered. The solvent is then removed under vacuum. The product was flash silica gel column chromatography (5% hexanes followed by preliminary silica gel TLC (2.5% acetone in hexanes) to give P-151 (47.6 mg, 26% yield). Acetone). 1H NMR (400 MHz, DMSO-d6) 7.35-7.27 (m, 4H), 7.22-7.16 (m, 4H), 7.11-7.07 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 3.909 (s, 2H), 3.73 (s, 2H). LCMS = 99.4% purity. MS (APCI +) = 338.1 (M).
Example 216. Preparation for P-170

  Synthesis of 1- [5 ′-(4-fluoro-benzyl) -4,2′-dimethoxy-biphenyl-3-yl] -ethanone (P-170). Nitrogen vapor was solved for I-186 (150 mg, 0.438 mmol) and 1,2-dimethoxyethane (4 mL) of 1- (5-bromo-2methoxyphenyl) -ethanone (110 mg, 0.482 mmol) for 10 minutes. ). And the addition of ethanol and aqueous solution (1: 1, 1 mL) followed. Palladium (II) acetate (9.8 mg, 0.044 mmol), triphenyl phosphine (23.0 mg, 0.0877 mmol) and solid potassium carbonate (181 mg, 1.32 mmol) were added under nitrogen, Bubbling nitrogen was continued for 5 minutes and the reaction was heated at 80 ° C. under nitrogen for 16 h. Ethyl acetate (50 mL) was added and the solvent was removed under vacuum. The organic solution was washed with water (3 × 50 mL) and brine (50 mL). The organic extract was removed under vacuum. The rest are two silica gel spare TLC plates (2 followed by 5% acetone in hexane with 6 developments) to give P-170 (43.0 mg, 27% yield) as orange oil. Purified with 10% ethyl acetate in hexane with development. 1H NMR (400 MHz, CDCl3): 7.63-7.60 (m, 2H), 7.29-7.25 (m, 2H), 7.21-7.07 (m, 5H), 7.02 (d, J = 8.4 Hz, 1H), 3.92 ( s, 3H), 3.91 (s, 2H), 3.32 (s, 3H), 2.55 (s, 3H). LCMS = 100.0% purity. MS (APCI +) = 365.1 (M + 1).

実施例２１７。Ｐ―１６２の準備 << General Reaction Process Formula 52 >>

Example 217. Preparation for P-162

Synthesis of 2-bromo-4-bromomethyl-1 methoxybenzene (I-42). In a 1 L circle, the bottom flask is loaded with 4-methoxybenzyl chloride (19.7 g, 125.8 mmol), glacial acetic acid (400 mL) and Br2 (9.1 mL, 177.5 mmol, dropwise over 5 min. )Met. The brown solution was stirred at room temperature for 20 hours and then poured into 10% (w / v) aqueous NaHSO 3 solution (2000 mL). After stirring at room temperature for 30 minutes, the solid was washed with water (4 × 500 mL) and the white solid was filtered through a coarse glass frit. The solid was dried in a 16 hour vacuum desiccator. I-42 (24.5 g, 74%) was obtained as a white solid.

Integration of 1- (3-bromo-4 methoxy benzyl) -pyrrolidine-2-1 (I-181). The solution was cooled to 0 ° C. and dried in a 100 mL circle, the bottom flask was addition pyrrolidine-2-1 (0.20 g, 2.34 mmol), dried DMF, 20 mL. The stop was stirred for 30 minutes at room temperature and NaH (110 mg, 2.76 mmol) was added. The reaction was stirred at 80 ° C. for 30 minutes and cooled to room temperature and I-42 (0.50 g, 2.12 mmol) was added. After extraction with dichloromethane (2 × 20 mL), the combined organic fertilizer was washed with water (4 × 20 mL), dried over sodium sulfate, filtered and concentrated. The remainder was fed with a pulley by flash column chromatography using 10% acetone / dichloromethane to obtain 482 mg (80%) of I-181 as a pale yellow oil.

Integration of 1- (6-methoxy-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-162). To a 20 mL vial with agitation, the stick was added I-181 (95.5 mg, 0.34 mmol), phenyl bromic acid (45 mg, 0.37 mmol), tri-phenyl phosphine (18 mg, 0.07 mmol), K2CO3. (139 mg, 1.01 mmol), DME (5 mL), water (0.5 mL) and ethanol (0.5 mL). N2 gas was bubbled by the stirred reaction for 10 minutes. N2 was bubbled for an additional 5 minutes and palladium (II) acetate (8 mg, 0.03 mmol) was added. The reaction was stirred at 80 ° C. for 18 hours and the vial was capped. 5 mL water and 5 mL ethyl acetate were added and the reaction was cooled to room temperature. The watery one was extracted with ethyl acetate (3 × 10 mL) and the layers were separated. Organic fertilizer was combined. And the remainder was purified by a preparatory TLC using 10% acetone / dichloromethane to obtain 38.9 mg (41%) of P-162 as a pale yellow oil and dried over sodium sulfate, Concentrated. 1H NMR (400 MHz, CDCl3) 1.98 (quin, J = 7.6 Hz, 2 H) 2.43 (t, J = 8.1 Hz, 2 H) 3.29 (t, J = 7.1 Hz, 2 H) 3.80 (s, 3 H 4.43 (s, 2 H) 6.94 (d, J = 8.2 Hz, 1 H) 7.17-7.24 (m, 2 H) 7.29-7.36 (m, 1 H) 7.40 (t, J = 7.5 Hz, 2 H) 7.51 (d, J = 7.3 Hz, 2 H) ppm. LC / MS = 100.0%, 282.1 (APCI +).
Example 218. Preparation for P-184

Integration of 1- (6,3'-dimethoxy-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-184). To a 20 mL vial with stirring, the sticks added I-181 (0.21 g, 0.73 mmol), 3 methoxyphenyl bromic acid (0.11 g, 0.73 mmol), tri-phenyl phosphine (39 mg, 0. 15 mmol), K2CO3 (0.31 g, 2.22 mmol), DME (5 mL), water (0.5 mL) and ethanol (0.5 mL). N2 gas was bubbled by the stirred reaction for 10 minutes. N2 bubbled by reaction for an additional 5 minutes and palladium (II) acetate (17 mg, 0.07 mmol) was added. The reaction was stirred at 80 ° C for 18 hours under N2. 5 mL water and 5 mL ethyl acetate were added and the reaction was cooled to room temperature. The watery one was extracted with ethyl acetate (3 × 10 mL) and the layers were separated. Organic fertilizer was combined, dried and concentrated with sodium sulfate. The remainder was purified by flash column chromatography using 10% acetone / dichloromethane to obtain 40.2 mg (17%) of P-184 as a brown oil. 1H NMR (400 MHz, CDCl3) 1.98 (quin, J = 7.6 Hz, 2 H) 2.43 (t, J = 8.1 Hz, 2 H) 3.28 (t, J = 7.1 Hz, 2 H) 3.80 (s, 3 H ) 3.84 (s, 3 H) 4.43 (s, 2 H) 6.88 (dd, J = 8.3, 2.0 Hz, 1 H) 6.93 (d, J = 8.2 Hz, 1 H) 7.04-7.11 (m, 2 H) 7.17-7.23 (m, 2 H) 7.32 (t, J = 7.9 Hz, 1 H) ppm. LC / MS = 100.0%, 312.1 (APCI +).
Example 219. Preparation for P-503

１―（６―メトキシ―３´―ニトロ―ビフェニル―３―イルメチル）―ピペリジン―２―１（Ｐ―１８８）の統合。撹拌を有する５０ｍＬの丸い底のフラスコに、棒は付加的な２―ピペリドン（８８ｍｇ、０．８９ｍｍｏｌ）、乾燥ＴＨＦ（５ｍＬ）、ＮａＨ（４２ｍｇ、１．０５ｍｍｏｌ）であった、そして、停止は室温で、１０分間撹拌された。反応が室温で、１８時間撹拌された及び、Ｉ―７０（２６１ｍｇ、０．８１ｍｍｏｌ）は加えられた。ＴＨＦが回転する蒸発により除去された及び、反応に、１０ｍＬのＨ２Ｏは加えられた。複合有機肥料が２０ｍＬの塩水によって、洗われた及び、製品は酢酸エチル（３×１０ｍＬ）により抽出されて、Ｎａ２ＳＯ４を通じて乾燥して、集中した。残りは、５ ― 淡い黄色半固体としてＰ―１８８の２０１ｍｇ（７３％）を得る１０％のアセトン／ジクロロメタン ― を用いたフラッシュ・カラムクロマトグラフィにより浄化された。
1H NMR (500 MHz ,CDCl3) 8.40 - 8.39 (m, 1H), 8.18 - 8.15 (m, 1H), 7.84 - 7.82 (m, 1H), 7.56 (t, J = 8.0 Hz), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.24 - 7.23 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.59 (s, 2H), 3.83 (s, 3H), 3.26 - 3.24 (m, 2H), 2.47 - 2.44 (m, 2H), 1.80 - 1.79 (m, 4H) ppm. 13C-NMR (100 MHz, CDCl3) δ 170.0, 155.9, 148.2, 140.1, 135.8, 130.7, 130.3, 129.9, 129.0, 128.3, 124.7, 122.0, 111.7, 55.9, 49.6, 47.4, 32.6, 23.4, 21.5 ppm. LC/MS = 100.0%, 341.1 (APCI+).
実施例２２１。Ｐ―１９２の準備

Integration of 1- (6-hydroxy-3'-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-503). To a 50 mL round bottom flask with stirring, the bars were addition P-029 (324.5 mg, 0.99 mmol) and dichloromethane (10 mL). BBr3 (3.0 mL, 2.98 mmol, 1.0 M in dichloromethane) was added and the solution was cooled to 0 ° C. The reaction was stirred at room temperature for 18 hours and water was added. The watery one was extracted with dichloromethane (4 × 15 mL) and the layers were separated. Organic fertilizer was combined, dried and concentrated with sodium sulfate. 284.4 mg (92%) of P-503 was obtained as a tan solid and the solid was triturated with ether. 1H NMR (400 MHz, DMSO-d6) 1.90 (quin, J = 7.5 Hz, 2 H) 2.26 (t, J = 8.1 Hz, 2 H) 3.24 (t, J = 7.0 Hz, 2 H) 4.32 (s, 2 H) 6.97 (d, J = 8.3 Hz, 1 H) 7.11 (dd, J = 8.3, 2.0 Hz, 1 H) 7.25 (d, J = 2.0 Hz, 1 H) 7.71 (t, J = 8.0 Hz, 1 H) 8.00 (d, J = 7.8 Hz, 1 H) 8.17 (dd, J = 8.2, 1.6 Hz, 1 H) 8.40 (t, J = 1.7 Hz, 1 H) 9.91 (br. S., 1 H ) ppm. LC / MS = 98.4%, 313.1 (APCI +).
Example 220. Preparation for P-188

Integration of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -piperidine-2-1 (P-188). To a 50 mL round bottom flask with stirring, the bar was additional 2-piperidone (88 mg, 0.89 mmol), dry THF (5 mL), NaH (42 mg, 1.05 mmol) and the stop was at room temperature And stirred for 10 minutes. The reaction was stirred at room temperature for 18 hours and I-70 (261 mg, 0.81 mmol) was added. THF was removed by rotary evaporation and 10 mL of H2O was added to the reaction. The complex organic fertilizer was washed with 20 mL brine and the product was extracted with ethyl acetate (3 × 10 mL), dried over Na 2 SO 4 and concentrated. The remainder was purified by flash column chromatography using 10% acetone / dichloromethane to give 201 mg (73%) of P-188 as a 5-light yellow semi-solid.
1H NMR (500 MHz, CDCl3) 8.40-8.39 (m, 1H), 8.18-8.15 (m, 1H), 7.84-7.82 (m, 1H), 7.56 (t, J = 8.0 Hz), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.24-7.23 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.59 (s, 2H), 3.83 (s, 3H), 3.26-3.24 (m, 2H), 2.47-2.44 (m, 2H), 1.80-1.79 (m, 4H) ppm.13C-NMR (100 MHz, CDCl3) δ 170.0, 155.9, 148.2, 140.1, 135.8, 130.7, 130.3, 129.9, 129.0, 128.3, 124.7, 122.0, 111.7, 55.9, 49.6, 47.4, 32.6, 23.4, 21.5 ppm. LC / MS = 100.0%, 341.1 (APCI +).
Example 221. Preparation for P-192

Synthesis of 2-bromo-4- (4-fluoro-phenylsulfanylmethyl) -1 methoxybenzene (I-199). To a 20 mL vial with stirring, the sticks were added I-42 (0.50 g, 1.90 mmol), 4-fluorothiophenol (0.27 g, 2.09 mmol), dichloromethane (5 mL) and TEA (0. 43 mL, 3.14 mmol). The solution was stirred at room temperature for 16 hours and concentrated. The remainder was purified by flash column chromatography using 15% acetone / hexanes to obtain I-199 which was used without further purification in the next step.

Synthesis of 5- (4-fluoro-phenylsulfanylmethyl) -2-methoxy-3'-nitro-biphenyl (I-200). To a 20 mL vial with agitation, the sticks added I-199 (0.40 g, 1.22 mmol), 3 nitrophenyl bromic acid (0.20 g, 1.22 mmol), K2CO3 (0.51 g, 3.67 mmol). , Triphenylphosphine (64 mg, 0.24 mmol), DME (5 mL), EtOH (0.5 mL) and H2O (0.5 mL). Mixing was degassed with N 2 for 10 minutes and palladium (II) acetate (27 mg, 0.12 mmol) was added. The reaction was stirred at 80 ° C. for 18 hours, then filtered through Celite and concentrated. The remainder was purified by flash column chromatography using 10% acetone / dichloromethane and then by flash column chromatography using 12% acetone / hexane. This was followed by preparative layer chromatography using 15% ethyl acetate / hexanes to give 102 mg (23%) of I-200 as a pale yellow oil. 1H NMR (400 MHz, CDCl3) 8.33 (s, 1 H), 8.17 (dd, J = 1.3, 8.3 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.35-7.27 (m, 2 H), 7.23 (dd, J = 2.1, 8.5 Hz, 1 H), 7.15 (d, J = 2.1 Hz, 1 H), 6.98 (t, J = 8.7 Hz, 2 H), 6.91 (d, J = 8.5 Hz, 1 H), 4.04 (s, 2 H), 3.82 (s, 3 H) ppm. LC / MS = 369.0 (APCI-).

Synthesis of 5- (4-fluoro-benzenesulfonylmethyl) -2-methoxy-3'-nitro-biphenyl (I-201). In a 20 mL vial with stirring, the bars were summed I-200 (38.4 mg, 0.10 mmol), dichloromethane (2 mL) and mCPBA (45 mg, 0.26 mmol). The reaction was added 30 minutes and then stirred at room temperature for 5 mL of saturated NaHCO 3 (water). The product was extracted with dichloromethane (2 × 5 mL) and concentrated. Purification by preparative layer chromatography using 35% acetone / hexanes gave 18.3 mg (44%) of I-201 as a colorless semi-solid. 1H NMR (400 MHz, CDCl3) 8.22 (d, J = 1.6 Hz, 1 H), 8.21-8.14 (m, 1 H), 7.76-7.67 (m, 3 H), 7.55 (t, J = 8.1 Hz, 1 H), 7.23-7.15 (m, 3 H), 7.01 (d, J = 2.3 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 4.30 (s, 2 H), 3.84 ( s, 3 H) ppm. LC / MS = 100.0%, 401.0 (APCI-)

Synthesis of 5- (4-fluoro-benzenesulfinylmethyl) -2-methoxy-3'-nitro-biphenyl (P-192). To a 20 mL vial with agitation, the stick was added I-200 (35.5 mg, 0.096 mmol), Glacial AcOH (0.5 mL) and H2O2 (1.1 mL, 0.096 mmol, AcOH 0.088 M). Solution). The reaction was stirred at room temperature for 1 hour and then 10 mL of saturated NaHCO 3 (water) and 1 mL of 1N NaOH was added until pH = 10. The product was extracted with dichloromethane (3 × 5 mL) and concentrated. Purification by preparative layer chromatography using 35% acetone / hexanes gave 21.0 mg (57%) of P-192 as a colorless semi-solid. 1H NMR (400 MHz, CDCl3) 8.24 (t, J = 1.8 Hz, 1 H), 8.17 (dd, J = 1.3, 8.3 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 1 H), 7.45-7.36 (m, 2 H), 7.17 (t, J = 8.5 Hz, 2 H), 7.07 (dd, J = 2.1, 8.5 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.85 (d, J = 2.3 Hz, 1 H), 4.03 (d, J = 2.7 Hz, 2 H), 3.83 (s, 3 H) ppm. LC / MS = 100.0%, 386.0 (APCI +).
Example 222. Preparation for P-195

Synthesis of 1- (3-bromo-4methoxybenzyl) -6-oxo-1,6-dihydro-pyridine-3-carbonitrile (I-202). To a 100 mL round bottomed flask with stirring, a stick was added I-42 (2.59 g, 9.84 mmol), 6-hydroxy-nicotinonitile (985 mg, 8.20 mmol), K2CO3 (2.49 g, 18.0 mmol) and DME (30 mL). The reaction was stirred at 80 ° C. for 20 hours, then cooled to room temperature and passed through a filter. The resulting light pink solid was triturated with 40 mL ether to obtain 529 mg (20%) of I-202 as a white solid and the filtrate was concentrated.

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -6-oxo-1,6-dihydro-pyridine-3-carbonitrile (P-195). In a 50 mL round bottom flask with agitation, the sticks added I-202 (510 mg, 1.60 mmol), 3 nitrophenyl bromic acid (0.40 g, 2.40 mmol), tri-phenyl phosphine (84 mg, 0.20 mmol). 32 mmol), K2CO3 (0.66 g, 4.79 mmol), DME (10 mL), H2O (1 mL), EtOH (1 mL) and the cessation was degassed with N2 for 5 min. The reaction was stirred at 80 ° C. for 18 hours and to this was added palladium (II) acetate (36 mg, 0.16 mmol). The product was extracted with ethyl acetate (3 × 20 mL) and 50 mL of H 2 O was added and the reaction was cooled to rt. The complex organic fertilizer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with ether (2 × 25 mL) to yield 391 mg (68%) of P-195 as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.84 (d, J = 2.1 Hz, 1 H), 8.30 (s, 1 H), 8.21 (d, J = 8.2 Hz, 1 H), 7.94 (d, J = 7.6 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.67 (dd, J = 2.4, 9.5 Hz, 1 H), 7.52 (d, J = 1.9 Hz, 1 H), 7.47 ( dd, J = 1.9, 8.5 Hz, 1 H), 7.16 (d, J = 8.6 Hz, 1 H), 6.51 (d, J = 9.5 Hz, 1 H), 5.09 (s, 2 H), 3.80 (s , 3 H) ppm. LC / MS = 93.4%, 362.6 (ESI +).
Example 223. Preparation for P-196

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -2-oxo-1,2-dihydro-pyridine-4-carbonitrile (P-196). To a 100 mL round bottom flask with stirring, a stick was added I-70 (2.76 g, 8.55 mmol), 2-hydroxy-isonicotinitol (934 mg, 7.78 mmol), K2CO3 (2.36 g, 17.11 mmol). ) And DME (30 mL). The stop was stirred at 80 ° C. and 18 days at 2 days rt. The reaction was passed through a filter, filtered water was concentrated, and the resulting solid was triturated with ether to give 2.12 g (75%) of P-196 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8.29 (s, 1 H), 8.20 (dd, J = 1.3, 8.3 Hz, 1 H), 8.12 (d, J = 7.1 Hz, 1 H), 7.93 (d, J = 7.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.43 (dd, J = 1.9, 8.5 Hz, 1 H), 7.16 (d, J = 8.6 Hz, 1 H), 7.04 (d, J = 1.3 Hz, 1 H), 6.56 (dd, J = 1.7, 7.0 Hz, 1 H), 5.12 (s, 2 H), 3.79 (s, 3 H) ppm. LC / MS = 96.1%, 361.0 (APCI-).
Example 224. Preparation for P-207

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -2-oxo-1,2-dihydro-pyridine-4-carboxylic acid amide (P-207). To a 20 mL vial with stirring, the bars were summed P-196 (132 mg, 0.37 mmol) and concentrated HCl (2 mL). The product was extracted with ethyl acetate (3 × 5 mL) and the reaction was stirred at rt for 18 h (basified with 4N aqueous NaOH). 5 mL of hexane was added and the complex organic fertilizer was concentrated in their first amount of half. The resulting solid was passed through a filter and washed with hexane and triturated with ether to yield 29.8 mg (22%) of P-207 as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.28 (s, 1 H), 8.20 (dd, J = 1.4, 8.3 Hz, 1 H), 8.05 (br. S., 1 H), 7.93 (t, J = 7.4 Hz, 2 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.61 (br s, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.42 (dd, J = 2.1, 8.5 Hz, 1 H), 7.15 (d, J = 8.5 Hz, 1 H), 6.84 (d, J = 1.5 Hz, 1 H), 6.54 (dd, J = 1.8, 7.0 Hz, 1 H), 5.10 ( s, 2 H), 3.79 (s, 3 H) ppm. MS: 380.1 (APCI +).
Example 225. Preparation for P-208

Integration of 1- (3-bromo-4methoxybenzyl) -5-nitro-1H-pyridine-2-1 (I-135). To a flask reached to the 100 mL round bottom with stirring, a stick was added I-42 (3.0 g, 11.41 mmol), 5-nitro-pyridine-2-ol (1.60 g, 11.41 mmol), K2CO3 (3.47 g, 25.10 mmol) and 30 mL DME. The reaction was stirred at 80 ° C. for 18 hours, then cooled to rt and passed through a filter. The resulting solid was triturated with 50 mL of ether to give 3.01 g (78%) of I-135 as a yellow solid and the filtrate was concentrated.

Integration of 5-amino-1- (3-bromo-4methoxybenzyl) -1H-pyridine-2-1 (I-203). To a 250 mL round bottom flask with stirring, the bars were summed I-135 (1.93 g, 5.69 mmol), 75 mL MeOH and 400 mg 10% Pd / C. The stop was stirred for 1 hour under H2 air and the celite was filtered and concentrated. The reaction was washed with dichloromethane (3 × 20 mL) and to the remainder 30 mL of 1N HCl was added. The watery portion was basified with 1N NaOH until pH = 10. It was then extracted with dichloromethane (3 × 15 mL). The organic fertilizer was concentrated with Na2SO4 to give 825 mg of I-203 as a light green solid that was dried and used without further purification.

Integration of 5-amino-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-pyridine-2-1 (I-204). To a 100 mL round bottom flask with agitation, the sticks added I-203 (802 mg, 2.59 mmol), 3 nitrophenyl bromic acid (433 mg, 2.59 mmol), tri-phenyl phosphine (136 mg, 0.52 mmol) , K2CO3 (1.07 g, 7.77 mmol), DME (15 mL), H2O (1.5 mL), EtOH (1.5 mL) and the cessation was degassed with N2 for 10 min. The reaction was stirred at 80 ° C. for 18 hours and to this was added palladium (II) acetate (58 mg, 0.26 mmol). After cooling to rt, the product was extracted with ethyl acetate (3 × 15 mL) and 5 mL of aqueous 1N NaOH was added. The combined organic fertilizer was filtered through celite and concentrated. The remainder was purified by flash column chromatography using 5% MeOH / dichloromethane to give 185 mg (21%) of I-204 as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8.28 (s, 1 H), 8.20 (dd, J = 1.3, 8.2 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.40 (d, J = 1.9 Hz, 1 H), 7.35 (dd, J = 1.9, 8.5 Hz, 1 H), 7.15 (d, J = 8.6 Hz, 1 H), 7.05 (dd, J = 2.9, 9.5 Hz, 1 H), 6.91 (d, J = 2.8 Hz, 1 H), 6.29 (d, J = 9.5 Hz, 1 H), 4.99 (s, 2 H), 4.29 (br. s., 2 H), 3.79 (s, 3 H) ppm. LC / MS = 100.0%, 352.1 (APCI +).

Synthesis of [1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -6-oxo-1,6-dihydro-pyridin-3-yl] -urea (P-208). To a 20 mL vial with stirring, the bars were summed I-204 (36.5 mg, 0.10 mmol), NaOCN (13.5 mg, 0.21 mmol), H 2 O (2 mL) and 1 mL of glacial acetic acid. The reaction was stirred as 40 ° C. for 2 hours and 10 mL of H 2 O was added and r. t. Cooled to. The suspension was filtered to obtain 19.8 mg (48%) of P-208 as a gray solid. 1H NMR (400 MHz, DMSO-d6) 8.29 (s, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.03 (s, 1 H), 7.92 (d, J = 7.6 Hz, 1 H ), 7.88 (d, J = 2.3 Hz, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 7.44 (s, 1 H), 7.40-7.35 (m, 1 H), 7.31 (dd, J = 2.5, 9.5 Hz, 1 H), 7.15 (d, J = 8.5 Hz, 1 H), 6.37 (d, J = 9.7 Hz, 1 H), 5.79 (s, 2 H), 5.07 (s, 2 H), 3.79 (s, 3 H) ppm. LC / MS = 90.5%, 395.1 (APCI +).
Example 226. Preparation for P-212

Synthesis of 1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid amide (P-212). In an 8 mL vial with stirring, the bars were summed P-195 (44 mg, 0.12 mmol) and concentrated HCl (2 mL). The reaction was carried out at 24 hours r.p. t. Was stirred at. The solution was basified with aqueous 4N NaOH and 5 mL of ethyl acetate was added to the reaction. The ethyl acetate layer was removed and concentrated. The resulting solid was triturated with ether to obtain 15.6 mg (34%) of P-212 as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.52 (d, J = 2.4 Hz, 1 H), 8.32-8.26 (m, 1 H), 8.20 (dd, J = 1.3, 8.3 Hz, 1 H), 7.93 ( d, J = 7.8 Hz, 1 H), 7.85 (dd, J = 2.5, 9.5 Hz, 1 H), 7.76 (br. s., 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.44 (dd, J = 2.0, 8.6 Hz, 1 H), 7.28 (br. S., 1 H), 7.16 (d, J = 8.6 Hz, 1 H ), 6.42 (d, J = 9.5 Hz, 1 H), 5.14 (s, 2 H), 3.79 (s, 3 H) ppm. LC / MS = 96.4%, 380.1 (APCI +).
Example 227. Preparation for P-213

Integration of 4-aminomethyl-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-pyridine-2-1 (P-213). In a 20 mL vial with stirring, a bar with P-196 (144 mg, 0.40 mmol) and 3 mL of THF was added BH3-THF (2.0 mL, 2.0 mmol, 1.0 M solution of THF). It was. The solution was stirred at 60 ° C for 4 hours and a solution of 2.0M HCl in ether was slowly added and cooled to 0 ° C. Then 5 mL of methanol followed. The solution was stirred at room temperature for 16 hours and concentrated. It was washed with dichloromethane, then basified with aqueous 4N NaOH, extracted with dichloromethane, concentrated and to the remainder aqueous 1N HCl was added. The remainder yields 7.2 mg (5%) of P-213 as a tan solid, 10-17% methanol / dichloromethane purified by flash column chromatography. 1H NMR (400 MHz, DMSO-d6) 8.27 (s, 1 H), 8.23-8.17 (m, 1 H), 7.92 (d, J = 7.6 Hz, 1 H), 7.79-7.67 (m, 2 H) , 7.45 (d, J = 1.9 Hz, 1 H), 7.39 (dd, J = 1.8, 8.4 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 6.35 (s, 1 H), 6.19 (dd, J = 1.5, 7.0 Hz, 1 H), 5.05 (s, 2 H), 3.78 (s, 2 H), 3.51 (s, 2 H) ppm. LC / MS = 98.4%, 366.1 (APCI + ).
Example 228. Preparation for P-215

[1- (6-Methoxy-3′-nitro-biphenyl-3-ylmethyl) -2-oxo-1,2-dihydro-pyridin-4-yl] -carbamic acid tert-butyl ester (I-206) Synthesis. In a 25 mL circle, the bottom flask was placed I-289 (97.5 mg, 0.26 mmol), diphenylphosphoryl azide (71 mg, 0.26 mmol), triethylamine (26 mg, 0.26 mmol) and t-BuOH ( 5 mL). The solution was refluxed for 16 hours and cooled to room temperature. The reaction was diluted with ethyl acetate (washed with saturated aqueous NaHCO3 and brine). After concentration of organic fertilizer, the remainder was purified by flash column chromatography eluting with acetone / hexanes by 40% to yield 61 mg (53%) of I-206 as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 9.60 (s, 1 H), 8.27 (s, 1 H), 8.20 (dd, J = 1.6, 8.2 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.78-7.65 (m, 2 H), 7.40 (d, J = 2.0 Hz, 1 H), 7.36 (dd, J = 2.0, 8.5 Hz, 1 H), 7.14 (d, J = 8.5 Hz , 1 H), 6.53 (d, J = 2.1 Hz, 1 H), 6.34 (dd, J = 2.3, 7.5 Hz, 1 H), 4.99 (s, 2 H), 3.78 (s, 3 H), 1.45 (s, 9 H) ppm. LC / MS = 93.0%, 452.1 (APCI +).

4-Amino-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-pyridine-2-1 (P-215) synthesis fo. In a 20 mL vial with stirring, the bars were summed I-206 (50 mg, 0.11 mmol), dichloromethane (2 mL) and 1 mL TFA. The reaction was stirred at room temperature for 4 hours and concentrated. The remainder was diluted with aqueous 1N HCl and washed with dichloromethane. The aqueous portion was basified with aqueous 4N NaOH and withdrawn with dichloromethane to concentrate to yield 22 mg (56%) of P-215 as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.27 (s, 1 H), 8.23-8.16 (m, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.41 (d, J = 7.4 Hz, 1 H), 7.38-7.30 (m, 2 H), 7.13 (d, J = 8.5 Hz, 1 H), 5.99 (s, 2 H), 5.66 ( dd, J = 2.3, 7.4 Hz, 1 H), 5.24 (d, J = 2.3 Hz, 1 H), 4.90 (s, 2 H), 3.78 (s, 3 H) ppm. LC / MS = 97.8%, 352.1 (APCI +).
Example 229. Preparation for P-209

Integration of 1- (3-bromo-4methoxybenzyl) -1H-pyridine-2-1 (I-205). To a 100 mL round bottom flask with stirring, a stick is added I-45 (2.56 g, 9.73 mmol), 2-hydroxypyridine (926 mg, 9.73 mmol), K2CO3 (2.96 g, 21.41 mmol). And 30 mL DME. The stop was stirred at 80 ° C for 18 hours and it was r. t. Was filtered and concentrated. The solid was triturated with ether to yield 2.20 g (77%) of I-205 as a white solid.

  Integration of 1- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -1H-pyridine-2-1 (P-209). In a 40 mL vial with agitation, the sticks added I-205 (250 mg, 0.81 mmol), 3 chlorophenyl bromic acid (126 mg, 0.81 mmol), triphenyl phosphine (42 mg, 0.16 mmol), K2CO3 (335 mg). 2.43 mmol), DME (10 mL), H 2 O (1 mL), EtOH (1 mL) and the cessation was degassed with N 2 for 10 minutes. The reaction was stirred at 80 ° C. for 18 hours and to this was added palladium (II) acetate (18 mg, 0.08 mmol). r. t. After cooling to, the product was extracted with ethyl acetate (3 × 15 mL) and 10 mL of H 2 O was added. Compound organic fertilizer was concentrated. The remainder was purified by flash column chromatography using 20%-35% acetone / hexanes to give 241 mg (91%) of P-209 as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.84 (dd, J = 1.3, 6.6 Hz, 1 H), 7.66-7.52 (m, 1 H), 7.51-7.31 (m, 6 H), 7.10 (d, J = 9.1 Hz, 1 H), 6.39 (d, J = 9.1 Hz, 1 H), 6.22 (t, J = 6.5 Hz, 1 H), 5.06 (s, 2 H), 3.76 (s, 3 H) ppm LC / MS = 97.6%, 326.2 (APCI +).

実施例２３０。Ｐ―１９３の準備 << Reaction Process Formula 53 >>

Example 230. Preparation for P-193

  Integration of 5-bromo-2-methoxy-3'-nitro-biphenyl (I-207). Of 5-bromo-2-methoxyphenyl bromate (500 mg, 2.17 mmol), 3-iodo-nitrobenzene (647 mg, 2.60 mmol) and potassium carbonate (599 mg, 4.33 mmol) in methanol (10 mL) and water (2 mL). The suspension was degassed for 30 minutes under a stream of nitrogen followed by the addition of palladium (II) acetate (9.72 mg, 0.0433 mmol). The reaction was stirred at room temperature for 4 h. Methanol was removed under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added, and the biphasic suspension was filtered. The organic was washed with water (50 mL) and the layers were separated. The aqueous wash was combined and extracted with ethyl acetate (2 × 50 mL) and the organic extracts combined. The organic solution was washed with water (3 × 50 mL). Saturated aqueous sodium bicarbonate (50 mL) (brine) is then dried over sodium sulfate and filtered. The solvent is then removed under vacuum to give a natural brown rubber. The product was purified by flash silica gel column chromatography (5% ethyl acetate in hexane) and crystallized by dissolving in diethyl ether (20 mL) and hexane (50 mL), 1/2 of the solvent under vacuum. Filtered and washed with hexane (2 × 10 mL) to give I-207 (417.8 mg, 63% yield). 1H NMR (400 MHz, CDCl3) 8.38 (t, J = 1.8 Hz, 1H), 8.21-8.19 (m, 1H), 7.81 (dt, J = 7.5 Hz, 1.3 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.50-7.45 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H) ppm.

Synthesis of 5- (4-fluoro-phenoxy) -2-methoxy-3′-nitro biphenyl (P-193). Discontinuation of I-207 (200 mg, 0.649 mmol) was followed by 1,4-dioxane (2 mL) of 4-fluorophenol (109 mg, 0.974 mmol), cesium carbonate (423 mg, 1.30 mmol) and N, N Dimethyl glycine (20.1 mg, 0.195 mmol) was added copper (I) iodide (12.4 mg, 0.0649 mmol) under argon and the reaction was heated to 105 ° C. The reaction was left to stir overnight at 105 ° C. under argon. The blue solution was diluted with ethyl acetate (50 mL). Brine (50 mL) (dried over sodium sulfate) was then filtered, washed with water (2 × 50 mL), and the solvent was removed under vacuum. The remainder is purified by flash silica gel column chromatography (10% ethyl acetate in hexane) to give P-193 (61.4 mg, 28% yield) as a white powder in diethyl ether ( Crystallized from 5 mL). 1 H NMR (400 MHz, CDCl3) 8.40 (t, J = 2.0 Hz, 1H), 8.19-8.16 (m, 1H), 7.82 (dt, J = 7.6 Hz, 1.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.04-6.95 (m, 7H), 3.83 (s, 3H) ppm. LCMS = 98.3% purity. MS (APCI-) = 339.2 (M).
Example 231. Preparation for P-230

  Integration of 5-bromo-3'-chloro-2-methoxy-biphenyl (I-208). I-208 is 5-bromo-2 methoxyphenyl bromic acid (2.00 g, 8.66 mmol) and 3-chloroiodo benzene (2.48 g, 10 using the same conditions for I-207. .4 mmol). The reaction time was extended to 16 h. Methanol was removed under vacuum and the residue was dissolved in ethyl acetate (100 mL). It was then washed with water (100 mL) and a watery wash was extracted with ethyl acetate (100 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate (2 × 200 mL). Water (2 × 200 mL) and brine (150 mL) (dried over sodium sulfate) are then filtered. The solvent is then removed under vacuum to give I-208 (2.56 g, 99% yields). 1H NMR (400 MHz, CDCl3) 7.49-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.36-7.31 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 3.80 (s , 3H) ppm.

Synthesis of 3'-chloro-2-fluoro-3- (4-fluoro-phenoxy) -6-methoxy-biphenyl (P-230). Discontinuation of I-208 (200 mg, 0.672 mmol) was followed by 1,4-dioxane (2 mL) of 4-fluorophenol (113 mg, 1.01 mmol), cesium carbonate (438 mg, 1.34 mmol) and N, N Dimethyl glycine hydrochloride (28.2 mg, 0.202 mmol) was (I) iodide (12.8 mg, 0.0672 mmol) of added copper under argon. The reaction was heated to 105 ° C. under argon and stirred at 105 ° C. overnight. The reaction was diluted with ethyl acetate (20 mL). It was then washed with water (20 mL) and a watery wash was extracted into ethyl acetate (20 mL). The combined organic extract was washed with 1N aqueous sodium hydroxide (20 mL), 1N aqueous hydrochloric acid (20 mL), water (2 × 20 mL), brine (20 mL). The solvent was then removed under vacuum and dried over sodium sulfate and passed through a filter. The product is purified by preliminary TLC eluting acetone with 3 developments by 5% to give P-230 (140.6 mg, 64% yield) as a yellow gum solid It was done. 1 H NMR (400 MHz, CDCl ₃ ) 7.51-7.51 (m, 1H), 7.38-7.30 (m, 3H), 7.023-6.93 (m, 7H), 3.81 (s, 3H) ppm. MS (ESI +) = 389.6 (M + 61), 328.2 (M), 279.5 (M-49).
Example 232; Preparation for P-236

Synthesis of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -6-oxo-1,6-dihydro-pyridine-2 carboxylic acid methyl ester (I-290). To a 20 mL vial with agitation, the stick was added I-70 (268 mg, 0.83 mmol), 6-hydroxy-pyridine-2 carboxylic acid methyl ester (98 mg, 0.64 mmol), K 2 CO 3 (195 mg, 1. 41 mmol) and DME (4 mL). The reaction was stirred at 80 ° C. for 4 hours, then cooled to room temperature and passed through a filter. The filtered water was concentrated and purified by flash column chromatography using 50% acetone / hexane to yield 98 mg (39%) of I-290 as a 15-tan solid.

Synthesis of 1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -6-oxo-1,6-dihydro-pyridine-2 carboxylic acid (I-209). To a 20 mL vial with stirring, the bars were summed I-290 (92 mg, 0.23 mmol), 1N aqueous NaOH (2 mL) and methanol (2 mL). The reaction was stirred at 60 ° C. for 18 hours, then cooled to room temperature and washed with dichloromethane. The watery portion was acidified with 6N aqueous HCl and extracted with ethyl acetate. The organic fertilizer was concentrated to dry over Na2SO4 to give I-209 (61 mg, 69%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.25 (s, 1 H), 8.19 (dd, J = 1.4, 8.3 Hz, 1 H), 7.88 (d, J = 7.8 Hz, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 7.48 (dd, J = 6.8, 9.1 Hz, 1 H), 7.24 (d, J = 1.7 Hz, 1 H), 7.21-7.15 (m, 1 H), 7.14-7.08 (m, 1 H), 6.71 (d, J = 6.6 Hz, 1 H), 6.63 (d, J = 9.0 Hz, 1 H), 5.50 (s, 2 H), 3.77 (s, 3 H) ppm. LC / MS = 99.9%, 381.0 (APCI +)

[1- (6-Methoxy-3′-nitro-biphenyl-3-ylmethyl) -6-oxo-1,6-dihydro-pyridin-2-yl] -carbamic acid tert-butyl ester (I-210) Synthesis. In a 20 mL vial, I-209 (48 mg, 0.13 mmol) (diphenylphosphoryl azide (35 mg, 0.13 mmol), triethylamine (13 mg, 0.13 mmol) and t-BuOH (4 mL) were placed. The mixture was stirred at 80 ° C. for 24 hours and cooled to room temperature, the solvent was evaporated and the residue was diluted with saturated aqueous NaHCO 3 and extracted with ethyl acetate. -Concentrated and purified by flash column chromatography eluting with acetone / dichloromethane by 15% to give 210 (43 mg, 75%) 1H NMR (400 MHz, DMSO-d6) 9.42 (br s, 1 H), 8.27 (s, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 7.40 (dd, J = 7.4 , 9.0 Hz, 1 H), 7.27-7.18 (m, 2 H), 7.12 (d, J = 8.3 Hz, 1 H), 6.31 (d, J = 9.0 Hz, 1 H), 6.14 (d, J = 7.0 Hz, 1 H), 5.28 (br s, 2 H), 3.76 (s, 3 H), 1.27 (s, 9 H) ppm. LC / MS = 94.2%, 452.1 (APCI +).

  Integration of 6-amino-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -1H-pyridine-2-1 (P-236). In a 20 mL vial with stirring, the bars were summed I-210 (22 mg, 0.049 mmol), dichloromethane (2 mL) and TFA (2 mL). After 6 hours at room temperature, the solution was concentrated. The remainder was purified by flash column chromatography using 5% methanol / dichloromethane to give 12.5 mg (74%) of P-236 as a 2-brown solid. 1H NMR (400 MHz, DMSO-d6) 8.27 (s, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 7.76-7.69 (m, 1 H), 7.39 (d, J = 1.7 Hz, 1 H), 7.25 (dd, J = 1.7, 8.5 Hz, 1 H), 7.15-7.08 (m, 2 H), 6.44 (s, 1 H), 5.76 (s, 2 H), 5.53 (d, J = 8.7 Hz, 1 H), 5.40 (d, J = 7.6 Hz, 1 H), 5.19 (br s, 1 H), 3.77 (s, 3 H) ppm. LC / MS = 100.0%, 352.1 (APCI +).

実施例２３３。Ｐ―２１８の準備 << Reaction process formula 54 >>

Example 233. Preparation for P-218

  Integration of 3'-chloro-2-methoxy-5-methyl-biphenyl (I-211). 2-Methoxy-5-methyl bromic acid (4.0 g, 24.1 mmol) was added to 1-chloro-3-iodo-benzene (6.32 g, 26.51 mmol), K2CO3 (8.33 g, 60.25 mmol) and palladium. (II) Acetate (0.27 g, 1.2 mmol) was added methanol (150 mL) and H 2 O (30 mL). Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at room temperature under argon for 20 h. The reaction mixture was concentrated and H2O and dichloromethane (60 mL each) were added. The aqueous layer was extracted with dichloromethane (2 × 60 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 1: 1 dichloromethane-hexane and then dichloromethane to yield 5.6 g (98%) of I-211 as mucus.

  Integration of 5-bromomethyl-3'-chloro-2methoxy biphenyl (I-154). To N-211 (1.68 g, 9.45 mmol) in I-211 (2.0 g, 8.59 mmol) and CCl4 (30 mL) was added benzoyl peroxide (0.1 g, 0.43 mmol). The reaction was stirred at 85 ° C. under N 2 for 5 h. The reaction was cooled to room temperature and concentrated. The rest is dissolved in a mixture of 5% ethyl acetate in hexane (20 mL) to yield 2.81 g (98%) of I-154 as a light yellow mucus to yield 5% acetic acid in hexane. It was purified by silica gel column chromatography using ethyl.

Integration of 1- (3'-chloro-6-methoxy-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-218). To a solution of 2-pyrrolidone (0.2 g, 2.41 mmol) in DMF (1 mL) was chilled (0 oC) of DMF (3 mL) NaH (0.1 g, 2.41 mmol) under Ar. Added to the slurry. The reaction mixture was slowly warmed to room temperature (stirred for 45 minutes and then cooled to 0 ° C.). To this, DMF (2 mL) of I-154 (0.5 g, 1.6 mmol) was added over 5 minutes. The reaction mixture was slowly warmed to room temperature, stirred for 20 h, poured into crushed ice water and extracted with ethyl acetate (2 × 60 mL). The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was dissolved in dichloromethane (20 mL) and purified by silica gel column chromatography using 5% ethyl acetate in hexane to yield 0.22 g (43%) of P-218 as a mucus. . 1H NMR (CDCl3, 400 MHz): 7.49-7.51 (m, 1 H), 7.27-7.4 (m, 4 H), 7.23 (dd, J = 8.4, 2.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 2 H), 4.43 (s, 2 H), 3.81 (s, 3 H), 3.28 (t, J = 7.2 Hz, 2 H), 2.44 (t, J = 8.0 Hz, 2 H), 1.95-2.05 (m, 2 H) ppm; MS (APCI +): 316.1 (M + 1), LC-MS: 100%.
Example 234. Preparation for P-211

Synthesis of N- [1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -6-oxo-1,6-dihydro-pyridin-3-yl] -acetamide (P-211). In a 20 mL vial with stirring, the bars were summed I-204 (113 mg, 0.32 mmol), dichloromethane (2 mL), Ac 2 O (46 uL, 0.48 mmol) and TEA (90 uL, 0.64 mmol). The product was extracted with dichloromethane, 1N aqueous HCl was added, the reaction was stirred for 4 hours at room temperature, and the organic fertilizer was concentrated. The remainder was purified by flash column chromatography using 25%-35% acetone / dichloromethane yielding 12.5 mg (10%) of P-211 as a tan solid. 1H NMR (400 MHz, DMSO-d6) 9.66 (s, 1 H), 8.28 (s, 1 H), 8.23-8.12 (m, 2 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.43 (d, J = 1.9 Hz, 1 H), 7.41-7.32 (m, 2 H), 7.16 (d, J = 8.5 Hz, 1 H), 6.42 ( d, J = 9.5 Hz, 1 H), 5.09 (s, 2 H), 3.79 (s, 3 H), 1.95 (s, 3 H) ppm. LC / MS = 95.5%.
Example 235. Preparation for P-223

Integration of 1- (3 ′, 4-difluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-223). Up to I-181 (0.15 g, 0.53 mmol), 3,4-difluorophenyl bromic acid (0.13 g, 0.79 mmol), triphenylphosphine (0.07 g, 0.26 mmol), K2CO3 (0 0.03 g, 0.21 mmol) and palladium (II) acetate (0.014 g, 0.06 mmol) were added dioxane (6 mL) and EtOH—H 2 O (1: 1, 3 mL). Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 85 ° C. under argon for 20 h. The reaction was cooled to room temperature and concentrated. The remainder was purified by silica gel column chromatography using 30-50% ethyl acetate in hexane to yield 0.15 g (89%) of P-223 as a light brown mucus. 1H NMR (CDCl3, 400 MHz): 7.33-7.38 (m 1 H), 7.14-7.24 (m, 4 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.43 (s, 2 H), 3.81 (s, 3 H), 3.29 (t, J = 7.2 Hz, 2 H), 2.44 (t, J = 8.4 Hz, 2 H), 1.95-2.05 (m, 2 H) ppm; MS (APCI +): 318.1 (M + 1), LC-MS: 100%.
Example 236. Preparation for P-240

Synthesis of 4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -benzamide (P-240). Discontinuation of I-154 (300 mg, 0.963 mmol), 4 aminocarboxyphenyl bromic acid (238 mg, 1.44 mmol), triphenyl phosphine (50.4 mg, 0.193 mmol) and water (1 mL) is 30 minutes The gas was removed by a stream of nitrogen. The reaction was heated to 90 ° C. under nitrogen with stirring overnight and palladium (II) acetate (22 mg, 0.0963 mmol) under nitrogen was added to the reaction. The product crystallized in hexane (50 mL) and the solvent was removed under vacuum. The product was purified by flash silica gel column chromatography (5% methanol in dichloromethane) to give P-240 (112 mg, 33% yield) as a gray solid. 1 H NMR (400 MHz, CDCl3) 7.75-7.73 (m, 2H), 7.49 (t, J = 1.6 Hz, 1H), 7.38-7.27 (m, 5H), 7.14-7.10 (m, 2H), 6.91 ( d, J = 8.0 Hz, 1H), 6.0 (br s, 1H), 5.75 (br s, 1H), 4.01 (s, 2H), 3.79 (s, 3H) ppm. LCMS = 92.3% purity. MS (APCI + ) = 352.1 (M + 1).
Example 237. Preparation for P-245

Integration of 1- (6-methoxy-3'-methylsulfanyl-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-245). Up to I-181 (0.15 g, 0.53 mmol) 3-methylsulfanylbenzenebromate (0.11 g, 0.639 mmol), triphenylphosphine (0.07 g, 0.26 mmol), K2CO3 (0. 03 g, 0.21 mmol) and palladium (II) acetate (0.014 g, 0.06 mmol) were added dioxane (6 mL) and EtOH—H 2 O (1: 1, 3 mL). Argon gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 85 ° C. under argon for 20 h. The reaction was cooled to room temperature and concentrated. The rest is silica gel column chromatography using 15% acetone in dichloromethane and then silica gel column using 5% methanol in dichloromethane to produce 0.013 g (8%) of P-245 as mucus. Chromatography then purifies by TLC under reverse phase (C18) using 40% acetonitrile in water. 1H NMR (CDCl3, 400 MHz): 7.39-7.45 (m 1 H), 7.2-7.34 (m, 4 H), 7.17 (d, J = 6.4 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.43 (s, 2 H), 3.8 (s, 3 H), 3.28 (t, J = 7.2 Hz, 2 H), 2.43 (t, J = 8.0 Hz, 2 H), 1.95-2.05 ( m, 2 H) ppm; MS (APCI +): 328.1 (M + 1), LC-MS: 93.2%.
Example 238. Preparation for P-248

  Integration of (S) -4- (tert-butyl-dimethyl-silanyloxy) -pyrrolidine-2-1 (I-212). A flask reached to the round bottom with stirring that was a stick to 100 mL was added (S) -4-hydroxy-pyrrolidine-2-1 (3.04 g, 30.07 mmol), TBSCl (4.99 g 33.07 mmol), imidazole (3.07 g, 45.10 mmol) and DMF (30 mL). After stirring for 18 hours at room temperature, the reaction was added to 100 mL of water and stirred for 30 minutes. The solid was filtered and washed with water. After drying the vacuum desiccator solid for 3 days, 5.97 g (92%) of I-212 was obtained.

Synthesis (S) -4- (tert-butyl-dimethyl-silanyloxy) -1- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (I-213). The flask was summed to I-212 (2.57 g, 11.95 mmol), THF, 150 mL into a flask that had been cooled to 0 ° C. and reached a 250 mL round bottom with stirring. The stop was stirred for 30 minutes at room temperature and NaH (0.56 g, 14.12 mmol) was added. To this, the product was extracted with ethyl acetate and the reaction was stirred at room temperature for 20 hours with 50 mL of water added and I-70 (3.50 g, 10.86 mmol) was added. The organic fertilizer was concentrated to obtain 8.9 g of I-213. And it was used as given in the next reaction.

Integration of (S) -4-hydroxy-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-248). Synthesis I-213 (8.9 g, 19.5 mmol) from the above step was added to a 100 mL round bottomed flask. This was followed by 10 mL THF and TBAF (29 mL, 29 mmol, 1.0 M THF). The solution was stirred at room temperature for 30 minutes with the addition of NH4Cl and brine. The product was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated. With 25% 5% methanol / dichloromethane emitting column chromatography purification, 50% acetone / dichloromethane followed by flash column chromatography, which was drawn off to 143 mg (4%, 2 steps) of P-248 Elute. 1H NMR (400 MHz, CDCl3) 8.40 (d, J = 1.6 Hz, 1 H), 8.21-8.14 (m, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.31-7.20 (m, 2 H), 6.98 (d, J = 8.5 Hz, 1 H), 4.63-4.48 (m, 2 H), 4.46-4.34 (m, 1 H), 3.83 (s, 3 H), 3.56 (dd, J = 5.6, 10.8 Hz, 1 H), 3.24 (dd, J = 1.6, 10.9 Hz, 1 H), 2.76 (dd, J = 6.5, 17.4 Hz, 1 H), 2.45 (dd, J = 2.1, 17.3 Hz, 1 H), 1.83 (d, J = 4.0 Hz, 1 H) ppm. LC / MS = 97.4%, 343.1 (APCI +).
Example 239. Preparation for P-253

Synthesis of carbamic acid (S) -1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -5-oxo-pyrrolidin-3-yl ester (P-253). In a 20 mL vial with agitation, the bar was added chlorosulfonyl group isocyanate (42 mg, 0.30 mmol), 1 mL dichloromethane, and 2 mL dichloromethane P-248 (51.3 mg, 0.15 mmol). It was. The reaction was stirred for 30 minutes at room temperature and for 18 hours at room temperature with 2 mL of water added. The watery one was extracted with dichloromethane and the layers were separated. The composite organic fertilizer was concentrated and then purified by a layer TLC of preparation with 50% acetone / dichloromethane to obtain P-253 (12.4 mg, 21%) as an off-white semi-solid. . 1H NMR (400 MHz, DMSO-d6) 8.30 (s, 1 H), 8.20 (dd, J = 2.1, 8.6 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.33-7.26 (m, 2 H), 7.16 (d, J = 9.0 Hz, 1 H), 6.59 (br. S., 2 H), 5.04 (t, J = 5.8 Hz, 1 H), 4.49-4.30 (m, 2 H), 3.80 (s, 3 H), 3.46-3.38 (m, 1 H), 3.21 (d, J = 11.4 Hz, 1 H), 2.78 (dd , J = 6.9, 17.5 Hz, 1 H), 2.23 (d, J = 18.1 Hz, 1 H) ppm. LC / MS = 100.0%, 386.1 (APCI +).
Example 240. Preparation for P-506

Integration of (R) -4-hydroxy-1- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-506). P-506 was prepared in a similar manner as it described above for P-248 except starting with (R) -4-hydroxy-pyrrolidine-2-1. 1H NMR (400 MHz, CDCl3) 8.40 (t, J = 1.9 Hz, 1 H), 8.17 (dd, J = 1.7, 8.2 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.30-7.27 (m, 1 H), 7.22 (d, J = 2.1 Hz, 1 H), 6.97 (d, J = 8.5 Hz, 1 H), 4.61- 4.48 (m, 2 H), 4.41 (d, J = 14.8 Hz, 1 H), 3.85-3.81 (m, 3 H), 3.56 (dd, J = 5.6, 10.9 Hz, 1 H), 3.24 (dd, J = 1.8, 10.8 Hz, 1 H), 2.75 (dd, J = 6.5, 17.3 Hz, 1 H), 2.44 (dd, J = 2.1, 17.4 Hz, 1 H), 2.12 (br s, 1 H) ppm LC / MS = 95.6%, 343.1 (APCI +).
Example 241. Preparation for P-266

Synthesis of 4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -benzene sulphonamide (P-266). P-266 is synthesized from I-154 (300 mg, 0.963 mmol) and 4-aminosulfonylphenyl bromate pinocolate ester (409 mg, 1.44 mmol) using the same conditions for the integration of P-240. It was. The rest was suspended in ethyl acetate (20 mL) and water (20 mL) and the solvent was removed under vacuum. Saturated aqueous sodium bicarbonate (40 mL), water (2 × 40 mL) and brine (40 mL) (dried over sodium sulfate) were filtered, the organic solution was washed with water (40 mL) and the layers were separated. And the solvent was removed under vacuum. The rest is then extracted by preliminary silica gel TLC (2.5% acetone in dichloromethane with 3 developments) to give P-266 (52.2 mg, 14% yield) as a clear rubber. To give purified material by flash silica gel column chromatography (2.5% acetone in dichloromethane). 1H NMR (400 MHz, CDCl3) 7.86-7.83 (m, 2H), 7.49-7.48 (m, 1H), 7.38-7.29 (m, 5H), 7.14-7.09 (m, 2H), 6.92 (d, J = 8.4 Hz, H), 4.71 (s, 2H), 4.03 (s, 2H), 3.80 (s, 3H) ppm. LCMS = 100.0% purity. MS (APCI-) = 386.0 (M-1), 217.0 (M -171)
Example 242. Preparation for I-216

  Synthesis of 3-bromo-2-fluoro-4methoxybenzaldehyde (I-30). A solution of 2-bromo-3-fluoroanisole (5.00 g, 24.4 mmol) in trifluoroacetic acid (25 mL) was heated to 80 ° C. and hexamethylenetetramine in trifluoroacetic acid (25 mL) A solution of (6.83 g, 48.8 mmol) was added dropwise over 1.5 h. After the addition was complete, the reaction was stirred at 80 ° C. for 1 h under nitrogen. Excess trifluoroacetic acid was removed under vacuum and the pH was adjusted to 7.5-8.0 by addition of saturated aqueous potassium carbonate (˜100 mL). The shaped white solid was filtered to give I-30 that was used without additional purification.

  Synthesis of formic acid 3-bromo-2-fluoro-4methoxyphenyl ester (I-215). The reaction was stirred overnight at room temperature and to the solution of dichloromethane (60 mL) of I-30 (4.84 g) was added meta-chloroperbenzoic acid (16.09 g). The reaction was diluted with dichloromethane (200 mL), washed with saturated aqueous sodium thiosulfate (300 mL) and extracted into dichloromethane (2 x 100 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate (3 × 400 mL), water (2 × 400 mL) and brine (400 mL). The solvent was then removed under vacuum to give I-215 (12: 5, 4.05 g) used as it was without additional purification and dried over sodium sulfate and transferred. It was. 1H NMR (400 MHz, CDCl3) d: 8.27 (t, J = 0.8 Hz, 1H), 7.10-7.06 (m, 1H), 6.70 (dd, J = 8.2 Hz, 1.0 Hz, 1H), 3.92 (s, 3H) ppm.

  Synthesis of 3-bromo-2-fluoro-4methoxy phenol (I-216). The brown solution was stirred overnight at room temperature and to the solution of ethyl I-215 (4.05 g), the alcohol (75 mL) was added solid potassium hydroxide pellets (1.71 g). The ethanol was removed under vacuum and the reaction was spoiled to pH 2 using concentrated hydrochloric acid. The material was diluted with water (300 mL) and extracted with dichloromethane (300 mL, 2 × 100 mL). The composite extract was washed with brine (500 mL), dried over sodium sulfate, transferred and the solvent removed under vacuum. The residue was then dissolved in diethyl ether (500 mL) and extracted with 1M aqueous sodium hydroxide (300 mL, 2 × 250 mL). The composite aqueous layer was acidified to pH 2 with concentrated hydrochloric acid and extracted into diethyl ether (2 × 300 mL). The combined diethyl ether extract was washed with water (500 mL) and brine (300 mL). The solvent was then removed under vacuum to give an orange solid and dried over sodium sulfate and transferred. The solid was purified by flash silica gel column chromatography eluting with dichloromethane to give I-216 (1.45 g) as a yellow powder. 1H NMR (400 MHz, CDCl3) 6.96-6.91 (m, 1H), 6.62 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 4.78 (d, J = 3.6 Hz, 1H), 3.86 (s, 3H) ppm.

実施例２４３。Ｐ―２５４の準備 << Reaction process formula 55 >>

Example 243. Preparation for P-254

  Integration of 3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ol (I-217). The solution of toluene (6 mL) of I-216 (390 mg, 1.76 mmol) was degassed by a 10 minute stream of nitrogen. The reaction was heated to 90 ° C overnight and 3-chlorophenyl bromic acid (331 mg, 2.12 mmol), 2M aqueous sodium carbonate (1.76 mL, 3.53 mmol) and the nitrogen flow was 15 minutes For To, this stop was followed by addition tetrakis (triphenylphosphine) palladium (0) (102 mg, 0.0882 mmol) under nitrogen, To this solution was ethanol (1 mL) Was added. The reaction was reacted at 90 degrees C for 24 h and added tetrakis (tri-phenylphosphine) palladium (0) (102 mg, 0.0882 mmol) was added under nitrogen and the reaction was 24 A third portion of tetrakis (tri-phenylphosphine) palladium (0) (102 mg, 0.0882 mmol) was added when heated to 90 ° C. of time. The remaining material was diluted with ethyl acetate (100 mL) and saturated aqueous ammonium chloride (100 mL) and approximately 1/2 of the solvent was removed under vacuum. The organic solution was washed with saturated aqueous sodium bicarbonate (2 × 100 mL), water (100 mL) and brine (50 mL) and separated, and the layer was passed through a filter. The solvent was dried over sodium sulfate (filtered) and the solvent removed under reduced pressure. The product was purified by flash silica gel column chromatography (drawn with 2.5% acetone in dichloromethane) to give I-217 (398 mg, 89% yield). 1H NMR (400 MHz, CDCl3) 7.41 (s, 1H), 7.39-7.28 (m, 3H), 6.97 (t, J = 9.4 Hz, 1H), 6.67 (dd, J = 9.2 Hz, 2.0 Hz, 1H) , 4.79 (s, 1H), 3.72 (s, 3H) ppm.

  Synthesis of 3'-Chloro-2-fluoro-6-methoxy-3- (4-nitro-phenoxy) -biphenyl (I-219). N-methyl pyrrolidone (4 mL) I-217 (200 mg, 0.792 mmol), 4-iodo nitrobenzene (179 mg, 0.720 mmol), cesium carbonate (469 mg, 1.44 mmol) and 2,2,6, A suspension of 6-tetramethylheptane-3,5-dione (37 uL, 0.180 mmol) was stirred under nitrogen. The reaction was heated to 100 ° C. under nitrogen overnight and to this the reaction was chloride (35.6 mg, 0.360 mmol) added copper (I). The reaction was diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic extract was combined and the aqueous wash was extracted with ethyl acetate (20 mL). The organic extract was washed with water (2 × 20 mL), 1N aqueous sodium hydroxide (2 × 20 mL), 1N aqueous hydrochloric acid (2 × 20 mL), brine (20 mL). And in the next reaction, the solvent was used as given and was removed under vacuum to give raw I-219 (181.0 mg, 61% yield) and dried over sodium sulfate. And passed through the filter.

  Synthesis of 4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yloxy) -phenyl-amine hydrochloride (I-221). To a suspension of I-219 (180 mg, 0.645 mmol) and iron, ethanol (2.6 mL) and water (0.8 mL) powder (126 mg, 2.26 mmol) was added solid ammonium chloride (193 mg, 3 .60 mmol). The reaction was removed by nitrogen and heated to 85 ° C. with stirring for 3 h. The material was diluted in ethyl acetate (50 mL) and water (50 mL) and the solvent was removed under vacuum. The aqueous layer was extracted with ethyl acetate (50 mL) and the layers were separated. Brine (50 mL) (dried over sodium sulfate) was filtered and the combined organic extract was washed with water (2 × 50 mL) and the solvent was removed under reduced pressure. The product was purified by flash silica gel column chromatography (5% acetone in dichloromethane) to give a free base of I-221 (136 mg). Diethyl ether (0.8 mL) 2N hydrogen chloride was a wise addition drop and the free base was decomposed in diethyl ether (2.5 mL). The suspension could be stirred for an additional 1.5 h and the salt began to precipitate out after 15 minutes. The solid was filtered and washed with diethyl ether (3 mL) and hexane (4 × 5 mL) to give I-221 (104 mg, 47% yield) as a beige powder. 1H NMR (400 MHz, DMSO-d6) 9.6 (br s, 2H), 7.51-7.45 (m, 3H), 7.36-7.25 (m, 4H), 7.08-7.01 (m, 3H), 3.77 (s, 3H ) ppm. MS (ESI +) = 345.5 (M + 1).

Synthesis of N- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yloxy) -phenyl] -methanesulfonamide (P-254). Discontinuation of I-221 (50.0 mg, 0.138 mmol) and pyridine (21.8 mg, 0.276 mmol) in chloroform (1 mL) was stirred for 10 minutes. The reaction was stirred overnight at room temperature and was stopped as methanesulfonyl chloride (15.8 mg, 0.138 mmol) was added. Preliminary silica gel TLC (5% acetone in dichloromethane, 2 developments, 0.5% acetone in dichloromethane, to give P-254 (26.1 mg, 47% yield) as the orange gum. Purified with 5 developments and 5% acetone in dichloromethane) and the solvent was removed under vacuum. 1 H NMR (400 MHz, CDCl3) 7.42-7.42 (m, 1H), 7.35-7.29 (m, 3H), 7.25-7.18 (m, 2H), 7.18 (t, J = 2.8 Hz, 1H), 7.00- 6.95 (m, 2H), 6.75 (dd, J = 7.4 Hz, 0.2 Hz, 1H), 6.20 (s, 1H), 3.80 (s, 3H), 2.98 (s 3H) ppm. MS (ESI +) = 421.6 ( M), 343.0 (M-79.0).
Example 244. Preparation for P-283

  Synthesis of 1- (2′-fluoro-3′-hydroxy-6′-methoxy-biphenyl-3-yl) -ethanone (I-218). A solution of I-216 (500 mg, 2.26 mmol) and 3 acetylphenyl bromic acid (446 mg, 2.72 mmol) in toluene (8 mL) was degassed with a stream of nitrogen. To this, the solution was added ethanol (1.5 mL) and 2M aqueous sodium carbonate (2.25 mL, 4.52 mmol). This was followed by the addition of tetrakis (triphenylphosphine) palladium (0) (130 mg, 0.113 mmol). The reaction was heated to 100 degrees C for 24 h. The reaction was heated to 100 ° C. overnight and an additional portion of tetrakis (triphenylphosphine) palladium (0) (130 mg, 0.113 mmol) was added under nitrogen. The reaction was heated to 100 ° C. for an additional 24 hours and an additional portion of 3-acetylphenyl bromic acid (223 mg, 1.36 mmol) was added. The layers were separated and the reaction was diluted with ethyl acetate (50 mL) and water (50 mL) (passed through a filter). The organic extracts were combined and the aqueous layer was extracted with ethyl acetate (50 mL). The organic solution was washed with water (2 × 100 mL), saturated aqueous sodium bicarbonate, 100 mL. Brine (50 mL) (dried over sodium sulfate) is then filtered. The solvent is then removed under vacuum. The product was purified by flash silica gel column chromatography (0-5% acetone in dichloromethane) to give I-218 (280 mg, 48% yield) as a brown solid.

  1H NMR (400 MHz, CDCl3) 8.01 (m, 1H), 7.97 (dt, J = 7.9 Hz, 1.5 Hz, 1H), 7.62 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.54 (t, J = 7.0 Hz, 1H), 6.99 (t, J = 9.2 Hz, 1H), 6.69 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 4.81 (d, J = 4.4 Hz, 1H), 3.73 (s, 3H), 2.63 (s, 3H) ppm.

  Synthesis of 1- [2′-fluoro-6′-methoxy-3 ′-(4-nitro-phenoxy) -biphenyl-3-yl] -ethanone (I-220). A solution of N-methyl pyrrolidone (5.5 mL) in I-218 (275 mg, 1.06 mmol) and 4-iodo nitrobenzene (264 mg, 1.06 mmol) was degassed with a 1 minute stream of nitrogen. The To was the solution was cesium carbonate (689 mg, 2.11 mmol), chloride (52.3 mg, 0.528 mmol) copper (I), 2,2,6,6-tetramethylheptane-3,5- Dione (48.6 mg, 0.264 mmol) was added and the reaction was heated to 90 ° C. for 18 h. The solvent was removed under vacuum and the reaction was cooled to room temperature. The rest was started in ethyl acetate (20 mL). The organic extracts were combined and washed with water (20 mL) (a watery wash extracted with ethyl acetate (20 mL)). The organic extract was washed with water (2 × 40 mL), 1N aqueous sodium hydroxide (40 mL), 1N aqueous hydrochloric acid (2 × 40 mL) and brine (50 mL). The solvent was dried over sodium sulfate and filtered under vacuum to give a brown solid. The rest is flash silica gel column chromatography (1-dichloromethane 1--20) followed by flash silica gel column chromatography (30% ethyl acetate in hexane) to give I-220 (78.4 mg, 19% yield). (5% acetone). 1H NMR (400 MHz, CDCl3) 8.23-8.20 (m, 2H), 8.02 (m, 1H), 7.98-7.96 (m, 1H), 7.62-7.60 (m, 1H), 7.55 (t, J = 7.8 Hz , 1H), 7.20 (t, J = 9.0 Hz, 1H), 7.05-7.02 (m, 2H), 6.84 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 3.83 (s, 3H), 2.63 (s , 3H) ppm.

  Synthesis of 4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-yloxy) -phenyl-amine hydrochloride (P-283). I-220 (75.0 mg, 0.197 mmol), ammonium chloride (53.5 mg, 1.00 mmol) and iron powder (38.5 mg, 0.690 mmol) in ethanol (0.8 mL) and water (0.25 mL) ) Was removed by nitrogen and stirred at 85 ° C. under nitrogen for 4 h. The remaining material was suspended in ethyl acetate (50 mL) and the solvent was removed under vacuum. The aqueous layer was extracted with ethyl acetate (50 mL), the organic stop was washed with water (50 mL), and the organic solution combined. Brine (50 mL) (dried over sodium sulfate) was filtered and the composite extract was washed with water (2 × 50 mL) and the solvent was removed under vacuum. The remainder was dissolved in diethyl ether (2 mL) and diethyl ether (400 uL) of 2N hydrogen chloride was added. The reaction was stirred for 1 h and passed through a filter to give P-283 (57.0 mg, 75% yield) as a white powder.

  1H NMR (400 MHz, DMSO-d6) d: 7.98 (dt, J = 7.3 Hz, 1.5 Hz, 1H), 7.93 (s, 1H), 7.66-7.59 (m, 2H), 7.34-7.29 (m, 3H ), 7.09-7.03 (m, 3H), 3.77 (s, 3H), 2.60 (s, 3H) ppm. MS (ESI +) = 352.9 (M + 1

実施例２４５。Ｉ―２２３の準備 << Reaction process formula 56 >>

Example 245. Preparation for I-223

  Synthesis of 3-bromo-2-fluoro-4methoxybenzaldehyde using (I-30) titanium (IV) chloride. A solution of 2-bromo-3-fluoroanisol (5.00 g, 24.3 mmol) in dichloromethane (120 mL) was cooled to 0 ° C. in a salt-ice bath and removed with nitrogen. The reaction could be stirred for 15 minutes under nitrogen. Following the reaction, the added titanium was chloride (23.1 g, 122 mmol) (IV) or 0 ° C α-α dichloromethyl methyl ether (4.21 g, 36.6 mmol) under nitrogen. . The reaction was allowed to heat to room temperature and stirred for 22 h. The red solution was poured into ice water (600 mL) and extracted into dichloromethane (3 × 200 mL). The organic extract was combined. And brine (400 mL) (dried over sodium sulfate) was filtered and the solvent was removed under vacuum and washed with saturated aqueous sodium bicarbonate (2 × 400 mL), water, 2 × 400 mL . The product was dried in a vacuum oven at 80 ° C. overnight to give I-30 (5.75 g, quantitative yield). 1H NMR (400 MHz, CDCl3) 10.22 (s, 1H), 7.86 (dd, J = 8.8 Hz, 7.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.01 (s, 3H) ppm.

  Synthesis of (3-bromo-2-fluoro-4methoxyphenyl) -methanol (I-31). Sodium borohydride (2.53 g, 66.9 mmol) was an additional portionwise and the discontinuation of I-30 (5.20 g, 22.3 mmol) in tetrahydrofuran (40 mL) and water (40 mL) was 0 degrees C chilled. The reaction was allowed to heat to room temperature and stirred for 3.5 h. The resulting solid was extracted into ethyl acetate (2 × 200 mL) and water was added (100 mL), tetrahydrofuran was removed under vacuum. Brine (200 mL) (dried over sodium sulfate) was filtered, the composite extract was washed with water (2 × 200 mL), and the solvent was I-31 (4.82 g, 92% as white powder) Removed under vacuum to give a yield). 1H NMR (400 MHz, CDCl3) 7.32 (t, J = 8.4 Hz, 1H), 6.71 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H), 3.92 (s , 3H), 1.70 (t, J = 6.0 Hz, 1H) ppm.

  Synthesis of 1- (2′-fluoro-3′-hydroxymethyl-6′-methoxy-biphenyl-3-yl) -ethanone (I-222). I-31 (4.00 g, 17.0 mmol), 3-acetylphenyl boronic acid (3.07 g, 18.7 mmol) in ethanol (17.5 mL), water (17.5 mL) and 1,4-dioxane (35 mL) ) Was degassed by a 30 minute stream of nitrogen. To the solution was added potassium carbonate (7.06 g, 51.1 mmol), tri-phenyl phosphine (1.34 g, 5.11 mmol) and palladium (II) acetate (382 mg, 1.70 mmol). The reaction was then stirred under nitrogen for 10 minutes. The reaction was heated to 85 ° C. for 4 h under nitrogen and added palladium (II) acetate (191 mg, 0.851 mmol) and tri-phenylphosphine (700 mg, 2.55 mmol) Added. Heating with stirring was continued for 4 h, the reaction was cooled to room temperature, and ethyl acetate (300 mL) was added. A watery wash was extracted with ethyl acetate (300 mL) and sodium chloride was added (˜1 g), the reaction was washed with water (300 mL). The organic extract was combined. The solvent was then removed under reduced pressure and washed with water (500 mL) and brine (500 mL) (dried over sodium sulfate, decolorized with activated carbon and passed through a filter). The crude product was purified by flash silica gel column chromatography (50% ethyl acetate in hexanes) to give pure I-222 (700 mg, 15% yield). 1H NMR (400 MHz, CDCl3) 8.00-8.00 (m, 1H), 7.97 (dt, J = 7.9 Hz, 1.6 Hz, 1H), 7.61 (dd, J = 6.2 Hz, 1.4 Hz, 1H), 7.53 (t , J = 7.6 Hz, 1H), 7.38 (t, J = 8.6 Hz, 1H), 6.80 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 4.74 (d, J = 6.0 Hz, 2H), 3.79 ( s, 3H), 2.63 (s, 3H), 1.74 (t, J = 6.0 Hz, 1H) ppm.

Synthesis of carbamic acid 3'-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester (I-223). A solution of I-222 (700 mg, 2.55 mmol) and pyridine (429 uL, 6.64 mmol) in tetrahydrofuran (10 mL) was cooled to 0 ° C. in an ice-water bath. To the solution was added methyl chloroformate (542 uL, 5.61 mmol) under nitrogen. The shaped white stop was stirred overnight at room temperature. The pH was adjusted to 1 by the addition of concentrated aqueous hydrochloric acid and the solution was extracted with dichloromethane (2 × 30 mL). The combined organic extract was washed with brine (30 mL). The solvent was then removed under vacuum to give I-223 (661.3 mg, 78% yield) as an orange syrup and dried over magnesium sulfate and passed through a filter. 1H NMR. (400 MHz, CDCl3) 7.98-7.95 (m, 2H), 7.61-7.58 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H) , 6.79 (dd, J = 8.6 Hz, 1.0 Hz, 1H), 5.22 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H) ppm.
Example 246. Preparation for P-304

Synthesis of 4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -benzenesulfinic acid amide (P-304). Allyl palladium chloride dimer (50.9 mg, 0.139 mmol) and bis (diphenylphosphino) pentane (123 mg, 0.278 mmol) were added and dimethylformamide (2 mL) I-223 (300 mg, 0.928 mmol), a suspension of 4 aminosulfonylbenzyl bromine pinocolate ester (289 mg, 1.02 mmol) and potassium carbonate (385 mg, 2.78 mmol) was removed by nitrogen. The reaction was heated to 65 ° C. overnight. Water (25 mL) and the layers were separated and to this the reaction was added ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (2 × 25 mL) and the organic extract was combined with brine (50 mL) and washed. The organic solution was dried over magnesium sulfate (filtered) and solvent removed under vacuum. The product is flash silica gel column chromatography (5% acetone in dichloromethane) followed by trituration with diethyl ether (25 mL) to give P-304 (117 mg, 30% yield) as a faint yellow powder Purified by 1H NMR (400 MHz, CDCl3) 7.99-7.98 (m, 1H), 7.95 (dt, J = 7.6 Hz, 1.4 Hz, 1H), 7.86-7.84 (m, 2H), 7.60-7.58 (m, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 8.6 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.74 ( s, 2H), 4.04 (s, 2H), 3.77 (s, 3H), 2.62 (s, 3H) ppm. LCMS = 100.0% purity. MS (APCI +) = 414.0 (M + 1).
Example 247. Preparation for P-305

  Synthesis of 4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -benzamide (P-305). Allyl palladium chloride dimer (50.9 mg, 0.139 mmol) and bis (diphenylphosphino) pentane (123 mg, 0.278 mmol) were added and I-223 (300 mg, 0 mL) of dimethylformamide (2 mL). .928 mmol), a suspension of 4 aminocarbonylbenzyl bromic acid (190 mg, 1.02 mmol) and potassium carbonate (385 mg, 2.78 mmol) was removed by nitrogen. The reaction was heated to 65 ° C. overnight. Water (25 mL) and the layers were separated and to this the reaction was added ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (2 × 25 mL) and the organic extracts were combined and washed with brine (50 mL). The organic solution was dried over magnesium sulfate (filtered) and solvent removed under vacuum to give the crude product. The product is flash silica gel column chromatography (5-10% acetone in dichloromethane) followed by grinding with diethyl ether (25 mL) to give P-305 (160 mg, 46% yield) as a white powder. Purified by 1H NMR (400 MHz, CDCl3) 7.99 (m, 1H), 7.95 (dt, J = 7.7 Hz, 1.3 Hz, 1H), 7.75-7.73 (m, 2H), 7.61-7.58 (m, 1H), 7.52 ( t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.11 (t, J = 8.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.97 (br s , 1 H), 5.54 (br s, 1H), 4.03 (s, 2H), 3.76 (s, 3H), 2.62 (s, 3H) ppm. LCMS = 96.5% purity. MS (APCI +) = 378.1 (M + 1).

Example 248. Preparation for P-276

Synthesis of 4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -benzoic acid methyl ester (P-276). Allyl palladium chloride dimer (50.9 mg, 0.139 mmol) and bis (diphenylphosphino) pentane (123 mg, 0.278 mmol) were added and I-223 (300 mg, 0 mL) of dimethylformamide (2 mL). .928 mmol) a suspension of 4-methoxycarbonylbenzyl bromate (184 mg, 1.02 mmol) and potassium carbonate (385 mg, 2.78 mmol) was removed by nitrogen. The reaction was heated to 65 ° C. overnight. To this, the reaction was added ethyl acetate (5 mL) and water (5 mL), the layer was filtered into celite, the celite washed with ethyl acetate (15 mL) and water (15 mL), and the layers separated . The aqueous layer was extracted with ethyl acetate (2 × 50 mL) and the organic extracts were combined and washed with brine (100 mL). The organic solution was dried over magnesium sulfate (filtered) and solvent removed under vacuum to give the crude product. The product was flash silica gel column chromatography (25% ethyl acetate in hexanes) with diethyl ether (5 mL) to give P-276 (72.4 mg, 20% yield) as a white powder ( Purified by preliminary silica gel TLC plates (followed by 25% ethyl acetate from hexnaes) and trituration. 1H NMR (400 MHz, CDCl3) 7.99-7.94 (m, 4H), 7.59-7.58 (m, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.80 \ Hz, 2H) , 7.11 (t, J = 8.6 Hz, 1H), 6.74-6.72 (m, 1H), 4.03 (s, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 2.62 (s, 3H) ppm LCMS = 96.6% purity. MS (APCI +) = 394.1 (M + 2).
Example 249. Preparation for I-226

Synthesis of 5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I-226). Of dimethylformamide (3.5 mL) of I-223 (500 mg, 1.50 mmol), 2-methyl carboxy pyridine-5 bromine acidic pinocol ester (435 mg, 1.65 mmol) and potassium carbonate (624 mg, 4.51 mmol) The discontinuation was degassed under a 15 minute stream of nitrogen. To this solution was added bis (diphenylphosphino) pentarate (199 mg, 0.451 mmol) and allyl palladium chloride dimer (82.7 mg, 0.226 mmol). The reaction was heated to 65 degrees. C for 50h. The reaction was diluted with ethyl acetate (50 mL) and filtered through celite. To the filtered water, water (50 mL) was added and the layers were separated. The aqueous laundry was extracted with ethyl acetate (2 × 50 mL) and all three organic extracts were combined and washed with brine (100 mL). The organic solution was dried over magnesium sulfate (filtered) and solvent removed under vacuum. The remainder was purified by flash silica gel column chromatography (5% acetone in dichloromethane) followed by trituration with diethyl ether (15 mL) to give I-226 (190.6 mg as a white powder). , 32% yield) was washed with diethyl ether (5 mL). 1H NMR (400 MHz, CDCl3) 8.66 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.97-7.94 (m, 2H), 7.67 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 7.57 (dd, J = 7.6 Hz, 1.6 Hz, H), 7.52 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 8.6 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.05 (s, 2H), 4.00 (s, 3H), 3.77 (s, 3H), 2.62 (s, 3H) ppm. LCMS = 100.0% purity. MS (APCI +) = 394.1 (M +1).
Example 250. Preparation for I-224

Synthesis of [4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -methyl-carbamic acid tert-butyl ester (I-224). To a suspension of I-223 (500 mg, 1.50 mmol) and 4- (tert-butoxycarbonyl-N-methylamine) phenyl bromate (415 mg, 1.65 mmol) and dimethylformamide (3.5 mL) ) Potassium carbonate (624 mg, 4.51 mmol) was added bis (diphenylphosphino) pentanoate (199 mg, 0.451 mmol) and allyl palladium chloride dimer (82.7 mg, 0.226 mmol) under nitrogen. )Met. The reaction was heated to 85 degrees. C for 29h. The reaction was diluted with ethyl acetate (30 mL) and water (30 mL) and filtered through a celite plug. Celite was washed with ethyl acetate (2 × 20 mL) and water (20 mL) and the layers were separated. The aqueous laundry was extracted with ethyl acetate (2 × 50 mL), and all three organic extracts were combined and washed with water (2 × 100 mL) and brine (100 mL). The organic solution was dried through sodium sulfate (filtered) and solvent removed under vacuum. The rest is flash silica gel column chromatography (dichloromethane) to give I-224 (624.3 mg, 90% yield) as the yellow oil used, as is without further purification. It was purified by. 1H NMR (400 MHz, CDCl3) 8.00 (d, J = 1.0 Hz, 1H), 7.95 (dt, J = 7.7 Hz, 1.3 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.19-7.09 (m, 5H), 6.72 (d, J = 8.4 Hz, 1H), 3.95 (s, 2H), 3.75 (s, 3H), 2.62 (s , 3H), 1.45 (s, 9H) ppm. LCMS = 94.1% purity. MS (APCI +) = 364.1 (M-100).
Example 251. Preparation for P-328

  Synthesis of 5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid (I-228). A solution of I-226 (150 mg, 0.381 mmol) in tetrahydrofuran (1 mL), methanol (1 mL), water (1 mL) and 1N aqueous sodium hydroxide (0.763 mL) was strred at room temperature for 18 h. Nearly half of the solvent was removed under vacuum. The remaining solution was adjusted to pH 3 by the addition of glacial acetic acid. The suspension was extracted with dichloromethane (10 mL), water (5 mL) was added to the laundry, and the watery laundry was extracted with added dichloromethane (2 × 10 mL). All three organic extracts were combined. And the rest was dried under high vacuum for 24 h, the solvent was removed under vacuum and dried over magnesium sulfate and passed through a filter. The resulting beige syrup crystallizes in diethyl ether (5 mL), stirred for 30 minutes and filtered to give I-226 (90.6 mg, 63% yield) as a white powder. Therefore, there was detergency with hexane (2 × 2 mL). 1H NMR (400 MHz, DMSO-d6) 8.62 (d, J = 2.0 Hz, 1H), 7.99-7.94 (m, 2H), 7.87 (s, 1H), 7.78 (dd, J = 7.8 Hz, 2.2 Hz, 1H), 7.58 (d, J = 5.2 Hz, 2H), 7.39 (t, J = 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.08 (s, 2H), 3.73 (s, 3H), 2.588 (s, 3H) ppm. LCMS = 100.0% purity (APCI +). MS (APCI +) = 424.1 (M + 45), 380.0 (M + 1).

Synthesis of 5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid amide (P-328). A solution of I-228 (50.0 mg, 0.184 mmol) in toluene (2 mL) was stirred under nitrogen. The reaction was heated to 100 ° C. for 2 h, which time it took from colorless to deep red and to this the reaction was added thionyl chloride (65.7 mg, 0.552 mmol). The remainder was dissolved in tetrahydrofuran (2 mL) and the dissolving and excess thionyl chloride was removed under reduced pressure. Aqueous ammonium hydroxide (40 uL) was then added to the solution. The reaction was stirred at room temperature for 1 h. The reaction was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (30 mL). The organic extract was combined and the aqueous wash was extracted with ethyl acetate (30 mL). The combined extract was washed with saturated aqueous sodium bicarbonate (25 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The rest is to elute the acetone of the preliminary silica gel TLC (12.5% by dichlormethane (3 developments) to give P-328 (12.6 mg, 18% yield) as a white powder. ). 1H NMR. (400 MHz, CDCl3) 8.47 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.98-7.94 (m, 2H), 7.78 (s, 1H), 7.69 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.96- 7.58 (m, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 8.6 Hz, 1H), 6.76 (d , J = 8.4 Hz, 1H), 5.48 (s, 1H), 4.05 (s, 3H), 3.77 (s, 3H), 2.62 (s, 3H) ppm. LCMS = 95.9% purity. MS (APCI +) = 379.1 (M + 1).
Example 252. Preparation for P-324

Synthesis of 2-bromo-6-methoxy-4-nitro-phenylamine (I-229). To a 2 L round bottom flask with stirring, a stick was added 2-methoxy-4-nitro-phenylamine (50.0 g, 297.4 mmol), CH3CN (1 L) and NBS (53.5 g, 297.4 mmol). )Met. While protected from light, the reaction was stirred at room temperature for 2 hours. The reaction was concentrated and 500 mL of water was added. The product was extracted with ethyl acetate and concentrated. The solid precipitated from the watery laundry was combined with the solid resulting from the organic concentration to give I-229 (59.6 g) which was used without further purification.

Synthesis of 1-bromo-3-methoxy-5-nitrobenzene (I-230). In 2 L, the flask reached the round bottom equipped with a mechanical stirrer was summed I-229 (59.8, 249.2 mmol), ethanol (167 mL), water (83 mL) and the mixing was Chilled to 0 ° C. H2SO4 (750 mL) was added followed by 75 mL of NaNO2 (25.8 g, 373.8 mmol) in water. The reaction was stirred at 0 ° C. for 15 minutes, 30 minutes at room temperature and 15 minutes at 60 ° C. And after that it was cooled to room temperature and filtered. The solids were washed with water (dried in a 1 hour 40 ° C vacuum oven and 5 days vacuum desiccator). After further drying in a 60oC vacuum oven for 6 hours, 47.3 g (84%) of I-230 was obtained as a rust colored solid.

Synthesis of 3-nitro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaboran-2-yl) -phenol (I-232). In a 250 mL circle, the bottom flask was placed I-231 (2.03 g, 9.31 mmol), bis (colioato) di-boron (2.60 g, 10.24 mmol), KOAc (2.74 g, 27 .93 mmol) and 50 mL of dioxane. After removing gas from the minutes with N 2 for 10, the reaction was stirred at 90 ° C. for 20 hours and PdCl 2 dppf—CH 2 Cl 2 (0.38 g, 0.47 mmol) was added. Brine was added and most of the solvent was removed by rotary evaporation. The organic fertilizer was filtered through celite, concentrated and the product was extracted with ethyl acetate. The remainder was purified by flash column chromatography eluting ethyl acetate / hexanes by 20% to yield 1.44 g (58%) of I-232.

Synthesis of 3- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -5-nitrophenol (I-233). To a 40 mL vial with stirring, a stick was added I-33 (597 mg, 1.81 mmol), I-232 (480 mg, 1.81 mmol), NaHCO3 (456 mg, 5.43 mmol), DME (10 mL), ethanol ( 1 mL) and water (1 mL). After removing gas from the minute for 10, the reaction was stirred at 65 ° C. for 18 hours and tetrakis (triphenylphosphine) palladium (0) (208 mg, 0.18 mmol) was added. The reaction was cooled to room temperature and diluted with 10 mL of water. The product was extracted with ethyl acetate, dried over Na2SO4 and concentrated. The remaining column chromatographic purification with 15-20% ethyl acetate / hexanes yielded 175 mg (25%) of I-233 as a yellow oil.

Synthesis of 3-amino-5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenol (P-324). To 40 mL, the vial was summed I-233 (175 mg, 0.39 mmol), Fe powder (89 mg, 1.35 mmol), NH 4 Cl (120 mg, 1.93 mmol), water (1 mL) and ethanol (3 mL). The stop was stirred at 80 ° C for 2 hours and the celite was filtered. The filtered water was diluted with ethyl acetate and washed with water and brine. After concentrating on organic fertilizer, the remainder is 50% ethyl acetate / hexane to give 104 mg (65%) of P-324 as 20-colorless oil purified by flash column chromatography. 1H NMR (400MHz, CDCl3) 7.40 (s, 1 H), 7.38-7.27 (m, 3 H), 7.11 (t, J = 8.6 Hz, 1 H), 6.74-6.61 (m, 2 H), 6.12 ( d, J = 17.4 Hz, 2 H), 6.04 (t, J = 1.9 Hz, 1 H), 3.80 (s, 2 H), 3.75 (s, 3 H), 3.63 (br s, 2 H) ppm. LC / MS = 97.7%, 358.2 (APCI +).
Example 253. Preparation of P-331 and P-338

[4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -methylamine hydrochloride (synthesis of P-331). The reaction could be stirred dropwise at room temperature for 4 h and to the solution of I-224 (485 mg, 1.05 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The solvent was removed under vacuum and the remainder was dissolved in ethyl acetate (20 mL) and water (10 mL). The pH of the aqueous layer was 8 using solid sodium bicarbonate. The organic solution was washed with brine and the layers were separated. The solvent was removed under vacuum and the organic extract was dried over sodium sulfate. The rest was dried under high vacuum overnight to give a free base. Some free base (44.5 mg) was decomposed in diethyl ether (2 mL). To the solution, diethyl ether (184 uL, 0.367 mmol) of 2N hydrogen chloride was added dropwise and the reaction was stirred at room temperature for 3 h. The resulting solid was filtered and dried under vacuum in an abderhaulden apparatus under acetone at reflux to give P-331 (28.8 mg). 1H NMR (400 MHz, DMSO-d6) 7.94 (m, 1H), 7.86 (s, 1H), 7.58 (d, J = 5.2 Hz, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.09 ( d, J = 8.4 Hz, 2H), 6.93 (d, J = 9.2 Hz, 1H), 6.77 (br m, 2H), 3.84 (s, 2H), 3.71 (s, 3H), 2.72 (s, 3H) , 2.59 (s, 3H) ppm.
LCMS = 94.4% purity. MS (APCI +) = 364.1 (M + 1).

  Synthesis of 1- [4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -1-methyl-urea (P-338). Discontinuation of the P-331 free base (180 mg, 0.495 mmol) in glacial acetic acid (1 mL) and water (1 mL) was stirred until a solution was formed. To the solution was added a solution of water (250 uL) in potassium cyanate (120 mg, 1.49 mmol) and the solution became cloudy. The reaction was stirred at room temperature for 2.5 h. Water (5 mL) and layers were separated and the reaction was diluted with diethyl ether (10 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (10 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The remainder was dissolved in diethyl ether (30 mL). Brine (30 mL) (dried over sodium sulfate) was then filtered and the solvent was removed under vacuum and washed with saturated aqueous sodium bicarbonate (30 mL). The rest was purified by preliminary silicon dioxide TLC (10% acetone in dichloromethane (2 developments)) to give P-338 (96.1 mg, 48% yield) as a white powder. Dried overnight in a vacuum oven at 40 ° C. 1H NMR (400 MHz CDCl3) d: 8.00 (d, J = 1.2 Hz, 1H), 7.95 (dt, J = 7.7 Hz, 1.4 Hz, 1H). 7.61 (dd, J = 7.6 Hz, 1.6 Hz, 1H) , 7.52 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.22-7.14 (m, 3H), 6.75 (d, J = 8.4 Hz, 1H), 4.34 (brs, 2H), 3.98 (s, 2H), 3.76 (s, 3H), 3.24 (s, 3H), 2.62 (s, 3H). LCMS = 96.1% purity. MS (APCI +) = 407.1 (M + 1).

実施例２５４。Ｐ―２７７の準備 << Reaction process formula 57 >>

Example 254. Preparation for P-277

Synthesis of 1- [3 '-(6-amino-pyridin-3-ylmethyl) -2,'-fluoro-6'-methoxy-biphenyl-3-yl] -ethanone (P-277). A solution of N, N-dimethylformamide (8 mL) in I-223 (1.00 g, 3.01 mmol) and 2-aminopyridine-5 bromine acidic pinacol ester (728 mg, 3.31 mmol) uses a 10 minute stream of nitrogen. The gas was removed. The stop was stirred at 65oC under nitrogen for 15h and the solution was potassium carbonate (1.25g, 9.03mmol), allyl palladium (II) chloride dimer under nitrogen The body (165 mg, 0.451 mmol) and bis (diphenylphosphino) pentane (398 mg, 0.903 mmol) were added. To the reaction was added ethyl acetate (50 mL) and water (50 mL) and biphasic filtration were filtered through celite (15 g). Celite was washed with ethyl acetate (2 × 20 mL) and water (2 × 20 mL) and filtered water were cut off. The organic extracts were combined and the aqueous layer was extracted with ethyl acetate (100 mL). Brine (200 mL) (dried over sodium sulfate) was filtered and the organic solution was washed with water (200 mL) and the solvent was removed under vacuum. The rest is 50% of flash silica gel column chromatography (product eluted with 12.5% dichloromethane in acetone) to give P-277 as an orange oil (653 mg, 62% yield). Of impurities eluted with ethyl acetate). 1H NMR (400 MHz, CDCl3) 7.99 (m, 1H), 7.95 (dt, J = 7.73 Hz, 1.6 Hz, 1H), 7.61-7.59 (m, 1H), 7.52 (t, J = 7.6 Hz, 1H) , 7.30 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 7.09 (t, J = 8.6 Hz, 1H), 6.71 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 4.33 (s, 2H), 3.83 (s, 2H), 3.75 (s, 3H), 2.62 (s, 3H). LCMS = 100.0% purity. MS (APCI +) = 351.1 (M + 1) .
Example 255. Preparation for P-361

  Synthesis of 1- [5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -3- (2-chloroethyl) -urea (I-237). The solution of P-277 (300 mg, 0.856 mmol) in chloroform (7.4 mL) was removed with nitrogen for 5 minutes at room temperature. To this solution was added 2-chloroethyl isocyanate (90.3 mg, 0.856 mmol) and the reaction was stirred at reflux for 24 h. The reaction was heated at reflux for a further 16 h and added 2-chloroethyl isocyanate (220 uL, 2.57 mmol) was added. The resulting red syrup is flash silica gel column chromatography (0-25% of dichloromethane) followed by preliminary thin layer chromatography to give I-237 (41.7 mg, 11% yield) as a yellow oil. The solvent was removed under vacuum.

Integration of 1- [5- (3'-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -imidazolidine-2-1 (P-361). A suspension of I-237 (40.0 mg, 0.0877 mmol) and sodium carbonate (27.9 mg, 0.263 mmol) in acetonitrile (1 mL) was stirred at reflux overnight. The reaction was cooled to room temperature and passed through a filter. The resulting yellow oil crystallizes in diethyl ether (2 mL), filtered and washed with hexane (2 × 1 mL) to give P-361 (17.1 mg, 46% as an off-white powder) Dried in a vacuum oven overnight at 40 ° C. to yield) and the solvent was removed under vacuum. 1H NMR (400 MHz, CDCl3) 8.10 (d, J = 1.6 Hz, 1 H), 7.99 (s, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.63-7.48 (m, 3 H ), 7.46-7.39 (m, 1 H), 7.14-7.05 (m, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 6.72 (d, J = 8.5 Hz, 1 H), 4.42 ( t, J = 7.9 Hz, 2 H), 3.89 (s, 2 H), 3.82 (t, J = 7.9 Hz, 2 H), 3.75 (s, 3 H), 2.62 (s, 3 H) ppm. LCMS = 91.4% purity. MS (APCI +) = 420.1 (M + 1).
Example 256. Preparation for P-355

Synthesis of 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridine-2-carbonitrile (I-238). A 250 mL round bottomed flask was charged with 5-bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol), bis (colioato) di-boron (4.58 g, 18.03 mmol), KOAc ( 5.47 g, 55.74 mmol) and 3.0 g of DMSO (100 mL) were added. After removing gas from the minute for 20, the solution was stirred at 80 ° C. for 24 hours and PdCl 2 dppf—CH 2 Cl 2 (1.39 g, 1.64 mmol) was added and at room temperature for 3 days. The product was extracted with ethyl acetate and 50 mL of water was added. The complex organic fertilizer was washed with brine, dried over Na2SO4 and concentrated. The dark color residue was purified by flash column chromatography eluting with acetone / hexanes by 20% to give a red solid. The solid was triturated with hexane to give 1.72 g (46%) of I-238 as a light pink solid.

Synthesis of [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid tert-butyl ester (P-355). To a 20 mL vial, I-33 (401 mg, 1.22 mmol), I-238 (336 mg, 1.46 mmol), K2CO3 (504 mg, 3.65 mmol) were added, DME (5 mL), water,. Remove gas with 5 mL ethanol (0.5 mL) and stop for 15 minutes. The reaction was stirred at 80 ° C. for 16 hours and Tetrakis (triphenylphosphine) palladium (0) (141 mg, 0.12 mmol) was added. The reaction was diluted with water and extracted with ethyl acetate. The organic fertilizer was concentrated by flash column chromatography and yielded 20% ethyl acetate / hexane yielding P-355 (64 mg, 15%) as a 15-light yellow oil that was purified to extract. 1H NMR (400 MHz, CDCl3) δ 8.62 (br s, 1 H), 7.68-7.56 (m, 2 H), 7.40-7.30 (m, 3 H), 7.26-7.21 (m, 1 H), 7.13 ( t, J = 8.4 Hz, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 4.03 (br s, 2 H), 3.78 (s, 3 H) ppm. LC / MS = 98.5%, 353.0 (APCI +).
Example 257. Preparation for P-344

Synthesis of C- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methylamine (P-344). In a 100 mL circle, the bottom flask was added P-355 (0.55 g, 1.56 mmol), methanol (20 mL), concentrated HCl (0.65 mL, 7.79 mmol) and 10% Pd / C (100 mg). Met. The stop was stirred under an 18 hour H2 balloon and the celite was filtered. The filtered water was concentrated. The product was extracted with dichloromethane and to the solid was added 1N aqueous NaOH. Dichloromethane was purified by concentration by flash column chromatography eluting with methanol / dichloromethane by 5-10% to give P-344 (89 mg, 16%) as a colorless oil. 1H NMR (400MHz, DMSO-d6) 8.55 (d, J = 1.2 Hz, 1 H), 8.32 (br s, 3 H), 7.71 (dd, J = 1.9, 7.9 Hz, 1 H), 7.50-7.37 ( m, 3 H), 7.36 (d, J = 5.4 Hz, 2 H), 7.27 (d, J = 6.6 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 1 H), 4.75 (br s, 2 H), 4.14 (q, J = 5.8 Hz, 2 H), 4.01 (s, 2 H), 3.73 (s, 3 H) ppm. LC / MS = 95.1%, 357.1 (APCI +).
Example 258. Preparation for P-367

Synthesis of [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid ethyl ester (P-367). To 8 mL, the vial was summed P-344 (43 mg, 0.12 mmol), dichloromethane (2 mL), triethylamine (33 uL, 0.24 mmol). Ethyl chloroformate (20 mg, 0.18 mmol) was added and the solution was cooled to 0 ° C. After 15 minutes at room temperature, the solution was concentrated. The remainder is purified by flash column chromatography 40- 60% ethyl acetate giving 23 mg (54%) of P-367 as a white solid. 1H NMR (400MHz, DMSO-d6) 8.39 (d, J = 1.5 Hz, 1 H), 7.63 (t, J = 6.0 Hz, 1 H), 7.59 (dd, J = 1.7, 8.1 Hz, 1 H), 7.50-7.40 (m, 2 H), 7.37 (s, 1 H), 7.33 (t, J = 8.7 Hz, 1 H), 7.28 (d, J = 6.6 Hz, 1 H), 7.20 (d, J = 7.9 Hz, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 4.22 (d, J = 6.2 Hz, 2 H), 4.03-3.96 (m, 2 H), 3.94 (s, 2 H) , 3.72 (s, 3 H), 1.16 (t, J = 7.1 Hz, 3 H) ppm. LC / MS = 100.0%, 429.1 (APCI +).
Example 259. Preparation for P-368

  Synthesis of [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -urea (P-368). To 8 mL, the vial was summed P-344 (43 mg, 0.12 mmol), dichloromethane (2 mL) and trimethylsilyl isocyanate (49 uL, 0.36 mmol). After 1 hour at 35 ° C, the solution was concentrated. The resulting solid was triturated with ether to yield P-368 (25 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.44 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.48-7.40 (m, 2 H), 7.37 (s, 1 H), 7.34 (t, J = 8.9 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 2 H), 6.94 (d, J = 8.6 Hz, 1 H), 6.51 (br s, 1 H), 5.64 (br s, 2 H), 4.25 (d, J = 5.0 Hz, 2 H), 3.97 (s, 2 H), 3.72 (s, 3 H). LC / MS = 96.4%, 400.1 (APCI +).

Example 260. Preparation for P-371

Synthesis of hydrochloric acid (P-371) 3- [5- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -1,1-dimethylurea. In an 8 mL vial, the oC. The reaction was cooled to and added P-344 (23 mg, 0.064 mmol), dichloromethane, 1.5 mL was triethylamine (18 uL, 0.13 mmol), stirred at room temperature for 18 hours and salified (9 uL). , 0.097) Dimethylcarbamic was added. The dichloromethane solution was washed and concentrated with water and brine. The remainder was purified by flash column chromatography eluting with methanol / dichloromethane by 5%. The resulting colorless oil was triturated with ether to obtain a white solid. The resulting solid was decomposed in 2 mL of 4.0 M HCl / dioxane and stirred at room temperature for 2 hours. The oil was treated with ether to form a solid. It was then filtered to obtain P-371 (6.1 mg, 20%). 1H NMR (400 MHz, DMSO-d6) 8.60 (s, 1 H), 8.08 (d, J = 7.4 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.50-7.35 (m, 4 H), 7.28 (d, J = 6.4 Hz, 1 H), 7.11 (br s, 1 H), 6.97 (d, J = 8.6 Hz, 1 H), 4.41 (br s, 2 H), 4.08 ( s, 2 H), 3.73 (s, 3 H), 2.82 (s, 6 H) ppm. LC / MS = 100.0%, 428.1 (APCI +).
Example 261. Preparation for P-372

Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -3-ethyl-urea (P-372). To an 8 mL vial, P-344 (23 mg, 0.064 mmol), dichloromethane, 1.5 mL was added and the solution was cooled to room temperature. The reaction was stirred at room temperature for 18 hours and concentrated and ethyl isocyanate (8 uL, 0.097 mmol) was added. The solution was stirred at room temperature for 18 hours and 4.0 M HCl / dioxane was added to the concentrated and resulting solid. The resulting oil was treated with ether to form a solid. It was then filtered to yield P-372 (15.1 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.63 (s, 1 H), 8.14 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 7.51-7.33 (m, 4 H), 7.28 (d, J = 6.3 Hz, 1 H), 6.98 (d, J = 8.6 Hz, 1 H), 6.62 (br s, 1 H), 6.31 (br s, 1 H), 4.42 ( s, 2 H), 4.10 (s, 2 H), 3.74 (s, 3 H), 3.01 (q, J = 7.1 Hz, 2 H), 0.99 (t, J = 7.1 Hz, 3 H) ppm. MS : 428.1 (APCI +).
Example 262. Preparation for P-373

Synthesis of 4-methyl-piperazine-1-carboxylic acid [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -amide (P-373). To 8 mL, the vial was summed P-344 (23 mg, 0.064 mmol), dichloromethane (1.5 mL), triethylamine (18 uL, 0.13 mmol). Chloride (10 mg, 0.097 mmol) 4-methyl-piperazine-1-carbonyl was added and the solution was cooled to 0 ° C. After 18 hours at room temperature, the reaction was washed with water. And salt water continued. The organic fertilizer is concentrated by flash column chromatography and 10% methanol / dichloromethane with room to afford 5-28 mg semi-solid purified to be withdrawn. The semi-solid was dissolved in 2 mL of 4.0 M HCl / dioxane, stirred at room temperature for 18 hours and concentrated. As the solid formed and ether was added. And it was filtered. To the solid was added 5N aqueous NaOH and the product was extracted with dichloromethane and concentrated. The remaining purification by flash column chromatography eluting with methanol / dichloromethane by 10% yielded P-373 (9.6 mg, 31%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8.38 (d, J = 1.5 Hz, 1 H), 7.57 (dd, J = 2.0, 8.1 Hz, 1 H), 7.48-7.39 (m, 2 H), 7.37 ( s, 1 H), 7.32 (t, J = 8.7 Hz, 1 H), 7.28 (d, J = 6.4 Hz, 1 H), 7.17 (d, J = 8.1 Hz, 1 H), 7.09 (t, J = 5.8 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 4.26 (d, J = 5.6 Hz, 2 H), 3.93 (s, 2 H), 3.72 (s, 3 H), 3.17 (d, J = 5.2 Hz, 4 H), 2.29-2.20 (m, 4 H), 2.16 (s, 3 H) ppm. LC / MS = 100.0%, 483.1 (APCI +).
Example 263. Preparation for P-374

Synthesis of 1- (2-chloroethyl) -3- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -urea (I-239). To an 8 mL vial was added P-344 (63 mg, 0.177 mmol), dichloromethane, 2 mL, and the reaction was cooled to 0 ° C. The reaction was stirred for 1 hour at room temperature and concentrated to obtain the used I-239 and chloroethyl isocyanate (19 mg, 0.177 mmol) was added.

Integration of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -imidazolidine-2-1 (P-374). To an 8 mL vial was added I-239 (82 mg, 0.177 mmol), THF, 2 mL, and the stop was cooled to 0 ° C. The reaction was stirred for 3 days at room temperature and sodium hydride (8 mg, 0.212 mmol) was added. The reaction was stirred at 50 ° C. for 1 hour and an additional 4 mg of sodium hydride was added. The product was extracted with ethyl acetate and water was added. The organic fertilizer is concentrated by flash column chromatography, 50% acetone / dichloromethane giving P-374 (35 mg, 47%, 2 steps) as a 25-white solid purified to be withdrawn. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J = 1.5 Hz, 1 H), 7.60 (dd, J = 1.9, 7.9 Hz, 1 H), 7.49-7.39 (m, 2 H), 7.37 ( s, 1 H), 7.34 (t, J = 8.7 Hz, 1 H), 7.28 (d, J = 6.7 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 6.41 (s, 1 H), 4.28 (s, 2 H), 3.95 (s, 2 H), 3.72 (s, 3 H), 3.31-3.19 (m, 4 H) ppm LC / MS = 100.0%, 426.1 (APCI +).
Example 264. Preparation for P-375

Integration of 1- [5- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -3-methyl-imidazolidine-2-1 (P-375) . To an 8 mL vial, P-374 (21 mg, 0.05 mmol), the solution was cooled to 0 ° C., and THF, 1 mL were added. Sodium hydride (3 mg, 0.076 mmol) was added and after 15 minutes at room temperature methyl iodide (6 uL, 0.101 mmoL) was added. The reaction was stirred at room temperature for 30 minutes and 1 mL of water was added. The product was extracted with ethyl acetate, concentrated and THF evaporated. The remainder is methanol that has passed through a silica gel plug to be extracted. And it yielded P-375 (18.1 mg, 82%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J = 1.6 Hz, 1 H), 7.60 (dd, J = 2.0, 7.9 Hz, 1 H), 7.50-7.39 (m, 2 H), 7.37 ( s, 1 H), 7.34 (t, J = 8.7 Hz, 1 H), 7.28 (d, J = 6.4 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 4.31 (s, 2 H), 3.95 (s, 2 H), 3.72 (s, 3 H), 3.24 (s, 4 H), 2.67 (s, 3 H) ppm. LC / MS = 97.8%, 440.1 (APCI +).
Example 265. Preparation for P-520

Synthesis of [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid phenyl ester (P-520). To 18 mL, the vial was summed P-344 (128 mg, 0.36 mmol), TEA (0.10 mL, 0.72 mmol) and dichloromethane (3 mL). Phenyl chloroformate (68 uL, 0.54 mmol) was added and the solution was cooled to 0 ° C. After stirring for 15 minutes at room temperature, the reaction was concentrated. Purification by flash column chromatography (25% -75% EtOAc / hexanes) yielded P-520 (102 mg, 59%) as an off-white solid. (400MHz, DMSO-d6) 8.44 (s, 1 H), 8.30 (t, J = 5.9 Hz, 1 H), 7.63 (dd, J = 1.5, 7.9 Hz, 1 H), 7.49-7.26 (m, 8 H), 7.24-7.17 (m, 1 H), 7.12 (d, J = 7.9 Hz, 2 H), 6.95 (d, J = 8.6 Hz, 1 H), 4.33 (d, J = 6.0 Hz, 2 H ), 3.96 (s, 2 H), 3.73 (s, 3 H) ppm. LC / MS = 100.0%, 477.1 (APCI +).
Example 266. Preparation for P-460

Hydrochloric acid (P-460) 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -3-methyl-urea. To 8 mL, the vial was summed P-520 (84 mg, 0.18 mmol), DMSO (2 mL) and 40% water. MeNH2 (0.14 mL). After stirring for 30 minutes at room temperature, 5 mL of water was added. The organic fertilizer was concentrated and the product was extracted with EtOAc (4 × 2 mL). The white solid was triturated with ether to give the free base compound. To the free base was added 4N HCl / dioxane (2 mL) and after stirring for 5 min at room temperature, the solution was concentrated. The remainder was triturated with ether to provide P-460 (42 mg, 53%) as a tan solid.
1H NMR (400 MHz, DMSO-d6) 8.64 (s, 1 H), 8.16 (d, J = 7.9 Hz, 1 H), 7.66 (d, J = 8.2 Hz, 1 H), 7.51-7.34 (m, 4 H), 7.28 (d, J = 6.4 Hz, 1 H), 6.98 (d, J = 8.6 Hz, 1 H), 6.80 (br s, 1 H), 6.30 (br s, 1 H), 4.44 ( s, 2 H), 4.10 (s, 2 H), 3.74 (s, 3 H), 2.55 (s, 3 H) ppm. LC / MS = 97.5%, 414.0 (APCI +).
Example 267. Preparation for P-461

1- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -3-ethyl-imidazolidin-2-1 hydrochloride (P-461) . To an 18 mL vial was added P-374 (65 mg, 0.16 mmol), THF, 3 mL, and the solution was cooled to 0 ° C. The stop was stirred for 15 minutes at room temperature and NaH (9 mg, 0.23 mmol) was added. The reaction was stirred at room temperature for 1 hour and EtI (25 uL, 0.31 mmol) was added. The product was extracted with EtOAc (3 × 3 mL) and water was added. The organic fertilizer was washed and concentrated with water (brine). To the rest, 2 mL of 4N HCl / dioxane was added. After stirring to dissolve, the solution was concentrated. The resulting residue was triturated with ether, filtered, washed with ether and dried to give P-461 (51 mg, 65%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.63 (br s, 2 H), 8.07 (br s, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.50-7.33 (m, 4 H) , 7.29 (d, J = 5.8 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 4.51 (s, 2 H), 4.09 (br s, 2 H), 3.74 (s, 3 H ), 3.57 (s, 2 H), 3.31 (s, 2 H), 3.19-3.10 (m, 2 H), 1.10-0.97 (m, 3 H) ppm. LC / MS = 84.2%, 454.2 (APCI +) .
Example 268. Preparation for P-462

1- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1-oxy-pyridin-2-ylmethyl] -3-ethyl-urea (P-462). To an 18 mL vial was added P-372 (66 mg, 0.15 mmol), dichloromethane, 4 mL, and the solution was cooled to 0 ° C. The reaction was stirred at room temperature for 1 hour when 5 mL of saturated aqueous NaHCO3 was added and mCPBA (69 mg, 0.31 mmol) was added. The organic layer was washed sequentially with 5 mL each of saturated aqueous NaHCO 3, H 2 O and brine and the layers were separated. The rest was then washed with 1N NaOH (2 × 5 mL), water (5 mL) and brine (5 mL). The product was concentrated to obtain P-462 (14.8 mg, 22%) as a white solid, dried over Na2SO4 and filtered. 1H NMR (400 MHz, DMSO-d6) 8.19 (s, 1 H), 7.53-7.34 (m, 4 H), 7.29 (d, J = 6.6 Hz, 1 H), 7.25-7.16 (m, 2 H) , 6.96 (d, J = 8.6 Hz, 1 H), 6.38 (t, J = 6.0 Hz, 1 H), 6.17 (t, J = 5.4 Hz, 1 H), 4.22 (d, J = 6.2 Hz, 2 H), 3.91 (s, 2 H), 3.73 (s, 3 H), 3.09-2.91 (m, 2 H), 0.97 (t, J = 7.2 Hz, 3 H) ppm. LC / MS = 100.0%, 444.1 (APCI +).
Example 269. Preparation for P-463

1- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1-oxy-pyridin-2-ylmethyl] -imidazolidine-2-1 (P-463). To an 18 mL vial, P-374 (62 mg, 0.15 mmol), dichloromethane, 4 mL were added and the solution was cooled to 0 ° C. The reaction was stirred at room temperature for 1 hour when 5 mL of aqueous 1N NaOH was added and mCPBA (82 mg, 0.36 mmol) was added. The aqueous layer was extracted with dichloromethane (2 × 3 mL) and the layers were separated. The organic fertilizer was combined, washed with water (5 mL) and brine (5 mL) and concentrated. It was washed with 5 mL brine and the remainder was started in 5 mL EtOAc, dried over Na 2 SO 4 and concentrated to a solid. The remainder was triturated with ether to yield P-463 (23.5 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.23 (s, 1 H), 7.49-7.34 (m, 4 H), 7.32-7.16 (m, 3 H), 6.96 (d, J = 8.6 Hz, 1 H) , 6.56 (s, 1 H), 4.31 (s, 2 H), 3.93 (s, 2 H), 3.73 (s, 3 H), 3.45-3.36 (m, 2 H), 3.32-3.25 (m, 2 H) ppm. LC / MS = 93.4%, 442.0 (APCI +).
Example 270. Preparation for P-465

[5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -carbamic acid 2-chloroethyl ester (I-240). To 18 mL, the vial was added P-344 (100 mg, 0.28 mmol), dichloromethane (4 mL), TEA (78 uL, 0.56 mmol), and 2-chloroethylchloro after the solution was cooled to 0 ° C. Formate (43 uL, 0.42 mmol) was added. The reaction was stirred at room temperature for 18 hours and 5 mL of water was added. The watery one was further extracted with 5 mL of dichloromethane and the layers were separated. The organic fertilizer was combined, washed with 5 mL water and 5 mL brine, dried over Na2SO4 and concentrated. In the next reaction, the resulting residue was used as given.

3- [5- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -oxazolidine-2-hydrochloride (P-465). To 18 mL, the vial was summed I-240 (0.28 mmol), THF (3 mL) and NaH (28 mg, 0.70 mmol). The reaction was stirred at room temperature for 18 hours (4 hours 50 ° C) and 3 days at room temperature. The product was extracted with EtOAc and 5 mL of water was added to the reaction. The organic fertilizer was washed with brine and dried over Na2SO4. The remainder was purified by withdrawal by 20% -50% acetone / hexane-flash column chromatography. The resulting free base was concentrated in 1 mL of 4N HCl / dioxane and concentrated. Synthesis P-465 was obtained as a tan solid (24.1 mg, 19% for 2 steps). 1H NMR (400 MHz, DMSO-d6) 8.52 (s, 1 H), 7.77 (br. S., 1 H), 7.49-7.32 (m, 6 H), 7.27 (br s, 1 H), 6.96 ( d, J = 8.6 Hz, 1 H), 4.47 (s, 2 H), 4.35-4.24 (m, 2 H), 4.01 (s, 2 H), 3.73 (s, 3 H), 3.57-3.50 (m , 2 H) ppm. LC / MS = 100.0%, 427.1 (APCI +).
Example 271. Preparation for P-521

N- [5- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -oxalamic acid ethyl ester (I-241). To 18 mL, the vial was summed P-344 (152 mg, 0.43 mmol), TEA (0.11 mL, 0.85 mmol) and dichloromethane (4 mL). Ethyl chloro oxoacetate (71 uL, 0.64 mmoL) was added and the solution was cooled to 0 ° C. At room temperature, the organic fertilizer was concentrated and after 20 minutes the reaction was washed with brine. The semi-solid was triturated with 1: 1 ether: EtOAc (filtered and washed with EtOAc to provide I-241 (69 mg, 35%) as a gray blue solid). 1H NMR (400 MHz, DMSO-d6) 9.38 (t, J = 6.0 Hz, 1 H), 8.41 (s, 1 H), 7.59 (dd, J = 4.0, 8.0 Hz, 2 H), 7.48-7.25 ( m, 8 H), 7.22 (d, J = 8.1 Hz, 2 H), 6.94 (d, J = 8.6 Hz, 2 H), 4.39 (d, J = 6.0 Hz, 2 H), 4.32-4.18 (m , 2 H), 3.94 (s, 2 H), 3.72 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm.

N- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-ylmethyl] -oxa fugitive sugar (P-521). To an 8 mL vial, I-241 (14.8 mg, 0.032 mmol) and 2 mL of 7N NH3 / MeOH were added. After stirring for 1 hour at room temperature, the solution was concentrated to yield P-521 (11.9 mg, 87%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) 9.15 (t, 1 H), 8.41 (d, J = 1.5 Hz, 1 H), 8.08 (br s, 1 H), 7.82 (br s, 1 H), 7.59 (dd, J = 1.9, 8.1 Hz, 1 H), 7.48-7.25 (m, 5 H), 7.19 (d, J = 8.1 Hz, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 4.39 (d, J = 6.2 Hz, 2 H), 3.94 (s, 2 H), 3.72 (s, 3 H) ppm. LC / MS = 98.9%, 428.0 (APCI +).
Example 272. Preparation for I-145.

  Synthesis of carbamic acid 3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester (I-145). Pyridine (2.31 g, 29.3 mmol) and tetrahydrofuran (40 mL) in (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -methanol (I-32, 3.00 g, 11.3 mmol) ) Was cooled to 0 ° C. in an ice-water bath. Methyl chloroformate (2.34 g, 24.8 mmol) was added and the reaction vessel was removed with nitrogen. The reaction was stirred overnight at room temperature and the ice bath was removed. The yellow biphasic solution was diluted with dichloromethane (200 mL) and water (150 mL) and the white stop was adjusted to pH 2 by addition of 1N aqueous hydrochloric acid (~ 25 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 100 mL). The dichloromethane extracts combined. Brine (200 mL) (dried over sodium sulfate) was then filtered and washed with water (2 × 200 mL) and the solvent gave I-145 (3.84 g, quantitative yield). For removal under vacuum.

  1H NMR (400 MHz, CDCl3) 7.41-7.32 (m, 4H), 7.29-7.26 (m, 1H), 6.76 (dd, J = 8.40 Hz, 0.80 Hz, 1H), 5.204 (s, 2H), 3.800 ( s, 3H), 3.795 (s, 3H) ppm.

LCMS = 98.2% purity. MS (APCI +) = 249.0 (M-78), MS (APCI-) = 249.0 (M-78).
Example 273. Preparation for P-376

  Synthesis of 2- (3-chlorophenyl) -3-methoxy-6-methyl-pyridine (I-243): 2-bromo-3-methoxy-6-methyl-pyridine (0.2 g, 1.0 mmol), 3- Chlorophenyl bromine acidic (1) (0.19 g, 1.2 mmol), PPh3 (0.13 g, 0.5 mmol), K2CO3 (0.06 g, 0.4 mmol) and Pd (OAc) to 2 (0.03 g 0.12 mmol) was added dioxane (3 mL) and EtOH—H 2 O (1: 1, 1.5 mL). Ar gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 180 ° C. for 15 m using a microwave oven (Biotage Initiator II). H2O and dichloromethane (40 mL each) were added and the reaction was cooled to room temperature and concentrated. The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. The remainder was purified by silica gel column chromatography using 1: 1 dichloromethane-hexane and then dichloromethane to yield 0.19 g (81%) of I-243 as mucus.

  Synthesis of 6-bromomethyl-2- (3-chlorophenyl) -3methoxy pyridine (I-244). To I-243 (1.02 g, 4.36 mmol) and CCl4 (20 mL) in NBS (0.78 g, 4.36 mmol), benzoyl peroxide (0.03 g, 0.12 mmol) was added. The reaction was stirred at 80 ° C. under N 2 for 20 h. The reaction was cooled to room temperature and concentrated. The remainder is dissolved in a mixture of dichloromethane and hexane (1: 1, 8 mL), using 1: 1 dichloromethane-hexane to yield 0.83 g (61%) of I-244 as a mucus. It was purified by silica gel column chromatography.

Synthesis of {4- [6- (3-chlorophenyl) -5-methoxy-pyridin-2-ylmethyl] -phenyl} -urea (P-376). Up to I-244 (0.31 g, 1.0 mmol), [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -urea (0. 39 g, 1.5 mmol), (PPh3) 4Pd (0.12 g, 0.1 mmol) and K3PO4 (0.42 g, 2.0 mmol) were added DME (8 mL) and EtOH-H2O (1: 1, 4 mL). )Met. Ar gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 160 ° C. for 20 m using a microwave oven (Biotage Initiator II). The reaction was cooled to room temperature. And H2O and dichloromethane (50 mL each) were added and aggregated. The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the organic layer was separated. The combined organic extract was dried over Na2SO4, filtered and concentrated. Rather than being triturated with 1: 1 ethyl acetate in hexane to yield 0.023 g (6%) of P-376 as an off-white solid, the remainder used 3-5% methanol in dichloromethane. Purified by silica gel column chromatography. 1H NMR (DMSO-d6, 400 MHz): 8.42 (s, 1 H), 7.84-7.93 (m, 2 H), 7.4-7.54 (m, 3 H), 7.3 (d, J = 8.4 Hz, 2 H ), 7.22 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 5.77 (s, 2 H), 3.99 (s, 2 H), 3.83 (s, 3 H ) ppm; MS (APCI +): 368.0 (M + 1), LC-MS: 92.5%.
Example 274. Preparation for P-379

5- [6- (3-Chlorophenyl) -5-methoxy-pyridin-2-ylmethyl] -pyridin-2-ylamine (P-379) To I-244 (0.1 g, 0.32 mmol), 5- (4 , 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -pyridine-2-ylamine (0.08 g, 0.38 mmol), (PPh3) 4Pd (0.04 g, 0.03 mmol) ) And K3PO4 (0.14 g, 0.64 mmol) were additional DME (3 mL) and EtOH—H 2 O (1: 1, 1.54 mL). Ar gas was bubbled by the stirred reaction for 5 minutes. The reaction was stirred at 150 ° C. for 20 m using a microwave oven (Biotage Initiator II). The reaction was cooled to room temperature (concentrated). The remainder was purified by a follow-up TLC using 70% ethyl acetate in hexane to yield 0.06 g (55%) of P-379 as mucus. 1H NMR (CDCl3, 400 MHz): 8.03 (d, J = 1.6 Hz, 1 H), 7.93-4 -7.96 (m, 1 H), 7.82-7.86 (m, 1 H), 7.34-7.58 (m, 3 H), 7.2 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 6.47 (dd, J = 8.4, 0.8 Hz, 1 H), 4.35 (s, 2 H), 4.01 (s, 2 H), 3.84 (s, 3 H) ppm; MS (APCI +): 326.1 (M + 1), LC-MS: 100%.
Example 275. Preparation for P-386

Synthesis of hydrochloric acid (P-386) 1- {5- [6- (3-chlorophenyl) -5-methoxy-pyridin-2-ylmethyl] -pyridin-2-yl} -3-ethyl-urea. Ethyl isocyanate (0.033 g, 0.46 mmol) was added to P-379 (0.05 g, 0.15 mmol) in pyridine (1.5 mL). The reaction was stirred at room temperature for 20 h. Water and ethyl acetate (20 mL each) were added. The aqueous layer was extracted with ethyl acetate (2 × 10 mL) and the organic layer was separated. The combined organic extracts were washed with water (2 × 30 mL), brine, 20 mL with Na 2 SO 4, filtered and concentrated. The rest was dissolved in ether (2 mL) and ether (0.5 ml) of 2M HCl was added. And it was stirred for 1 h. The ether layer was moved. It was triturated with ether (2 × 2 mL). It was then dried to yield 0.045 g (68%) of P-386 as a light yellow solid. 1H NMR (DMSO-d6, 400 MHz): 10.03 (br s, 1 H), 7.84-7.9 (m, 3 H), 7.76 (br s, 1 H), 7.58 (d, J = 8.8 Hz, 1 H ), 7.44 -7.5 (m, 2 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.8 Hz, 1 H), 4.08 (s, 2 H), 3.85 (s, 3 H), 3.15-3.23 (m, 2 H), 1.08 (t, J = 7.2 Hz, 3 H) ppm; MS (APCI +): 397.1 (M + 1), LC-MS: 99%, HPLC 97.9% pure.
Example 276. Preparation for P-099

Synthesis of (4-fluoro-phenyl)-(2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl) -methanone (I-246). In an 8 mL vial with stirring, the bars were placed nitrobenzene (1.0 mL) and AlCl 3 (92.7 mg, 0.695 mmol). After stirring for 5 minutes, the mixture could be stirred for 1 hour at room temperature and chloride (83.2 μL, 0.695 mmol) 4-fluorobenzoyl was added. The reaction mixture was then stirred at room temperature for 19 hours and I-81 (150 mg, 0.579 mmol) was added. Reaction mixture quenched with water (25 mL) and extracted with EtOAc (2 × 30 mL). The extracts were combined, washed with brine (30 mL), dried (MgSO4) and concentrated to a yellow solid. The solid was collected by suction filtration and the crude material was triturated with Et2O (5 mL). After the solid was washed with Et2O, 64.5 mg of I-246 was isolated as a light yellow solid in 30% yield. MS (APCI): 366.0 (M-1)

In an 8 mL vial equipped with a stir bar, the synthesis of 3- (4-fluoro-benzyl) -6-methoxy-3′-nitro-biphenyl-2-ol (P-099) was performed according to the configuration of I-246 (60 mg, 0.163 mmol) and triethylsilane (350 μL). The mixture was cooled in an ice-water bath and TFA (350 μL) was added. The reaction mixture was warmed to room temperature and reacted for 17 hours. After this time, additional triethylsilane (1.1 mL) and TFA (1.1 mL) were introduced and the reaction mixture was heated to 60 ° C. in a 24 hour oil bath. The reaction mixture was concentrated by a stream of N2, quenched with water (20 mL) and extracted with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 15% EtOAc / hexane as eluent to yield 33% yield of viscous, tan oil that yielded 18.9 mg P-099. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 3.94 (s, 2 H), 4.73 (s, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.96-7.00 ( m, 2 H), 7.01 (d, J = 8 Hz, 1 H), 7.19-7.22 (m, 2 H), 7.63 (t, J = 7 Hz, 1 H), 7.69 (dt, J = 8, 2 Hz, 1 H), 8.22-8.26 (m, 2 H) ppm. MS (APCI-): 352.1 (M-1); LC-MS: 98%.
Example 277. Preparation for P-137

Synthesis of 4- (2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-carbonyl) -benzonitrile (I-247). In an 8 mL vial with stirring, the bars were placed nitrobenzene (2.0 mL) and AlCl 3 (515 mg, 3.86 mmol). After stirring for 5 minutes, the mixture could be stirred for 30 minutes at room temperature and chloride (83.2 μL, 0.695 mmol) 4-cyanobenzoyl was added. The reaction mixture was then stirred at 60 degrees C for 17 hours and I-81 (200 mg, 0.771 mmol) was added. Water was added (20 mL) and then extracted with dichloromethane (2 × 30 mL), the reaction was quenched with 1M HCl (4 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The material began to solidify or increased with the addition of hexane (4 mL). The solid was collected by suction filtration. It was then washed with hexane (3 × 1 mL) to yield 147 mg of I-247 as a 51% yield light yellow solid. MS (APCI): 373.1 (M-1), LC-MS: 91%.

Synthesis of 4- [hydroxy- (2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl) -methyl] -benzonitrile (P-137). In an 8 mL vial with stirring, the bar is placed in anhydrous THF (400 μL) followed by placed I-247 (20 mg, 0.0534 mmol), absolute EtOH (300 μL), NaBH 4 (40.5 mg, 1.07 mmol). )Met. The reaction mixture was stirred at room temperature for 17 hours. The reaction was quenched with water (20 mL) and extracted with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL) and dried (MgSO4) and concentrated to yield 12.0 mg P-137 as an off-white solid in 63% yield. . 1H NMR (400 MHz, CDCl3) δ 3.01 (d, J = 3 Hz, 1 H), 3.74 (s, 3 H), 6.08 (m, 1 H), 6.55 (d, J = 8 Hz, 1 H) , 6.99 (d, J = 9 Hz, 1 H), 7.13 (s, 1 H), 7.54 (d, J = 8 Hz, 2 H), 7.59 (t, J = 8 Hz, 1 H), 7.67 ( d, J = 8 Hz, 2 H), 7.69-7.72 (m, 1 H), 8.19-8.22 (m, 1 H), 8.26-8.27 (m, 1 H) ppm. MS (APCI-): 375.1 ( M-1).
Example 278. Preparation for P-138

4- (2-Hydroxy-6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -benzonitrile (synthesis of P-138). In 8 mL vials with agitation, the bars were placed I-247 (60 mg, 0.160 mmol) and triethylsilane (600 μL). The reaction mixture was cooled in an ice-water bath and TFA (600 μL) was added. The mixture was heated to 70 degrees C for 23 hours. The reaction mixture was concentrated by a stream of N 2 followed by addition of water (20 mL) and extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 25% EtOAc / hexane as eluent to yield 21.9 mg P-138 as a pale yellow solid in 38% yield). 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 4.02 (s, 2 H), 4.77 (s, 1 H), 6.56 (d, J = 8 Hz, 1 H), 7.11 (d, J = 8 Hz, 1 H), 7.35 (d, J = 9 Hz, 2 H), 7.57 (d, J = 8 Hz, 2 H), 7.64-7.70 (m, 2 H), 8.24-8.27 (m , 2 H) ppm. MS (APCI-): 359.1 (M-1), LC-MS:> 99%.
Example 279. Preparation for P-157

Synthesis of (4-dimethylamino-phenyl)-(2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl) -methanone (I-248). In an 8 mL vial with agitation, the bars were placed nitrobenzene (2.5 mL) and AlCl 3 (773 mg, 5.80 mmol). After stirring for 5 minutes, the mixture could be stirred for 30 minutes at room temperature and 4-dimethylamino-benzoyl chloride (533 mg, 2.90 mmol) was added. The reaction mixture was then stirred at 60 ° C. for 23 hours and I-81 (300 mg, 1.16 mmol) was added. Water was added (20 mL) and then extracted with dichloromethane (2 × 30 mL), the reaction was quenched with 1M HCl (4 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 10% EtOAc / hexane as eluent to yield 167 mg of I-248 as a 37% yield yellow solid.

Synthesis of 3- (4-dimethylamino-benzyl) -6-methoxy-3'-nitro-biphenyl-2-ol (P-157). In an 8 mL vial with stirring, the bars were placed I-248 (165 mg, 0.420 mmol) and trimethylsilane (1.6 mL). The reaction mixture was cooled in an ice-water bath and TFA (1.6 mL) was added. The mixture was heated to 65 degrees C for 17 hours. The reaction mixture was concentrated by a stream of N 2 followed by addition of water (25 mL) and extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 50% EtOAc / hexane as eluent to yield 52.4 mg P-157 as a 33% yield orange red viscous oil. 1H NMR (400 MHz, CDCl3) δ 2.91 (s, 6 H), 3.73 (s, 3 H), 3.90 (s, 2 H), 4.86 (s, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.69 (2, J = 9 Hz, 2 H), 7.11-7.15 (m, 3 H), 7.57 (t, J = 8 Hz, 1 H), 7.70 (d, J = 8 Hz, 1 H), 8.17-8.20 (m, 1 H), 8.25 (s, 1 H) ppm. MS (APCI +): 379.1 (M + 1); LC-MS:> 99%.
Example 280. Preparation for P-173

Synthesis of (2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl)-(4-pyrazol-1-yl-phenyl) -methanone (I-249). In an 8 mL vial with stirring, the bars were placed nitrobenzene (2.4 mL) and AlCl 3 (515 mg, 3.86 mmol). After stirring for 5 minutes, the mixture could be stirred for 45 minutes at room temperature and 4-pyrazol-1-yl-benzoyl chloride (318 mg, 1.54 mmol) was added. The reaction mixture was then stirred at 60 degrees C for 17 hours and I-81 (250 mg, 0.964 mmol) was added. Water was added (15 mL) and then extracted with dichloromethane (2 × 30 mL), the reaction was quenched with 1M HCl (10 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 50% EtOAc / hexane as eluent to yield 257 mg I-249 as a 64% yield yellow solid.

Synthesis of 6-methoxy-3′-nitro-3- (4-pyrazol-1-yl-benzyl) -biphenyl-2-ol (P-173). In an 8 mL vial with stirring, the bars were placed I-249 (150 mg, 0.361 mmol) and trimethylsilane (1.3 mL, 8.14). The reaction mixture was cooled in an ice-water bath and TFA (1.3 mL, 17.5 mmol) was added. The mix was heated to 70 degrees C for 16 hours. The reaction mixture was concentrated by a stream of N 2 followed by addition of water (20 mL) and extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 20% EtOAc / hexane as eluent to yield 105 mg P-173 as a 33% yield yellow viscous oil.
1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3 H), 4.01 (s, 2 H), 4.79 (s, 1 H), 6.44-6.45 (m, 1 H), 6.56 (d, J = 8 Hz, 1 H), 7.13 (d, J = 8 Hz, 1 H), 7.33 (d, J = 8 Hz, 2 H), 7.60-7.65 (m, 3 H), 7.69-7.71 (m, 2 H ), 7.88 (d, J = 3 Hz, 1 H), 8.22-8.23 (m, 1 H), 8.24-8.26 (m, 1 H) ppm.
MS (APCI +): 402.1 (M + 1); LC-MS:> 99%.
Example 281. Preparation for P-174

In an 8 mL vial equipped with a stir bar, [4- (3,5-dimethyl-isoxazol-4-yl) -phenyl]-(2-hydroxy-6-methoxy-3′-nitro-biphenyl-3- The synthesis of yl) -methanone (I-250) was arranged nitrobenzene (2.4 mL) and AlCl3 (515 mg, 3.86 mmol). After stirring for 5 minutes, the mixture could be stirred for 45 minutes at room temperature and chloride (246 mg, 1.54 mmol) 3,5-dimethyl-isoxazole-4-carbonyl was added. The reaction mixture was then stirred at 60 degrees C for 17 hours and I-81 (250 mg, 0.964 mmol) was added. Water was added (15 mL) and then extracted with dichloromethane (2 × 30 mL), the reaction was quenched with 1M HCl (10 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 50% EtOAc / hexane as eluent to yield 194 mg of I-250 as a 55% yield of light brown solid.

  Synthesis of 3- [4- (3,5-dimethyl-isoxazol-4-yl) -benzyl] -6-methoxy-3'-nitro-biphenyl-2-ol (P-174). In 8 mL vials with stirring, the bars were placed TFA (114 μL, 1.22 mmol) and anhydrous dichloromethane (450 μL). The available solution is 40 to -50 degrees C. in a chilled-acetone-dried ice bath. NaBH4 (46.2 mg, 1.22 mmol) was then a sensible additional part over 5 minutes. The reaction mixture was warmed to 0 ° C. in an ice-water bath and the solution of anhydrous dichloromethane (450 μL) I-250 (45 mg, 0.122 mmol) was a wise additional drop over 5 minutes. The reaction mixture was warmed to room temperature and reacted for 18 hours. The reaction mixture was slowly quenched with water (20 mL) and extracted with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 30% EtOAc / hexane as the eluent to yield 16.9 mg P-174 as a 39% yield of pale yellow viscous oil.

1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3 H), 2.32 (s, 3 H), 3.62 (s, 2 H), 3.71 (s, 3 H), 4.84 (s, 1 H), 6.51 (d, J = 7 Hz, 1 H), 6.95 (d, J = 7 Hz, 1 H), 7.66-7.70 (m, 2 H), 8.24-8.28 (m, 2 H) ppm. MS (APCI +) : 355.1 (M + 1); LC-MS:> 99%.
Example 282. Preparation for P-180

4- (2-Hydroxy-6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -benzaldehyde (synthesis of P-180). In an 8 mL vial equipped with agitation, the bars were placed P-138 (105 mg, 0.291 mmol) and anhydrous THF (950 μL). The solution was chilled in a 10 minute ice-water bath and DIBAL-H (hexane, 1.46 mL, 1.46 mmol of 1.0 M) was added. The reaction mixture was warmed to room temperature and reacted for 17 hours. The reaction was cooled in an ice-water bath. It was then slowly quenched with 1M HCl (4 mL) by addition of water (20 mL) and extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO.sub.2 column chromatography utilizing 25% EtOAc / hexane as the eluent yielding 32.4 mg P-180 as a 31% yield off-white solid. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 4.05 (s, 2 H), 4.76 (s, 1 H), 6.57 (d, J = 8 Hz, 1 H), 7.13 (d, J = 8 Hz, 1 H), 7.42 (d, J = 8 Hz, 2 H), 7.63-7.70 (m, 2 H), 7.81 (d, J = 8 Hz, 2 H), 8.24-8.26 (m , 2 H), 9.97 (s, 1 H) ppm. MS (APCI-): 362.1 (M-1); LC-MS: 99%.
Example 283. Preparation for P-183

3- (4-Hydroxymethyl-benzyl) -6-methoxy-3′-nitro-biphenyl-2-ol (synthesis of P-183). In 8 mL vials with stirring, the bars were P-180 (23 mg, 0.0630 mmol) and anhydrous MeOH (250 μL) placed. Mixing was cooled in an ice-water bath and NaBH4 (11.9 mg, 0.315 mmol) in which the reaction mixture was in solution was added. The reaction was stirred at room temperature for 22 hours, quenched with 1M aqueous HCl (4 mL) and water (20 mL) and extracted with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by SiO2 column chromatography utilizing 50% EtOAc / hexane as the eluent yielding 15.1 mg P-183 as a 65% yield orange viscous oil. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 3.98 (s, 2 H), 4.67 (s, 2 H), 4.74 (s, 1 H), 6.55 (d, J = 9 Hz, 1 H), 7.13 (d, J = 9 Hz, 1 H), 7.24-7.32 (m, 4 H), 7.62 (t, J = 8 Hz, 1 H), 7.68-7.71 (m, 1 H), 8.21-8.25 (m, 2 H) ppm. MS (APCI +): 348.1 (M-17); LC-MS:> 99%.
Example 284. Preparation for P-190

Synthesis of N- [4- (2-hydroxy-6-methoxy-3′-nitro-biphenyl-3-carbonyl) -phenyl] -acetamide (I-251). In an 18 mL vial with agitation, the bars were placed nitrobenzene (4.6 mL) and AlCl 3 (1.23 g, 9.24 mmol). After stirring for 5 minutes, the mixture could be stirred for 30 minutes at room temperature and 4-acetylamino-benzoyl chloride (913 mg, 4.62 mmol) was added. The reaction mixture was then stirred at 70 ° C. for 21 hours and I-81 (600 mg, 2.31 mmol) was added. Water was added (100 mL) and then extracted with dichloromethane (2 × 50 mL), the reaction was quenched with 1M aqueous HCl (10 mL). The organic portions were combined, washed with brine (200 mL), dried (MgSO4) and concentrated. The remainder is triturated with Et 2 O (35 mL) and collected by suction filtration to yield 333 mg of I-251 as a pale orange solid in 35% yield, Et 2 O (5 × 2 mL). Washed by. MS (APCI +): 407.0 (M + 1)

  Synthesis of N- [4- (2-hydroxy-6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -phenyl] -acetamide (P-190). In an 8 mL vial with stirring, the bars were placed I-251 (200 mg, 0.492 mmol) and trimethylsilane (1.80 mL, 11.3). The reaction mixture was cooled in an ice-water bath and TFA (1.80 mL, 24.6 mmol) was added. The mixture was heated to 70 degrees C for 18 hours. The reaction mixture was concentrated by a stream of N 2 followed by addition of water (30 mL) and extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was purified by SiO2 column chromatography utilizing 5% 1M NH3 in MeOH / dichloromethane as eluent to yield 36.6 mg P-190 as a 19% yield light yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3 H), 3.72 (s, 3 H), 3.94 (s, 2 H), 4.74 (s, 1 H), 6.55 (d, J = 9 Hz, 1 H), 7.09 (bs, 1 H), 7.7.11 (d, J = 8 Hz, 1 H), 7.20 (d, J = 8 Hz, 2 H), 7.42 (d, J = 8 Hz, 2 H), 7.62 (t, J = 8 Hz, 1 H), 7.68-7.70 (m, 1 H), 8.21-8.25 (m, 2 H) ppm. MS (APCI +): 393.1 (M + 1); LC -MS: 93%.

実施例２８５。Ｐ―２６０の準備 << Reaction process formula 58 >>

Example 285. Preparation for P-260

  Synthesis of 3-iodo-4 methoxy phenyl amine (I-252). 3- At the neck, a 250 mL round bottom flask equipped with stir bar, condenser and N2 wire was placed in place with iron powder (3.50 g, 62.7 mmol), ammonium chloride (4.88 g, 91.3 mmol), ethanol (72 mL) and water (23 mL). The mixture was heated to 85 ° C. and 2-iodo-1-methoxy-4-nitrobenzene (5.0 g, 17.9 mmol) was a wise additional part over about 2 minutes. The mixture could be stirred at 85 ° C. for 2 hours and the celite was filtered. The filtrate was concentrated and the celite was washed with EtOH (100 mL). The concentrated material was additional water (100 mL) and ethyl acetate (150 mL). The watery portion was re-drawn with ethyl acetate (150 mL) and the organic portion was removed. The organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The remainder was purified by column chromatography utilizing 50% EtOAc / hexane as the eluent to yield 3.92 g of I-252 as a brown semi-solid in 88% yield. MS (ESI +): 250.1 (M + 1).

  Synthesis of 1- (5′-amino-2′-methoxy-biphenyl-3-yl) -ethanone (I-253). 3- At the neck, a 100 mL round bottom flask equipped with a condenser, stir bar and N2 wire was placed in I-252 (2.92 g, 11.7 mmol), 3 acetylphenyl bromic acid (2 .11 g, 12.9 mmol), potassium carbonate (4.85 g, 35.1 mmol), triphenylphosphine (921 mg, 3.51 mmol), 1,4-dioxane (23 mL), palladium (II) acetate (263 mg) 1.17 mmol) followed by 50% aqueous ethanol (23 mL). The mixture was heated to 90 ° C. for 16 hours and cooled to room temperature. The palladium catalyst was removed via filtration and added to filtered water 1M aqueous HCl (50 mL) and water (50 mL). The organic portions were combined, washed with brine (75 mL), dried (MgSO 4) and the concentrated, water-like portion was withdrawn with ethyl acetate (2 × 75 mL). The remainder was purified by column chromatography utilizing 50% EtOAc / hexane as the eluent to yield 1.18 g of I-253 as a 42% yield of pale orange oil. MS (APCI +): 242.0 (M + 1).

  Synthesis of 1- [2'-methoxy-5 '-(4-nitro-phenylamine) -biphenyl-3-yl] -ethanone (I-254). In a 40 mL vial equipped with a stir bar, 1-iodo-4-nitrobenzene (1.26 g, 5.07 mmol) (cesium carbonate (2.20 g, 6.76 mmol) (±) was placed −2 , 2'-bis (diphenylphosphino) -1,1'-binaphthalene (316 mg, 0.507 mmol) and toluene (13.5 mL) solution of I-253 (816 mg, 3.38 mmol). And tris (dibenzylideneacetone) di-palladium (0) (310 mg, 0.338 mmol) and the mixture was heated for 16 hours to 110 ° C. The reaction was cooled to room temperature and Celite was filtered and the filtrate was treated with water (40 mL), 1M HCl (40 mL), then ethyl acetate (2 × 75 mL). The organic portions were combined, washed with brine (75 mL), dried (MgSO4) and concentrated, the remainder being 277 mg of I as a dark orange solid in 23% yield. Purified by column chromatography utilizing 35% EtOAc / hexane as eluent to yield -254.

  1- [5 ′-(4-Amino-phenylamine) -2, ′-methoxy-biphenyl-3-yl] -ethanone hydrochloride (synthesis of P-260). In an 18 mL vial with agitation, the bar is placed iron powder (148 mg, 2.66 mmol), ammonium chloride (207 mg, 3.87 mmol), absolute EtOH (3.1 mL) and water (1. 0 mL). The mixture was heated to 85 ° C. and the mixture was heated for 2 hours and I-254 (275 mg, 0.759 mmol) was added. The reaction was cooled to room temperature, filtered through celite and extracted with ethyl acetate (2 × 40 mL). The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The remainder was purified by column chromatography utilizing 75% EtOAc / hexane as eluent to produce 207 mg of free base as a 82% yield of dark orange oil. The free base was treated with 4.0 M HCl in 1,4-dioxane (1.0 mL) and stirred at room temperature for 3 hours. The solid was collected via suction filtration and the reaction mixture was treated with diethyl ether (4 mL). After washing the solid with diethyl ether (3 × 2 mL), 20 mg of P-260 was isolated as a 44% yield brown solid.

1H NMR (400 MHz, DMSO-d6) δ 2.61 (s, 3 H), 3.75 (s, 3 H), 4.63 (br s, 1 H), 7.02-7.20 (m, 7H), 7.57 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 8.02 (t, J = 2 Hz, 1 H), 9.42 (br s, 3H ) ppm. MS (APCI-): 366.9 (M-2)
Example 286. Preparation for P-267

  Synthesis of N- [4- (3′-acetyl-6-methoxy-biphenyl-3-ylamino) -phenyl] -methanesulfonamide (P-267). In an 8 mL vial with agitation, the bars are placed P-260 (free base) (60.0 mg, 0.180 mmol), anhydrous dichloromethane (600 μL), pyridine (14.6 μL, 0.180 mmol), It was methanesulfonyl chloride (13.9 μL, 0.180 mmol). The reaction mixture was stirred at room temperature for 17 hours and then quenched with 1M aqueous HCl to pH 1-2. After adding water (20 mL), the organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated, extraction was performed with dichloromethane (2 × 30 mL). The remainder utilizes 10% acetone / dichloromethane as eluent to yield 25 mg P-267 as a 34% yield off-white solid after drying in a high vacuum oven at 40 ° C. for 2 hours. Purified by pillar.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.2.63 (s, 3 H), 2.96 (s, 3 H), 3.81 (s, 3 H), 6.08 (br s, 1 H), 6.91-6.98 ( m, 3 H), 7.11-7.14 (m, 4 H), 7.51 (t, J = 8 Hz, 1 H), 7.72 (dt, J = 8, 1 Hz, 1 H), 7.92 (d, J = 8 Hz, 1 H), 8.10 (t, J = 2 Hz, 1 H) ppm. MS (APCI +): 411.1 (M + 1)
LC-MS: 97%.
Example 287. Preparation for P-261

Synthesis of [4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -carbamic acid tert-butyl ester (I-255). In an 8 mL vial with stirring, the stick is placed I-223 (295 mg, 0.888 mmol), 4-[(tert-butoxycarbonyl) amino] -phenyl bromic acid (232 mg, 0.977 mmol), Potassium carbonate (270 mg, 1.95 mmol), 1,5-bis (diphenylphosphino) pentane (39.1 mg, 0.0888 mmol), allyl palladium (II) chloride dimer (16.2 mg, 0.0444 mmol) And dimethylformamide (1.5 mL). The reaction mixture was heated to 80 ° C. for 17 hours. The reaction mixture could be stirred at 80 ° C. for 17 hours to consume the remaining I-223 and added allyl palladium (II) chloride dimer (32.5 mg, 0.0888 mmol). ) And 1,5-bis (diphenylphosphino) pentane (78.2 mg, 0.178 mmol) were added. The reaction mixture was filtered through celite and additional water (40 mL) and saturated ammonium chloride solution (40 mL) in filtered water. After extraction with ethyl acetate (2 × 50 mL), the organic portions were combined, washed with brine (50 mL), dried (MgSO 4) and concentrated. The remainder was purified by column chromatography utilizing 30% EtOAc / hexane as eluent to yield 365 mg of I-255 as a 91% yield of pale yellow solid.

Synthesis of 1- [3 ′-(4-amino-benzyl) -2, ′-fluoro-6′-methoxy-biphenyl-3-yl] -ethanone, hydrochloride (P-261). In an 8 mL vial with stirring, the bars were placed I-255 (265 mg, 0.590 mmol), dichloromethane (2.0 ml) and trifluoroacetic acid (438 μL, 5.90 mmol). The reaction mixture was stirred for 4 hours at room temperature and then quenched to pH 7 with saturated sodium bicarbonate solution. After addition of water (30 mL) and extraction with dichloromethane (2 × 30 mL), the organic portions were combined, washed with brine (30 mL), dried (MgSO 4) and concentrated. The crude material was treated with diethyl ether (1 mL) in diethyl ether (3 mL) and 2.0 M HCl and allowed to stir at room temperature for 2 hours. The solid has diethyl ether (3 × 2 mL) yielding 139 mg of P-261 as a collected 61% yield light orange powder collected. 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3 H), 3.72 (s, 3 H), 3.96 (s, 2 H), 6.96 (d, J = 8 Hz, 1 H), 7.20- 7.34 (m, 5 H), 7.57 (d, J = 5 Hz, 2 H), 7.85 (bs, 1 H), 7.94-7.97 (m, 1 H) ppm. MS (APCI +): 350.1 (M + 1 -HCl).
Example 288. Preparation for P-269

Synthesis of [4- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-269). In an 8 mL vial with agitation, the bar is filled with cyanide (20.9 mg, 0.321 mmol), P-261 (31 mg, 0.0803 mmol), water (400 μL), acetic acid (200 μL) and sodium. there were. The mixture was stirred for 4 hours at room temperature, and water (20 mL) was added followed by extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with saturated sodium bicarbonate solution (30 mL) and brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by column chromatography utilizing 75% acetone / dichloromethane as eluent to yield 18 mg P-269 as a 56% yield off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.62 (s, 3 H), 3.75 (s, 3 H), 3.95 (s, 2 H), 4.59 (br s, 2 H), 6.27 (br s, 1 H), 6.72 (d, J = 8 Hz, 1 H), 7.11 (t, J = 9 Hz, 1 H), 7.21 (s, 4H), 7.52 (t, J = 8 Hz, 1 H), 7.60 (dd, J = 9, 1 Hz, 1 H), 7.95 (d, J = 8 Hz, 1 H), 7.99 (br s, 1 H) ppm. MS (APCI +): 393.1 (M + 1); LC -MS: 95%.

実施例２８９。Ｐ―２８０の準備 << Reaction process formula 59 >>

Example 289. Preparation for P-280

  Integration of 3'-chloro-2-methoxy-5-nitro-biphenyl (I-256). In a 3-necked 500 mL round bottom flask equipped with a stir bar, condenser and 2-iodo-1-methoxy-4-nitrobenzene (7.0 g, 25. 1 mmol), 3-chlorophenyl bromic acid (4.32 g, 27.6 mmol), potassium carbonate, 10.4 g, 75.3 mmol, triphenylphosphine (1.98 g, 7.53 mmol), 1,4-dioxane ( 50 mL) followed by palladium acetate (564 mg, 2.51 mmol) followed by 50% aqueous EtOH. The mixture was heated to 90 ° C. in a 16 hour oil bath and then quenched with 1M aqueous HCl (80 mL). After the reaction mixture was filtered through celite, water (100 mL) and 1M aqueous HCl (100 mL) were added followed by extraction with ethyl acetate (3 × 150 mL). The organic portions were combined, washed with brine (250 mL), dried (MgSO4) and concentrated. The remainder was clarified by a column utilizing 20% EtOAc / Hexanes as the eluent yielding 4.26 g of I-256 as a 64% yield orange solid. MS (ESI +): 263.3 (M +).

  Integration of 3'-chloro-6-methoxy-biphenyl-3-ylamine (I-257). 3- At the neck, 250 mL around the flask reached to the bottom equipped with a stir bar, condenser and nitrogen line was placed iron powder (3.17 g, 56.7 mmol), ethanol (66 mL) and Water (21 mL). Mixing was heated to 85 ° C. in an oil bath, and the reaction was continued at 85 ° C. for 2 hours and I-256 (4.26 g, 16.2 mmol) was added. The reaction mixture was cooled to room temperature and filtered through celite. Extraction was performed with ethyl acetate (3 × 100 mL) and to the filtered water was added water (150 mL). The organic portions were combined, washed with brine (100 mL), dried (MgSO4) and concentrated. The crude material was purified by a column utilizing 65% EtOAc / Hexanes as the eluent to yield 2.87 g of I-257 as a 76% yield of orange viscous oil. MS (APCI +): 234.0 (M + 1)

  Synthesis of (3'-chloro-6-methoxy-biphenyl-3-yl)-(4-nitrophenyl) -amine (I-258). 3- At the neck, a 100 mL round bottom flask equipped with a stir bar, condenser and nitrogen line was placed in I-257 (1.2 g, 5.13 mmol) (4-iodo-nitrobenzene ( 1.92 g, 7.70 mmol) (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthalene (480 mg, 0.770 mmol), cesium carbonate (3.34 g, 10 .3 mmol) followed by toluene (21 mL) followed by tris (dibenzylideneacetone) di-palladium (0) (470 mg, 0.513 mmol) The mixture was heated to 100 ° C. in an oil bath for 17 hours and then And quenched with 1M aqueous HCl (50 mL) The reaction mixture was filtered through celite and filtered into ethyl acetate (2 X75 mL) followed by additional water (50 mL) The organic portions were combined, washed with brine (100 mL), dried (MgSO4) and concentrated. Purified by a column utilizing 25% EtOAc / Hexanes as the eluent to yield 1.36 g of I-258 as a red-orange solid of 75% yield.MS (APCI +): 355.1 (M + 1)

  Synthesis of N- (3′-chloro-6-methoxy-biphenyl-3-yl) -benzene-1,4-diamine, hydrochloride (P-280). In a 40 mL vial with agitation, the bars were iron powder (330 mg, 5.92 mmol), ethanol (6.9 mL) and water (2.2 mL) placed. Mixing was heated to 85 ° C. in an oil bath and the reaction was continued at 85 ° C. for 2 hours and I-258 (600 mg, 1.69 mmol) was added. The reaction mixture was cooled to room temperature and filtered through celite. Extraction was performed with ethyl acetate (2 × 50 mL) and to the filtered water was added water (50 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The remainder was cleaned by a column utilizing 75% EtOAc / Hexanes as the eluent to produce 480 mg of P-280 free base. Et2O (2 mL) and a mixture of 2.0 M HCl were stirred for 1 hour at room temperature and Et2O (4 mL) was added to the free base. The solid was collected and washed with Et 2 O (10 mL) and dichloromethane (8 mL), and then 35 ° C. for 2 hours to yield 355 mg of P-280 as a pale blue solid in 58% yield. Dried in a high vacuum oven set at

1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 7.02-7.21 (m, 7 H), 7.38-7.45 (m, 3 H), 7.51-7.53 (m, 1 H), 9.97 (br s, 3 H) ppm. MS (ESI +): 326.4 [(M + 1) -HCl]. LC / MS: 92%.
Example 290. Preparation for P-294

[4- (3′-Chloro-6-methoxy-biphenyl-3-ylamino) -phenyl] -urea (synthesis of P-294). In an 8 mL vial with agitation, the stick is labeled with P-280 (150 mg, 0.415 mmol), water (2.4 mL), acetic acid (1.2 mL) and cyanic acid (108 mg, 1.66 mmol) and It was sodium. The mixture was stirred for 72 hours at room temperature, and water (20 mL) was added followed by extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by a column utilizing 40% acetone / dichloromethane as the eluent, yielding 46 mg P-294 as a light purple solid in 30% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 3 H), 5.67 (br s, 2 H), 6.90-6.92 (m, 3 H), 7.01 (s, 2 H), 7.23 (d, J = 9 Hz, 2 H), 7.37-7.49 (m, 4 H), 7.68 (s, 1 H), 8.23 (br s, 1 H) ppm. MS (APCI +): 368.1 (M + 1); LC -MS: 95%.
Example 291. Preparation for P-281

1- [3 ′-(2-Amino-pyrimidin-5-ylmethyl) -2, ′-fluoro-6′-methoxy-biphenyl-3-yl] -ethanone hydrochloride (synthesis of P-281). In an 18 mL vial with agitation, the stick is placed I-223 (704 mg, 2.12 mmol), 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) -pyrimidin-2-ylamine (515 mg, 2.33 mmol), potassium carbonate (879 mg, 6.36 mmol), 1,5-bis (diphenylphosphino) pentane (280 mg, 0.636 mmol), allyl palladium ( II) Chloride dimer (116 mg, 0.318 mmol) and dimethylformamide (4.2 mL). The reaction mixture was heated to 70 ° C. for 65 hours. The reaction mixture was filtered through celite, and water (40 mL) and saturated ammonium chloride solution (40 mL) were added to the filtered water. After extraction with ethyl acetate (2 × 50 mL), the organic portions were combined, washed with brine (50 mL), dried (MgSO 4) and concentrated. The remainder utilized 20% acetone / dichloromethane (gradient elution increased to 30%, and 40% acetone / dichloromethane) as eluent to yield a total of 341 mg P-281 per off-white with a 46% yield. Purified by column chromatography. The mixture was then heated to form a solution and P-281 (20 mg, 0.0569 mmol) was treated with 1,4-dioxane (1 mL). The mixture was stirred for 3 hours at room temperature and to this solution was added 1,4-dioxane (1 mL) of 4.0 M HCl. The resulting solid was triturated with diethyl ether (1 mL) and collected via suction filtration to produce 12 mg of P-281 HCl salt as a 55% yield light yellow solid. Washed with diethyl ether (3 × 1 mL) and the solvent was removed via a stream of nitrogen. 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3 H), 3.73 (s, 3 H), 3.83 (s, 2 H), 6.97 (d, J = 8 Hz, 1 H), 7.35 ( t, J = 9 Hz, 1 H), 7.59 (d, J = 6 Hz, 2 H), 7.88 (bs, 1 H), 7.95-7.97 (m, 1 H), 8.36 (bs, 2 H). MS (APCI +): 352.1 [(M + 1) -HCl]; LC-MS: 98%.
Example 292. Preparation for P-284

N- [5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrimidin-2-yl] -methanesulfonamide (synthesis of P-284). In an 8 mL vial with agitation, the bars are placed P-281 (free base) (70.0 mg, 0.199 mmol), pyridine (800 μL) and methane sulfonyl chloride (15.4 μL, 0.199 mmol) Met. The reaction mixture was stirred at room temperature for 2 hours, then heated to 50 ° C. for 2 hours and then quenched with aqueous 1M HCl to pH 1-2. After adding water (20 mL), the organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated, extraction was performed with ethyl acetate (2 × 30 mL). . The rest utilizes 20% acetone / dichloromethane as eluent to yield 29 mg P-284 as a 34% yield light yellow solid after drying in a high vacuum oven at 35 ° C. for 2 hours. Purified by pillars. 1H NMR (400 MHz, CDCl3) δ 2.62 (s, 3 H), 3.44 (s, 3 H), 3.77 (s, 3 H), 3.91 (s, 2 H), 6.76 (d, J = 8 Hz, 1 H), 7.158 (t, J = 8 Hz, 1 H), 7.53 (t, J = 8 Hz, 1 H), 7.59 (dd, J = 8, 1 Hz, 1 H), 7.95 (t, J = 1 Hz, 1 H), 7.97 (m, 1 H), 8.51 (s, 2 H), 9.85 (br s, 1H) ppm. MS (APCI +): 430.0 (M + 1); LC-MS: 92 %. HPLC: 97%.
Example 293. Preparation for P-315

Synthesis and stirring in 1- [5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrimidin-2-yl] -3-ethyl-urea (P-315) In the 8 mL vial provided, the bars are placed P-281 (free base) (80 mg, 0.228 mmol), pyridine (1.0 mL) and ethyl isocyanate (36.1 μL, 0.456 mmol) Met. The reaction mixture was stirred at room temperature for 18 hours. TLC analysis indicated that the reaction mixture consisted mostly of starting material. The mixture was heated to 55 ° C. for 65 hours and to the reaction mixture was added ethyl isocyanate (180 μL, 2.28 mmol). The resulting solid was collected, washed with water (3 × 2 mL), and ethyl acetate (3 × 1 mL) for 4 hours to yield 59 mg of P-315 as a 61% yield white solid. In a high vacuum oven set at 40 ° C., the reaction mixture was dried and quenched with water (3 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J = 7 Hz, 3 H), 2.59 (s, 3 H), 3.18-3.26 (m, 2 H), 3.73 (s, 3 H), 3.90 (s, 2 H), 6.97 (d, J = 9 Hz, 1 H), 7.36 (t, J = 9 Hz, 1 H), 7.57-7.59 (m, 2 H), 7.88 (s, 1 H ), 7.94-7.97 (m, 1 H), 8.46 (s, 2 H), 8.91 (t, J = 4 Hz, 1 H), 9.61 (s, 1 H) ppm. MS (APCI +): 423.1 (M +1); LC-MS: 94%, HPLC: 93%.
Example 294. Preparation for P-325

Synthesis of 1- [3 ′-(2-dimethylamino-pyrimidin-5-ylmethyl) -2, ′-fluoro-6′-methoxy-biphenyl-3-yl] -ethanone (P-325). In an 8 mL vial with agitation, the stick is placed I-223 (200 mg, 0.602 mmol), dimethyl- [5- (4,4,5,5-tetramethyl- [1,3,2]. ] Dioxaboran-2-yl) -pyrimidin-2-yl] -amine (165 mg, 0.662 mmol), potassium carbonate (250 mg, 1.81 mmol), 1,5-bis (diphenylphosphino) pentane (79.6 mg, 0.181 mmol), allyl palladium (II) chloride dimer (33.0 mg, 0.0903 mmol) and dimethylformamide (1.2 mL). The reaction mixture was heated to 65 ° C. for 18 hours. The reaction mixture was filtered through celite, and water (40 mL) and saturated ammonium chloride solution (40 mL) were added to the filtered water. After extraction with ethyl acetate (2 × 50 mL), the organic portions were combined, washed with brine (50 mL), dried (MgSO 4) and concentrated. The remainder was purified by column chromatography utilizing 50% ethyl acetate / hexane as the eluent to yield 90 mg P-325 as a 39% yield yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3 H), 3.07 (s, 6 H), 3.72 (s, 3 H), 3.77 (s, 2 H), 6.94 (d, J = 9 Hz, 1 H), 7.30 (t, J = 9 Hz, 1 H), 7.58 (d, J = 5 Hz, 2 H), 7.87 (s, 1 H), 7.94-7.96 (m, 1 H), 8.24 (s, 2 H) ppm. MS (APCI +): 380.1 (M + 1); LC-MS:> 99%.
Example 295. Preparation for P-362

Synthesis of [5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrimidin-2-yl] -urea (P-362). In an 8 mL vial with agitation, the sticks are placed P-281 (free base) (30 mg, 0.0854 mmol), 1,4-dioxane (800 μL) pyridine (34.5 μL, 0.427 mmol) and Trimethylsilyl isocyanate (57.8 μL, 0.427 mmol). The reaction mixture was heated to 90 ° C. for 18 hours and extraction with water (15 mL) and 1M HCl (15 mL) with dichloromethane (2 × 30 mL) was subsequently added. The organic portions were combined, dried (MgSO4) and concentrated. The remaining solid was collected and washed with hexane (3 × 1 mL) to yield 8 mg P-362 as a pale yellow solid in 23% yield at 40 ° C. for 4 hours. In a high vacuum oven set, it was added hexane to dry and cloudy. 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3 H), 3.73 (s, 3 H), 3.80 (s, 2 H), 6.96 (d, J = 9 Hz, 1 H), 7.34 ( t, J = 9 Hz, 1 H), 7.58-7.59 (m, 2H), 7.87 (s, 1 H), 7.94-7.97 (m, 1 H), 8.29 (s, 2 H) ppm. LC-MS :> 99%.
Example 296. Preparation for P-366

Synthesis of 1- [5- (3′-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrimidin-2-yl] -3- (2-chloroethyl) -urea (P-366). In an 8 mL vial with agitation, the bars are placed P-281 (free base) (70 mg, 0.199 mmol), chloroform (1.5 mL) and chloroethyl isocyanate (17.0 μL, 0.199 mmol) Met. The reaction mixture was heated to 65 ° C. for 18 hours. TLC analysis indicated that a small amount of starting material was present. The mixture was stirred at 75 ° C. for 22 hours and to the reaction mixture chloroethyl isocyanate (50.90 μL, 0.597 mmol) was added. The reaction disappeared with water (30 mL) and was extracted with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was purified by column chromatography utilizing 15% acetone / dichloromethane and recrystallized by: cracking the solid with dichloromethane (1 mL) and hexanes until cloudy. To add. The solid was collected. It was then washed with hexane (3 × 1 mL) to yield 9 mg of P-366 as a 10% yield white solid. 1H NMR (400 MHz, CDCl3) δ 2.62 (s, 3 H), 3.69-3.72 (m, 4 H), 3.77 (s, 3 H), 3.89 (s, 2 H), 6.76 (d, J = 8 Hz, 1 H), 7.15 (t, J = 9 Hz, 1 H), 7.45 (s, 1 H), 7.51-7.59 (m, 2 H), 7.94-7.98 (m, 2 H), 8.38 (s , 2 H), 9.36 (br s, 1 H) ppm. MS (APCI +): 457.1 (M + 1).
Example 297. Preparation for P-288

  In a 40 mL vial equipped with synthesis and stirring in (3′-chloro-6-methoxy-biphenyl-3-yl) -methyl- (4-nitrophenyl) -amine (I-259), the rod is Arranged I-258 (600 mg, 1.69 mmol), anhydrous DMF (6.8 mL), NaH (60%) (94.6 mg, 2.37 mmol) and methyl iodide (579 μL, 9.30 mmol) methyl . The reaction mixture was stirred at 50 ° C. for 17 hours and then quenched with water (30 mL) and saturated ammonium chloride solution (30 mL). After extracting with EtOAc (2 × 50 mL), the extracts were combined, washed with brine (50 mL), dried (MgSO 4) and concentrated. The remainder was purified by a column utilizing 20% EtOAc / hexane as the eluent yielding 490 mg of I-259 as a 79% yield of yellow orange solid.

Synthesis of N- (3′-chloro-6-methoxy-biphenyl-3-yl) -N-methyl-benzene-1,4-diamine, hydrochloride (P-288). In a 40 mL vial with stirring, the bars were iron powder (260 mg, 4.66 mmol), ethanol (5.3 mL) and water (1.7 mL) placed. The mixture was heated to 85 ° C. in an oil bath and the reaction was continued at 85 ° C. for 2 hours and I-259 (490 mg, 1.33 mmol) was added. The reaction mixture was cooled to room temperature and filtered through celite. Extraction was performed with ethyl acetate (2 × 50 mL) and to the filtered water was added water (50 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The remainder was purified by a column utilizing 50% EtOAc / hexane as the eluent to produce 376 mg of P-288 free base as an orange (viscous oil). Et2O (3 mL) and a mixture of 2.0 M HCl were stirred for 2 h at room temperature and to the free base Et2O (5 mL) was added. The solid is collected and washed with Et2O (6 mL) to set in a high vacuum oven at 40 ° C. for 3 hours to yield 225 mg of P-288 as a 54% yield of light brown solid. And dried. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (s, 3 H), 3.79 (s, 3 H), 6.85 (d, J = 9 Hz, 2 H), 7.12 (d, J = 2 Hz, 1 H), 7.15-7.21 (m, 4 H), 7.38-7.44 (m, 3 H), 7.52-7.54 (m, 1 H), 9.84 (br s, 3 H) ppm.
MS (APCI +): 339.1 (M + 1- HCl); LC-MS: 99%.
Example 298. Preparation for P-293

  Synthesis of {4-[(3′-chloro-6-methoxy-biphenyl-3-yl) -methyl-amino] -phenyl} -urea (P-293). In an 8 mL vial equipped with agitation, the stick is filled with cyanic acid (69.2 mg, 1.06 mmol), P-288 (100 mg, 0.266 mmol), water (1.6 mL), acetic acid (800 μL) and It was sodium. The mixture was stirred at room temperature for 72 hours and water (30 mL) was subsequently added with extraction with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The remainder was triturated with diethyl ether (2 mL) to yield 49 mg of P-293 as a 48% yield off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.19 (s, 3 H), 3.73 (s, 3 H), 5.72 (br s, 2 H), 6.87-6.89 (m, 3 H), 6.94 (dd, J = 9, 3 Hz, 1 H), 7.04 (d, J = 8 Hz, 1 H), 7.28 (d, J = 9 Hz, 2 H), 7.36-7.43 (m, 3 H), 7.48 (br s, 1 H), 8.34 (br s, 1 H) ppm. MS (APCI +): 382.1 (M + 1); LC-MS: 98%.

実施例２９９。Ｐ―３３４の準備 << Reaction process formula 60 >>

Example 299. Preparation for P-334

  Synthesis of 1- [2′-fluoro-6′-methoxy-3 ′-(4-nitro-benzyl) -biphenyl-3-yl] -ethanone (I-261) in an 18 mL vial equipped with a stir bar Are arranged I-223 (600 mg, 1.81 mmol), 4 nitrophenyl bromic acid (332 mg, 1.99 mmol), potassium carbonate (750 mg, 5.43 mmol), 1,5-bis (diphenylphosphino) pentane. (239 mg, 0.543 mmol), allyl palladium (II) chloride dimer (99.3 mg, 0.272 mmol) and dimethylformamide (3.6 mL). The reaction mixture was heated to 80 ° C. for 18 hours. The reaction mixture was filtered through celite, and water (40 mL) and saturated ammonium chloride solution (40 mL) were added to the filtered water. After extraction with ethyl acetate (2 × 50 mL), the organic portions were combined, washed with brine (50 mL), dried (MgSO 4) and concentrated. The remainder was purified by column chromatography utilizing 30% ethyl acetate / hexane as eluent to yield 410 mg of I-261 as a red orange (60% yield wet solid). MS (ESI): 378.5 (M-1).

  Synthesis of 1- [2′-fluoro-6′-hydroxy-3 ′-(4-nitro-benzyl) -biphenyl-3-yl] -ethanone (I-262). In an 18 mL vial with stirring, the bars were placed I-261 (351 mg, 0.925 mmol) and dichloromethane (3.0 mL). The solution was cooled to −78 ° C. in a dry ice / acetone bath for 15 minutes, and the vial could be gradually heated to room temperature over 2 hours and boron tribromide (dichloromethane 1.0M) (2.78 mL, 2.78 mmol) was added. The reaction was poured into ice water (40 mL) and then extracted with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (50 mL) and dried (MgSO4) and concentrated to yield 274 mg of I-262 as a brown solid in 81% yield.

  1- [6'-ethoxy-2'-fluoro-3'(4-nitro-benzyl) - - biphenyl-3-yl] - ethanone (I-263). In an 18 mL vial with stirring, the bars were summed I-262 (200 mg, 0.547 mmol), dimethylformamide (3.6 mL) and iodoethane (131 μL, 1.64 mmol). Mixture was stirred for 5 minutes, then the reaction mixture was stirred at room temperature for 18 hours and potassium carbonate (227 mg, 1.64 mmol) was added. The reaction mixture is quenched with water (30 mL), it was acidified to pH 1 with HCl of 1M. The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated to yield 185 mg of I-263 as a red orange oil in 86% yield and extraction was Performed with dichloromethane (2 × 30 mL).

  Synthesis of 1- [3 ′-(4-amino-benzyl) -6, ′-ethoxy-2′-fluoro-biphenyl-3-yl] -ethanone, hydrochloride (P-334). In an 18 mL vial with stirring, the bars were iron powder (129 mg, 2.31 mmol), ethanol (5.6 mL) and water (850 μL) placed. Mixing was heated to 85 ° C. in the oil bath and the reaction was continued at 85 ° C. for 3 hours and I-263 (260 mg, 0.661 mmol) was added. The reaction mixture was cooled to room temperature and filtered through celite. Extraction was performed with ethyl acetate (2 × 50 mL) and to the filtered water was added water (50 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The remainder was clarified by a column utilizing 40% EtOAc / hexane as the eluent. Et2O (1.5 mL) and a mixture of 2.0 M HCl were stirred for 1 hour at room temperature and to this purified material (free base) was added Et2O (3 mL). The solid was collected and dried in a high vacuum oven set at 40 ° C. for 3 hours to yield 46 mg P-334 as a 17% yield orange solid. 1H NMR (400 MHz, DMSO-d6) δ 1.18 (t, J = 7 Hz, 3 H), 2.59 (s, 3 H), 3.47 (br s, 2 H), 3.96 (s, 2 H), 4.03 (q, J = 7 Hz, 2 H), 6.94 (d, J = 9 Hz, 1 H), 7.20-7.32 (m, 5 H), 7.55-7.62 (m, 2 H), 7.91 (s, 1 H), 7.94 (dt, J = 7, 2 Hz, 1 H) ppm.

MS (APCI +): 364.1 (M + 1- HCl); LC-MS: 98%.
Example 300. Preparation for P-335

Synthesis of [4- (3′-acetyl-6-ethoxy-2-fluoro-biphenyl-3-ylmethyl) -phenyl] -urea (P-335). In an 8 mL vial with agitation, the bar is filled with P-334 (38 mg, 0.0950 mmol), water (500 μL), acetic acid (250 μL) and sodium arranged in cyanic acid (24.7 mg, 0.380 mmol). there were. Mixing was stirred at room temperature for 18 hours and water (3 mL) was added and the pH matched 6 with saturated sodium bicarbonate solution. The resulting solid was collected and dried in a high vacuum oven set at 40 ° C. for 4 hours to yield 20 mg of P-335 as a pale orange solid in 53% yield. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7 Hz, 3 H), 2.62 (s, 3 H), 3.94 (s, 2 H), 3.99 (q, J = 7 Hz, 2 H) , 4.65 (s, 2 H), 6.40 (s, 1 H), 6.70 (d, J = 8 Hz, 1 H), 7.078 (t, J = 8 Hz, 1 H), 7.21 (s, 4 H) , 7.50 (t, J = 8 Hz, 1 H), 7.62 (dd, J = 8, 1 Hz, 1 H), 7.94 (dt, J = 8, 2 Hz, 1 H), 8.03 (br s, 1 H) ppm.
Example 301. Preparation for P-340

Synthesis of {4- [2-fluoro-3 '-(1-hydroxyethyl) -6-methoxy-biphenyl-3-ylmethyl] -phenyl} -urea (P-340). In an 8 mL vial with agitation, the bars were placed P-269 (21 mg, 0.0535 mmol), methanol (200 μL) and sodium borohydride (6.1 mg, 0.161 mmol). The mixture was stirred for 1 hour at room temperature and then quenched with water (2 mL) and 1M aqueous HCl (4 mL). After stirring for 20 minutes, saturated sodium bicarbonate solution was used to adjust the mix to pH 7-8. After what was extracted with dichloromethane (2 × 30 mL), the organic portions were combined, dried (MgSO 4) and concentrated. The remainder was purified via column chromatography utilizing 40% acetone / dichloromethane as 10 mg of eluent product of P-340 as a white solid in 49% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.33 (d, J = 6 Hz, 3 H), 3.69 (s, 3 H), 3.83 (s, 2 H), 4.70-4.78 (m, 1 H), 5.15 (d, J = 4 Hz, 1 H), 5.76 (s, 2H), 6.89 (d, J = 9 Hz, 1 H), 7.06 (d, J = 8 Hz, 2 H), 7.13 (d, J = 7 Hz, 1 H), 7.21 (t, J = 9 Hz, 1 H), 7.25-7.36 (m, 4 H), 8.42 (s, 1 H) ppm. MS (APCI +): 377.1 [(M +1) -18]; LC-MS:> 99%.
Example 302. Preparation for P-381

Synthesis of N- [4- (2-fluoro-6-methoxy-3′-pyrrolidine-1-yl-biphenyl-3-ylmethyl) -phenyl] -acetamide (P-381). In an 8 mL vial with agitation, the bars were P-168 (100 mg, 0.233 mmol), 1,4-dioxane (800 μL) and pyrrolidine (117 μL, 1.40 mmol) placed. Mixing was degassed with nitrogen for 20 minutes and dichloro bis (chloro tert-butyl phosphine) palladium (50.2 mg, 0.0932 mmol) was added. The mixture was heated to 85 ° C. for 20 hours and the celite was filtered. The filtered water was treated with water (20 mL) and saturated ammonium chloride solution (20 mL). After extraction with ethyl acetate (2 × 30 mL), the organic portions were combined, washed with brine (30 mL), dried (MgSO 4) and concentrated. The remainder was purified by column chromatography utilizing 20% acetone / dichloromethane as the eluent and to yield 31 mg P-381 as a pale orange solid in 32% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.38 (d, J = 14 Hz, 4 H), 2.01 (s, 3 H), 3.24 (m, 4 H), 3.65 (s, 3 H), 3.84 ( s, 2 H), 6.76 (d, 1 H), 6.84 (d, J = 8 Hz, 1 H), 6.93 (t, J = 8 Hz, 1 H), 7.11 (d, J = 8 Hz, 2 H), 7.17 (t, J = 8 Hz, 1 H), 7.23 (br s, 1 H), 7.30-7.32 (m, 1 H), 7.48 (d, J = 8 Hz, 2 H), 9.83 ( s, 1 H) ppm. LC-MS: 92%.
Example 303. Preparation for P-390

Synthesis of N- [4- (2-fluoro-6-methoxy-3'-morpholin-4-yl-biphenyl-3-ylmethyl) -phenyl] -acetamide (P-390). In an 8 mL vial with agitation, the sticks were placed P-168 (80 mg, 0.187 mmol), sodium tert-butoxide (27.0 mg, 0.281 mmol), toluene (700 μL), morpholine (19. 6 μL, 0.224 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabiccyclo [3.3.3] undecane (13.3 μL, 0.0374 mmol). . Mixing was done for 15 minutes and then degassed with nitrogen for tris (dibenzylideneacetone) -di-palladium (0) (8.56 mg, 0.00935 mmol) was added. The mixture was heated to 90 degrees C for 18 hours and the celite was filtered. The filtered water was treated with water (20 mL) and saturated ammonium chloride solution (20 mL). After extraction with ethyl acetate (2 × 30 mL), the organic portions were combined, washed with brine (30 mL), dried (MgSO 4) and concentrated. The remainder was purified by column chromatography utilizing 10% acetone / dichloromethane as the eluent and yielding 21 mg P-390 as an off-white solid in 26% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.01 (s, 3 H), 3.09 (t, J = 5 Hz, 4 H), 3.69 (s, 3 H), 3.72 (t, J = 5 Hz, 4 H), 3.85 (s, 2 H), 6.72 (d, J = 7 Hz, 1 H), 6.83 (br s, 1 H), 6.87 (d, J = 9 Hz, 1 H), 6.92 (dd, J = 8, 2 Hz, 1 H), 7.13 (d, J = 8 Hz, 2 H), 7.18-7.27 (m, 2 H), 7.47 (d, J = 8 Hz, 2 H), 7.69-7.80 (m, 1 H) ppm. MS (APCI +): 435.1 (M + 1); LC-MS: 95%.
Example 304. Preparation for P-385

Synthesis of 4- [5 ′-(4-fluoro-benzyl) -2, ′-methoxy-biphenyl-3-yl] -morpholine (P-385). In an 8 mL vial with agitation, the stick is placed I-185 (200 mg, 0.678 mmol), 4- [3- (4,4,5,5-tetramethyl- [1,3,2] ] Dioxaborolan-2-yl) -phenyl] -morpholine (216 mg, 0.746 mmol), potassium carbonate (281 mg, 2.03 mmol), triphenylphosphine (53.3 mg, 0.203 mmol), 1,4-dioxane (1.1 mL) followed by palladium (II) acetate (15.2 mg, 0.0678 mmol) followed by 50% aqueous ethanol (1.1 mL). The mixture was heated to 90 ° C. for 18 hours and cooled to room temperature. The palladium catalyst was removed via filtration through celite. To the filtered water, water (30 mL) and saturated ammonium chloride solution (30 mL) were added. After the aqueous portion was withdrawn with ethyl acetate (2 × 30 mL), the organic portion was combined, washed with brine (30 mL), dried (MgSO 4) and concentrated. The remainder is purified by column chromatography utilizing 20% EtOAc / hexane as eluent to yield 137 mg of P-385 as a 54% yield of yellow viscous oil. Dried in a high vacuum oven set at degree C. 1H NMR (400 MHz, CDCl3) δ 3.18 (t, J = 5 Hz, 4 H), 3.78 (s, 3 H), 3.87 (t, J = 5 Hz, 4 H), 3.92 (s, 2 H) , 6.87-7.01 (m, 5 H), 7.04 (t, J = 2 Hz, 1 H), 7.09 (dd, J = 8, 3 Hz, 1 H), 7.12-7.17 (m, 3 H), 7.30 (t, J = 8 Hz, 1 H) ppm. MS (APCI +): 378.1 (M + 1); LC-MS:> 99%
Example 305. Preparation for P-391

  Synthesis of 2-chloro-6- [5- (4-fluoro-benzyl) -2-methoxyphenyl] -pyridine (P-391). In an 8 mL vial with agitation, the stick is placed I-185 (250 mg, 0.847 mmol), 2-chloro-6- (4,4,5,5-tetramethyl- [1,3, 2] Dioxaborolan-2-yl) -pyridine (243 mg, 1.02 mmol), sodium tert-butoxide (122 mg, 1.27 mmol) and 1,4-dioxane. Mixing was degassed with nitrogen for 20 minutes and dichloro bis (chloro tert-butyl phosphine) palladium (122 mg, 0.127 mmol) was added. The mixture was heated to 90 ° C. for 18 hours and the celite was filtered. The filtered water was treated with water (20 mL) and saturated ammonium chloride solution (20 mL). After extraction with ethyl acetate (2 × 30 mL), the organic portions were combined, washed with brine (30 mL), dried (MgSO 4) and concentrated. The remainder was purified by column chromatography utilizing 10% ethyl acetate / hexane as the eluent. The hexane yielded 29 mg of P-391 as a 10% white solid yielded and the material was then recrystallized with diethyl ether.

1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3 H), 3.96 (s, 2 H), 6.91 (d, J = 8 Hz, 1 H), 6.94-6.98 (m, 2 H), 7.12- 7.17 (m, 2 H), 7.23 (dd, J = 8, 1 Hz, 1 H), 7.64 (t, J = 8 Hz, 1 H), 7.69 (d, J = 2 Hz, 1 H), 7.79 (dd, J = 8, 1 Hz, 1 H) ppm. MS (APCI +): 328.0 (M + 1);
LC-MS: 97%.

実施例３０６。Ｐ―３９５の準備 << Reaction process formula 61 >>

Example 306. Preparation for P-395

  Synthesis of carbonic acid 3'-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester (I-266). In an 18 mL vial with agitation, the bars were placed I-265 (465 mg, 1.81 mmol), anhydrous tetrahydrofuran (6.0 mL) and pyridine (381 μL, 4.71 mmol). The resulting clear solution was cooled in an ice-water bath for 10 minutes, and the reaction mixture was slowly warmed to room temperature, reacted for 17 hours, and methyl chloroformate (308 μL, 3.98 mmol) was added. Extraction with water (30 mL) with dichloromethane (2 × 60 mL) was subsequently added, the reaction was acidified to pH 1 with 1M HCl. The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. After drying in a high vacuum oven at 45 ° C. for 2 hours, 378 mg of I-266 was isolated as a pale yellow in 66% yield.

Synthesis of 3 '-(2-amino-pyrimidin-5-ylmethyl) -2,'-fluoro-6'-methoxy-biphenyl-3-carbonitrile (P-395). In an 8 mL vial with agitation, the stick is placed I-266 (120 mg, 0.381 mmol), 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) -pyrimidin-2-ylamine (92.7 mg, 0.419 mmol), potassium carbonate (158 mg, 1.14 mmol), 1,5-bis (diphenylphosphino) pentane (50.3 mg, 0.114 mmol) , Allyl palladium (II) chloride dimer (20.9 mg, 0.0572 mmol) and dimethylformamide (1.3 mL). The reaction mixture was heated to 85 ° C. for 18 hours. The reaction mixture was filtered through celite and to the filtered water was added water (30 mL) and saturated ammonium chloride solution (30 mL). After extraction with ethyl acetate (2 × 30 mL), the organic portions were combined, washed with brine (40 mL), dried (MgSO 4) and concentrated. The remainder was purified by column chromatography utilizing 10% acetone / dichloromethane and then 30% acetone / dichloromethane as the eluent to yield 62 mg P-395 as a 49% yield of light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 5 H), 6.47 (s, 2 H), 6.96 (d, J = 8 Hz, 1 H), 7.33 (t, J = 9 Hz, 1 H), 7.61-7.69 (m, 2 H), 7.82-7.84 (m, 2 H), 8.12 (s, 2 H) ppm. MS (APCI +): 335.1 (M + 1); LC-MS: 94% .
Example 307. Preparation for P-399

  Synthesis of 1- [5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrimidin-2-yl] -3-ethyl-urea (P-399). In an 8 mL vial with agitation, the bars were placed P-395 (60 mg, 0.180 mmol), pyridine (600 μL) and ethyl isocyanate (71.2 μL, 0.900 mmol). The reaction mixture was stirred at room temperature for 18 hours. TLC analysis indicated that the reaction mixture consisted of about 50% starting material. The mixture was heated to 55 ° C. for 5 hours and to the reaction mixture was added ethyl isocyanate (71.2 μL, 0.900 mmol). The resulting solid was collected, washed with water (3 × 2 mL), and ethyl acetate (3 × 2 mL) for 18 hours to yield 36 mg of P-399 as a white solid in 49% yield. In a high vacuum oven set at 40 degrees C, the reaction mixture was dried and quenched with water (4 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J = 7 Hz, 3 H), 3.19-3.25 (m, 2 H), 3.74 (s, 3 H), 3.89 (s, 2 H), 6.98 (d, J = 9 Hz, 1 H), 7.39 (t, J = 9 Hz, 1 H), 7.61-7.70 (m, 2 H), 7.83-7.85 (m, 2 H), 8.46 (s, 2 H), 8.91 (t, J = 6 Hz, 1 H), 9.611 (s, 1 H) ppm. MS (APCI +): 406.1 (M + 1); LC-MS: 92%.

実施例３０８。Ｐ―４００の準備 << Reaction process formula 62 >>

Example 308. Preparation for P-400

  In a 40 mL vial equipped with a stir bar, the synthesis of 5- (3-bromo-4 methoxybenzyl) -pyridin-2-ylamine (I-267) was performed using the arranged I-42 (1.0 g, 3 .57 mmol), 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin-2-ylamine (865 mg, 3.93 mmol), potassium phosphate (tri Basic) (1.52 g, 7.14 mmol), dimethoxyethane (6.0 mL) and 50% aqueous ethanol (6.0 mL). Mixing was degassed with nitrogen for 20 minutes and then additional tetrakis (triphenylphosphine) palladium (0) (619 mg, 0.536 mmol). Mixing was heated to 60 ° C. for 4 hours and the palladium catalyst was filtered off. To the filtered water, water (50 mL) and saturated ammonium chloride solution (50 mL) were added. After extracting the acetate salt (2 × 60 mL) with ethyl, the organic portions were combined, washed with brine (50 mL), dried (MgSO 4) and concentrated. The remainder utilized 10% acetone / dichloromethane, 30% acetone / dichloromethane, 40% acetone / dichloromethane as eluent to yield 308 mg of I-267 as a 29% yield of yellow viscous oil. It was purified by the pillar. MS (APCI +): 295.0 (M + 1), LC-MS:> 99%.

  Synthesis of 1- [5- (3-Bromo-4methoxybenzyl) -pyridin-2-yl] -3-ethyl-urea (I-268). In an 8 mL vial with stirring, the bars were placed I-267 (300 mg, 1.02 mmol), pyridine (3.5 mL) and ethyl isocyanate (646 μL, 8.16 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (30 mL) and 1M aqueous HCl (30 mL). After what was extracted with dichloromethane (2 × 60 mL), the organic portion was washed with 1 M aqueous HCl (40 mL), brine, 40 mL dried (MgSO 4) and concentrated. The natural sticky material was recrystallized with diethyl ether (2 mL), ethyl acetate (1 mL) and hexane (700 μL). The resulting solid was collected by suction filtration and washed with diethyl ether (2 × 1 mL) to yield 49 mg of I-268 as a 13% yield of off-white solid. MS (APCI +): 366.0 (M + 1), LC-MS: 98%.

Synthesis of 1- [5- (3′-cyano-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -3-ethyl-urea (P-400). In an 8 mL vial with agitation, the sticks were placed I-268 (47 mg, 0.129 mmol), 3 cyanophenylbromate (22.7 mg, 0.155 mmol), potassium phosphate (tri-basic ) (54.8 mg, 0.258 mmol), dimethoxyethane (250 μL) and 50% aqueous ethanol (250 μL). Mixing was degassed with nitrogen for 15 minutes and then additional tetrakis (tri-phenylphosphine) palladium (0) (14.9 mg, 0.0129 mmol). The mixture was heated to 85 ° C. for 18 hours and the palladium catalyst was filtered off. To the filtered water, water (20 mL) and saturated ammonium chloride solution (20 mL) were added. After extracting the acetate salt (2 × 30 mL) with ethyl, the organic portions were combined, washed with brine (30 mL), dried (MgSO 4) and concentrated. The remainder was clarified by a column utilizing 15% acetone / dichloromethane as the eluent to yield 27 mg P-400 as a 55% yield white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (t, J = 7 Hz, 3 H), 3.13-3.20 (m, 2 H), 3.75 (s, 3 H), 3.84 (s, 2 H), 7.07 (d, J = 8 Hz, 1 H), 7.23 (s, 1 H), 7.25 (s, 1 H), 7.55-7.62 (m, 3 H), 7.77-7.82 (m, 1 H), 7.90 (m, 1 H), 8.10 (br s, 1 H), 9.06 (s, 1 H) ppm. MS (APCI +): 387.1 (M + 1); LC-MS: 98%.
Example 309. Preparation for P-433

Synthesis of 4-tributylsilanyl-pyridine-2-carbonitrile (I-214). In a 40 mL vial with agitation, the bars are placed 4-iodo-pyridine-2-carbonitrile (1.26 g, 5.48 mmol), 1,4-dioxane (18 mL) and bis (tributyl) tin. (3.32 mL, 6.58 mmol). After the reaction mixture was degassed with nitrogen between bis, tri-phenyl, and phosphine for 15 minutes, -dichloride (192 mg, 0.274 mmol) palladium (II) was added. The reaction mixture was heated to 90 ° C. for 18 hours and then quenched with 2.2 M aqueous potassium fluoride (100 ml) to consume excess tin reagent. After stirring for 2 hours at room temperature, the mixture was filtered through celite. To what was filtered, water (50 mL) (followed by extraction with ethyl acetate (5 × 100 mL)) was added. The organic portions were combined, washed with 2.2 M aqueous potassium fluoride (150 mL), water (150 mL) and brine (150 mL). After drying the organic portion with magnesium sulfate, the material is a column utilizing 5% ethyl acetate / hexane as the eluent to yield 1.24 g of I-214 as a colorless oil in 58% yield. Concentrated and purified by chromatography. MS (APCI +): 394.0 (M + 1)

Synthesis of 4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carbonitrile (P-433). In an 18 mL vial with stirring, the bars were placed I-33 (162 mg, 0.492 mmol), 1,4-dioxane (2.3 mL), and I-214 (232 mg, 0.590 mmol). It was. After the reaction mixture was degassed with nitrogen between bis, tri-phenyl, and phosphine for 20 minutes, -dichloride (17.3 mg, 0.0246 mmol) palladium (II) was added. The reaction mixture was heated to 80 ° C. for 18 hours. To the reaction mixture was added water (40 mL) followed by extraction with ethyl acetate (2 × 60 mL). The organic portions were combined, washed with brine (40 mL), dried (magnesium sulfate) and concentrated. The remainder was purified by column chromatography utilizing 30% ethyl acetate / hexane as the eluent to yield 102 mg P-433 as a 59% yield of orange oil. 1H NMR (400 MHz, DMSO-d6) δ3.74 (s, 3 H), 4.06 (s, 2 H), 6.98 (d, J = 9 Hz, 1 H), 7.28-7.30 (m, 1 H) , 7.38-7.47 (m, 4 H), 7.56 (d, J = 5 Hz, 1 H), 7.93 (s, 1 H), 8.65 (d, J = 5 Hz, 1 H) ppm.
MS (APCI +): 354.0 (M + 1); LC-MS: 97%.
Example 310. Preparation for P-437

  Synthesis of C- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -methylamine (P-437). In an 8 mL vial with agitation, the stick is placed on P-433 (95 mg, 0.269 mmol), methanol (2.8 mL), concentrated HCl (113 μL, 1.35 mmol), activated carbon (19.0 mg). Of 10% palladium. The hydrogen balloon was then attached. The mixture could be stirred for 2 hours at room temperature and the celite was filtered. To the filtered water, which was pH 10-11 with 1M NaOH, water (20 mL) was added and extraction was done with ethyl acetate (2 × 60 mL). The organic portions were combined, washed with brine (50 mL), dried (magnesium sulfate) and concentrated. The remainder was purified by column chromatography utilizing 10% methanol / dichloromethane to yield 14 mg P-437 as black (14% yield semi-solid). 1H NMR (400 MHz, DMSO-d6) δ 3.17 (s, 2 H), 3.74 (s, 3 H), 3.78 (s, 2 H), 3.95 (s, 2 H), 6.96 (d, J = 8 Hz, 1 H), 7.06-7.07 (m, 1 H), 7.28-7.47 (m, 6 H), 8.37 (d, J = 5 Hz, 1 H) ppm. MS (APCI +): 358.0 (M + 1 LC-MS: 96%.

実施例３１１。Ｐ―４５４の準備 << Reaction process formula 63 >>

Example 311. Preparation for P-454

  Synthesis of 2-bromo-1-methoxy-4- (4-nitro-benzyl) -benzene (I-269). In a 100 mL round bottomed flask equipped with agitation, the stick was placed I-42 (2.0 g, 7.14 mmol), 4 nitrophenyl bromic acid (2.27 g, 7.85 mmol), Potassium phosphate (tribasic) (3.03 g, 14.3 mmol), dimethoxyethane (12 mL) and 50% aqueous ethanol (12 mL). Mixing was degassed with nitrogen for 20 minutes and tetrakis (triphenylphosphine) palladium (0) (825 mg, 0.714 mmol) was added. Mixing was heated to 60 ° C. for 4 hours and the palladium catalyst was filtered off. To the filtered water, water (50 mL) and saturated ammonium chloride solution (100 mL) were added. After extracting the acetate salt (3 × 100 mL) with ethyl, the organic portions were combined, washed with brine (150 mL), dried (MgSO 4) and concentrated. The remainder was purified by a column utilizing 15% ethyl acetate / hexane as the eluent yielding 1.06 g of I-269 as a 46% yield of a pale yellow solid. MS (APCI): 321.2 (M-1).

  Synthesis of 3'-chloro-2-methoxy-5- (4-nitro-benzyl) -biphenyl (I-270). In a 40 mL vial equipped with a stir bar, I-269 (960 mg, 2.98 mmol) (3 chlorophenyl bromate (559 mg, 3.58 mmol) was placed), potassium phosphate (tri basic) (1.27 g, 5.96 mmol), dimethoxyethane (5 mL) and 50% aqueous ethanol (5 mL) and tetrakis (triphenylphosphine) palladium (0) (344 mg, 0.298 mmol). Mixing was heated to 67 ° C. for 65 hours and the palladium catalyst was filtered off. To the filtered water, water (50 mL) and saturated ammonium chloride solution (70 mL) were added. After extracting the acetate salt (3 × 75 mL) with ethyl, the organic portions were combined, washed with brine (80 mL), dried (MgSO 4) and concentrated. The remainder was purified by a column utilizing 10% ethyl acetate / hexane as the eluent yielding 1.05 g of I-270 as a quantitative yield of a yellow viscous oil. MS (APCI): 351.8 (M-2).

  Synthesis of 4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenylamine (I-271). In a 40 mL vial with agitation, the bar was iron powder placed (586 mg, 10.5 mmol), ethanol (12 mL) and water (3.8 mL). Mixing was heated to 85 ° C. in the oil bath and the reaction was continued at 85 ° C. for 2 hours and I-270 (1.05 g, 3.00 mmol) was added. The reaction mixture was cooled to room temperature and filtered through celite. Extraction was performed with ethyl acetate (2 × 60 mL) and to the filtered water was added water (60 mL). The organic portions were combined, washed with brine (60 mL) and dried (MgSO4) to yield 862 mg of I-271 as a pale orange viscous oil in 89% yield. Concentrated. MS (APCI +): 324.1 (M + 1), LC-MS: 97%.

Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -thiazol-2-yl-amine (P-454). In an 8 mL vial with stirring, the sticks were placed I-271 (70 mg, 0.216 mmol), 2-bromothiazole (38.5 μL, 0.432 mmol), 10% aqueous ethanol (1. 1 mL) and concentrated hydrochloric acid (36.0 μL, 0.432 mmol). The mixture was heated to 95 ° C. for 18 hours and combined with the reaction mixture from the exact same type of 50 mg scale reaction. After adding water (30 mL) and 5% aqueous potassium carbonate (30 mL), the organic portion was combined and the water-like portion was withdrawn with ethyl acetate (2 × 30 mL), water (40 mL) Dry, brine, 40 mL (magnesium sulfate) and wash intensively. The crude material was purified by column chromatography utilizing 47% yield of viscous, 3% acetone / dichloromethane as eluent to yield 70 mg P-454 as a light yellow oil (400 MHz, CDCl3) δ 3.79 (s, 3 H), 3.94 (s, 2 H), 6.61 (d, J = 4 Hz, 1 H), 6.91 (d, J = 8 Hz, 1 H), 7.12-7.19 (m, 5 H), 7.27-7..33 (m, 4 H), 7.38 (dt, J = 7, 2 Hz, 1 H), 7.50 (t, J = 2 Hz, 1 H). MS ( (APCI +): 407.0 (M + 1); LC-MS: 99%.
Example 312. Preparation for P-458

Synthesis of 2-{[5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyrimidin-2-yl] -methyl-amino} -ethanol (P-458). In an 8 mL vial with agitation, the sticks were placed I-177 (40 mg, 0.110 mmol), 2- (methyl amine) -ethanol (13.2 μL, 0.165 mmol), isopropanol (600 μL). ) And diisopropylethylamine (57.5 μL, 0.330 mmol). The mixture was heated to 80 ° C. for 18 hours, combined with the same 20 mg scale reaction, then extracted with water (30 mL) with 1M HCl (20 mL) and dichloromethane (2 × 50 mL). Was processed. The organic portions were combined, washed with brine (50 mL), dried (magnesium sulfate) and concentrated. The remainder was purified by silica gel column chromatography utilizing 10% acetone / dichloromethane as eluent to yield 35 mg P-458 as a colorless, viscous oil in 52% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.10 (s, 3 H), 3.52-3.53 (m, 4 H), 3.72 (s, 3 H), 3.75 (s, 2 H), 4.64 (t, J = 5 Hz, 1 H), 6.93 (d, J = 8 Hz, 1 H), 7.27-7.32 (m, 2 H), 7.38 (s, 1 H), 7.43-7.47 (m, 2 H), 8.22 (s, 2 H) ppm.
MS (APCI +): 402.0 (M + 1); LC-MS: 99%.
Example 313. Preparation for P-467

Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl]-(1-methyl-1H-imidazol-2-yl) -amine (P-467). In an 8 mL vial with agitation, the sticks are placed I-271 (150 mg, 0.463 mmol), 2-bromo-1-methyl-1H-imidazole (67.8 μL, 0.695 mmol), p- Toluenesulfonic acid (106 mg, 0.556 mmol) and toluene (2.0 mL). The mixture was heated to 115 ° C. for 18 hours and then treated with water (30 mL) followed by pH 10 adjustment with 5% aqueous potassium carbonate. After extracting the acetate salt (2 × 35 mL) with ethyl, the organic portions were combined, washed with brine (50 mL), dried (MgSO 4) and concentrated. The remainder was purified by silica gel column chromatography utilizing 5% current 50% acetone / dichloromethane as eluent to yield 89 mg P-467 as a light orange solid with a yield of 47%. 1H NMR (400 MHz, DMSO-d6) δ 3.45 (s, 3 H), 3.74 (s, 3 H), 3.82 (s, 2 H), 6.61 (d, J = 2 Hz, 1 H), 6.81 ( d, J = 2 Hz, 1 H), 7.02-7.07 (m, 3 H), 7.15 (d, J = 2 Hz, 1 H), 7.19 (dd, J = 8, 2 Hz, 1 H), 7.24 (d, J = 8, 2 H), 7.35-7.44 (m, 3 H), 7.48 (bs, 1 H), 8.09 (s, 1 H) ppm; MS (APCI +): 404.1 (M + 1).
LC-MS:> 99%.

実施例３１４。Ｐ―５１５の準備 << Reaction process formula 64 >>

Example 314. Preparation for P-515

  Synthesis of 4- [4- (3-Bromo-2-fluoro-4methoxybenzyl) -pyridin-2-yl] -piperazine-1-carboxylic acid tert-butyl ester (I-273). In a 40 mL vial with agitation, the stick is placed I-31 (642 mg, 2.15 mmol), 4- [4- (4,4,5,5-tetramethyl- [1,3,2] ] Dioxaborolan-2-yl) -pyridin-2-yl] -piperazine-1-carboxylic acid tert-butyl ester (922 mg, 2.37 mmol), potassium phosphate (tri-basic) (913 mg, 4.30 mmol) , Dimethoxyethane (3.6 mL) and 50% aqueous ethanol (3.6 mL). After removing gas from the minutes by nitrogen for 15, tetrakis (tri-phenyl-phosphine) palladium (0) (248 mg, 0.215 mmol) was added. The mixture was heated to 60 ° C. for 5 hours and the palladium catalyst was removed by filtering the celite. To the filtered water, water (50 mL) and saturated ammonium chloride solution (50 mL) were added. After extracting the acetate salt (3 × 75 mL) with ethyl, the organic portions were combined, washed with brine (75 mL), dried (MgSO 4) and concentrated. The remainder was purified by a column utilizing 48% yield of yellow, 35% ethyl acetate / hexane as eluent to yield 495 mg of I-273 as a viscous oil. MS (APCI +): 480.0 (M + 1);

  4- [4- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -piperazine-1-carboxylic acid tert-butyl ester (I-274) Synthesis. In an 18 mL vial with agitation, the stick is placed I-273 (490 mg, 1.02 mmol), 3-chlorophenylbromate (191 mg, 1.22 mmol), potassium phosphate (tribasic) ( 433 mg, 2.04 mmol), dimethoxyethane (2.0 mL) and 50% aqueous ethanol (2.0 mL). After removing gas from the minutes with nitrogen for 15, tetrakis (tri-phenyl-phosphine) palladium (0) (118 mg, 0.102 mmol) was added. The mixture was heated to 90 ° C. for 22 hours and the palladium catalyst was removed by filtering the celite. Water (150 mL) followed by extraction with ethyl acetate (3 × 75 mL) was added to the filtered water. The organic portions were combined, washed with brine (75 mL), dried (MgSO4) and concentrated. The remainder was cleaned by a column utilizing 25% and 35% ethyl acetate / hexane as eluent yielding 360 mg of I-274 as a 69% pale yellow solid yields. MS (APCI +): 512.1 (M +)

In a 40 mL vial equipped with a stir bar 1- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -piperazine (P-515) The synthesis of was I-274 arranged (360 mg, 0.703 mmol) and dichloromethane (2.3 mL). The solution was cooled in an ice-water bath for 10 minutes, and trifluoroacetic acid (522 μL, 7.03 mmol) was added. The solution was stirred at room temperature for 3 hours and concentrated by a stream of nitrogen. Water (50 mL) was added to the oil followed by extraction with saturated sodium bicarbonate solution (until pH 8) with dichloromethane (2 × 75 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The remainder was clarified by columns utilizing 10%, 15% and then 20% methanol / dichloromethane as eluent to yield 120 mg P-515 as a 41% yield off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.80 (t, J = 5 Hz, 4 H), 3.39 (t, J = 5 Hz, 4 H), 3.73 (s, 3 H), 3.84 (s, 2 H), 6.46 (d, J = 5 Hz, 1 H), 6.69 (s, 1 H), 6.94 (d, J = 8 Hz, 1 H), 7.28 (bd, J = 7 Hz, 1 H), 7.32 (t, J = 9 Hz, 1 H), 7.36 (s, 1 H), 7.41-7.47 (m, 2 H), 7.98 (d, J = 5 Hz, 1 H) ppm. MS (APCI +): 412.1 (M + 1); LC-MS:> 99%.
Example 315. Preparation for P-518

Synthesis of 4- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -piperazine-1-carboxylic acid amide (P-518). In an 8 mL vial with agitation, the bar is filled with cyanic acid (31.5 mg, 0.484 mmol), P-515 (50 mg, 0.121 mmol), water (800 μL), acetic acid (400 μL) and sodium. there were. The mixture was stirred at room temperature for 18 hours and water (30 mL) was added. After adjusting to pH 8 with saturated sodium bicarbonate solution, the watery portion was withdrawn with dichloromethane (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated to yield an off-white solid. The remainder was triturated with diethyl ether (1 mL) and collected to dry in a high vacuum oven for 18 hours to yield 17 mg P-518 as a 30% yield off-white solid. . 1H NMR (400 MHz, DMSO-d6) δ 3.36-3.44 (m, 8 H), 3.73 (s, 3 H), 3.85 (s, 2 H), 6.03 (s, 2 H), 6.48 (d, J = 5 Hz, 1 H), 6.76 (s, 1 H), 6.94 (d, J = 9 Hz, 1 H), 7.28 (d, J = 7 Hz, 1 H), 7.33 (t, J = 9 Hz , 1 H), 7.37 (s, 1 H), 7.41-7.47 (m, 2 H), 8.00 (d, J = 5 Hz, 1 H) ppm. MS (APCI +): 455.1 (M + 1).
Example 316. Preparation for P-519

Synthesis of 4- [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -piperazine-1-carboxylic acid ethylamide (P-519). In an 8 mL vial with stirring, the bars were placed P-515 (60 mg, 0.146 mmol), pyridine (500 μL) and ethyl isocyanate (92.5 μL, 1.17 mmol). The mixture was stirred at room temperature for 18 hours and then treated with water (20 mL) and saturated sodium bicarbonate solution (20 mL). After extraction with dichloromethane (3 × 30 mL), dry 1M HCl (2 × 30 mL), brine, 40 mL (MgSO 4) and wash intensively to yield an off-white solid, the organic portion is Combined. The crude material was triturated with diethyl ether (1 mL) and collected to dry in a high vacuum oven for 18 hours to yield a 31% yield of 22 mg P-519. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (t, J = 4 Hz, 3 H), 3.05-3.18 (m, 2 H), 3.42 (br s, 4 H), 3.53 (br s, 4 H ), 3.74 (s, 3 H), 3.93 (s, 2 H), 6.57 (m, 2 H), 6.96 (d, J = 8 Hz, 2 H), 7.28 (d, J = 7 Hz, 1 H ), 7.35-7.48 (m, 3 H), 7.96 (d, J = 5 Hz, 1 H) ppm.
MS (APCI +): 483.1 (M + 1); LC-MS: 98%.
Example 317. Preparation for P-527

  Synthesis of 2- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-pyrazol-4-yl] -pyridine (P-527). In an 8 mL vial with agitation, the stick is placed 2- (1H-pyrazol-4-yl) -pyridine (31.4 mg, 0.216 mmol), DMF (600 μL) and hydrogenated (60%) (11.9 mg, 0.296 mmol) sodium. Mixing was stirred for 25 minutes at room temperature, and the reaction mixture was stirred for 18 hours at room temperature, and a solution of I-33 (75 mg, 0.228 mmol) and DMF (600 μL) was added. The reaction was quenched with water (40 mL) and extracted with dichloromethane (2 × 35 mL). The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The remainder was purified by silica gel column chromatography utilizing 30% acetone / dichloromethane to yield 58 mg (65%) of P-527 as a colorless viscous oil.

1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.39 (s, 2 H), 7.00 (d, J = 9 Hz, 1 H), 7.15-7.18 (m, 1 H), 7.29-7.31 (m, 1 H), 7.36 (d, J = 9 Hz, 1 H), 7.39 (s, 1 H), 7.42-7.49 (m, 2 H), 7.65 (dt, J = 8, 1 Hz, 1 H), 7.74 (td, J = 8, 2 Hz, 1 H), 8.03 (s, 1 H), 8.36 (s, 1 H), 8.48-8.50 (m, 1 H) ppm. MS ( (APCI +): 394.1 (M + 1); LC-MS: 92%.
Example 318. Preparation for P-528

  Synthesis of 4- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-pyrazol-4-yl] -pyridine (P-528). In an 8 mL vial with stirring, the stick is placed 4- (1H-pyrazol-4-yl) -pyridine (31.4 mg, 0.216 mmol), DMF (600 μL) and hydrogenated (60%) (11.9 mg, 0.296 mmol) sodium. Mixing was stirred for 25 minutes at room temperature, and the reaction mixture was stirred for 18 hours at room temperature, and a solution of I-33 (75 mg, 0.228 mmol) and DMF (600 μL) was added. The reaction was quenched with water (40 mL) and extracted with dichloromethane (2 × 35 mL). The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The remainder was purified by silica gel column chromatography utilizing 40% acetone / dichloromethane to yield 41 mg P-528 as a 46% yield white solid.

1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.38 (s, 2 H), 7.00 (d, J = 8 Hz, 1 H), 7.30 (br d, J = 7 Hz, 1 H), 7.36 (d, J = 9 Hz, 1 H), 7.39 (s, 1 H), 7.42-7.48 (m, 2 H), 7.57-7.58 (m, 2 H), 8.09 (s, 1 H), 8.49 (m, 3 H) ppm.
MS (APCI +): 394.1 (M + 1); LC-MS: 90%.
Example 319. Preparation for P-544

Synthesis of 2- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-pyrazol-4-yl] -pyridine hydrochloride (P-544). In an 8 mL vial with agitation, the stick was placed 2- (1H-pyrazol-3-yl) -pyridine (41.8 mg, 0.288 mmol), DMF (800 uL) and hydrogenated (15.8 mg). 0.394 mmol) sodium. The reaction mixture was stirred at room temperature for 25 minutes, and the reaction mixture was stirred at room temperature for 18 hours and a solution of DMF (800 uL) I-33 (100 mg, 0.303 mmol) was added. The reaction disappeared with water (20 mL) and was extracted with ethyl acetate (2 × 30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 15% acetone / dichloromethane as the eluent to yield 79 mg as a colorless, viscous oil. The hydrochloride salt formed was treated with the purified product with 1,4-dioxane (500 uL) of 1,4-dioxane (500 uL) and 4.0 M HCl. After stirring for 1 hour at room temperature, the reaction mixture was concentrated in a high vacuum oven set at 35 degrees C for 18 hours to provide 80 mg P-544 as a white solid in 62% yield. , Dried. 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.49 (s, 2 H), 7.01 (d, J = 8 Hz, 1 H), 7.09 (s, 1 H), 7.30 ( br d, J = 7 Hz, 1 H), 7.36-7.40 (m, 2 H), 7.43-7.49 (m, 2 H), 7.59 (br s, 1 H), 8.01 (d, J = 2 Hz, 1 H), 8.16 (bs, 2 H), 8.65 (d, J = 5 Hz, 1 H) ppm. MS (APCI +): 394.1 (M + 1-HCl); LC-MS:> 99%.
Example 320. Preparation for P-545

Synthesis of 2- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-pyrazol-4-yl] -pyrazine (P-545). Same as the procedure for P-544. The target compound was broken from DMF with the addition of a wash with water (6 mL), prepaid solid, water (3 × 2 mL). It was then dried in a vacuum oven to yield 46 mg (35%) of P-545 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.42 (s, 2 H), 7.01 (d, J = 8 Hz, 1 H), 7.30 (br d, J = 7 Hz, 1 H), 7.39 (t, J = 8 Hz, 2 H), 7.43-7.48 (m, 2 H), 8.14 (s, 1 H), 8.41 (d, J = 2 Hz, 1 H), 8.50 ( s, 1 H), 8.54-8.55 (m, 1 H), 8.99 (d, J = 2 Hz, 1 H) ppm. MS (APCI +): 395.1 (M + 1); LC-MS: 99%.
Example 321. Preparation for P-546

Synthesis of 4- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-pyrazol-4-yl] -pyrimidine hydrochloride (P-546). Same as the procedure for P-544. Purification was performed using 30% acetone / dichloromethane as the eluent. The HCl salt structure formed 73 mg of P-546 HCl salt as a 56% yield white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.43 (s, 2 H), 7.01 (d, J = 8 Hz, 1 H), 7.30 (br d, J = 7 Hz, 1 H), 7.39 (br s, 1 H), 7.40-7.49 (m, 3 H), 7.79 (dd, J = 6, 1 Hz, 1 H), 8.21 (s, 1 H), 8.61 (s, 1 H), 8.71 (br d, J = 5 Hz, 1 H), 9.07 (s, 1 H) ppm. MS (APCI +): 395.1 (M + 1-HCl); LC-MS:> 99%.
Example 322. Preparation for P-549

Synthesis of 3- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -1H-imidazol-2-yl] -pyridine hydrochloride (P-549). Same as the procedure for P-544. Purification was performed using 5% methanol / dichloromethane as eluent. The HCl salt structure provided 14 mg of P-549 as a light yellow solid in 11% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3 H), 5.47 (s, 2 H), 6.96 (d, J = 9 Hz, 1 H), 7.21-7.23 (m, 1 H), 7.28-7.31 (m, 2 H), 7.44-7.46 (m, 2 H), 7.67-7.70 (m, 1 H), 7.88 (s, 2 H), 8.23 (dt, J = 8, 2 Hz, 1 H), 8.85 (dd, J = 5, 2 Hz, 1 H), 8.94 (d, J = 2 Hz, 1 H) ppm.
MS (APCI +): 394.1 (M + 1-HCl); LC-MS:> 99%.
Example 323. Preparation for P-559

Synthesis of 1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-thiophen-2-yl-1H-imidazole hydrochloride (P-559). Same as the procedure for P-544. Purification was performed using 5% methanol / dichloromethane as eluent. The HCl salt structure provided a 46% yield of 61 mg of P-559. 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.52 (s, 2 H), 6.84 (d, J = 9 Hz, 1 H), 7.18 (t, J = 8 Hz, 1 H), 7.27-7.28 (m, 1 H), 7.31-7.34 (m, 1 H), 7.37 (bs, 1 H), 7.44-7.49 (m, 2 H), 7.70-7.75 (m, 3 H) , 8.00 (br d, J = 4 Hz, 1 H) ppm. MS (APCI +): 399.1 (M + 1-HCl); LC-MS:> 99%.
Example 324. Preparation for P-551

  2- [1- (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -5-trifluoromethyl-1H-pyrazol-3-yl] -pyridine hydrochloride (P-551) Synthesis of. Same as the procedure for P-544. Purification was performed using 3% methanol / dichloromethane as the eluent. The HCl salt structure provided 49 mg of P-551 as a white solid in 32% yield.

1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.58 (s, 2 H), 7.01 (d, J = 8 Hz, 1 H), 7.26 (d, J = 9 Hz, 1 H), 7.28-7.30 (m, 1 H), 7.38 (s, 1 H), 7.44-7.48 (m, 3 H), 7.50 (s, 1 H), 7.94-8.06 (m, 2 H), 8.64 -8.66 (m, 1 H) ppm. MS (APCI +): 462.1 (M + 1-HCl); LC-MS:> 99%.
Example 325. Preparation for P-552

  3- [2- (3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -5-trifluoromethyl-2H-pyrazol-3-yl] -pyridine hydrochloride (P-552) Synthesis of. Same as the procedure for P-544. Purification was performed using 20% acetone / dichloromethane as the eluent. The HCl salt structure provided 53 mg of P-552 as an off-white solid in 35% yield.

1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3 H), 5.58 (s, 2 H), 7.01 (d, J = 9 Hz, 1 H), 7.27-7.31 (m, 2 H), 7.37 (s, 1 H), 7.43-7.49 (m, 2 H), 7.72 (t, J = 8 Hz, 2 H), 8.48 (br d, J = 8 Hz, 1 H), 8.70 (dd, J = 5, 1 Hz, 1 H), 9.17 (d, J = 2 Hz, 1 H) ppm. MS (APCI +): 462.1 (M + 1-HCl); LC-MS: 98%.
Example 326. Preparation for P-388

  Synthesis of 1- (2-chloroethyl) -3- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -urea (I-272). . To a solution of chloroform (4 mL) in P-252 (180 mg, 0.525 mol), 2-chloroethyl isocyanate (66.4 mg, 0.630 mmol) under nitrogen was added. The solution was stirred at room temperature for 48 h. Added 2-chloroethyl isocyanate (33.2 mg, 315 mmol) was added and the reaction was stirred at 80 ° C. overnight. The crude residue was purified by flash silica gel column chromatography (0-5% acetone in dichloromethane) to give I-272 (86.9 mg, 37% yield) and the solvent removed under vacuum It was. 1H NMR (400 MHz, CDCl3): 9.75 (s, 1H), 8.10 (m, 1H), 7.47-7.38 (m, 1H), 7.38-7.26 (m, 4H), 7.10 (t, J = 8.4 Hz, 1H), 6.90 (s, 1H), 6.72 (d, J = 9.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 3.89 (s, 2H), 3.76 (s, 3H), 3.72- 3.67 (m, 4H) ppm. LCMS = 55.1% purity. MS (APCI +) = 448.0 (M).

Integration of 1- [5- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -imidazolidin-2-1 (P-388). A suspension of I-272 (85.0 mg, 0.190 mmol) in acetonitrile (2 mL) and sodium carbonate (60.3 mg, 0.569 mmol) was stirred at reflux for 21 h. The reaction was cooled to room temperature and sodium carbonate, which was removed by filtration. The solid was washed with ethyl acetate (3 × 5 mL) and filtered water removed under vacuum. The rest is eluting dichloromethane acetone with 15% thinly cleaned by pre-silica gel, using 2 developments (powdered in diethyl ether (2 mL)), red pink powder Layer chromatography being filtered to give P-388 (11.8 mg, 15% yield) as. 1H NMR (400 MHz, CDCl3) d: 8.09 (s, 1H), 7.43-7.28 (m, 5H), 7.08 (t, J = 8.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 4.42 (t, J = 8.0 Hz, 2H), 3.88 (s, 2H), 3.82 (t, J = 7.8 Hz, 2H), 3.75 (s, 3H) ppm LCMS = 95.9% purity. MS (APCI +) = 412.1 (M + 1).
Example 327. Preparation for I-275

Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I-275). I-275 is a similar processture from I-145 (516 mg, 1.59 mmol) and 2-methyl carboxy pyridine-5 brominated acidic pinocol ester (460 mg, 1.75 mmol) to P-252 used. . The crude material was purified by flash silica gel column chromatography (0-5% acetone in dichloromethane) to give I-275 (381 mg, 62% yield) as an orange syrup. 1H NMR (400 MHz, CDCl¬3): 8.65 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.37-7.33 (m, 3H), 7.26-7.24 (m, 1H), 7.11 (t, J = 8.6 Hz, 1H), 6.73 (dd, J = 8.6 Hz, 1.0 Hz, 1H), 4.04 (s, 2H ), 4.00 (s, 3H), 3.77 (s, 3H) ppm. LCMS = 96.8% purity. MS (APCI +) = 386.0 (M + 1).
Example 328. Preparation for I-276

  Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid (I-276). To resolve I-275 (317 mg, 0.822 mmol) in tetrahydrofuran (2.2 mL), methanol (2.2 mL) and water (2.2 mL), 1N aqueous sodium hydroxide (1.64 mL, 1.64 mmol) was Added. The resulting solution was stirred at room temperature for 23 h. The pH was adjusted to pH 4 with glacial acetic acid. Approximately 3/4 of the solvent was removed under vacuum, and the remaining stop was diluted with water (10 mL). The suspending agent was extracted with dichloromethane (3 × 10 mL), and the composite extract was removed under vacuum to give I-276 (250.8 mg, 82% yield) as a beige solid. (Filtered) and dried through solvent.

1H NMR (400 MHz, CDCl3): 8.50 (m, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.76-7.71 (m, 1H), 7.37-7.32 (m, 3H), 7.26-7.24 ( m, 1H), 7.13 (t, J = 8.6 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.05 (s, 2H), 3.77 (s, 3H) ppm.MS (APCI +) = 327.2 (M-44), MS (APCI-) = 327.9 (M-44).
Example 329. Preparation for P-382

Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid dimethylamide (P-382). I-276 (50.0 mg, 0.134 mmol), dimethylamine (ethanol, 26.6 uL, 33% by weight of 0.148 mmol), EDCI (28.4 mg, 0.148 mmol) and HOBt (20.0 mg, 0 .148 mmol) was stirred at room temperature for 36 h. The residue was dissolved in ethyl acetate (5 mL) and the solvent was removed under vacuum. The organic solution was washed with water (5 mL) and the aqueous wash extracted the acetate (5 mL) with ethyl. The organic extract was combined. Water (5 mL) and brine (5 mL) (dried over sodium sulfate) were then filtered, washed with aqueous saturated sodium bicarbonate (10 mL), and the solvent was removed in vacuo. The raw yellow oil was purified by preparative thin layer chromatography (dichloromethane) with silica gel and a clear syrup. Dried under high vacuum at room temperature for 4 h to give P-382 (28.6 mg, 54% yield) as: 1 H NMR (400 MHz, CDCl 3): 8.48 (s, 1H), 7.63-7.58 (m, 2H), 7.39-7.28 (m, 4H), 7.12 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.00 (s, 2H ), 3.770 (s, 3H), 3.13 (s, 3H), 3.10 (s, 3H) ppm. LCMS = 97.4% purity. MS (APCI +) = 399.1 (M + 1).
Example 330. Preparation for P-401

  Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid amide (P-401). To the suspension of I-276 (100 mg, 0.269 mmol) in toluene (3 mL) was added thionyl chloride (70.5 uL, 0.807 mmol). The reaction was stirred at 115 ° C. for 4 h which was sealed with nitrogen and turned it into a deep brown solution. Solvent and excess thionyl chloride were removed under reduced pressure, and the remainder was dissolved in anhydrous tetrahydrofuran (3 mL). The brown stop was stirred at room temperature until morning and to the yellow solution was added aqueous concentrated ammonium hydroxide (5.8 uL, 0.807 mmoL). The brown stop was decomposed in ethyl acetate (50 mL) and water (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The two organic extracts were combined. Brine (50 mL) (dried over sodium sulfate) was then filtered, washed with water (50 mL), and the solvent was removed under vacuum to give the crude product. The product is an off-white solid purified by preparative thin layer chromatography (withdrawn with 10% acetone from dichoromethane) by silica gel-silica gel. 1 HNMR (400 MHz, DMSO-d6) 8.54 (s, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.78 (dd, J = 8.0 Hz, 2.0 Hz, 1H) , 7.57 (s, 1H), 7.45-7.35 (m, 4H), 7.28 (d, J = 6.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.06 (s, 2H), 3.73 ( s, 3H) ppm. LCMS = 100.0% purity. MS (APCI +) = 371.0 (M + 1).

実施例３３１。Ｉ―２８０の準備 << Reaction process formula 65 >>

Example 331. Preparation for I-280

  Synthesis of carbonic acid 3'-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester (I-278). I-278 is a sticky white solid as I-145 that gives I-278 (466 mg, 75% yields). Using the same conditions, synthesized from 2'-fluoro-3'-hydroxymethyl-6'-methoxy-biphenyl-3-carbonitrile (500 mg, 1.94 mmol). 1H NMR (400 MHz, CDCl3): 7.71 (m, 1H), 7.65-7.63 (m, 2H), 7.54 -7.52 (m, 1H), 7.45-7.41 (m, 1H), 6.79 (d, J = 9.2 Hz, 1H), 5.21 (s, 2H), 3.80 (s, 3H), 3.80 (s, 3H) ppm. LCMS = 95.9% purity. MS (APCI-) = 240.1 (M-75). MS (APCI +) = 279.1 (M-32).

  Synthesis of 5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid methyl ester (I-279). I-279 uses I-278 (440.0 mg, 1.40 mmol) and 2-methyl carboxy-pyridine-5-brominated acid pinocol ester (405 mg, 1.50) using conditions similar to the preparation of P-252. 54 mmol). The crude product was purified by trituration with diethyl ether (25 mL) and filtered to give I-279 (354 mg, 67% yield) as a yellow powder, diethyl ether (2 × 5 mL). ). 1H NMR (400 MHz, CDCl3): 8.65 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.69-7.60 (m, 4H), 7.51 (t, J = 7.8 Hz , 1H), 7.15 (t, J = 8.6 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.05 (s, 2H), 4.00 (s, 3H), 3.78 (s, 3H) ppm. LCMS = 96.3% purity. MS (APCI +) = 377.1 (M + 1).

Synthesis of 5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid (I-280). A solution of I-279 (150 mg, 0.399 mmol) and 1N aqueous sodium hydroxide (797 uL, 0.797 mmol) in methanol (1.5 mL), water (1.5 mL) and tetrahydrofuran (1.5 mL) was 11. Stir at room temperature for 5 h. The remaining stop was spoiled by glacial acetic acid (2 mL) and approximately 1/2 of the solvent was removed under vacuum. The suspension was diluted with water (50 mL) and extracted into dichloromethane (2 × 30 mL). The composite extract was washed with brine (50 mL). The solvent was then removed under vacuum to give I-280 (109 mg, 76% yield) as a yellow foam and dried over sodium sulfate and passed through a filter.
Example 332. Preparation for P-415

  Synthesis of 5- (3′-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine-2-carboxylic acid amide (P-415). P-415 was synthesized from I-280 (100 mg, 0.276 mmol) using the same conditions for the P-401 follow-up operation. The crude oil product was purified by silica gel and preliminary thin layer chromatography (withdrawn with 25% acetone in dichloromethane). It was then triturated with diethyl ether (5 mL), filtered and washed with hexane (2 mL) to give P-415 (10.0 mg, 10% yield) as a beige powder. It was. 1H NMR (400 MHz, CDCl3): 8.46 (m, 1H), 8.13 (d, J = 8.00 Hz, 1H), 7.78 (s, 1H), 7.70-7.61 (m, 4H), 7.51 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 8.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.55 (s, 1H), 4.04 (s, 2H), 3.78 (s, 3H) ppm. LCMS purity = 94.6%. MS (APCI +) = 362.1 (M + 1).

HPLC (254 nanometers), 92.23%. [Mobile Phase A and Mobil Phase B = Water and Acetonitrile (Symmetry C18) (250 × 4.6 mm, 5 μm) Flow = 1.0 mL / min (Inj. ) = ACN (Inj) is washed. Vol. = 10 uL. Retention time = 24.17 minutes]
Example 333. Preparation for P-504

  Synthesis of 1- (2,6-dimethoxy-3'-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (I-281). To the stirred solution starting with I-81 (1.93 mmol, 1.0 formula) and 1-hydroxymethyl-pyrrolidine-2-1 (1.93 mmol, 1.0 eq) of nitrobenzene was added at room temperature to the added aluminum chloride (1.93 mmol, 1.0 eq). The resulting mixture was stirred at room temperature for 16 h. The reaction was diluted with water and extracted with two portions of dichloromethane. The filtered water was concentrated in a vacuum and the composite organic fertilizer was washed with brine (dried over magnesium sulfate). The remainder was purified via silica gel plug filtration. A methanol / dichloromethane gradient was then used as the eluent to yield I-281 as a 72% yield glassy solid. 1H NMR (400 MHz, CDCl3) 2.03 (quintet, J = 8.0, 7.6 Hz, 2H), 2.46 (dd, J = 8.4, 8.0 Hz, 2H), 3.28 (s, 3H), 3.34 (dd, J = 8.8 , 6.8 Hz, 2H), 3.75 (s, 3H), 4.51 (s, 2H), 6.76 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4, 7.6 Hz, 1H), 7.77 (dt, J = 7.6, 1.2 Hz, 1H), 8.21 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 8.32 (dd, J = 2.0, 1.6 Hz, 1H) ppm. LC / MS (100%): APCI (+) found: 357.1 (M + 1); calc'd: 356.4 m / z.

  Synthesis of 1- (2,6-Dihydroxy-3′-nitro-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P-504). One formula of boron tribromide as a 1.0 M solution of dichloromethane was added to a stirred solution I-281 of dichloromethane at −70 ° C. The resulting mixing was able to heat up to room temperature. After 3 h, another formula of boron tribromide solution was added and the reaction was re-cooled to -70 degrees C. and the reaction was heated to room temperature and could be stirred for 16 h. . The reaction was added to boron tribromide solution cooled to -70 degrees C and excess (formula 3.6), and the reaction was heated to room temperature with stirring over 18 h. The reaction disappeared with water and was extracted with ethyl acetate. The composite extract was washed sequentially with water and brine, and the dried (MgSO4) solution was concentrated to yield P-504 as a tan solid in 59% yield.

¹ H NMR, (400 MHz, DMSO-d ₆ ): 1.96 (quintet, J = 7.6 Hz, 2H), 2.33 (dd, J = 8.4, 8.0 Hz, 2H), 3.43 (t, J = 7.2 Hz, 2H ), 4.27 (s, 2H), 6.48 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 8.8, 8.0 Hz, 1H), 7.78 (d , J = 8.0 Hz, 1H), 8.12-8.14 (m, 2H), 9.45 (s, 1H), 9.55 (s, 1H) ppm .LC / MS (90.9%): APCI ^- found: 327.1 (M-1 ); calc'd: 328.3 m / z.
Example 334. Preparation of P-504, I-282 and P-229

(Demethylation of I-281: To a stirred solution of dichloromethane at 70 ° C. in I-281 was added a 1.0 M solution of dichloromethane in boron tribromide over 1 minute. The resulting solution was at room temperature. I was able to get a fever and was stirred all night,
There, positional TLC analysis showed no progress. The reaction was added to -70 ° C. and added boron tribromide solution (one formula) over 1 minute, cooled again, resulting in a solution that can be heated to room temperature for 1 minute. Stirred, where the reaction mixture is poured into ice water and extracted with three portions of ethyl acetate. The composite excerpt was washed with three parts of water and brine. The solution was dried through magnesium sulfate, vacuum concentrated and the rest, purified through preliminary thin layer chromatography using 30% acetone in hexane to allow room for the above compounds, P-504, I-282 , P-229.

I-282: ¹ H NMR (400 MHz, DMSO-d ₆ ): 1.93 (quintet, J = 7.6 Hz, 2H), 2.28 (dd, J = 8.0, 7.6 Hz, 2H), 3.20 (s, 3H), 3.24-3.30 (M, 2H), 4.34 (s, 2H), 6.77 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 9.2, 7.6 Hz , 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 8.19-8.21 (M, 2H), 9.76 (s, 1H) ppm
LC / MS (97%) APCI ⁺ found: 343.1 (M + 1); calc'd: 342.4 m / z

P-229: ¹ H NMR (400 MHz, DMSO-d ₆ ): 1.96 (quintet, J = 7.6 Hz, 2H), 2.33 (t, J = 8.0 Hz, 2H), 3.44 (t, J = 7.2 Hz, 2H), 3.68 (s, 3H), 4.32 (s, 2H), 6.65 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.73 (dt, J = 7.6, 1.6, 1.2 Hz, 1H), 8.07 (m, 1H), 8.15 (ddd, J = 8.4, 1.6, 1.2 Hz, 1H) 9.53 (s, 1H) ppm.
LC / MS (100%) APCI ⁺ found: 343.1 (M + 1); calc'd: 342.4 m / z
Example 335. Preparation for P-394

Synthesis of [4- (3′-cyano-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-384). 5 mL dimethoxyethane and 1.6 mL 50% aqueous ethanol I-285 (0.60 mmol, 1.0 eq), 3-cyanophenyl bromic acid (1.2 mmol, 2 eq), potassium phosphate (1.2 mmol, 2 eq) and tetrakis (triphenylphosphine) palladium (0.06 mmol, 0.1 eq) were degassed with nitrogen for 10 minutes. The resulting mixture was heated at 80 degrees C for 18 h and cooled to ambient temperature. The cake was washed with ethyl acetate and the solids were removed by filtration. The filtered water was washed with successive portions of water and brine, dried over magnesium sulfate and filtered. The filtered water was concentrated to a volume of 5 mL under a stream of nitrogen and the solid collected by filtration and washed with two portions of ethyl acetate to give the title compound (P- 394) was dried under vacuum over ethyl acetate vapor for 3 h. ¹ H NMR, (400 MHz, DMSO-d ₆ ): 3.75 (s, 3H), 3.83 (s, 2H), 5.76 (s, 2H), 7.04-7.10 (m, 3H), 7.20-7.22 (m, 2H), 7.27-7.29 (m, 2H), 7.60 (dd, J = 8.0, 7.6 Hz, 1H), 7.77-7.80 (m, 2H), 7.89 (dd, J = 1.6, 1.2 Hz, 1H), 8.40 (s, 1H) ppm. LC / MS = 98.5% purity: APCI ⁺ found: 358.1 calc'd: 357.4 m / z
Example 336. Preparation for P-421

  Synthesis of [4- (3′-chloro-6-hydroxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-421). Discontinuation of P-378 (2.2 mmol, formula of 1.0) with -70 degrees dichloromethane, C 5 min, 1.0 M solution of boron tribromide in dichloromethane (6.6 mmol, 3 eq). Added. The resulting mixture was stirred and allowed to heat to ambient temperature and stirred for 20 minutes. The reaction was poured into ice water (100 mL). The cake was then washed with a continuous portion of water and hexane and stirred for 30 minutes and passed through a filter. The solid was dried under vacuum over ethyl acetate vapor for 4 h to give P-421 to the title compound, which was subjected to further reaction. Some P-421 was further purified via chromatography on acetone using dichloromethane silica gel as eluent. This was followed by grinding with dichloromethane to yield the pure P-421 compound as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): 3.78 (s, 2H), 5.75 (s, 2H), 6.86 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.4, 2.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.4 (m, 1H), 7.41 (dd, J = 8.0, 7.6 Hz, 1H), 4.47 (m, 1H), 7.56 (m, 1H), 8.40 (s, 1H), 9.50 (s, 1H) ppm.
LC / MS = 100% purity. APCI ⁺ found: 353.0 calc'd: 352.8 m / z
Example 337. Preparation for P-420

Synthesis of [4- (3′-chloro-6-ifluoromethoxy-2-fluoro-biphenyl-3-ylmethyl) -phenyl] -urea (P-420). To a solution of 10 mL of dimethylformamide P-421 (0.992 mmol, 1.0 eq) was added sodium hydroxide (2.98 mmol, 3 eq) and the resulting stop was stirred for 5 minutes. Sodium chlorodifluoroacetate (4.96 mmol, 5 eq) was added and the mixture was stirred at 50 ° C. for 18 h and cooled to ambient temperature. Added sodium hydroxide (2 mmol, 2 eq) and sodium chlorodifluoroacetate (3 mmol, 3 eq) were added and the reaction was stirred at 50 ° C. for an additional 5 h. The reaction was poured into 50 mL of water and extracted with three portions of ethyl acetate. The composite organic fertilizer was washed with successive portions of water and brine, dried over magnesium sulfate, filtered and concentrated. The remainder was purified three times by flash column chromatography on silica gel (as a yellow solid, followed by TLC to give P-420 to the title compound). 1H NMR (400 MHz, DMSO-d6): 3.89 (s, 2H), 5.76 (s, 2H), 7.10 (t, J = 74.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.22 (s, 1H), 7.27-7.31 (m, 3H), 7.33 (d, J = 2.0 Hz, 1H), 7.39-7.50 (m, 4H), 8.41 (s, 1H) ppm.
LC / MS = 98.1% purity. APCI ⁺ found: 403.0 calc'd: 402.8 m / z
Example 338. Preparation for P-468

  Synthesis of [4- (3′-chloro-2-fluoro-6-hydroxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-468). Discontinuation of P-243 (3.9 mmol, 1.0 formula) with -70 degrees dichloromethane, C was added a 1.0 M solution of boron tribromide in dichloromethane (12 mmol, 3 eq) for 30 seconds. It was. The resulting mixture was stirred and allowed to heat to ambient temperature and stirred for 1 h. The cake was washed with successive portions of water and hexane and the reaction was poured into ice water (75 mL) (passed through a filter). The solid was dried in vacuo at 40-45 degrees C for 16 h to give P-468 to the title compound, which was subjected to further reaction. Some of the title compound P-468 was further purified via chromatography on acetone using dichloromethane silica gel as a marginal eluent with pure P-468 title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): 3.78 (s, 2H), 5.76 (s, 2H), 6.73 (d, J = 8.4 Hz, 1H), 7.04-7.08 (m, 3H), 7.28-7.33 ( m, 3H), 7.38-7.46 (m, 3H), 8.41 (s, 1H), 9.82 (s, 1H) ppm. HPLC purity: 99.5%

実施例３３９。Ｉ―２８６、Ｉ―２８７、Ｉ―１５０、Ｉ―１４７およびＩ―２８８の準備 << Reaction process formula 66 >>
Preparation of I-286, I-287, I-150, I-147 and I-288

Example 339. Preparation of I-286, I-287, I-150, I-147 and I-288

  Synthesis of 3-bromo-4-difluoromethoxy-benzaldehyde (I-286). Suspension of 3-bromo-4-hydroxy-benzaldehyde (4.97 mmol, 1.0 formula), cesium carbonate (7.46 mmol, 1.5 formula) and sodium chlorodifluoroacetate is 65 ° C. for 5.5 h. Was stirred at. The mixture was partitioned with ethyl acetate and water, and the watery portion was withdrawn with diethyl ether. The combined extract was washed with successive portions of water and brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound (I-286) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): 7.49 (t, J = 72.4 Hz, 3H), 7.54 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 8.4, 2.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 9.96 (s, 1H) ppm.

  Integration of 3'-chloro-6-difluoromethoxy-biphenyl-3-carbon aldehyde (I-287). 20 mL of DMF I-286 (7.98 mmol, 1.0 eq), 3 chlorophenyl bromic acid (8.76 mmol, 1.1 eq), cesium carbonate (15.9 mmol, 2.0 eq) and palladium (II) acetate The (0.40 mmol, 0.05 eq) hybrid was degassed with nitrogen for 5 minutes. Added palladium (II) acetate (0.40 mmol, 0.05 eq) was added and the resulting stop wsa was heated to 50 degrees C for 2 h (cooled to environment for 16 h) And the reaction became hot again at 50 degrees C for 2 h. The reaction was cooled to <30 ° C. and the solid was removed by filtration. The filtered water was partitioned with ethyl acetate and water, and the watery portion was withdrawn with ethyl acetate. The combined extract was washed with successive portions of 5% lithium chloride, 0.5N HCl, water and brine, dried over magnesium sulfate, filtered and the title compound (98% oil as 98% yield). I concentrated because I could afford I-287). 1HNMR (400 MHz, DMSO-d6): 7.40 (t, J = 72.8 Hz, 1H), 7.49-7.62 (m, 5H), 8.02-8.04 (m, 2H), 10.04 (s, 1H) ppm.

  Synthesis of (3'-chloro-6-difluoromethoxy-biphenyl-3-yl) -methanol (I-150). To a solution of 18-mL THF hybrid I-287 (6.8 mmol, 1.0 eq) and 0-5 degrees 6 mL water, C was added sodium borohydride (10 mmol, 1.5 eq), and The resulting mixture was stirred for 10 minutes. The reaction was extracted with two portions of ethyl acetate, pH adapted to 8 with 15% ammonium chloride and diluted with 10 mL of water. The complex organic fertilizer was washed with successive portions of water and brine, dried over magnesium sulfate, filtered, and concentrated to afford the quantitative yield of the title compound (I-150). 1H NMR (400 MHz, DMSO-d6): 4.54 (d, J = 5.6 Hz, 2H), 5.28 (t, J = 5.2 Hz, 1H), 7.14 (t, J = 74.0 Hz, 1H), 7.27 (d , J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.42-7.52 (m, 6H) ppm.

  Integration of 5-bromomethyl-3'-chloro-2-difluoromethoxy-biphenyl (I-147). In the solution of 0-5 degrees dichloromethane in I-150 (3.5 mmol, 1.0 eq), C was added, especially tribromide containing trivalent phosphorus (1.8 mmol, 0.5 eq), and The resulting solution was agitated and could naturally heat up to ambient temperature of 2 h or more. To the reaction, 15 mL of ice water was added and the watery portion was withdrawn by two portions of ethyl acetate. I-147 as an oil of 53% yields, complex organic fertilizer is washed with successive portions of saturated sodium bicarbonate, water and brine, dried over sodium sulfate, filtered to afford the title compound Concentrated to be. 1H NMR (400 MHz, DMSO-d6): 4.77 (s, 2H), 7.21 (t, J = 74.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.41-7.60 (m, 6H) ppm.

  Synthesis of 5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -2-fluoro-pyridine (I-288). A-stop hybrid in I-147 (1.7 mmol, 1.0 eq), 2-fluoro-pyridine-5-bromate (1.9 mmol, 1.1 eq) and potassium phosphate (3.4 mmol, 2.0 eq) In dimethoxyethane (11 mL), mixing was further degassed for 2 minutes and 50% ethanol (5.4 mL) was degassed and the reaction was 5 min To Tetrakis (triphenylphosphine) palladium (0.09 mmol, 0.05 eq) with nitrogen for the added stop was heated to 65 degrees C for 1.5 h. Thiol functionalized silica gel (0.344 mmol) was then added for 3 h and allowed to cool to ambient temperature with stirring. The solid was removed by filtration, filtered water splitting with ethyl acetate and water, and the watery one was extracted with ethyl acetate. The composite organic fertilizer was washed with successive portions of water and brine, dried over magnesium sulfate, filtered and concentrated. The remainder was purified via flash column chromatography on acetone using silica gel of hexane as a marginal eluent with the title compound as a 55% yield oil.

¹ H NMR (400 MHz, DMSO-d ₆ ): 4.03 (s, 2H), 7.12 (t, J = 70.0 Hz, 1H), 7.11 (dd, J = 8.4, 3.2 Hz, 1H), 7.25 (s, 1H), 7.31 (s, 1H), 7.36 (dd, J = 6.4, 2.4 Hz, 1H), 7.41-7.52 (m, 6H), 7.90 (td, J = 8.4, 2.4 Hz, 1H), 8.22 (d , J = 2.4 Hz, 1H) ppm.
Example 340. Preparation for P-614

  Synthesis of 2-azetidin-1-yl-5- (3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl) -pyridine (P-614). Hybridization of I-288 (0.404 mmol, 1.0 formula) and azetidine, (0.445 mmol, 1.1 formula) excessively, DBU was heated to 160 ° C. for 2.5 h and brought to room temperature. Could be cooled. The resulting mixture was partitioned with dichloromethane and 0.5N HCl and the watery portion was withdrawn with dichloromethane. The organic fertilizer was washed with 0.5N HCl and water, dried over magnesium sulfate, filtered and concentrated. The remainder was purified by flash column chromatography on acetone using dichloromethane silica gel as a marginal eluent with the title compound (P-614) as a 32% yield oil.

¹ H NMR (400 MHz, DMSO-d ₆ ): 3.83-3.88 (m, 6H), 6.29 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 74.0 Hz, 1H), 7.22 (s, 1H), 7.27-7.50 (m, 8H), 8.01 (d, J = 2.0 Hz, 1H) ppm.LC/MS (99%)-found: 402.4 calc'd: 400.9 m / z.
Example 341. Preparation for P-422

Synthesis of 5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -2-tetrazol-1-yl-pyridine (P-422). Discontinuation of P-252 (0.18 g, 0.53 mmol) and sodium azide of glacial acetic acid (5 mL) (0.1 g, 1.58 mmol) was trimethylorthoformate (0.17 g , 1.58 mmol) was added when stirred at room temperature for 18. The reaction was diluted with cold water (60 mL) and sitting basified. NaHCO3 solution. The suspension was extracted with dichloromethane (2 × 5 mL), washed with brine (10 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo. P-422 free base white solid. A hexane preparative thin layer chromatograph of 40% ethyl acetate with room to spare with a free base of P-422 (0.13 g, 62% yield) as part A, the remainder is a silica gel column with dichloromethane Purified by chromatography (0.04 g, 0.1 mmol), ether (2 mL), then 2 M HCl in ether (0.3 ml) was added. And stirred for 4 h. The ether layer was moved. It was triturated with ether (2 × 2 mL). It was then dried to yield P-422 (0.03 g, 64% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 10.13 (s, 1 H), 8.58 (s, 1 H), 8.0 (d, J = 1.6 Hz, 1 H), 7.36-7.48 (m, 4 H), 7.26- 7.34 (m, 1 H), 6.98 (d, J = 9.2 Hz, 1 H), 4.11 (s, 2 H), 3.74 (s, 3 H) ppm; MS (APCI +): 368.0 (M + 1 ), LC-MS: 100%.
Example 342. Preparation for P-434

Synthesis of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl) -phenyl] -urea (P-434). Into I-134 (0.14 g, 0.36 mmol), THF (2.0 mL) was added pyridine (0.5 mL) and trimethylsilylocyanate (0.06 g, 0.54 mmol). The reaction was stirred at room temperature for 90 h and concentrated under vacuum. The rest was then triturated with 1: 1 dichloromethane-hexane (5 mL) and dried to yield P-434 (0.16 g, 98% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 9.08 (br s, 1 H), 7.34-7.78 (m, 8 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.09 (s, 2 H) , 3.85 (s, 3 H) ppm. MS (APCI +): 399 (M + 1), LC-MS: 100%
Example 343. Preparation for P-441

  Synthesis of {4- [1- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -1-hydroxyethyl] -phenyl} -urea (P-441). To the I-135 (0.06 g, 0.15 mmol) in THF (10.0 mL) was added bromine (diethyl ether, 0.2 mL, 0.6 mmol of 3M solution) methyl magnesium. The reaction was stirred at room temperature for 4 h, cooled to 0 ° C. and quenched with saturated ammonium chloride solution (3 mL). The reaction was extracted with ethyl acetate (2 × 60 mL), washed with brine (40 ml), dried over Na 2 SO 4, filtered and concentrated. The remainder was purified by preparative thin layer chromatography using 6% methanol-in dichloromethane to yield P-441 (0.04 g, 61% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): 8.42 (s, 1 H), 7.70 (t, J = 8.8 Hz, 1 H), 7.14-7.42 (m, 7 H), 6.96 (d, J = 8.4 Hz, 2 H), 5.76 (s, 2 H), 5.60 (s, 1 H), 3.74 (s, 3 H), 1.82 (s, 3 H) ppm. MS (APCI +): 397 (M-16 ), LC-MS: 99.0%.
Example 344. Preparation for P-532

  Synthesis of 3'-chloro-3- [bis-secondary- (4-nitrophenyl) -methyl] -2-fluoro-6 methoxy biphenyl (I-291). A solution of (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-nitrophenyl) -methanone (500 mg, 1.30 mmol) in dichloromethane (10 mL) was removed by nitrogen. It was. The reaction was cooled to 0 ° C. in an ice-water bath and Trifluoroacetic acid (2.49 mL, 32.40 mmol) was added. To the solution, a sensible sodium-boron-containing deuteride (543 mg, 12.96 mmol) over 45 minutes was added and the reaction was stirred for 20 h. And he forgave him because of the heat at room temperature. The reaction was neutralized to pH 7.5 with saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate (50 mL). The excerpt was washed with water (2 × 25 mL) and brine (25 mL). It was then dried over sodium sulfate and the solvent was removed under reduced pressure to give raw I-291. The product was purified by flash silica gel column chromatography eluting ethyl acetate in hexane by 20% to give I-291 (157 mg, 32% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6): 8.18-8.15 (m, 2H), 7.52-7.37 (m, 5H), 7.29-7.27 (m, 1H), 6.97 (d, J = 8.8 Hz, 1H), 3.74 (s, 3H) ppm.

  Synthesis of 4-[(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -bisdutero-methyl] -phenylamine (I-292). Suspension of I-291 (140 mg, 0.375 mmol), iron powder (73.2 mg, 1.31 mmol) and solid ammonium chloride (102 mg, 1.91 mmol) in ethanol (1.5 mL) and water (500 uL) Was heated to 105 ° C. for 1 h. The solvent was removed under vacuum. The residue was then drifted in water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extract was washed with water (2 × 20 mL) and brine (20 mL). It was then dried over magnesium sulfate and the solvent was removed under vacuum to give raw I-292. The product was purified by flash silica gel column chromatography to give I-292 (103 mg, 30.0% yield) as an orange oil. 1H NMR (400 MHz, CDCl3): 7.39 (m, 1H), 7.36-7.26 (m, 3H), 7.07 (t, J = 8.6 Hz, 1H), 7.03-7.00 (m, 2H), 6.68 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 6.65-6.61 (m, 2H), 3.74 (s, 3H), 3.57 (s, 2H) ppm.

Synthesis of {4-[(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl) -bisdutero-methyl] -phenyl} -urea (P-532). A solution of I-292 (80 mg, 0.233 mmol) and sodium cyanate (30.2 mg, 0.465 mmol) in water (4 mL) and glacial acetic acid (2 mL) was stirred at room temperature for 2 h. Reaction basified with saturated aqueous sodium bicarbonate (25 mL) and extracted with dichloromethane (2 × 30 mL). The extract was dried over magnesium sulfate and solvent removed under vacuum to give the crude product. Crude oil product was spare thin, eluting dichloromethane acetone by 5% to give P-532 (35.4 mg, 39% yield) as white powder by silica gel Layer chromatography was purified. 1H NMR (400 MHz, DMSO-d6): 8.42 (s, 1H), 7.47-7.41 (m, 2H), 7.36 (s, 1H), 7.30-7.24 (m, 4H), 7.07 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 9.2 Hz, 1H), 5.76 (s, 2H), 3.72 (s, 3H) ppm.LCMS = 100.0% purity MS (APCI +) = 387.1 (M + 1); HPLC (254 nm); 98.747%. [Mobile Phase A and Mobile Phase B = Water and Acetonitrile (Symmetry C18) (250 × 4.6 mm, 5 μm) Flow = 1.0 mL / min (Inj.) = Wash ACN (Inj). Vol. = 10 uL. Retention time = 27.89 minutes]
Example 345. Preparation for P-402

Synthesis of 2-bromo-5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridine (P-402). A solution of 1,2-dimethoxyethane (12 mL) in I-33 (400 mg, 1.21 mmol) and 2-bromopyridine-5 bromic acid (282 mg, 1.39 mmol) was gassed with a stream of nitrogen for 10 minutes. Removed. To the solution was added potassium phosphate (770 mg, 3.63 mmol) (reaction stirred under nitrogen for 2 h and ethanol (2.5 mL), water (2.5 mL) and tetrakis (triphenylphosphine). Palladium (0) (140 mg, 0.12 mmol) was added, ethanol and dimethoxyethane were removed under vacuum, and the aqueous solution was extracted with ethyl acetate (3 × 20 mL). Washed with water (10 mL) and brine (10 mL), dried over sodium sulfate and the solvent removed in vacuo The crude product eluted with 10% ethyl acetate in hexane. Purified by flash silica gel column chromatography, P-402 (243 mg, 9% is yielded) followed by preparative thin layer chromatography on silica gel eluting with 15% hexane ethyl acetate to give 1H NMR (CDCl3, 400 MHz): 8.27 (s, 1 H ), 7.24-7.41 (m, 6 H), 7.09 (t, J = 8.6 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 3.91 (s, 2 H), 3.76 (s, 3 H) ppm.Calc. 406.68; APCI + (M + 1): 407.9, 96%.
Example 346. Preparation for P-469

Integration of 3- [5- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -oxazolidine-2-1 (P-469). Dissolution of P-402 (100 mg, 0.246 mmol) and 2-oxazolidinone (21.4 mg, 0.246 mmol) in dioxane (1 mL) and water (7 uL) was degassed with a 15 minute stream of nitrogen. To the solution was added sodium tert-butoxide (33.0 mg, 0.344 mmol), xantphos (8.5 mg, 0.0148 mmol) and palladium (II) acetate (1.65 mg, 0.00737 mmol) The reaction was then heated to 100 ° C. with stirring for 20 h. Additional 2-oxazolidinone (21.4 mg, 0246 mmol), sodium tert-butoxide (33.0 mg, 0.344 mmol), xantphos (8.5 mg, 0.0148 mmol) and palladium (II) acetate (1.65 mg, 0.00737 mmol) was added and reacted with stirring overnight at reflux. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (25 mL). The organic extract was washed with water (25 mL). Brine (25 mL) (dried over sodium sulfate) and solvent were then removed under vacuum. The rest gives a crude product purified by silica gel on a preparative thin layer chromatography (hexane x 4 hexane x 2, 35% ethyl acetate 10% ethyl acetate). To the crude oil, the oil was diethyl ether added diethyl ether (2 mL) and 2N hydrochloric acid. The suspension was stirred for 2 h and filtered to give P-469 (22.9 mg, 21% yield) as a yellow powder. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.27 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.6 Hz, 2.6 Hz, 1H ), 7.48-7.27 (m, 6H), 6.94 (d, J = 8.8 Hz, 1H), 4.44 (t, J = 8.0 Hz, 2H), 4.14 (t, J = 8.0 Hz, 2H), 3.73 (s , 3H).
LCMS purity = 97.43%. MS (APCI +) = 413.0 (M + 1).
Example 347. Preparation for P-470

  Integration of 1- [5- (3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -3-methyl-imidazolidine-2-1 (P-470) . A solution of dioxane (1 mL) in P-402 (115 mg, 0.283 mmol), 1-methyl-imidazolidin-2-1 (56.7 mg, 0.566 mmol) and xantphos (9.0 mg, 0.0170 mmol) was 15 The gas was removed under a stream of nitrogen for a minute. To the solution To was added sodium tert-butoxide (38.0 mg, 0.396 mmol), water (7 uL) and palladium (II) acetate (1.90 mg, 0.00848 mmol) under nitrogen. The reaction was stirred at 100 ° C. for 24 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The organic extract was combined. It was then washed with water (30 mL) and brine (30 mL). It was then dried over sodium sulfate and the solvent was removed under vacuum. Crude oil product was purified by thin gel chromatography eluting ethyl acetate in hexane by 40% with silica gel, P-470 (76.1 mg, 63% yield) Developed 6 times to give.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.49-7.27 (m, 5H), 7.08 (t, J = 8.6 Hz, 1H), 6.69 (dd, J = 9.8 Hz, 1.0 Hz, 1H), 4.02 (t, J = 8.0 Hz, 2H), 3.90 (s, 2H), 3.75 (s, 3H), 3.46 (t , J = 8.0 Hz, 2H), 2.90 (s, 3H) ppm
Example 348. Preparation for P-423

  Synthesis of 1- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -piperazine (P-423). Carbon acid 3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester (0.2 g, 0.62 mmol), 1- [5- (4,4,5,5 -Tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin-2-yl] -piperazine (0.2 g, 0.68 mmol), bisdiphenylphosphinopentane (0.08 g, 0.18 mmol) To, potassium carbonate (0.26 g, 1.85 mmol) and allyl palladium, (II) chloride dimer (0.034 g, 0.09 mmol) was added dimethylformamide (6 mL). The reaction was degassed by a 10 minute stream of argon. The reaction was stirred at 85 ° C. for 18 h. The reaction was passed through a filter, washed with water, dried over sodium sulfate, passed through a filter and cooled to room temperature (injected onto crushed ice water (150 mL)) and the solvent was vacuumed Removed below. The remainder was purified by silica gel column chromatography using 10% methanol in dichloromethane to yield P-423 (0.05 g, 18% yield) as a light brown rubber solid. 1H NMR (400 MHz, DMSO-d6): 3.20 (br s, 3 H) 3.55-3.99 (m, 10 H), 6.95 (d, J = 8.59 Hz, 1 H), 7.11 (br s, 1 H) , 7.23-7.39 (m, 3 H), 7.39-7.55 (m, 2 H), 7.69 (br s, 1 H), 8.02 (s, 1 H), 9.33 (br s, 2 H) ppm. Calc. 411.9; APCI + (M + 1): 412.1, 97%.

Example 349. Preparation for P-514

  Synthesis of hydrochloric acid (P-514) 4- [5- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -piperazine-1-carboxylic acid ethylamide. In P-423 (0.05 g, 0.11 mmol), pyridine (1.5 mL) was added ethyl isocyanate (0.023 g, 0.33 mmol). The reaction was stirred at room temperature for 20 h and concentrated under vacuum. The remainder was purified by thin layer chromatography prepared with 5% methanol in dichloromethane to give the crude material. The solid was decomposed in diethyl ether (2 mL) and the reaction was stirred for 1 h, 2 M HCl in diethyl ether (0.5 ml) was added to give P-514 (0.035 g, 0.035 g, 58% concentrated under vacuum to yield).

¹ H NMR (400 MHz, DMSO-d ₆ ): 8.20-8.26 (m, 1 H), 7.93 (s, 1 H), 7.74 (br s, 1 H), 7.4-7.48 (m, 2 H), 7.26-7.38 (m, 3 H), 7.21 (br s, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.59 (br s, 1 H), 3.89 (s, 2 H), 3.73 (s, 3 H), 3.40-3.75 (m, 8 H), 3.01-3.16 (m, 2 H), 1.00 -1.08 (m, 3 H) ppm. MS (APCI +): 483.1 (M + 1), LC-MS: 99.1%.

<< Reaction Process Formula 67 >> Integrated Example 350 of P-564. Preparation for P-564

Synthesis of 4- (4-fluoro-phenyl) -1-methyl-piperidine-4-ol (I-293). A solution of diethyl ether (10 mL) in N-methyl-piperidine-4-1 (1.50 g, 13.3 mmol) was degassed under a stream of nitrogen. The solution was cooled to 0 ° C in a salt ice bath. To the active solution bromide (1.74 g, 14.6 mmol) 4-fluorophenylmagnesium was added over 5 minutes, the solid added dropwise added halfway and added Diethyl ether was added (2 mL). The reaction was then stirred at 0 ° C. for 2 h. To stop, aqueous ammonium chloride (15 mL) was added. The biphasic solution was diluted with ethyl acetate (40 mL) and added saturated aqueous ammonium chloride (20 mL). The layers were separated and the organic extract washed with brine (50 mL) (dried over sodium sulfate) was filtered and the solvent was I-293 as a brown powder (965 mg, 32% yielded) To be removed under vacuum. The product was loaded without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.51-7.48 (m, 2H), 7.13-7.09 (m, 2H), 4.80 (s, 1H), 2.52-2.53 (m, 3H), 2.36-2.30 (m, 2H), 2.19 (s, 3H), 1.94-1.87 (m, 2H), 1.57-1.54 (m, 2H) ppm.

  Synthesis of 4- (3′-chloro-6-methoxy-biphenyl-3-yl) -4- (4-fluoro-phenyl) -1-methyl-piperidine (P564). To the nitrobenzene (2 mL) was added a solution of dimethylformamide (1.5 mL) of I-293 (286 mg, 1.37 mmol). Trichloride (304 mg, 2.28 mmol) aluminum was added and the reaction was stirred under a nitrogen atmosphere to cool the ice water bath ot 0 ° C. The reaction was stirred at 0 ° C. for 30 minutes above the time the solution turned from orange to purple. To the solution was added dimethylformamide (0.5 mL) of I-294 (250 mg, 1.14 mmol). The solution was agitated for 2 h, allowing heat to reach room temperature. When the solvent was removed under vacuum and the reaction was dried over sodium sulfate, transferred and washed with ethyl acetate (50 mL) (washed with saturated aqueous ammonium chloride (50 mL), water (50 mL) and brine (50 mL)). Diluted. The residue was dissolved in ethyl acetate (50 mL) and extracted into 4N aqueous hydrochloric acid (50 mL). The aqueous extract was basified to pH 9 with solid sodium bicarbonate, the product was extracted with ethyl acetate (3 × 50 mL), and the solvent was removed under vacuum. The product was purified by flash silica gel column chromatography eluting with 10% hexane ethyl acetate. The impure product was diluted with dichloromethane, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue floated in diethyl ether (filtered) and mother liquor removed under vacuum to give P-564 (109 mg, 23% yield) as a yellow orange powder. 1H NMR (400 MHz, CDCl3): 7.46-7.46 (s, 1H), 7.32-7.26 (m, 3H), 7.24-7.20 (m, 2H), 7.16-7.15 (m, 2H), 6.99-6.94 (m , 2H), 6.90-6.87 (m, 1H), 3.78 (s, 3H), 2.46 (m, 8 H), 2.24 (s, 3H) ppm. LCMS = 96.14% purity MS [APCI +] = 410.1 (M + 1),

実施例３５１。Ｐ―５１６の準備 << Reaction process formula 68 >> Integration of P-516

Example 351. Preparation for P-516

Synthesis of 3-bromo-4-trieduteromethoxy-benzaldehyde (I-295). Discontinuation of dimethylformamide (150 mL) of 3-bromo-4-hydroxy-benzaldehyde (15.0 g, 74.6 mmol) and solid potassium carbonate (10.3 g, 74.6 mmol) was stirred at room temperature for 15 minutes. To the reaction was stirred at room temperature for 60 h and To was added iodinated (21.6 g, 149.2 mmol) tri-secondary methyl. The reaction was diluted with water (1000 mL) and extracted with ethyl acetate (2 × 600 mL). The combined organic extract was washed with brine (1000 mL). It was then dried over sodium sulfate and the solvent was removed under vaccum to give I-295 (16.33 g) as a rubber beige solid that was taken on without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) d: 9.86 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.32 ( d, J = 8.8 Hz, 1H) ppm.

  Integration of 3'-chloro-6-trideutero methoxy-biphenyl-3-carbaldehyde (I-296). Carbonate (45 mL) was degassed by nitrogen flow for 30 minutes, dimethylformamide (225 mL) and 1N aqueous cesium stopped of f I-296 (10.0 g, 45.9 mmol) and 3-chlorophenylboronic acid (7.90 g, 50.45 mmol). The reaction was stirred overnight at 50 ° C. and To was stopped To was added palladium (II) acetate (1.04 g, 4.59 mmol). The stop was filtered through celite and washed with dimethylformamide (100 mL). The solution was diluted with water (1000 mL) and extracted with ethyl acetate (2 × 600 mL). The composite extract was washed with brine (500 mL), dried over sodium sulfate, transferred and the solvent removed under vacuum. Natural brown product is a flash silica gel eluting acetone in hexane by 15% to give I-296 (10.29 g, 90% yield) as a clear oil solidified to a yellow powder -Purified by column chromatography.

  1H NMR (400 MHz, DMSO-d6): 9.94 (s, 1H), 7.96 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H ), 7.49-7.44 (m, 3H), 7.35 (d, J = 8.4 Hz, 1H) ppm.

  Synthesis of (3′-chloro-6-trisecondary methoxy-biphenyl-3-yl) -methanol (I-297). A solution of I-296 (9.75 g, 39.05 mmol) in tetrahydrofuran (75 mL) and water (75 mL) was cooled to 0 ° C. in an ice-water bath. Over 5 minutes was added solid sodium borohydride (2.22 g, 58.58 mmol). The reaction was stirred. And he allowed it because the heat was at room temperature over 3h. The reaction was diluted with ethyl acetate (250 mL). It was then washed with water (125 mL) and a watery wash was extracted with ethyl acetate (250 mL). The composite excerpt was washed with salt water. It was then dried over sodium sulfate and the solvent was removed under vacuum to convey the product. The crude material was dried under high vacuum to give I-297 (9.01 g, 92% yield) as a pale yellow oil.

  Integration of 5-bromomethyl-3′-chloro-2-trideuteromethoxy-biphenyl (I-298). A solution of I-297 (9.00 g, 35.76 mmol) and phosphorus tribromide (4.84 g, 17.9 mmol) in dichloromethane (50 mL) was stirred at 0 ° C. and heated to room temperature with stirring for 18.5 h. I was able to enter. 150 mL of water was added and the reaction was cooled in an ice-water bath. The reaction was extracted with dichloromethane (2 × 100 mL). Brine (100 mL) (dried over magnesium sulfate) was filtered and the composite extract was washed with aqueous saturated sodium bicarbonate (250 mL) and the solvent was I-298 (10.5 g, 92% Removed under vacuum to give a yield). 1H NMR (400 MHz, DMSO-d6): 7.51-7.40 (m, 6H), 7.12 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H) ppm.

Synthesis of [5- (3′chloro-6-trisecondary methoxy-biphenyl-3-ylmethyl) -pyridin-2-yl] -urea (P-516). A suspension of phosphoric acid (6.75 g, 31.79 mmol) I-298 (5.00 g, 15.89 mmol), 1- (uriedo) phenylboronic acid pinacol ester (4.16 g, 15.89 mmol) and solid potassium is The gas was removed by nitrogen flow for 15 minutes in 1,2-dimethoxyethane (40 mL), water (10 mL) and ethyl alcohol (10 mL). The reaction was stirred for 17 h overnight and to the end palladium tetrakis (tri-phenyl phosphine) (3.67 g, 3.18 mmol) was added. The stop was diluted with ethyl acetate (250 mL). Brine (100 mL) (dried over sodium sulfate) was then filtered and the solvent was removed under vacuum and washed with water (200 mL). Natural dark red gum was dissolved in 100 mL DCM and silia-thiol (10 g) was added. The stop was stirred overnight at room temperature. The suspending agent was filtered and the solvent was removed under vacuum. The crude material is purified by flash silica gel column chromatography (10% isopropyl alcohol in dichloromethane) to give P-516 (1.20 g, 20% yield) as a white powder overnight high Dry under vacuum. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.48-7.47 (m, 1H), 7.44-7.35 (m, 3H), 7.29-7.27 (m, 2H), 7.20-7.15 (m, 2H), 7.10 -7.07 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 3.83 (s, 2H) ppm. LCMS = 94.2% purity. MS (ESI +) = 370.4 (M + 1).

  HPLC (254 nanometers), 97.000%. [Mobile Phase A and Mobil Phase B = Water and Acetonitrile (Symmetry C18) (250 × 4.6 mm, 5 μm) Flow = 1.0 mL / min (Inj. ) = ACN (Inj) is washed. Vol. = 10 uL. Retention time = 26.69 minutes]

実施例３５２。Ｉ―２９９およびＩ―２７１の準備 << Reaction process formula 69 >>

Example 352. Preparation of I-299 and I-271

I-154 (3.90 g, 12.5 mmol) of N- [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -acetamide (I-299) A solution and 1,2 2-acetoimide-pyridine-5 bromine acidic pinocol in which the ester of dimethoxyethane (100 mL) (3.60 g, 13.8 mmol) was degassed by a stream of nitrogen for 15 minutes. To addde ethanol (12.5 mL), water, 12.5 mL gas was continued for 20 minutes and the solution was hard potassium phosphate (5.30 g, 25.0 mmol). To, the resulting termination, triphenyl phosphine (985 mg, 3.78 mmol) and palladium (II) acetate (281 mg, 1.25 mmol) were added under nitrogen. The stop was heated to 85 ° C for stirring for 4 h. The reaction was diluted with ethyl acetate (500 mL) (washed with water (2 × 250 mL) and brine (250 mL), dried over sodium sulfate and transferred) and solvent removed under vacuum. The crude material was purified by flash silica gel column chromatography eluting ethyl acetate in hexane by 40% to give I-299 (2.20 g, 48% yield) as a yellow oil. . ¹ H NMR. (400 MHz, DMSO-d ₆ ): 7.49 (t, J = 1.8 Hz, 1H), 7.42-7.28 (m, 5H), 7.16-7.10 (m, 5H), 6.89 (d, J = 8.4 Hz, 1H), 3.92 (s, 2H), 3.79 (s, 3H), 2.16 (s, 3H) ppm.

  4- (3'-Chloro-6-methoxy-biphenyl-3-ylmethyl) -phenylamine hydrochloride (I-271). A solution of I-299 (2.20 g, 6.01 mmol) in ethanol (90 mL) and concentrated aqueous hydrochloric acid (90 mL) was stirred at room temperature for 1 h and further heated to 80 ° C. for 2 h. The reaction was diluted with water (500 m), basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (3 × 250 mL). The composite extract was washed with water (250 mL) and brine (250 mL), dried over sodium sulfate, transferred, and the solvent was removed under vacuum. The crude product was stirred in 2N hydrogen chloride in ethyl ether (15 mL) for 3 h at room temperature. The suspension was filtered to give I-271 (1.55 g, 80% yield) as a beige powder.

¹ H NMR (400 MHz, DMSO-d ₆ ) d: 9.95 (br s, 2H), 7.49-7.34 (m, 6H), 7.25-7.20 (m, 4H), 7.05 (d, J = 8.4 Hz, 1H ), 3.94 (s, 2H), 3.74 (s, 3H) ppm. LCMS = 94.5% purity. MS (APCI +) = 324.1 (M + 1)
Example 353. Preparation for P-129

Synthesis of (2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl) -isoxazol-5-yl-methanone (P-129). Nitrobenzene (1 mL) and AlCl 3 (154 mg, 1.15 mmol) were placed in an 8 mL vial with a stir bar and stirred at room temperature for 10 minutes. The solution could be stirred for an additional 30 minutes at room temperature and chloride (151 mg, 1.15 mmol) isoxazole-5-carbonyl was added. The resulting solution was then stirred at room temperature for 20 hours and 1 hour of heating and addition I-81 (250 mg, 0.96 mmol) was added. The reaction mixture was diluted with water washed ethyl acetate (90 mL) and dried over Na2SO4 with brine. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexanes to obtain 100 mg (32%) of P-129. 1H NMR (400 MHz, CDCl3) 3.91 (s, 3 H) 6.71-6.78 (m, 1 H) 7.10-7.15 (m, 1 H) 7.52-7.64 (m, 1 H) 7.57-7.64 (m, 1 H ), 7.72-7.77 (m, 1 H) 8.21-8.30 (m, 1 H) 8.44-8.47 (m, 1 H), 8.48-8.53 (m, 1 H), 12.62 (s, 1H) ppm.
Example 354. Preparation for P-130

Integration of 3-isoxazol-5-ylmethyl-6-methoxy-3'-nitro-biphenyl-2-ol (P-130). Synthetic P-129 (80 mg, 0.24 mmol) was diluted with TFA (2 mL) and cooled to −20 ° C. NaBH4 was added slowly and the solution was a purge with N2 for 2 minutes. The reaction mixture was stirred at room temperature for 20 hours under N2. The pH was matched to ￣6 using saturated aqueous NaHCO3 and the reaction was extinguished by ice / water (20 mL). The combined ethyl acetate extract was washed with brine, dried over Na 2 SO 4 and the solution was extracted with ethyl acetate (2 × 30 mL). After filtration and removal of the solvent, the remainder was clarified by a preparative chromatography plate with 30% ethyl acetate / hexane to produce 52 mg of compound (P-130). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.73 (s, 3 H), 4.12 (s, 2 H), 4.89 (s, 1 H), 5.99 (s, 1 H), 6.57 (d, J = 8.59 Hz, 1 H), 7.20 (d, J = 8.59 Hz, 1 H), 7.63-7.73 (m, 2 H), 8.14 (s, 1 H), 8.22-8.29 (m, 2 H) ppm. LC- MS (APCI +): 327.1 (M + 1).
Example 355. Preparation for P-133

Synthesis of 3- (6-methoxy-3'-nitro-biphenyl-3-ylmethyl) -benzylamine (P-133). Synthesis I-70 (300 mg, 0.93 mmol), 2- [2- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyl] -iso-indole- 1,3-dione (338 mg, 0.93 mmol), triphenylphosphine (73 mg, 0.28 mmol), K3PO4 (394 mg, 1.86 mmol), 1,2-dimethoxyethane (8 mL) Pd (OAc) ₂ The reaction mixture of (20.8 mg, 0.09 mmol), ethanol (0.8 mL) and water (0.8 mL) was stirred at 80 ° C. for 20 hours under Ar. The reaction mixture was diluted with ethyl acetate (40 mL), washed with water and dried over Na2SO4 with brine. After filtration and removal of the solvent, the remainder is silica gel with ethyl acetate / hexanes to produce 370 mg of product that has been treated with hydrazine hydrate (0.11 mL, 2.34 mmol) in ethanol (10 mL). Purified by column chromatography. The reaction mixture was stirred at 80 ° C. for 2 hours. The filtrate was concentrated and the mixture was filtered. The resulting remainder was triturated with diethyl ether to obtain 150 mg (77%) of synthetic P-133. ¹ H NMR (400 MHz, CDCl ₃ ) 1.45 (br s, 2 H), 3.80 (s, 3 H), 3.86 (s, 2 H), 4.07 (s, 2 H), 6.92 (d, J = 8.0 Hz, 1 H), 7.08-7.31 (m, 5 H), 7.37 (d, J = 7.0 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.80 (d, J = 7.8 Hz , 1 H) 8.15 (dd, J = 8.2, 1.34 Hz, 1 H) 8.38 (s, 1 H) ppm. LC-MS (APCI +): 349.1 (M + 1) 100%.
Example 356. Preparation for P-158

Synthesis of N- [2- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -benzyl] -formamide (P-158). Formic acid (0.18 mL, 4.57 mmol) was added to acetic anhydride (0.42 mL, 4.57 mmol) at 0 ° C. The reaction mixture was then heated at 50 ° C. for 2 hours. 0.3 mL of the above mixture was added dropwise to a DCM (1 mL) solution of P-133 (50 mg, 0.14 mmol) at −30 ° C. and then stirred at −10 ° C. for 30 minutes and then at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4 with brine. After removal of the solvent, the remainder was purified by 2 g silica gel column chromatography with ethyl acetate / hexane as eluent to give 53 mg of product P-158. Yield: 100%. 1H NMR (400 MHz, CDCl3) δ ppm 3.81 (s, 3 H) 4.05 (s, 2 H) 4.50 (d, J = 5.77 Hz, 2 H) 5.50 (br. S., 1 H ) 6.93 (d, J = 8.99 Hz, 1 H) 7.03-7.14 (m, 2 H) 7.16-7.35 (m, 4 H) 7.54 (t, J = 7.98 Hz, 1 H) 7.80 (d, J = 7.51 (Hz, 1 H) 8.13-8.19 (m, 2 H) 8.37 (s, 1 H) LC-MS (APCI +): 349.1 (M + 1) 98.2%.
Example 357. Preparation for P-501

Synthesis of N- [2- (6-hydroxy-3′-nitro-biphenyl-3-ylmethyl) -benzyl] -formamide (P-501). To a hybrid of synthesis P-158 (30 mg, 0.08 mmol) in dichloromethane (2 mL) was added −78 ° C. BBr3 (dichloromethane, 0.24 mL, 0.24 mmol of 1M) under N2. The reaction mixture was stirred at room temperature and room temperature to −78 ° C. until morning. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 6 mL). The ethyl acetate extract was washed with water (brine) and dried over Na2SO4. After filtration and removal of the solvent, the remainder is obtained by a preparative chromatography plate with 2% methanol (7M NH3) / dichloromethane (2 developments) to give 20 mg (69%) of synthesis P-501. Purified. ¹ H NMR (400 MHz, CDCl3) 4.03 (s, 2 H), 4.49 (d, J = 5.6 Hz, 2 H), 5.52 (br s, 1 H), 6.83-6.90 (m, 1 H), 6.98 -7.10 (m, 2 H), 7.19-7.33 (m, 4 H), 7.58 (t, J, =, 7.9 Hz, 1 H), 7.84 (d, J, =, 7.5 Hz, 1 H), 8.12 -8.22 (m, 2 H), 8.39 (s, 1 H) ppm; LC-MS (APCI +): 363.1 (M + 1) 100%.
Example 358. Preparation for P-160

Synthesis of [3- (6-Methoxy-3′-nitro-biphenyl-3-ylmethyl) -benzyl] -carbamic acid tert-butyl ester (llx6) (P-160). Synthesis I-70 (400 mg, 1.24 mmol), 3- (n-Boc-aminomethyl) phenylboronic acid (312 mg, 1.24 mmol), triphenylphosphine (98 mg, 0.37 mmol), K3PO4 (526 mg, 2.48 mmol), 1,2-dimethoxyethane (10 mL) in Pd (OAc) ₂ (27.8 mg, 0.12 mmol), ethanol (1 mL) and water (1 mL) were reacted under 80 ° C. 20 under Ar. Stirred in time. The reaction mixture was diluted with ethyl acetate (40 mL), washed with water and dried over Na2SO4 with brine. After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane to obtain 200 mg of product P-160. Yield: 36% ¹ H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9 H) 3.81 (s, 3 H) 3.97 (s, 2 H) 4.28 (br. S., 2 H) 4.80 (br. s., 1 H) 6.94 (d, J = 8.32 Hz, 1 H) 7.05-7.22 (m, 5 H) 7.22-7.30 (m, 1 H) 7.54 (t, J = 7.98 Hz, 1 H) 7.83 ( d, J = 7.65 Hz, 1 H) 8.16 (dd, J = 8.25, 1.14 Hz, 1 H) 8.39 (s, 1 H); LC-MS (APCI-): 448.2 (M-1) 100%.
Example 359. Preparation for P-161

Synthesis of 3- (6-methoxy-3′-nitro-biphenyl-3-ylmethyl) -benzylamine (P-161). To a mixture of synthesis P-160 (53 mg, 0.12 mmol) in dichloromethane (2 mL), TFA (3 mL) was added. The reaction mixture was stirred for 1 h, room temperature. Stirred with for. After removal of most of the solvent, the remainder was dissolved in dichloromethane (5 mL) and washed with saturated aqueous NaHCO 3 (2 × 10 mL), dried with water, brine, and Na 2 SO 4. After filtration and removal of the solvent, the remainder was purified by a preparative chromatography plate with 2% methanol (7M NH 3) / dichloromethane to obtain 30 mg (73%) of synthesis P-161. ¹ H NMR (400 MHz, CDCl ₃ ) 3.81 (s, 3 H), 3.84 (s, 2 H), 3.98 (s, 2 H), 6.94 (d, J = 8.3 Hz, 1 H), 7.09 (d , J = 7.51 Hz, 1 H), 7.13-7.23 (m, 4 H), 7.22-7.31 (m, 1 H), 7.54 (t, J = 7.98 Hz, 1 H), 7.83 (d, J = 7.78 Hz, 1 H), 8.11-8.20 (m, 1 H), 8.39 (s, 1 H) ppm; LC-MS (APCI +): 349.1 (M + 1) 100%.
Example 360. Preparation for P-179

  1- (3-Bromo-4methoxybenzyl) -1H-pyridine-2-1 (I-205). Synthesis I-42 (550 mg, 1.96 mmol) (1,2-dimethoxyethane (5 mL) in K 2 CO 3 (538 mg, 3.89 mmol) was stirred at 80 ° C. under Ar for 20 hours, pyridine-2-ol ( 170 mg, 1.78 mmol) reaction mixture, diluted with dichloromethane (15 mL), washed with water and dried over Na2SO4 with brine, After filtration and removal of the solvent, the rest Purified by silica gel column chromatography with ethyl acetate / hexanes to obtain 230 mg (39%) of -205.

Integration of 1- (3′-acetyl-6-methoxy-biphenyl-3-ylmethyl) -1H-pyridine-2-1 (P-179). Synthesis I-205 (100 mg, 0.35 mmol), 3-acetylphenylbromate (58 mg, 0.35 mmol), triphenylphosphine (18 mg, 0.07 mmol), K2CO3 (145 mg, 1.05 mmol), 1 , 2-Dimethoxyethane (3 mL) in Pd (OAc) ₂ (9.5 mg, 0.04 mmol), ethanol (0.5 mL) and water (0.5 mL) was stirred at 80 ° C. for 20 hours under Ar. Was stirred at. The reaction mixture was diluted with ethyl acetate (15 mL), washed with water and dried over Na2SO4 with brine. After filtration and removal of the solvent, the remainder was purified by a preparative chromatography plate with 2% methanol (7M NH 3) / dichloromethane to give 52 mg (46%) of synthesis P-179. ¹ H NMR (400 MHz, CDCl ₃ ) 2.63 (s, 3 H), 3.80 (s, 3 H), 5.13 (s, 2 H), 6.10-6.18 (m, 1 H), 6.55-6.64 (m, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 7.27-7.37 (m, 4 H), 7.45-7.53 (m, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 8.07 (s, 1 H) ppm. LC-MS (APCI +): 334.1 (M + 1).
Example 361. Preparation for P-172

1- (3'-acetyl-6-methoxy-biphenyl-3-ylmethyl) -pyrrolidine-2-1 (P172). Synthesis I-181 (120 mg, 0.42 mmol), 3-acetylphenylbromate (69.2 mg, 0.42 mmol), triphenylphosphine (22 mg, 0.08 mmol), K2CO3 (174 mg, 1.26 mmol) , 1,2-dimethoxyethane (4 mL) in Pd (OAc) ₂ (9.5 mg, 0.04 mmol), ethanol (0.5 mL) and water (0.5 mL) was stirred under Ar for 20 h. Of 80 ° C. The reaction mixture was diluted with ethyl acetate (15 mL), washed with water and dried over Na2SO4 with brine. After filtration and removal of the solvent, the remainder was clarified by a preparative chromatography plate with 2% methanol (7M NH3) / dichloromethane to give 48 mg (34%) of synthesis P-172. ¹ H NMR (400 MHz, CDCl ₃ ) 1.93-2.06 (m, 2 H), 2.44 (t, J = 8.1 Hz, 2 H), 2.64 (s, 3 H), 3.30 (t, J = 7.0 Hz, 2 H), 3.81 (s, 3 H), 4.45 (s, 2 H), 6.96 (d, J = 8.4 Hz, 1 H), 7.20 (d, J = 2.1 Hz, 1 H), 7.22-7.29 ( m, 1H), 7.45-7.56 (m, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 8.09 (s, 1 H) ppm. LC-MS (APCI +): 324.1 (M + 1).
Example 362. Preparation for P-241

Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -dimethylamine (P-241). Synthesis I-154 (200 mg, 0.64 mmol), 4- (dimethylamino) phenyl bromic acid (138 mg, 0.83 mmol), triphenylphosphine (34 mg, 0.12 mmol), K2CO3 (132 mg, 0.96 mmol) , 1,2-dimethoxyethane (2 mL) in Pd (OAc) ₂ (14.0 mg, 0.06 mmol), ethanol (0.25 mL) and water (0.25 mL) were added under Ar. Stir for 5 hours at 80 ° C. The reaction mixture was diluted with water (10 mL) with ethyl acetate (3 × 5 mL) and the extract, washed with brine and dried over Na 2 SO 4. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane to obtain 140 mg of product P-241 as free base. The remainder was dissolved in 0.5 hour ether (3 mL) and stirring. The solution was then stirred for an additional 2 hours, followed by addition of ether (3 mL) 2M HCl solution. Removal of the solvent formed P-241 HCl salt (120 mg, 77%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) 3.14 (s, 6 H), 3.80 (s, 3 H), 3.99 (s, 2 H), 6.92 (d, J = 8.3 Hz, 1 H), 7.08 (d , J = 2.0 \ Hz, 1 H), 7.09-7.14 (m, 1 H), 7.27-7.39 (m, 5 H), 7.48 (s, 1 H), 7.67 (d, J = 8.3 Hz, 2 H ), 14.64 (br s. 1H) ppm.
Example 363. Preparation for P-246

Synthesis of N- [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -methanesulfonamide (P-246). Synthesis I-145 (300 mg, 0.96 mmol), 4- (N-phenyl-methanesulfonamido) bromic acid (228 mg, 0.96 mmol), triphenylphosphine (75 mg, 0.29 mmol), K3PO4 (407 mg, 0.92 mmol), 1,2-dimethoxyethane (4 mL) in Pd (OAc) ₂ (22.0 mg, 0.10 mmol), ethanol (0.5 mL) and water (0.5 mL) was added to Under stirring at 80 ° C for 16 hours. The reaction mixture was diluted with water (20 mL) with ethyl acetate (3 × 5 mL) and the extract, washed with brine and dried over Na 2 SO 4. Afterfiltration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane as the eluent to give 46 mg (16%) of P-246. ¹ H NMR (400 MHz, CDCl ₃ ) 2.99 (s, 3 H) 3.79 (s, 3 H) 3.94 (s, 2 H) 6.20 (br. S., 1 H) 6.91 (d, J = 8.32 Hz, 1 H) 7.08-7.17 (m, 4 H) 7.16-7.22 (m, 2 H) 7.27-7.34 (m, 2 H) 7.35-7.41 (m, 1 H) 7.48 (s, 1 H)
Example 364. Preparation for P-476

Synthesis of [4- (3′-chloro-6-hydroxy-biphenyl-3-ylmethyl) -phenyl] -methyl-carbamic acid tert-butyl ester (I-300). Synthesis I-33 (300 mg, 0.96 mmol), methyl- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -carbamic acid tert- Butyl ester (417 mg, 1.25 mmol), triphenyl phosphine (52 mg, 0.20 mmol), K3PO4 (414 mg, 2.0 mmol), 1,2-dimethoxyethane (4 mL) in Pd (OAc) ₂ (52 0.0 mg, 0.20 mmol), ethanol (0.5 mL) and water (0.5 mL) were stirred at 80 ° C. for 3 h under Ar. The reaction mixture was diluted with water (10 mL) with ethyl acetate (3 × 5 mL) and the extract, washed with brine and dried over Na 2 SO 4. After solvent fitting and removal, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane as eluent to give 340 mg (81%) of product I-300.

Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -methylamine hydrochloride (P-476). I-300 (90 mg, 0.21 mmol) was decomposed in dichloromethane (1 mL) and the mixture was stirred for 0.5 h at room temperature and TFA (1 mL) was added. Continue in vacuo by removal TFA. The material was acidified with aqueous 1M HCl to pH = 2 and extracted with ether (3 × 3 mL). The combined extract was concentrated and the aqueous layer was then basified with aqueous 2M Na 2 CO 3 to pH = 9 and then extracted with ethyl acetate (3 × 3 mL). The mixture could be stirred for 2 hours and ether (3 mL) in 2M HCl solution was added and the rest was dissolved in ether (3 mL). The solid was a vacuum that was passed through a filter to yield 32 mg (41%, 2 steps) of P-476 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 2.98 (s, 3 H), 3.79 (s, 3 H), 3.95 (s, 2 H), 6.90 (d, J = 8.3 Hz, 1 H), 7.04-7.12 (m, 2 H), 7.27-7.39 (m, 5 H), 7.45-7.54 (m, 3 H), 11.47 (br s, 2 H) ppm.
Example 365. Preparation for P-247

Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -carbamic acid tert-butyl ester (I-301). Synthesis I-154 (300 mg, 0.96 mmol), 4- (N-Boc-amino) phenyl bromic acid (228 mg, 0.96 mmol), triphenylphosphine (75 mg, 0.29 mmol), K3PO4 (407 mg, 1 .92 mmol), 1,2-dimethoxyethane (4 mL) in Pd (OAc) ₂ (22.0 mg, 0.10 mmol), ethanol (0.5 mL) and water (0.5 mL) under Ar. And stirred at 80 ° C for 3 hours. The reaction mixture was diluted with water (20 mL) with ethyl acetate (3 × 5 mL) and the extract, washed with brine and dried over Na 2 SO 4. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane to obtain 200 mg (50%) of product I-301.

  Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -ethyl-carbamic acid tert-butyl ester (I-302) I-301 (140 mg, 0.33 mmol) is Dissolved in 2 mL of DMF and stirred for 10 minutes under N2, then NaH was added. Vigor ends. The reaction mixture was stirred for 2 hours at room temperature, quenched with 20 mL water and ethyl iodide was added. The mixture was extracted with ethyl acetate (3 × 5 mL) and the combined organic extract was washed with brine and dried over Na 2 SO 4. After filtration and removal of the solvent, 120 mg (81%) of I-302 was collected.

Synthesis of [4- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -ethylamine, HCl salt (P-247). The compound I-302 (120 mg, 0.27 mmol) was dissolved in dichloromethane (1 mL) and TFA (1 mL) was added and the mixture was stirred for 0.5 h at room temperature. . The mixture could be stirred for an additional 2 hours and 2M HCl solution in ether (2 mL) was added and the remainder was dissolved in ether (2 mL) and the mixture was centrerated. The solid was a vacuum that was passed through a filter to yield 30 mg (29%, 2 steps) of P-247 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 1.32-1.43 (m, 3 H), 3.32 (br s, 2 H), 3.79 (s, 3 H), 3.94 (s, 2 H), 6.90 (d, J = 8.3 Hz, 1 H), 7.03-7.14 (m, 2 H), 7.23-7.39 (m, 5H), 7.44-7.55 (m, 3 H), 11.40 (br. S., 1 H) ppm.
Example 366. Preparation for P-477

Synthesis of N- [3- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -acetamide (P-477). Synthesis I-154 (500 mg, 1.60 mmol), 3- (N-phenyl-acetamido) bromic acid (280 mg, 1.60 mmol), triphenyl phosphine (126 mg, 0.48 mmol), K3PO4 (678 mg, 3. 20 mmol), 1,2-dimethoxyethane (5 mL) in Pd (OAc) ₂ (36.0 mg, 0.16 mmol), ethanol (0.5 mL) and water (0.5 mL) under Ar. Stirred at 80 ° C for 16 hours. The reaction mixture was diluted with water (20 mL) with ethyl acetate (3 × 5 mL) and the extract, washed with brine and dried over Na 2 SO 4. After removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane and methanol / dichloromethane to obtain 178 mg (30%) of P-477 ¹ H NMR (400 MHz, CDCl ₃ ) 2.11-2.23 (m, 3 H), 3.79 (s, 3 H), 3.94 (s, 2 H), 6.90 (d, J = 8.32 Hz, 1 H), 6.95 (d, J = 7.51 Hz, 1 H), 7.04-7.09 (m, 1 H), 7.09-7.16 (m, 2 H), 7.19-7.34 (m, 4 H), 7.34-7.42 (m, 2 H), 7.50 (s, 1 H ) ppm.
Example 367. Preparation for P-255

Synthesis of 3- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenylamine (P-255). The reaction mixture was stirred at 85 ° C until morning and up to 24 mL the vial was P-477 (80 mg, 0.22 mmol), concentrated HCl (4 mL) and EtOH (4 mL). A white solid formed immediately upon cooling to room temperature. The mixture was then stirred at room temperature for 20 minutes through a filter to obtain 75 mg (95%) of P-255 and to the vial H2O (10 mL) was added. ¹ H NMR (400 MHz, CDCl ₃ ) 3.77 (s, 3 H), 3.96 (s, 2 H), 6.84-6.96 (m, 1 H), 7.03-7.14 (m, 2 H), 7.16-7.44 ( m, 7 H), 7.50 (s, 1 H), 10.50 (br s, 2 H) ppm.
Example 368. Preparation for P-270

Synthesis of [3- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -urea (P-270). In a 24 mL vial, P-255 (60 mg, 0.17 mmol) (NaOCN (21.7 mg, 0.33 mmol), AcOH, 1 mL) and H2O, 2 mL were placed. The reaction mixture was stirred at room temperature until morning. The white solid formed was passed through a filter to obtain 54 mg. In P-270. (87%) ¹ H NMR (400 MHz, DMSO-d ₆ ) 3.74 (s, 3 H), 3.86 (s, 2 H), 5.76 (s, 2 H), 6.78 (m, 1 H), 7.04 ( d, J = 8 Hz, 1 H), 7.11 (t, J = 8 Hz, 1 H), 7.17-7.20 (m, 3 H), 7.23-7.25 (m, 1 H), 7.35-7.43 (m, 3 H), 7.48 (m, 1 H), 8.43 (s, 1H) ppm.
Example 369. Preparation for P-271

Synthesis of N- [3- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -methanesulfonamide (P-271). To a 4 mL vial, P-255 (60 mg, 0.17 mmol) (0 μC (13 μL) pyridine chloride (2 mL) followed by methanesulfonyl) was added. The resulting solution could be stirred overnight at room temperature. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic fertilizer was concentrated under vacuum and the remainder was purified by silica gel column chromatography with methanol / dichloromethane to obtain 36.7 mg (55%) of P-271). ¹ H NMR (400 MHz, CDCl ₃ ) 2.98 (s, 3 H), 3.79 (s, 3 H), 3.94 (s, 2 H), 6.53 (s, 1 H), 6.91 (d, J = 8.4 Hz , 1 H), 6.99-7.17 (m, 5 H), 7.22-7.35 (m, 3 H), 7.34-7.41 (m, 1 H), 7.48 (s, 1 H) ppm.
Example 370. Preparation for P-282

Synthesis of 3- (3′-chloro-6-methoxy-biphenyl-3-ylmethyl) -benzamide (P-282). Synthesis I-154 (200 mg, 0.64 mmol), 3-benzamido bromic acid (129 mg, 0.96 mmol), triphenylphosphine (50 mg, 0.20 mmol), K3PO4 (271 mg, 1.28 mmol), 1,2 A reaction mixture of Pd (OAc) ₂ (14.0 mg, 0.06 mmol), ethanol (0.25 mL) and water (0.25 mL) in dimethoxyethane (2.5 mL) was stirred at 80 ° C. overnight under Ar. It was done. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 3 mL), and the combined organic extracts were washed with brine and dried over Na 2 SO 4. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography eluting acetate / hexane and dichloromethane with ethyl to obtain 108 mg (48%) of P-282).

¹ H NMR (400 MHz, CDCl ₃ ) 3.78 (s, 3 H), 3.99 (s, 2 H), 6.12 (br s, 2 H), 6.89 (d, J = 8.32 Hz, 1 H), 7.08- 7.15 (m, 2 H), 7.23-7.39 (m, 5 H), 7.48 (s, 1 H), 7.57-7.64 (m, 1 H), 7.69 (s, 1 H) ppm.
Example 371. Preparation for P-303

Synthesis of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -dimethylamine (P-303). Synthesis I-33 (100 mg, 0.30 mmol), 4-N, N-dimethylphenyl bromic acid (60 mg, 0.36 mmol), 1,2-dimethoxyethane (4 mL) in K3PO4 (127 mg, 0.60 mmol), ethanol The reaction mixture of (0.5 mL) and water (0.5 mL) was stripped with argon for 5 minutes before adding palladium tetrakis (triphenylphosphine) (18 mg, 0.02 mmol), and then the argon Stirred overnight at 80 ° C. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic extract was washed with brine and dried over Na2SO4. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane and methanol / ethyl acetate as eluent to give P-303 to the free base. The resulting solution was then stirred for 30 minutes and HCl (2M of ether) was added and P-303 was decomposed in ether (2 mL). The combined filtration yielded 53 mg (43%) of the P-303 HCl salt. ¹ H NMR (400 MHz, CDCl ₃ ) 2.91 (s, 6 H), 3.74 (s, 3 H), 3.87 (s, 2 H), 6.62-6.74 (m, 3 H), 7.01-7.13 (m, 3 H), 7.24-7.36 (m, 3 H), 7.40 (s, 1 H) ppm.
Example 372. Preparation for P-310

Synthesis of 2- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -5-ethoxy-thiophene (P-310). Synthesis I-33 (100 mg, 0.30 mmol), 4-ethoxythiophene bromic acid (50 mg, 0.36 mmol), 1,2-dimethoxyethane (4 mL) in K3PO4 (127 mg, 0.60 mmol), ethanol (0. The reaction mixture of 5 mL) and water (0.5 mL) was removed with Ar for 5 min before adding palladium tetrakis (tri-phenyl phosphine) (18 mg, 0.02 mmol), and then in the morning under Ar Until 80 ° C. The reaction mixture was diluted with water (10 mL) with ethyl acetate (3 × 3 mL) and the extract. The combined organic extract was washed with brine and dried over Na2SO4. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane and methanol / ethyl acetate as eluent to give 40 mg (35%) of P-310. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.39 (t, J = 8 Hz, 3 H), 3.74 (s, 3 H), 3.89 (2, 2 H), 4.00 (q, 2 H), 6.80 ( m, 1 H), 7.05-7.40 (m, 7H) ppm.
Example 373. Preparation for P-311

  Synthesis of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -methyl-carbamic acid tert-butyl ester (I-303). Synthesis I-33 (300 mg, 0.91 mmol), methyl- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -carbamic acid tert- Butyl ester (240 mg, 1.09 mmol), palladium tetrakis (triphenylphosphine) (53 mg, 0.05 mmol), 1,3-dimethoxyethane (10 mL) in K3PO4 (380 mg, 1.82 mmol), ethanol (1 mL) ) And water (1 mL) were removed by argon for 5 minutes before adding palladium tetrakis (tri-phenyl phosphine) (53 mg, 0.05 mmol) and then 80 ° C. for 2 hours under argon. Was stirred at. The reaction mixture was diluted with water (10 mL) with ethyl acetate (3 × 5 mL) and the extract. The combined organic extract was washed with brine and dried over Na2SO4. After filtration and removal of the solvent, the remainder was purified by silica gel column chromatography with ethyl acetate / hexane as the eluent to give 240 mg (60%) of I-303.

Synthesis of [4- (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl) -phenyl] -methylamine (P-311). I-303 (240 mg, 0.21 mmol) was dissolved in dichloromethane (1 mL) and the mixture was stirred at room temperature for 0.5 h and TFA (1 mL) was added. The mixture was stirred for 2 hours at room temperature and the remainder was diluted with ether (3 mL) and HCl (2M of ether) (2 mL) and the solvent was removed. The resulting solid was passed through a filter to provide 130 mg (70%) of P-311 HCl salt. ¹ H NMR (400 MHz, CDCl ₃ ) 2.99 (br s, 3 H), 3.76 (s, 3 H), 3.95 (s, 2 H), 6.71 (d, J = 8.5 Hz, 1 H), 7.07 ( t, J = 8.5 Hz, 1 H), 7.27-7.40 (m, 6 H), 7.47-7.55 (m, 2 H), 11.46 (br s, 1 H) ppm.
Example 374. Preparation for P-326

Synthesis of 1- [3 ′-(4-dimethylamino-benzyl) -2, ′-fluoro-6′-methoxy-biphenyl-3-yl] -ethanone (P-326). In a 24 mL vial with stirring, the sticks were placed I-223 (150 mg, 0.45 mmol), 4- (dimethylamino) phenyl bromic acid (89.1 mg, 0.54 mmol), potassium carbonate (136 mg 0.99 mmol), 1,5-bis (diphenylphosphino) pentane (60 mg, 0.14 mmol), allyl palladium (II) chloride dimer (26 mg, 0.07 mmol) and dimethylformamide (3 mL). It was. The reaction mixture was heated to 80 ° C. overnight under N2. The reaction mixture was filtered through celite and additional water (10 mL) to the filtered water. After extraction with ethyl acetate (3 × 10 mL), the organic portions were combined, washed with brine (50 mL), dried (Na 2 SO 4), filtered and concentrated. The remainder was purified with EtOAc / hexane utilizing column chromatography as the eluent to convey the free base product. Conversion of the free base product to the HCl salt was accomplished by decomposing the free base of ether (2 mL), and the resulting mixture was stirred for 0.5 h and HCl (2N of ether) was added. It was. The resulting solid was passed through a filter to provide 66.2 mg (39%) of P-326 HCl salt. ¹ H NMR (400 MHz, CDCl ₃ ) 2.62 (s, 3 H), 2.91 (s, 6 H), 3.74 (s, 3 H), 3.88 (s, 2 H), 6.70 (d, J = 8.6 Hz , 3 H), 7.04-7.14 (m, 3 H), 7.47-7.55 (m, 1 H), 7.54-7.64 (m, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 8.00 ( s, 1 H) ppm.
Example 375. Preparation for P-332

Synthesis of 1- [3 ′-(6-dimethylamino-pyridin-3-ylmethyl) -2, ′-fluoro-6′-methoxy-biphenyl-3-yl] -ethanone (P-332). In a 24 mL vial with stirring, the sticks were placed I-223 (150 mg, 0.45 mmol), 6- (dimethylamino) pyridin-3-yl-bromic acid (155 mg, 0.54 mmol), carbonate Potassium (136 mg, 0.99 mmol), 1,5-bis (diphenylphosphino) pentane (60 mg, 0.14 mmol), allyl palladium (II) chloride dimer (26 mg, 0.07 mmol) and dimethylformamide (3 mL) )Met. The reaction mixture was heated to 80 ° C. overnight under N2. The reaction mixture was filtered through celite and additional water (10 mL) to the filtered water. After extraction with ethyl acetate (3 × 10 mL), the organic portions were combined, washed with brine (50 mL), dried (Na 2 SO 4), filtered and concentrated. The remainder was purified with EtOAc / hexane utilizing column chromatography as the eluent to convey the free base product. Conversion of the free base product to the HCl salt was accomplished by: dissolving it in dichloromethane (1 mL) and then adding HCl (2N of ether) and stirring for 0.5 h. After filtration, 100 mg (595) of P-332 HCl salt was obtained.
¹ H NMR (400 MHz, CDCl ₃ ) δ 3.40 (br s, 6 H), 3.77 (s, 3 H), 3.85 (s, 2 H); 6.7-8.1 (m, 9H).
1H NMR spectrum table

Claims (54)

A compound of formula I or a salt thereof wherein R1 is an optionally substituted carbon cycle or optionally substituted with 3 or fewer ring heterocycles;

R2 is an optionally substituted carbon cycle or optionally substituted with 2 or fewer ring heterocycles;
R3 is -C (= O) NH2- (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkyl-R30, (C2-C6) alkyl-R31 and methyl selected from H A saturated 4- or 5-membered heterocycle optionally substituted by
R30 is selected —C (═O) NH 2 and a 4- or 5-membered heterocycle optionally substituted by methyl;
R31 is selected from an alkoxyl group (C1-C4), an amine, a hydroxy, an alkyl amine (C1-C6), di (C1-C6) alkylamino;
R4 is selected from H and F;
R6 is selected from H, (C1-C6) alkyl and halogen;
X is N, N → O or C—R5;
R5 is selected from H (halogen) to OH ((C1-C6) alkyl (alkoxy (C1-C6)) CF3, CN, NH2, CH2OH, CH2NH2 and C≡CH);
M is selected from a direct bond and -C (R20) (R21)-O-NR22-S (O) n-C (= O) -C (R20) (R21) C (R20) (R21 ) -C (R20) = C (R21) -C (R20) (R21) -OC (R20) (R21) -NR22-C (R20) (R21) -S (O) n-C (R20) ) (R21) -C (= O) -OC (R20) (R21) -NR22-C (R20) (R21) -S (O) nC (R20) (R21)-C (= O)- C (R20) (R21)-and;

here,

Rings with 5 or 6 members are optionally substituted by methyl;
And n is zero (1 or 2);
And R20, R21 and R22 are independently selected at each occurrence with H and (C1-C4) alkyl;
With conditions below
(a)
When R3 is methyl, R2 is a 5-membered ring heterocycle and M is CH2 and R1 cannot be pentamethyltetralin;
(b)
When R3 is methyl, R1 is a 5-membered ring heterocycle and M is CH2 and R2 cannot be pentamethyltetralin. The compound or salt according to claim 1, wherein X is N or N → O:

2. A compound or salt according to claim 1 wherein X is official CR5:

Wherein R2 is selected from pyrazolyl and substituted phenyl. A compound or salt according to any one of the preceding claims (M or 2 selected from direct bond) -CH2-CH (OH)-C [] (CH3) (OH)-C [] (CH3) (NH2)-C (= O)-O-NH-N (CH3) -S (O) n, CH2NH-CH2CH2-CH = CH-CH2S (O) n, CH2O- and

.   4. A compound or salt according to any one of claims 1, 2 or 3, wherein R1 is substituted phenyl.   R1 is pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydro-isoquinoline, benzofuran, benzo-dioxane, benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine, thien, furan, oxazole, oxazoline, oxazolidine, Isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, purine, imidazolopyridine, pyrazine, thiazole-idine, iso-thiazole (octane [2.2. 2]) Quinuclidine (iso-thiazole-idine) benzimidazole (thia-diazole) benzopyran (benzothiazole) benzo Triazole (benzoxazole) benzoxadiazole (tetrahydrofuran) tetrahydro pyran (benzothien) thia morpholine (thia morpholine sulfoxide) thia morpholine sulfone (oxa diazole) triazole (tetrazole) iso indole (pyrrolopyridine) 3. An optionally substituted heterocycle selected from triazolopyridine, and dihydro and its tetrahydro analogs, 1,2-thiazine-1, 1-dioxide 2,6,7-trioxabicyclo. The compound or salt according to any one of 1, 2, or 3   Optionally substituted heterocycle wherein R1 is selected from pyrazole, benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine, thien, oxazolidine, isoxazole, azetidine, piperazine, pyrrolidine, imidazole, imidazolidine, Imidazopyridine, pyrazine, 1,2-thiazine-1,1-dioxide, benzimidazole, thia-diazole, benzo-triazole, benzoxazole, oxa-diazole, triazole, tetrazole, iso-indole, pyrrolopyridine, tria 7. A compound or salt according to claim 6 and its tetrahydro congener which is zolopyridine and dihydro.   6. A salt in accordance with claim 5 wherein the compound or said substituted phenyl is substituted by a substituent selected from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl. (Sulfonyl) hydroxy, alkoxy, halo-alkoxy, oxa-alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxy-alkyl, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamide, aminocarbonyloxy, alkyl-amino Carbonyl, dialkylaminocarbonyl, cyano, aminocarbonylalkyl, acetoxy (nitro) amino, alkylamino, di Alkylamino, aminoalkyl, (alkyl) (aryl) aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl (hydroxyalkyl) amino, heterocyclylalkoxy (including monovalent SH group) alkylthio, alkylsulfonyl, Alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, Phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino Alkoxyimino, oxa-alkyl, amino-sulfonyl, trityl, amidino, guanidino, ureido, NHC (= O) NHalkyl, NHC (= O) NH-heterocyclyl, alkylNHC (= O) N (alkyl) 2, heterocyclylalkyl Carbonylamino, phenyl containing benzyl group, benzyloxy, amino acid residue, amino acid amide, amino acid amide protected residue, amino acid amide protected residue, N methylated amino acid and N methylated amino acid amide. 6. The compound or salt according to claim 5, OEt, C (= O) NH2, wherein the substituted phenyl is substituted by a substituent selected from CH3, CH2CF3, CF3, CHO, COOH, CN, halogen, OH. C (= O) NHEt, C (= O) NMe2 COOCH3, COOEt, CH2NHC (= O) NH2, CH (CH3) NHC (= O) NH2, CH2NHC (= O) H, CH2NHC (= O) CH3, CH2C (= O) NH2, CH2COOH, CH2COOEt, CH2NHC (= O) OEt, CH2NHC (= O) O-C6H5, CH2NHC (= O) C (= O) NH2, CH2NHC (= O) NHEt, C (CH3) 2OH , CH2NHC (= O) N (CH3) 2, CH2NHC (= O) NHCH3, CH2NH2, CH (C H3) NH2, C (CH3) 2NH2, CH2OH, CH2CH2OH, CH2NHSO2CH3, CH2OC (= O) NHEt, OCH3, OC (= O) NH2, OCH2CH2N (CH3) 2, OCH2CH2OCH3, NHC (= O) NH2, NHC (= O) NHEt, NHCH3, NHEt, NH (tBoc), NHCH2COOH, N (CH3) CH2COOH, NHC (= O) NHCH2CH2Cl, NHSO2NH2, NHEt, N (CH3) 2, NH2, NH (CH3) C (= O) NH2 -NHSO2CH3-N (SO2CH3) 2, NHC (= O) OCH3, NHC (= O) OtBu, NHC (= O) CH3, SO2NH2, NHC (= O) CH2CH2COOH, NHC (= O) NHCH2COOH, CH2NHCHO NHC (= O) NHCH2COOEt, NHC (= O) NH (CH2) 3COOEt, NHC (= O) NH (CH2) 2COOEt, N (CH3) CH2CH2OH, NHC (= O) OEt, N (Et) C (= O ) OEt, NHC (= O) NH (CH2) 2COOH, NHC (= O) CH2N (CH3) 2NHC (= O) NH (CH2) 3COOH, NHC (= O) CH2NH2, NHC (= O) CH2CH2NH2, NHC ( = O) CH2NH (tBoc),

.   A salt in accordance with claim 6 wherein the compound or the substituted heterocycle is substituted by a substituent selected from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl. -Sulfonyl) hydroxy, alkoxy, halo-alkoxy, oxa-alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamide, aminocarbonyloxy, alkyl-aminocarbonyl, dialkylaminocarbonyl, cyano And aminocarbonylalkyl, acetoxy (nitro) amino, alkylamino, dialkylamino, aminoalkyl, (alkyl) (aryl Aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl (hydroxy alkyl) amino, heterocyclylalkoxy (including monovalent SH group) alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio , Arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino , Hydroxyimino, alkoxyimino, oxa alkyl, amino sulfoni , Trityl, amidino, guanidino, ureido, NHC (= O) NHalkyl, NHC (= O) NH-heterocyclyl, alkylNHC (= O) N (alkyl) 2, heterocyclylalkylcarbonylamino, phenyl containing benzyl, benzyl Oxy, amino acid residue, amino acid amide, protected amino acid residue, amino acid amide protected residue, N-methylated amino acid and N-methylated amino acid amide. 7. A compound or salt according to claim 6, OEt, C (= O) NH2 wherein the substituted heterocycle is substituted by a substituent selected from CH3, CH2CF3, CF3, CHO, COOH, CN, halogen, OH. C (= O) NHEt, C (= O) NMe2COOCH3, COOEt, CH2NHC (= O) NH2, CH (CH3) NHC (= O) NH2, CH2NHC (= O) H, CH2NHC (= O) CH3, CH2C (= O) NH2, CH2COOH, CH2COOEt, CH2NHC (= O) OEt, CH2NHC (= O) O-C6H5, CH2NHC (= O) C (= O) NH2, CH2NHC (= O) NHEt, C (CH3) 2OH, CH2NHC (= O) N (CH3) 2, CH2NHC (= O) NHCH3, CH2NH2, CH (CH 3) NH2, C (CH3) 2NH2, CH2OH, CH2CH2OH, CH2NHSO2CH3, CH2OC (= O) NHEt, OCH3, OC (= O) NH2, OCH2CH2N (CH3) 2, OCH2CH2OCH3, NHC (= O) NH2, NHC (= O) NHEt, NHCH3, NHEt, NH (tBoc), NHCH2COOH, N (CH3) CH2COOH, NHC (= O) NHCH2CH2Cl, NHSO2NH2, NHEt, N (CH3) 2, NH2, NH (CH3) C (= O) NH2 -NHSO2CH3-N (SO2CH3) 2, NHC (= O) OCH3, NHC (= O) OtBu, NHC (= O) CH3, SO2NH2, NHC (= O) CH2CH2COOH, NHC (= O) NHCH2COOH, CH2NHCHO, HC (= O) NHCH2COOEt, NHC (= O) NH (CH2) 3COOEt, NHC (= O) NH (CH2) 2COOEt, N (CH3) CH2CH2OH, NHC (= O) OEt, N (Et) C (= O ) OEt, NHC (= O) NH (CH2) 2COOH, NHC (= O), CH2N (CH3) 2, NHC (= O) NH (CH2) 3COOH, NHC (= O) CH2NH2, NHC (= O) CH2CH2NH2 , NHC (= O) CH2NH (tBoc),

.   A compound or salt according to any of claims 1 (2 or 3 selected from phenyl optionally substituted R2) optionally monocyclic unsaturated heterocycle, unsubstituted bicyclic unsaturated heterocycle And substituted fluoro-substituted bicyclic unsaturated heterocycles.   9. The method of claim 8, wherein R2 is selected from optionally substituted phenyl, indole, benzodioxole, benzoxadiazole, benzo-dioxane, benzimidazole, oxa-diazole, pyrazole, pyridine and pyridine N-oxide. Compound or salt.   14. A compound or salt according to claim 13 wherein R2 is selected from meta-substituted phenyl, indole, benzodioxole, 2,2-difluorobenzodioxole, benzo oxa diazole, benzimidazole, 5- ( Pyridin-4-yl) [1,2,4] oxa-diazole, 5- (pyridin-4-yl) [1,3,4] oxa-diazole, benzo-dioxane, 4-chloro-pyrazole, 4- ( Pyridin-4-yl) pyrazole, 6-chloro pyridine, 3- (trifluoromethyl) pyrazole and pyridine N-oxide. 14. A compound or salt according to claim 13 wherein R2 is substituted with phenyl:

Where R7 is a halo (C1-C6) alkyl selected from hydrogen (halogen) to nitro (cyano), alkoxyl group (C1-C6), hydroxy (C1-C6), oxa-alkyl, carboxy, (C1-C6) Alkoxycarbonyl, aminocarbonyl (—CONH 2), (C 1 -C 6) alkyl aminocarbonyl, acyl, hydroxy (C 1 -C 6) alkyl are (C 1 -C 6) alkoxy, amino (C 1 -C 6) alkyl, amino, (C 1- C6) Cap the alkylamino, di [alkyl] (C1-C6) amino. And (C1-C6) alkylthio, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonamide, acylamino, amidino, phenyl, benzyl, which contain a monovalent SH group Atypical cyclo yl, phenoxy, benzyloxy and heteroaryloxy; and R8 and R13 are independently selected from H and F.   Wherein the compounds or salts consistent with claim 15 wherein R8 and R13 are H and R7 are chloro, cyano, bromo (nitro) acetyl, trifluoromethyl (methoxy) selected from hydrogen (fluoro) ) Trifluoromethoxy, oxadiazolyl, tetrazolyl, methylthio, methanesulfinyl, methanesulfonyl, methanesulfonamide, amino, methoxymethyl, hydroxyethyl and morpholinyl.   4. A compound or salt according to any of claims 1, 2 or 3 wherein R1 is optionally selected, optionally substituted with phenyl and optionally substituted with 5 several heteroaryls A six-membered heteroaryl was substituted, optionally a non-aryl heterocycle consisting of several parts of 4-7, and optionally a fused bicycle. 18. A compound or salt according to claim 17 wherein R1 is selected from optionally substituted phenyl;
Heteroaryl consisting of several optionally substituted five moieties selected from thiazole, thiadiazole, pyrazole, oxadiazole, isoxazole, triazole, imidazole, thiophene, tetrazole and oxazole; pyridine, pyrimidine, pyridazinone, pyrimidinone , Pyridinone, pyrazine and diazine optionally substituted six-part heteroaryl; several parts non-aryl heterocycle optionally selected from tetrahydro-thiophene 5- and 6-piperazine, oxazolidinone, imidazolidinone, morpholine, piperidine, pyrrolidinone, pyrrolidinedione, pyrrolidine, piperidinone, piperidinedione and trioxabicyclo [2.2.2] o And optionally substituted selected from benzoxazolone, indole, isoindolinedione, 2H-pyrrolopyridinedione, purine, indolinedione, triazolopyridinone, benzimidazole, benzoxadiazole, quinoline and quinolones Bicycle with a fuse; where the substituents are hydrogen, halogen, halo (C1-C6) alkyl, alkoxyl group (C1-C6), independent of hydroxyl, carboxy, (C1-C6) alkoxycarbonyl, Aminocarbonyl (—CONH2), (C1-C6) alkyl aminocarbonyl is selected. Carbonyl (oxo), acyl, hydroxy (C1-C6) alkyl is (C1-C6) alkoxy, amino (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkyl, nitro, amino, ( C1-C6) alkylamino, di [alkyl] (C1-C6) cyano, which caps amino. And (C1-C6) alkylthio, sulfoxide, sulfone, sulfonate, sulfone-imide, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, amino containing monovalent SH group Carbonyl (C1-C6) alkyl, (C1-C6) alkoxycarbonyl (C1-C6) alkyl, carboxy (C1-C6) alkyl, formylamino (C1-C6) alkyl, carboxy (C1-C6) alkylamino- (CH2) p-NR12CO- (CH2) q-NR9R10-NHSO2R11-OCH2CH2NR9R10-NHSO2NR9R10-SO2NR9R10- (CH2) p-NHCOR9, OCONR9R10 and NR12COOR11;
R3 is selected —CH3-CH2CH3-CF3-CHF2 and —CH2F;
R5 is selected from H -F-OH-CH3-OCH3-CF3-CN-NH2 and -C≡CH;
R7 is selected from H, halogen, nitro, acetyl, hydroxyethyl, and R2 is (a) phenyl —NH 2 —SCH 3, methoxy carbonyl —SOCH 3 —SO 2 CH 3 —OCH 3 —OCF 3 —CN—CF 3 —CH 2 OCH 3;
Or (b) benzoxadiazole, benzodioxole, 2,2-difluorobenzodioxole, benzoxadiazole, benzo-dioxane, benzimidazole, oxa-diazole, pyrazole, pyridine and pyridine N-oxide;
R9 is H, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carboxy (C1-C6) alkyl, (C1-C6) alkoxy carboxy (C1-C6) alkyl Selected from;
Alternatively, taken together, R10 is H ((C1-C6) alkyl), or R9 and R10 together form a heterocycle optionally substituted by (C1-C6) alkyl;
R12 is H or (C1-C6) alkyl, R11 is linear (C1-C6) alkyl, q is 0, 1 or 2, p is 0 or 1;
Or two adjacent substituents together form an optionally substituted fused heterocycle;
(I) has the condition that when R5 is H, R3 is —CH3 and R1 are substituted or unsubstituted pyrazole, and R2 is m-nitrophenyl or optionally heterocyclic Replaced;
(ii) when R5 is H, R3 is-then R1 is not, R2 is meta (trifluoromethyl) phenyl

And CH3;
(iii) R3 is, when R5 is H—CH3 and R2 are m-nitrophenyl, and R1 is not;

as well as
(iv) when R5 is H, R3 is -R2 is m-methoxyphenyl or m-acetyl phenyl and CH3, then R1 is not

. A compound or salt according to the official claim 1:

Wherein R1a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, non-aryl heterocycle consisting of several parts of 4-7 or a fused bicycle;
R14 is selected from H-CH2NHC (= O) NH2-NHC (= O) NH2-NHC (= O) NHEt, CH3, CH2CF3, CH2NHC (= O) CH3, NHCH3, NHEt, NH (tBoc), CHO, NHC (= O) NHCH2CH2Cl, NHSO2NH2, NHEt, N (CH3) 2, NH2, COOH, C (= O) NH2, CH2C (= O) NH2, CH2COOH, CH2COOEt, CN, OCH3, OC (= O) NH2, NH (CH3) C (= O) NH2, halogen, CH2NHC (= O) OEt-NHSO2CH3-N (SO2CH3) 2, NHC (= O) OCH3, OH, CH2NHC (= O) N (CH3) 2, CH2NH2, CH2OH, CH2CH2OH-SO2NH2-NHC (= O) NHCH COOH, CH2NHCHO, NHCNHCH2COOEt (= O), COOCH3, COOEt, NHCNH (= O) (CH2) 3COOEt, NHCNH (= O) (CH2) 2COOEt, NHC (Et) OEt (= O), NHCNH (= O) ( CH2) 2COOH, CH2NHSO2CH3, OEt, NHCCH2N (= O) (CH3) 2, NHCNH (= O) (CH2) 3COOH, NHCCH2NH2 (= O), NHCCH2CH2NH2 (= O), NHCCH2NH (= O) (tBoc), OCH2CH2N (CH3) 2, OCH2CH2OCH3, 3'-nitro-6-methoxybiphenyl-3-ylmethyl, tetrahydroimidazol-2-yl, three methyltetrahydroimidazol-2-1-1-yl, pyra On Lumpur-1-yl 1,

R15 is selected from H, NO2, OH, NH2, and -NHSO2NH2;
Or, R14 and R15 form methylene dioxy;
R27 is selected from hydrogen (halogen) to nitro (cyano), halo (C1-C6) alkyl, alkoxyl group (C1-C6), hydroxy (C1-C6), oxa-alkyl, carboxy, (C1-C6) ) Alkoxycarbonyl, aminocarbonyl (—CONH2), (C1-C6) alkyl aminocarbonyl, acyl, hydroxy (C1-C6) alkyl are (C1-C6) alkoxy, amino (C1-C6) alkyl, amino, ( C1-C6) Alkylamino, di [alkyl] (C1-C6) amino is overlaid. And (C1-C6) alkylthio, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonamide, acylamino, amidino, phenyl, benzyl, which contain a monovalent SH group Atypical cyclo yl, phenoxy, benzyloxy and heteroaryloxy;
R28 is selected from H and F, or R28 and R27 form a 5-membered ring. 20. A compound or salt according to claim 19 wherein R27 and R28 represent fused heterocycles at the 3 and 4 positions such that the phenyl to which they are attached and R28 are selected from the following and the rest are formed from R27:

  Wherein the compound or salt corresponding to R27 in claim 19 is trifluoromethoxy and is nitro, acetyl, selected from halogen which is 1,3,4, thiadiazol-2-yl. Hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, cyano, or R8 is methylenedioxy or difluoromethylenedioxy and together Bring R7.   22. A compound or salt according to claim 21, wherein R1a is selected from a benzene ring, triazole, pyridine or pyridine-N-oxide (pyrazole, tetrahydro-thiophene, imidazole, pyrimidine, thiadiazole and imidazopyridine).   The compound or salt according to any one of claims 1 to 3, wherein R5 is fluoro, H, CN or OH.   The compound or salt according to any one of claims 1 to 3, wherein R3 is methyl or fluoromethyl. A compound or salt according to the official claim 1:

Wherein R3 is methyl or methyl fluoride;
Y is CH or N;
R27a is selected from halogen (cyano) acetyl, methylthio, nitro and trifluoromethyl;
R16 is selected from NR17C (= O) NR18R19, and

here,

A 4-7 membered ring and a heterocycle attached by its nitrogen;
R17 and R18 are each selected from H, (C1-C6) alkyl and halo (C1-C6) alkyl;
R19 is-[(C1-C6) alkyl] COOH and-[(C1-C6) alkyl] COO (C1-C6) alkyl selected from H, (C1-C6) alkyl, halo (C1-C6) alkyl ;
And R20 is selected from carboxylic acids, carboxamides, carboxylic esters, primary, secondary, tertiary alcohols, and primary, secondary, tertiary amines. 26. A compound or salt according to claim 25 wherein X is CH, CF or N—O;
M is —CH 2 — or —S;
R27a is selected from chloro (cyano) acetyl and methylthio;
R16 is selected from NR17C (= O) NR18R19 and

. 27. A compound or salt according to claim 26 wherein Y is CH;
M is -CH2;
R27a is chloro;
And R16 is -NR17C (= O) NR18R19.   28. A compound or salt according to claim 27 wherein R16 is -NR17C (= O) NR18R19 and R17 (R19 is all hydrogen and R18).   29. A salt of the compound of any of claims 1-3 or 25-28, wherein the salt is a pharmaceutically acceptable salt.   A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a synthetic or pharmaceutically acceptable salt according to any of claims 1-3 or 25-28. A pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier;
A synthetic or pharmaceutically acceptable salt (b) according to any of claims 1-3 or 25-28;
And a second drug selected from a cholinesterase inhibitor, an NMDA antagonist, a calpain inhibitor and an antioxidant (c).   32. The pharmaceutical composition according to claim 31, wherein the second drug is selected from tacrine, huperzine, donepezil, ranisemin, remacemide, neramexane, memantine, vitamin E and coenzyme Q10.   The method for the treatment or prophylaxis of a disease or condition was mediated by phosphodiesterase 4 comprising providing a mammal with a therapeutically effective amount consistent with synthesis according to any of claims 1-3 or 25-28.   34. The method of claim 33, wherein the disease or condition is selected from stroke, myocardial infarction and cardiovascular inflammatory conditions.   34. The method of claim 33, wherein the disease or condition is cancer.   34. The method of claim 33, wherein the disease or condition is selected from asthma and COPD.   A method of enhancing cognitive function comprising providing a mammal with a therapeutically effective amount consistent with synthesis in any of claims 1-3 or 25-28.   38. The method of claim 37, wherein the recognition function is memory or recognition.   38. The method of claim 37 for treating a learning disorder.   A method of treating schizophrenia or Huntington's chorea comprising providing a mammal with a therapeutically effective amount consistent with synthesis in any of claims 1-3 or 25-28.   A method of treating or preventing bone loss comprising providing a mammal with a therapeutically effective amount consistent with synthesis according to any of claims 1-3 or 25-28.   A method of addressing a decline or concern comprising providing a mammal with a therapeutically effective amount consistent with synthesis in any of claims 1-3 or 25-28.   29. A method of treating bladder inflammation, bladder overreaction and pain resulting from bladder inflammation comprising providing a therapeutically effective amount consistent with synthesis to a mammal to either of claims 1-3 or 25-28.   Use of a compound or salt according to any of claims 1-3 or 25-28 for the treatment, prevention or amelioration of a disorder responsive to the inhibition of the subject phosphodiesterase 4 thereof.   45. Use according to claim 44, wherein the disorder is selected from stroke, myocardial infarction and cardiovascular inflammatory conditions.   45. Use according to claim 44, wherein the disorder is cancer.   45. Use according to claim 44, wherein the disorder is selected from asthma and COPD.   25-28 for enhancing the use or cognitive function of a compound or salt according to any of claims 1-3.   49. Use according to claim 48, wherein the cognitive function is memory, learning impairment or cognition.   Use of a compound or salt according to any of claims 1-3 or 25-28 for the treatment, prevention or amelioration of schizophrenia or Huntington's chorea.   Use of a compound or salt according to any of claims 1-3 or 25-28 for treatment or prevention of bone loss.   Use of a compound or salt according to any of claims 1-3 or 25-28 for the treatment, prevention or amelioration of reduction or concern.   Use of a compound or salt according to any of claims 1-3 or 25-28 for the treatment, prevention or amelioration of bladder inflammation, bladder hyperreactivity and pain resulting from bladder inflammation.   Use, prevention or improvement of a compound or salt of any of claims 1-3 or 25-28 in the manufacture of a medicament for treatment selected from stroke, myocardial infarction, cardiovascular inflammatory conditions, cancer Is done. Asthma arising from bladder inflammation, COPD, memory, learning impairment, cognition, schizophrenia, Huntington's chorea, bone loss, decline, concerns, bladder inflammation, bladder overreaction or pain.