JP4926241B2 - Bicyclic derivatives as CETP inhibitors - Google Patents

Description

〔式中、
環Ｂと縮合した環Ａは、置換もしくは非置換炭素環式芳香族性基または置換もしくは非置換ヘテロ環式基を意味し；
式中、Ａｒは置換もしくは非置換炭素環式芳香族性基を意味し；
Ｒ_１は要素−Ｃ（＝Ｏ）−Ｒ_３、−Ｃ（＝Ｏ）−Ｏ−Ｒ_３、−Ｃ（＝Ｏ）−ＮＲ_４Ｒ_５、−Ｓ（Ｏ）_ｍ−Ｒ_３、−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）であり、各場合においてｍは整数０、１または２であるか、またはＲ_１はＺであり、
Ｒ_２は−ＣＮ、−ＯＲ_３、−ＣＯＲ_３、−Ｃ（＝Ｏ）−Ｏ−Ｒ_３、−Ｃ（＝Ｏ）−ＮＲ_４Ｒ_５、−Ｎ（Ｒ_４）（Ｒ_５）、−Ｓ（Ｏ）_ｍＲ_３、−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）および−ＮＲ_３−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）から成る群から選択され、各場合においてｍは整数０、１または２であるかまたは、Ｒ_２はＺであり；
Ｚは（ｉ）置換もしくは非置換単環式シクロアルキルまたは置換もしくは非置換単環式シクロアルケニル、（ｉｉ）置換もしくは非置換炭素環式芳香族性基または置換もしくは非置換ヘテロ環式基から成る群から選択され；
Ｒ_３は独立して、水素、アルキル、ハロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、シクロアルキル基において置換もしくは非置換シクロアルキル−アルキル、シクロアルケニル基において置換もしくは非置換シクロアルケニル−アルキル、置換もしくは非置換炭素環式芳香族性基、置換もしくは非置換ヘテロ環式基またはアリール基において置換もしくは非置換アラルキルを意味し； The present invention relates to compounds of formula (I) in free or salt form.

[Where,
Ring A fused with Ring B means a substituted or unsubstituted carbocyclic aromatic group or a substituted or unsubstituted heterocyclic group;
In which Ar represents a substituted or unsubstituted carbocyclic aromatic group;
R ₁ is an element —C (═O) —R ₃ , —C (═O) —O—R ₃ , —C (═O) —NR ₄ R ₅ , —S (O) _m —R ₃ , —S. (O) _m -N (R ₄ ) (R ₅ ), in which case m is an integer 0, 1 or 2 or R ₁ is Z;
R ₂ is —CN, —OR ₃ , —COR ₃ , —C (═O) —O—R ₃ , —C (═O) —NR ₄ R ₅ , —N (R ₄ ) (R ₅ ), — Selected from the group consisting of S (O) _m R ₃ , —S (O) _m —N (R ₄ ) (R ₅ ) and —NR ₃ —S (O) _m —N (R ₄ ) (R ₅ ). , In each case m is an integer 0, 1 or 2 or R ₂ is Z;
Z consists of (i) a substituted or unsubstituted monocyclic cycloalkyl or substituted or unsubstituted monocyclic cycloalkenyl, (ii) a substituted or unsubstituted carbocyclic aromatic group or a substituted or unsubstituted heterocyclic group Selected from the group;
R ₃ is independently hydrogen, alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkyl-alkyl in a cycloalkyl group, substituted or unsubstituted cycloalkenyl in a cycloalkenyl group Means substituted or unsubstituted aralkyl in an alkyl, substituted or unsubstituted carbocyclic aromatic group, substituted or unsubstituted heterocyclic group or aryl group;

R ₄ and R ₅ are independently of each other hydrogen, alkyl, halogen, hydroxy, —N (R ₄ ) (R ₅ ), —C (═O) —O—R ₃ , —C (═O) —NR _{4 R 5, -S (O)} m -R 3, -S (O) m -N (R 4) (R 5), substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heteroaryl Means alkyl substituted with one or more substituents selected from the group consisting of cyclic groups; or R ₄ and R _5, independently of one another, of substituted or unsubstituted heterocyclic groups, substituted or Means unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted carbocyclic aromatic groups;
R ₄ and R ₅ together are substituted or unsubstituted alkylene, or substituted or unsubstituted alkylene interrupted by O, NR ₃ ′ or S; R ₃ ′ is R ₃ or —C (═O ) —OR ₃ ; and here, when the groups R ₄ and R ₅ are related to R ₁ , R ₄ and R ₅ mean hydrogen;
m is an integer 0, 1 or 2;
X is CR ₆ or N and Y is N; or X is N and Y is CR ₆ ;
R ₆ is hydrogen, halogen, NO ₂ , CN, OH, alkyl, alkoxy-alkyl, hydroxy-alkyl, halo-alkyl, alkoxy, alkoxy-alkoxy, haloalkoxy, —C (═O) —R ₃ , —C ( ═O) —O—R ₃ , —N (R ₄ ) (R ₅ ), —C (═O) —NR ₄ R ₅ , —S (O) _m —R ₃ , —S (O) _m —N (R ₄ ) (R ₅ ), —NR ₃ —S (O) _m —N (R ₄ ) (R ₅ ) (where m is an integer 0, 1 or 2 in each case); alkanoyl, substituted Or an unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl; a substituted or unsubstituted aralkyl in an aryl group and a substituted or unsubstituted heterocyclyl-alkyl in a heterocyclyl group; and Le or substituted cycloalkenyl, or substituted alkylene, each alkyl, _{alkoxy, -C (= O) -O-} R 3, -C (= O) -NR 4 R 5, -N (R 4) (R 5), From the group consisting of cycloalkyl-alkyl, substituted or unsubstituted carbocyclic aromatic groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aralkyl in aryl groups, and substituted or unsubstituted heterocyclyl-alkyl in heterocyclyl groups Substituted with one or more selected substituents; and wherein a carbocyclic aromatic group or heterocyclic aromatic group or heterocyclic group, a substituted or unsubstituted aralkyl in an aryl group, heterocyclyl Substituted or unsubstituted heterocyclyl-alkyl in the group, or ring A or Ar are independently of each other Or is unsubstituted or substituted by _halogen, NO 2, CN, OH, alkyl, alkoxy - alkyl, hydroxy - alkyl, halo - alkyl, alkoxy, alkoxy - alkoxy, _{haloalkoxy, -C (= O) -R 3} , - C (═O) —O—R ₃ , —N (R ₄ ) (R ₅ ), —C (═O) —NR ₄ R ₅ , —S (O) _m —R ₃ , —S (O) _{m -N (R 4) (R 5} ), - NR 3 -S (O) m -N (R 4) (R 5) and alkanoyl (m is an integer 0, 1 or 2 in each case); and substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl; selected from the group consisting of substituted or unsubstituted aralkyl on aryl groups and substituted or unsubstituted heterocyclyl-alkyl on heterocyclyl groups Substituted with one or more substituents]
Or a salt thereof; a process for the preparation of these compounds; the use of these compounds; and a pharmaceutical formulation comprising said compound (I) in free or salt form, in particular in pharmaceutically acceptable salt form.

〔式中、
環Ｂと縮合した（annellated）環Ａは、置換もしくは非置換炭素環式芳香族性基または置換もしくは非置換ヘテロ環式芳香族性基を意味し；
式中、Ａｒは置換もしくは非置換炭素環式芳香族性基を意味し；
Ｒ_１は要素−Ｃ（＝Ｏ）−Ｒ_３、−Ｃ（＝Ｏ）−Ｏ−Ｒ_３、−Ｃ（＝Ｏ）−ＮＲ_４Ｒ_５、−Ｓ（Ｏ）_ｍ−Ｒ_３、−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）であり、各場合においてｍは整数０、１または２であるか、またはＲ_１はＺであり、
Ｚは（ｉ）置換もしくは非置換単環式シクロアルキルまたは置換もしくは非置換単環式シクロアルケニル、（ｉｉ）置換もしくは非置換炭素環式芳香族性基または置換もしくは非置換ヘテロ環式基から成る群から選択され；
Ｒ_２は−Ｃ（＝Ｏ）Ｒ_３、−Ｃ（＝Ｏ）−Ｏ−Ｒ_３、−Ｎ（Ｒ_４）（Ｒ_５）、−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）および−ＮＲ_３−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）から成る群から選択され、各場合においてｍは整数０、１または２であり；
Ｒ_３は独立して、水素、アルキル、ハロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、シクロアルキル基において置換もしくは非置換シクロアルキル−アルキル、シクロアルケニル基において置換もしくは非置換シクロアルケニル−アルキル、置換もしくは非置換炭素環式芳香族性基、置換もしくは非置換ヘテロ環式基またはアリール基において置換もしくは非置換アラルキルを意味し；
Ｒ_４およびＲ_５は互いに独立して、水素、アルキルまたはシクロアルキルを意味し、当該アルキルは置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、および置換もしくは非置換ヘテロ環式基から成る群から選択される１個以上の置換基で置換されており；
Ｒ_７およびＲ_８は互いに独立して、置換もしくは非置換ヘテロ環式基の、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニルまたは置換もしくは非置換炭素環式芳香族性基を意味するか；または
Ｒ_４とＲ_５は一体となって、置換もしくは非置換アルキレン、またはＯ、ＮＲ_３’もしくはＳで中断されている置換もしくは非置換アルキレンであり；Ｒ_３’はＲ_３または−Ｃ（＝Ｏ）−ＯＲ_３であり；そして In one embodiment, the present invention provides compounds of formula (I) in free or salt form:

[Where,
Ring A fused with ring B means a substituted or unsubstituted carbocyclic aromatic group or a substituted or unsubstituted heterocyclic aromatic group;
In which Ar represents a substituted or unsubstituted carbocyclic aromatic group;
R ₁ is an element —C (═O) —R ₃ , —C (═O) —O—R ₃ , —C (═O) —NR ₄ R ₅ , —S (O) _m —R ₃ , —S. (O) _m -N (R ₄ ) (R ₅ ), in which case m is an integer 0, 1 or 2 or R ₁ is Z;
Z consists of (i) a substituted or unsubstituted monocyclic cycloalkyl or substituted or unsubstituted monocyclic cycloalkenyl, (ii) a substituted or unsubstituted carbocyclic aromatic group or a substituted or unsubstituted heterocyclic group Selected from the group;
R ₂ is —C (═O) R ₃ , —C (═O) —O—R ₃ , —N (R ₄ ) (R ₅ ), —S (O) _m —N (R ₄ ) (R ₅ ) And —NR ₃ —S (O) _m —N (R ₄ ) (R ₅ ), wherein in each case m is an integer 0, 1 or 2;
R ₃ is independently hydrogen, alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkyl-alkyl in a cycloalkyl group, substituted or unsubstituted cycloalkenyl in a cycloalkenyl group Means substituted or unsubstituted aralkyl in an alkyl, substituted or unsubstituted carbocyclic aromatic group, substituted or unsubstituted heterocyclic group or aryl group;
R ₄ and R _5, independently of one another, denote hydrogen, alkyl or cycloalkyl, wherein the alkyl is a group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclic groups Substituted with one or more substituents selected from;
Do R ₇ and R ₈ independently of each other represent a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted carbocyclic aromatic group of a substituted or unsubstituted heterocyclic group? Or R ₄ and R ₅ together are substituted or unsubstituted alkylene, or substituted or unsubstituted alkylene interrupted by O, NR ₃ ′ or S; R ₃ ′ is R ₃ or —C ( = O) -OR ₃ ; and

m is an integer 0, 1 or 2;
X is CR ₆ or N and Y is N; or X is N and Y is CR ₆ ;
R ₆ is hydrogen, halogen, NO ₂ , CN, OH, alkyl, alkoxy-alkyl, hydroxy-alkyl, halo-alkyl, alkoxy, alkoxy-alkoxy, haloalkoxy, —C (═O) —R ₃ , —C ( ═O) —O—R ₃ , —N (R ₄ ) (R ₅ ), —C (═O) —NR ₄ R ₅ , —S (O) _m —R ₃ , —S (O) _m —N (R ₄ ) (R ₅ ), —NR ₃ —S (O) _m —N (R ₄ ) (R ₅ ) (where m is an integer 0, 1 or 2 in each case); alkanoyl, substituted Or an unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl; a substituted or unsubstituted aralkyl in an aryl group and a substituted or unsubstituted heterocyclyl-alkyl in a heterocyclyl group; and Le or substituted cycloalkenyl, or substituted alkylene, each alkyl, _{alkoxy, -C (= O) -O-} R 3, -C (= O) -N ( alkyl) (alkyl), - N (alkyl) (alkyl) , H ₂ N—C (═O) —, H ₂ N—C (═O) -alkyl—, formyl, formyl-alkyl-, cycloalkyl-alkyl, carbocyclic aromatic group, heterocycle Substituted with one or more substituents selected from the group consisting of a formula group, aralkyl and heterocyclyl-alkyl; and wherein the carbocyclic aromatic group or heterocyclic aromatic group or heterocyclic A group, a substituted or unsubstituted aralkyl in an aryl group, a substituted or unsubstituted heterocyclyl-alkyl in a heterocyclyl group, or ring A or Ar, independently of one another, Or substituted, or _halogen, NO 2, CN, OH, alkyl, alkoxy - alkyl, hydroxy - alkyl, halo - alkyl, alkoxy, alkoxy - alkoxy, _{haloalkoxy, -C (= O) -R 3} , -C (═O) —O—R ₃ , —N (R ₄ ) (R ₅ ), —C (═O) —NR ₄ R ₅ , —S (O) _m —R ₃ , —S (O) _m — N (R ₄ ) (R ₅ ), —NR ₃ —S (O) _m —N (R ₄ ) (R ₅ ) and alkanoyl (where m is an integer 0, 1 or 2 in each case); and substitution or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl; 1 selected from the group consisting of substituted or unsubstituted aralkyl on an aryl group and substituted or unsubstituted heterocyclyl-alkyl on a heterocyclyl group Is substituted with or more substituents]
The novel compound or a salt thereof.

  Compound (I) may exist as a salt, particularly a pharmaceutically acceptable salt. When compounds (I) have, for example, at least one basic center, they can form acid addition salts. Compound (I) having at least one acidic group can also form salts with bases. Also included are salts that are not suitable for pharmaceutical use but can be used, for example, for the isolation or purification of the free compound (I) or a pharmaceutically acceptable salt thereof. In view of the close relationship between the free form of the new compound and its salt form, in this specification the free compound or salt thereof corresponds to what is also meant the corresponding salt or free compound, and It can be advantageously understood.

  When a salt is a salt that is not excluded for chemical reasons readily understood by one of ordinary skill in the art, inter alia any of the pharmaceutically acceptable salts of the compounds of formula (I) or the intermediates described herein It is a common salt. They are formed at least partly when there are salt-forming groups, such as basic or acidic groups, which may be present in dissociated form in aqueous solution, for example in the pH range 4 to 10, or in particular solid In particular, it can be isolated in crystalline form.

  Such salts are, for example, as base addition salts, in particular as pharmaceutically acceptable salts, preferably organic or inorganic bases and compounds of formula (I) having any of the acidic carboxy groups or any of those described herein Formed from intermediates. Suitable metal ions derived from inorganic bases are, for example, alkali metal or alkaline earth metals, such as sodium, potassium, magnesium or calcium salts. Suitable organic bases are for example ammonium salts with ammonia, or suitable organic amines such as tertiary monoamines such as triethylamine or tri (2-hydroxyethyl) amine, or heterocyclic bases such as N-ethyl-piperidine or N , N′-dimethylpiperazine.

  Because of the presence of positively charged groups such as amino, salts can also form with acids. Such salts are preferably formed, for example as acid addition salts with organic or inorganic acids. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids such as acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid , Methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protic acids such as ascorbic acid.

  When a basic group and an acidic group are present in the same molecule, the compound of formula (I) or any intermediate described herein may form an inner salt.

  For the isolation or purification of the compound of formula (I) or any of the intermediates generally described herein, pharmaceutically unacceptable salts such as picrates or perchlorates may also be used. it can. For therapeutic use, only pharmaceutically acceptable salts or free compounds of formula (I) are used (included in the pharmaceutical formulation, if applicable), so that they are at least of formula (I) Preferred in the case of compounds.

  In view of the close relationship between compounds and intermediates, eg in free and salt forms, for example as intermediates, eg salts that can be used for the purification or identification of the compounds or salts thereof, “compounds”, “ Any reference to a “starting material” and “intermediate”, especially a compound of formula (I), refers to one or more salts thereof, or the corresponding free compounds, intermediates or starting materials and one or more salts thereof. Mixtures are also understood to mean, are appropriate and expedient, and unless stated otherwise, each of the compounds of formula (I) or solvates of one or more of these salts, metabolic precursors such as esters or amides Is also intended to be included. Different crystal forms can be obtained and are also included.

  For purposes of understanding this specification, the following definitions apply and whenever appropriate, terms used in the singular include the plural and vice versa.

Unless otherwise defined, the general definitions used herein have the following meanings:
Unless otherwise defined, an alkyl that is a group or part of a group is especially C ₁ -C ₇ -alkyl, preferably C ₁ -C ₄ -alkyl. Alkyl is a straight or branched chain (one or optionally possibly multiple), has up to 20 carbon atoms, and more preferably C ₁ -C 7 _- alkyl. The terms “lower” or “C ₁ -C ₇ —” are branched (one or more) or straight-chain having up to 7, in particular up to 4 carbon atoms, with terminal or non-terminal carbons. Define a group bonded via Lower or _C 1 -C ₇ - alkyl, for example n- pentyl, n- hexyl or n- heptyl or preferably _C 1 -C _4, - alkyl, especially methyl, ethyl, n- propyl, sec- propyl, n- Butyl, isobutyl, sec-butyl, tert-butyl.

Substituted or unsubstituted aryl (carbocyclic aromatic groups) are preferably mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl groups having 6 to 22 carbon atoms, especially phenyl or naphthyl, and is unsubstituted or _C 1 -C _7, - alkyl, especially _methyl, C 1 -C ₇ - _alkenyl, C 1 -C ₇ - alkynyl, halo _-C 1 -C ₇ - alkyl such as trifluoromethyl, halo, especially fluoro, chloro, bromo or iodo, _hydroxy, C 1 -C ₇ - alkoxy, especially methoxy, phenyloxy, naphthyloxy, phenyl - or naphthyl _-C 1 -C ₇ - alkoxy, C ₁ -C ₇ - alkanoyloxy, phenyl - or naphthyl _-C 1 -C ₇ - Arukanoiruoki , Amino, N- mono- - or N, N- di - _(C 1 -C ₇ - alkyl, phenyl, naphthyl, phenyl _-C 1 -C ₇ - alkyl, naphthyl _-C 1 -C ₇ - alkyl, _{C 1} - C ₇ -alkanoyl and / or phenyl- or naphthyl-C ₁ -C ₇ -alkanoyl) -amino, carboxy, C ₁ -C ₇ -alkoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl-C ₁ -C ₇ -alkyl Oxycarbonyl, naphthyl-C ₁ -C ₇ -alkoxycarbonyl, carbamoyl, N-mono- or N, N-di- (C ₁ -C ₇ -alkyl, phenyl, naphthyl, phenyl-C ₁ -C ₇ -alkyl and / or naphthyl _-C 1 -C ₇ - alkyl) - aminocarbonyl, cyano, sulfo, Rufamoiru, N- mono- - or N, N- di - _(C 1 -C ₇ - alkyl, phenyl, naphthyl, phenyl _-C 1 -C ₇ - alkyl and / or naphthyl _-C 1 -C ₇ - alkyl) - amino Substituted with one or more, especially 1 to 3 groups independently selected from the group consisting of sulfonyl, nitro and heterocyclyl, especially morpholinyl. More preferred aryl substituents are C ₁ -C ₇ -alkyl, especially methyl, halo, especially fluoro, chloro, bromo or iodo, C ₁ -C ₇ -alkoxy, especially methoxy, N-mono- or N, N-di. Selected from the group consisting of-(C ₁ -C ₇ -alkyl) -amino, N-mono- or N, N-di- (C ₁ -C ₇ -alkyl) -aminocarbonyl, carboxy, cyano and heterocyclyl, especially morpholinyl Is done. A carbocyclic aromatic group is especially phenyl, biphenylyl or naphthyl. Biphenylyl is, for example, 4-biphenylyl and 2- or 3-biphenylyl. Naphthyl is 1- or 2-naphthyl.

  Heterocyclic groups are inter alia heteroaryl which is a 5-14 membered monocyclic- or bicyclic- or fused polycyclic ring system having 1-8 heteroatoms selected from N, O or S. is there. Preferably the heteroaryl is a 5-10 membered ring system. Heteroaromatic groups can be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. Heterocyclic groups can also be partially or fully saturated heteroaryl.

  Heterocyclic groups are especially substituted or unsubstituted 5- to 6-membered heterocyclic rings having 1, 2, 3 or 4 heteroatoms selected from N, S and O.

  Heterocyclic groups are especially substituted or unsubstituted benzo-fused heterocyclic rings having 1 or 2 heteroatoms selected from N, S and O and saturated or 1 or 2 double bonds Is a heterocyclic ring having

  Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1, 2,4 -Triazolyl, 4- or 5-1, 2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-- or 5-pyrazinyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl is included.

  A heteroaromatic group is also a heteroaromatic ring fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the group or position of attachment is on the heteroaromatic ring. Non-limiting examples include, but are not limited to, 1-, 2-, 3-, 5-, 6-, 7- or 8-indolidinyl, 1-, 3-, 4-, 5-, 6- Or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5 -, 6-, 7- or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolidinyl, 2-, 3-, 4-, 5-, 6 -, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, -, 5-, 6-, 7- or 8-cinolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8 -4aH-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- Or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5- 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5- 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-3 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 2 -, 3-, 4-, 5-, 6- or l-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinolinyl, 2-3 -, 4- or thieno [2,3-b] furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino [2,3-c Carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo [3,2-b] -pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido [2,3-d] -o-oxazinyl, 1-, 3- or 5-1H-pyrazolo [4,3-d] -oxazolyl, 2-, 4- or 54H-i Midazo [4,5-d] thiazolyl, 3-, 5- or 8-pyrazino [2,3-d] pyridazinyl, 2-, 3-, 5- or 6-imidazo [2,1-b] thiazolyl, 1 -, 3-, 6-, 7-, 8- or 9-furo [3,4-c] cinolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido [2,3-c] carbazolyl, 2-, 3-, 6- or 7-imidazo [1,2-b] [1,2,4] triazinyl, 7-benzo [b] Thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6 -Or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, -, 4-, 5-, 6-, 7- or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11- 1H-pyrrolo [1,2-b] [2] benzazapinyl is included. Exemplary fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo [b] Thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 5-, 6- or 7 -Benzothiazolyl is included.

  A suitable 5- or 6-membered monocycle containing up to 4 identical or different heteroatoms such as nitrogen, oxygen or sulfur atoms, preferably 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms Formula group. Suitable 5-membered heteroaryl groups are, for example, monoaza-, diaza-, triaza-, tetraaza-, monooxa- or monothia-cyclic aryl groups, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl and thienyl, Suitable and suitable 6-membered groups are especially pyridyl and pyrimidyl. Suitable aromatic groups are groups which may be mono- or poly-substituted, for example di- or tri-substituted, for example with the same or different groups.

Pyrrolyl is, for example, 2- or 3-pyrrolyl. Pyrazolyl is 3- or 4-pyrazolyl. Imidazolyl is 2- or 4-imidazolyl. Triazolyl is, for example, 1,3,5-1H-triazol-2-yl or 1,3,4-triazol-2-yl. Tetrazolyl is, for example, 1,2,3,4-tetrazol-5-yl. Furyl is 2- or 3-furyl and thienyl is 2- or 3-thienyl, but preferred pyridyl is 2-, 3- or 4-pyridyl.
1,2,3,4-tetrazol-5-yl or 1,3,4-triazol-2-yl is preferred.

  A benzo-fused heterocyclic ring having 1 or 2 heteroatoms selected from N, S and O and a heterocyclic ring which is saturated or has 1 or 2 double bonds is, for example, indole Quinoline, indoline or tetrahydroisoquinoline.

  5- to 6-membered heterocyclic rings having 1, 2 or 3 heteroatoms selected from N, S and O are especially substituted tetrazoles, substituted triazoles such as methyltriazole, substituted pyrimidines or substituted pyrazoles such as Methylpyrazole. Further include substituted pyridines, substituted triazines, imidazoles, oxazoles, thiazoles. Preferred substituents are alkyl such as methyl.

  A 5-14 membered monocyclic- or bicyclic- or fused polycyclic-ring system having 1 to 8 heteroatoms selected from N, O and S is also partially or fully saturated.

  A moiety having 1, 2, 3 or 4 heteroatoms selected from N, S and O or a fully saturated heteroaryl 5- to 6-membered heterocyclic ring such as a pyrroline, pyrrolidine, dihydro- or tetrahydro -Thienyl group, dihydro- or tetrahydro-furan group, dihydro- or tetrahydro-pyridine group, imidazoline or imidazolidine group, pyrazoline or pyrazolidine group, thiazoline or thiazolidine group, oxazoline or oxazolidine group, dihydro- or tetrahydro-pyridine or piperidine group Or a dihydro- or tetrahydro-pyran group. Preferred 5- to 6-membered N-heterocyclic groups are attached, for example, via the N-atom, especially via the pyrrolidin-1-yl group.

  Heterocyclic groups are unsubstituted or substituted with one or more, for example 2 or 3, substituents. The corresponding C-substituted group is preferred.

Cycloalkyl is, for example, C ₃ -C 7 _- cycloalkyl, and for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is, for example, C ₃ -C ₇ -cycloalkenyl and is, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Cyclopentenyl and cyclohexenyl are preferred.

  Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably fluoro, chloro or bromo.

Halo-alkyl is, for example, halo-C ₁ -C ₇ alkyl, especially halo-C ₁ -C ₄ alkyl, such as trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl or chloromethyl. A preferred halo-C ₁ -C ₇ alkyl is trifluoromethyl.

Aralkyl, for example, carboxyl aryl - alkyl, such as benzyl or 2-phenethyl - alkyl, preferably phenyl _-C 1 -C ₄ in.

Alkoxy is for example C ₁ -C ₇ -alkoxy and for example methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and the corresponding pentyloxy , Hexyloxy and heptyloxy groups. C ₁ -C ₄ alkoxy is preferred.

Alkanoyl is, for example, C ₂ -C ₇ -alkanoyl and is, for example, acetyl, propionyl, butyryl, isobutyryl or pivaloyl. C ₂ -C ₅ -alkanoyl, especially acetyl is preferred.

Substituted alkylene of the substituted _C 2 -C ₇ - alkylene - substituted _C 2 -C ₇ which is interrupted by an alkylene or even O, N or S. The alkylene is, for example, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy-C ₁ -C ₇ -alkyl, carboxy, C ₁ -C ₇ -alkoxy-carbonyl, C ₃ -C ₇ -cycloalkyl or C ₃ -C 7 on whether or spiro form are annealed is bonded to the alkylene _- may be substituted by cycloalkyl.

  Alkoxyalkyl can be linear or branched. The alkoxy group preferably contains 1 to 4, especially 1 or 2 C atoms, and the alkyl group preferably contains 1 to 4 C atoms. For example, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5- Ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

Group preferred embodiment of the preferred embodiment described below the present invention of the present invention is not considered as an exclusive one, but rather for example, to replace general expressions or symbols with more specific definitions, compounds The group parts can be interchanged or exchanged with the above definitions, or with appropriate exclusions, and each of the more specific definitions can be independently of each other, independently or another more specific one. With more than one definition, it can be introduced for other more general expressions or symbols.

Preferred ring A is a benzo ring which is unsubstituted or substituted with one or more, for example 2 or 3 substituents. Preferred substituents for ring A are C ₁ -C ₇ -alkyl, especially methyl, halo, especially fluoro, chloro, bromo or iodo, C ₁ -C ₇ -alkoxy, especially methoxy, N-mono- or N, N- From the group consisting of di- (C ₁ -C ₇ -alkyl) -amino, N-mono- or N, N-di- (C ₁ -C ₇ -alkyl) -aminocarbonyl, carboxy, cyano and heterocyclyl, especially morpholinyl Selected. The most preferred ring A substituents are selected from the group consisting of F, Cl, Br, OMe, Me, CN, CO ₂ H, NMe ₂ , C (═O) NMe ₂ and morphine.

Other preferred rings A are unsubstituted or C ₁ -C ₇ -alkyl, especially methyl, halo, especially fluoro, chloro, bromo or iodo, C ₁ -C ₇ -alkoxy, especially methoxy, N-mono - or N, N- di - _(C 1 -C ₇ - alkyl) - amino, N- mono- - or N, N- di - _(C 1 -C ₇ - alkyl) - aminocarbonyl, carboxy, cyano and heterocyclyl, In particular, it is a quinoline ring substituted with 1 to 3 substituents selected from the group consisting of morpholinyl. Most preferred ring A substituents are selected from F, Cl, Br, OMe, Me, CN, CO ₂ H, NMe ₂ , C (═O) NMe _2, morphine, and the like.

Other preferred rings A are pyrrole rings which are unsubstituted or substituted with one or more, for example 2 or 3 substituents. A preferred ring A substituent is C ₁ -C ₇ -alkyl, such as methyl.

Preferred Ar is phenyl substituted with 1 or 2 substituents. Preferred substituents are halogen and haloalkyl, such as Cl and CF ₃ .

である。
より好ましくは、Ｒ_１は２−Ｃ_１−Ｃ_７−アルキル−２Ｈ−テトラゾール−５−イルである。 Particularly preferred examples of R ₁ are:

It is.
More preferably, R ₁ is 2-C ₁ -C ₇ -alkyl-2H-tetrazol-5-yl.

である。 Particularly preferred examples of R ₂ are:

It is.

Preferred X is N.
Preferred Y is CH.

  As used herein, the terms “a”, “an”, “the” and like terms used in the context of the present invention (especially in the context of the claims) Unless stated, both singular and plural are included. The value ranges herein are intended to be used merely as a simple way to mean each individual value within the range. Unless stated otherwise, each individual value is incorporated herein as individually referred to herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise explicitly indicated by context. The use of any and all examples provided herein, or exemplary language (eg, “e.g.”) is intended only for better explanation of the invention and unless otherwise stated in the claims. It is not intended to limit the scope of the invention. The language of the specification should not be construed as elements that are not within the scope of the claims essential to the practice of the invention.

  Through extensive pharmacological investigations, cholesterol ester transfer protein inhibitors, especially Compound I and their pharmaceutically acceptable salts, have clear selectivity for inhibition of, for example, CEPT (cholesterol ester transfer protein). It was found. CETP is involved in all lipoprotein metabolism in organisms and is deeply involved in the reverse cholesterol transfer system. That is, CETP has attracted attention as a mechanism for preventing cholesterol accumulation in peripheral cells and preventing arteriosclerosis. In fact, for HDL, which has an important role in the reverse cholesterol transfer system, many epidemiological studies indicate that the reduction of CE (cholesteryl ester) in blood HDL is one of the risk factors for coronary artery disease. It is shown. CETP activity varies depending on the animal species, and arteriosclerosis due to cholesterol load is hardly induced in animals with lower activity, and conversely more easily induced in animals with higher activity, And hyperHDLemia and low LDL (low density lipoprotein) emia have been shown to be induced in cases of CETP deficiency, thus making it difficult to develop arteriosclerosis, resulting in the significance of circulating HDL, The significance of CETP mediating the transfer of HDL CE to blood LDL has been recognized. In recent years, many attempts have been made to develop a drug that inhibits the activity of CETP, but a compound having a satisfactory activity has not yet been developed.

The compound CETP inhibitor effect of the present invention can be measured using test models known to those skilled in the art, for example, the following test models:
(1) Production of human pro- apolipoprotein AI (pro-apoAI) Human pro-apoAI cDNA (NCBI accession number: NM — 000039) was cloned from human liver Quick-Clone ™ cDNA (Clontech, CA) and expressed in bacteria. For insertion into the pET28a vector (Novagen, Germany). The protein expressed as a fusion protein with 6xHis-tag at the N-terminus of BL-21 Gold (DE3) (Strategene, CA) is purified using HiTrap Chelating (GE Healthcare, CT).

(2) Production of donor microemulsion Pro-apoAI-containing microemulsion is produced as donor particles as described above (J. Biol. Chem., 280: 14918-22). Glyceryl trioleate (62.5 ng, Sigma, MO), 3-sn-phosphatidylcholine (583 ng, Wako Pure Chemical Industries, Japan), and cholesterol BODIPY® FL C ₁₂ (250 ng, Invitrogen, Calif.). Dissolve in 1 mL of chloroform. The solution is evaporated and the residual solvent is removed under vacuum for over 1 hour. The anhydrous lipid mixture was dissolved in 500 μl of assay buffer (containing 50 mM Tris-HCl (pH 7.4), 150 mM NaCl and 2 mM EDTA) and microtips (MICROSON ™ ULTRASONIC CELL DISRUPTOR, Misonix, Farmingdale, NY) at 50 ° C. Then sonicate at output 006 for 2 minutes. After sonication, the solution is allowed to cool to 40 ° C., 100 μg human pro-apoAI is added and sonicated at 40 ° C. for 5 minutes at output 004. A solution of BODIPY-CE microemulsion as a donor molecule is filtered through a 0.45 μm PVDF filter and then stored at 4 ° C.

(3) In vitro CETP activity assay in human plasma A human EDTA plasma sample derived from a healthy human is purchased from New Drug Development Research Center, Inc. A donor solution is prepared by diluting the donor microemulsion with assay buffer. Human plasma (50 μL), assay buffer (35 μL) and test compound dimethyl sulfoxide (1 μL) solution are added to each well of a 96 well half area black flat bottom plate. Donor solution (14 μL) is added to initiate the reaction. The fluorescence intensity is measured every 30 minutes at 37 ° C. with an excitation wavelength of 485 nm and an emission wavelength of 535 nm. CETP activity (FI / min) is defined as the change in fluorescence intensity from 30 to 90 minutes. IC ₅₀ values are obtained using the Origin software, version 7.5 SR3, according to the logistic equation (Y = Bottom + (Top−Bottom) / (1+ (x / IC ₅₀ ) ^ Hill slope). Inhibiting activity of IC50 values in the range of 0.001 to 100 μM, especially 0.01 to 10 μM.

(4) Effects on plasma HDL levels in hamsters :
The effect of compounds on HDL-cholesterol levels in hamsters is investigated by previously reported methods with some modifications (Eur, J. Phamacol, 466 (2003) 147-154). Briefly, a male Syrian hamster (SLC, Shizuoka, Japan) is fed with a high cholesterol diet for 2 weeks. The animal is administered once with the compound suspended in the carboxymethylcellulose solution. HDL-cholesterol levels are measured after precipitation of apolipoprotein B (apoB) -containing lipoprotein containing 13% polyethylene glycol 6000 using a commercially available kit (Wako Pure Chemical, Japan). The compound increases HDL-cholesterol levels by 5% or more compared to the control.

  The compound of the present invention or a pharmaceutically acceptable salt thereof has excellent CETP inhibitory activity in mammals (eg, humans, monkeys, cows, horses, dogs, cats, rabbits, etc.), and is used as a CETP inhibitor. can do. Furthermore, by utilizing the excellent CETP inhibitory activity of the compound of the present invention or a pharmaceutically acceptable salt thereof, the compound of the present invention can be used for diseases involving CETP (eg, hyperlipidemia, arteriosclerosis, Atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hyperalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, coronary Arterial heart disease, coronary artery disease, coronary artery disease, angina pectoris, ischemia, cardiac ischemia, thrombosis, heart infarction like myocardial infarction, stroke, peripheral vascular disease, reperfusion injury, angiogenesis restenosis, hypertension , Congestive heart failure, diabetes such as type II diabetes, diabetic vascular complications, obesity or endotoxemia, etc.), effective in preventing or treating or delaying progession to avert As a medicament, especially for the prevention or treatment of hyperlipidemia or arteriosclerotic diseases, and the treatment of schistosome infection (or egg embryonation).

  Further aspects of the invention are selected from the group consisting of coronary heart disease, coronary artery disease, coronary artery disease, myocardial infarction, stroke, peripheral vascular disease, diabetes such as type II diabetes, congestive heart failure, and reperfusion injury Use of a CETP inhibitor for the prevention or treatment of the disease treated or for the delay of progression.

〔式中、
ＸがＮであり、そしてＹがＣＨまたはＮであり；
Ｒ_１が

から成る群から選択される、各場合において非置換であるか、またはＣ_１−Ｃ_７−アルキル、Ｃ_３−Ｃ_７−シクロアルキル−Ｃ_１−Ｃ_７−アルキル、Ｃ_１−Ｃ_７−アルコキシ、ヒドロキシル−Ｃ_１−Ｃ_７−アルキル−、Ｃ_１−Ｃ_７−アルコキシ−Ｃ_１−Ｃ_７−アルキル−、（Ｒ_４）（Ｒ_５）Ｎ−Ｃ_１−Ｃ_７−アルキル−、−Ｎ（Ｒ_４）（Ｒ_５）およびフェニル−Ｃ_１−Ｃ_７−アルキル−から成る群から選択される置換基でＮまたはＣ−置換されているヘテロ環式環であり；
Ｒ_２が−Ｃ（＝Ｏ）Ｒ_３、−Ｃ（＝Ｏ）−Ｏ−Ｒ_３、−Ｎ（Ｒ_４）（Ｒ_５）、−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）および−ＮＲ_３−Ｓ（Ｏ）_ｍ−Ｎ（Ｒ_４）（Ｒ_５）から成る群から選択され、ｍが各場合において整数０、１または２であるか；またはＲ_２がＺであり；
Ｚが（ｉ）置換もしくは非置換Ｃ_３−Ｃ_７−シクロアルキルまたは置換もしくは非置換Ｃ_３−Ｃ_７−シクロアルケニル、および（ｉｉ）置換もしくは非置換炭素環式フェニル、ナフチルまたはビフェニリル基または置換もしくは非置換ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、テトラゾリル、フリル、チエニル、ピリジル、ピリミジル、ピロリニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル、ホモピペリジニル、ホモピペラジニル、ジヒドロ−もしくはテトラヒドロ−チエニル、ジヒドロ−もしくはテトラヒドロ−フラニル、ジヒドロ−もしくはテトラヒドロ−ピリジニル、イミダゾリニルまたはイミダゾリジニル、ピラゾリニルまたはピラゾリジニル、チアゾリニルまたはチアゾリジニル、オキサゾリニルまたはオキサゾリジニル、ジヒドロ−もしくはテトラヒドロ−ピリジニルまたはピペリジニルまたはジヒドロ−もしくはテトラヒドロ−ピラニルから成る群から選択され；
Ｒ_３が独立して、水素、Ｃ_１−Ｃ_７−アルキル、ハロ−Ｃ_１−Ｃ_７−アルキル、置換もしくは非置換Ｃ_３−Ｃ_７−シクロアルキル、置換もしくは非置換Ｃ_３−Ｃ_７−シクロアルケニル、シクロアルキル基において置換もしくは非置換Ｃ_３−Ｃ_７−シクロアルキル−Ｃ_１−Ｃ_７−アルキル、シクロアルキル基において置換もしくは非置換Ｃ_３−Ｃ_７−シクロアルキル−Ｃ_２−Ｃ_７−アルケニル、置換もしくは非置換フェニルもしくはナフチル、置換もしくは非置換ヘテロ環式芳香族性基、またはアリール基において置換もしくは非置換フェニル−Ｃ_１−Ｃ_７−アルキルを意味し； The invention is preferably of formula (IA) or (IB)

[Where,
X is N and Y is CH or N;
R ₁ is

C ₁ -C ₇ -alkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy in each case selected from the group consisting of , hydroxyl _-C 1 -C ₇ - alkyl _-, C 1 -C ₇ - alkoxy _-C 1 -C ₇ - alkyl _{-, (R 4) (R} 5) N-C 1 -C 7 - alkyl -, - N A heterocyclic ring N or C-substituted with a substituent selected from the group consisting of (R ₄ ) (R ₅ ) and phenyl-C ₁ -C ₇ -alkyl-;
R ₂ is —C (═O) R ₃ , —C (═O) —O—R ₃ , —N (R ₄ ) (R ₅ ), —S (O) _m —N (R ₄ ) (R ₅ ) And —NR ₃ —S (O) _m —N (R ₄ ) (R ₅ ), where m is the integer 0, 1 or 2 in each case; or R ₂ is Z ;
Z is (i) substituted or unsubstituted _C 3 -C ₇ - cycloalkyl or substituted or unsubstituted _C 3 -C ₇ - cycloalkyl, and (ii) a substituted or unsubstituted carbocyclic, phenyl, naphthyl or biphenylyl group or a substituted Or unsubstituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, dihydro- or tetrahydro-thienyl, dihydro- or tetrahydro-furanyl, dihydro -Or tetrahydro-pyridinyl, imidazolinyl or imidazolidinyl, pyrazolinyl or pyrazolidinyl, thiazolinyl or thiazolidinyl, oxazo Cycloalkenyl or oxazolidinyl, dihydro - or tetrahydro - pyridinyl or piperidinyl, or dihydro - or tetrahydro - is selected from the group consisting of pyranyl;
R ₃ is independently _hydrogen, C 1 -C ₇ - alkyl, halo _-C 1 -C ₇ - alkyl, substituted or unsubstituted _C 3 -C ₇ - cycloalkyl, substituted or unsubstituted _C 3 -C ₇ - Cycloalkenyl, substituted or unsubstituted C ₃ -C ₇ -cycloalkyl-C ₁ -C ₇ -alkyl in a cycloalkyl group, substituted or unsubstituted C ₃ -C ₇ -cycloalkyl-C ₂ -C _{7 in} a cycloalkyl group Means alkenyl, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heterocyclic aromatic group, or aryl group substituted or unsubstituted phenyl-C ₁ -C ₇ -alkyl;

R ₄ and R ₅ independently of each other represent C ₁ -C ₇ -alkyl, C ₃ -C ₇ -cycloalkyl, wherein the C ₁ -C ₇ -alkyl is substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted with 1 or 2 substituents selected from the group consisting of substituted cycloalkenyl and substituted or unsubstituted heterocyclic groups;
Here, substituted cycloalkyl or substituted cycloalkenyl or substituted alkylene is alkyl, alkoxy, —C (═O) —O—R ₃ , —C (═O) —N (alkyl) (alkyl), —N (alkyl), respectively. ) _{(alkyl), H 2 N-C (} = O) -, H 2 N-C (= O) - alkyl -, formyl, formyl - alkyl -, cycloalkyl - alkyl, carbocyclic aromatic Substituted with 1 or 2 substituents selected from the group consisting of a group, a heterocyclic group, aralkyl and heterocyclyl-alkyl; or R ₉ and R ₁₀ independently of one another, hydrogen, halogen, NO _{2 , CN, OH, C 1 -C} 7 - alkyl, phenyl _-C 1 -C ₇ - alkyl, naphthyl _-C 1 -C ₇ - alkyl, pyridyl _-C 1 -C ₇ - alkyl, C -C ₇ - cycloalkyl _-C 1 -C ₇ - _alkyl, C 1 -C ₇ - alkoxy _-C 1 -C ₇ - alkyl, phenyl _-C 1 -C ₇ - alkoxy, naphthyl _-C 1 -C ₇ - alkoxy , Pyridyl-C ₁ -C ₇ -alkoxy, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₇ -alkoxy, halo-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy, C ₁ -C ₇ -alkoxy-C ₁ -C ₇ -alkoxy, carboxy, C ₁ -C ₇ -alkoxy-carbonyl, C ₁ -C ₇ -alkyl-S (O) _m- , phenyl-C ₁ -C ₇ -alkyl-S (O) _m , naphthyl-C ₁ -C ₇ -alkyl-S (O) _m , pyridyl-C ₁ -C ₇ -alkyl-S (O) _m , halo-C ₁ -C ₇ -alkoxy and C _2- C ₇ Alkanoyl (oxy) (m is an integer 0, 1 or 2 in each _case), C 3 -C ₇ - _cycloalkyl, C 3 -C ₇ - cycloalkyl, substituted in the phenyl group or unsubstituted phenyl -C ₁ - C ₇ -alkyl, and substituted or unsubstituted pyridyl-C ₁ -C ₇ -alkyl in the pyridyl group; and where the corresponding cycloalkyl group, cycloalkenyl group, carbocyclic aromatic group, heterocyclic A group or a heterocyclic aromatic group is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy;
p is 0 or 1 or 2 or 3;
n is 0 or 1 or 2 or 3;
R ₁₁ is C ₁ -C ₇ -alkyl;
And substituent bound to Z independently of one another, hydrogen or halogen, OH, NH _2, carbonyl _{(= O), C 1 -C} 7 - _alkyl, C 3 -C ₇ - _cycloalkyl, C 3 -C ₇ -cycloalkyl-C ₁ -C ₇ -alkyl-, C ₁ -C ₇ -alkoxy-C ₁ -C ₇ -alkyl-, C ₃ -C ₇ -cycloalkyloxy-C ₁ -C ₇ -alkyl-, Phenyl-C ₁ -C ₇ -alkoxy-, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₇ -alkoxy-, halo-C ₁ -C ₇ -alkyl-, C ₁ -C ₇ -alkoxy-, C ₁ -C ₇ - alkoxy _-C 1 -C ₇ - alkoxy -, carboxy _-, C 1 -C ₇ - alkoxy - carbonyl _-, C 1 -C ₇ - alkyl -S _{(O) m} -, phenyl -C ₁ - C ₇ -Alky Ru-S (O) _m- , halo-C ₁ -C ₇ -alkoxy- and C ₂ -C ₇ -alkanoyl-, C ₁ -C ₇ -alkoxy-C ₃ -C ₇ -cycloalkyl-, phenyl-C _1- C ₇ -alkoxy-C ₃ -C ₇ -cycloalkyl-, hydroxy-C ₃ -C ₇ -cycloalkyl-, hydroxy-C ₁ -C ₇ -alkyl-C ₃ -C ₇ -cycloalkyl-, formyl -C ₃ -C ₇ - cycloalkyl -, formyl _-C 1 -C ₇ - alkyl _-C 3 -C ₇ - cycloalkyl -, carboxy _-C 3 -C ₇ - cycloalkyl -, carboxy _-C 1 -C ₇ - alkyl _-C 3 -C ₇ - cycloalkyl _{-, H 2 NC (= O} ) -C 3 -C 7 - cycloalkyl _{-, H 2 NC (= O} ) -C 1 -C 7 - alkyl -C ₃ - C ₇ - Black alkyl - is one or more substituents selected from the group consisting of]
Or a salt thereof.

〔式中、
ＸがＮであり、そしてＹがＣＨまたはＮであり；
Ｒ_１が２−Ｃ_１−Ｃ_７−アルキル−２Ｈ−テトラゾール−５−イルであり；
要素−Ｎ（Ｒ_４）（Ｒ_５）がＣ_１−Ｃ_７−アルキル−、Ｃ_３−Ｃ_７−シクロアルキル−、Ｃ_３−Ｃ_７−シクロアルキル−メチル−、Ｃ_１−Ｃ_７−アルコキシ−メチル−、ヒドロキシ−Ｃ_１−Ｃ_２−アルキル−Ｃ_３−Ｃ_７−シクロアルキル−、ホルミル−Ｃ_３−Ｃ_７−シクロアルキル−、ホルミル−Ｃ_１−Ｃ_２−アルキル−Ｃ_３−Ｃ_７−シクロアルキル−、ＨＯ_２Ｃ−Ｃ_３−Ｃ_７−シクロアルキル−、ＨＯ_２Ｃ−Ｃ_１−Ｃ_２−アルキル−Ｃ_３−Ｃ_７−シクロアルキル−、Ｈ_２ＮＣ（＝Ｏ）−Ｃ_３−Ｃ_７−シクロアルキル−またはＨ_２ＮＣ（＝Ｏ）−Ｃ_１−Ｃ_２−アルキル−Ｃ_３−Ｃ_７−シクロアルキル−から成る群から選択される１または２個の置換基で置換されたピロリジン−１−イルであり；
Ｒ_９が水素、−ＣＮ、Ｃ_１−Ｃ_７−アルキル−、Ｃ_１−Ｃ_７−アルコキシ、（Ｃ_１−Ｃ_７−アルキル）（Ｃ_１−Ｃ_７−アルキル−）アミン−、ハロ−Ｃ_１−Ｃ_７−アルキルまたはハロゲンから選択される１または２個の置換基であり；
Ｒ_１２およびＲ_１３が互いに独立して、ハロ−Ｃ_１−Ｃ_７−アルキルまたはハロゲンであり；ここでｐが０または１または２であるか；または
Ｒ_４が（Ｃ_１−Ｃ_４）アルキル−または（Ｃ_３−Ｃ_５）シクロアルキル−であり；そして
Ｒ_５が、所望によりヒドロキシル、アルコキシ、ＨＯ_２Ｃ−、ＨＯ_２Ｃ−（Ｃ_１−Ｃ_３）アルキル−、ヒドロキシ−（Ｃ_１−Ｃ_３）アルキル−、（Ｃ_１−Ｃ_６）アルコキシ−カルボニル−または（Ｃ_１−Ｃ_６）アルコキシ−カルボニル−（Ｃ_１−Ｃ_３）アルキル−から選択される１または２個の置換基で置換された（Ｃ_３−Ｃ_７）シクロアルキル−（Ｃ_１−Ｃ_２）アルキル−である〕
の化合物、またはその塩に関する。 The present invention more preferably has the formula (IC)

[Where,
X is N and Y is CH or N;
R ₁ is 2-C ₁ -C ₇ -alkyl-2H-tetrazol-5-yl;
The element —N (R ₄ ) (R ₅ ) is C ₁ -C ₇ -alkyl-, C ₃ -C ₇ -cycloalkyl-, C ₃ -C ₇ -cycloalkyl-methyl-, C ₁ -C ₇ -alkoxy. - methyl -, hydroxy _-C 1 -C ₂ - alkyl _-C 3 -C ₇ - cycloalkyl -, formyl _-C 3 -C ₇ - cycloalkyl -, formyl _-C 1 -C ₂ - alkyl _-C 3 -C ₇ - cycloalkyl _{-, HO 2 C-C 3} -C 7 - cycloalkyl _{-, HO 2 C-C 1} -C 2 - alkyl _-C 3 -C ₇ - cycloalkyl _{-, H 2 NC (= O} ) - C ₃ -C ₇ - with one or two substituents selected from the group consisting of - cycloalkyl - or _{H 2 NC (= O) -C} 1 -C 2 - alkyl _-C 3 -C ₇ - cycloalkyl With substituted pyrrolidin-1-yl Ri;
R ₉ is hydrogen, _-CN, C 1 -C ₇ - alkyl _-, C 1 -C ₇ - _{alkoxy, (C} 1 -C ₇ - _{alkyl) (C} 1 -C ₇ - alkyl -) amine -, halo -C ₁ or 2 substituents selected from ₁ -C ₇ -alkyl or halogen;
R ₁₂ and R ₁₃ are, independently of one another, halo-C ₁ -C ₇ -alkyl or halogen; where p is 0 or 1 or 2; or R ₄ is (C ₁ -C ₄ ) alkyl - or _(C 3 -C ₅₎ cycloalkyl -; and _{R 5} is optionally a hydroxyl, _{alkoxy, HO 2 C-, HO 2 C-} (C 1 -C 3) alkyl -, hydroxy - _{(C 1} -C ₃₎ alkyl _{-, (C} 1 -C ₆₎ alkoxy - carbonyl - or _(C 1 -C ₆₎ alkoxy - carbonyl - _(C 1 -C ₃₎ alkyl - 1 or 2 substituents selected from (C ₃ -C ₇ ) cycloalkyl- (C ₁ -C ₂ ) alkyl-substituted with
Or a salt thereof.

〔式中、ｐは０または１または２であり；
Ｒａはハロゲンまたは（Ｃ_１−Ｃ_４）−アルコキシまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_１２およびＲ_１３は独立して、ハロゲンまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_２は式（ＩＩＩ）：

（式中、Ｒ_６は（Ｃ_１−Ｃ_４）アルキル−または（Ｃ_３−Ｃ_５）シクロアルキル−であり；Ｒｂは−（ＣＨ_２）_ｎ−Ｒｃであり；ｎは０または１または２または３であり；Ｒｃはカルボキシ、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシまたは（Ｃ_１−Ｃ_４）−アルコキシカルボニルである）
である〕
の化合物；またはその塩に関する。好ましくは、ｎが０であり、Ｒｃがヒドロキシまたは（Ｃ_１−Ｃ_４）−アルコキシである。また好ましくは、ｎが１または２または３であり、Ｒｃがカルボキシ、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシまたは（Ｃ_１−Ｃ_４）−アルコキシカルボニルである。 In one embodiment, the present invention provides a compound of formula (II)

[Wherein p is 0, 1 or 2;
Ra halogen or _(C 1 -C ₄₎ is - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₁₂ and R ₁₃ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ represents formula (III):

Wherein R ₆ is (C ₁ -C ₄ ) alkyl- or (C ₃ -C ₅ ) cycloalkyl-; Rb is — (CH ₂ ) _n —Rc; n is 0 or 1 or 2 or be a 3; Rc is carboxy, _{hydroxy, (C} 1 -C ₄₎ - alkoxy or _(C 1 -C ₄₎ - alkoxycarbonyl)
Is)
Or a salt thereof. Preferably n is 0 and Rc is hydroxy or (C ₁ -C ₄ ) -alkoxy. Also preferably, n is 1 or 2 or 3, and Rc is carboxy, hydroxy, (C ₁ -C ₄ ) -alkoxy or (C ₁ -C ₄ ) -alkoxycarbonyl.

〔式中、ｐが０または１または２であり；
Ｒａがハロゲンまたは（Ｃ_１−Ｃ_４）−アルコキシまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_１２およびＲ_１３が独立して、ハロゲンまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_２が式（ＩＩＩＡ）：

（式中、Ｒ_６は（Ｃ_１−Ｃ_４）アルキル−または（Ｃ_３−Ｃ_５）シクロアルキル−であり；Ｒｂは−（ＣＨ_２）_ｎ−Ｒｃであり；ｎは０または１または２または３であり；Ｒｃはカルボキシ、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシまたは（Ｃ_１−Ｃ_４）−アルコキシカルボニルである）
の化合物；またはその塩に関する。好ましくは、ｎが０であり、Ｒｃがヒドロキシまたは（Ｃ_１−Ｃ_４）−アルコキシである。また好ましくは、ｎが１または２または３であり、Ｒｃがカルボキシ、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシまたは（Ｃ_１−Ｃ_４）−アルコキシカルボニルである。 In another embodiment, the present invention provides compounds of formula (II)

[Wherein p is 0, 1 or 2;
Ra is halogen or _(C 1 -C ₄₎ - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₁₂ and R ₁₃ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ is of formula (IIIA):

Wherein R ₆ is (C ₁ -C ₄ ) alkyl- or (C ₃ -C ₅ ) cycloalkyl-; Rb is — (CH ₂ ) _n —Rc; n is 0 or 1 or 2 or be a 3; Rc is carboxy, _{hydroxy, (C} 1 -C ₄₎ - alkoxy or _(C 1 -C ₄₎ - alkoxycarbonyl)
Or a salt thereof. Preferably n is 0 and Rc is hydroxy or (C ₁ -C ₄ ) -alkoxy. Also preferably, n is 1 or 2 or 3, and Rc is carboxy, hydroxy, (C ₁ -C ₄ ) -alkoxy or (C ₁ -C ₄ ) -alkoxycarbonyl.

〔式中、ｐが０または１または２または３であり；
Ｒａがハロゲンまたは（Ｃ_１−Ｃ_４）−アルコキシまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_１２およびＲ_１３が独立して、ハロゲンまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_２が式（ＩＶ）：

（式中、Ｒｂは−（ＣＨ_２）_ｎ−Ｒｃであり；ｎは０または１または２または３であり；Ｒｃはカルボキシ、ヒドロキシ、ホルミル、（Ｃ_１−Ｃ_４）−アルコキシ、Ｈ_２ＮＣ（＝Ｏ）−、（Ｃ_１−Ｃ_４）−アルコキシカルボニル、またはハロ−（Ｃ_１−Ｃ_４）−アルコキシカルボニルである）
の化合物；またはその塩に関する。 In another embodiment, the present invention provides compounds of formula (II)

[Wherein p is 0 or 1 or 2 or 3;
Ra is halogen or _(C 1 -C ₄₎ - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₁₂ and R ₁₃ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ represents formula (IV):

Wherein Rb is — (CH ₂ ) _n —Rc; n is 0 or 1 or 2 or 3; Rc is carboxy, hydroxy, formyl, (C ₁ -C ₄ ) -alkoxy, H ₂ NC _{(= O) -, (C} 1 -C 4) - alkoxycarbonyl or _{halo, - (C 1 -C 4)} - alkoxycarbonyl)
Or a salt thereof.

〔式中、Ｒｂが−（ＣＨ_２）_ｎ−Ｒｃであり；ｎが０または１または２または３であり；Ｒｃがカルボキシル、ヒドロキシ、ホルミル、（Ｃ_１−Ｃ_４）−アルコキシ、Ｈ_２ＮＣ（＝Ｏ）−、Ｈ_２ＮＣ（＝Ｏ）−（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）−アルコキシカルボニル、またはハロ−（Ｃ_１−Ｃ_４）−アルコキシカルボニルである〕
である、式（ＩＩ）化合物；またはその塩に関する。 In another embodiment, the present invention provides that R ₂ has the formula (IVA):

[Wherein Rb is — (CH ₂ ) _n —Rc; n is 0, 1 or 2 or 3; Rc is carboxyl, hydroxy, formyl, (C ₁ -C ₄ ) -alkoxy, H ₂ NC _{(= O) -, H 2} NC (= O) - (C 1 -C 4) _{alkyl, (C} 1 -C ₄₎ - alkoxycarbonyl or _{halo, - (C 1 -C 4)} - alkoxycarbonyl]
A compound of formula (II); or a salt thereof.

In other embodiments, the invention provides that R ₂ is formula (IVA), p is 1 or 2, Ra is halogen; R ₁₂ and R ₁₃ are halo- (C ₁ -C ₄ ) alkyl Yes; Rb is — (CH ₂ ) _n —Rc, where n is 0 or 1; Rc is carboxyl or (C ₁ -C ₄ ) -alkoxycarbonyl or halo- (C ₁ -C ₄ ) — Alkoxycarbonyl;
It relates to a compound of formula (II), or a pharmaceutically acceptable salt.

〔式中、ｐが０または１または２であり；
Ｒａがハロゲンまたは（Ｃ_１−Ｃ_４）−アルコキシまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_１２およびＲ_１３が独立して、ハロゲンまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_２が式（ＩＩＩ）または（ＩＶ）：

（式中、Ｒｂは−（ＣＨ_２）_ｎ−Ｃ（Ｏ）−Ｏ−Ｒｃであり；ｎは１または２または３であり；Ｒｃは水素、Ｈ_２Ｎ−−、（Ｃ_１−Ｃ_４）−アルキル、またはハロ−（Ｃ_１−Ｃ_４）アルキルである）
である〕
の化合物；またはその塩に関する。 In another embodiment, the present invention provides compounds of formula (II)

[Wherein p is 0, 1 or 2;
Ra is halogen or _(C 1 -C ₄₎ - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₁₂ and R ₁₃ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ represents formula (III) or (IV):

Wherein Rb is — (CH ₂ ) _n —C (O) —O—Rc; n is 1 or 2 or 3; Rc is hydrogen, H ₂ N—, (C ₁ -C ₄ ) -Alkyl, or halo- (C ₁ -C ₄ ) alkyl)
Is)
Or a salt thereof.

〔式中、ｐが０または１または２であり；
Ｒａがハロゲンまたは（Ｃ_１−Ｃ_４）−アルコキシまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_７およびＲ_８が独立して、ハロゲンまたはハロ−（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ_２が式（ＩＩＩ）または（ＩＶ）：

（式中、Ｒｂは−（ＣＨ_２）_ｎ−Ｃ（Ｏ）−Ｏ−Ｒｃであり；ｎは０または１または２または３であり；Ｒｃは水素、Ｈ_２Ｎ−−、（Ｃ_１−Ｃ_４）−アルキル、またはハロ−（Ｃ_１−Ｃ_４）アルキルである）
である〕
の化合物；またはその塩に関する。 In another embodiment, the present invention provides compounds of formula (II)

[Wherein p is 0, 1 or 2;
Ra is halogen or _(C 1 -C ₄₎ - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₇ and R ₈ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ represents formula (III) or (IV):

Wherein Rb is — (CH ₂ ) _n —C (O) —O—Rc; n is 0 or 1 or 2 or 3; Rc is hydrogen, H ₂ N—, (C ₁ — C ₄₎ - alkyl or halo, - _(C 1 -C ₄₎ alkyl)
Is)
Or a salt thereof.

  In yet another aspect, the present invention relates, inter alia, to the novel compounds described in the Examples and the methods of manufacture described herein.

Abbreviations:
Ac: acetyl, AcOEt: ethyl acetate, AIBN: 2,2′-azobisisobutyronitrile, BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, BPO: benzoyl peroxide, n-BuLi : N-butyllithium, DCC: N, N′-dicyclohexylcarbodiimide, DHP: 3,4-dihydro-2H-pyran, DIPEA: N, N-diisopropylethylamine, DMAP: 4-N, N-dimethylaminopyridine, mCPBA : M-chloroperbenzoic acid, EtOH: ethanol, EDC: N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide, HATU :, Hex: n-hexane, KOt-Bu: potassium tert-butoxide, LiAlH ₄ : water Lithium aluminum hydride, MeOH: methanol, Ms: methanesulfonyl, NaBH _4: tetraborate sodium hydrogen, NBS: N-bromosuccinimide, POCl _3: phosphorus (III) oxychloride, sat. : Saturated, TEA: triethylamine, THF: tetrahydrofuran, Ms: methanesulfonyl, DMF: N, N-dimethylformamide, TFA: trifluoroacetic acid, UPLC: ultrahigh performance liquid chromatography.

The present invention relates to a process for producing the compounds of the present invention. The preparation of a compound of formula (I) or a salt thereof comprises, for example, the following general scheme:
Scheme 1

Intermediates 1-1, 1-2 and 1-3 utilized in the present invention can be purchased or prepared as shown in Scheme 1. Suitably, substituted arylamine 1-1, wherein ring A is as defined herein or in claims, is substituted with acetic anhydride (Ac ₂ O) or acetyl chloride (AcCl) and a catalytic amount of 4-N, It was treated in _CH 2 Cl ₂ at N- dimethylaminopyridine (DMAP), to give the corresponding intermediates 1-2. Intermediate 1-2 can be treated with phosphoryl chloride (POCl ₃ ) in DMF to cyclize the Vilsmeier type to give the corresponding intermediate 1-3 [eg: Meth-Cohn et al., J. Chem. Soc., Perkin Trans. 1 1520 (1981)].

本発明で利用する中間体２−１、２−２、２−３および２−４を購入するか、またはスキーム２に示すとおりに製造することができる。環Ａが本明細書または特許請求の範囲に定義の通りである適当な置換アリールブロマイド２−１をｍ−クロロペル安息香酸（ｍ−ＣＰＢＡ）等のような酸化試薬で、ＣＨ_２Ｃｌ_２等のような適当な溶媒中で処理することによって対応する中間体２−２を得ることができる。中間体２−２をホスホリルクロライド（ＰＯＣｌ_３）で処理して塩素化させて、対応する中間体２−３を得ることができる［例えば：Grig-Alexa et al., Synlett 11, 2000 (2004)参照］。中間体２−３のホルミル化をｎ−ＢｕＬｉおよびＤＭＦで行って、対応する中間体２−４を得ることができる。あるいは、ホルミル化を炭素モノオキシドおよびギ酸ナトリウムまたは水素で、パラジウム触媒の存在下で行うことができる［例えば：Okano et al., Bull. Chem. Soc. Jap. 67, 2329 (1994)参照］。 Scheme 2

Intermediates 2-1, 2-2, 2-3 and 2-4 utilized in the present invention can be purchased or prepared as shown in Scheme 2. A suitable substituted aryl bromide 2-1 wherein ring A is as defined herein or in the claims is an oxidizing reagent such as m-chloroperbenzoic acid (m-CPBA) and the like, such as CH ₂ Cl ₂ The corresponding intermediate 2-2 can be obtained by treatment in an appropriate solvent. Intermediate 2-2 can be chlorinated by treatment with phosphoryl chloride (POCl ₃ ) to give the corresponding intermediate 2-3 [eg: Grig-Alexa et al., Synlett 11, 2000 (2004) reference]. Intermediate 2-3 can be formylated with n-BuLi and DMF to give the corresponding intermediate 2-4. Alternatively, formylation can be carried out with carbon monoxide and sodium formate or hydrogen in the presence of a palladium catalyst [see, eg, Okano et al., Bull. Chem. Soc. Jap. 67, 2329 (1994)].

環Ａが本明細書または特許請求の範囲に定義の通りである本発明の中間体３−１を、購入するか、またはスキーム１および２に示されている方法に従って製造することができる。適当な置換アリールクロライド３−１と適当な置換アミン［（Ｒ_４）（Ｒ_５）ＮＨ］またはＨ−Ｚ（ここで、環Ａ、Ｒ_４、Ｒ_５、およびＺは本明細書または特許請求の範囲に定義のとおりである）のカップリング反応を、トリエチルアミン（ＴＥＡ）、炭酸カリウム（Ｋ_２ＣＯ_３）等のような適当な塩基の存在下、テトラヒドロフラン（ＴＨＦ）、トルエン、トルエン／水のような適当な溶媒中で行って、対応する中間体３−２（ここで、環Ａ、Ｒ_２、Ｚ、Ｒ_４およびＲ_５は本明細書または特許請求の範囲に定義のとおりである）を得ることができる。あるいは中間体３−２は、３−１を適当なアミン［Ｒ_４−ＮＨ_２またはＲ_５−ＮＨ_２］で処理し、その後適当な試薬［Ｒ_５−ＬまたはＲ_４−Ｌ（Ｌ：ハロゲン、−ＯＭｓ等のような脱離基）］でアルキル化することによって製造することができる。アルデヒド３−２を水素化ホウ素ナトリウム等のような還元剤でメタノールまたはエタノール等中で還元して、対応するアルコール３−４を得ることができる。あるいは、クロライド３−１を水素化ホウ素ナトリウム等のような還元剤で還元し、その後適当な置換アミン［（Ｒ４）（Ｒ５）ＮＨ］またはＨ−Ｚでアミノ化して対応するアルコール３−４を得ることができる。 Scheme 3

Intermediates 3-1 of the present invention in which Ring A is as defined herein or in the claims can be purchased or prepared according to the methods shown in Schemes 1 and 2. Appropriate substituted aryl chlorides 3-1 and appropriate substituted amines [(R ₄ ) (R ₅ ) NH] or HZ (wherein rings A, R ₄ , R ₅ , and Z are defined or claimed herein) In the presence of a suitable base such as triethylamine (TEA), potassium carbonate (K ₂ CO ₃ ), etc., in the presence of a suitable base such as triethylamine (TEA), potassium carbonate (K ₂ CO ₃ ), etc. The corresponding intermediate 3-2 (wherein ring A, R ₂ , Z, R ₄ and R ₅ are as defined herein or in the claims). Can be obtained. Alternatively, intermediate 3-2 can be prepared by treating 3-1 with an appropriate amine [R ₄ —NH ₂ or R ₅ —NH ₂ ], followed by an appropriate reagent [R ₅ -L or R ₄ -L (L: halogen , Leaving groups such as —OMs etc.)]. Aldehyde 3-2 can be reduced in methanol or ethanol with a reducing agent such as sodium borohydride to give the corresponding alcohol 3-4. Alternatively, chloride 3-1 is reduced with a reducing agent such as sodium borohydride and then aminated with an appropriate substituted amine [(R4) (R5) NH] or HZ to give the corresponding alcohol 3-4. Obtainable.

本発明で利用する、環Ａが本明細書または特許請求の範囲に定義の通りである中間体４−１、４−２および４−３を購入するか、またはスキーム４に示すとおりに製造することができる。［例えば：Katou et al., Heterocycles, 52, 911 (2000)参照］． Scheme 4

Utilizing the present invention, intermediates 4-1, 4-2 and 4-3 are purchased or prepared as shown in Scheme 4 where ring A is as defined herein or in the claims. be able to. [For example: see Katou et al., Heterocycles, 52, 911 (2000)].

環ＡおよびＹが本明細書または特許請求の範囲に定義の通りである本発明の中間体５−１を、購入するか、スキーム３に示されている方法に従って製造することができる。適当な置換アリールクロライド５−１と適当な置換アミン［（Ｒ_４）（Ｒ_５）ＮＨ］またはＨ−Ｚ（ここで、環Ａ、Ｒ_４、Ｒ_５およびＺは本明細書または特許請求の範囲に定義のとおりである）のカップリング反応を、トリエチルアミン（ＴＥＡ）、炭酸カリウム（Ｋ_２ＣＯ_３）等のような適当な塩基の存在下で、テトラヒドロフラン（ＴＨＦ）、トルエン、トルエン／水のような溶媒中で行って、環Ａ、Ｒ_２およびＹが本明細書または特許請求の範囲に定義のとおりである対応する中間体５−２を得ることができる。あるいは、中間体５−２を、５−１を適当なアミン［Ｒ_４−ＮＨ_２またはＲ_５−ＮＨ_２］で処理し、その後適当な試薬［Ｒ_５−ＬまたはＲ_４−Ｌ（Ｌ：ハロゲン、−ＯＭｓ等のような脱離基）］でアルキル化させて製造することができる。中間体５−２のハロゲン化をＮ−ブロモスクシンイミド等のようなハロゲン化試薬で、触媒量の２，２’−アゾビスイソブチロニトリル（ＡＩＢＮ）またはベンゾイルペルオキシド（ＢＰＯ）の存在下、ＣＣｌ_４中で行って、対応するベンジルハライド５−３を得ることができる。 Scheme 5

Intermediates 5-1 of the present invention in which rings A and Y are as defined herein or in the claims can be purchased or prepared according to the methods shown in Scheme 3. A suitable substituted aryl chloride 5-1 and a suitable substituted amine [(R ₄ ) (R ₅ ) NH] or HZ (wherein rings A, R ₄ , R ₅ and Z are as defined or claimed herein) In the presence of a suitable base such as triethylamine (TEA), potassium carbonate (K ₂ CO ₃ ) and the like. Can be carried out in such a solvent to give the corresponding intermediate 5-2 in which rings A, R ₂ and Y are as defined herein or in the claims. Alternatively, intermediate 5-2 is treated with 5-1 in the appropriate amine [R ₄ —NH ₂ or R ₅ —NH ₂ ] followed by the appropriate reagent [R ₅ -L or R ₄ -L (L: Alkylating with a leaving group such as halogen, -OMs, etc.]. Halogenation of intermediate 5-2 with a halogenating reagent such as N-bromosuccinimide in the presence of catalytic amounts of 2,2′-azobisisobutyronitrile (AIBN) or benzoyl peroxide (BPO) _{In 4} to give the corresponding benzyl halide 5-3.

環Ａ、Ａｒ、Ｒ_１、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりである本発明の化合物６−３を、スキーム６に示されている方法に従って製造することができる。環Ａ、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりである本発明の中間体６−１および６−２（Ｌ：ハロゲン、−ＯＭｓ等のような脱離基）を、スキーム３およびスキーム５にそれぞれ示されている方法に従って製造することができる。適当な置換アルコール６−１を塩化チオニルまたはメタンスルホニルクロライド等で、トリエチルアミニンおよびＮ，Ｎ−ジイソプロピルエチルアミン等のような塩基の存在下、または非存在下で、ＴＨＦまたはトルエンのような溶媒中で処理して、対応する中間体６−２を得ることができる。あるいは、中間体６−２を、６−１を４臭素化炭素およびトリフェニルホスフィンで、ジクロロメタン等のような適当な溶媒中で処理して、製造することができる。好ましい脱離基はブロマイドまたはクロライドであるが、アイオダイド、メシレート、トシレート等であってもよい。中間体６−２を、適当なアミン［（Ａｒ−ＣＨ_２−）（Ｒ_１）ＮＨ］、（ここで、ＡｒおよびＲ_１は本明細書または特許請求の範囲に定義のとおりである）およびカリウムｔｅｒｔ−ブトキシド等のような塩基で、ＤＭＦまたはＴＨＦのような溶媒中で処理して、対応するカップリング生成物６−３を得ることができる。 Scheme 6

Preparation of compounds 6-3 of the invention according to the method shown in Scheme 6 wherein Ring A, Ar, R ₁ , R ₂ , X and Y are as defined herein or in the claims. Can do. Intermediates 6-1 and 6-2 of the present invention wherein rings A, R ₂ , X and Y are as defined herein or in the claims (L: leaving groups such as halogen, —OMs, etc. ) Can be prepared according to the methods shown in Scheme 3 and Scheme 5, respectively. Appropriate substituted alcohol 6-1 is thionyl chloride or methanesulfonyl chloride in a solvent such as THF or toluene in the presence or absence of a base such as triethylaminine and N, N-diisopropylethylamine. To give the corresponding intermediate 6-2. Alternatively, intermediate 6-2 can be prepared by treating 6-1 with tetrabrominated carbon and triphenylphosphine in a suitable solvent such as dichloromethane. The preferred leaving group is bromide or chloride, but may also be iodide, mesylate, tosylate and the like. Intermediate 6-2 is converted to a suitable amine [(Ar—CH ₂ —) (R ₁ ) NH], wherein Ar and R ₁ are as defined herein or in the claims. Treatment with a base such as potassium tert-butoxide in a solvent such as DMF or THF can provide the corresponding coupling product 6-3.

環Ａ、Ａｒ、Ｒ_１、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりである本発明の化合物７−３を、スキーム７に示されている方法に従って製造することができる。環Ａ、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりである本発明の中間体７−１を、スキーム３に示されている方法に従って製造することができる。適当な置換アルデヒド７−１をアリール−メチルアミンで、水素化ホウ素ナトリウム、シアノホウ化水素ナトリウム、トリアセトキシボロヒドリド（botohydride）等のような還元剤、および酢酸、トリフルオロ酢酸等のような酸の存在下で、メタノール、エタノール、ＣＨ_２Ｃｌ_２、１，２−ジクロロエタン等中で処理して、対応する中間体７−２を得ることができる。あるいは、中間体７−２を、ベンジルアミンおよび触媒量のｐ−トルエンスルホン酸等のような酸で、トルエン中で処理して対応するイミンを得て、その後得られたイミンを水素化ホウ素ナトリウムのような還元剤を用いて還元して、製造することができる。化合物７−２を、アシルクロライド、アルコキシカルボニルクロライド、置換クロロピリジン、置換クロロピリミジン等のような適当なＲ１−Ｌで、トルエン、ＴＨＦ、ＤＭＦ等のような適当な溶媒中で、炭酸カリウム、トリエチルアミン、水素化ナトリウム、カリウムビス（トリメチルシリル）アミド等のような適当な塩基の存在下で処理して、化合物７−３に変換することができる。 Scheme 7

Preparation of compounds 7-3 of the invention according to the method shown in Scheme 7 wherein Ring A, Ar, R ₁ , R ₂ , X and Y are as defined herein or in the claims. Can do. Intermediates 7-1 of the present invention in which rings A, R ₂ , X and Y are as defined herein or in the claims can be prepared according to the method shown in Scheme 3. A suitable substituted aldehyde 7-1 is aryl-methylamine, a reducing agent such as sodium borohydride, sodium cyanoborohydride, triacetoxyborohydride and the like, and an acid such as acetic acid, trifluoroacetic acid and the like. Treatment in methanol, ethanol, CH ₂ Cl ₂ , 1,2-dichloroethane, etc. in the presence can give the corresponding intermediate 7-2. Alternatively, intermediate 7-2 can be treated in toluene with an acid such as benzylamine and a catalytic amount of p-toluenesulfonic acid to obtain the corresponding imine, after which the resulting imine is sodium borohydride. It can reduce and manufacture using a reducing agent like. Compound 7-2 is converted to potassium carbonate, triethylamine in an appropriate solvent such as toluene, THF, DMF and the like with an appropriate R1-L such as acyl chloride, alkoxycarbonyl chloride, substituted chloropyridine, substituted chloropyrimidine and the like. Can be converted to compound 7-3 by treatment in the presence of a suitable base such as sodium hydride, potassium bis (trimethylsilyl) amide, and the like.

環Ａ、Ａｒ、Ｒ_１、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりであり、−（リンカー）−ＣＯ_２ＨがＲ_２［例えば、−Ｎ（Ｃ_１−Ｃ_４−アルキル）（Ｃ_１−Ｃ_４−アルキル−Ｃ_３−Ｃ_７−シクロアルキル−Ｃ_１−Ｃ_３−アルキル−ＣＯ_２Ｈ）］に記載されている本発明の化合物８−２を、スキーム８に示されている方法に従って製造することができる。
環Ａ、Ａｒ、Ｒ_１、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりであり、Ｗ_２がＣ_１−Ｃ_６アルキルである本発明の化合物８−１を、スキーム６または７に示されている方法に従って製造することができる。中間体８−１を水酸化リチウム、水酸化ナトリウム、水酸化カリウム等のような塩基で、メタノール、エタノール、ＴＨＦ等のような適当な溶媒中で処理して、対応するカルボン酸８−２を得ることができる。 Scheme 8

Rings A, Ar, R ₁ , X and Y are as defined herein or in the claims, and — (linker) —CO ₂ H is R ₂ [eg, —N (C ₁ -C ₄ — Alkyl) (C ₁ -C ₄ -alkyl-C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkyl-CO ₂ H)]]. It can be produced according to the methods shown.
Compounds of the invention 8-1 in which Ring A, Ar, R ₁ , X and Y are as defined herein or in the claims and W ₂ is C ₁ -C ₆ alkyl are represented by Scheme 6 or 7 can be produced according to the method shown in FIG. Intermediate 8-1 is treated with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. in a suitable solvent such as methanol, ethanol, THF, etc. to give the corresponding carboxylic acid 8-2. Obtainable.

環Ａ、Ａｒ、Ｒ_１、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりである本発明の化合物９−２、９−３、および９−４を、スキーム９に示されている方法に従って製造することができる。環Ａ、Ａｒ、Ｒ_１、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりであり、ハロゲンが好ましくはヨードまたはブロモである本発明の化合物９−１を、スキーム６または７に示されている方法に従って製造することができる。化合物９−１をＣｕＣＮで、ＤＭＦ中、高温で処理して、対応する化合物９−２を得ることができる。あるいは、ニトリル９−２を、化合物９−１とＫＣＮをＣｕＩおよびパラジウム（ＩＩ）塩の存在下、またはある銅もしくはニッケル錯体の存在下でカップリング反応させることによって製造することができる。カルボン酸９−３を、９−２を水酸化リチウム、水酸化ナトリウム等で、メタノール、エタノール、ＴＨＦ等のような適当な溶媒中で処理することによって、製造することができる。カルボン酸９−３の塩素化を、塩化オキサリルおよび触媒量のＤＭＦで、ＣＨ_２Ｃｌ_２またはチオニルクロライドのような適当な溶媒中で、トルエンのような適当な溶媒中で行うことができる。続くアミノ化をジメチルアミンのようなアミンで、ＴＨＦ等中で行って、アミド９−４を得ることができる。あるいは、アミド９−４を、アミンで、ＤＣＣ、ＥＤＣ、ＢＯＰ、ＨＡＴＵ等のようなカップリング試薬の存在下で、ＣＨ_２Ｃｌ_２、ＴＨＦ等のような適当な溶媒中でアミノ化させることによって製造することができる。 Scheme 9

Compounds 9-2, 9-3, and 9-4 of the present invention in which Ring A, Ar, R ₁ , R ₂ , X, and Y are as defined herein or in the claims are represented in Scheme 9 It can be produced according to the methods shown. Compounds of the invention 9-1 in which Ring A, Ar, R ₁ , R ₂ , X and Y are as defined herein or in the claims and the halogen is preferably iodo or bromo are represented by Scheme 6 Or it can manufacture according to the method shown by 7. Compound 9-1 can be treated with CuCN at high temperature in DMF to give the corresponding compound 9-2. Alternatively, nitrile 9-2 can be prepared by coupling compound 9-1 and KCN in the presence of CuI and palladium (II) salts, or in the presence of certain copper or nickel complexes. Carboxylic acid 9-3 can be prepared by treating 9-2 with lithium hydroxide, sodium hydroxide or the like in a suitable solvent such as methanol, ethanol, THF or the like. Chlorination of carboxylic acid 9-3 can be carried out with oxalyl chloride and catalytic amounts of DMF in a suitable solvent such as toluene in a suitable solvent such as CH ₂ Cl ₂ or thionyl chloride. Subsequent amination can be performed with an amine such as dimethylamine in THF or the like to give amide 9-4. Alternatively, amide 9-4 is aminated with an amine in the presence of a coupling reagent such as DCC, EDC, BOP, HATU, etc. in a suitable solvent such as CH ₂ Cl ₂ , THF, etc. Can be manufactured.

環Ａ、Ａｒ、Ｒ_１、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりであり、Ｒがアルキル、アルコキシ、ジアルキルアミンまたは環状アミンである本発明の化合物１０−２または１０−４を、スキーム１０に示されている方法に従って製造することができる。Ａｒ、Ｒ_１、Ｒ_２、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりであり、ハロゲンが好ましくはヨードまたはブロモである本発明の化合物１０−１または１０−３を、スキーム６または７に示されている方法に従って製造することができる化合物１０−１または１０−３と適当なアルコール、アミン、またはアルキルＧｒｉｇｎａｒｄ試薬のカップリング反応を、ＮａＯｔ−Ｂｕ、ＫＯｔ−Ｂｕ等のような塩基、パラジウムもしくはニッケル触媒、および２−（ジ−ｔ−ブチルホスフィノ）ビフェニル等のようなリガンドの存在下で、トルエン、ＴＨＦ、ジオキサン等のような適当な溶媒中で、高温で行って、対応するカップリング生成物１０−２または１０−４を得ることができる。 Scheme 10

Compounds of the Invention 10-2 wherein Ring A, Ar, R ₁ , R ₂ , X and Y are as defined herein or in the Claims and R is an alkyl, alkoxy, dialkylamine or cyclic amine Or 10-4 can be prepared according to the method shown in Scheme 10. Compounds of the invention 10-1 or 10-3 according to the invention, wherein Ar, R ₁ , R ₂ , X and Y are as defined herein or in the claims and the halogen is preferably iodo or bromo A coupling reaction of compound 10-1 or 10-3, which can be prepared according to the method shown in 6 or 7, and a suitable alcohol, amine, or alkyl Grignard reagent is performed as in NaOt-Bu, KOt-Bu, etc. In a suitable solvent such as toluene, THF, dioxane, etc. in the presence of a basic, palladium or nickel catalyst, and a ligand such as 2- (di-t-butylphosphino) biphenyl. The corresponding coupling product 10-2 or 10-4 can be obtained.

Ａｒ、Ｒ_１、Ｒ_４、Ｒ_５、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりであり、ｐが本明細書または特許請求の範囲に定義の整数である本発明の化合物１１−２、１１−３、１１−４および１１−５を、スキーム１１に示されている方法に従って製造することができる。Ａｒ、Ｒ_１、Ｒ_４、Ｒ_５、ＸおよびＹが本明細書または特許請求の範囲に定義のとおりであり、ｐが本明細書または特許請求の範囲に定義の整数である本発明の化合物１１−１を、スキーム６または７に示されている方法に従って製造することができる。化合物１１−１（Ｐｒｏ：アルコールのための適当な保護基、例えばベンジル、テトラヒドロピラニル等）の脱保護を、Peter G,M Wuts and Theodora W. Greene “Protective Groups in Organic Synthesis”. 4^th Ed., Wiley およびそれに記載の文献に記載の方法に従い行って、アルコール１１−２を得ることができる。化合物１１−２をアルデヒド１１−３またはカルボン酸１１−４に、ＰＣＣ、ＰＤＣ、ＫＭｎＯ_４のような酸化剤で酸化、またはＳｗｅｒｎ酸化、Ｄｅｓｓ−Ｍａｒｔｉｎ酸化、ＴＥＭＰＯ酸化等によって、適当な溶媒中で変換することができる。アルデヒド１１−３をカルボン酸１１−４に、ＫＭｎＯ_４のような酸化剤での酸化または亜塩素酸ナトリウム酸化（例えばＮａＣｌＯ_２／ＮａＨ_２ＰＯ_４／２−メチル−２−ブテン）、ＴＥＭＰＯ酸化等によって、適当な溶媒中で変換することができる。カルボン酸１１−４をＮＨ_４Ｃｌで、ＤＣＣ、ＥＤＣ、ＢＯＰ、ＨＡＴＵ等のようなカップリング試薬およびトリエチルアミン等のような塩基で、ＣＨ_２Ｃｌ_２、ＴＨＦ等のような適当な溶媒中で処理して、アミド１１−５を得ることができる。あるいは、カルボン酸１１−４を酸クロライドに、塩化チオニル、塩化オキサリル等でトルエン、ＣＨ_２Ｃｌ_２等のような適当な溶媒中で反応させて変換し、その後アンモニアとＴＨＦ、ＣＨ_２Ｃｌ_２等のような適当な溶媒中で反応させて、アミド１１−５を得ることができる。 Scheme 11

A compound of the invention wherein Ar, R ₁ , R ₄ , R ₅ , X and Y are as defined herein or in the claims and p is an integer as defined in the specification or claims. 11-2, 11-3, 11-4 and 11-5 can be prepared according to the method shown in Scheme 11. A compound of the invention wherein Ar, R ₁ , R ₄ , R ₅ , X and Y are as defined herein or in the claims and p is an integer as defined in the specification or claims. 11-1 can be prepared according to the methods shown in Scheme 6 or 7. Deprotection of compound 11-1 (Pro: a suitable protecting group for alcohols such as benzyl, tetrahydropyranyl, etc.) was performed by Peter G, M Wuts and Theodora W. Greene “Protective Groups in Organic Synthesis”. 4 ^th Ed ., Wiley and the literature described therein can be used to give alcohol 11-2. Compound 11-2 is oxidized to aldehyde 11-3 or carboxylic acid 11-4 with an oxidizing agent such as PCC, PDC, KMnO ₄ , or in a suitable solvent by Swern oxidation, Dess-Martin oxidation, TEMPO oxidation, etc. Can be converted. Oxidation of aldehyde 11-3 to carboxylic acid 11-4 with an oxidizing agent such as KMnO ₄ or sodium chlorite oxidation (eg NaClO ₂ / NaH ₂ PO ₄ / 2-methyl-2-butene), TEMPO oxidation, etc. Can be converted in a suitable solvent. Treatment of carboxylic acid 11-4 with NH ₄ Cl in a suitable solvent such as CH ₂ Cl ₂ , THF, etc. with a coupling reagent such as DCC, EDC, BOP, HATU etc. and a base such as triethylamine etc. Thus, amide 11-5 can be obtained. Alternatively, carboxylic acid 11-4 is converted to acid chloride by reacting with thionyl chloride, oxalyl chloride or the like in an appropriate solvent such as toluene, CH ₂ Cl _2, etc., and then ammonia and THF, CH ₂ Cl _2, etc. The amide 11-5 can be obtained by reaction in a suitable solvent such as

  In view of the close relationship between the free form of the new compound and its salt form, in this specification the free compound or salt thereof corresponds to what is also meant the corresponding salt or free compound, and It can be advantageously understood.

  Depending on the choice of starting materials and methods, the novel compounds may be in the form of possible isomers or mixtures thereof, for example as optically pure isomers, for example as enantiomers, or mixtures of isomers, for example racemates, dia Depending on the number of asymmetric carbon atoms, it can be present as a mixture of stereomers or racemates.

  The present invention also implements the remaining steps using compounds available as intermediates at any step of the process as starting materials, or in the form of derivatives or salts, and / or racemates or enantiomers thereof. It relates to an embodiment of the process using starting materials or, in particular, formed under reaction conditions.

  In the process of the present invention, the starting materials are preferably used to derive compounds which are initially described as being particularly useful. The invention likewise relates to new starting materials specifically developed for the preparation of the compounds of the invention, their use and methods for their preparation.

  The invention likewise relates to the combination of each compound of formula (I), (IA), (IB), (IC) or (II) with a further active substance.

The combinations are for example
(I) an HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(Ii) an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof,
(Iii) an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(Iv) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(V) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(Vi) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(Vii) a dual angiotensin converting enzyme / neutral endopeptidase (ACE / NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(Viii) an endothelin antagonist or a pharmaceutically acceptable salt thereof,
(Ix) a renin inhibitor or a pharmaceutically acceptable salt thereof,
(X) a diuretic or a pharmaceutically acceptable salt thereof,
It can be an active substance selected from the group consisting of (xi) ApoA-I mimics, and (Xii) DGAT inhibitors.

An angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof is understood to be an active ingredient that binds to the AT-1 receptor subtype of angiotensin II receptor but does not activate the receptor. As a result of inhibition of the AT ₁ receptor, these antagonists can be used, for example, as antihypertensive agents or in the treatment of congestive heart failure.

Ｅ−１４７７と称される化合物、下記式

のＳＣ−５２４５８と称される化合物、および下記式

のＺＤ−８７３１と称される化合物、または各場合において、それらの薬学的に許容される塩から成る群から選択される化合物について言及することができる。 The class of AT ₁ receptor antagonists includes compounds with different structural characteristics, with non-peptidic ones being highly preferred. For example, valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan,

A compound called E-1477, the following formula

A compound designated SC-52458 of the formula

Can be referred to as a compound selected from the group consisting of: ZD-8731, or in each case their pharmaceutically acceptable salts.

Preferred AT ₁ receptor antagonists are those that are commercially available, most preferably valsartan or a pharmaceutically acceptable salt thereof.

  HMG-Co-A reductase inhibitors (also called β-hydroxy-β-methylglutaryl-coenzyme-A reductase inhibitors) are drugs that can be used to lower lipid levels including blood cholesterol Understood.

  The class of HMG-Co-A reductase inhibitors includes compounds with different structural characteristics. For example, atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and verostatin, or in each case, their pharmaceutically acceptable salts It may be mentioned that the compound is selected from the group consisting of:

  Preferred HMG-Co-A reductase inhibitors are those that are commercially available, most preferably fluvastatin and pitavastatin, or in each case, their pharmaceutically acceptable salts.

  Blocking the enzymatic degradation of angiotensin I to angiotensin II with so-called ACE inhibitors (also called angiotensin converting enzyme inhibitors) is a good variation for the control of blood pressure and thus for the treatment of congestive heart failure It can also be used as a treatment method.

  The class of ACE inhibitors includes compounds with different structural characteristics. For example, in alaspril, benazepril, benazeprilat, captopril, celonapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, mobilepril, perindopril, quinapril, ramipril, spirapril, and spiropril It can be mentioned whether the compound is selected from the group consisting of pharmaceutically acceptable salts.

  Preferred ACE inhibitors are those that are commercially available, most preferably benazepril and enalapril.

  The class of CCB includes essentially dihydropyridine (DHP) and non-DHP, such as diltiazem type and verapamil type CCB.

  CCBs useful for said combination are preferably represented by DHP selected from the group consisting of amlodipine, felodipine, liocidin, isradipine, rasidipine, nicardipine, nifedipine, nigurdipine, nildipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, and preferably Represented by non-DHP selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, galopamil, mibefradil, anipamyl, thiapamil and verapamil, and in each case their pharmaceutically acceptable salts. All of these CCBs are used therapeutically, for example as antihypertensive, antianginal or antiarrhythmic drugs.

  Preferred CCBs include amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil, or pharmaceutically acceptable salts thereof, for example depending on the specific CCB. Amlodipine or a pharmaceutically acceptable salt thereof, especially besylate, is particularly preferred. Verapamil or a pharmaceutically acceptable salt thereof, especially hydrochloride, is a particularly preferred representative of non-DHP.

  An aldosterone synthase inhibitor is an enzyme that converts corticosterone to aldosterone by hydroxylating corticosterone to form 18-OH-corticosterone and converting 18-OH-corticosterone to aldosterone. is there. The class of aldosterone synthase inhibitors is known to apply to the treatment of hypertension, and primary aldosteronism includes both steroidal and non-steroidal aldosterone synthase inhibitors, the latter being preferred.

  Commercially available aldosterone synthase inhibitors or aldosterone synthase inhibitors approved by health authorities are preferred.

  The class of aldosterone synthase inhibitors includes compounds with different structural characteristics. For example, non-steroidal aromatase inhibitors anastrazol, fadrozole (including its (+)-enantiomer), and steroidal aromatase inhibitor exemestane, or pharmaceutically acceptable when applicable in each case It may be mentioned that the compound is selected from the group consisting of

のファドロゾール塩酸塩の（＋）−エナンチオマー（米国特許４６１７３０７および４８８９８６１）である。 The most preferred non-steroidal aldosterone synthase inhibitor has the formula

(+)-Enantiomers of US Pat. Nos. 4,617,307 and 4,888,861.

のエプレレノンまたはスピロノラクトンである。 Preferred steroidal aldosterone antagonists are of formula

Eplerenone or spironolactone.

  Preferred dual angiotensin converting enzyme / neutral endopeptidase (ACE / NEP) inhibitors are, for example, omapatrilate (see EP 629627), fasidotolyl or fasidotrilate, or, where appropriate, their pharmaceutically acceptable salts. is there.

  Preferred endothelin antagonists are, for example, bosentan (see EP 526708A), also tezosentan (see WO 96/19459), or in each case their pharmaceutically acceptable salts.

の化合物（化学的には、２（Ｓ），４（Ｓ），５（Ｓ），７（Ｓ）−Ｎ−（３−アミノ−２，２−ジメチル−３−オキソプロピル）−２，７−ジ（１−メチルエチル）−４−ヒドロキシ−５−アミノ−８−［４−メトキシ−３−（３−メトキシ−プロポキシ）フェニル］−オクタンアミドと定義される）である。この代表例は、ＥＰ６７８５０３Ａに具体的に記載されている。ヘミフマル酸塩がとりわけ好ましい。 Renin inhibitors are for example non-peptidic renin inhibitors such as formula

(Chemically 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3-oxopropyl) -2,7 -Di (1-methylethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) phenyl] -octaneamide). This representative example is specifically described in EP 678503A. Hemifumarate is particularly preferred.

  The diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorosalidon. Hydrochlorothiazide is most preferred.

  ApoA-I mimetics are, for example, D4F peptides, in particular peptides of the formula DWF-K-A-F-Y-D-K-V-V-A-E-K-K-F-K-E-A-F It is.

  The DGAT inhibitor is, for example, one or more of those described in WO2005072740 and US Provisional Application No. 60 / 787,859.

  Preferably, a co-therapeutically effective amount of the active agents of the combination of the present invention can be administered simultaneously or sequentially, in any order, individually or in a fixed combination.

  The structure of the active agent identified by its generic name or trade name can be obtained from the current edition of the standard overview “The Merck Index” or from a database, for example IMS LifeCycle (eg IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Those skilled in the art can identify active agents and, based on these literatures, can also be manufactured and tested for pharmaceutical applications and properties in standard test models, both in vitro and in vivo .

  The present invention especially relates to compounds of formula (I), (IA), (IB), (IC) or (II) or their pharmaceutically acceptable salts, respectively, for the treatment of the human or animal body. .

  The invention likewise relates to the use of compounds of formula I or pharmaceutically acceptable salts of this type of compound having salt-forming properties, in particular as pharmacologically active substances, mainly as CETP inhibitors. In this context, they can preferably be used in the form of pharmaceutically acceptable formulations, methods for the preventive and / or therapeutic treatment of animals or the human body, in particular as inhibitors of CETP.

  The present invention includes, inter alia, optionally at least one cardiovascular disease of each of the compounds of formula (I), (IA), (IB), (IC) or (II) or a pharmaceutically acceptable salt thereof and Diseases involving CETP (eg, hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia) in combination with related conditions as well as compositions for treatment of the diseases described herein , Hyperbetalipoproteinemia, hyperalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, coronary heart disease, coronary artery disease, coronary artery disease, narrow Heart disease, ischemia, cardiac ischemia, thrombosis, cardiac infarction such as myocardial infarction, stroke, peripheral vascular disease, reperfusion injury, angiogenic restenosis, hypertension, congestive heart failure, type II diabetes As a prophylactic or therapeutic agent for hyperlipidemia or arteriosclerotic disease, especially for the manufacture of a medicament for the prevention or treatment or delay of progression of such diabetes, diabetic vascular complications, obesity or endotoxemia, etc. About the use of.

  The present invention also relates to diseases involving CETP (eg, hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, high beta lipoproteinemia, high alpha lipoproteinemia Hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, coronary heart disease, coronary artery disease, coronary artery disease, angina, ischemia, cardiac ischemia, thrombosis, myocardium Infarcted heart infarction, stroke, peripheral vascular disease, reperfusion injury, angiogenic restenosis, hypertension, congestive heart failure, diabetes such as type II diabetes, diabetic vascular complications, obesity or endotoxemia) A method for the prevention or treatment of or delay of progression of an animal, including humans in need thereof, especially as a prophylactic or therapeutic agent for hyperlipidemia or arteriosclerotic disease, ( Each of the compounds of A), (IB), (IC) or (II) or pharmaceutically acceptable salts thereof, optionally, of at least one cardiovascular disease and related condition and the diseases described herein. It relates to a method comprising administering in combination with a therapeutic composition.

  The present invention likewise relates to each compound of formula (I), (IA), (IB), (IC) or (II) or a pharmaceutically acceptable salt thereof, optionally with at least one cardiovascular disease. And associated conditions as well as in combination with the compositions for treating diseases described herein, wherein the composition involves CETP (eg, hyperlipidemia, arteriosclerosis, atherosclerosis) Peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hyperalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, coronary heart disease, Coronary artery disease, coronary vascular disease, angina pectoris, ischemia, cardiac ischemia, thrombosis, heart infarction like myocardial infarction, stroke, peripheral vascular disease, reperfusion injury, angiogenic restenosis, hypertension, congestive heart Preventive or treatment or delay of progression, especially for diabetes such as type II diabetes, diabetic vascular complications, obesity or endotoxemia, etc. The present invention relates to a pharmaceutical composition as a therapeutic agent.

  The pharmaceutical preparation of the present invention containing the compound of the present invention or a pharmaceutically acceptable salt thereof is present as such in a warm-blooded animal, or pharmacologically active ingredient together with a pharmaceutically acceptable carrier. For enteral, eg, oral, also rectal, and parenteral administration. The daily dose of the active ingredient depends on the age and individual condition and on the method of administration.

  The dose of the active ingredient depends on the warm-blooded animal species, age and individual condition, and the method of administration.

  The following examples illustrate the invention described above, but they are not intended to limit the content in any way. Temperature is given in degrees Celsius.

メタンスルホニルクロライド（ＭｓＣｌ、１５ｍｇ、０．１３ｍｍｏｌ）を｛２−［Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミノ］キノリン−３−イル｝メタノール（２５ｍｇ、０．０８８ｍｍｏｌ）およびＮ，Ｎ−ジイソプロピルエチルアミン（２３ｍｇ、０．１８ｍｍｏｌ）のトルエン（１ｍＬ）溶液に滴下し、反応混合物を周囲温度で２時間攪拌する。混合物に、１Ｎ ＨＣｌ水溶液および酢酸エチルを加える。有機層をｓａｔ． ＮａＨＣＯ_３水溶液、塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、真空下で濃縮する。Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミン（２９ｍｇ、０．０８９ｍｍｏｌ）およびＤＭＦ（１ｍＬ）を残渣に加えた後、混合物を攪拌し、カリウムｔｅｒｔ−ブトキシド（１１ｍｇ、０．０９８ｍｍｏｌ）を加え、混合物をさらに１時間攪拌する。１Ｎ ＨＣｌ水溶液を加えた後、混合物を酢酸エチルで抽出する。合併した有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。得られた混合物をシリカゲルカラムクロマトグラフィーで精製してＮ−［（３−｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）キノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
¹H-NMR (400MHz, CDCl₃),δ (ppm): 1.03-1.10 (m, 2H), 1.08 (t, 3H), 1.37-1.60 (m, 6H), 2.03-2.20 (m, 1H), 3.18 (q, 2H), 3.23 (d, 2H), 4.22 (s, 3H), 4.67 (s, 2H), 4.83 (s, 2H), 7.32 (m, 1H), 7.56 (d, 1H), 7.57 (m, 1H), 7.66 (s, 2H), 7.72 (s, 1H), 7.78 (s, 1H), 7.85 (d. 1H).
ESI-MS m/z: 592 [M+1]⁺ Example:
Example 1 N-[(3- {N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(2-methyl-2H-tetrazol-5-yl) amino} methyl) quinoline- Synthesis of 2-yl] -N- (cyclopentylmethyl) ethylamine

Methanesulfonyl chloride (MsCl, 15 mg, 0.13 mmol) was added to {2- [N- (cyclopentylmethyl) -N-ethylamino] quinolin-3-yl} methanol (25 mg, 0.088 mmol) and N, N-diisopropylethylamine. (23 mg, 0.18 mmol) in toluene (1 mL) is added dropwise and the reaction mixture is stirred at ambient temperature for 2 hours. To the mixture is added 1N aqueous HCl and ethyl acetate. The organic layer was washed with sat. Wash with aqueous NaHCO ₃ solution, brine, dry over magnesium sulfate, filter and concentrate under vacuum. After adding N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine (29 mg, 0.089 mmol) and DMF (1 mL) to the residue. The mixture is stirred, potassium tert-butoxide (11 mg, 0.098 mmol) is added and the mixture is stirred for an additional hour. After adding 1N aqueous HCl, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting mixture was purified by silica gel column chromatography to obtain N-[(3- {N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazole-5. -Yl) amino} methyl) quinolin-2-yl] -N- (cyclopentylmethyl) ethylamine is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.03-1.10 (m, 2H), 1.08 (t, 3H), 1.37-1.60 (m, 6H), 2.03-2.20 (m, 1H), 3.18 (q, 2H), 3.23 (d, 2H), 4.22 (s, 3H), 4.67 (s, 2H), 4.83 (s, 2H), 7.32 (m, 1H), 7.56 (d, 1H), 7.57 (m, 1H), 7.66 (s, 2H), 7.72 (s, 1H), 7.78 (s, 1H), 7.85 (d. 1H).
ESI-MS m / z: 592 [M + 1] ⁺

Example 2 : The following compounds are substituted with substituted {2- [N- (cycloalkylmethyl) -N-ethylamino] quinolin-3-yl} methanol and N- [3,5-bis (trifluoromethyl) benzyl]- Prepared according to the method of Example 1 from N- (2-methyl-2H-tetrazol-5-yl) amine.

Example 3 The following compound is obtained from substituted quinolin-3-yl-methanol and N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine. , Manufactured according to the method of Example 1.

エチルトランス−［４−（｛Ｎ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）キノリン−２−イル］−Ｎ−エチルアミノ｝メチル）シクロヘキシル］アセテート（３９ｍｇ、０．０５６ｍｍｏｌ）のＴＨＦ−メタノール（２：１、０．９ｍＬ）混合物に、２Ｎ ＬｉＯＨ（０．１ｍＬ）を加え、混合物を４０℃で３時間攪拌する。混合物を１Ｎ ＨＣｌおよび酢酸エチルで希釈し、有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮してトランス−［４−（｛Ｎ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）キノリン−２−イル］−Ｎ−エチルアミノ｝メチル）シクロヘキシル］酢酸を得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.80-0.93 (m, 4H), 1.05-1.80 (m, 9H), 2.16 (2H, d), 3.00-3.55 (br, 4H), 4.21 (s, 3H), 4.72 (brs, 2H), 4.79 (brs, 2H), 7.57 (d, 1H), 7.65 (s, 2H), 7.73 (s, 1H), 7.73-8.10 (br, 4H).
ESI-MS m/z: 664 [M+1]⁺ Example 4 : trans- [4-({N- [3-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl ) Amino} methyl) quinolin-2-yl] -N-ethylamino} methyl) cyclohexyl] acetic acid

Ethyltrans- [4-({N- [3-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino} Methyl) quinolin-2-yl] -N-ethylamino} methyl) cyclohexyl] acetate (39 mg, 0.056 mmol) in THF-methanol (2: 1, 0.9 mL) was charged with 2N LiOH (0.1 mL). In addition, the mixture is stirred at 40 ° C. for 3 hours. The mixture is diluted with 1N HCl and ethyl acetate and the organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated to trans- [4-({N- [3-({N ′-[3 , 5-bis (trifluoromethyl) benzyl] -N ′-(2-methyl-2H-tetrazol-5-yl) amino} methyl) quinolin-2-yl] -N-ethylamino} methyl) cyclohexyl] acetic acid. obtain.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.80-0.93 (m, 4H), 1.05-1.80 (m, 9H), 2.16 (2H, d), 3.00-3.55 (br, 4H), 4.21 (s, 3H), 4.72 (brs, 2H), 4.79 (brs, 2H), 7.57 (d, 1H), 7.65 (s, 2H), 7.73 (s, 1H), 7.73-8.10 (br, 4H) .
ESI-MS m / z: 664 [M + 1] ⁺

Example 5 Prepared according to the method of Example 4 from tetrazol-5-yl) amino} methyl) -substituted quinolin-2-yl] -N-ethylamino} methyl) cyclohexyl] acetate.

Ｎ−［（３−｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−７−ブロモキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミン（１４０ｍｇ、０．２１ｍｍｏｌ）およびＣｕＣＮ（１１０ｍｇ、１．２３ｍｍｏｌ）のＤＭＦ懸濁液を、１６５℃で１６時間攪拌する。反応混合物を室温に冷却させ、アンモニア水および酢酸エチルで希釈する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製して３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−２−［Ｎ’−（シクロペンチルメチル）−Ｎ’−エチルアミノ］キノリン−７−カルボニトリルを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.03-1.12 (m, 2H), 1.10 (t, 3H), 1.41-1.60 (m, 6H), 2.11-2.20 (m, 1H), 3.23 (q, 2H), 3.26 (d, 2H), 4.23 (s, 3H), 4.67 (s, 2H), 4.80 (s, 2H), 7.44 (dd, 1H), 7.60 (d, 1H), 7.63 (s, 2H), 7.71 (s, 1H), 7.78 (s, 1H), 8.18 (s, 1H).
ESI-MS m/z: 617 [M+1]⁺ Example 6 : 3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -2- [N'- Synthesis of (cyclopentylmethyl) -N′-ethylamino] quinoline-7-carbonitrile

N-[(3- {N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(2-methyl-2H-tetrazol-5-yl) amino} methyl) -7-bromoquinoline- A suspension of 2-yl] -N- (cyclopentylmethyl) ethylamine (140 mg, 0.21 mmol) and CuCN (110 mg, 1.23 mmol) is stirred at 165 ° C. for 16 hours. The reaction mixture is allowed to cool to room temperature and diluted with aqueous ammonia and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give 3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl. ) -2- [N ′-(cyclopentylmethyl) -N′-ethylamino] quinoline-7-carbonitrile.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.03-1.12 (m, 2H), 1.10 (t, 3H), 1.41-1.60 (m, 6H), 2.11-2.20 (m, 1H), 3.23 (q, 2H), 3.26 (d, 2H), 4.23 (s, 3H), 4.67 (s, 2H), 4.80 (s, 2H), 7.44 (dd, 1H), 7.60 (d, 1H), 7.63 (s, 2H), 7.71 (s, 1H), 7.78 (s, 1H), 8.18 (s, 1H).
ESI-MS m / z: 617 [M + 1] ⁺

３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−２−［Ｎ’−（シクロペンチルメチル）−Ｎ’−エチルアミノ］キノリン−７−カルボニトリル（４０ｍｇ、０．０６ｍｍｏｌ）および２Ｎ ＬｉＯＨ水溶液（２．０ｍＬ）のＥｔＯＨ（２ｍＬ）懸濁液を攪拌し、２時間還流させる。反応混合物を室温に冷却させ、１Ｎ ＨＣｌおよび酢酸エチルで希釈する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮して３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−２−［Ｎ’−（シクロペンチルメチル）−Ｎ’−エチルアミノ］キノリン−７−カルボン酸を得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.03-1.15 (m, 2H), 1.12 (t, 3H), 1.41-1.60 (m, 6H), 2.12-2.22 (m, 1H), 3.22-3.30 (m, 4H), 4.23 (s, 3H), 4.70 (s, 2H), 4.83 (s, 2H), 7.62 (d, 1H), 7.70 (s, 2H), 7.73 (s, 1H), 7.83 (s, 1H), 7.95 (dd, 1H), 8.66 (s, 1H).
ESI-MS m/z: 636 [M+1]⁺ Example 7 3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -2- [N'- Synthesis of (cyclopentylmethyl) -N′-ethylamino] quinoline-7-carboxylic acid

3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -2- [N ′-(cyclopentylmethyl) A suspension of -N'-ethylamino] quinoline-7-carbonitrile (40 mg, 0.06 mmol) and 2N aqueous LiOH (2.0 mL) in EtOH (2 mL) is stirred and refluxed for 2 hours. The reaction mixture is cooled to room temperature and diluted with 1N HCl and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to 3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazole. -5-yl) amino} methyl) -2- [N '-(cyclopentylmethyl) -N'-ethylamino] quinoline-7-carboxylic acid.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.03-1.15 (m, 2H), 1.12 (t, 3H), 1.41-1.60 (m, 6H), 2.12-2.22 (m, 1H), 3.22-3.30 (m, 4H), 4.23 (s, 3H), 4.70 (s, 2H), 4.83 (s, 2H), 7.62 (d, 1H), 7.70 (s, 2H), 7.73 (s, 1H) , 7.83 (s, 1H), 7.95 (dd, 1H), 8.66 (s, 1H).
ESI-MS m / z: 636 [M + 1] ⁺

３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−２−［Ｎ’−（シクロペンチルメチル）−Ｎ’−エチルアミノ］キノリン−７−カルボン酸（３０ｍｇ、０．０４７ｍｍｏｌ）、塩化オキサリル（１０μｌ）、および触媒量のＤＭＦのＣＨ_２Ｃｌ_２（２ｍＬ）混合物を室温で３時間攪拌し、真空下で濃縮する。残渣をＴＨＦに溶解させ、２Ｍ ジメチルアミンでＴＨＦ中で処理し、得られたＴＨＦ混合物を室温で３時間攪拌する。混合物を１Ｎ ＨＣｌでクエンチし、ＥｔＯＡｃで抽出する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製して３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−２−［Ｎ’−（シクロペンチルメチル）−Ｎ’−エチルアミノ］キノリン−７−カルボン酸ジメチルアミドを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.02-1.11 (m, 2H), 1.09 (t, 3H), 1.65-1.38 (m, 6H), 2.08-2.18 (m, 1H), 3.05 (s, 3H), 3.16 (s, 3H), 3.00-3.26 (m, 4H), 4.23 (s, 3H), 4.68 (s, 2H), 4.81 (s, 2H), 7.36 (d, 1H), 7.59 (d, 1H), 7.64 (s, 2H), 7.72 (s, 1H), 7.79 (s, 1H), 7.89 (s,1H).
ESI-MS m/z: 663.7 [M+1]⁺ Example 8 3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -2- [N'- Synthesis of (cyclopentylmethyl) -N′-ethylamino] quinoline-7-carboxylic acid dimethylamide

3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -2- [N ′-(cyclopentylmethyl) A mixture of —N′-ethylamino] quinoline-7-carboxylic acid (30 mg, 0.047 mmol), oxalyl chloride (10 μl), and a catalytic amount of DMF in CH ₂ Cl ₂ (2 mL) was stirred at room temperature for 3 hours and vacuumed. Concentrate under. The residue is dissolved in THF, treated with 2M dimethylamine in THF, and the resulting THF mixture is stirred at room temperature for 3 hours. Quench the mixture with 1N HCl and extract with EtOAc. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give 3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl. ) -2- [N ′-(cyclopentylmethyl) -N′-ethylamino] quinoline-7-carboxylic acid dimethylamide is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.02-1.11 (m, 2H), 1.09 (t, 3H), 1.65-1.38 (m, 6H), 2.08-2.18 (m, 1H), 3.05 (s, 3H), 3.16 (s, 3H), 3.00-3.26 (m, 4H), 4.23 (s, 3H), 4.68 (s, 2H), 4.81 (s, 2H), 7.36 (d, 1H) , 7.59 (d, 1H), 7.64 (s, 2H), 7.72 (s, 1H), 7.79 (s, 1H), 7.89 (s, 1H).
ESI-MS m / z: 663.7 [M + 1] ⁺

Ｎ−［（３−｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−７−ブロモキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミン（１１０ｍｇ、０．１６ｍｍｏｌ）、ジメチルアミン（ＴＨＦ中 ２Ｍ、０．１８ｍＬ、０．３６ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（２５ｍｇ、０．２６ｍｍｏｌ）、Ｐｄ_２（ｄｂａ）_３（８ｍｇ、０．００８７ｍｍｏｌ）および２−（ジ−ｔ−ブチルホスフィノ）ビフェニル（５ｍｇ、０．０１７ｍｍｏｌ）のトルエン（１ｍＬ）混合物を１００℃で４時間攪拌する。反応混合物を室温に冷却させ、水および酢酸エチルで希釈する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してＮ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−７−Ｎ”，Ｎ”−ジメチルアミノキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
¹H-NMR (400MHz, CDCl₃),δ (ppm): 1.02-1.11 (m, 2H), 1.04 (t, 3H), 1.37-1.63 (m, 6H), 2.11-2.20 (m, 1H), 3.07 (s, 6H), 3.15 (d, 2H), 3.86 (d, 2H), 4.21 (s, 3H), 4.63 (s, 2H), 4.80 (s, 2H), 6.95-6.98 (m, 2H), 7.40-7.43 (m, 1H), 7.63 (s, 1H), 7.66 (s, 2H), 7.72 (s, 1H).
ESI-MS m/z: 635.7 [M+1]⁺ Example 9 : N- [3-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino} methyl) -7 Synthesis of -N ", N" -dimethylaminoquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine.

N-[(3- {N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(2-methyl-2H-tetrazol-5-yl) amino} methyl) -7-bromoquinoline- 2-yl] -N- (cyclopentylmethyl) ethylamine (110 mg, 0.16 mmol), dimethylamine (2M in THF, 0.18 mL, 0.36 mmol), NaOt-Bu (25 mg, 0.26 mmol), Pd ₂ ( A toluene (1 mL) mixture of dba) ₃ (8 mg, 0.0087 mmol) and 2- (di-t-butylphosphino) biphenyl (5 mg, 0.017 mmol) is stirred at 100 ° C. for 4 hours. The reaction mixture is allowed to cool to room temperature and diluted with water and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(2-methyl-2H-tetrazole-5 Yl) amino} methyl) -7-N ″, N ″ -dimethylaminoquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.02-1.11 (m, 2H), 1.04 (t, 3H), 1.37-1.63 (m, 6H), 2.11-2.20 (m, 1H), 3.07 (s, 6H), 3.15 (d, 2H), 3.86 (d, 2H), 4.21 (s, 3H), 4.63 (s, 2H), 4.80 (s, 2H), 6.95-6.98 (m, 2H) , 7.40-7.43 (m, 1H), 7.63 (s, 1H), 7.66 (s, 2H), 7.72 (s, 1H).
ESI-MS m / z: 635.7 [M + 1] ⁺

Example 10 The following compound is converted to N-[(3- {N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(2-methyl-2H-tetrazol-5-yl) amino}. Prepared according to the method of Example 9 from methyl) -7-bromoquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine.

Ｎ−（３−｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］メチル｝−７−フルオロキノリン−２−イル）−Ｎ−（シクロペンチルメチル）エチルアミン（６１０ｍｇ、１．２ｍｍｏｌ）、５−ブロモ−２−クロロピリミジン（４４９ｍｇ、２．３ｍｍｏｌ）およびＫ_２ＣＯ_３（３２１ｍｇ、２．３ｍｍｏｌ）のトルエン懸濁液を、攪拌し、５日間還流させる。反応混合物を室温に冷却させ、水およびＣＨ_２Ｃｌ_２で希釈する。有機層を相分離器で濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してＮ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（５−ブロモピリミジン−２−イル）アミノ｝メチル）−７−フルオロキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
Ｒｆ値＝０．６９（ヘキサン／ＡｃＯＡｔ＝９／１）
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.04-1.12 (m, 2H), 1.10 (t, 3H), 1.41-1.61 (m, 6H), 2.13-2.20 (m, 1H), 3.21 (dd, 2H), 3.25 (d, 2H), 4.80 (s, 2H), 4.95 (s, 2H), 7.08 (ddd, 1H), 7.48 (ddd, 1H), 7.52 (s, 1H), 7.65 (s, 2H), 7.72 (s, 1H), 8.42 (s. 2H). Example 11 : N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(5-bromopyrimidin-2-yl) amino} methyl) -7-fluoroquinoline Synthesis of 2-yl] -N- (cyclopentylmethyl) ethylamine.

N- (3- {N '-[3,5-bis (trifluoromethyl) benzylamino] methyl} -7-fluoroquinolin-2-yl) -N- (cyclopentylmethyl) ethylamine (610 mg, 1.2 mmol) Toluene suspension of 5-bromo-2-chloropyrimidine (449 mg, 2.3 mmol) and K ₂ CO ₃ (321 mg, 2.3 mmol) is stirred and refluxed for 5 days. The reaction mixture is allowed to cool to room temperature and diluted with water and CH ₂ Cl ₂ . The organic layer is filtered through a phase separator and concentrated. The crude product was purified by silica gel column chromatography to give N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(5-bromopyrimidin-2-yl) amino. } Methyl) -7-fluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine.
Rf value = 0.69 (hexane / AcOAt = 9/1)
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.04-1.12 (m, 2H), 1.10 (t, 3H), 1.41-1.61 (m, 6H), 2.13-2.20 (m, 1H), 3.21 (dd, 2H), 3.25 (d, 2H), 4.80 (s, 2H), 4.95 (s, 2H), 7.08 (ddd, 1H), 7.48 (ddd, 1H), 7.52 (s, 1H), 7.65 (s, 2H), 7.72 (s, 1H), 8.42 (s. 2H).

Ｎ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（５−ブロモピリミジン−２−イル）アミノ｝メチル）−７−フルオロキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミン（４２０ｍｇ、０．６１ｍｍｏｌ）、モルホリン（８０μＬ、０．９３ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（９４ｍｇ、０．９８ｍｍｏｌ）、Ｐｄ_２（ｄｂａ）_３（２８ｍｇ、０．０３１ｍｍｏｌ）、および２−（ジ−ｔ−ブチルホスフィノ）ビフェニル（１８ｍｇ、０．０６０ｍｍｏｌ）のトルエン（４ｍＬ）懸濁液を１００℃で２．５時間攪拌する。反応混合物を室温に冷却させ、水および酢酸エチルで希釈する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してＮ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（５−モルホリン−４−イル−ピリミジン−２−イル）アミノ｝メチル）−７−フルオロキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.87-1.11 (m, 2H), 1.09 (t, 3H), 1.38-1.62 (m, 6H), 2.13-2.20 (m, 1H), 3.07-3.09 (m, 4H), 3.18-3.27 (m, 4H), 3.87-3.90 (m, 4H), 4.81 (s 2H), 4.93 (s, 2H), 7.55-7.60 (m, 1H), 7.60 (s, 1H), 7.66 (s, 2H), 7.70 (s, 1H), 8.18 (s. 2H).
ESI-MS m/z: 691 [M+1]⁺ Example 12 : N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(5-morpholin-4-yl-pyrimidin-2-yl) amino} methyl) Synthesis of -7-fluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine.

N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(5-bromopyrimidin-2-yl) amino} methyl) -7-fluoroquinolin-2-yl ] -N- (cyclopentylmethyl) ethylamine (420 mg, 0.61 mmol), morpholine (80 μL, 0.93 mmol), NaOt-Bu (94 mg, 0.98 mmol), Pd ₂ (dba) ₃ (28 mg, 0.031 mmol) , And a suspension of 2- (di-t-butylphosphino) biphenyl (18 mg, 0.060 mmol) in toluene (4 mL) is stirred at 100 ° C. for 2.5 hours. The reaction mixture is allowed to cool to room temperature and diluted with water and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-(5-morpholin-4-yl-pyrimidine- 2-yl) amino} methyl) -7-fluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.87-1.11 (m, 2H), 1.09 (t, 3H), 1.38-1.62 (m, 6H), 2.13-2.20 (m, 1H), 3.07-3.09 (m, 4H), 3.18-3.27 (m, 4H), 3.87-3.90 (m, 4H), 4.81 (s 2H), 4.93 (s, 2H), 7.55-7.60 (m, 1H), 7.60 (s, 1H), 7.66 (s, 2H), 7.70 (s, 1H), 8.18 (s. 2H).
ESI-MS m / z: 691 [M + 1] ⁺

Example 13 The following compound is prepared from N- (3- {N ′-[3,5-bis (trifluoromethyl) benzylamino] methyl} -substituted quinolin-2-yl) -N- (cyclopentylmethyl) ethylamine. Prepared according to the methods of Examples 11 and 12.

工程１：
Ｎ−｛３−［（Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−｛２−［２−（テトラヒドロピラン−２−イルオキシ）エチル］−２Ｈ−テトラゾール−５−イル｝アミノ）メチル］−５，７−ジフルオロキノリン−２−イル｝−Ｎ−（シクロペンチルメチル）エチルアミンを、２−クロロ−５，７−ジフルオロキノリン−３−カルボアルデヒド、Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミンおよびＮ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−｛２−［２−（テトラヒドロピラン−２−イルオキシ）エチル］−２Ｈ−テトラゾール−５−イル｝アミンから、実施例１およびＡの方法に従って製造する。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.03-1.12 (m, 2H), 1.11 (t, 3H), 1.41-1.79 (m, 12H), 2.12-2.22 (m, 1H), 3.20-3.26 (m, 4H), 3.43-3.49 (m, 1H), 3.67-3.73 (m, 1H), 3.97 (ddd, 1H), 4.20 (ddd, 1H), 4.58-4.61 (m, 1H), 4.63-4.69 (m, 4H), 4.80 (s, 2H), 6.75-6.80 (m, 1H), 7.25-7.28 (m, 1H), 7.64 (s, 2H), 7.71 (s, 1H), 7.93 (d, 1H).
ESI-MS m/z: 742 [M+1]⁺ Example 14 N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] amino } Methyl) -5,7-difluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine

Process 1 :
N- {3-[(N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-{2- [2- (tetrahydropyran-2-yloxy) ethyl] -2H-tetrazole-5 Yl} amino) methyl] -5,7-difluoroquinolin-2-yl} -N- (cyclopentylmethyl) ethylamine, 2-chloro-5,7-difluoroquinoline-3-carbaldehyde, N- (cyclopentylmethyl) From -N-ethylamine and N- [3,5-bis (trifluoromethyl) benzyl] -N- {2- [2- (tetrahydropyran-2-yloxy) ethyl] -2H-tetrazol-5-yl} amine Prepared according to the methods of Examples 1 and A.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.03-1.12 (m, 2H), 1.11 (t, 3H), 1.41-1.79 (m, 12H), 2.12-2.22 (m, 1H), 3.20-3.26 (m, 4H), 3.43-3.49 (m, 1H), 3.67-3.73 (m, 1H), 3.97 (ddd, 1H), 4.20 (ddd, 1H), 4.58-4.61 (m, 1H), 4.63-4.69 (m, 4H), 4.80 (s, 2H), 6.75-6.80 (m, 1H), 7.25-7.28 (m, 1H), 7.64 (s, 2H), 7.71 (s, 1H), 7.93 ( d, 1H).
ESI-MS m / z: 742 [M + 1] ⁺

Process 2 :
5N HCl (0.2 mL) aqueous solution was added to N- {3-[(N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-{2- [2- (tetrahydropyran-2-yloxy)]. Ethyl] -2H-tetrazol-5-yl} amino) methyl] -5,7-difluoroquinolin-2-yl} -N- (cyclopentylmethyl) ethylamine (0.25 g, 0.34 mmol) in MeOH / THF (1 / 4, 2.5 mL) and the mixture is stirred at room temperature for 12 hours. The reaction mixture is quenched by the addition of aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated to N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-[2- (2-Hydroxyethyl) -2H-tetrazol-5-yl] amino} methyl) -5,7-difluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.03-1.12 (m, 2H), 1.10 (t, 3H), 1.41-1.62 (m, 6H), 2.12-2.22 (m, 1H), 2.29 (t, 1H), 3.21-3.26 (m, 4H), 4.14-4.16 (m, 2H), 4.62-4.65 (m, 2H), 4.67 (s, 2H), 4.81 (s, 2H), 6.76- 6.81 (m, 1H), 7.26-7.28 (m, 1H), 7.64 (s, 2H), 7.72 (s, 1H), 7.95 (d, 1H).
ESI-MS m / z: 658 [M + 1] ⁺

ＮａＨ（油中６０％、５ｍｇ、０．１３ｍｍｏｌ）をＮ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−［２−（２−ヒドロキシエチル）−２Ｈ−テトラゾール−５−イル］アミノ｝メチル）−５，７−ジフルオロキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミン（７０ｍｇ、０．１１ｍｍｏｌ）のＤＭＦ（０．５ｍＬ）溶液に加え、０℃で３０分間攪拌する。ＭｅＩ（１０μＬ、０．１６ｍｍｏｌ）を混合物に加え、得られた混合物を室温で２時間攪拌する。反応混合物をｓａｔ． ＮＨ_４Ｃｌ水溶液を加えてクエンチし、ＣＨ_２Ｃｌ_２で抽出する。有機層を相分離器で濾過して濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してＮ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−［２−（２−メトキシエチル）−２Ｈ−テトラゾール−５−イル］アミノ｝メチル）−５，７−ジフルオロキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
Ｒｆ値＝０．６３（ヘキサン／ＡｃＯＥｔ＝４／１）
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.04-1.11 (m, 2H), 1.09 (t, 3H), 1.40-1.63 (m, 6H), 2.12-2.20 (m, 1H), 3.24 (t, 3H), 3.35 (s, 3H), 3.90 (t, 2H), 4.63-4.66 (m, 4H), 4.80 (s, 2H), 6.75-6.80 (m, 1H), 7.64 (s, 2H), 7.70 (s, 1H), 7.95 (s. 1H). Example 15 : N- [3-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-methoxyethyl) -2H-tetrazol-5-yl] amino } Methyl) -5,7-difluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine

NaH (60% in oil, 5 mg, 0.13 mmol) was added to N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] amino} methyl) -5,7-difluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine (70 mg, 0.11 mmol) in DMF (0.5 mL) solution Stir at 0 ° C. for 30 minutes. MeI (10 μL, 0.16 mmol) is added to the mixture and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with sat. Quench with aqueous NH ₄ Cl and extract with CH ₂ Cl ₂ . The organic layer is filtered through a phase separator and concentrated. The crude product was purified by silica gel column chromatography to give N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-[2- (2-methoxyethyl) -2H. -Tetrazol-5-yl] amino} methyl) -5,7-difluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine.
Rf value = 0.63 (hexane / AcOEt = 4/1)
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.04-1.11 (m, 2H), 1.09 (t, 3H), 1.40-1.63 (m, 6H), 2.12-2.20 (m, 1H), 3.24 (t, 3H), 3.35 (s, 3H), 3.90 (t, 2H), 4.63-4.66 (m, 4H), 4.80 (s, 2H), 6.75-6.80 (m, 1H), 7.64 (s, 2H), 7.70 (s, 1H), 7.95 (s. 1H).

ＭｓＣｌ（２０ｍｇ、０．１７ｍｍｏｌ）をＮ−［３−（｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−［２−（２−ヒドロキシエチル）−２Ｈ−テトラゾール−５−イル］アミノ｝メチル）−５，７−ジフルオロキノリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミン（７０ｍｇ、０．１１ｍｍｏｌ）およびＮ，Ｎ−ジイソプロピルエチルアミン（２５ｍｇ、０．１９ｍｍｏｌ）のトルエン（２ｍＬ）混合物で処理し、室温で１４時間攪拌する。混合物を１Ｎ ＨＣｌ水溶液でクエンチし、ＥｔＯＡｃで抽出する。有機層をｓａｔ． ＮａＨＣＯ_３水溶液および塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮して粗メシレートを得る。得られたメシレートを２Ｍ ジメチルアミンと共にＴＨＦ（１．０ｍＬ）に溶解させ、混合物を７０℃で２時間攪拌する。反応混合物を室温に冷却し、水およびＣＨ_２Ｃｌ_２で希釈する。有機層を相分離器で濾過して濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製して、Ｎ−｛３−［（Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−｛２−［２−（Ｎ”，Ｎ”−ジメチルアミノ）エチル］−２Ｈ−テトラゾール−５−イル｝アミノ）メチル］−５，７−ジフルオロキノリン−２−イル｝−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
Ｒｆ値＝０．２２（ヘキサン／ＡｃＯＥｔ＝３／１）
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.02-1.13 (m, 2H), 1.10 (t, 3H), 1.39-1.65 (m, 6H), 2.12-2.20 (m, 1H), 2.29 (s, 6H), 2.88-2.98 (m, 2H), 3.21-3.26 (m, 4H), 4.57-4.60 (m, 2H), 4.65 (s, 2H), 4.80 (s, 2H), 6.75-7.00 (m, 1H), 7.24-7.29 (m, 1H), 7.64 (s, 2H), 7.71 (s, 1H), 7.95 (s. 1H). Example 16 : N- {3-[(N '-[3,5-bis (trifluoromethyl) benzyl] -N'-{2- [2- (N ", N" -dimethylamino) ethyl]- Synthesis of 2H-tetrazol-5-yl} amino) methyl] -5,7-difluoroquinolin-2-yl} -N- (cyclopentylmethyl) ethylamine.

MsCl (20 mg, 0.17 mmol) was added to N- [3-({N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-[2- (2-hydroxyethyl) -2H-tetrazole- Of 5-yl] amino} methyl) -5,7-difluoroquinolin-2-yl] -N- (cyclopentylmethyl) ethylamine (70 mg, 0.11 mmol) and N, N-diisopropylethylamine (25 mg, 0.19 mmol) Treat with a mixture of toluene (2 mL) and stir at room temperature for 14 hours. The mixture is quenched with 1N aqueous HCl and extracted with EtOAc. The organic layer was washed with sat. Wash with aqueous NaHCO ₃ and brine, dry over magnesium sulfate, filter and concentrate to obtain the crude mesylate. The resulting mesylate is dissolved in THF (1.0 mL) with 2M dimethylamine and the mixture is stirred at 70 ° C. for 2 hours. Cool the reaction mixture to room temperature and dilute with water and CH ₂ Cl ₂ . The organic layer is filtered through a phase separator and concentrated. The crude product was purified by silica gel column chromatography to obtain N- {3-[(N ′-[3,5-bis (trifluoromethyl) benzyl] -N ′-{2- [2- (N ″, N "-dimethylamino) ethyl] -2H-tetrazol-5-yl} amino) methyl] -5,7-difluoroquinolin-2-yl} -N- (cyclopentylmethyl) ethylamine is obtained.
Rf value = 0.22 (hexane / AcOEt = 3/1)
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.02-1.13 (m, 2H), 1.10 (t, 3H), 1.39-1.65 (m, 6H), 2.12-2.20 (m, 1H), 2.29 (s, 6H), 2.88-2.98 (m, 2H), 3.21-3.26 (m, 4H), 4.57-4.60 (m, 2H), 4.65 (s, 2H), 4.80 (s, 2H), 6.75- 7.00 (m, 1H), 7.24-7.29 (m, 1H), 7.64 (s, 2H), 7.71 (s, 1H), 7.95 (s. 1H).

トランス−Ｎ−（２−｛（Ｒ）−２−［４−（２−ベンジルオキシメチル）シクロヘキシル］ピロリジン−１−イル｝−６，７−ジフルオロキノリン−３−イルメチル）−Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］（２−メチル−２Ｈ−テトラゾール−５−イル）アミン（７．４７ｇ、９．７ｍｍｏｌ）のＣＨ_２Ｃｌ_２（８０ｍＬ）攪拌溶液に、ＢＢｒ_３（１．０Ｍ ＣＨ_２Ｃｌ_２溶液、１１．６ｍＬ、１１．６ｍｍｏｌ）を０℃で滴下し、室温で１時間攪拌する。反応混合物をｓａｔ． ＮａＨＣＯ_３水溶液を０℃で添加してクエンチし、酢酸エチルで抽出し、有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してトランス−２−（４−｛（Ｒ）−１−［３−（｛［Ｎ−３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）メタノールを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.73-0.95 (m, 2H), 1.00-1.13 (m, 2H), 1.21 (t, 1H), 1.34-1.44 (m, 1H), 1.57-1.61 (m, 1H), 1.64-1.79 (m, 6H), 1.83-1.92 (m, 1H), 1.98-2.02 (m, 1H), 3.18-3.24 (m, 1H), 3.39 (t, 2H), 3.48-3.57 (m, 1H), 4.21 (s, 3H), 4.56 (d, 1H), 4.57 (d, 1H), 4.62-4.70 (m, 1H), 4.78 (d, 1H), 4.99 (d, 1H), 7.22 (dd, 1H), 7.48 (dd, 1H), 7.56 (s, 1H), 7.63 (s, 2H), 7.73 (s. 1H).
ESI-MS m/z: 684 [M+1]⁺ Example 17 : trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazole-5 Yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) synthesis of methanol.

Trans-N- (2-{(R) -2- [4- (2-benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -6,7-difluoroquinolin-3-ylmethyl) -N- [3 To a stirred solution of 5-bis (trifluoromethyl) benzyl] (2-methyl-2H-tetrazol-5-yl) amine (7.47 g, 9.7 mmol) in CH ₂ Cl ₂ (80 mL) was added BBr ₃ (1. 0M CH ₂ Cl ₂ solution, 11.6 mL, 11.6 mmol) is added dropwise at 0 ° C. and stirred at room temperature for 1 hour. The reaction mixture is washed with sat. Quench by adding aqueous NaHCO ₃ at 0 ° C., extract with ethyl acetate, wash the organic layer with brine, dry over magnesium sulfate, filter and concentrate. The crude product was purified by silica gel column chromatography to obtain trans-2- (4-{(R) -1- [3-({[N-3,5-bis (trifluoromethyl) benzyl] -N- ( 2-methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) methanol.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.73-0.95 (m, 2H), 1.00-1.13 (m, 2H), 1.21 (t, 1H), 1.34-1.44 (m, 1H), 1.57-1.61 (m, 1H), 1.64-1.79 (m, 6H), 1.83-1.92 (m, 1H), 1.98-2.02 (m, 1H), 3.18-3.24 (m, 1H), 3.39 (t, 2H ), 3.48-3.57 (m, 1H), 4.21 (s, 3H), 4.56 (d, 1H), 4.57 (d, 1H), 4.62-4.70 (m, 1H), 4.78 (d, 1H), 4.99 ( d, 1H), 7.22 (dd, 1H), 7.48 (dd, 1H), 7.56 (s, 1H), 7.63 (s, 2H), 7.73 (s. 1H).
ESI-MS m / z: 684 [M + 1] ⁺

Example 18 The following compound is trans-N- (2-{(R) -2- [4- (2-benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -substituted-quinolin-3-ylmethyl) -N Prepared according to the method of Example 17 from [substituted-benzyl] (2-methyl-2H-tetrazol-5-yl) amine.

Ｄｅｓｓ−Ｍａｒｔｉｎペルヨージネート（４．０７ｇ、９．６ｍｍｏｌ）をトランス−（４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）メタノール（６．２５ｇ、９．１ｍｍｏｌ）のＣＨ_２Ｃｌ_２（７５ｍＬ）懸濁液に０℃で加え、得られた混合物を室温で２０分間攪拌する。反応混合物をｓａｔ． ＮａＨＣＯ_３水溶液を加えてクエンチし、ＣＨ_２Ｃｌ_２で抽出する。合併した有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製して、トランス−４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキサンカルボアルデヒドを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.04-1.28 (m, 4H), 1.65-2.15 (m, 10H), 3.19-3.25 (m, 1H), 3.50-3.57 (m, 1H), 4.20 (s, 3H), 4.56 (d, 1H), 4.60 (d, 1H), 4.66-4.73 (m, 1H), 4.81 (d, 1H), 4.97 (d, 1H), 7.23 (dd, 1H), 7.48 (dd, 1H), 7.57 (s, 1H), 7.65 (s, 2H), 7.74 (s, 1H), 9.55 (d. 1H).
ESI-MS m/z: 682 [M+1]⁺ Example 19 : trans-4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl ) Amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexanecarbaldehyde.

Dess-Martin periodinate (4.07 g, 9.6 mmol) was trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N -(2-Methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) methanol (6.25 g, 9.1 mmol) in CH _{To a 2} Cl ₂ (75 mL) suspension is added at 0 ° C. and the resulting mixture is stirred at room temperature for 20 minutes. The reaction mixture is washed with sat. Quench by adding aqueous NaHCO ₃ and extract with CH ₂ Cl ₂ . The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain trans-4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2- Methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexanecarbaldehyde is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.04-1.28 (m, 4H), 1.65-2.15 (m, 10H), 3.19-3.25 (m, 1H), 3.50-3.57 (m, 1H ), 4.20 (s, 3H), 4.56 (d, 1H), 4.60 (d, 1H), 4.66-4.73 (m, 1H), 4.81 (d, 1H), 4.97 (d, 1H), 7.23 (dd, 1H), 7.48 (dd, 1H), 7.57 (s, 1H), 7.65 (s, 2H), 7.74 (s, 1H), 9.55 (d. 1H).
ESI-MS m / z: 682 [M + 1] ⁺

Example 20 The following compound is converted into trans- (4-{(R) -1- [3-({N- [substituted-benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino}. Prepared according to the method of Example 19 from methyl) -substituted-quinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) methanol.

ＮａＣｌＯ_２（２．２０ｇ、２４ｍｍｏｌ）およびＮａＨ_２ＰＯ_４（２．１９ｇ １８ｍｍｏｌ）の水（４０ｍＬ）混合物を、トランス−４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキサンカルボアルデヒド（４．１５ｇ、６．１ｍｍｏｌ）の２−メチル−２−ブテン（６．４ｍＬ）／ｔ−ＢｕＯＨ（４０ｍＬ）溶液に０℃で滴下し、得られた混合物を室温で１．５時間攪拌する。反応混合物をｓａｔ． ＮＨ_４Ｃｌ水溶液を０℃で加えてクエンチし、酢酸エチルで抽出する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してトランス−４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキサンカルボン酸を得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.01-1.14 (m, 2H), 1.22-1.43 (m, 2H), 1.55-1.80 (m, 5H), 1.85-2.05 (m, 4H), 2.21 (tt, 1H), 3.17-3.24 (m, 1H), 3.49-3.56 (m, 1H), 4.19 (s, 3H), 4.57 (d, 1H), 4.60 (d, 1H), 4.64-4.70 (m, 1H), 4.79 (d, 1H), 4.95 (d, 1H), 7.23 (dd, 1H), 7.47 (dd, 1H), 7.57 (s, 1H), 7.64 (s, 2H), 7.74 (s. 1H).
ESI-MS m/z: 698 [M+1]⁺ Example 21 : trans-4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl ) Synthesis of amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexanecarboxylic acid.

A mixture of NaClO ₂ (2.20 g, 24 mmol) and NaH ₂ PO ₄ (2.19 g 18 mmol) in water (40 mL) was added to trans-4-{(R) -1- [3-({N- [3,5 -Bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexanecarbaldehyde (4.15 g, 6.1 mmol) in 2-methyl-2-butene (6.4 mL) / t-BuOH (40 mL) is added dropwise at 0 ° C., and the resulting mixture is stirred at room temperature for 1.5 hours. . The reaction mixture is washed with sat. Quench by adding aqueous NH ₄ Cl at 0 ° C. and extract with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain trans-4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl -2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexanecarboxylic acid.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.01-1.14 (m, 2H), 1.22-1.43 (m, 2H), 1.55-1.80 (m, 5H), 1.85-2.05 (m, 4H ), 2.21 (tt, 1H), 3.17-3.24 (m, 1H), 3.49-3.56 (m, 1H), 4.19 (s, 3H), 4.57 (d, 1H), 4.60 (d, 1H), 4.64- 4.70 (m, 1H), 4.79 (d, 1H), 4.95 (d, 1H), 7.23 (dd, 1H), 7.47 (dd, 1H), 7.57 (s, 1H), 7.64 (s, 2H), 7.74 (s. 1H).
ESI-MS m / z: 698 [M + 1] ⁺

Example 22 The following compound is converted into trans- (4-{(R) -1- [3-({N-substituted-benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl. ) -Substituted-quinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) prepared from methanol according to the method of Example 21.

トランス−（４−｛（Ｒ）−１−［３−（｛Ｎ−［置換−ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−置換−キノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）酢酸（１３５ｍｇ、０．１９ｍｍｏｌ）、ＮＨ_４Ｃｌ（２１ｍｇ、０．３８ｍｍｏｌ）、Ｎ−エチル−Ｎ’−（３−ジメチルアミノプロピル）カルボジイミドヒドロクロライド（ＥＤＣ・ＨＣｌ、５６ｍｇ、０．２９ｍｍｏｌ）、１−ヒドロキシ−７−アザベンゾトリアゾール（ＨＯＡｔ、２６ｍｇ、０．１９ｍｍｏｌ）およびトリエチルアミン（０．０５４ｍＬ、０．３８ｍｍｏｌ）のＤＭＦ（１ｍＬ）混合物を、室温で３時間攪拌する。Ｈ_２Ｏを加えた後、反応混合物をＥｔＯＡｃで抽出する。有機層を塩水で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ真空下で濃縮する。残渣をシリカゲルカラムクロマトグラフィーで精製してトランス−４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキサンカルボン酸アミドを無色シロップとして得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.03-1.16 (m, 2H), 1.24-1.35 (m, 2H), 1.35-1.45 (m, 2H), 1.63-1.81 (m, 5H), 1.87-1.97 (m, 3H), 1.99-2.11 (m, 2H), 3.20-3.26 (m, 1H), 3.50-3.58 (m, 1H), 4.19 (s, 3H), 4.58 (d, 1H), 4.60 (d, 1H), 4.66 (dd, 1H), 4.79 (d, 1H), 4.95 (d, 1H), 5.14 (s, 1H), 5.34 (s, 1H), 7.23 (dd, 1H), 7.47 (dd, 1H), 7.57 (s, 1H), 7.65 (s, 2H), 7.74 (s, 1H).
ESI-MS m/z: 697 [M+1]⁺ Example 23 : trans-4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl ) Synthesis of amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexanecarboxylic acid amide.

Trans- (4-{(R) -1- [3-({N- [substituted-benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -substituted-quinoline-2 -Yl] pyrrolidin-2-yl} cyclohexyl) acetic acid (135 mg, 0.19 mmol), NH ₄ Cl (21 mg, 0.38 mmol), N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) HCl, 56 mg, 0.29 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 26 mg, 0.19 mmol) and triethylamine (0.054 mL, 0.38 mmol) in DMF (1 mL) at room temperature Stir for hours. After adding H ₂ O, the reaction mixture is extracted with EtOAc. The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain trans-4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H -Tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexanecarboxylic acid amide is obtained as a colorless syrup.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.03-1.16 (m, 2H), 1.24-1.35 (m, 2H), 1.35-1.45 (m, 2H), 1.63-1.81 (m, 5H ), 1.87-1.97 (m, 3H), 1.99-2.11 (m, 2H), 3.20-3.26 (m, 1H), 3.50-3.58 (m, 1H), 4.19 (s, 3H), 4.58 (d, 1H ), 4.60 (d, 1H), 4.66 (dd, 1H), 4.79 (d, 1H), 4.95 (d, 1H), 5.14 (s, 1H), 5.34 (s, 1H), 7.23 (dd, 1H) , 7.47 (dd, 1H), 7.57 (s, 1H), 7.65 (s, 2H), 7.74 (s, 1H).
ESI-MS m / z: 697 [M + 1] ⁺

トランス−Ｎ−［２−（（Ｒ）−２−｛４−［２−（ベンジルオキシ）エチル］シクロヘキシル｝ピロリジン−１−イル）−６，７−ジフルオロキノリン−３−イルメチル］−Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］（２−メチル−２Ｈ−テトラゾール−５−イル）アミン（１１．０ｇ、１４．０ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１２０ｍＬ）攪拌溶液にＢＢｒ_３（１．０Ｍ ＣＨ_２Ｃｌ_２溶液、１８．０ｍＬ、１８．０ｍｍｏｌ）を０℃で滴下し、室温で１０分間攪拌する。反応混合物をｓａｔ． ＮａＨＣＯ_３水溶液を加えてクエンチし、酢酸エチルで抽出し、有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してトランス−２−（４−｛（Ｒ）−１−［３−（｛［３，５−ビス（トリフルオロメチル）ベンジル］（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）エタノールを得る。
¹H-NMR (400MHz, CDCl₃),δ (ppm): 0.72-0.93 (m, 2H), 1.01-1.18 (m, 3H), 1.26-1.36 (m, 1H), 1.39-1.44 (m, 2H), 1.47-1.55(m, 1H), 1.63-1.77 (m, 6H), 1.83-1.90 (m, 1H), 1.97-2.05 (m, 1H), 3.18-3.24 (m, 1H), 3.48-3.55 (m, 1H), 3.62-3.67 (m, 2H), 4.21 (s, 3H), 4.24 (d, 1H), 4.56 (d, 1H), 4.61-4.67 (m, 1H), 4.79 (d, 1H), 4.99 (d, 1H), 7.22 (dd, 1H), 7.47 (dd, 1H), 7.56 (s, 1H), 7.63 (s, 2H), 7.73 (s. 1H).
ESI-MS m/z: 698 [M+1]^＋ Example 24 : trans-2- (4-{(R) -1- [3-({[3,5-bis (trifluoromethyl) benzyl] (2-methyl-2H-tetrazol-5-yl) amino } Methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) ethanol.

Trans-N- [2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -6,7-difluoroquinolin-3-ylmethyl] -N- [ 3,5-bis (trifluoromethyl) benzyl] (2-methyl-2H-tetrazol-5-yl) amine (11.0 g, 14.0 mmol) in a stirred solution of CH ₂ Cl ₂ (120 mL) with BBr ₃ (1 0.0 M CH ₂ Cl ₂ solution, 18.0 mL, 18.0 mmol) is added dropwise at 0 ° C. and stirred at room temperature for 10 minutes. The reaction mixture is washed with sat. Quench with the addition of aqueous NaHCO ₃ and extract with ethyl acetate, wash the organic layer with brine, dry over magnesium sulfate, filter and concentrate. The crude product was purified by silica gel column chromatography to obtain trans-2- (4-{(R) -1- [3-({[3,5-bis (trifluoromethyl) benzyl] (2-methyl-2H -Tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) ethanol.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.72-0.93 (m, 2H), 1.01-1.18 (m, 3H), 1.26-1.36 (m, 1H), 1.39-1.44 (m, 2H ), 1.47-1.55 (m, 1H), 1.63-1.77 (m, 6H), 1.83-1.90 (m, 1H), 1.97-2.05 (m, 1H), 3.18-3.24 (m, 1H), 3.48-3.55 (m, 1H), 3.62-3.67 (m, 2H), 4.21 (s, 3H), 4.24 (d, 1H), 4.56 (d, 1H), 4.61-4.67 (m, 1H), 4.79 (d, 1H ), 4.99 (d, 1H), 7.22 (dd, 1H), 7.47 (dd, 1H), 7.56 (s, 1H), 7.63 (s, 2H), 7.73 (s. 1H).
ESI-MS m / z: 698 [M + 1] ⁺

Example 25 The following compound is trans-N- (2-{(R) -2- [4- (2-benzyloxyethyl) cyclohexyl] pyrrolidin-1-yl} -substituted-quinolin-3-ylmethyl) -N Prepared according to the method of Example 24 from [substituted-benzyl] (2-methyl-2H-tetrazol-5-yl) amine.

Ｄｅｓｓ−Ｍａｒｔｉｎペルヨージネート（６．４０ｇ、１５ｍｍｏｌ）をトランス−２−（４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）エタノール（８．８０ｇ、１２．６ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１６０ｍＬ）懸濁液に０℃で加え、得られた混合物を室温で４０分間攪拌する。反応混合物をｓａｔ． ＮａＨＣＯ_３水溶液を加えてクエンチし、ＣＨ_２Ｃｌ_２で２回抽出する。合併した有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してトランス−（４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）アセトアルデヒドを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.80-1.01 (m, 2H), 1.04-1.16 (m, 2H), 1.55-1.83 (m, 8H), 1.85-1.93 (m, 1H), 1.98-2.04 (m, 1H), 2.24 (dd, 2H), 3.18-3.24 (m, 1H), 3.48-3.56 (m, 1H), 4.21 (s, 3H), 4.54 (d, 1H), 4.57 (d, 1H), 4.63-4.69 (m, 1H), 4.79 (d, 1H), 4.98 (d, 1H), 7.22 (dd, 1H), 7.47 (dd, 1H), 7.56 (s, 1H), 7.63 (s, 2H), 7.73 (s, 1H), 9.72 (t, 1H).
ESI-MS m/z: 696 [M+1]⁺ Example 26 : trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazole-5- Yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetaldehyde.

Dess-Martin periodinate (6.40 g, 15 mmol) was added to trans-2- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N -(2-Methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) ethanol (8.80 g, 12.6 mmol) in CH _{To a 2} Cl ₂ (160 mL) suspension is added at 0 ° C. and the resulting mixture is stirred at room temperature for 40 minutes. The reaction mixture is washed with sat. Quench by adding aqueous NaHCO ₃ and extract twice with CH ₂ Cl ₂ . The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2- Methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetaldehyde is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.80-1.01 (m, 2H), 1.04-1.16 (m, 2H), 1.55-1.83 (m, 8H), 1.85-1.93 (m, 1H ), 1.98-2.04 (m, 1H), 2.24 (dd, 2H), 3.18-3.24 (m, 1H), 3.48-3.56 (m, 1H), 4.21 (s, 3H), 4.54 (d, 1H), 4.57 (d, 1H), 4.63-4.69 (m, 1H), 4.79 (d, 1H), 4.98 (d, 1H), 7.22 (dd, 1H), 7.47 (dd, 1H), 7.56 (s, 1H) , 7.63 (s, 2H), 7.73 (s, 1H), 9.72 (t, 1H).
ESI-MS m / z: 696 [M + 1] ⁺

Example 27 : The following compound was converted to trans- (4-{(R) -1- [3-({N- [substituted-benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl ) -Substituted-quinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) prepared from ethanol according to the method of Example 26.

ＮａＣｌＯ_２（４．６０ｇ、５１ｍｍｏｌ）およびＮａＨ_２ＰＯ_４（４．３０ｇ、３６ｍｍｏｌ）の水（２０ｍＬ）混合物を、トランス−（４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）アセトアルデヒド（７．１０ｇ、１０．２ｍｍｏｌ）の２−メチル−２−ブテン（１５ｍＬ）／ｔ−ＢｕＯＨ（１１５ｍＬ）溶液に室温で滴下し、得られた混合物を室温で１時間攪拌する。反応混合物をＮＨ_４Ｃｌ水溶液を０℃で加えてクエンチし、酢酸エチルで抽出する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してトランス−（４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）酢酸を得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.78-1.00 (m, 2H), 1.03-1.17 (m, 2H), 1.60-1.80 (m, 8H), 1.83-1.93 (m, 1H), 1.96-2.06 (m, 1H), 2.17 (d, 2H), 3.15-3.24 (m, 1H), 3.46-3.54 (m, 1H), 4.20 (s, 3H), 4.54 (d, 1H), 4.57 (d, 1H), 4.60-4.68 (m, 1H), 4.79 (d, 1H), 4.98 (d, 1H), 7.22 (dd, 1H), 7.47 (dd, 1H), 7.56 (s, 1H), 7.63 (s, 2H), 7.72 (s. 1H).
ESI-MS m/z: 712 [M+1]⁺ Example 28 : trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazole-5- Yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetic acid synthesis.

A mixture of NaClO ₂ (4.60 g, 51 mmol) and NaH ₂ PO ₄ (4.30 g, 36 mmol) in water (20 mL) was added to trans- (4-{(R) -1- [3-({N- [3 , 5-Bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl ) A solution of acetaldehyde (7.10 g, 10.2 mmol) in 2-methyl-2-butene (15 mL) / t-BuOH (115 mL) is added dropwise at room temperature, and the resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched by the addition of aqueous NH ₄ Cl at 0 ° C. and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2- Methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetic acid is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.78-1.00 (m, 2H), 1.03-1.17 (m, 2H), 1.60-1.80 (m, 8H), 1.83-1.93 (m, 1H ), 1.96-2.06 (m, 1H), 2.17 (d, 2H), 3.15-3.24 (m, 1H), 3.46-3.54 (m, 1H), 4.20 (s, 3H), 4.54 (d, 1H), 4.57 (d, 1H), 4.60-4.68 (m, 1H), 4.79 (d, 1H), 4.98 (d, 1H), 7.22 (dd, 1H), 7.47 (dd, 1H), 7.56 (s, 1H) , 7.63 (s, 2H), 7.72 (s. 1H).
ESI-MS m / z: 712 [M + 1] ⁺

Example 29 The following compound was converted to trans- (4-{(R) -1- [3-({N- [substituted-benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} Prepared according to the method of Example 28 from methyl) -substituted-quinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetaldehyde.

トランス−（４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）酢酸（８５ｍｇ、０．１２ｍｍｏｌ）のＤＭＦ（３ｍＬ）溶液にＮＨ_４Ｃｌ（１０ｍｇ、０．１８ｍｍｏｌ）、Ｎ−エチル−Ｎ’−（３−ジメチルアミノプロピル）カルボジイミドヒドロクロライド（ＥＤＣ・ＨＣｌ ４１ｍｇ、０．１８ｍｍｏｌ）、１−ヒドロキシ−７−アザベンゾトリアゾール（ＨＯＡｔ、２４ｍｇ、０．１８ｍｍｏｌ）、および少量のトリエチルアミンを加える。２時間室温で攪拌した後、反応混合物をＥｔＯＡｃで希釈し、水および塩水で連続的に洗浄し、硫酸マグネシウムで乾燥させる。溶媒を蒸発させ、酢酸エチル−ヘキサンを用いてシリカゲルカラムで精製して、トランス−（４−｛（Ｒ）−１−［３−（｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）−６，７−ジフルオロキノリン−２−イル］ピロリジン−２−イル｝シクロヘキシル）酢酸アミドを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.79-0.98 (m, 2H), 1.05-1.14 (m, 2H), 1..47-1.81 (m, 8H), 1.87-1.93 (m, 1H), 2.02-2.07 (m, 3H), 3.19-3.27 (m, 1H), 3.50-3.59 (m, 1H), 4.20 (s, 3H), 4.55 (d, 2H), 4.57-4.68 (m, 1H), 4.78 (d, 1H), 4.97 (d, 1H), 5.30 (bs, 2H), 7.20-7.24 (m, 2H), 7.35-7.40 (m, 1H), 7.63 (s, 2H), 7.73 (s, 1H).
ESI-MS m/z: 710 [M+1]⁺ Example 30 : trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazole-5 Synthesis of yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetamide.

Trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino} (Methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetic acid (85 mg, 0.12 mmol) in DMF (3 mL), NH ₄ Cl (10 mg, 0.18 mmol), N— Ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC • HCl 41 mg, 0.18 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 24 mg, 0.18 mmol), and a small amount of triethylamine. Add. After stirring for 2 hours at room temperature, the reaction mixture is diluted with EtOAc, washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated and purified on a silica gel column with ethyl acetate-hexane to give trans- (4-{(R) -1- [3-({N- [3,5-bis (trifluoromethyl) benzyl]. ] -N- (2-methyl-2H-tetrazol-5-yl) amino} methyl) -6,7-difluoroquinolin-2-yl] pyrrolidin-2-yl} cyclohexyl) acetamide is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.79-0.98 (m, 2H), 1.05-1.14 (m, 2H), 1..47-1.81 (m, 8H), 1.87-1.93 ( m, 1H), 2.02-2.07 (m, 3H), 3.19-3.27 (m, 1H), 3.50-3.59 (m, 1H), 4.20 (s, 3H), 4.55 (d, 2H), 4.57-4.68 ( m, 1H), 4.78 (d, 1H), 4.97 (d, 1H), 5.30 (bs, 2H), 7.20-7.24 (m, 2H), 7.35-7.40 (m, 1H), 7.63 (s, 2H) , 7.73 (s, 1H).
ESI-MS m / z: 710 [M + 1] ⁺

カリウムｔｅｒｔ−ブトキシド（１１ｍｇ、０．０９８ｍｍｏｌ）をＮ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミン（４６ｍｇ、０．１４ｍｍｏｌ）のＤＭＦ（１ｍＬ）溶液に５℃で加え、混合物を同じ温度で２０分間攪拌する。混合物にＮ−［３−（ブロモメチル）キノキサリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミン（３８ｍｇ、０．１１ｍｍｏｌ）のＤＭＦ（１ｍＬ）溶液を３分間にわたって滴下し、混合物をさらに３０分間攪拌する。１Ｎ ＨＣｌ水溶液を加えた後、混合物を酢酸エチルで抽出する。合併した有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。得られた混合物をシリカゲルカラムクロマトグラフィーで精製してＮ−［（３−｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ｝メチル）キノキサリン−２−イル］−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.03-1.10 (m, 2H), 1.14 (t, 3H), 1.37-1.68 (m, 6H), 2.11-2.21 (m, 1H), 3.31 (q, 2H), 3.31 (d, 2H), 4.13 (s, 3H), 4.93 (s, 4H), 7.45 (ddd, 1H), 7.57 (ddd, 1H), 7.71 (s, 1H), 7.77 (s, 2H), 7.75-7.80 (m, 2H).
ESI-MS m/z: 593 [M+1]⁺ Example 31 N-[(3- {N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino} methyl) quinoxaline- Synthesis of 2-yl] -N- (cyclopentylmethyl) ethylamine

Potassium tert-butoxide (11 mg, 0.098 mmol) was added to N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine (46 mg, 0.14 mmol). ) In DMF (1 mL) at 5 ° C. and the mixture is stirred at the same temperature for 20 minutes. To the mixture was added dropwise a solution of N- [3- (bromomethyl) quinoxalin-2-yl] -N- (cyclopentylmethyl) ethylamine (38 mg, 0.11 mmol) in DMF (1 mL) over 3 minutes and the mixture was stirred for an additional 30 minutes. To do. After adding 1N aqueous HCl, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting mixture was purified by silica gel column chromatography to obtain N-[(3- {N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazole-5. -Yl) amino} methyl) quinoxalin-2-yl] -N- (cyclopentylmethyl) ethylamine is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.03-1.10 (m, 2H), 1.14 (t, 3H), 1.37-1.68 (m, 6H), 2.11-2.21 (m, 1H), 3.31 (q, 2H), 3.31 (d, 2H), 4.13 (s, 3H), 4.93 (s, 4H), 7.45 (ddd, 1H), 7.57 (ddd, 1H), 7.71 (s, 1H), 7.77 (s, 2H), 7.75-7.80 (m, 2H).
ESI-MS m / z: 593 [M + 1] ⁺

｛５−［Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミノ］−１−メチル−１Ｈ−ピロロ［３，２−ｂ］ピリジン−６−イル｝メタノール（８５ｍｇ、０．３０ｍｍｏｌ）のトルエン（１．５ｍＬ）溶液に、ジイソプロピルエチルアミン（０．０６２ｍＬ、０．３５ｍｍｏｌ）およびメタンスルホニルクロライド（０．０２７ｍＬ、０．３５ｍｍｏｌ）を室温で加える。１時間攪拌した後、Ｈ_２Ｏを加える。混合物をＥｔＯＡｃで抽出し、塩水で洗浄し、硫酸ナトリウムで乾燥させ、真空下で濃縮する。Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−Ｎ−（２−メチル−２Ｈ−テトラゾール−５−イル）アミン（１０６ｍｇ、０．３３ｍｍｏｌ）のＤＭＦ（１．５ｍＬ）溶液に、カリウムｔｅｒｔ−ブトキシド（５４ｍｇ、０．４４ｍｍｏｌ）を０℃で加える。３０分間攪拌した後、残渣のＤＭＦ（１ｍＬ）溶液をゆっくりと加え、反応混合物を１時間攪拌する。反応混合物をＨ_２Ｏでクエンチし、混合物をＥｔＯＡｃで抽出する。有機層を塩水で洗浄し、硫酸ナトリウムで乾燥させ、濃縮し、シリカゲルカラムクロマトグラフィーで精製してＮ−（６−｛Ｎ’−［３，５−ビス（トリフルオロメチル）ベンジル−Ｎ’−（２−メチル−２Ｈ−テトラゾール−５−イル）アミノ］メチル｝−１−メチル−１Ｈ−ピロロ［３，２−ｂ］ピリジン−５−イル）−Ｎ−（シクロペンチルメチル）エチルアミンを無色油状物として得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.96-1.12 (m, 5H), 1.34-1.58 (m, 6H), 1.94-2.13 (m, 1H), 2.95-3.15 (m, 2H), 3.65-3.80 (m, 4H), 4.13-4.23 (m, 4H), 4.71 (s, 2H), 4.85-5.00 (m, 2H), 6.60 (s, 1H), 7.20 (s, 1H), 7.41 (s, 1H), 7.68 (s, 2H), 7.75 (s, 1H).
ESI-MS m/z: 595 [M+1]⁺ Example 32: N- (6- {N '-[3,5-bis (trifluoromethyl) benzyl-N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -1-methyl Synthesis of -1H-pyrrolo [3,2-b] pyridin-5-yl) -N- (cyclopentylmethyl) ethylamine

{5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3,2-b] pyridin-6-yl} methanol (85 mg, 0.30 mmol) in toluene (1. To the 5 mL) solution, diisopropylethylamine (0.062 mL, 0.35 mmol) and methanesulfonyl chloride (0.027 mL, 0.35 mmol) are added at room temperature. After stirring for 1 hour, H ₂ O is added. The mixture is extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated under vacuum. To a solution of N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine (106 mg, 0.33 mmol) in DMF (1.5 mL) was added potassium. Add tert-butoxide (54 mg, 0.44 mmol) at 0 ° C. After stirring for 30 minutes, a solution of the residue in DMF (1 mL) is added slowly and the reaction mixture is stirred for 1 hour. The reaction mixture is quenched with H ₂ O and the mixture is extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated, purified by silica gel column chromatography and purified by N- (6- {N ′-[3,5-bis (trifluoromethyl) benzyl-N′- (2-Methyl-2H-tetrazol-5-yl) amino] methyl} -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -N- (cyclopentylmethyl) ethylamine as a colorless oil Get as.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.96-1.12 (m, 5H), 1.34-1.58 (m, 6H), 1.94-2.13 (m, 1H), 2.95-3.15 (m, 2H ), 3.65-3.80 (m, 4H), 4.13-4.23 (m, 4H), 4.71 (s, 2H), 4.85-5.00 (m, 2H), 6.60 (s, 1H), 7.20 (s, 1H), 7.41 (s, 1H), 7.68 (s, 2H), 7.75 (s, 1H).
ESI-MS m / z: 595 [M + 1] ⁺

¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.99 (t, 3H), 1.03-1.12 (m, 2H), 1.34-1.56 (m, 6H), 1.94-2.08 (m, 1H), 2.32 (s, 3H), 3.00-3.09 (m, 4H), 3.59 (s, 3H), 4.20 (s, 3H), 4.66 (s, 2H), 4.94 (s, 2H), 6.93 (d, 1H), 7.33 (s, 1H), 7.67 (s, 2H), 7.72 (s, 1H).
ESI-MS m/z: 609 [M+1]⁺ Example 33: N- (6- {N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino} methyl-1,3 -Dimethyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -N- (cyclopentylmethyl) ethylamine is converted to {5- [N- (cyclopentylmethyl) ethylamino] -1,3-dimethyl-1H -From pyrrolo [3,2-b] pyridin-6-yl} methanol and N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine Prepared according to the method of Example 32.

¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.99 (t, 3H), 1.03-1.12 (m, 2H), 1.34-1.56 (m, 6H), 1.94-2.08 (m, 1H), 2.32 (s, 3H), 3.00-3.09 (m, 4H), 3.59 (s, 3H), 4.20 (s, 3H), 4.66 (s, 2H), 4.94 (s, 2H), 6.93 (d, 1H) , 7.33 (s, 1H), 7.67 (s, 2H), 7.72 (s, 1H).
ESI-MS m / z: 609 [M + 1] ⁺

Example 34: Compound inhibitory activity

工程１：
２−クロロキノリン−３−カルボアルデヒド（５０ｍｇ、０．２６ｍｍｏｌ）、Ｎ−（シクロペンチル−メチル）−Ｎ−エチルアミン（５０ｍｇ、０．３９ｍｍｏｌ）および炭酸カリウム（５４ｍｇ、０．３９ｍｍｏｌ）のトルエン懸濁液を、マイクロウェーブリアクター内で３０分間照射する。反応混合物をシリカゲルカラムクロマトグラフィーで精製して２−［Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミノ］キノリン−３−カルボアルデヒドを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.11-1.23 (m, 2H), 1.21 (t, 3H), 1.45-1.60 (m, 4H), 1.65-1.74 (m, 2H), 2.34 (m, 1H), 3.48 (d, 2H), 3.53 (q, 2H), 7.32 (ddd, 1H), 7.66 (ddd, 1H), 7.76 (dd, 1H), 7.79 (dd, 1H), 8.45 (s, 1H), 10.15 (s, 1H). The starting material can be prepared as follows:
Example A : Preparation of {2- [N- (cyclopentylmethyl) -N-ethylamino] quinolin-3-yl} methanol

Process 1 :
Toluene suspension of 2-chloroquinoline-3-carbaldehyde (50 mg, 0.26 mmol), N- (cyclopentyl-methyl) -N-ethylamine (50 mg, 0.39 mmol) and potassium carbonate (54 mg, 0.39 mmol) Are irradiated for 30 minutes in a microwave reactor. The reaction mixture is purified by silica gel column chromatography to give 2- [N- (cyclopentylmethyl) -N-ethylamino] quinoline-3-carbaldehyde.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.11-1.23 (m, 2H), 1.21 (t, 3H), 1.45-1.60 (m, 4H), 1.65-1.74 (m, 2H), 2.34 (m, 1H), 3.48 (d, 2H), 3.53 (q, 2H), 7.32 (ddd, 1H), 7.66 (ddd, 1H), 7.76 (dd, 1H), 7.79 (dd, 1H), 8.45 (s, 1H), 10.15 (s, 1H).

Process 2 :
To a solution of 2- [N- (cyclopentylmethyl) -N-ethylamino] quinoline-3-carbaldehyde (25 mg, 0.088 mmol) in ethanol (1 mL) was added sodium borohydride (5 mg, 0.13 mmol) and the mixture Is stirred for 1 hour. sat. After adding ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give {2- [N- (cyclopentylmethyl) -N-ethylamino] quinolin-3-yl} methanol, which Is used without further purification.

工程１：
ＤＭＦ（２３ｍＬ）およびホスホリルクロライド（７８．４ｍＬ）から０−１０℃で製造したＶｉｌｓｍｅｉｅｒ試薬を、３−フルオロアセトアニリド（１８．５ｇ、０．１２ｍｏｌ）にゆっくりと滴下し、得られた混合物を１００℃で１４時間攪拌する。混合物を氷水に注ぎ、ＣＨ_２Ｃｌ_２で２回抽出する。合併した有機層を乾燥させ、濾過し、濃縮する。結晶を回収し、ＣＨ_２Ｃｌ_２で洗浄して２−クロロ−７−フルオロキノリン−３−カルボアルデヒドを褐色粉末として得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 7.45 (ddd, 1H), 7.72 (dd, 1H), 8.01 (dd, 1H), 8.76 (s, 1H), 10.55 (s, 1H). Example B : Preparation of {2- [N- (cyclohexylmethyl) -N-ethylamino] -7-fluoroquinolin-3-yl} methanol

Process 1 :
Vilsmeier reagent prepared at 0-10 ° C. from DMF (23 mL) and phosphoryl chloride (78.4 mL) was slowly added dropwise to 3-fluoroacetanilide (18.5 g, 0.12 mol) and the resulting mixture was added to 100 ° C. For 14 hours. The mixture is poured into ice water and extracted twice with CH ₂ Cl ₂ . The combined organic layers are dried, filtered and concentrated. The crystals were collected to obtain and washed with _CH 2 Cl ₂ to 2-chloro-7-fluoro-3-carbaldehyde as a brown powder.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 7.45 (ddd, 1H), 7.72 (dd, 1H), 8.01 (dd, 1H), 8.76 (s, 1H), 10.55 (s, 1H) .

Process 2 :
Toluene of 2-chloro-7-fluoroquinoline-3-carbaldehyde (200 mg, 0.95 mmol), N- (cyclohexylmethyl) -N-ethylamine (140 mg, 0.99 mmol) and potassium carbonate (140 mg, 1.0 mmol) (3 mL) The suspension is stirred and refluxed for 14 hours. The reaction mixture is allowed to cool to room temperature and diluted with water and ethyl acetate. The organic layer is washed with 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give 2- [N- (cyclohexylmethyl) -N-ethylamino] -7-fluoroquinoline-3-carbaldehyde.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.83-0.93 (m, 2H), 1.08-1.20 (m, 4H), 1.22 (t, 3H), 1.62-1.81 (m, 5H), 3.40 (d, 2H), 3.52 (q, 2H), 7.08 (ddd, 1H), 7.38 (dd, 1H), 7.73 (dd, 1H), 8.40 (s, 1H), 10.09 (s, 1H).

Step 3 :
2- [N- (Cyclohexylmethyl) -N-ethylamino] -7-fluoroquinoline-3-carbaldehyde (230 mg, 0.73 mmol) in ethanol (2 mL) in sodium borohydride (30 mg, 0.79 mmol) And the mixture is stirred for 2 hours. sat. After adding ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated to give [N- (cyclopentylmethyl) -N-ethylamino] quinolin-3-yl} methanol, which is further purified. Use without.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.85-0.95 (m, 2H), 1.10-1.20 (m, 3H), 1.15 (t, 3H), 1.56-1.71 (m, 4H), 1.73-1.79 (m, 4H), 3.21 (d, 2H), 3.28 (q, 2H), 3.48 (brs, 1H), 4.82 (s, 2H), 7.14 (ddd, 1H), 7.48 (dd, 1H) , 7.67 (dd, 1H), 7.98 (s, 1H).

工程１：
ホスホリルクロライド（１４７．１ｍＬ）をＤＭＦ（３２．５ｍＬ）に０−１５℃で注意深く加えて、ｖｉｌｓｍｅｉｅｒ試薬のホスホリルクロライド溶液を製造し、混合物を３０℃に温めて透明淡黄色混合物を得る。３，４−ジフルオロアセトアニリド（３０ｇ、０．１２ｍｏｌ）を混合物に加え、得られた混合物を８０℃で３０分間、９０℃で３０分間、１００℃で１８時間そして最後に１２０℃で２時間攪拌する。混合物を室温に冷却させ、氷水（１５００ｍＬ）に注ぎ、ＣＨ_２Ｃｌ_２で７回（合計３０００ｍＬ）抽出する。合併した有機層を硫酸マグネシウムで乾燥させ、濾過し、濃縮する。褐色結晶を回収し、ＣＨ_２Ｃｌ_２で洗浄して２−クロロ−６，７−ジフルオロキノリン−３−カルボアルデヒドを淡黄色粉末として得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 7.73 (dd, 1H), 7.84 (dd, 1H), 8.69 (s, 1H), 10.55 (s, 1H). Example C : Preparation of {2- [N- (cyclopentylmethyl) -N-ethylamino] -6,7-difluoroquinolin-3-yl} methanol

Process 1 :
Phosphoryl chloride (147.1 mL) is carefully added to DMF (32.5 mL) at 0-15 ° C. to produce a solution of the vilsmeier reagent in phosphoryl chloride and the mixture is warmed to 30 ° C. to give a clear pale yellow mixture. 3,4-Difluoroacetanilide (30 g, 0.12 mol) is added to the mixture and the resulting mixture is stirred at 80 ° C. for 30 minutes, 90 ° C. for 30 minutes, 100 ° C. for 18 hours and finally at 120 ° C. for 2 hours. . Allow the mixture to cool to room temperature, pour into ice water (1500 mL) and extract 7 times with CH ₂ Cl ₂ (total 3000 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated. The brown crystals were collected, to obtain a washed to give 2-chloro-6,7-difluoro-3-carbaldehyde as a pale yellow powder with _CH 2 Cl _2.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 7.73 (dd, 1H), 7.84 (dd, 1H), 8.69 (s, 1H), 10.55 (s, 1H).

Step 2:
2-Chloro-6,7-difluoroquinoline-3-carbaldehyde (0.13 g, 0.56 mmol), N- (cyclopentylmethyl) -N-ethylamine (0.15 g, 1.2 mmol) and potassium carbonate (0. A suspension of 15 g, 1.1 mmol) in toluene (2.0 mL) is stirred and refluxed for 15 hours. The reaction mixture is purified by silica gel column chromatography to give 2- [N- (cyclopentylmethyl) -N-ethylamino] -6,7-difluoroquinoline-3-carbaldehyde.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.11-1.23 (m, 2H), 1.23 (t, 3H), 1.47-1.63 (m, 4H), 1.67-1.76 (m, 2H), 2.33 (sep, 1H), 3.47 (d, 2H), 3.54 (q, 2H), 7.49 (dd, 1H), 7.63 (dd, 1H), 8.36 (s, 1H), 10.12 (s, 1H).

Step 3 :
2- [N- (cyclopentylmethyl) -N-ethylamino] -6,7-difluoroquinoline-3-carbaldehyde (0.10 g, 0.31 mmol) in a mixture of ethanol (2.0 mL) with sodium borohydride ( 14 mg, 0.37 mmol) is added and the mixture is stirred for 2 hours. sat. After adding ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated to {2- [N- (cyclopentylmethyl) -N-ethylamino] -6,7-difluoroquinolin-3-yl}. Methanol is obtained and used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.11-1.20 (m, 2H), 1.17 (t, 3H), 1.48-1.63 (m, 4H), 1.67-1.76 (m, 2H), 2.13 (sep, 1H), 3.23-3.28 (m, 4H), 3.85 (brs, 1H), 4.83 (brs, 2H), 7.43 (dd, 1H), 7.62 (dd, 1H), 7.91 (s, 1H) .

２−クロロキノリン−３−カルボアルデヒド（９３ｍｇ、０．４９ｍｍｏｌ）、エチルトランス−｛４−［（Ｎ−エチルアミノ）メチル］シクロヘキシル｝アセテート（１６５ｍｇ、０．７３ｍｍｏｌ）および炭酸カリウム（１３４ｍｇ、０．９７ｍｍｏｌ）のトルエン（２ｍＬ）懸濁液を攪拌し、３日間乾留させる。反応混合物を室温に冷却させ、水および酢酸エチルで希釈する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗残渣をエタノール（１．５ｍＬ）で溶解させ、水素化ホウ素ナトリウム（１８ｍｇ、０．４８ｍｍｏｌ）で処理する。混合物を室温で２時間攪拌する。ｓａｔ． 塩化アンモニウムおよび水を加えた後、混合物を酢酸エチルで抽出する。合併した有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製してエチルトランス−［４−（｛Ｎ−エチル−Ｎ−［３−（ヒドロキシメチル）キノリン−２−イル］アミノ｝メチル）シクロヘキシル］アセテートを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 0.86-1.02 (m, 4H), 1.14 (t, 3H), 1.22 (t, 3H), 1.48-1.53 (m, 1H), 1.65-1.87 (m, 5H), 2.13 (d, 2H), 3.21 (d, 2H), 3.25 (q, 2H), 3.87 (brs, 1H), 4.85 (s, 2H), 7.39 (ddd, 1H), 7.60 (ddd, 1H), 7.71 (dd, 1H), 7.87 (d, 1H), 7.99 (s, 1H). Example D : Preparation of ethyltrans- [4-({N-ethyl-N- [3- (hydroxymethyl) quinolin-2-yl] amino} methyl) cyclohexyl] acetate.

2-chloroquinoline-3-carbaldehyde (93 mg, 0.49 mmol), ethyltrans- {4-[(N-ethylamino) methyl] cyclohexyl} acetate (165 mg, 0.73 mmol) and potassium carbonate (134 mg, 0. 97 mmol) in toluene (2 mL) is stirred and allowed to dry for 3 days. The reaction mixture is allowed to cool to room temperature and diluted with water and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue is dissolved with ethanol (1.5 mL) and treated with sodium borohydride (18 mg, 0.48 mmol). The mixture is stirred at room temperature for 2 hours. sat. After adding ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give ethyl trans- [4-({N-ethyl-N- [3- (hydroxymethyl) quinolin-2-yl] amino} methyl) cyclohexyl] acetate.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.86-1.02 (m, 4H), 1.14 (t, 3H), 1.22 (t, 3H), 1.48-1.53 (m, 1H), 1.65- 1.87 (m, 5H), 2.13 (d, 2H), 3.21 (d, 2H), 3.25 (q, 2H), 3.87 (brs, 1H), 4.85 (s, 2H), 7.39 (ddd, 1H), 7.60 (ddd, 1H), 7.71 (dd, 1H), 7.87 (d, 1H), 7.99 (s, 1H).

Example E : Preparation of (R) -2-cyclohexylpyrrolidine (R) -2-cyclohexylpyrrolidine is prepared using the same method as (S) -2-cyclopentylpyrrolidine as follows ((S)-(+ ) -Phenylglycinol is used instead of (R)-(−)-phenylglycinol, see J. Org. Chem., 1992, 57, 1656-1662).

工程１：
ＰＳ−ＤＩＥＡ（Argonaut Technologies、１．３５ｇ、４．５ｍｍｏｌ）をＣ−（テトラヒドロピラン−４−イル）メチルアミン（３４５ｍｇ、３．０ｍｍｏｌ）のＣＨ_２Ｃｌ_２（２０ｍＬ）混合物に周囲温度で加える。無水酢酸（３６７ｍｇ、３．６ｍｍｏｌ）を混合物に加える。周囲温度で１８時間攪拌した後、ポリスチレンメチルイソシアネート（Novabiochem、１．８４ｇ、３．０ｍｍｏｌ）およびＮ−（２−アミノエチル）アミノメチルポリスチレン（Novabiochem、１．０７ｇ、３．０ｍｍｏｌ）を加える。室温で４時間攪拌した後、樹脂を濾過によって取り除き、樹脂をジクロロメタンで洗浄する。濾液および洗浄液を合併し、溶媒を真空下で蒸発させて除去して、Ｎ−（テトラヒドロピラン−４−イルメチル）アセトアミドを得る。
ESI-MS m/z: 158 [M+1]⁺
UPLC 保持時間: 0.94分. Example F : Preparation of ethyl [(tetrahydropyran-4-yl) methyl)] amine.

Process 1 :
PS-DIEA (Argonaut Technologies, 1.35g , 4.5mmol) is added at ambient temperature to _CH 2 _Cl 2 (20mL) mixture of C- (tetrahydropyran-4-yl) methylamine (345 mg, 3.0 mmol). Acetic anhydride (367 mg, 3.6 mmol) is added to the mixture. After stirring for 18 hours at ambient temperature, polystyrene methyl isocyanate (Novabiochem, 1.84 g, 3.0 mmol) and N- (2-aminoethyl) aminomethyl polystyrene (Novabiochem, 1.07 g, 3.0 mmol) are added. After stirring at room temperature for 4 hours, the resin is removed by filtration and the resin is washed with dichloromethane. The filtrate and washings are combined and the solvent is removed by evaporation under vacuum to give N- (tetrahydropyran-4-ylmethyl) acetamide.
ESI-MS m / z: 158 [M + 1] ⁺
UPLC retention time: 0.94 minutes.

Process 2 :
A solution of 1M borane-THF complex in THF (10.2 mL, 10.2 mmol) is added to a solution of N- (tetrahydropyran-4-ylmethyl) acetamide (235 mg, 1.50 mmol) in THF (15 mL) at ambient temperature with nitrogen gas. Add under atmosphere. After stirring for 2 days, methanol (5 mL) is added to the reaction mixture at ambient temperature. After stirring for 1 hour, 1N HCl (50 mL) is added to the mixture and a portion of the THF is removed by evaporation under vacuum. The mixture is washed with ether and 5N NaOH is added to the mixture. The product is extracted with CH ₂ Cl ₂ and the organic phase is washed with brine, dried over magnesium sulfate and concentrated to give N-ethyl-N-[(tetrahydropyran-4-yl) methyl)] amine.
ESI-MS m / z: 144 [M + 1] ⁺
HPLC retention time: 0.58 minutes.

工程１：
ヨウ化メチル（４５ｍＬ、１．２当量、０．７２ｍｏｌ）を５−アミノテトラゾール（５１．１ｇ、０．６０ｍｏｌ）およびＣｓ_２ＣＯ_３（２３５．０ｇ、１．２当量、０．７２ｍｏｌ）のアセトニトリル（５００ｍＬ）混合物に加え、得られた混合物を５０℃で１８時間攪拌する。混合物を（５０℃で）濾過し、残渣を熱アセトニトリル（５０℃）で洗浄する。濾液を濃縮して所望の５−アミノ−２−メチルテトラゾールおよび５−アミノ−１−メチルテトラゾールの混合物を得る。 Example G : Preparation of N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine <Method 1>

Step 1:
Methyl iodide (45 mL, 1.2 eq, 0.72 mol) of 5-aminotetrazole (51.1 g, 0.60 mol) and _Cs 2 _CO 3 _(235.0g, 1.2 equiv, 0.72 mol) in acetonitrile (500 mL) is added to the mixture and the resulting mixture is stirred at 50 ° C. for 18 hours. The mixture is filtered (at 50 ° C.) and the residue is washed with hot acetonitrile (50 ° C.). The filtrate is concentrated to give the desired mixture of 5-amino-2-methyltetrazole and 5-amino-1-methyltetrazole.

Step 2:
The crude mixture of 5-amino-2-methyltetrazole and 5-amino-1-methyltetrazole was treated with 3,5-bis (trifluoromethyl) benzaldehyde (48 mL, 71 g, 0.29 mol) in toluene (780 mL). The mixture is stirred and refluxed for 5 hours. The resulting mixture is filtered to remove insoluble solid (5-amino-1-methyltetrazole) and the residue is washed with hot toluene. The filtrate is concentrated to give crude 2-methyl-N- [3,5-bis (trifluoromethyl) phenylmethylene] -2H-tetrazol-5-amine (70.1 g).

Step 3 :
NaBH ₄ (8.2 g, 0.22 mol) was added to a solution of crude 2-methyl-N- [3,5-bis (trifluoromethyl) phenylmethylene] -2H-tetrazol-5-amine in EtOH (700 mL). Slowly add in small portions at 0 C and stir the mixture at room temperature for 1 hour. sat. After adding aqueous NH ₄ Cl and water at 0 ° C., the mixture is concentrated to remove 300 mL of EtOH and extracted with CH ₂ Cl ₂ (300 mL × 4 times). The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel column chromatography to give N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine as a white crystalline solid.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.61 (s, 3H), 4.66 (d, 2H), 5.03 (t, 1H), 7.79 (s, 1H), 7.83 (s, 1H) .

工程１：
５−アミノ−２−メチルテトラゾール（５．００ｇ、５０ｍｍｏｌ）および３，５−ビス（トリフルオロメチル）ベンズアルデヒド（１９．５ｇ、８１ｍｍｏｌ）のトルエン（１００ｍＬ）混合物を攪拌し、３時間還流させる。得られた混合物を濃縮して、粗２−メチル−Ｎ−［３，５−ビス（トリフルオロメチル）フェニルメチレン］−２Ｈ−テトラゾール−５−アミンを得る。 <Method 2>

Process 1 :
A toluene (100 mL) mixture of 5-amino-2-methyltetrazole (5.00 g, 50 mmol) and 3,5-bis (trifluoromethyl) benzaldehyde (19.5 g, 81 mmol) is stirred and refluxed for 3 hours. The resulting mixture is concentrated to give crude 2-methyl-N- [3,5-bis (trifluoromethyl) phenylmethylene] -2H-tetrazol-5-amine.

Process 2 :
NaBH ₄ (1.2 g, 64 mmol) was added to a solution of crude 2-methyl-N- [3,5-bis (trifluoromethyl) phenylmethylene] -2H-tetrazol-5-amine in EtOH (100 mL) at 0 ° C. Slowly add in small portions and stir the mixture at room temperature for 1 hour. sat. After aqueous NH ₄ Cl and water are added at 0 ° C., the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel column chromatography to give N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine as a white crystalline solid.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.61 (s, 3H), 4.66 (d, 2H), 5.03 (t, 1H), 7.79 (s, 1H), 7.83 (s, 1H) .

工程１：
５−アミノテトラゾール（１０．０ｇ、０．１２ｍｏｌ）、ブロモアセテートエチル（２０．０ｇ、０．１２ｍｏｌ）、およびＣｓ_２ＣＯ_３（４０．０ｇ、０．１３ｍｏｌ）のアセトニトリル（２２０ｍＬ）混合物を攪拌し、５時間還流させる。混合物を５０℃に冷却させ、濾過する。得られた濾液を濃縮して粗カップリング生成物を得る。粗生成物および３，５−ビス（トリフルオロメチル）ベンズアルデヒド（２５．０ｇ、０．１０ｍｏｌ）のトルエン（２２０ｍＬ）混合物を攪拌し、５時間還流させる。室温に冷却させた後、得られた混合物を濃縮する。ＮａＢＨ_４（４．４ｇ、０．１２ｍｏｌ）を得られた残渣のＥｔＯＨ（２２０ｍＬ）溶液に少量ずつゆっくりと加え、混合物を室温で２日間攪拌する。ｓａｔ． ＮＨ_４Ｃｌ水溶液および水を加えた後、混合物を酢酸エチルで抽出する。合併した有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物をシリカゲルカラムクロマトグラフィーで精製して２−（５−｛Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］アミノ｝テトラゾール−２−イル）エタノールを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 2.43-2.55 (m, 1H), 4.08-4.12 (m, 2H), 4.55-4.58 (m, 2H), 4.67 (d, 2H), 5.07-5.12 (m, 1H), 7.80 (s, 1H), 7.84 (s, 2H). Example H : Preparation of N- [3,5-bis (trifluoromethyl) benzyl] -N- {2- [2- (tetrahydropyran-2-yloxy) ethyl] -2H-tetrazol-5-yl} amine

Process 1 :
Stir a mixture of 5-aminotetrazole (10.0 g, 0.12 mol), ethyl bromoacetate (20.0 g, 0.12 mol), and Cs ₂ CO ₃ (40.0 g, 0.13 mol) in acetonitrile (220 mL). Reflux for 5 hours. Allow the mixture to cool to 50 ° C. and filter. The resulting filtrate is concentrated to give the crude coupling product. A mixture of the crude product and 3,5-bis (trifluoromethyl) benzaldehyde (25.0 g, 0.10 mol) in toluene (220 mL) is stirred and refluxed for 5 hours. After cooling to room temperature, the resulting mixture is concentrated. NaBH ₄ (4.4 g, 0.12 mol) is slowly added portionwise to a solution of the resulting residue in EtOH (220 mL) and the mixture is stirred at room temperature for 2 days. sat. After adding aqueous NH ₄ Cl and water, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give 2- (5- {N- [3,5-bis (trifluoromethyl) benzyl] amino} tetrazol-2-yl) ethanol.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 2.43-2.55 (m, 1H), 4.08-4.12 (m, 2H), 4.55-4.58 (m, 2H), 4.67 (d, 2H), 5.07-5.12 (m, 1H), 7.80 (s, 1H), 7.84 (s, 2H).

Step 2:
2- (5- {N- [3,5-bis (trifluoromethyl) benzyl] amino} tetrazol-2-yl) ethanol (0.68 g, 1.9 mmol), 3,4-dihydro-2H-pyran ( A mixture of DHP, 0.35 g, 4.2 mmol) and a catalytic amount of pyridinium p-toluenesulfonate (PPTS, 0.050 g, 0.20 mmol) in CH ₂ Cl ₂ (10 mL) is stirred at room temperature for 10 hours. The resulting mixture was washed with sat. Quench by adding aqueous NaHCO ₃ and extract with EtOAc. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give N- [3,5-bis (trifluoromethyl) benzyl] -N- {2- [2- (tetrahydropyran-2-yloxy) ethyl] -2H-tetrazole. -5-yl} amine is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.42-1.76 (m, 6H), 3.43-3.48 (m, 1H), 3.68 (ddd, 1H), 3.89-3.95 (m, 1H), 4.12-4.18 (m, 1H), 4.57-4.58 (m, 1H), 4.61 (t, 2H), 4.67 (d, 2H), 4.89-4.97 (m, 1H), 7.79 (s, 1H), 7.84 ( s, 2H).

Example I : Preparation of trans- (R) -2-[(4-benzyloxymethyl) cyclohexyl] pyrrolidine

Process 1 :
Stir a mixture of 4-ethoxycarbonylcyclohexanone (175 g, 1.03 mol), ethylene glycol (70 mL) and p-toluenesulfonic acid (2.1 g) in toluene (700 mL) and continue to water using a Dean-Stark apparatus. Reflux for 6 hours. After cooling to room temperature, sat. Aqueous NaHCO ₃ (1500 mL) and EtOAc (800 mL) are added to the reaction mixture. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude 1,4-dioxa-spiro [4.5] decane-8-carboxylic acid ethyl ester (220 g) as a yellow oil. This is used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.24 (t, 3H), 1.50-1.60 (m, 2H), 1.75-1.86 (m, 4H), 1.90-1.98 (m, 2H), 2.29-2.35 (m, 1H), 3.94 (s, 4H), 4.12 (q, 2H).

Process 2 :
To a mixture of lithium aluminum hydride (50.5 g, 1.06 mol) in THF (800 mL), crude 1,4-dioxa-spiro [4.5] decane-8-carboxylic acid ethyl ester (220 g) in THF (700 mL). Is carefully added at 0 ° C. over 2.5 hours under an argon atmosphere. After stirring for 1 hour at ambient temperature, Na ₂ SO ₄ -10H ₂ O (175 g) is added at 0 ° C. and the mixture is stirred for another 10 minutes. Insoluble material is filtered and the filtrate is concentrated in vacuo to give crude (1,4-dioxa-spiro [4.5] dec-8-yl) methanol as a colorless oil that is further purified. Use without.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.22-1.33 (m, 2H), 1.45-1.60 (m, 3H), 1.75-1.83 (m, 4H), 3.49 (d, 2H), 3.91-3.98 (m, 4H).

Step 3 :
To a mixture of NaH (60% in oil, 60.9 g, 1.52 mol) in DMF (1500 mL) was added crude (1,4-dioxa-spiro [4.5] dec-8-yl) methanol (50 mL). 150 g) is carefully added at 10 ° C. under an argon atmosphere and the mixture is stirred for a further hour at the same temperature. To the mixture is added benzyl bromide (181 mL) at 10 ° C. and stirring is continued for 3 hours at room temperature. After H ₂ O (70 mL) is added over 10 minutes, the mixture is poured into a mixture of H ₂ O (4500 mL) and EtOAc (2000 mL). The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude 8-benzyloxymethyl-1,4-dioxa-spiro [4.5] decane. Is obtained as a yellow oil. The crude product is used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.22-1.33 (m, 2H), 1.50-1.59 (m, 2H), 1.62-1.74 (m, 1H), 1.73-1.86 (m, 4H ), 3.31 (d, 2H), 3.90-3.97 (m, 4H), 4.50 (s, 2H), 7.26-7.35 (m, 5H).

Step 4 :
To a mixture of crude 8-benzyloxymethyl-1,4-dioxa-spiro [4.5] decane (297 g) in THF (600 mL) is added 3N HCl (900 mL) at room temperature and the mixture is stirred overnight. sat. After adding aqueous NaHCO ₃ solution, the mixture is extracted with EtOAc. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude mixture is purified by silica gel column chromatography to give 4-benzyloxymethylcyclohexanone.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.41-1.53 (m, 2H), 2.03-2.18 (m, 3H), 2.28-2.43 (m, 4H), 3.39 (d, 2H), 4.53 (s, 2H), 7.26-7.38 (m, 5H).

Process 5 :
4-Benzyloxymethylcyclohexanone (168 g, 0.77 mol) is dissolved in ethanol (2000 mL) and triethylorthoformate (350 mL) and p-toluenesulfonic acid (13.3 g) are added. The resulting mixture is stirred and refluxed for 6 hours. After adding triethylamine (10.5 mL) at room temperature, the mixture is concentrated (500 mL). sat. After adding aqueous NaHCO ₃ solution, the resulting mixture is extracted with EtOAc. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by short pad silica gel column chromatography to give (4,4-diethoxycyclohexylmethoxymethyl) benzene.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.12-1.19 (m, 2H), 1.16 (t, 3H), 1.17 (t, 3H), 1.31-1.42 (m, 2H), 1.62- 1.75 (m, 3H), 1.97-2.04 (m, 2H), 3.31 (d, 2H), 3.41 (q, 2H), 4.50 (q, 2H), 4.50 (s, 2H), 7.25-7.37 (m, 5H).

Step 6:
A mixture of tin tetrachloride (199 g, 0.77 mol) in CH ₂ Cl ₂ (1800 mL) was added to (4,4-diethoxycyclohexylmethoxymethyl) benzene (225 g) and 1,2-bis (CH ₂ Cl ₂ (900 mL). Trimethylsiloxy) cyclobutene (176 g, 0.77 mol) is added over 40 minutes at -56 to -47 ° C. The mixture is stirred for 15 minutes at −50 ° C. The cooled reaction mixture is poured into water (5000 mL) and the aqueous layer is extracted with CH ₂ Cl ₂ . The combined organic layer is sat. Wash with aqueous NaHCO ₃ and brine, dry over magnesium sulfate, and concentrate under reduced pressure. The crude product is purified by short pad silica gel column chromatography to give ethyl 4- [4- (benzyloxymethyl) cyclohexyl] -4-oxobutyrate (cis / trans = 1/1) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ , cis: trans 1: 1 mixture), δ (ppm): 0.97-1.08 (m, 1H), 1.24 (t, 3H), 1.33-1.44 (m, 2H), 1.55 -1.67 (m, 3H), 1.77-1.98 (m, 3H), 2.34 (tt, 0.5H), 2.51-2.58 (m, 0.5H), 2.57 (t, 2H), 2.74 (t, 1H), 2.75 (t, 1H), 3.29 (d, 1H), 3.32 (d, 1H), 4.12 (q, 2H), 4.48 (s, 1H), 4.49 (s, 1H), 7.25-7.37 (m, 5H).

Step 7 :
Potassium hydroxide (17.0 g, 0.30 mol) was added to ethyl 4- [4- (benzyloxymethyl) cyclohexyl] -4-oxobutyrate (cis / trans = 1/1, 33.0 g, 0.10 mol). Add to EtOH (300 mL) solution and stir the mixture at 85 ° C. for 2 h. After cooling to 0 ° C., 5N HCl is added to the mixture (to reach pH 2-3) and the mixture is concentrated to remove ethanol. The crude mixture is extracted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude 4- [4- (benzyloxymethyl) cyclohexyl] -4-oxobutyric acid. (Cis / trans = about 1/6). A mixture of ether-hexane (˜1: 4, 120 mL) is added to the resulting solid and sonicated. The crystals are collected by filtration, washed with a small amount of ether-hexane (1: 4) and dried to give trans-4- [4- (benzyloxymethyl) cyclohexyl] -4-oxobutyric acid as a pale yellow solid.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.97-1.09 (m, 2H), 1.31-1.43 (m, 2H), 1.56-1.68 (m, 1H), 1.89-1.98 (m, 4H ), 2.34 (tt, 1H), 2.62 (t, 2H), 2.76 (t, 2H), 3.29 (d, 2H), 4.49 (s, 2H), 7.26-7.38 (m.5H).

Process 8 :
To a stirred solution of (S)-(+)-phenylglycinol (6.85 g, 50 mmol) in toluene (150 mL) was added trans-4- [4- (benzyloxymethyl) cyclohexyl] -4-oxobutyric acid (15.2 g). 50 mmol), and the resulting mixture is heated and dry distilled for 4 hours with continuous removal of water using a Dean-stark apparatus. The obtained mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain trans- (3S, 7aS) -7a- [4- (benzyloxymethyl) cyclohexyl] -3-phenyltetrahydropyrrolo [2, 1-b] Oxazol-5-one is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.73-0.89 (m, 2H), 1.08-1.21 (m, 2H), 1.51 (tt, 1H), 1.53-1.63 (m, 1H), 1.83-2.97 (m, 4H), 1.98 (tt, 1H), 2.43 (ddd, 1H), 2.58 (ddd, 1H), 2.75 (dt, 1H), 3.23 (d, 2H), 4.07 (dd, 1H) , 4.46 (s, 2H), 4.64 (t, 1H), 5.19 (t, 1H), 7.19-7.22 (m, 2H), 7.24-7.38 (m. 8H).

Step 9 :
To a cooled (0 ° C.) cooled (0 ° C.) mixture of anhydrous AlCl ₃ (4.70 g, 35 mmol) slowly added lithium aluminum hydride (4.34 g, 115 mmol) and the resulting mixture was stirred at the same temperature for 30 minutes. To do. To the resulting stirred and cooled (−78 ° C.) THF mixture, trans- (3S, 7aS) -7a- [4- (benzyloxymethyl) cyclohexyl] -3-phenyltetrahydropyrrolo [2,1-b] oxazole-5 Add a solution of ON (15.5 g, 38 mmol) in THF (80 mL) over 30 min. The resulting mixture is stirred at the same temperature for 1.5 hours, warmed to room temperature and stirred for an additional 15 minutes. The resulting mixture is allowed to cool to 0 ° C. and quenched by careful addition of Na ₂ SO ₄ -10H ₂ O (5.0 g) and stirred for an additional 30 minutes at room temperature. Insoluble material was filtered and the filtrate was concentrated in vacuo to give crude trans- (S) -2-{(R) -2- [4-benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -2-phenyl. Ethanol is obtained and used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.95 -1.16 (m, 4H), 1.40 -1.66 (m, 6H), 1.67 -1.76 (m, 1H), 1.77 -1.85 (m, 1H ), 1.86-1.94 (m, 2H), 2.20-2.28 (m, 1H), 2.58-2.66 (m, 1H), 2.87-2.93 (m, 1H), 3.31 (dd, 2H), 3.59-3.65 (m , 1H), 3.96-4.04 (m, 2H), 4.51 (s, 2H), 7.15-7.17 (m, 2H), 7.25-7.49 (m. 8H).

Step 10 :
Anhydrous ammonium formate (6.87 g, 0.11 mol) and trans- (S) -2-{(R) -2- [4-benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -2-phenylethanol ( To a stirred mixture of 10.7 g, 0.027 mol) of MeOH (135 mL) is added 10% palladium on carbon (0.54 g) and the resulting mixture is stirred at room temperature under a nitrogen atmosphere for 2 hours. Anhydrous ammonium formate (3.45 g) and 10% palladium on carbon (0.54 g) are added and the mixture is stirred at room temperature under a nitrogen atmosphere for an additional 3 hours. The reaction mixture is filtered and the filtrate is concentrated. The crude residue (18.26 g) is dissolved in 1N HCl and extracted with ether to remove phenethyl alcohol. The aqueous layer is neutralized by adding 2N NaOH and extracted with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give crude trans- (R) -2- [4-benzyloxymethyl) cyclohexyl] pyrrolidine (6.54 g). obtain. To a mixture of crude trans- (R) -2- [4-benzyloxymethyl) cyclohexyl] pyrrolidine in EtOH (20 mL) is added L-tartaric acid (3.59 g, 0.024 mol). The mixture is warmed to 60 ° C. until the mixture is clear and the mixture is allowed to cool slowly to room temperature. The resulting precipitate is filtered and rinsed with additional EtOH to give pure trans- (R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidine tartrate as off-white crystals. The tartrate salt is dissolved in 1N aqueous NaOH and extracted with CH ₂ Cl ₂ . The organic layer is dried over magnesium sulfate, filtered and evaporated to give pure trans- (R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidine.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.89-1.06 (m, 4H), 1.11-1.20 (m, 1H), 1.24-1.34 (m, 1H), 1.46-1.78 (m, 4H ), 1.80-1.89 (m, 3H), 1.95-2.00 (m, 1H), 2.62 (dt, 1H), 2.81 (ddd, 1H), 2.99 (ddd, 1H), 3.27 (d, 2H), 4.49 ( s, 2H), 7.22-7.36 (m. 5H).

Example J : trans-N- (2-{(R) -2- [4- (2-benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -6,7-difluoroquinolin-3-ylmethyl) -N -Preparation of [3,5-bis (trifluoromethyl) benzyl] (2-methyl-2H-tetrazol-5-yl) amine

Process 1 :
2-chloro-6,7-difluoroquinoline-3-carbaldehyde (4.97 g, 18 mmol), trans- (R) -2-[(4-benzyloxymethyl) cyclohexyl] pyrrolidine (5.39 g, 20 mmol) and A suspension of potassium carbonate (2.97 g, 21 mol) in toluene (100 mL) and water (10 mL) is stirred and refluxed for 3 hours. The reaction mixture is allowed to cool to room temperature and diluted with water and ethyl acetate. The organic layer is washed with water, aqueous citric acid, brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give 2-{(R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -6,7-difluoroquinoline-3-carbaldehyde. Obtain as a yellow syrup.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.81-1.04 (m, 2H), 1.08-1.21 (m, 2H), 1.55-1.74 (m, 3H), 1.76-1.90 (m, 4H ), 1.91-2.07 (m, 3H), 3.18-3.24 (m, 1H), 3.25 (d, 2H), 3.69 (dt, 1H), 4.47 (s, 2H), 4.66-4.74 (m, 1H), 7.26-7.34 (m, 5H), 7.40-7.47 (m, 2H), 8.31 (s, 1H), 10.13 (s, 1H).

Step 2:
2-{(R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -6,7-difluoroquinoline-3-carbaldehyde (7.25 g, 16 mmol) in ethanol (80 mL). Dissolve and treat with sodium borohydride (0.30 g, 7.9 mmol) at 0 ° C. and stir the resulting mixture at room temperature for 30 minutes. After adding water and ethyl acetate, the mixture is partially concentrated to remove ethanol. The mixture was extracted with EtOAc and the organic layer was washed with brine, sat. Wash with aqueous NH ₄ Cl, dry over magnesium sulfate, filter and concentrate. The crude product was purified by silica gel column chromatography and (2- {R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -6,7-difluoroquinolin-3-yl) methanol Is obtained as a yellow syrup.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.74-0.97 (m, 2H), 1.00-1.14 (m, 2H), 1.49-1.63 (m, 2H), 1.69-1.84 (m, 6H ), 1.88-2.05 (m, 2H), 2.44 (dd, 1H), 3.21 (d, 2H), 3.27-3.33 (m, 1H), 3.60 (dt, 1H), 4.45 (s, 2H), 4.62- 4.66 (m, 1H), 4.73 (dd, 1H), 4.87 (dd, 1H), 7.22-7.34 (m, 5H), 7.37 (dd, 1H), 7.48 (dd, 1H), 7.93 (s, 1H) .

Step 3 :
Methanesulfonyl chloride (1.52 mL, 20 mmol) was added to (2-{(R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -6,7-difluoroquinolin-3-yl) methanol. (7.03 g, 15 mmol) and N, N-diisopropylethylamine (DIPEA, 3.41 mL, 15 mmol) in toluene (75 mL) are added dropwise at 0 ° C. The reaction mixture is stirred at ambient temperature for 1 hour. Water and ethyl acetate were added to the mixture and the organic layer was washed with sat. Wash with aqueous NaHCO ₃ solution, brine, dry over magnesium sulfate, filter and concentrate under vacuum. The residue was dissolved in toluene and concentrated in vacuo to give crude 2-{(R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -3- (chloromethyl) -6,7 -Difluoroquinoline is obtained. To a mixture of N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine (5.88 g, 18 mmol) in DMF (60 mL) was added potassium tert-butoxide. (2.03 g, 18 mmol) is added at 0 ° C. and the resulting mixture is stirred for 30 minutes at the same temperature. Crude 2-{(R) -2- [4- (benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -3- (chloromethyl) -6,7-difluoroquinoline in DMF (30 mL) was added to the mixture. Add dropwise at 0 ° C. and stir the resulting mixture for 1 hour at the same temperature. Tert-butoxide potassium (1.70 g, 14 mmol) is added to the reaction mixture and the mixture is stirred for an additional hour at room temperature. After adding water, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting mixture was purified by silica gel column chromatography to obtain trans-N- (2-{(R) -2- [4- (2-benzyloxymethyl) cyclohexyl] pyrrolidin-1-yl} -6,7- Difluoroquinolin-3-ylmethyl) -N- [3,5-bis (trifluoromethyl) benzyl] (2-methyl-2H-tetrazol-5-yl) amine is obtained as a yellow amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ), δ (ppm): 0.74-0.95 (m, 2H), 0.99-1.12 (m, 2H), 1.48-1.59 (m, 2H), 1.64-1.83 (m, 6H ), 1.84-1.90 (m, 1H), 1.96-2.04 (m, 1H), 3.16-3.22 (m, 1H), 3.22 (d, 2H), 3.49-3.55 (m, 1H), 4.20 (s, 3H ), 4.46 (s, 2H), 4.55 (d, 1H), 4.57 (d, 1H), 4.60-4.65 (m, 1H), 4.78 (d, 1H), 4.98 (d, 1H), 7.21 (dd, 1H), 7.25-7.33 (m, 5H), 7.47 (dd, 1H), 7.55 (s, 1H), 7.63 (s, 2H), 7.72 (s. 1H).

Example K : Preparation of trans- (R) -2- [4- (2-benzyloxyethyl) cyclohexyl] pyrrolidine

Process 1 :
Triethylphosphonoacetate (146 mL, 0.74 mol) was added to a suspension of NaH (60% in oil, 29.5 g, 0.74 mol) in THF (2500 mL) at 0-5 ° C. and the mixture was at the same temperature for 30 minutes. Stir. To the mixture is added 1,4-cyclohexanedione monoethylene acetal (100 g, 0.64 mol) in THF (700 mL) at 0-5 ° C. and stirring is continued for 1 hour at the same temperature. After adding H ₂ O (1500 mL), the mixture is extracted with EtOAc (3000 mL). The aqueous layer was extracted with EtOAc (1500 mL × 2) and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 8-ethoxycarbonylmethylidene-1,4-dioxaspiro [4.5 Decane (172.9 g) is obtained as a colorless oil. The crude product is used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.28 (t, 3H), 1.74-1.80 (m, 4H), 2.38 (ddd, 2H), 3.00 (ddd, 2H), 3.98 (s, 4H), 4.15 (q, 2H), 5.67 (s, 1H).

Process 2 :
8-Ethoxycarbonylmethylidene-1,4-dioxaspiro [4.5] decane (crude, 172.9 g), 10% Pd-C (53.2% wet, 6.5 g) EtOAc / MeOH (1250 mL and 400 mL) ) The suspension is stirred for 4 hours at room temperature under H ₂ atmosphere. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give crude 8-ethoxycarbonylmethyl-1,4-dioxaspiro [4.5] decane. The crude product is used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.25 (t, 3H), 1.27-1.37 (m, 2H), 1.57 (ddd, 2H), 1.70-1.78 (m, 4H), 1.80- 1.90 (m, 1H), 2.22 (d, 2H), 3.91-3.95 (m, 4H), 4.13 (q, 2H).

Step 3 :
A mixture of lithium aluminum hydride (42.5 g, 1.12 mol) in THF (1200 mL) and crude 8-ethoxycarbonylmethyl-1,4-dioxaspiro [4.5] decane (174.7 g) in THF (640 mL) Is carefully added at 0 ° C. under an argon atmosphere. After stirring for 10 minutes at ambient temperature, Na ₂ SO ₄ -10H ₂ O (360.9 g) is added at 0 ° C. and the mixture is stirred for a further 3 hours. The insoluble material is filtered, washed with EtOAc, and the filtrate is concentrated in vacuo to give crude 2- (1,4-dioxaspiro [4.5] dec-8-yl) ethanol (139.5 g). The crude product is used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.22-1.36 (m, 4H), 1.44-1.58 (m, 4H), 1.70-1.78 (m, 4H), 3.69 (dt, 2H), 3.94 (s, 4H).

Step 4 :
To a mixture of NaH (60% in oil, 43.6 g, 1.09 mol) in DMF (900 mL) was added crude 2- (1,4-dioxaspiro [4.5] dec-8-yl) ethanol (139 in DMF (300 mL). 0.5 g) is carefully added at 0-5 ° C. and the mixture is stirred for 30 minutes at the same temperature. Benzyl bromide (129.6 mL, 1.09 mol) is added dropwise to the mixture at 0-5 ° C. and stirring is continued for 1 hour at the same temperature. After adding H ₂ O (1000 mL), the mixture is extracted with EtOAc-hexane (3: 1, 1200 mL). The aqueous layer was extracted with EtOAc-hexane (3: 1, 1200 mL × 2) and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 8- [2- (benzyloxy ) Ethyl] -1,4-dioxaspiro [4.5] decane. The crude product is used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.25 (m, 2H), 1.52 (m, 5H), 1.74 (m, 4H), 3.50 (t, 2H), 3.93 (s, 4H) , 4.49 (s, 2H), 7.34 (m, 5H).

Process 5 :
To a mixture of crude 8- [2- (benzyloxy) ethyl] -1,4-dioxaspiro [4.5] decane (227.8 g) in THF (500 mL) was added 5N HCl (600 mL) at room temperature and the mixture was 10 minutes. Stir at the same temperature. After adding aqueous NaHCO ₃ (300 g in 500 mL water), the mixture is extracted with EtOAc (1500 mL). The aqueous layer is extracted with EtOAc (1000 mL × 2) and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude mixture is purified by silica gel column chromatography to give 4- (2-benzyloxyethyl) cyclohexanone.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.35-1.46 (m, 2H), 1.63 (dt, 2H), 1.87-2.00 (m, 1H), 2.01-2.09 (m, 2H), 2.28-2.42 (m, 4H), 3.54 (t, 2H), 4.52 (s, 2H), 7.27-7.36 (m, 5H).

Process 6 :
4- (2-Benzyloxyethyl) cyclohexanone (133.0 g, 0.57 mol) was dissolved in ethanol (1200 mL), triethylorthoformate (296 mL) and p-toluenesulfonic acid monohydrate (10.9 g, 0.057 mol) is added. The resulting mixture is stirred and refluxed for 2 hours. After adding triethylamine (8.8 mL, 0.063 mol) at room temperature, the mixture is concentrated. sat. After adding aqueous NaHCO ₃ (500 mL), the resulting mixture is extracted with EtOAc (1000 mL). The aqueous layer is extracted with EtOAc (1000 mL × 2) and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by short pad silica gel column chromatography to give [2- (4,4-diethoxycyclohexyl) ethoxymethyl] benzene as a pale yellow oil.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.12-1.17 (m, 2H), 1.16 (t, 3H), 1.17 (t, 3H), 1.36 (ddd, 2H), 1.42-1.48 ( m, 1H), 1.52-1.64 (m, 4H), 1.93-2.01 (m, 2H), 3.40 (q, 2H), 3.49 (q, 2H), 3.50 (t, 2H), 4.50 (s, 2H) , 7.25-7.38 (m, 5H).

Step 7 :
To a mixture of tin tetrachloride (131 mL, 1.23 mol) in CH ₂ Cl ₂ (2600 mL) was added [2- (4,4-diethoxycyclohexyl) ethoxymethyl] benzene (344 g, 1.500 mL) in CH ₂ Cl ₂ (1500 mL). 12 mol) and 1,2-bis (trimethylsiloxy) cyclobutene (317 mL, 1.23 mol) are added at -70 ° C. The mixture is stirred for 2 hours at −40 ° C. Pour the cooled mixture into water (1000 mL) and extract with CH ₂ Cl ₂ (1000 mL). The combined organic layer is sat. Wash with aqueous NaHCO ₃ and brine, dry over magnesium sulfate, and concentrate under reduced pressure. The crude mixture was purified by silica gel column chromatography to obtain ethyl 4-{[4- (2-benzyloxy) ethyl] cyclohexyl} -4-oxobutyrate (cis / trans = 1/1) as a pale yellow oil. obtain.
¹ H-NMR (400MHz, CDCl ₃ , cis: trans = 1/1), δ (ppm): 0.90-1.02 (m, 1H), 1.25 (t, 3H), 1.33-1.44 (m, 2H), 1.50 -1.67 (m, 5H), 1.79-1.94 (m, 3H), 2.33 (tt, 0.5H), 2.47-2.53 (m, 0.5H), 2.56 (t, 1H), 2.57 (t, 1H), 2.74 (t, 2H), 3.47 (t, 1H), 3.50 (t, 1H), 4.12 (q, 2H), 4.48 (s, 1H), 4.49 (s, 1H), 7.25-7.37 (m, 5H).

Process 8 :
Potassium hydroxide (192 g, 3 mol) was added to a solution of ethyl 4-{[4- (2-benzyloxy) ethyl] cyclohexyl} -4-oxobutyrate (346.2 g, 1.0 mol) in EtOH (2000 mL), The resulting mixture is stirred and refluxed for 3 hours. After adding 5N HCl at 0 ° C. (becomes pH 2), the mixture is extracted with EtOAc (4000 mL). The aqueous layer is extracted with EtOAc (1000 mL) and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a brown solid. The solid was suspended in Et ₂ O-hexane (1: 4), collected by filtration, and trans-4-{[4- (2-benzyloxy) ethyl] cyclohexyl} -4-oxobutyric acid was obtained as a pale yellow solid. Get as.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.90-1.02 (m, 2H), 1.22-1.45 (m, 3H), 1.54 (dt, 2H), 1.80-1.94 (m, 4H), 2.32 (tt, 1H), 2.62 (t, 2H), 2.76 (t, 2H), 3.50 (t, 2H), 4.49 (s, 2H), 7.26-7.36 (m, 5H).

Step 9 :
To a stirred solution of (S)-(+)-phenylglycinol (16.4 g, 0.12 mol) in toluene (450 mL), trans-4-{[4- (2-benzyloxy) ethyl] cyclohexyl} -4- Oxobutyric acid (38.0 g, 0.12 mol) is added. The resulting mixture is heated to reflux temperature for 5 hours with continuous removal of water using a Dean-stark apparatus. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain trans- (3S, 7aS) -7a- [4- (benzyloxyethyl) cyclohexyl] -3-phenyltetrahydropyrrolo [2,1-b. ] Oxazol-5-one is obtained as a colorless solid.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.67-0.84 (m, 2H), 1.06-1.21 (m, 2H), 1.30-1.52 (m, 4H), 1.73-1.93 (m, 4H ), 1.96 (dt, 1H), 2.43 (ddd, 1H), 2.58 (ddd, 1H), 2.75 (dt, 1H), 3.47 (t, 2H), 4.06 (dd, 1H), 4.48 (s, 2H) , 4.64 (t, 1H), 5.19 (t, 1H), 7.19-7.23 (m, 2H), 7.24-7.36 (m. 8H).

Step 10 :
To a cooled (0 ° C.) cooled (0 ° C.) mixture of anhydrous AlCl ₃ (6.30 g, 47 mmol) slowly added lithium aluminum hydride (5.95 g, 157 mmol) and the resulting mixture was stirred at the same temperature for 10 min To do. To the resulting stirred and cooled (−65 ° C.) THF mixture, trans- (3S, 7aS) -7a- [4- (benzyloxyethyl) cyclohexyl] -3-phenyltetrahydropyrrolo [2,1-b] oxazole-5 Add a solution of ON (22.0 g, 52 mmol) in THF (150 mL) over 30 min. The resulting mixture is stirred at the same temperature for 2 hours, warmed to room temperature and stirred for an additional hour. The resulting mixture is cooled to 0 ° C., quenched by careful addition of Na ₂ SO ₄ -10H ₂ O and stirred for an additional 30 minutes at room temperature. Insoluble material was filtered and the filtrate was concentrated in vacuo to give crude trans- (S) -2-{(R) -2- [4- (benzyloxyethyl) cyclohexyl] pyrrolidin-1-yl} -2- Phenylethanol is obtained and used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.94-1.13 (m, 4H), 1.35-1.88 (m, 12H), 2.20-2.29 (m, 1H), 2.58-2.63 (m, 1H ), 2.86-2.94 (m, 1H), 3.52 (t, 2H), 3.61-3.66 (m, 1H), 3.95-4.04 (m, 2H), 4.51 (s, 2H), 7.14-7.18 (m, 2H ), 7.28-7.52 (m. 8H).

Step 11 :
Anhydrous ammonium formate (15.8 g, 0.25 mol) and trans- (S) -2-{(R) -2- [4- (benzyloxyethyl) cyclohexyl] pyrrolidin-1-yl} -2-phenylethanol (20.5 g, 0.050 mol) in MeOH (200 mL) with stirring mixture was added 10% palladium on carbon (1.00 g) and the resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 hours and at 35 ° C. for 3 hours. To do. The reaction mixture is filtered and the filtrate is concentrated. The crude residue is dissolved in 1N HCl and extracted with ether to remove phenethyl alcohol. Neutralize the aqueous layer by adding 2.5 N NaOH and extract with CH ₂ Cl ₂ . The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated to give crude trans- (R) -2- [4- (benzyloxyethyl) cyclohexyl] pyrrolidine. To a mixture of crude trans- (R) -2- [4- (benzyloxyethyl) cyclohexyl] pyrrolidine in EtOH (65 mL) is added L-tartaric acid (7.60 g, 0.050 mol). The resulting mixture is warmed to 60 ° C. and allowed to cool slowly to room temperature. The precipitate is filtered and rinsed with additional EtOH to give trans- (R) -2- [4- (benzyloxyethyl) cyclohexyl] pyrrolidine tartrate as off-white crystals. The tartrate salt was dissolved in 1N aqueous NaOH and extracted with CH ₂ Cl ₂ , the organic layer was dried over magnesium sulfate, filtered and evaporated to give pure trans- (R) -2- [4- (benzyloxyethyl) Cyclohexyl] pyrrolidine is obtained.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.86-1.05 (m, 4H), 1.09-1.19 (m, 1H), 1.21-1.43 (m, 2H), 1.51 (dt, 2H), 1.60-1.94 (m, 7H), 2.62 (dt, 1H), 2.80 (ddd, 1H), 2.99 (ddd, 1H), 3.50 (t, 2H), 4.49 (s, 2H), 7.22-7.36 (m. 5H).

Example L : trans-N- [2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -6,7-difluoroquinolin-3-ylmethyl] Preparation of -N- [3,5-bis (trifluoromethyl) benzyl] (2-methyl-2H-tetrazol-5-yl) amine.

Process 1 :
2-chloro-6,7-difluoroquinoline-3-carbaldehyde (8.30 g, 36 mmol), trans- (R) -2- [4- (benzyloxyethyl) cyclohexyl] pyrrolidine (10.5 g, 36 mmol), And a suspension of potassium carbonate (7.60 g, 55 mmol) in toluene (90 mL) and water (12 mL) is stirred and refluxed for 4 hours. The reaction mixture is cooled to room temperature and diluted with 1N aqueous HCl and ethyl acetate. The organic layer was washed with sat. Washed with aqueous NaHCO ₃ , brine, dried over magnesium sulfate, filtered and concentrated to 2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -6,7-difluoroquinoline-3-carbaldehyde is obtained as a yellow syrup which is used without further purification.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.77-1.00 (m, 2H), 1.07-1.20 (m, 2H), 1.30-1.43 (m, 1H), 1.49 (dt, 2H), 1.51-1.88 (m, 6H), 1.91-2.04 (m, 3H), 3.18-3.24 (m, 1H), 3.48 (t, 2H), 3.69 (dt, 1H), 4.49 (s, 2H), 4.66- 4.73 (m, 1H), 7.24-7.35 (m, 5H), 7.40-7.47 (m, 2H), 8.31 (s, 1H), 10.12 (s, 1H).

Process 2 :
Crude 2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -6,7-difluoroquinoline-3-carbaldehyde was added to ethanol-THF (120 mL / 20 mL). ) And treated with sodium borohydride (1.33 g, 36 mmol) at 5 ° C. and the resulting mixture is stirred for 30 minutes at the same temperature. sat. After adding aqueous NH ₄ Cl and ethyl acetate, the mixture is partially concentrated to remove ethanol. The mixture is extracted with EtOAc and the organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain [2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -6,7-difluoroquinoline- 3-yl] methanol is obtained as a yellow syrup.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.74-0.92 (m, 2H), 0.98-1.13 (m, 2H), 1.26-1.39 (m, 1H), 1.45 (dt, 2H), 1.55-1.82 (m, 7H), 1.90-2.04 (m, 2H), 2.44-2.49 (m, 1H), 3.26-3.33 (m, 1H), 3.45 (t, 2H), 3.60 (dt, 1H), 4.47 (s, 2H), 4.61-4.67 (m, 1H), 4.72 (dd, 1H), 4.87 (d, 1H), 7.23-7.33 (m, 5H), 7.37 (dd, 1H), 7.48 (dd, 1H), 7.93 (s, 1H).

Step 3 :
Methanesulfonyl chloride (5.5 mL, 71 mmol) was added to [2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -6,7-difluoroquinoline-3. -Yl] methanol (13.7 g, 28.5 mmol) and N, N-diisopropylethylamine (DIPEA, 12.4 mL, 71 mmol) in toluene (150 mL) dropwise at 5 ° C. and the reaction mixture at ambient temperature for 2 h. Stir. To the mixture was added water and ethyl acetate and the organic layer was washed with sat. Wash with aqueous NaHCO ₃ , brine, dry over magnesium sulfate, filter, and concentrate under vacuum to give crude 2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidine- 1-yl) -3- (chloromethyl) -6,7-difluoroquinoline is obtained. 2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -3- (chloromethyl) -6,7-difluoroquinoline and N- [3,5 -Bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amine (13.9 g, 43 mmol) in DMF (120 mL) to tert-butoxide potassium (4.80 g, 43 mmol) ) At 5 ° C. The resulting mixture is stirred for 1 hour at the same temperature. sat. After adding aqueous NH ₄ Cl, the mixture is extracted with ethyl acetate. The combined organic layer is washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting mixture was purified by silica gel column chromatography to obtain trans-N- [2-((R) -2- {4- [2- (benzyloxy) ethyl] cyclohexyl} pyrrolidin-1-yl) -6, 7-Difluoroquinolin-3-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl] (2-methyl-2H-tetrazol-5-yl) amine is obtained as a yellow amorphous.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 0.69-0.93 (m, 2H), 0.97-1.11 (m, 2H), 1.25-1.38 (m, 1H), 1.43-1.54 (m, 3H ), 1.60-1.76 (m, 6H), 1.82-1.93 (m, 1H), 1.95-2.05 (m, 1H), 3.18-3.24 (m, 1H), 3.46 (t, 2H), 3.45-3.54 (m , 1H), 4.20 (s, 3H), 4.47 (s, 2H), 4.54 (d, 1H), 4.56 (d, 1H), 4.58-4.66 (m, 1H), 4.78 (d, 1H), 4.99 ( d, 1H), 7.22 (dd, 1H), 7.26-7.34 (m, 5H), 7.47 (dd, 1H), 7.56 (s, 1H), 7.63 (s, 2H), 7.72 (s. 1H).

工程１：
２−クロロ−３−メチルキノキサリン（５００ｍｇ、２．８ｍｍｏｌ）、Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミン（９００ｍｇ、７．１ｍｍｏｌ）、炭酸カリウム（９７０ｍｇ、７．０ｍｍｏｌ）のトルエン（２．５ｍＬ）懸濁液を、１５０℃で１４時間攪拌する。反応混合物を室温に冷却し、水および酢酸エチルで希釈する。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮する。粗生成物を逆相ＨＰＬＣ（０．１％ ＴＦＡからアセトニトリル）で精製してＮ−（３−メチルキノキサリン−２−イル）−Ｎ−（シクロペンチルメチル）エチルアミンを得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.15-1.20 (m, 2H), 1.19 (t, 3H), 1.45-1.73 (m, 8H), 2.21 (m, 1H), 2.69 (s, 3H), 3.37 (d, 2H), 3.39 (q, 2H), 7.47 (ddd, 1H), 7.55 (ddd, 1H), 7.79 (dd, 1H), 7.86 (dd, 1H). Example M : Preparation of N- [3- (bromomethyl) quinoxalin-2-yl] -N- (cyclopentylmethyl) ethylamine

Process 1 :
2-chloro-3-methylquinoxaline (500 mg, 2.8 mmol), N- (cyclopentylmethyl) -N-ethylamine (900 mg, 7.1 mmol), potassium carbonate (970 mg, 7.0 mmol) in toluene (2.5 mL) The suspension is stirred at 150 ° C. for 14 hours. The reaction mixture is cooled to room temperature and diluted with water and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by reverse phase HPLC (0.1% TFA to acetonitrile) to give N- (3-methylquinoxalin-2-yl) -N- (cyclopentylmethyl) ethylamine.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.15-1.20 (m, 2H), 1.19 (t, 3H), 1.45-1.73 (m, 8H), 2.21 (m, 1H), 2.69 ( s, 3H), 3.37 (d, 2H), 3.39 (q, 2H), 7.47 (ddd, 1H), 7.55 (ddd, 1H), 7.79 (dd, 1H), 7.86 (dd, 1H).

Process 2 :
N- (3-methylquinoxalin-2-yl) -N- (cyclopentylmethyl) ethylamine (160 mg, 0.59 mmol), N-bromosuccinimide (130 mg, 0.73 mmol), and 2,2′-azobisisobuty Stir a CCl ₄ mixture of ronitrile (10 mg) and reflux for 1 hour. The reaction mixture is purified by silica gel column chromatography to give N- [3- (bromomethyl) quinoxalin-2-yl] -N- (cyclopentylmethyl) ethylamine.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.10-1.25 (m, 2H), 1.22 (t, 3H), 1.45-1.73 (m, 8H), 2.22 (m, 1H), 3.42 ( d, 2H), 3.49 (q, 2H), 4.73 (s, 2H), 7.51 (ddd, 1H), 7.62 (ddd, 1H), 7.81 (dd, 1H), 7.94 (dd, 1H).

工程１：
２−クロロ−６−メチル−５−ニトロニコチノニトリル（９９７ｍｇ、５．０５ｍｍｏｌ）、Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミン（７７０ｍｇ、６．０５ｍｍｏｌ）、およびＫ_２ＣＯ_３（１．７ｇ、１２．３ｍｍｏｌ）のトルエン（２０ｍＬ）混合物を１１０℃に加熱する。３時間攪拌した後、反応混合物を濾過して得られた沈殿を除去する。濾液をＥｔＯＡｃで希釈し、Ｈ_２Ｏおよび塩水で洗浄する。有機層を硫酸ナトリウムで乾燥させ、真空下で濃縮する。残渣をシリカゲルカラムクロマトグラフィーで精製して２−［Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミノ］−６−メチル−５−ニトロニコチノニトリルを橙色油状物として得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm): 1.30 (t, 3H), 1.22-1.33 (m, 2H), 1.55-1.64 (m, 2H), 1.65-1.76 (m, 2H), 1.75-1.85 (m, 2H), 2.32 (ddt, 1H), 2.78 (s, 3H), 3.77 (d, 2H), 3.88 (dd, 2H), 8.54 (s, 1H). Example N : Preparation of {5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3,2-b] pyridin-6-yl} methanol

Step 1:
2-Chloro-6-methyl-5-nitronicotinonitrile (997 mg, 5.05 mmol), N- (cyclopentylmethyl) -N-ethylamine (770 mg, 6.05 mmol), and K ₂ CO ₃ (1.7 g, A mixture of 12.3 mmol) of toluene (20 mL) is heated to 110 ° C. After stirring for 3 hours, the reaction mixture is filtered to remove the resulting precipitate. The filtrate is diluted with EtOAc and washed with H ₂ O and brine. The organic layer is dried over sodium sulfate and concentrated under vacuum. The residue is purified by silica gel column chromatography to give 2- [N- (cyclopentylmethyl) -N-ethylamino] -6-methyl-5-nitronicotinonitrile as an orange oil.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.30 (t, 3H), 1.22-1.33 (m, 2H), 1.55-1.64 (m, 2H), 1.65-1.76 (m, 2H), 1.75-1.85 (m, 2H), 2.32 (ddt, 1H), 2.78 (s, 3H), 3.77 (d, 2H), 3.88 (dd, 2H), 8.54 (s, 1H).

Step 2:
To a mixture of 2- [N- (cyclopentylmethyl) -N-ethylamino] -6-methyl-5-nitronicotinonitrile (1.22 g, 4.23 mmol) in DMF (10 mL) was added N, N-dimethylformamide diethyl. Acetal (1.09 mL, 6.35 mmol) is added. After stirring at 85 ° C. for 30 minutes, the reaction mixture is cooled to room temperature and H ₂ O is added. The mixture is extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum. The resulting solid is rinsed with MeOH to give an orange solid. The solid is dissolved in MeOH (200 mL) and EtOAc (200 mL) and treated with palladium activated carbon ethylenediamine complex (Pd / C (en), 470 mg). The mixture is stirred at room temperature for 2.5 hours under H ₂ atmosphere. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in EtOAc / hexane and passed through a silica gel pad. The resulting mixture is concentrated under vacuum and the residue is dissolved in DMF (10 mL). To this mixture is added NaH (0.54 g, 13.5 mmol) at 0 ° C. and after 30 minutes iodomethane (0.28 mL, 4.50 mmol) is added. After stirring for 1 hour, the reaction is quenched with H ₂ O. The mixture is extracted with EtOAc and washed with brine. The organic layer is dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3,2-b] pyridine-6-carbonitrile as a colorless oil. Get as.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.19 (t, 3H), 1.16-1.26 (m, 2H), 1.44-1.55 (m, 2H), 1.56-1.66 (m, 2H), 1.67-1.75 (m, 2H), 2.24 (ddt, 1H), 3.46 (d, 2H), 3.58 (dd, 2H), 3.76 (s, 3H), 6.47 (d, 1H), 7.31 (d, 1H) , 7.76 (s, 1H).

Step 3:
5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3,2-b] pyridine-6-carbonitrile (0.30 g, 1.06 mmol) in methoxyethanol (6 mL) ) Treat the solution with 5N aqueous NaOH (6 mL). The reaction mixture is stirred at 130 ° C. for 60 hours. After cooling to room temperature, the mixture is acidified with 1N HCl. The mixture is extracted with CH ₂ Cl ₂ , dried over sodium sulfate and concentrated under vacuum. To a solution of the resulting residue in THF (5 mL) is added triethylamine (0.14 mL, 1.00 mmol) and ethyl chloroformate (0.10 mL, 1.00 mmol) at room temperature. After stirring for 1 hour, the resulting precipitate is removed by filtration and the filtrate is concentrated in vacuo. To a solution of the residue in EtOH (3 mL) is added sodium borohydride (41 mg, 1.08 mmol) at 0 ° C. After stirring for 1 hour, the reaction is quenched with H ₂ O. The mixture is extracted with EtOAc and washed with brine. The organic layer is dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, and {5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3,2-b] pyridin-6-yl} methanol was colorless. Obtained as an oil.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.08 (t, 3H), 1.14-1.23 (m, 2H), 1.42-1.50 (m, 2H), 1.71-1.79 (m, 2H), 2.01-2.10 (m, 2H), 3.12-3.22 (m, 4H), 3.78 (s, 3H), 4.87 (s, 2H), 5.98 (s, 1H), 6.60 (d, 1H), 7.21 (d, 1H), 7.42 (s, 1H).

工程１：
５−［Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミノ］−１−メチル−１Ｈ−ピロロ［３，２−ｂ］ピリジン−６−カルボニトリル（１０５ｍｇ、０．３７ｍｍｏｌ）のＤＭＦ（２ｍＬ）混合物にＮ−ブロモスクシンイミド（ＮＢＳ、６６ｍｇ、０．３７ｍｍｏｌ）を０℃で加える。３０分間攪拌した後、Ｈ_２Ｏを加え、反応混合物をＥｔＯＡｃで抽出する。有機層を硫酸ナトリウムで乾燥させ、濃縮し、シリカゲルカラムクロマトグラフィーで精製して３−ブロモ−５−［Ｎ−（シクロペンチルメチル）−Ｎ−エチルアミノ］−１−メチル−１Ｈ−ピロロ［３，２−ｂ］ピリジン−６−カルボニトリルを黄色固体として得る。
¹H-NMR (400MHz, CDCl₃), δ (ppm):1.26 (t, 3H), 1.20-1.30 (m, 2H), 1.48-1.54 (m, 2H), 1.58-1.67 (m, 2H), 1.68-1.79 (m, 2H), 2.31 (ddt, 1H), 3.57 (d, 2H), 3.68 (d, 2H), 3.74 (s, 3H), 7.32 (s, 1H), 7.73 (s, 1H). Example O : Preparation of {5- [N- (cyclopentylmethyl) ethylamino] -1,3-dimethyl-1H-pyrrolo [3,2-b] pyridin-6-yl} methanol

Step 1:
To a DMF (2 mL) mixture of 5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3,2-b] pyridine-6-carbonitrile (105 mg, 0.37 mmol). N-bromosuccinimide (NBS, 66 mg, 0.37 mmol) is added at 0 ° C. After stirring for 30 minutes, H ₂ O is added and the reaction mixture is extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 3-bromo-5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3, 2-b] Pyridine-6-carbonitrile is obtained as a yellow solid.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.26 (t, 3H), 1.20-1.30 (m, 2H), 1.48-1.54 (m, 2H), 1.58-1.67 (m, 2H), 1.68-1.79 (m, 2H), 2.31 (ddt, 1H), 3.57 (d, 2H), 3.68 (d, 2H), 3.74 (s, 3H), 7.32 (s, 1H), 7.73 (s, 1H) .

Step 2:
3-bromo-5- [N- (cyclopentylmethyl) -N-ethylamino] -1-methyl-1H-pyrrolo [3,2-b] pyridine-6-carbonitrile (1.05 g, 2.91 mmol) and A mixture of [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (PdCl ₂ (dppf) -CH ₂ Cl ₂ , 0.24 g, 0.29 mmol) in THF (20 mL) was added to methyl. Treat with magnesium bromide (0.93M in THF, 7.8 mL) at 0 ° C. The reaction mixture is stirred at 75 ° C. for 22 hours. After cooling to room temperature, H ₂ O is added and the reaction mixture is extracted with EtOAc. The organic layer was washed with sat. Wash with NaHCO ₃ and brine, dry over sodium sulfate and concentrate. The residue was purified by silica gel column chromatography to give 5- [N- (cyclopentylmethyl) -N-ethylamino] -1,3-dimethyl-1H-pyrrolo [3,2-b] pyridine-6-carbonitrile colorless. Obtained as an oil.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.23 (t, 3H), 1.19-1.29 (m, 2H), 1.46-1.52 (m, 2H), 1.58-1.65 (m, 2H), 1.66-1.77 (m, 2H), 2.22-2.33 (m, 4H), 3.49 (d, 2H), 3.60 (dd, 2H), 3.68 (s, 3H), 7.09 (s, 1H), 7.68 (s, 1H).

Step 3:
{5- [N- (cyclopentylmethyl) ethylamino] -1,3-dimethyl-1H-pyrrolo [3,2-b] pyridin-6-yl} methanol is converted to 5- [N- (cyclopentylmethyl) -N- Prepared according to the method of Example N (Step 3) from ethylamino] -1,3-dimethyl-1H-pyrrolo [3,2-b] pyridine-6-carbonitrile.
¹ H-NMR (400MHz, CDCl ₃ ), δ (ppm): 1.09 (t, 3H), 1.13-1.23 (m, 2H), 1.42-1.51 (m, 2H), 1.51-1.63 (m, 2H), 1.68-1.79 (m, 2H), .1.99-2.10 (m, 1H), 2.33 (s, 3H), 3.12-3.19 (m, 4H), 3.70 (s, 3H), 4.85 (s, 2H), 6.98 (s, 1H), 7.32 (s, 1H).

General UPLC (ultra high performance liquid chromatography) conditions.
Column: Waters ACQUITY UPLC BEH C18, 1.7 μM
Mobile phase: CH ₃ CN / H ₂ O (0.1% TFA)

Claims (12)

Formula (IC)

[X is N and Y is CH or N;
R ₁ is 2-C ₁ -C ₇ -alkyl-2H-tetrazol-5-yl;
The element —N (R ₄ ) (R ₅ ) is C ₁ -C ₇ -alkyl-, C ₃ -C ₇ -cycloalkyl-, C ₃ -C ₇ -cycloalkyl-methyl-, C ₁ -C ₇ -alkoxy. - methyl -, hydroxy _-C 1 -C ₂ - alkyl _-C 3 -C ₇ - cycloalkyl -, formyl _-C 3 -C ₇ - cycloalkyl -, formyl _-C 1 -C ₂ - alkyl _-C 3 -C ₇ - cycloalkyl _{-, HO 2 C-C 3} -C 7 - cycloalkyl _{-, HO 2 C-C 1} -C 2 - alkyl _-C 3 -C ₇ - cycloalkyl _{-, H 2 NC (= O} ) - C ₃ -C ₇ - with one or two substituents selected from the group consisting of - cycloalkyl - or _{H 2 NC (= O) -C} 1 -C 2 - alkyl _-C 3 -C ₇ - cycloalkyl With substituted pyrrolidin-1-yl Ri;
R ₉ is selected from —CN , C ₁ -C ₇ -alkoxy, (C ₁ -C ₇ -alkyl) (C ₁ -C ₇ -alkyl-) amine-, halo-C ₁ -C ₇ -alkyl or halogen. 1 or 2 substituents;
R ₁₂ and R ₁₃ are, independently of one another, halo-C ₁ -C ₇ -alkyl or halogen; where p is 1 or 2; or R ₄ is (C ₁ -C ₄ ) alkyl- or (C ₃ -C ₅ ) cycloalkyl-; and R ₅ is optionally hydroxyl, alkoxy, HO ₂ C—, HO ₂ C— (C ₁ -C ₃ ) alkyl-, hydroxy- (C ₁ -C ₃₎ alkyl _{-, (C} 1 -C ₆₎ alkoxy - substituted by 1 or 2 substituents selected from - carbonyl - or _(C 1 -C ₆₎ alkoxy - carbonyl - _(C 1 -C ₃₎ alkyl (C ₃ -C ₇ ) cycloalkyl- (C ₁ -C ₂ ) alkyl-
Compound or a salt thereof, of. Formula (II)

[Wherein p is 0, 1 or 2;
Ra halogen or _(C 1 -C ₄₎ is - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₁₂ and R ₁₃ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ represents formula (III):

Wherein R ₆ is (C ₁ -C ₄ ) alkyl- or (C ₃ -C ₅ ) cycloalkyl-; Rb is — (CH ₂ ) _n —Rc; n is 0 or 1 or 2 or be a 3; Rc is carboxy, _{hydroxy, (C} 1 -C ₄₎ - alkoxy or _(C 1 -C ₄₎ - alkoxycarbonyl)
Is)
Or a salt thereof. Formula (II)

[Wherein p is 0, 1 or 2;
Ra is halogen or _(C 1 -C ₄₎ - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₁₂ and R ₁₃ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ is of formula (IIIA):

Wherein R ₆ is (C ₁ -C ₄ ) alkyl- or (C ₃ -C ₅ ) cycloalkyl-; Rb is — (CH ₂ ) _n —Rc; n is 0 or 1 or 2 or be a 3; Rc is carboxy, _{hydroxy, (C} 1 -C ₄₎ - alkoxy or _(C 1 -C ₄₎ - alkoxycarbonyl)
Is)
The compound of claim 2; or a salt thereof. Formula (II)

[Wherein p is 0 or 1 or 2 or 3;
Ra is halogen or _(C 1 -C ₄₎ - alkoxy or halo - _(C 1 -C ₄₎ alkyl;
R ₁₂ and R ₁₃ are independently halogen or halo- (C ₁ -C ₄ ) alkyl;
R ₂ represents formula (IV):

Wherein Rb is — (CH ₂ ) _n —Rc; n is 0 or 1 or 2 or 3; Rc is carboxy, hydroxy, formyl, (C ₁ -C ₄ ) -alkoxy, H ₂ NC _{(= O) -, H 2} NC (= O) - (C 1 -C 4) _{alkyl, (C} 1 -C ₄₎ - alkoxycarbonyl or _{halo, - (C 1 -C 4)} - alkoxycarbonyl)
Is)
Or salts thereof; compounds of. R ₂ is of formula (IVA):

[Wherein Rb is — (CH ₂ ) _n —Rc; n is 0, 1 or 2 or 3; Rc is carboxyl, hydroxy, formyl, (C ₁ -C ₄ ) -alkoxy, H ₂ NC _{(= O) -, H 2} NC (= O) - (C 1 -C 4) _{alkyl, (C} 1 -C ₄₎ - alkoxycarbonyl or _{halo, - (C 1 -C 4)} - alkoxycarbonyl]
In a compound of claim 4; or a salt thereof. p is 1 or 2; Ra is halogen; R ₁₂ and R ₁₃ are halo- (C ₁ -C ₄ ) alkyl; Rb is — (CH ₂ ) _n —Rc, where n is is 0 or 1; Rc is carboxyl or _(C 1 -C ₄₎ - alkoxycarbonyl or halo - _(C 1 -C ₄₎ - is alkoxycarbonyl;
6. A compound according to claim 5 , or a pharmaceutically acceptable salt. Following group

Or a salt thereof in each case. 8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 for the treatment of the human or animal body. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (I) an HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(Ii) an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof,
(Iii) an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(Iv) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(V) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(Vi) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(Vii) a dual angiotensin converting enzyme / neutral endopeptidase (ACE / NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(Viii) an endothelin antagonist or a pharmaceutically acceptable salt thereof,
(Ix) a renin inhibitor or a pharmaceutically acceptable salt thereof,
(X) a diuretic or a pharmaceutically acceptable salt thereof,
8. A compound according to any one of claims 1 to 7 , or a pharmaceutically acceptable salt thereof, in combination with an active substance selected from the group consisting of (xi) ApoA-I mimetic, and (xii) a DGAT inhibitor. salt. CETP is for the manufacture of a delay medicament prevention or treatment or progression of the involved diseases, the use of a compound according to any one of 請 Motomeko 1-8 and 10. The disease is hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, high beta lipoproteinemia, high alpha lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, family sex hypercholesterolemia, cardiovascular disorder, coronary heart disease, coronary artery disease, coronary vascular disease, angina, ischemia, heart ischemia, thrombosis, heart infarction, stroke, peripheral vascular disease, reperfusion injury , angioplasty restenosis, hypertension, congestive heart failure, diabetes, a diabetic vascular complications, obesity or endotoxemia etc. the use of claim 11.