JP2009263234A - Composition of phosphodiesterase inhibitor of type iv - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for treating autoimmune, inflammatory or allergic diseases or disorders. <P>SOLUTION: Provided is a pharmaceutical composition comprising at least one phosphodiesterase inhibitor of type IV (PDE-IV) and at least one another active ingredient selected from among muscarinic receptor antagonists (MRA), β2-agonists, p38 MAP kinase inhibitors, and corticosteroids, and optionally one or more pharmaceutically acceptable excipients and/or other therapeutic agents. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  As used herein, one or more type IV phosphodiesterase inhibitors (“PDE-IV”), such as muscarinic receptor antagonists (MRAs), β2-agonists, p38 MAP kinase inhibitors, or corticosteroids Pharmaceutical compositions are provided comprising at least one other active ingredient, and optionally one or more pharmaceutically acceptable excipients. In addition, methods for treating autoimmunity, inflammation or allergic diseases or disorders are provided.

  Cyclic adenosine-3 ', 5'-1 phosphate (cAMP) is known to play an important role acting as an intracellular second messenger. Intracellular hydrolysis of cAMP to adenosine 5'-1 phosphate (AMP) causes a number of inflammatory diseases including, but not limited to, psoriasis, allergic rhinitis, shock, atopic dermatitis , Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, and ulcerative colitis. Cyclic nucleotide phosphodiesterase (PDE), a biochemically and functionally highly variable superfamily of enzymes, is the most important factor in the control of cAMP (as well as cGMP) levels. Eight distinct families with over 15 gene products are now recognized. PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, but only the PDE IV and PDE VII types are highly selective for cAMP hydrolysis. Therefore, inhibitors of PDE, in particular PDE IV inhibitors such as rolipram or Ro-1724, are known as cAMP enhancers. Immune cells contain PDE IV and PDE III, of which PDE IV is predominant in human mononuclear cells. Thus, inhibition of phosphodiesterase type IV has been modulated in a range of disease processes and thus has been targeted for therapeutic intervention. The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolysis activity in cyclic nucleotide phosphodiesterase (PDE) enzymes. More recently, distinct classes of PDE have been recognized, and their selective inhibition has led to improved drug therapy. Thus, it was recognized that inhibition of PDE IV could lead to the release of inflammatory mediators and inhibition of airway smooth muscle relaxation.

  In particular, 3-aryl-2-isoxazoline compounds are known as anti-inflammatory agents, and special isoxazoline compounds are known as inhibitors of TNF release. However, there remains a need for new selective inhibitors of phosphodiesterase (PDE) type IV, as well as their compositions in combination with one or more other therapeutic agents.

In one embodiment, selected from one or more type IV phosphodiesterase inhibitors (“PDE-IV”), and muscarinic receptor antagonists (MRAs), β2-agonists, p38 MAP kinase inhibitors, or corticosteroids. Comprising at least one other active ingredient, and optionally one or more pharmaceutically acceptable excipients, wherein the PDE-IV inhibitor is one or more compounds having the structure of Formula Ia or Formula Ib ,
here,
a. Formula Ia is:

式Ｉａ
およびその医薬上許容される塩、医薬上許容される溶媒和物、エナンチオマー、ジアステレオマーまたはＮ−オキサイドであり、ここに、
Ｘが酸素である場合、
Ｒ₁は水素、アルキル、ヘテロシクリル、−（ＣＨ₂）_mＣ（＝Ｏ）Ｒ₃、または（ＣＨ₂）_1-4ＯＲ’であり（ここに、ｍは０ないし２の整数であり、Ｒ₃はアルキル、シクロアルキル、ヘテロシクリル、または所望により置換されていてもよいＲ_pまたはＲ_qであり、ここに、Ｒ_pはヘテロシクリルまたはヘテロアリール環であり、ここに、該環はＮを介して（ＣＨ₂）_mＣ（＝Ｏ）に結合しており、Ｒ_qはヘテロシクリルまたはヘテロアリール環であり、ここに該環はＣを介して−（ＣＨ₂）_mＣ（＝Ｏ）に結合しており、ここに、Ｒ’はアルキル、アルケニル、アルキニル、飽和または不飽和シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールであり）；
Ｒ₂は（ＣＨ₂）_mＣ（＝Ｏ）Ｒ₃、−（ＣＨ₂）_1-4ＯＲ’、またはＣ（＝Ｏ）ＮＲ_xＲ_yであり｛ここに、ｍ、Ｒ₃およびＲ’は前記定義の通りであり、ここに、Ｒ_xおよびＲ_yは、各々、独立して、水素、アルキル、Ｃ₃−Ｃ₆アルケニル、Ｃ₃−Ｃ₆アルキニル、シクロアルキル、カルボキシ、−Ｓ（Ｏ）_mＲ₅であり（ここに、Ｒ₅は水素、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、アルカリール、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルまたはヘテロシクリルアルキルであり）、アリール、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり｝、あるいはＲ₁およびＲ₂は一緒になって、所望により置換されていてもよいシクロアルキルまたはヘテロシクリル環を形成し、ここに、該所望の置換基はオキソ、アルキル、アルケニル、アルキニル、ハロゲン、ニトロ、−ＮＨ₂、−ＮＨＣ（＝Ｏ）ＯＲ₆、−Ｃ（＝Ｏ）ＮＲ_xＲ_y、シアノ、ヒドロキシ、アルコキシ、または置換されたアミノであり（ここに、Ｒ₆はアルキル、アルケニル、アルキニル、シクロアルキル、アルカリール、ヘテロアリールアルキルまたはヘテロシクリルアルキルであり）、但し、もしＲ₁が−（ＣＨ₂）_1-4ＯＲ’であれば、Ｒ₂は−（ＣＨ₂）_1-4ＯＲ’でもあり、但し、もしＲ₁がＣ（＝Ｏ）ＮＲ_xＲ_yであれば、Ｒ₂はＣ（＝Ｏ）ＮＲ_xＲ_yでもあり；
Ｒ₄は水素；アルキル；−ＯＲ₅；ハロゲン；−ＮＨ₂、置換されたアミノ；シアノ；カルボキシ；または−Ｃ（＝Ｏ）ＮＲ_xＲ_yであり（ここに、Ｒ₅、Ｒ_xおよびＲ_yは前記定義の通りであり）；あるいはＲ₂およびＲ₄は、０ないし４のＮ、ＯおよびＳから成る群より選択されたヘテロ原子を有する環Ｂと縮合した所望により置換されていてもよい４ないし１２員の飽和または不飽和単環または二環の環系を形成し、ここに、該置換基はアルキル、ハロゲン、ヒドロキシ、アルコキシ、−ＮＨ₂または置換されたアミノの１以上であり（ここに、Ｒ₅およびＲ_xおよびＲ_yは前記定義の通りであり）、但し、Ｒ₂およびＲ₄は一緒になって−ＣＨ₂−Ｏ−ＣＨ₂−Ｏ−ＣＨ₂−を形成せず；
Ｒ₇は水素、アルキル、アルケニル、アルキニル、−ＯＲ₅、ハロゲン、シアノ、−ＮＨ₂、または置換されたアミノであり；
Ｘ₁およびＸ₂は、各々、独立して、水素、アルキル、アルカリール、シクロアルキル、アルカリール、アルケニル、シクロアルキルアルキル、ヘテロシクリル、ヘテロアリール、ヘテロシクロアルキル、−（ＣＨ₂）_gＣ（＝Ｏ）ＮＲ_xＲ_y、−（ＣＨ₂）_g1Ｃ（＝Ｏ）ＯＲ₃またはヘテロアリールアルキルであり；ここに、_g1は１ないし３の整数であり（ここに、Ｒ_x、Ｒ_y、ｇおよびＲ₃は前記定義の通りであり）；
Ｙは、各々、独立して、酸素原子；硫黄原子；または−ＮＲであり（ここに、Ｒは水素、アシル、アリール、またはアルキルであり）；
Ｙ₁およびＹ₂は、各々、独立して、水素；アルキル；−ＯＲ；−ＳＲ；または−ＮＨＲであり（ここに、Ｒは前記定義の通りであり）；
ここに、Ｙ₁およびＸ₂、ならびにＸ₁およびＹ₂のいずれかは所望により一緒になって環Ａと縮合した環を形成し、該環は該環内に３ないし５の炭素原子を含有し、かつ１ないし３のＮ、ＯおよびＳのようなヘテロ原子を有し、およびＸ₁およびＸ₂は所望により一緒になって環Ａと縮合した環を形成し、該環は該環内に３ないし５の炭素原子を含有し、かつ２ないし３のＮ、ＯおよびＳのようなヘテロ原子を有し、および
ＸがＮＲ₇またはＳ（ここに、Ｒ₇は水素またはＣ_1-6アルキルであり得る）である場合、
Ｒ₁およびＲ₂は、独立して、アルキル、アルケニル、アルキニル、アルコキシ、ヒドロキシ、シアノ、ニトロ、ハロゲン、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクリルアルキル、ＮＨ₂、置換されたアミノ、カルボキシ、−（ＣＨ₂）_mＣ（＝Ｏ）Ｒ₃、−Ｃ（＝Ｏ）ＮＲ_xＲ_y、または（ＣＨ₂）_1-4ＯＲ’であり｛ここに、ｍは０ないし２の整数であり、Ｒ₃はアルキル、シクロアルキル、ヘテロシクリル、または所望により置換されていてもよいＲ_pまたはＲ_qであり（ここに、Ｒ_pはヘテロシクリルまたはヘテロアリール環であり、ここに、該環はＮを介して（ＣＨ₂）_mＣ（＝Ｏ）に結合し、およびＲ_qはヘテロシクリルまたはヘテロアリール環であり、ここに、該環はＣを介して−（ＣＨ₂）_mＣ（＝Ｏ）に結合し）、ここに、Ｒ’はアルキル、アルケニル、アルキニル、飽和または不飽和シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールであり、および、ここに、Ｒ_xおよびＲ_yは、各々、独立して、水素、アルキル、Ｃ₃−Ｃ₆アルケニル、Ｃ₃−Ｃ₆アルキニル、シクロアルキル、カルボキシ、−Ｓ（Ｏ）_mＲ₅であり（ここに、Ｒ₅は水素、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、アルカリール、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルまたはヘテロシクリルアルキルであり）、アリール、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり｝、あるいはＲ₁およびＲ₂は一緒になって所望により置換されていてもよいシクロアルキルまたはヘテロシクリル環を形成し、ここに、該所望の置換基はオキソ、アルキル、アルケニル、アルキニル、ハロゲン、ニトロ、−ＮＨ₂、−ＮＨＣ（＝Ｏ）ＯＲ₆（ここに、Ｒ₆はアルキル、アルケニル、アルキニル、シクロアルキル、アルカリール、ヘテロアリールアルキルまたはヘテロシクリルアルキルであり）、−Ｃ（＝Ｏ）ＮＲ_xＲ_y、シアノ、ヒドロキシ、アルコキシ、または置換されたアミノであり；
Ｒ₄は水素；アルキル；−ＯＲ₅；ハロゲン；−ＮＨ₂、置換されたアミノ；シアノ；カルボキシ；または−Ｃ（＝Ｏ）ＮＲ_xＲ_yであり（ここに、Ｒ₅、Ｒ_xおよびＲ_yは前記定義の通りである）；あるいはＲ₂およびＲ₄は、０ないし４のＮ、ＯおよびＳより成る群から選択されたヘテロ原子を有する環Ｂに縮合した所望により置換されていてもよい４ないし１２員の飽和または不飽和単環または二環の環系を形成し、ここに、該置換基はアルキル、ハロゲン、ヒドロキシ、アルコキシまたは置換されたアミノの１以上であることができ（ここに、Ｒ₃およびＲ_xおよびＲ_yは前記定義の通りであり）、但し、Ｒ₂およびＲ₄は一緒になって−ＣＨ₂−Ｏ−ＣＨ₂−Ｏ−ＣＨ₂−を形成せず；
Ｒ₇は水素、アルキル、アルケニル、アルキニル、−ＯＲ₅、ハロゲン、シアノ、−ＮＨ₂、または置換されたアミノであり；
Ｘ₁およびＸ₂は、各々、独立して、アルキル、シクロアルキル、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり；
Ｙは、各々、独立して酸素原子；硫黄原子；または−ＮＲであり（ここに、Ｒは水素、アシル、アリール、またはアルキルであり）；
Ｙ₁およびＹ₂は、各々、独立して、水素、アルキル、−ＯＲ、−ＳＲ、または−ＮＨＲであり（ここに、Ｒは前記定義の通りであり）；
ここに、Ｙ₁およびＸ₂、ならびにＸ₁およびＹ₂は所望により一緒になって環Ａに縮合した環を形成し、該環は該環内に３ないし５の炭素原子を含有し、かつＮ、ＯおよびＳのような１ないし３のヘテロ原子を有し；
Ｘ₁およびＸ₂は所望により一緒になって、該環Ａと縮合した環状環を形成でき、該環は該環内に３ないし５の炭素原子を含有し、かつ２ないし３のＮ、ＯおよびＳのようなヘテロ原子を有し、および
ｂ．式Ｉｂは：

Formula Ia
And pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides thereof, wherein
When X is oxygen,
R ₁ is hydrogen, alkyl, heterocyclyl, — (CH ₂ ) _m C (═O) R ₃ , or (CH ₂ ) _1-4 OR ′ (where m is an integer from 0 to 2, ₃ is an alkyl, cycloalkyl, heterocyclyl, or optionally substituted R _p or R _q , wherein R _p is a heterocyclyl or heteroaryl ring, wherein the ring is Bonded to (CH ₂ ) _m C (═O), R _q is a heterocyclyl or heteroaryl ring, wherein the ring is bonded to — (CH ₂ ) _m C (═O) via C; Wherein R ′ is alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl);
R ₂ is (CH ₂ ) _m C (═O) R ₃ , — (CH ₂ ) _1-4 OR ′, or C (═O) NR _x R _y {where m, R ₃ and R ′ Is as defined above, wherein R _x and R _y are each independently hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, cycloalkyl, carboxy, —S ( O) _m R ₅ where R ₅ is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl,}, or R ₁ and R ₂ together may be optionally substituted by Shikuroa Forming Kill or heterocyclyl ring, where the substituents of said desired oxo, alkyl, alkenyl, alkynyl, halogen, _{nitro, -NH 2, -NHC (= O} ) OR 6, -C (= O) NR x R _y , cyano, hydroxy, alkoxy, or substituted amino (where R ₆ is alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), provided that R ₁ Is — (CH ₂ ) _1-4 OR ′, R ₂ is also — (CH ₂ ) _1-4 OR ′, provided that if R ₁ is C (═O) NR _x R _y , R ₂ is also C (═O) NR _x R _y ;
R ₄ is hydrogen; alkyl; -OR _5; halogen; -NH _2, substituted amino, cyano, carboxy; or -C (= O) a NR _x R _y (herein, R _5, R _x and R _y is as defined above; or alternatively R ₂ and R ₄ may be optionally substituted fused with ring B having a heteroatom selected from the group consisting of 0 to 4 N, O and S Form a good 4- to 12-membered saturated or unsaturated monocyclic or bicyclic ring system, wherein the substituent is one or more of alkyl, halogen, hydroxy, alkoxy, —NH ₂ or substituted amino (Where R ₅ and R _x and R _y are as defined above), provided that R ₂ and R ₄ together form —CH ₂ —O—CH ₂ —O—CH ₂ —. Z;
R ₇ is hydrogen, alkyl, alkenyl, alkynyl, —OR ₅ , halogen, cyano, —NH ₂ , or substituted amino;
X ₁ and X ₂ are each independently hydrogen, alkyl, alkaryl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocycloalkyl, — (CH ₂ ) _g C (= O) NR _x R _y , — (CH ₂ ) _g1 C (═O) OR ₃ or heteroarylalkyl; where _g1 is an integer from 1 to 3 (where R _x , R _y , g And R ₃ is as defined above);
Y is each independently an oxygen atom; a sulfur atom; or —NR (where R is hydrogen, acyl, aryl, or alkyl);
Y ₁ and Y ₂ are each independently hydrogen; alkyl; —OR; —SR; or —NHR (where R is as defined above);
Where Y ₁ and X ₂ and either X ₁ and Y ₂ are optionally joined together to form a fused ring with ring A, the ring containing from 3 to 5 carbon atoms in the ring And having 1 to 3 heteroatoms such as N, O and S, and X ₁ and X ₂ are optionally joined together to form a fused ring with ring A, wherein the ring is within the ring Containing 3 to 5 carbon atoms and 2 to 3 heteroatoms such as N, O and S, and X is NR ₇ or S (where R ₇ is hydrogen or C _1-6 Can be alkyl)
R ₁ and R ₂ are independently alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, nitro, halogen, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, NH ₂ , substituted amino, carboxy, — (CH ₂ ) _m C (═O) R ₃ , —C (═O) NR _x R _y , or (CH ₂ ) _1-4 OR ′ {where m is an integer from 0 to 2, R ₃ is alkyl, cycloalkyl, heterocyclyl, or optionally substituted R _p or R _q (where R _p is a heterocyclyl or heteroaryl ring, wherein the ring is Te (CH ₂₎ attached to _m C (= O), and R _q is heterocyclyl or heteroaryl ring, where said ring via a C - (CH _{2) m} C ( Bound to O)), herein, R 'is alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl, and wherein the, R _x and R _y are each independently And hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, cycloalkyl, carboxy, —S (O) _m R ₅ (where R ₅ is hydrogen, alkyl, alkenyl, alkynyl). , Aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl}, or R ₁ and R ₂ optionally substituted together Forming a which may cycloalkyl or heterocyclyl ring, wherein the substituents of said desired oxo, alkyl, alkenyl, alkynyl, halogen, nitro, -NH _2, a -NHC (= O) OR ₆ (wherein, R ₆ Is alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), —C (═O) NR _x R _y , cyano, hydroxy, alkoxy, or substituted amino;
R ₄ is hydrogen; alkyl; -OR _5; halogen; -NH _2, substituted amino, cyano, carboxy; or -C (= O) a NR _x R _y (herein, R _5, R _x and R _y is as defined above; or R ₂ and R ₄ may be optionally substituted fused to ring B having a heteroatom selected from the group consisting of 0 to 4 N, O and S; Form a good 4- to 12-membered saturated or unsaturated monocyclic or bicyclic ring system, wherein the substituent can be one or more of alkyl, halogen, hydroxy, alkoxy or substituted amino ( Wherein R ₃ and R _x and R _y are as defined above), provided that R ₂ and R ₄ together do not form —CH ₂ —O—CH ₂ —O—CH ₂ —. ;
R ₇ is hydrogen, alkyl, alkenyl, alkynyl, —OR ₅ , halogen, cyano, —NH ₂ , or substituted amino;
X ₁ and X ₂ are each independently alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl;
Y is each independently an oxygen atom; a sulfur atom; or —NR (where R is hydrogen, acyl, aryl, or alkyl);
Y ₁ and Y ₂ are each independently hydrogen, alkyl, —OR, —SR, or —NHR (where R is as defined above);
Wherein Y ₁ and X ₂ , and X ₁ and Y ₂ are optionally joined together to form a ring fused to ring A, the ring containing from 3 to 5 carbon atoms in the ring, and Having 1 to 3 heteroatoms such as N, O and S;
X ₁ and X ₂ can optionally be combined to form a cyclic ring fused with the ring A, the ring containing 3 to 5 carbon atoms in the ring and 2 to 3 N, O Having a heteroatom such as and S; and b. Formula Ib is:

式Ｉｂ

およびその医薬上許容される塩、医薬上許容される溶媒和物、エナンチオマー、ジアステレオマー、Ｎ−オキシドであり、ここに、
Ｒ₁およびＲ₂は一緒になって所望により置換されていてもよいシクロアルキルまたはヘテロシクリル環を形成し、ここに、１以上の所望の置換基はオキソ、アルキル、アルカリール、アルケニル、アルキン、ヘテロシクリルアルキル、シクロアルキルアルキル、−ＳＯ₂ＮＲ_xＲ_y、ハロゲン、−ＮＨ₂、−（ＣＨ₂）_gＣ（＝Ｏ）ＮＲ_xＲ_y、−ＮＨＣ（＝Ｏ）ＯＲ₆、−ＮＨＣ（＝Ｏ）ＮＲ_xＲ_y、−Ｃ（＝Ｏ）ＯＲ₃、−ＮＨＣ（＝Ｏ）Ｒ_x、−ＳＯ₂Ｒ₃、シアノ、ヒドロキシ、アルコキシ、置換されたアミノ、または−Ｃ（＝Ｏ）Ｒ₃であり（ここに、Ｒ_x、Ｒ_y、ｇ、Ｒ₆およびＲ₃は前記定義の通りであり）；
Ｒ₄は水素；アルキル、ヒドロキシル、ハロゲン、またはカルボキシであり；
Ｒ₇は水素、またはアルキルであり；
Ｒ₁は独立して水素またはアルキルであり、およびＲ₂およびＲ₄は、０ないし４のＮ、ＯおよびＳより成る群から選択されたヘテロ原子を有する環Ｂに縮合した所望により置換されていてもよい４ないし１２員の飽和または不飽和単環または二環の環系を形成し、ここに、該置換基はオキソ、アルキル、−ＯＣ（＝Ｏ）ＯＲ₃、−ＳＯ₂Ｒ₃、ハロゲン、ヒドロキシ、アルコキシ、−ＮＨ₂または置換されたアミノの１以上であり（ここに、Ｒ₃は後の定義の通りであり）、但し、Ｒ₂およびＲ₄は一緒になって−ＣＨ₂−Ｏ−ＣＨ₂−Ｏ−ＣＨ₂−を形成せず；
Ｘ₁およびＸ₂は水素、アルキル、シクロアルキル、アルカリール、アルケニル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクリルアルキル、−（ＣＨ₂）_gＣ（＝Ｏ）ＮＲ_xＲ_yまたは−（ＣＨ₂）_g1Ｃ（＝Ｏ）ＯＲ₃であり（ここに、ｇは０ないし３の整数であり得、ｇ１は１ないし３の整数であり得、およびＲ_x、Ｒ_yおよびＲ₃は前記定義の通りであり）；
Ｘ₁およびＸ₂は一緒になって、所望により、式Ｉに示した環Ａと縮合した環状環を形成でき、該環は該環内に３ないし５の炭素原子を含有し、および２ないし３のヘテロ原子Ｎ、ＯまたはＳを有し；
ここに、Ｒ₃はアルキル、シクロアルキルまたはヘテロシクリルであり；
ここに、該ハロゲンはＦ、Ｃｌ、Ｂｒ、またはＩであり得；Ｒ_xおよびＲ_yは、各々、独立して、ハロゲン、アルキル、Ｃ₃−Ｃ₆アルケニル、Ｃ₃−Ｃ₆アルキニル、カルボキシ、シクロアルキル、−Ｓ（Ｏ）_mＲ₅、アリール、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、およびヘテロシクリルアルキルであり得；ｍは０ないし２の間の整数であり得；Ｒ₆はアルキル、アルケニル、アルキニル、シクロアルキル、アルカリール、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり得；および
ここに、Ｒ₅は水素、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、アルカリール、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルまたはヘテロシクリルアルキルであることを特徴とする医薬組成物が提供される。

Formula Ib

And pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides thereof, wherein
R ₁ and R ₂ together form an optionally substituted cycloalkyl or heterocyclyl ring, wherein one or more desired substituents are oxo, alkyl, alkaryl, alkenyl, alkyne, heterocyclyl Alkyl, cycloalkylalkyl, —SO ₂ NR _x R _y , halogen, —NH ₂ , — (CH ₂ ) _g C (═O) NR _x R _y , —NHC (═O) OR ₆ , —NHC (═O _{) NR x R y, -C (} = O) oR 3, -NHC (= O) R x, -SO 2 R 3, cyano, hydroxy, alkoxy, substituted amino or -C (= O) R _3, Where R _x , R _y , g, R ₆ and R ₃ are as defined above;
R ₄ is hydrogen; alkyl, hydroxyl, halogen, or carboxy;
R ₇ is hydrogen or alkyl;
R ₁ is independently hydrogen or alkyl, and R ₂ and R ₄ are optionally substituted fused to ring B having a heteroatom selected from the group consisting of 0 to 4 N, O and S. Optionally forms a 4- to 12-membered saturated or unsaturated monocyclic or bicyclic ring system wherein the substituents are oxo, alkyl, —OC (═O) OR ₃ , —SO ₂ R ₃ , One or more of halogen, hydroxy, alkoxy, —NH ₂ or substituted amino (where R ₃ is as defined below) provided that R ₂ and R ₄ together represent —CH _2. Does not form —O—CH ₂ —O—CH ₂ —;
X ₁ and X ₂ are hydrogen, alkyl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, — (CH ₂ ) _g C (═O) NR _x R _y or _{- (CH 2) g1 C (} = O) is oR ₃ (here, g can be a integer of 0 to 3, g1 may be a an integer of 1 to 3, and R _x, R _y and R ₃ Is as defined above);
X ₁ and X ₂ together can optionally form a cyclic ring fused to ring A shown in Formula I, which contains 3 to 5 carbon atoms in the ring, and 2 to Having 3 heteroatoms N, O or S;
Where R ₃ is alkyl, cycloalkyl or heterocyclyl;
Wherein the halogen can be F, Cl, Br, or I; R _x and R _y are each independently halogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, carboxy , Cycloalkyl, —S (O) _m R ₅ , aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl; m can be an integer between 0 and 2; R ₆ is Can be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl, or heterocyclylalkyl; and wherein R ₅ is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, hetero Arylalkyl, heterocyclyl or heterocyclylalkyl Pharmaceutical compositions are provided, wherein the door.

  In another embodiment, such as one or more type IV phosphodiesterase inhibitors ("PDE-IV"), and muscarinic receptor antagonists (MRAs), beta2-agonists, p38 MAP kinase inhibitors, and corticosteroids Provided is a pharmaceutical composition comprising at least one other active ingredient, and one or more pharmaceutically acceptable excipients, wherein the PDE-IV inhibitor is a compound of the formula described herein, One or more compounds having the structure of Ia and Formula Ib.

Each pharmaceutical composition of the above aspects can comprise one or more of the following aspects. For example, the one or more compounds of Formula Ia and Formula Ib can be selected from the following compounds:
In another embodiment, the β2-agonist is albuterol, salbutamol, virtuterol, pyrbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, alformoterol, formoterol, or a pharmaceutical thereof Selected from acceptable salts or solvates. In yet another embodiment, the corticosteroid is alclomethasone, amsinonide, amelomethasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, croticazone, cyclomethasone, deflazacort, deprodon, dexbudesonide, diflorazone, diflupredone, flurizone, It is selected from halopredone, hydrocortisone, hydrocortisone, methylprednisolone, mometasone, prednisocarbate, prednisolone, rimexolone, thixcortol, triamcinolone, urobetasol, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the p38 kinase inhibitor is a 1- [5-tert-butyl-2-p-tolyl-2H-pyrazole-3- 1 disclosed in co-pending US patent application 60 / 605,344. Yl] -3- [4- (2-morpholin-4-ylethoxy) naphthalen-1-yl] urea; 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3 -[4- (2- (1-oxothiomorpholin-4-yl) ethoxy) naphthalen-1-yl] urea; 1- [5-tert-butyl-2- (2-methylpyridin-5-yl)- 2H-pyrazol-3-yl] -3- [4-2-2-pyridin-4-ylethoxy] naphthalen-1-yl] urea; 1- [5-tert-butyl-2- (2-methoxypyridin-5-yl) ) -2H-pyrazo Ru-3-yl] -3- [4- (2-morpholin-4-ylethoxy) naphthalen-1-yl] urea; and 1- [5-tert-butyl-2-methyl-2H-pyrazol-3-yl ] -3- [4- (2-morpholin-4-ylethoxy) naphthalen-1-yl] urea;
Other p38 kinase inhibitors can be selected from, for example, the following compounds:
In another embodiment, the corticosteroid is alclomethasone, amsinonide, amelomethasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, croticazone, cyclomethasone, deflazacort, deprodon, dexibudesonide, difurazone, diflupredone, flurizone, flurizone, Halopredone, hydrocortisone, hydrocortisone, methylprednisolone, mometasone, prednisocarbate, prednisolone, rimexolone, thixocortorol, triamcinolone, tolterodine, oxybutynin, urobetasol, rofleponide, KSR592, EP 4285937 ST-126 disclosed in 1344526, dexamethasone, And pharmaceutically acceptable salts and solvates thereof. Preferred corticosteroids include, for example, flunizolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclezonide, and dexamethasone, while budesonide, fluticasone, mometasone, ciclesonide. Examples of possible salts or derivatives include sodium salt, sulfobenzoate, phosphate, isonicotinate, acetate, propionate, dihydrogen phosphate, palmitate, pivalate, or furoate . In some cases, corticosteroids can also occur in their hydrated form.

In another embodiment, the muscarinic receptor antagonist can be selected from, for example, tiotropium, methanthelin, ipratropium, propantheline, dicyclomine, scopolamine, telenzepine, benztropine, atropine.
Other muscarinic receptor antagonists can be selected from, for example, the following compounds.

  One or more PDE-IV inhibitors and one or more muscarinic receptor antagonists (MRAs) can be present in the compositions described herein in a ratio of 1:10 to 10: 1.

  One or more PDE-IV inhibitors and one or more β2-agonists can be present in the compositions described herein in a ratio of 1:10 to 10: 1.

  One or more PDE-IV inhibitors and one or more p38 MAP kinase inhibitors can be present in the compositions described herein in a ratio of 1:10 to 10: 1.

  One or more PDE-IV inhibitors and one or more corticosteroids can be present in the compositions described herein in a ratio of 1:10 to 10: 1.

  In another aspect, provided herein is a method of treating an autoimmune, inflammatory, or allergic disease or disorder comprising administering one or more pharmaceutical compositions described herein. The autoimmunity, inflammation or allergic disease or disorder is a respiratory disorder, asthma, chronic bronchitis, chronic obstructive pulmonary disease, whooping cough, eosinophilic granulomas, psoriasis, and other benign or malignant proliferative skin diseases, Eczema, inflammatory bowel disease, endotoxic shock, anaphylactic shock, horseshoe inflammation in horses, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory arthritis, periodontitis, chronic Glomerulonephritis, atopic dermatitis, hives, adult respiratory distress syndrome, infant respiratory distress syndrome, transplant rejection, rhinitis, pruritus, diabetes insipidus, ophthalmitis, allergic rhinitis, allergic conjunctivitis, spring catarrh, arterial re Stenosis, orcerosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, osteoporosis, osteoarthritis, inflammation, ankylosing spondylitis, transplant rejection, graft pair Major rejection, gastric acid hypersecretion, bacteria, fungus-induced sepsis, virus-induced sepsis, fungus-induced sepsis shock, virus-induced sepsis shock, inflammation-mediated chronic tissue degeneration, cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia , Muscle wasting, depressive memory damage, tumor growth, normal tissue cancer invasion, Hashimoto's thyroiditis (low-active thyroid), Grave's disease (overactive thyroid), lupus and acquired immune deficiency syndrome.

According to an embodiment, one or more PDE-IV inhibitors, and at least one other active ingredient selected from a muscarinic receptor antagonist (MRA), a β2-agonist, a p38 MAP kinase inhibitor, and a corticosteroid, and desired Wherein the PDE-IV is one or more compounds having the structure of Formula Ia or Formula Ib;
here,
a. Formula Ia is:

式Ｉａ

およびその医薬上許容される塩、医薬上許容される溶媒和物、エナンチオマー、ジアステレオマーまたはＮ−オキサイドであり、ここに、
Ｘが酸素である場合、
Ｒ₁は水素、アルキル、ヘテロシクリル、−（ＣＨ₂）_mＣ（＝Ｏ）Ｒ₃、または（ＣＨ₂）_1-4ＯＲ’であり（ここに、ｍは０ないし２の整数であり、Ｒ₃はアルキル、シクロアルキル、ヘテロシクリル、または所望により置換されていてもよいＲ_pまたはＲ_qであり、ここに、Ｒ_pはヘテロシクリルまたはヘテロアリール環であり、ここに、該環はＮを介して（ＣＨ₂）_mＣ（＝Ｏ）に結合しており、Ｒ_qはヘテロシクリルまたはヘテロアリール環であり、ここに該環はＣを介して−（ＣＨ₂）_mＣ（＝Ｏ）に結合しており、ここに、Ｒ’はアルキル、アルケニル、アルキニル、飽和または不飽和シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールであり）；
Ｒ₂は（ＣＨ₂）_mＣ（＝Ｏ）Ｒ₃、−（ＣＨ₂）_1-4ＯＲ’、またはＣ（＝Ｏ）ＮＲ_xＲ_yであり｛ここに、ｍ、Ｒ₃およびＲ’は前記定義の通りであり、ここに、Ｒ_xおよびＲ_yは、各々、独立して、水素、アルキル、Ｃ₃−Ｃ₆アルケニル、Ｃ₃−Ｃ₆アルキニル、シクロアルキル、カルボキシ、−Ｓ（Ｏ）_mＲ₅であり（ここに、Ｒ₅は水素、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、アルカリール、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルまたはヘテロシクリルアルキルであり）、アリール、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり｝、あるいはＲ₁およびＲ₂は一緒になって、所望により置換されていてもよいシクロアルキルまたはヘテロシクリル環を形成し、ここに、該所望の置換基はオキソ、アルキル、アルケニル、アルキニル、ハロゲン、ニトロ、−ＮＨ₂、−ＮＨＣ（＝Ｏ）ＯＲ₆、−Ｃ（＝Ｏ）ＮＲ_xＲ_y、シアノ、ヒドロキシ、アルコキシ、または置換されたアミノであり（ここに、Ｒ₆はアルキル、アルケニル、アルキニル、シクロアルキル、アルカリール、ヘテロアリールアルキルまたはヘテロシクリルアルキルであり）、但し、もしＲ₁が−（ＣＨ₂）_1-4ＯＲ’であれば、Ｒ₂は−（ＣＨ₂）_1-4ＯＲ’でもあり、但し、もしＲ₁がＣ（＝Ｏ）ＮＲ_xＲ_yであれば、Ｒ₂はＣ（＝Ｏ）ＮＲ_xＲ_yでもあり；
Ｒ₄は水素；アルキル；−ＯＲ₅；ハロゲン；−ＮＨ₂、置換されたアミノ；シアノ；カルボキシ；または−Ｃ（＝Ｏ）ＮＲ_xＲ_yであり（ここに、Ｒ₅、Ｒ_xおよびＲ_yは前記定義の通りであり）；あるいはＲ₂およびＲ₄は、０ないし４のＮ、ＯおよびＳより成る群より選択されたヘテロ原子を有する環Ｂと縮合した所望により置換されていてもよい４ないし１２員の飽和または不飽和単環または二環の環系を形成し、ここに、該置換基はアルキル、ハロゲン、ヒドロキシ、アルコキシ、−ＮＨ₂または置換されたアミノの１以上であり（ここに、Ｒ₅およびＲ_xおよびＲ_yは前記定義の通りであり）、但し、Ｒ₂およびＲ₄は一緒になって−ＣＨ₂−Ｏ−ＣＨ₂−Ｏ−ＣＨ₂−を形成せず；
Ｒ₇は水素、アルキル、アルケニル、アルキニル、−ＯＲ₅、ハロゲン、シアノ、−ＮＨ₂、または置換されたアミノであり；
Ｘ₁およびＸ₂は、各々、独立して、水素、アルキル、アルカリール、シクロアルキル、アルカリール、アルケニル、シクロアルキルアルキル、ヘテロシクリル、ヘテロアリール、ヘテロシクリルアルキル、−（ＣＨ₂）_gＣ（＝Ｏ）ＮＲ_xＲ_y、−（ＣＨ₂）_g1Ｃ（＝Ｏ）ＯＲ₃またはヘテロアリールアルキルであり；ここに、ｇ１は１ないし３の整数であり（ここに、Ｒ_x、Ｒ_y、ｇおよびＲ₃は前記定義の通りであり）；
Ｙは、各々、独立して、酸素原子；硫黄原子；または−ＮＲであり（ここに、Ｒは水素、アシル、アリール、またはアルキルであり）；
Ｙ₁およびＹ₂は、各々、独立して、水素；アルキル；−ＯＲ；−ＳＲ；または−ＮＨＲであり（ここに、Ｒは前記定義の通りであり）；
ここに、Ｙ₁およびＸ₂、ならびにＸ₁およびＹ₂のいずれかは所望により一緒になって環Ａと縮合した環を形成し、該環は該環内に３ないし５の炭素原子を含有し、かつ１ないし３のＮ、ＯおよびＳのようなヘテロ原子を有し、およびＸ₁およびＸ₂は所望により一緒になって環Ａと縮合した環を形成し、該環は該環内に３ないし５の炭素原子を含有し、かつ２ないし３のＮ、ＯおよびＳのようなヘテロ原子を有し、および
ＸがＮＲ₇またはＳ（ここに、Ｒ₇は水素またはＣ_1-6アルキルであり得る）である場合、
Ｒ₁およびＲ₂は、独立して、アルキル、アルケニル、アルキニル、アルコキシ、ヒドロキシ、シアノ、ニトロ、ハロゲン、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクリルアルキル、ＮＨ₂、置換されたアミノ、カルボキシ、−（ＣＨ₂）_mＣ（＝Ｏ）Ｒ₃、−Ｃ（＝Ｏ）ＮＲ_xＲ_y、または（ＣＨ₂）_1-4ＯＲ’であり｛ここに、ｍは０ないし２の整数であり、Ｒ₃はアルキル、シクロアルキル、ヘテロシクリル、または所望により置換されていてもよいＲ_pまたはＲ_qであり（ここに、Ｒ_pはヘテロシクリルまたはヘテロアリール環であり、ここに、該環はＮを介して（ＣＨ₂）_mＣ（＝Ｏ）に結合し、およびＲ_qはヘテロシクリルまたはヘテロアリール環であり、ここに、該環はＣを介して−（ＣＨ₂）_mＣ（＝Ｏ）に結合し）、ここに、Ｒ’はアルキル、アルケニル、アルキニル、飽和または不飽和シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールであり、および、ここに、Ｒ_xおよびＲ_yは、各々、独立して、水素、アルキル、Ｃ₃−Ｃ₆アルケニル、Ｃ₃−Ｃ₆アルキニル、シクロアルキル、カルボキシ、Ｓ−（Ｏ）_mＲ₅であり（ここに、Ｒ₅は水素、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、アルカリール、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルまたはヘテロシクリルアルキルであり）、アリール、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり｝、あるいはＲ₁およびＲ₂は一緒になって所望により置換されていてもよいシクロアルキルまたはヘテロシクリル環を形成し、ここに、該所望の置換基はオキソ、アルキル、アルケニル、アルキニル、ハロゲン、ニトロ、−ＮＨ₂、−ＮＨＣ（＝Ｏ）ＯＲ₆（ここに、Ｒ₆はアルキル、アルケニル、アルキニル、シクロアルキル、アルカリール、ヘテロアリールアルキルまたはヘテロシクリルアルキルであり）、−Ｃ（＝Ｏ）ＮＲ_xＲ_y、シアノ、ヒドロキシ、アルコキシ、または置換されたアミノであり；
Ｒ₄は水素；アルキル；−ＯＲ₅；ハロゲン；−ＮＨ₂、置換されたアミノ；シアノ；カルボキシ；または−Ｃ（＝Ｏ）ＮＲ_xＲ_yであり（ここに、Ｒ₅、Ｒ_xおよびＲ_yは前記定義の通りである）；あるいはＲ₂およびＲ₄は、０ないし４のＮ、ＯおよびＳより成る群から選択されたヘテロ原子を有する環Ｂに縮合した所望により置換されていてもよい４ないし１２員の飽和または不飽和単環または二環の環系を形成し、ここに、該置換基はアルキル、ハロゲン、ヒドロキシ、アルコキシまたは置換されたアミノの１以上であることができ（ここに、Ｒ₃およびＲ_xおよびＲ_yは前記定義の通りであり）、但し、Ｒ₂およびＲ₄は一緒になって−ＣＨ₂−Ｏ−ＣＨ₂−Ｏ−ＣＨ₂−を形成せず；
Ｒ₇は水素、アルキル、アルケニル、アルキニル、−ＯＲ₅、ハロゲン、シアノ、−ＮＨ₂、または置換されたアミノであり；
Ｘ₁およびＸ₂は、各々、独立して、アルキル、シクロアルキル、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり；
Ｙは、各々、独立して酸素原子；硫黄原子；または−ＮＲであり（ここに、Ｒは水素、アシル、アリール、またはアルキルであり）；
Ｙ₁およびＹ₂は、各々、独立して、水素、アルキル、−ＯＲ、−ＳＲ、または−ＮＨＲであり（ここに、Ｒは前記定義の通りであり）；
ここに、Ｙ₁およびＸ₂、ならびにＸ₁およびＹ₂は所望により一緒になって環Ａに縮合した環を形成し、該環は該環内に３ないし５の炭素原子を含有し、かつＮ、ＯおよびＳのような１ないし３のヘテロ原子を有し；
Ｘ₁およびＸ₂は所望のより一緒になって、該環Ａと縮合した環状環を形成でき、該環は該環内に３ないし５の炭素原子を含有し、かつＮ、ＯおよびＳのような２ないし３のヘテロ原子を有し、および
ｂ．式Ｉｂは：

Formula Ia

And pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides thereof, wherein
When X is oxygen,
R ₁ is hydrogen, alkyl, heterocyclyl, — (CH ₂ ) _m C (═O) R ₃ , or (CH ₂ ) _1-4 OR ′ (where m is an integer from 0 to 2, ₃ is an alkyl, cycloalkyl, heterocyclyl, or optionally substituted R _p or R _q , wherein R _p is a heterocyclyl or heteroaryl ring, wherein the ring is Bonded to (CH ₂ ) _m C (═O), R _q is a heterocyclyl or heteroaryl ring, wherein the ring is bonded to — (CH ₂ ) _m C (═O) via C; Wherein R ′ is alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl);
R ₂ is (CH ₂ ) _m C (═O) R ₃ , — (CH ₂ ) _1-4 OR ′, or C (═O) NR _x R _y {where m, R ₃ and R ′ Is as defined above, wherein R _x and R _y are each independently hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, cycloalkyl, carboxy, —S ( O) _m R ₅ where R ₅ is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl,}, or R ₁ and R ₂ together may be optionally substituted by Shikuroa Forming Kill or heterocyclyl ring, where the substituents of said desired oxo, alkyl, alkenyl, alkynyl, halogen, _{nitro, -NH 2, -NHC (= O} ) OR 6, -C (= O) NR x R _y , cyano, hydroxy, alkoxy, or substituted amino (where R ₆ is alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), provided that R ₁ Is — (CH ₂ ) _1-4 OR ′, R ₂ is also — (CH ₂ ) _1-4 OR ′, provided that if R ₁ is C (═O) NR _x R _y , R ₂ is also C (═O) NR _x R _y ;
R ₄ is hydrogen; alkyl; -OR _5; halogen; -NH _2, substituted amino, cyano, carboxy; or -C (= O) a NR _x R _y (herein, R _5, R _x and R _y is as defined above; or R ₂ and R ₄ may be optionally substituted fused with ring B having a heteroatom selected from the group consisting of 0 to 4 N, O and S Form a good 4- to 12-membered saturated or unsaturated monocyclic or bicyclic ring system, wherein the substituent is one or more of alkyl, halogen, hydroxy, alkoxy, —NH ₂ or substituted amino (Where R ₅ and R _x and R _y are as defined above), provided that R ₂ and R ₄ together form —CH ₂ —O—CH ₂ —O—CH ₂ —. Z;
R ₇ is hydrogen, alkyl, alkenyl, alkynyl, —OR ₅ , halogen, cyano, —NH ₂ , or substituted amino;
X ₁ and X ₂ are each independently hydrogen, alkyl, alkaryl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, — (CH ₂ ) _g C (═O ) NR _x R _y , — (CH ₂ ) _g1 C (═O) OR ₃ or heteroarylalkyl; where g1 is an integer from 1 to 3 (where R _x , R _y , g and R ₃ is as defined above);
Y is each independently an oxygen atom; a sulfur atom; or —NR (where R is hydrogen, acyl, aryl, or alkyl);
Y ₁ and Y ₂ are each independently hydrogen; alkyl; —OR; —SR; or —NHR (where R is as defined above);
Where Y ₁ and X ₂ and either X ₁ and Y ₂ are optionally joined together to form a fused ring with ring A, the ring containing from 3 to 5 carbon atoms in the ring And having 1 to 3 heteroatoms such as N, O and S, and X ₁ and X ₂ are optionally joined together to form a fused ring with ring A, wherein the ring is within the ring Containing 3 to 5 carbon atoms and 2 to 3 heteroatoms such as N, O and S, and X is NR ₇ or S (where R ₇ is hydrogen or C _1-6 Can be alkyl)
R ₁ and R ₂ are independently alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, nitro, halogen, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, NH ₂ , substituted amino, carboxy, — (CH ₂ ) _m C (═O) R ₃ , —C (═O) NR _x R _y , or (CH ₂ ) _1-4 OR ′ {where m is an integer from 0 to 2, R ₃ is alkyl, cycloalkyl, heterocyclyl, or optionally substituted R _p or R _q (where R _p is a heterocyclyl or heteroaryl ring, wherein the ring is Te (CH ₂₎ attached to _m C (= O), and R _q is heterocyclyl or heteroaryl ring, where said ring via a C - (CH _{2) m} C ( Bound to O)), herein, R 'is alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl, and wherein the, R _x and R _y are each independently Hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, cycloalkyl, carboxy, S— (O) _m R ₅ , where R ₅ is hydrogen, alkyl, alkenyl, alkynyl. , Aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl}, or R ₁ and R ₂ optionally substituted together Forming a which may cycloalkyl or heterocyclyl ring, wherein the substituents of said desired oxo, alkyl, alkenyl, alkynyl, halogen, nitro, -NH _2, a -NHC (= O) OR ₆ (wherein, R ₆ Is alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), —C (═O) NR _x R _y , cyano, hydroxy, alkoxy, or substituted amino;
R ₄ is hydrogen; alkyl; -OR _5; halogen; -NH _2, substituted amino, cyano, carboxy; or -C (= O) a NR _x R _y (herein, R _5, R _x and R _y is as defined above; or R ₂ and R ₄ may be optionally substituted fused to ring B having a heteroatom selected from the group consisting of 0 to 4 N, O and S; Form a good 4- to 12-membered saturated or unsaturated monocyclic or bicyclic ring system, wherein the substituent can be one or more of alkyl, halogen, hydroxy, alkoxy or substituted amino ( Wherein R ₃ and R _x and R _y are as defined above), provided that R ₂ and R ₄ together do not form —CH ₂ —O—CH ₂ —O—CH ₂ —. ;
R ₇ is hydrogen, alkyl, alkenyl, alkynyl, —OR ₅ , halogen, cyano, —NH ₂ , or substituted amino;
X ₁ and X ₂ are each independently alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl;
Y is each independently an oxygen atom; a sulfur atom; or —NR (where R is hydrogen, acyl, aryl, or alkyl);
Y ₁ and Y ₂ are each independently hydrogen, alkyl, —OR, —SR, or —NHR (where R is as defined above);
Wherein Y ₁ and X ₂ , and X ₁ and Y ₂ are optionally joined together to form a ring fused to ring A, the ring containing from 3 to 5 carbon atoms in the ring, and Having 1 to 3 heteroatoms such as N, O and S;
X ₁ and X ₂ can be combined together as desired to form a cyclic ring fused with the ring A, the ring containing 3 to 5 carbon atoms in the ring, and N, O and S Having 2 to 3 heteroatoms, and b. Formula Ib is:

式Ｉｂ

およびその医薬上許容される塩、医薬上許容される溶媒和物、エナンチオマー、ジアステレオマー、Ｎ−オキシドであり、ここに、
Ｒ₁およびＲ₂は一緒になって所望により置換されていてもよいシクロアルキルまたはヘテロシクリル環を形成し、ここに、１以上の所望の置換基はオキソ、アルキル、アルカリール、アルケニル、アルキン、ヘテロシクリルアルキル、シクロアルキルアルキル、−ＳＯ₂ＮＲ_xＲ_y、ハロゲン、−ＮＨ₂、−（ＣＨ₂）_gＣ（＝Ｏ）ＮＲ_xＲ_y、−ＮＨＣ（＝Ｏ）ＯＲ₆、−ＮＨＣ（＝Ｏ）ＮＲ_xＲ_y、−Ｃ（＝Ｏ）ＯＲ₃、−ＮＨＣ（＝Ｏ）Ｒ_x、−ＳＯ₂Ｒ₃、シアノ、ヒドロキシ、アルコキシ、置換されたアミノ、または−Ｃ（＝Ｏ）Ｒ₃であり（ここに、Ｒ_x、Ｒ_y、ｇ、Ｒ₆およびＲ₃は前記定義の通りであり）；
Ｒ₄は水素；アルキル、ヒドロキシル、ハロゲン、またはカルボキシであり；
Ｒ₇は水素、またはアルキルであり；
Ｒ₁は独立して水素またはアルキルであり、およびＲ₂およびＲ₄は、０ないし４のＮ、ＯおよびＳより成る群から選択されたヘテロ原子を有する環Ｂに縮合した所望により置換されていてもよい４ないし１２員の飽和または不飽和単環または二環の環系を形成し、ここに、該置換基はオキソ、アルキル、−ＯＣ（＝Ｏ）ＯＲ₃、−ＳＯ₂Ｒ₃、ハロゲン、ヒドロキシ、アルコキシ、−ＮＨ₂または置換されたアミノの１以上であり（ここに、Ｒ₃は後の定義の通りであり）、但し、Ｒ₂およびＲ₄は一緒になって−ＣＨ₂−Ｏ−ＣＨ₂−Ｏ−ＣＨ₂−を形成せず；
Ｘ₁およびＸ₂は水素、アルキル、シクロアルキル、アルカリール、アルケニル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクリルアルキル、−（ＣＨ₂）_gＣ（＝Ｏ）ＮＲ_xＲ_yまたは−（ＣＨ₂）_g1Ｃ（＝Ｏ）ＯＲ₃であり（ここに、ｇは０ないし３の整数であり得、ｇ１は１ないし３の整数であり得、およびＲ_x、Ｒ_yおよびＲ₃は前記定義の通りであり）；
Ｘ₁およびＸ₂は一緒になって、所望により、式Ｉに示した環Ａと縮合した環状環を形成でき、該環は該環内に３ないし５の炭素原子を含有し、および２ないし３のヘテロ原子Ｎ、ＯまたはＳを有し；
ここに、Ｒ₃はアルキル、シクロアルキルまたはヘテロシクリルであり；
ここに、該ハロゲンはＦ、Ｃｌ、Ｂｒ、またはＩであり得；Ｒ_xおよびＲ_yは、各々、独立して、水素、アルキル、Ｃ₃−Ｃ₆アルケニル、Ｃ₃−Ｃ₆アルキニル、カルボキシ、シクロアルキル、−Ｓ（Ｏ）_mＲ₅、アリール、アルカリール、ヘテロアリール、ヘテロシクリル、ヘテロアリールアルキル、およびヘテロシクリルアルキルであり得；ｍは０ないし２の間の整数であり得；Ｒ₆はアルキル、アルケニル、アルキニル、シクロアルキル、アルカリール、ヘテロアリールアルキル、またはヘテロシクリルアルキルであり得；
ここに、Ｒ₅は水素、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、アルカリール、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルまたはヘテロシクリルアルキルであることを特徴とする組成物が提供される。

Formula Ib

And pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides thereof, wherein
R ₁ and R ₂ together form an optionally substituted cycloalkyl or heterocyclyl ring, wherein one or more desired substituents are oxo, alkyl, alkaryl, alkenyl, alkyne, heterocyclyl Alkyl, cycloalkylalkyl, —SO ₂ NR _x R _y , halogen, —NH ₂ , — (CH ₂ ) _g C (═O) NR _x R _y , —NHC (═O) OR ₆ , —NHC (═O _{) NR x R y, -C (} = O) oR 3, -NHC (= O) R x, -SO 2 R 3, cyano, hydroxy, alkoxy, substituted amino or -C (= O) R _3, Where R _x , R _y , g, R ₆ and R ₃ are as defined above;
R ₄ is hydrogen; alkyl, hydroxyl, halogen, or carboxy;
R ₇ is hydrogen or alkyl;
R ₁ is independently hydrogen or alkyl, and R ₂ and R ₄ are optionally substituted fused to ring B having a heteroatom selected from the group consisting of 0 to 4 N, O and S. Optionally forms a 4- to 12-membered saturated or unsaturated monocyclic or bicyclic ring system wherein the substituents are oxo, alkyl, —OC (═O) OR ₃ , —SO ₂ R ₃ , One or more of halogen, hydroxy, alkoxy, —NH ₂ or substituted amino (where R ₃ is as defined below) provided that R ₂ and R ₄ together represent —CH _2. Does not form —O—CH ₂ —O—CH ₂ —;
X ₁ and X ₂ are hydrogen, alkyl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, — (CH ₂ ) _g C (═O) NR _x R _y or _{- (CH 2) g1 C (} = O) is oR ₃ (here, g can be a integer of 0 to 3, g1 may be a an integer of 1 to 3, and R _x, R _y and R ₃ Is as defined above);
X ₁ and X ₂ together can optionally form a cyclic ring fused to ring A shown in Formula I, which contains 3 to 5 carbon atoms in the ring, and 2 to Having 3 heteroatoms N, O or S;
Where R ₃ is alkyl, cycloalkyl or heterocyclyl;
Wherein the halogen may be F, Cl, Br, or I; R _x and R _y are each independently hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, carboxy , Cycloalkyl, —S (O) _m R ₅ , aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl; m can be an integer between 0 and 2; R ₆ is Can be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl, or heterocyclylalkyl;
There is provided a composition wherein R ₅ is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl.

  In another embodiment, selected from one or more type IV phosphodiesterase inhibitors (“PDE-IV”), and muscarinic receptor antagonists (MRAs), β2-agonists, p38 MAP kinase inhibitors, and corticosteroids. A pharmaceutical composition comprising at least one other active ingredient and one or more pharmaceutically acceptable excipients, wherein the PDE-IV inhibitor is described herein, One or more compounds having the structure of Formula Ia and Formula Ib.

Each pharmaceutical composition of the above embodiments can comprise, for example, one or more of the exemplary compounds of formula Ia or formula Ib:
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-6-ol (Compound No. 1),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -N- (4-fluorophenyl) -1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-carboxamide (compound Number 2),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -7- (tetrahydrofuran-3-ylcarbonyl) -1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 3) ),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -N, N-dimethyl-1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-sulfonamide (Compound No. 4 ),
N-butyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-carboxamide (Compound No. 5),
2- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-en-7-yl} acetamide (Compound No. 6),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8-propyl-1-oxa-2,8-diazaspiro [4.5] dec-2-ene hydrochloride (Compound No. 7),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -8- (2-morpholin-4-yl-ethyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene ( Compound No. 8),
N-butyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-8-carboxamide (Compound No. 9),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8- (methylsulfonyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 10),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.4] non-2-ene (Compound No. 11),
3- [3,4-bis (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 12),
3- (3,4-diisopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 13),
3- [3-methoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 14),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-8-one (Compound No. 15),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-8-ol (Compound No. 16),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -7-isopropyl-1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 17),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -7- (cyclopropylcarbonyl) -1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 18),
N-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-carboxamide (Compound No. 19),
7-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 20),
Tert-butyl 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene-7-carboxylate (Compound No. 21),
N-butyl-N ′-{3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} urea (Compound No. 22),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} -N ′-(2-methoxyphenyl) ) Urea (compound number 23),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-ol (Compound No. 24),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene hydrochloride (Compound No. 25),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-one (Compound No. 26),
3- [3,4-bis (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 27),
3- [3,4-bis (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 28),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-4-ol (Compound No. 29),
(R) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 30),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8- (cyclopropylmethyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 31),
N-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-8-carboxamide (Compound No. 32),
3- [3,4-bis (benzyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 33),
4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) benzene-1,2-diol (Compound No. 34),
7-amino-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-en-6-one (Compound No. 35),
Ethyl 8-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-4-carboxylate (Compound No. 36) ,
3- [3- (cyclopentyloxy) -4- [methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-ene-4-carboxylic acid (Compound No. 37),
8-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 38),
Ethyl 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-ene-4-carboxylate (Compound No. 39);
3- [3- (difluoromethoxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 40),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 41),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-en-6-one (Compound No. 42),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 6a-dimethyl-3aH-cyclopenta [d] isoxazole-4,6 (5H, 6aH) -dione (Compound No. 43),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 4,6,6a-tetrahydrofuro [3,4-d] isoxazole (Compound No. 44),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -6,6a-dihydrofuro [3,4-d] isoxazol-4 (3aH) -one (Compound No. 45),
[({3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} amino) carbonyl] carbamate tert-butyl (Compound No. 46),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} cyclopentanecarboxamide (Compound No. 47),
8-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 48),
8- (cyclopentylcarbonyl) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 49),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -8- (2-piperidin-1-ylethyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 50),
3- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 51),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,8-dioxa-2-azaspiro [4.5] dec-2-ene (Compound No. 52),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3aH-cyclopenta [d] isoxazole-4,6 (5H, 6aH) -dione (Compound No. 53),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8-ethyl-1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 54),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8-vinyl-1-oxa-2-azaspiro [4.5] dec-2-en-8-ol (Compound No. 55),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 4,5,6,7,7a-hexahydro-1,2-benzisoxazole (Compound No. 56),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole (Compound No. 57),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} methanesulfonamide (Compound No. 58),
3- [3- (cyclopentyloxy)]-4-methoxyphenyl] -8-methyl-1-oxa-2-azaspiro [4.5] dec-2-en-8-ol (Compound No. 59),
3- [3- (allyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 60),
3- [3- (2-chloroethoxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 61),
2- (cyclopentyloxy) -4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 62),
3- (4-butoxy-3-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 63),
3- (3-isobutoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 64),
3- [3-butoxy-4- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 65),
3- (3-butoxy-4-ethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 66),
3- [3-butoxy-4- (cyclohexyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 67),
3- [3- (cyclohexylmethoxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 68),
3- [3- (cyclohexylmethoxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 69),
3- [4-butoxy-3- (cyclohexylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 70),
3- (4-isobutoxy-3-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 71),
3- (4-butoxy-3-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 72),
3- [4- (cyclohexylmethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 73),
3- [3-isopropoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 74),
3- [3- (cyclopropylmethoxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 75),
3- [3- (cyclopropylmethoxy) -4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 76),
3- [4-butoxy-3- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 77),
3- [3- (cyclopropylmethoxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 78),
3- (3-isobutoxy-4-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 79),
3- [4- (cyclopropylmethoxy) -3-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 80),
3- [4- (cyclohexyloxy) -3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 81),
3- [4- (cyclohexylmethoxy) -3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 82),
3- [4- (cyclopropylmethoxy) -3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 83),
3- [3- (cyclopentyloxy) -4-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 84),
3- [3- (cyclopentyloxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 85),
3- [3- (cyclopropylmethoxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 86),
3- [4- (cyclopentyloxy) -3-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 87),
3- [3-isopropoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 88),
3- (4-ethoxy-3-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 89),
3- [3- (cyclopentyloxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 90),
3- [4-butoxy-3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 91),
3- [3- (cyclopentyloxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 92),
3- [3- (cyclopentyloxy) -4- (cycloheptyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 93),
3- [3- (cyclopentyloxy) -4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 94),
3- [4- (cyclohexylmethoxy) -3-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 95),
3- [4- (cyclohexylmethoxy) -3- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 96),
3- [3- (cyclopropylmethoxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 97),
3- [4- (cyclopentyloxy) -3- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 98),
3- [4- (cyclopropylmethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 99),
3- [4- (cyclopentyloxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 100),
3- (3-isopropoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 101),
3- (4-ethoxy-3-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 102),
3- [3-butoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 103),
3- [3-butoxy-4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 104),
3- (3-butoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 105),
3- (3-butoxy-4-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 106),
3- [3- (cyclohexylmethoxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 107),
3- [3- (cyclohexylmethoxy) -4-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 108),
3- [3- (cyclohexylmethoxy) -4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 109),
3- [3- (cyclohexylmethoxy) -4- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 110),
3- [4- (cyclohexylmethoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 111),
3- [4- (cyclopropylmethoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 112),
3- [4- (cyclopentyloxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 113),
3- [4- (3-isobutoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 114),
3- [3- (cycloheptyloxy) -4- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 115),
3- [3- (cycloheptyloxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 116),
3- [4-butoxy-3- (cycloheptyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 117),
3- [3- (cycloheptyloxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 118),
3- [3- (cycloheptyloxy) -4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 119),
3- (3-ethoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 120),
3- [4- (cycloheptyloxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 121),
3- [4- (cyclopropylmethoxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 122),
3- [4- (cyclohexylmethoxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 123),
(S) -3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 124),
3- (3-butoxy-4-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 125),
3- (3-ethoxy-4-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 126),
3- [4- (cyclopentyloxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 127),
3- (4-butoxy-3-ethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 128),
3- (3-ethoxy-4-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 129),
3- [3- (cycloheptyloxy) -4-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 130),
3- [3- (cycloheptyloxy) -4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 131),
3- [3- (cycloheptyloxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 132),
3- (4-butoxy-3-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 133),
3- (4-ethoxy-3-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 134),
3- [4- (morpholin-4-ylethoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 135),
3- (4-isopropoxy-3-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 136),
2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] cyclopentanol (Compound No. 137),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} -2-fluorobenzamide (Compound No. 138) ),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} benzamide (Compound No. 139),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] isoxazole (Compound No. 140),
7- (cyclopentylcarbonyl) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene (Compound No. 141),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3a, 4,6,6a-tetrahydro-5H-pyrrolo [3,4-d] isoxazole-5-carboxylate tert-butyl (Compound No. 142 ),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-8-carboxamide (Compound No. 143),
N-butyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene-7-carboxamide (Compound No. 144),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -7- (methylsulfonyl) -1-oxa-2,7-diazaspiro [4.5] dec-2-ene (Compound No. 145),
3- [4-methoxy-3- (pyridin-3-ylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 146),
5-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] isoxazole (Compound No. 147),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -5- (methylsulfonyl) -4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] isoxazole (Compound No. 148) ,
4-bromo-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 149),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 5,6,7a-tetrahydro-1,2-benzisoxazol-7 (4H) -one (Compound No. 150),
3- [4- (Difluoromethoxy) -3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene ( Compound No. 151),
3- [4- (Cyclopentyloxy) -3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene ( Compound No. 152),
3- [4-Butoxy-3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 153 ),
3- (3-{[3- (benzyloxy) cyclopentyl] oxy} -4-methoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 154),
7-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene (Compound No. 155),
3- [4-methoxy-3- (pyridin-2-ylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 156),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 157 ),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 158) ),
3- [4- (Cyclopropylmethoxy) -3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 159),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 160),
2- (2,3-dihydro-1H-inden-2-yloxy) -4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 161) ),
N-cyclopropyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] acetamide (Compound No. 162),
3- [4-methoxy-3- (piperidin-3-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene hydrochloride (Compound No. 163),
2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] acetamide (Compound No. 164),
[5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] ethyl acetate (Compound No. 165),
[5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] acetonitrile (Compound No. 166),
3- {3-[(2,6-dichloropyridin-4-yl) methoxy] -4-methoxyphenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 167 ),
[3- (3-Cyclopentyloxy-4-methoxyphenyl) -5- (4-carboxylic acid tertbutyl ester-piperazin-1-yl-carbonyl) -4,5-dihydroisoxazol-5-yl]-({ 4-carboxylic acid-tertbutyl ester piperazin-1-yl) ethanone (Compound No. 168),
1- {1- [5- (4-acetyl-4-phenyl-piperidine-1-carbonyl) -3- (3-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-isoxazole-5- Yl] -4-acetyl-4-phenyl-piperidin-4-yl} -ethanone (Compound No. 169),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (pyrrolidin-1-carbonyl) -4,5-dihydro-isoxazol-5-yl] -pyrrolidin-1-yl-ethanone (Compound No. 170),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (piperidin-1-carbonyl) -4,5-dihydro-isoxazol-5-yl] -piperidin-1-yl-ethanone (Compound No. 171),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (pyrrolidine-2-carboxylic acid methyl ester-1-carbonyl) -4,5-dihydro-isoxazol-5-yl)-[{pyrrolidine- 2-Carboxylic acid methyl ester-5-yl] ethanone (Compound No. 172),
[5- [4- (4-Chlorophenyl) -4-hydroxy-piperidine-1-carbonyl] -3- (3-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-isoxazol-5-yl ]-[4- (4-Chlorophenyl) -4-hydroxy-piperidin-1-yl] -ethanone (Compound No. 173),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (hydroxymethyl-piperidin-1-carbonyl) -4,5-dihydro-isoxazol-5-yl]-(4-hydroxymethyl-piperidine -1-yl) -ethanone (Compound No. 174),
[5- (5-Benzyl-2,5-diazabicyclo [2.2.1] heptane-2- (carbonyl) -3- (3-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-iso Oxazol-5-yl] -5-benzyl-2,5-diazabicyclo- [2.2.1] hept-2-yl-ethanone (Compound No. 175),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -piperzin-1-yl-methanone (Compound No. 176),
4- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (Compound No. 177) ),
1- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-carbonyl] -pyrrolidine-2-carboxylic acid (Compound No. 178),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -pyrrolidine-2-carboxylic acid methyl ester (Compound No. 179),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -pyrrolidin-1-yl-methanone (Compound No. 180),
[1-4] -Bipiperidinyl-1-yl- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] methanone (Compound No. 181 ),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -4-phenyl-piperidin-4-yl} -ethanone (compound Number 182),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-methyl-piperazin-1-yl) -methanone (Compound No. 183),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -piperazin-1-yl-methanone (Compound No. 184),
[4- (4-Chloro-phenyl) -4-hydroxy-piperidin-1-yl]-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydroisoxazole- 5-yl] -methanone (Compound No. 185),
{4- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl]-[1,4] diazepan-1-yl}-[ 3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (Compound No. 186),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-cyclopropylmethyl-piperazin-1-yl) -methanone ( Compound No. 187),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-isobutyl-1-piperazin-1-yl) -methanone ( Compound No. 188),
[3-Hydroxymethyl-piperidin-1-yl]-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (compound Number 189),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-hydroxy-piperidin-1-yl) -methanone (Compound No. 190),
(4-Benzyl-piperidin-1-yl)-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (Compound No. 191),
1- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -piperidin-4-one (Compound No. 192),
[4- (4-Bromophenyl) -4-hydroxy-piperidin-1-yl]-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole- 5-yl] -methanone (Compound No. 193),
(5-Benzyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro -Isoxazol-5-yl] -methanone (Compound No. 194),
(4-Benzyl-piperazin-1-yl)-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (Compound No. 195),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -pyrrolidine-2-carboxylic acid methylamide (Compound No. 196),
1- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -pyrrolidine-2-carboxylic acid diethylamide (Compound No. 197),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(2-hydroxymethyl-pyrrolidin-1-yl) -methanone (compound Number 198),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydroisoxazole-5-carbonyl] -piperidine-2-carboxylic acid methyl ester (Compound No. 199),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carboxyl] -pyrrolidine-2-carboxylic acid amide (Compound No. 200),
3- [3- (3-Cyclopentyloxy-4-methyl-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -bicyclo [2.2.1] heptan-2-one ( Compound No. 201),
3- [3-cyclopentyloxy-4-methoxy-phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-en-6-one (Compound No. 202),
3- [3-Cyclopentyloxy-4-methoxy-phenyl) -7-methyl-1-oxa-2,7-diaza-spiro [4.4] non-2-ene-6,9-dione (Compound No. 203) ),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl- (2-methoxymethyl-pyrrolidin-1-yl) -methanone (compound number 204),
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 205),
3- (3-cyclopropylmethoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 206),
3- (4-difluoromethoxy-3-propoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 207),
3- (4-difluoro-3-butoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 208),
3- (4-difluoromethoxy-3-isobutoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 209),
3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 210),
3- (3-benzyloxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 211),
3- (4-difluoromethoxy-3-cyclopentyloxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 212),
3- (3,4-bis-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 213),
3- (3-butoxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 214),
3- [3- (Bicyclo [2.2.1] hept-2-yloxy) -4-difluoromethoxy-phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 215),
3- (4-difluoromethoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 216),
3- (4-benzyloxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 217),
3- (3-cycloheptyloxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 218),
4- (1,7-dioxa-2-aza-spiro [4.4] non-2-en-3-yl) -2-methoxy-phenol (Compound No. 219),
3- [3- (Indan-2-yloxy) -4-methoxy-phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 220),
3- (4-ethoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 221),
3- (3-methoxy-4-propoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 222),
3- (4-Isopropoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 223),
3- (4-butoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 224),
3- (4-cyclopentyloxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 225),
3- (4- (isobutoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 226),
3- (4-cyclohexyloxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 227),
3- (4-cyclopropylmethoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 228),
3- (3,4-dimethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 229),
3- (3-ethoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 230),
3- (4-methoxy-3-propoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 231),
3- (3-isopropoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 232),
3- (3-butoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 233),
3- (3-isobutoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 234),
3- [4-methoxy-3- (3-methyl-butoxy) -phenyl-1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 235),
3- (3-cyclohexyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 236),
3- (3-cycloheptyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 237),
3- [4-Methoxy-3- (2-morpholin-4-yl-ethoxy) -phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 238) ,
3- (3-benzyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 239),
5- (1,7-dioxa-2-aza-spiro [4.4] non-2-en-3-yl) -2-methoxy-phenol (Compound No. 240),
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carboxylic acid isopropyl ester (Compound No. 241),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene hydrochloride (Compound No. 242),
4-Chloro-N- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carbonyl] -benzene Sulfonamide (Compound No. 243),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carboxylic acid- (2,6-difluoro-phenyl ) -Amide (Compound No. 244),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carboxylic acid- (2,4-dichloro-phenyl ) -Amide (Compound No. 245),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-en-8-yl] -carbamic acid isopropyl ester (Compound No. 246) ,
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-en-8-ylamine hydrochloride (Compound No. 247),
2- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-en-8-yl] -isoindole-1,3- Dione (Compound No. 248),
7- (3-cyclopentyloxy-4-methoxy-phenyl) -5-oxa-6-aza-spiro [3.4] oct-6-ene (Compound No. 249),
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-ene (Compound No. 250),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,7-diaza-spiro [4.4] non-2-ene-7-carboxylic acid tert-butyl ester (Compound No. 251) ,
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,7-diaza-spiro [4.4] non-2-ene hydrochloride (Compound No. 252),
3- [3-{[(3S) -1-benzylpyrrolidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 253),
3- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] propan-1-ol (Compound No. 254),
[2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] acetonitrile (Compound No. 255),
4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 256),
4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 257),
5-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 258),
(5S or 5R) -3- (3,4-dimethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 259),
(5R or 5S) -3- (3,4-dimethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 260),
2- (benzyloxy) -4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 261),
2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] ethanol (Compound No. 262),
3- [4- (difluoromethoxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 263),
3- [3- (cyclohexyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 264),
(5R or 5S) -3- [4- (difluoromethoxy) -3-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 265),
(5S or 5R) -3- [4- (difluoromethoxy) -3-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 266),
[2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] ethyl acetate (Compound No. 267),
3- [4- (difluoromethoxy) -3- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 268),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylcyclohexanecarboxylate (Compound No. 269),
5- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pentanoic acid (Compound No. 270),
3- [3- (2,2,2-trifluoroethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 271) ,
3- [3- (cyclopentylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 272),
N-cyclopropyl-2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] acetamide (Compound No. 273) ,
2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] acetamide (Compound No. 274),
2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] -N-methylacetamide (Compound No. 275),
3- [3- (Cyclopentyloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 276) ,
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylcyclopropanecarboxylate (Compound No. 277),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylmorpholine-4-carboxylate (Compound No. 278),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylbenzoate (Compound No. 279),
5- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pentanamide (Compound No. 280),
3- [3-propoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 281),
3- [3-isopropoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 282),
3- [3- (Cyclopropylmethoxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 283) ),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4 ] Non-2-ene (Compound No. 284),
5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenol (Compound No. 285),
3- [3-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 286),
3- [3-ethoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 287),
3- [3-butoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene 10019955 (Compound No. 288),
3- [3- (Cyclohexylmethoxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 289) ,
3-{[2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] methyl} benzonitrile (Compound No. 290),
2- {2- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] ethyl} -1H-isoindole- 1,3 (2H) -dione (Compound No. 291),
3- [3- (Cyclohexyloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 292) ,
[5- (1,7-Dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy] ethyl acetate (Compound No. 293 ),
3- [3- (cyclohexylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 294),
[2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] tert-butyl acetate (Compound No. 295),
N-cyclopropyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy Acetamide (Compound No. 296),
2- (cyclopentyloxy) -4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 297),
2- (cyclopentyloxy) -4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 298),
N-benzyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy] Acetamide (Compound No. 299),
N-cyclopentyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy] Acetamide (Compound No. 300),
4- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] piperidine-1-carboxylic acid tert-butyl (compound Number 301),
3- [4- (difluoromethoxy) -3- (piperidin-4-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene hydrochloride (Compound No. 302),
3- {3-[(1-Acetylpiperidin-4-yl) oxy] -4- (difluoromethoxy) phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 303),
(3S) -3- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pyrrolidine-1-carboxylic acid tert -Butyl (compound no. 304),
(3R) -3- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pyrrolidine-1-carboxylic acid tert -Butyl (compound no. 305),
3- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] piperidine-1-carboxylic acid tert-butyl (compound Number 306),
(2S) -2-{[2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] methyl} pyrrolidine-1- Tert-butyl carboxylate (Compound No. 307),
(5R or 5S) -3- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 308),
(5S or 5R) -3- (3-isopropoxy-4-methoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 309),
(5S or 5R) -3- [3- (Cyclopropylmethoxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 310)
2- (cyclopropylmethoxy) -4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 311),
4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-isopropoxyphenol (Compound No. 312),
(5S or 5R) -3- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 313),
(5S or 5R) -3- [3- (Cyclopropylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 314) ,
(5S or 5R) -3- [4- (difluoromethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 315),
(5R or 5S) -3- [4- (difluoromethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 316),
2- (cyclopropylmethoxy) -4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 317),
4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-isopropoxyphenol (Compound No. 318),
(5R or 5S) -3- [3- (Cyclopropylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 319) ,
(5R or 5S) -3- [4- (difluoromethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 320),
Hydrochloride of 3- {4- (difluoromethoxy) -3-[(3S) -pyrrolidin-3-yloxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (compound Number 321),
Hydrochloride of 3- {4- (difluoromethoxy) -3-{(2S) -pyrrolidin-2-ylmethoxy} phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (compound Number 322),
Hydrochloride of 3- {4- (difluoromethoxy) -3-[(2R) -pyrrolidin-2-ylmethoxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (compound Number 323),
3- [4- (Difluoromethoxy) -3-{[(2R) -1-propionylpyrrolidin-2-yl] methoxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 324),
3- [3-{[(2S) -1-acetylpyrrolidin-2-yl] methoxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 325),
3- [3-{[(3S) -1-Benzoylpyrrolidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 326),
3- [4- (Difluoromethoxy) -3-{[(3S) -1-propionylpyrrolidin-3-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 327),
(5S or 5R) -3- [3- (benzyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 328),
2- (benzyloxy) -4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 329),
(5S or 5R) -3- [3- (Benzyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 330),
3- {4- (Difluoromethoxy) -3-[(1-propionylpiperidin-4-yl) oxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 331),
3- [4- (Difluoromethoxy) -3-{[1- (4-fluorobenzoyl) piperidin-4-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] nona-2 -Ene (compound number 332),
3- [3-{[1- (Cyclopropylcarbonyl) piperidin-4-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 333),
3- [3-{[1- (Cyclopentylcarbonyl) piperidin-4-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 334),
3- [4- (Difluoromethoxy) -3-({1-[(trifluoromethyl) sulfonyl] piperidin-4-yl} oxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] nona -2-ene (Compound No. 335),
3- {3-[(1-Acetylpiperidin-3-yl) oxy] -4- (difluoromethoxy) phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 336),
3- {4- (Difluoromethoxy) -3-[(1-propionylpiperidin-3-yl) oxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 337),
3- [4- (Difluoromethoxy) -3-{[1- (4-fluorobenzoyl) piperidin-3-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] nona-2 -Ene (compound no. 338),
3- [3-{[1- (Cyclopropylcarbonyl) piperidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 339),
3- [3-{[1- (Cyclopentylcarbonyl) piperidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 340),
3- [4- (Difluoromethoxy) -3-{[1- (ethylsulfonyl) piperidin-3-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 341),
3- [3- (Benzyloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 342) ,
2- (difluoromethoxy) -5-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 343),
5-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 344).

Provided herein are pharmaceutical dosage forms comprising a therapeutically effective amount of one or more compounds of Formula Ia and Formula Ib, and one or more pharmaceutically acceptable excipients.

  In another aspect, there is provided herein a therapeutically effective amount of one or more compounds of Formula Ia or Formula Ib, a therapeutically effective amount of one or more muscarinic receptor antagonists (MRAs), and one or more pharmaceutical agents. Pharmaceutical dosage forms comprising the above acceptable excipients are provided. The pharmaceutical dosage form comprises a therapeutically effective amount of one or more corticosteroids, one or more β2-agonists, one or more p38 MAP kinase inhibitors, one or more anticholinergic agents, one or more antiallergic agents, one or more. Or a combination of one or more leukotriene antagonists, one or more EGFR kinase inhibitors, or one or more additional PDE-IV inhibitors, or combinations thereof.

  In another aspect, there is provided herein a therapeutically effective amount of one or more compounds of Formula Ia or Formula Ib, a therapeutically effective amount of one or more β2-agonists, and one or more pharmaceutically acceptable doses. A pharmaceutical dosage form comprising the form is provided. The pharmaceutical dosage form comprises a therapeutically effective amount of one or more corticosteroids, one or more muscarinic receptor antagonists, one or more p38 MAP kinase inhibitors, one or more anticholinergics, one or more antiallergic agents, It can also include one or more PAF antagonists, one or more leukotriene antagonists, one or more EGFR kinase inhibitors, or one or more additional PDE-IV inhibitors, or combinations thereof.

  In yet another aspect, there is provided herein a therapeutically effective amount of one or more compounds of Formula Ia or Formula Ib, a therapeutically effective amount of one or more p38 MAP kinase inhibitors, and one or more pharmaceutically acceptable agents. A pharmaceutical dosage form comprising the excipient is provided. The pharmaceutical dosage form comprises a therapeutically effective amount of one or more β2-agonists, one or more muscarinic receptor antagonists, one or more corticosteroids, one or more anticholinergic agents, one or more antiallergic agents, one or more Or a combination of one or more leukotriene antagonists, one or more EGFR kinase inhibitors, or one or more additional PDE-IV inhibitors, or combinations thereof.

In yet another aspect, a therapeutically effective amount of one or more compounds of formula Ia or formula Ib, a therapeutically effective amount of one or more corticosteroids, and one or more pharmaceutically acceptable compounds. Pharmaceutical dosage forms comprising excipients are provided. The pharmaceutical dosage form comprises a therapeutically effective amount of one or more β2-agonists, one or more muscarinic receptor antagonists, one or more p38 MAP kinase inhibitors, one or more anticholinergics, one or more antiallergic agents, It can also include one or more PAF antagonists, one or more leukotriene antagonists, one or more EGFR kinase inhibitors, or one or more additional PDE-IV inhibitors, or combinations thereof.
tert-Butyl 4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} piperidine-1-carboxylic acid (Compound No. 1a),
Hydrochloric acid of 6- (2-methylphenyl) -2- (piperidin-4-ylamino) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one Salt (Compound No. 2a),
2-[(1-Acetylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 3a),
6- (2-Methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 4a),
2-[(1-Benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 5a),
N-isopropyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} piperidine-1-carboxamide (Compound No. 6a),
N- (4-fluorophenyl) -4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3- d] pyrimidin-2-yl] amino} piperidine-1-carboxamide (Compound No. 7a),
2-{[1- (Ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 8a),
2-[(1-Benzyl-piperidin-4-yl) amino] -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine-7 (8H) -one (Compound No. 9a),
N- (4-fluorophenyl) -4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3- d] pyrimidin-2-yl] amino} piperidine-1-carbothioamide (Compound No. 10a),
Methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N- [4- (tri Fluoromethyl) phenyl] piperidine-1-carboxamide (Compound No. 11a),
6- (2-Methylphenyl) -2-[(1-methylpiperidin-4-yl) amino] -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 12a),
6- (2-Methylphenyl) -2-[(4-methylpiperazin-4-yl) amino] -8- (tetrahydro-2H-pyran-1-yl) pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 13a),
2-{[1- (Isopropylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 14a),
4-{[6- (2-chlorophenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} Tert-butyl piperidine-1-carboxylate (Compound No. 15a),
6- (2-Methylphenyl) -2- (piperidin-1-ylamino) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one (compound Number 16a),
2- (Cyclobutylamino) -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 17a) ),
4-{[6- (2-Methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino } -N-propylpiperidine-1-carboxamide (Compound No. 18a),
N-[(1S) -1,2-dimethylpropyl] -4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8- Dihydropyrido [2,3-d] pyrimidin-2-yl] amino} piperidine-1-carboxamide (Compound No. 19a),
N-cyclohexyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl [amino] piperidine-1-carboxamide (Compound No. 20a),
2-{[1- (4-Fluorobenzoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d Pyrimidin-7 (8H) -one (Compound No. 21a),
N- (cyclopentylmethyl) -4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] Pyrimidin-2-yl] amino} piperidine-1-carboxamide (Compound No. 22a),
4-{[6- (2-Methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino } -N- (1,1,3,3-tetramethylbutyl) piperidine-1-carboxamide (Compound No. 23a),
4-{[6- (2-Methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino } -N-octylpiperidine-1-carboxamide (Compound No. 24a),
N-cyclopentyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} piperidine-1-carboxamide (Compound No. 25a),
N-isopropyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} piperidine-1-carbothioamide (Compound No. 26a),
4-{[6- (2-Methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino } -N-octylpiperidine-1-carbothioamide (Compound No. 27a),
N-tert-butyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine -2-yl] amino} piperidine-1-carbothioamide (Compound No. 28a),
6- (2-Methylphenyl) -2-[(1-pyrimidin-2-ylpiperidin-4-yl) amino] -8-tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 29a),
N-cyclopropyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine- 2-yl] amino} piperidine-1-carboxamide (Compound No. 30a),
N-[(1R) -1-cyclohexylethyl] -4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [ 2,3-d] pyrimidin-2-yl] amino} piperidine-1-carboxamide (Compound No. 31a),
2-{[1- (Cyclopentylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 32a),
6- (2-Methylphenyl) -2-{[1- (pyrrolidin-1-ylcarbonyl) piperidin-4-yl] amino} -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3 -D] pyrimidin-7 (8H) -one (compound no. 33a),
6- (2-Methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) -2- (tetrahydro-2H-pyran-4-ylamino) pyrido [2,3-d] pyrimidine-7 (8H) -One (compound no. 34a),
6- (2-Methylphenyl) -2-[(1,2,2,6,6-pentamethylpiperidin-4-yl) amino] -8- (tetrahydro-2H-pyran-4-yl) pyrido [2 , 3-d] pyrimidin-7 (8H) -one (Compound No. 35a),
4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydrofuran-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} piperidine-1 -Tert-butyl carboxylate (compound no. 36a),
N-cyclopropyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydrofuran-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] Amino} piperidine-1-carboxamide (Compound No. 37a),
6- (2-Methylphenyl) -7-oxo-2-{[1- (pyrrolidin-1-ylcarbonyl) piperidin-4-yl] amino} -1- (tetrahydrofuran-3-yl) -7,8- Dihydropyrido [2,3-d] pyrimidine-1-ium (compound no. 38a),
2-{[1- (Ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -7-oxo-1- (tetrahydrofuran-3-yl) -7,8-dihydropyrido [2, 3-d] pyrimidine-1-ium (Compound No. 39a),
6- (2-Methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} -8- (tetrahydrofuran-3-yl) pyrido [2,3-d] pyrimidine-7 (8H -One (compound no. 40a),
N-cyclopropyl-4-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydrofuran-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] Amino} piperidine-1-carboxamide (Compound No. 41a),
6- (2-Methylphenyl) -2-{[(3S) -1- (methylsulfonyl) pyrrolidin-3-yl] amino} -8- (tetrahydrofuran-3-yl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 42a),
4-({6- (2-methylphenyl) -7-oxo-8-[(3S) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl} amino ) Piperidine-1-carboxylate tert-butyl (Compound No. 43a),
6- (2-Methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 44a),
N-isopropyl-4-({6- (2-methylphenyl) -7-oxo-8-[(3S) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl} amino) piperidine-1-carboxamide (Compound No. 45a),
6- (2-Methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 46a),
N-isopropyl-4-({6- (2-methylphenyl) -7-oxo-8-[(3R) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl} amino) piperidine-1-carboxamide (Compound No. 47a),
4-({6- (2-methylphenyl) -7-oxo-8-[(3R) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl} amino ) Piperidine-1-carboxylate tert-butyl (Compound No. 48a),
Hydrochloric acid of 6- (2-methylphenyl) -2- (piperidin-4-ylamino) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidin-7 (8H) -one Salt (Compound No. 49a),
Hydrochloric acid of 6- (2-methylphenyl) -2- (piperidin-4-ylamino) -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidin-7 (8H) -one Salt (Compound No. 50a),
2-{[1- (Ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 51a),
N-cyclopropyl-4-({6- (2-methylphenyl) -7-oxo-8-[(3S-tetrahydrofuran-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} piperidine-1-carboxamide (Compound No. 52a),
N-cyclopropyl-4-({6- (2-methylphenyl) -7-oxo-8-[(3R-tetrahydrofuran-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} piperidine-1-carboxamide (Compound No. 53a),
2-[(1-Benzylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 54a),
2- (Cyclobutylamino) -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 55a) ),
2- (Cyclopropylamino) -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 56a) ),
2-{[1- (Ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 57a),
2-[(1-Acetylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 58a),
2-{[1- (4-Fluorobenzoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d Pyrimidin-7 (8H) -one (Compound No. 59a),
2-{[1- (Cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] Pyrimidine-7 (8H) -one (Compound No. 60a),
2-{[1- (Cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] Pyrimidine-7 (8H) -one (Compound No. 61a),
2-{[1- (cyclopentylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 62a),
2-{[1- (Cyclopentylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 63a),
2-[(1-Benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 64a),
2-[(1-Benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 65a),
2-{[1- (4-Fluorobenzoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d Pyrimidin-7 (8H) -one (Compound No. 66a),
N- (4-fluorophenyl) -4-({6- (2-methylphenyl) -7-oxo-8-[(3R) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3- d] pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 67a),
2-[(1-Acetylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 ( 8H) -one (Compound No. 68a),
N- (4-fluorophenyl) -4-({6- (2-methylphenyl) -7-oxo-8-[(3S) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3- d] pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 69a),
(3S) -3-({6- (2-Methylphenyl) -7-oxo-8-[(3R) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl} amino) piperidine-1-carboxylate tert-butyl (compound no. 70a),
(3S) -N-isopropyl-3-({6- (2-methylphenyl) -7-oxo-8-[(3R) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 71a),
(3S) -3-({6- (2-Methylphenyl) -7-oxo-8-[(3S) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl} amino) piperidine-1-carboxylate tert-butyl (compound no. 72a),
(3R) -3-({6- (2-methylphenyl) -7-oxo-8-[(3R) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl} amino) piperidine-1-carboxylate tert-butyl (compound no. 73a),
(3R) -N-isopropyl-3-({6- (2-methylphenyl) -7-oxo-8-[(3R) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 74a)
(3S) -N-isopropyl-3-({6- (2-methylphenyl) -7-oxo-8-[(3S) -tetrahydrofuran-3-yl] -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 75a)
6- (2-Methylphenyl) -2-{[(3S) -1- (methylsulfonyl) piperidin-3-yl] amino} -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3 -D] pyrimidin-7 (8H) -one (compound no. 76a),
6- (2-Methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} -8-[(3S) -1- (methylsulfonyl) pyrrolidin-3-yl] pyrido [2 , 3-d] pyrimidin-7 (8H) -one (Compound No. 77a),
6- (2-Methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} -8-[(3S) -1- (methylsulfonyl) pyrrolidin-3-yl] pyrido [2 , 3-d] pyrimidin-7 (8H) -one (Compound No. 78a),
4-({6- (2-methylphenyl) -7-oxo-8-[(3S) -pyrrolidin-3-yl] -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl} amino ) Piperidine-1-carboxylate tert-butyl (Compound No. 79a),
4-({8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl} amino) -N-isopropylpiperidine-1-carboxamide (Compound No. 80a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidine-7 (8H)- ON hydrochloride (Compound No. 81a),
(3S) -3-{[6- (2-Methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} pyrrolidine-1-carboxylate tert-butyl (Compound No. 82a),
(3S) -N-isopropyl-3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl] amino} pyrrolidine-1-carboxamide (Compound No. 83a),
(3S) -N-isopropyl-3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl] amino} pyrrolidine-1-carbothioamide (Compound No. 84a),
6- (2-Methylphenyl) -2-{[(3S) -1- (methylsulfonyl) pyrrolidin-3-yl] amino} -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3 -D] pyrimidin-7 (8H) -one (Compound No. 85a),
2-{[(3S) -1- (ethylsulfonyl) pyrrolidin-3-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3 -D] pyrimidin-7 (8H) -one (Compound No. 86a),
2-{[(3S) -1-acetylpyrrolidin-3-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] Pyrimidine-7 (8H) -one (Compound No. 87a),
(3S) -N-cyclopropyl-3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3- d] pyrimidin-2-yl] amino} pyrrolidine-1-carboxamide (Compound No. 88a),
(3S) -N-butyl-3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl] amino} pyrrolidine-1-carboxamide (Compound No. 90a),
(3S) -N-cyclopentyl-3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl] amino} pyrrolidine-1-carboxamide (Compound No. 91a),
(3S) -N-[(1S) -1,2-dimethylpropyl] -3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl)- 7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} pyrrolidine-1-carboxamide (Compound No. 92a),
2-{[(3R) -1-benzylpyrrolidin-3-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] Pyrimidine-7 (8H) -one (Compound No. 93a),
2-{[(3S) -1-benzylpyrrolidin-3-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] Pyrimidine-7 (8H) -one (Compound No. 94a),
(3S) -N-cyclohexyl-3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d ] Pyrimidin-2-yl] amino} pyrrolidine-1-carboxamide (Compound No. 95a),
(3S) -3-{[6- (2-Methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} -N-octylpyrrolidine-1-carboxamide (Compound No. 96a),
2-{[(3S) -1- (cyclopropylcarbonyl) -pyrrolidin-3-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2 , 3-d] pyrimidin-7 (8H) -one (Compound No. 97a),
2-{[(3S) -1- (cyclopentylcarbonyl) -pyrrolidin-3-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (Compound No. 98a),
6- (2-Methylphenyl) -2-{[(3S) -1-pyrimidin-2-yl-pyrrolidin-3-yl] amino} -8- (tetrahydro-2H-pyran-4-yl) pyrido [2 , 3-d] pyrimidin-7 (8H) -one (Compound No. 99a),
(3S) -N-[(1R) -1-cyclohexylethyl] -3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydro-2H-pyran-4-yl) -7, 8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} pyrrolidine-1-carboxamide (Compound No. 100a),
6- (2-Methylphenyl) -2-{[(3S) -1- (pyrrolidin-1-ylcarbonyl) pyrrolidin-3-yl] amino} -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 101a),
2-{[(3S) -1- (cyclopentylacetyl) pyrrolidin-3-yl] amino} -6- (2-methylphenyl) -8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3 -D] pyrimidin-7 (8H) -one (Compound No. 102a),
(3S) -3-{[6- (2-Methylphenyl) -7-oxo-8- (tetrahydrofuran-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino } Pyrrolidine-1-carboxylate tert-butyl (Compound No. 103a),
4-({8-[(3S) -1-benzylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl} amino (piperidine-1-carboxylate tert-butyl (Compound No. 104a),
(3S) -N-isopropyl-3-{[6- (2-methylphenyl) -7-oxo-8- (tetrahydrofuran-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} pyrrolidine-1-carboxamide (Compound No. 105a),
4-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} Tert-butyl piperidine-1-carboxylate (Compound No. 106a),
4-{[6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} Tert-butyl piperidine-1-carboxylate (Compound No. 107a),
8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -2-[(1-methylpiperidin-4-yl) amino] pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound no. 108a),
8- (1-benzylpiperidin-4-yl-2- (cyclobutylamino) -6- (2-methylphenyl) pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 109a),
(3S) -3-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} pyrrolidine-1-carboxylate (Compound No. 110a),
(3S) -3-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-isopropylpyrrolidine-1-carboxamide (Compound No. 111a),
Hydrochloride of 8- (1-benzylpiperidin-4-yl) -6- (2-methylphenyl) -2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 112a),
Hydrochloride of 6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) -2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 113a),
4-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-isopropylpiperidine-1-carboxamide (Compound No. 114a),
4-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-cyclohexylpiperidine-1-carboxamide (Compound No. 115a),
4-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-cyclopentylpiperidine-1-carboxamide (Compound No. 116a),
4-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-isobutylpiperidine-1-carboxamide (Compound No. 117a),
4-{[8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-[(1R) -1-cyclohexylethyl] piperidine-1-carboxamide (Compound No. 118a),
N-isopropyl-4-{[6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} piperidine-1-carboxamide (Compound No. 119a),
N-cyclopropyl-4-{[6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2 -Yl] amino} piperidine-1-carboxamide (Compound No. 120a),
8- (1-Benzylpiperidin-4-yl) -2-{[1- (cyclopentylacetyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 121a),
8- (1-Benzylpiperidin-4-yl) -2-{[1- (cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 122a),
8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -2-{[1- (phenylsulfonyl) piperidin-4-yl] amino} pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 123a),
8- (1-Benzylpiperidin-4-yl) -6- (2-methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 124a),
8- (1-Benzylpiperidin-4-yl) -2-{[1- (ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 125a),
6- (2-Methylphenyl) -8- (1-methylpiperidin-4-yl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 126a),
2-{[1- (Ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 127a),
2-{[1- (Isopropylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 128a),
6- (2-Methylphenyl) -8- (1-methylpiperidin-4-yl) -2-{[1- (pyrrolidin-1-ylcarbonyl) piperidin-4-yl] amino} pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 129a),
2-[(1-Benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound no. 130a),
2-[(1-Benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound no. 130a),
4-{[6- (2-methylphenyl) -7-oxo-8-piperidin-4-yl-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} piperidine-1-carvone Tert-butyl acid (Compound No. 131a),
6- (2-methylphenyl) -8-piperidin-4-yl-2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 132a),
N-isopropyl-4-{[6- (2-methylphenyl) -7-oxo-8-piperidin-4-yl-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} piperidine -1-carboxamide (Compound No. 133a),
4-{[8- {1-[(Isopropylamino) carbonyl] piperidin-4-yl} -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- 2-yl] amino} piperidine-1-carboxylate tert-butyl (Compound No. 134a),
N-isopropyl-4- [6- (2-methylphenyl) -7-oxo-2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidin-8 (7H) -yl] pyrimidine-1- Carboxamide hydrochloride (Compound No. 135a),
N-isopropyl-4- [2-{(1-[(isopropylamino) carbonyl] piperidin-4-yl) amino} -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine- 8 (7H) -yl] piperidine-1-carboxamide (Compound No. 136a),
4- [2-({1-[(Cyclopropylamino) carbonyl] piperidin-4-yl} amino) -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine-8 (7H ) -Yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 137a),
4- [2-({1-[(tert-Butylamino) carbonyl] piperidin-4-yl} amino) -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine-8 ( 7H) -yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 138a),
4- [2-({1-[(cyclohexylamino) carbonyl] piperidin-4-yl} amino) -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine-8 (7H) -Yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 139a),
N-isopropyl-4- [6- (2-methylphenyl) -2-{[1- (morpholin-4-ylcarbonyl) piperidin-4-yl] amino} -7-oxopyrido [2,3-d] pyrimidine -8 (7H) -yl] piperidine-1-carboxamide (Compound No. 140a),
6- [2-{[1- (4-Fluorobenzoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine-8 (7H)- Yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 141a),
N-isopropyl-4- [6- (2-methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} -7-oxopyrido [2,3-d] pyrimidine-8 (7H ) -Yl] piperidine-1-carboxamide (Compound No. 142a),
4- [2-{[1- (Ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 143a),
N-isopropyl-4- [2-{[1- (cyclopropylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine-8 ( 7H) -yl] piperidine-1-carboxamide (Compound No. 144a),
4- [2-{[1- (Cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl } -N-isopropylpiperidine-1-carboxamide (Compound No. 145a),
4- [2-[(1-Benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl] -N- Isopropyl piperidine-1-carboxamide (Compound No. 146a),
4- [2-[(1-Acetylpiperidin-4-yl) amino] -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl] -N- Isopropyl piperidine-1-carboxamide (Compound No. 147a),
N-isopropyl-4- [6- (2-methylphenyl) -2-[(1-methylpiperidin-4-yl) amino] -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl Piperidine-1-carboxamide (Compound No. 148a),
4- [2-[(1-Benzylpiperidin-4-yl) amino] -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl] -N- Isopropyl piperidine-1-carboxamide (Compound No. 149a),
8- (1-acetylpiperidin-4-yl) -2-[(1-acetylpiperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound number 150a),
4- [2-{[1- (4-Fluorobenzoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine-8 (7H)- Yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 151a),
4-({6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl } Amino) tert-butyl piperidine-1-carboxylate (Compound No. 152a),
Of 6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] 2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidin-7 (8H) -one Hydrochloride (Compound No. 153a),
N-isopropyl-4-({6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine -2-yl} amino) piperidine-1-carboxamide (Compound No. 154a),
N- (tert-butyl) -4-({6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -7-oxo-7,8-dihydropyrido [2,3 -D] pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 155a),
N-cyclohexyl-4-({6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine -2-yl} amino) piperidine-1-carboxamide (Compound No. 156a),
N- (4-fluorophenyl) -4-({6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 157a),
6- (2-Methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -2-{[1- (morpholin-4-ylcarbonyl) piperidin-4-yl] amino} pyrido [2 , 3-d] pyrimidin-7 (8H) -one (Compound No. 158a),
6- (2-Methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} pyrido [2,3-d Pyrimidin-7 (8H) -one (Compound No. 159a),
2-{[1- (Ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] pyrido [2,3-d Pyrimidin-7 (8H) -one (Compound No. 160a),
2-{[1- (Isopropylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] pyrido [2,3-d Pyrimidin-7 (8H) -one (Compound No. 161a),
2-{[1- (Cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 162a),
2-[(1-Acetylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 163a),
2-[(1-Benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 164a),
2-{[1- (4-Fluorobenzoyl) piperidin-4-yl] amino] -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] pyrido [2,3 -D] pyrimidin-7 (8H) -one (Compound No. 165a),
4-{[8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} Piperidine-1-carboxylate tert-butyl (Compound No. 166a),
8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidin-7 (8H) -one (compound number) 166a),
4-{[8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-isopropylpiperidine-1-carboxamide (Compound No. 168a),
4-{[8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-cyclopropylpiperidine-1-carboxamide (Compound No. 169a),
4-{[8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N- (tert-butyl) piperidine-1-carboxamide (Compound No. 170a),
4-{[8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N-cyclohexylpiperidine-1-carboxamide (Compound No. 171a),
4-{[8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -N- (4-fluorophenyl) piperidine-1-carboxamide (Compound No. 172a),
8- (1-Acetylpiperidin-4-yl) -6- (2-methylphenyl) -2-{[1- (morpholin-4-ylcarbonyl) piperidin-4-yl] amino} pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 173a),
8- (1-acetylpiperidin-4-yl) -6- (2-methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 174a),
8- (1-Acetylpiperidin-4-yl) -2-{[1- (ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 175a),
8- (1-acetylpiperidin-4-yl) -2-{[1- (isopropylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 176a),
8- (1-Acetylpiperidin-4-yl) -2-{[1- (cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 177a),
8- (1-acetylpiperidin-4-yl) -2-{[1- (4-fluorobenzoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] Pyrimidine-7 (8H) -one (Compound No. 178a),
{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] Amino} piperidine-1-carboxylate tert-butyl (Compound No. 179a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidine-7 (8H)- ON hydrochloride (Compound No. 180a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-ylamino) pyrido [2,3-d] Pyrimidine-7 (8H) -one (Compound No. 181a),
2-[(1-Acetylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- (1-methylpiperidin-4-yl) pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound number 182a),
6- (2-Methylphenyl) -8-[(3S) -1- (methylsulfonyl) pyrrolidin-3-yl] -2- (piperidin-4-ylamino) pyrido [2,3-d] pyrimidine-7 ( 8H) -one hydrochloride (Compound No. 183a),
4-{[8-[(3R) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} piperidine-1-carboxylic acid-tert-butyl (Compound No. 184a),
Hydrochloric acid of 6- (2-methylphenyl) -2-[(3S) -pyrrolidin-3-ylamino] -8- (tetrahydrofuran-3-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one Salt (Compound No. 185a),
6- (2-Methylphenyl) -2-[(3S) -piperidin-3-ylamino] -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 (8H) -On hydrochloride (compound no. 186a),
6- (2-Methylphenyl) -2-[(3S) -piperidin-3-ylamino] -8-[(3S) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 ( 8H) -one hydrochloride (Compound No. 187a),
6- (2-Methylphenyl) -2-[(3R) -pyrrolidin-3-ylamino] -8-[(3R) -tetrahydrofuran-3-yl] pyrido [2,3-d] pyrimidine-7 (8H) -On hydrochloride (compound no. 188a),
4- [2-[(1-{[(4-Fluorophenyl) amino] carbonyl} piperidin-4-yl) amino] -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine -8 (7H) -yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 189a),
4-{[8- {1-[(Isopropylamino) carbonyl] piperidin-4-yl} -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- 2-yl] amino} -N-morpholin-4-ylpiperidine-1-carboxamide (Compound No. 190a),
4- [2-{[1- (2,2-dimethylpropanoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -7-oxopyrido [2,3-d] pyrimidine-8 ( 7H) -yl] -N-isopropylpiperidine-1-carboxamide (Compound No. 191a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -2-[(1-benzylpiperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 192a),
N-cyclopropyl-4-({6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-2-yl} amino) piperidine-1-carboxamide (Compound No. 193a),
4-({6- (2-methylphenyl) -8-{[1- (methylsulfonyl) piperidin-4-yl] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl} amino) -N-morpholine-4-ylpiperidine-1-carboxamide (Compound No. 194a),
2-{[1- (2,2-dimethylpropanoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl] pyrido [ 2,3-d] pyrimidin-7 (8H) -one (Compound No. 195a),
6- (2-Methylphenyl) -2-[(1-methylpiperidin-4-yl) amino] -8- [1- (methylsulfonyl) piperidin-4-yl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 196a),
2-[(1-Benzylpiperidin-4-yl) amino] -6- (2-methylphenyl) -8- [1- (methylsulfonyl) piperidin-4-yl) pyrido [2,3-d] pyrimidine- 7 (8H) -one (Compound No. 197a),
8- (1-Acetylpiperidin-4-yl) -2-[(1-benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound number 198a),
8- (1-acetylpiperidin-4-yl) -2-{[1- (2,2-dimethylpropanoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3 -D] pyrimidin-7 (8H) -one (Compound No. 199a),
8- (1-Acetylpiperidin-4-yl) -6- (2-methylphenyl) -2-[(1-methylpiperidin-4-yl) amino] pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound number 200a),
8- (1-Acetylpiperidin-4-yl) -2-[(1-benzylpiperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine-7 (8H ) -One (compound number 201a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-cyclopropylpiperidine-1-carboxamide (Compound No. 202a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N- (tert-butyl) piperidine-1-carboxamide (Compound No. 203a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-cyclohexylpiperidine-1-carboxamide (Compound No. 204a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N- (4-fluorophenyl) piperidine-1-carboxamide (Compound No. 205a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-morpholine-4-ylpiperidine-1-carboxamide (Compound No. 206a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -2-{[1- (ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 207a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2-{[1- (propylsulfonyl) piperidin-4-yl] amino} pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 208a),
8-[(3R) -1-acetylpyrrolidin-3-yl] -2-{[1- (cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3 -D] pyrimidin-7 (8H) -one (Compound No. 209a),
2-[(1-Acetylpiperidin-4-yl) amino] -8-[(3R) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (compound number 210a),
8-[(3R) -1-acetylpyrrolidin-3-yl] -2-[(1-benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (compound number 211a),
8-[(3R) -1-acetylpyrrolidin-3-yl] -2-{[1- (4-fluorobenzoyl) piperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (Compound No. 212a),
8-[(3R) -1-acetylpyrrolidin-3-yl] -2-{[1- (2,2-dimethylpropanoyl) piperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidin-7 (8H) -one (Compound No. 213a),
8-[(3R) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2-[(1-methylpiperidin-4-yl) amino] pyrido [2,3-d] pyrimidine -7 (8H) -one (compound number 214a),
8-[(3R) -1-acetylpyrrolidin-3-yl] -2-[(1-benzylpiperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 215a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} piperidine-1-carboxylate tert-butyl (Compound No. 216a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2-[(1-methylpiperidin-4-yl) amino] pyrido [2,3-d] pyrimidine -7 (8H) -one (Compound No. 217a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-isopropylpiperidine-1-carboxamide (Compound No. 218a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-cyclopropylpiperidine-1-carboxamide (Compound No. 219a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N- (tert-butyl) piperidine-1-carboxamide (Compound No. 220a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-cyclohexylpiperidine-1-carboxamide (Compound No. 221a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N- (4-fluorophenyl) piperidine-1-carboxamide (Compound No. 222a),
4-{[8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Yl] amino} -N-morpholine-4-ylpiperidine-1-carboxamide (Compound No. 223a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2-{[1- (methylsulfonyl) piperidin-4-yl] amino} pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 224a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -2-{[1- (ethylsulfonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 225a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) -2-{[1- (propylsulfonyl) piperidin-4-yl] amino} pyrido [2,3- d] Pyrimidin-7 (8H) -one (Compound No. 226a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -2-{[1- (cyclopropylcarbonyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3 -D] pyrimidin-7 (8H) -one (compound no. 227a),
2-[(1-Aminopiperidin-4-yl) amino] -8-[(3S) -1-acetylpyrrolidin-3-yl] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) one (Compound No. 228a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -2-[(1-benzoylpiperidin-4-yl) amino] -6- (2-methylphenyl) pyrido [2,3-d] pyrimidine -7 (8H) one (Compound No. 229a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -2-{[1- (4-fluorobenzoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2, 3-d] pyrimidin-7 (8H) one (Compound No. 230a),
8-[(3S) -1-acetylpyrrolidin-3-yl] -2-{[1- (2,2-dimethylpropanoyl) piperidin-4-yl] amino} -6- (2-methylphenyl) pyrido [2,3-d] pyrimidin-7 (8H) one (Compound No. 231a) was disclosed in co-pending patent application No. 2602 / DEL / 2005; and US Pat. Nos. 60 / 598,621, 60/630, 517, 1098 / DEL / 2005 and 211 / DEL / 2005 can be selected. The p38 MAP kinase inhibitor may be selected from, but not limited to, compounds described in WO 98/47829, WO 00/43384, and WO 98/27098.

  Examples of p38 MAP kinase inhibitors include, but are not limited to, Vx-745 disclosed in WO 98/27098, BIRB-796 disclosed in WO 00/43384, RWJ disclosed in WO 98/47892 -66757, and SB-239063 disclosed in WO 97/25048. Any reference to a p38 kinase inhibitor described above includes any pharmacologically acceptable acid addition salts thereof that may be present. The physiologically or pharmacologically acceptable acid addition salts thereof that can be formed by the p38 kinase inhibitor are, according to the invention, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, It means a pharmaceutically acceptable salt selected from succinic acid, lactic acid, citric acid, tartaric acid and maleic acid salts.

  The β2-agonist can be selected from those described in the art or subsequently disclosed. β2-agonists are, for example, U.S. Pat. Nos. 3,705,233; 3,644,353; 3,642,896; 3,700,681; 4,579,985; No. 3,994,974; No. 3,937,838; No. 4,419,364; No. 5,126,375; No. 5,243,076; No. 4,992,474; One or more compounds described in US Pat.

  Suitable β2-agonists are, for example, albuterol, salbutamol, virtuterol, pyrbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, alformoterol, formoterol, and their pharmaceuticals One or more of the acceptable salts, or solvates thereof.

  Suitable corticosteroids can be selected from those described in the art. Suitable corticosteroids are, for example, U.S. Pat. Nos. 3,312,590; 3,983,233; 3,929,768; 3,721,687; 3,436,389. 3,506,694; 3,639,434; 3,992,534; 3,928,326; 3,980,778; 3,780,177; 3,652,554; 3,947,478; 4,076,708; 4,124,707; 4,158,055; 4,298,604; 335, 121; 4,081,541; 4,226,862; 4,290,962; 4,587,236; 4,472,392; 4,472, No. 393; No. 4,242,334; No. 4,014,909 4,098,803; 4,619,921; 5,482,934; 5,837,699; 5,889,015; 5,278,156; , 015,746; 5,976,573; 6,337,324; 6,057,307; 6,723,713; 6,127,353; One or more compounds described in 180,781 can be included.

  Suitable corticosteroids include, for example, alclomethasone, amsinonide, amelomethasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, croticazone, cyclomethasone, deflazacort, deprodon, dexbudezonide, diflorazone, diflupredone, fluticadone, fluticasone, , Hydrocortisone, methylprednisolone, mometasone, prednisocarbate, prednisolone, rimexolone, thixocortol, triamcinolone, tolterodine, oxybutynin, urobetasol, rofleponide, disclosed in US Pat. No. 4,285,937, KSR592, EP 1344526 ST-126, dexamethasone and its physician Above acceptable salts, can include one or more solvate. Preferred corticosteroids include, for example, flunizolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone, budesonide, fluticasone, mometasone, ciclesonide. Examples of possible salts or derivatives are: sodium salt, sulfobenzoate, phosphate, isonicotinate, acetate, propionate, dihydrogen phosphate, palmitate, pivalate, or furoic acid Contains salt. In some cases, corticosteroids can also occur in their hydrated form.

Suitable muscarinic receptor antagonists (MRAs) include substances that directly or indirectly block the activation of muscarinic cholinergic receptors. Examples include, but are not limited to, quaternary amines (eg, tiotropium salts, methaneserine, ipratropium, propaneserine), tertiary amines (eg, dicyclomine, scopolamine) and tricyclic amines (eg, telenzepine) including. Other suitable muscarinic receptor antagonists are benztropine, hexahydro-sila-diphenidol hydrochloride (Lambrecht et al., Trends in Pharmacol. Sci. 10 (Suppl): commercially available as COGENTIN from Merck: 60 (1989) HHSID hydrochloride); (+/−)-3-quinuclidinylxanthene-9-carboxylate hemioxalate (QLX-hemioxalate; Birdsall et al., Trends in Pharmacol. Sci., 4: 459 (1983)); telenzepin dihydrochloride (Coruzzi et al., Arch. Int. Pharmacodin. Ther., 302: 232 (1989); and Kawas ima et al, Gen.Pharmacol, 21:.. 17 (1990)), and an atropine.
Other muscarinic receptor antagonists are, for example,
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 1aa),
Cyclohexyl (hydroxy) (4-methylphenyl) hydrochloride 1H-imidazol-1-ylmethyl (Compound No. 2aa),
2- (4-fluorophenyl) -2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 3aa),
2-cyclobutyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 4aa),
2-cyclopentyl-2- (4-fluoropentyl) -2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] acetamide (Compound No. 5aa),
2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2, 2-diphenylacetamide (Compound No. 6aa),
2-cyclohexyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 7aa),
2-cyclopentyl-2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 8aa),
2-cyclohexyl-2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2phenylacetamide (Compound No. 9aa),
2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2-phenyl-2-pyridin-3-ylacetamide (Compound No. 10aa),
2- (4-fluorophenyl) -2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (compound 11aa),
2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2, 2-diphenylacetamide (Compound No. 12aa),
Cyclopentyl (hydroxy) phenylacetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 13aa),
(2R) -cyclopentyl (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 14aa),
1-cyclopentyl-1-hydroxy-1- (4-methoxyphenyl) -3- (2-methyl-1H-imidazol-1-yl) acetone (Compound No. 15aa),
(2R) -2-cyclopentyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 16aa),
2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenyl-2-pyridin-3-ylacetamide (Compound No. 17aa),
2-cyclopentyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 18aa),
2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenyl-2-pyridin-3-ylacetamide (Compound No. 19aa),
2-cyclohexyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 20aa),
2- (4-fluorophenyl) -2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 21aa),
2-cyclopentyl-2- (4-fluoropentyl) -2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] acetamide (Compound No. 22aa),
2-cyclobutyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 23aa),
2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2,2-diphenylacetamide (Compound No. 24aa),
3,3,3-trifluoro-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylphenyl) propanamide (Compound No. 25aa),
N- [2- (2-Methyl-1H-imidazol-1-yl) ethyl] -2,2-diphenylacetamide (Compound No. 26aa),
2-cyclopentyl-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 27aa),
2-cyclopentyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylphenyl) acetamide (Compound No. 28aa),
2-cyclohexyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylpentyl) acetamide (Compound No. 29aa),
2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylphenyl) -2-phenylacetamide (Compound No. 30aa),
2-cyclopentyl-2-hydroxy-N- [3- (1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 31aa),
2-cyclohexyl-2-hydroxy-N- [3- (1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 32aa),
2-cyclopentyl-2-hydroxy-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 33aa),
2-cyclohexyl-2-hydroxy-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 34aa),
(2R) -2- (3,3-difluorocyclopentyl) -2-hydroxy-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 35aa),
2-cyclopentyl-2-hydroxy-N-methyl-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 36aa),
2-cyclohexyl-2-hydroxy-N-methyl-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 37aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -N-methyl-2-phenylacetamide (Compound No. 38aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-4-yl) ethyl] -2-phenylacetamide (Compound No. 39aa),
N- [2- (1-Benzyl-1H-imidazol-4-yl) ethyl] -2-cyclopentyl-2-hydroxy- (4-methylphenyl) acetamide (Compound No. 40aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazole) ethyl] -2- (4-methylphenyl) acetamide (Compound No. 41aa),
2-cyclohexyl-2-hydroxy-N- [2- (1H-imidazol-4-yl) ethyl] -2- (4-methylphenyl) acetamide (Compound No. 42aa),
2-hydroxy-N- [2- (1H-imidazol-4-yl) ethyl] -2, 2-diphenylacetamide (Compound No. 43aa),
N- [2- (1-benzyl-1H-imidazol-4-yl) ethyl] -2-cyclohexyl-2-hydroxy-2- (4-methylphenyl) acetamide (Compound No. 44aa),
N- [2- (1-benzyl-1H-imidazol-4-yl) ethyl] -2-hydroxy-2, 2-diphenylacetamide (Compound No. 45aa),
Cyclopentyl (hydroxy) phenyl acetate 1H-imidazol-1-ylmethyl (Compound No. 46aa),
Cyclohexyl (hydroxy) phenyl acetate 1H-imidazol-1-ylmethyl (Compound No. 47aa),
(2R) -cyclopentyl (hydroxy) phenyl acetate 1H-imidazol-1-ylmethyl (Compound No. 48aa),
Cyclopentyl (hydroxy) (4-methoxyphenyl) acetate 1H-imidazol-1-ylmethyl (Compound No. 49aa),
1-Cyclohexyl-1-hydroxy-3- (1H-imidazol-1-yl) -1-
Phenylacetone (compound no. 50aa),
1-cyclohexyl-1-hydroxy-3- (2-methyl-1H-imidazol-1-yl) -1-phenylacetone (Compound No. 51aa),
1-cyclopentyl-1-hydroxy-3- (2-isopropyl-1H-imidazol-1-yl) -1- (4-methoxyphenyl) acetone (Compound No. 52aa),
1-cyclohexyl-1-hydroxy-3- (2-isopropyl-1H-imidazol-1-yl) -1-phenylacetone (Compound No. 53aa),
1-cyclohexyl-1-hydroxy-3- (2-methyl-4,5-dihydro-1H-imidazol-1-yl) -1-phenylacetone (Compound No. 54aa),
1-cyclopentyl-1-hydroxy-1- (4-methoxyphenyl) -3- (2-methyl-4,5-dihydro-1H-imidazol-1-yl) acetone (Compound No. 55aa),
1-cyclopentyl-1-hydroxy-3- (1H-imidazol-1-yl) -1- (4-methoxyphenyl) acetone (Compound No. 56aa),
2-cyclohexyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -N-methyl-2-phenylacetamide (Compound No. 57aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -N-methyl-2-phenylacetamide (Compound No. 58aa),
Cyclopentyl (phenyl) acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 59aa),
Cyclohexyl (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 60aa),
Cyclopentyl (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 61aa),
(2R)-[(1R) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 62aa),
2R-2- (1S or 1R) (3,3-difluorocyclohexyl) (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 63aa),
Cyclohexyl (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 64aa),
Cyclopentyl (hydroxy) phenyl acetate 2- (1H-imidazol-1-yl) ethyl (Compound No. 65aa),
(2R)-[1S] -3,3-difluorocyclopentyl 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 66aa),
Cyclohexyl (hydroxy) phenyl acetate 2- (1H-imidazol-1-yl) ethyl (Compound No. 67aa),
Cyclopentyl (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 68aa),
(2R)-[(1R) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 69aa),
Cycloheptyl (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 70aa),
Cycloheptyl (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 71aa),
Bromide 3-benzyl-1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-isopropyl-1H-imidazol-3-ium (Compound No. 72aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-1H -Imidazole-3-ium (compound no. 73aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-1H -Imidazole-3-ium (compound no. 74aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-isopropyl-1H-imidazol-3-ium (Compound No. 75aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound no. 76aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1R) -3, -3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H-imidazol-3-ium (Compound No. 77aa),
Bromide 3- (4-fluorobenzyl-1- [2-({(2R) -2-[(1R) -3, -3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 78aa),
Bromide 3-benzyl-1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 79aa),
Bromide 3- (4-bromobenzyl) -1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-methyl-1H-imidazol-3-ium (compound no. 80aa),
Iodide 1- [2-({(2R) -2-[(1S) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-3-methyl- 1H-imidazol-3-ium (Compound No. 81aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (4-fluorobenzyl)- 2-isopropyl-1H-imidazol-3-ium (Compound No. 82aa),
1- (2-{[2-cyclohexyl-2-hydroxy-2-phenylacetyl] oxy} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (compound number 83aa),
Iodide 1- (2-{[cyclopentyl (hydroxy) phenylacetyl] oxy} ethyl) -3-methyl-1H-imidazol-3-ium (Compound No. 84aa),
1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H-imidazole- 3-ium (compound number 85aa),
Iodide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H- Imidazol-3-ium (Compound No. 86aa),
Iodide 1- (2-{[cyclohexyl (hydroxy) phenylacetyl] oxy} ethyl) -3-methyl-1H-imidazol-3-ium (Compound No. 87aa),
Iodide 1-({[Cyclopentyl (hydroxy) phenylacetyl] oxy} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (Compound No. 88aa),
1- (2-{[cyclopentyl (hydroxy) phenylacetyl] amino} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 89aa),
1- (2-{[cyclohexyl (hydroxy) phenylacetyl] amino} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (compound no. 90aa),
1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 91aa),
1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (Compound No. 92aa),
Iodide 1- [2-({(2R) -2-[(1R) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-3-methyl- 1H-imidazol-3-ium (Compound No. 93aa),
Iodide 1- (3-{[(2R) -2- (3,3-Difluorocyclopentyl) -2-hydroxy-2-phenylacetyl] amino} propyl) -2,3-dimethyl-1H-imidazole-3- Ium (compound number 94aa),
1- (3-{[cyclopentyl (hydroxy) phenylacetyl] amino} propyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 95aa),
1- (3-{[cyclohexyl (hydroxy) phenylacetyl] amino} propyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 96aa),
1- (2-{[cyclopentyl (hydroxy) phenylacetyl] (methyl) amino} ethyl) -3-methyl-1H-imidazol-3-ium (compound no. 97aa),
1- (3-{[cyclopentyl (hydroxy) phenylacetyl] (methyl) amino} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 98aa),
1- (3-{[cyclopentyl (hydroxy) phenylacetyl] oxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 99aa),
Iodide 1- [3-({(2R) -2-[(1S) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H- Imidazol-3-ium (Compound No. 100aa),
Bromide 3-benzyl-1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (Compound No. 101aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 102aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 103aa),
Bromide 3-benzyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound no. 104aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 105aa),
Bromide 1- [3-({(2R) -2-[(1S or 1R) -3,3-difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 106aa),
Bromide 3-benzyl-1- [3-({(2R) -2 [(1R or 1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl- 1H-imidazol-3-ium (Compound No. 107aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2 [(1R or 1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H-imidazol-3-ium (Compound No. 108aa),
1- (2-{[cyclopentyl (hydroxy) phenylacetyl] (methyl) amino} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 109aa),
3- (2-methyl-1imidazol-1-yl) propyl (2R)-[(1S) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate (Compound No. 110aa),
1- (2-{[cyclohexyl (hydroxy) phenylacetyl] oxy} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 111aa),
(2R)-[(1S) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 112aa),
(2R)-[(1R) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 113aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) ethyl] -2- Methyl-1H-imidazol-3-ium (Compound No. 114aa),
Iodide 1- [2-({(2R) -2-[(1R) -3,3-Difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H-imidazole- 3-ium (compound number 115aa),
Bromide 1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-methyl-3- (4-methylbenzyl) -1H-imidazol-3-ium (Compound No. 116aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3- (4- Methylbenzyl) -1H-imidazol-3-ium (Compound No. 117aa),
Iodide 1- [3-({(2R) -2-[(1R) -3,3-Difluoro cyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2, 3-dimethyl-1H -Imidazole-3-ium (compound no. 118aa),
1,1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 119aa),
Bromide 1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2-methyl-3- (4-methylbenzyl) -1H-imidazol-3-ium (Compound No. 120aa),
Bromide 3- (4-bromobenzyl) -1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 121aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 122aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) ethyl] -2-methyl-3- (4-methylbenzyl) ) -1H-imidazol-3-ium (Compound No. 123aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (4-fluorobenzyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 124aa),
Bromide 3- [2- (1,3-Benzodioxo-5-yl) ethyl] -1- (3- [cycloheptyl (hydroxy) phenylacetyl] oxy) propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 125aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (4-fluorobenzyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 126aa),
Bromide 1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -3- (4-fluorobenzyl) -2-methyl-1H-imidazol-3-ium (Compound No. 127aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 128aa),
Bromide 3- (4-fluorobenzyl) -1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 129aa),
Chloride 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) ethyl] -2-methyl-1H-imidazol-3-ium (Compound No. 130aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) ethyl] -2-methyl-1H-imidazol-3-ium (compound number) 131aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) ethyl] -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 132aa) ,
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) propyl] -3-isopropyl-2-methyl-1H-imidazol-3-ium (Compound No. 133aa),
Iodide 1- [3-({(2R) -2-[(1R) -3,3-Difluorocyclopentyl]} oxy) propyl] -3-ethyl-2-methyl-1H-imidazol-3-ium (compound Number 134aa),
Bromide 3- (cyclopropylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) propyl] -2-methyl-1H-imidazole-3- Ium (compound number 135aa),
Bromide 3- (cyclohexylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2- Methyl-1H-imidazol-3-ium (Compound No. 136aa),
Chloride 1- [3-({(2R) -2-[(1R) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- [4- (Trifluoromethyl) benzyl] -1H-imidazol-3-ium (Compound No. 137aa),
Chloride 3- (4-Chlorobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 138aa),
Bromide 3- (3-bromobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 139aa),
Chloride 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H-imidazole-3 -Ium (compound no. 140aa),
Chloride 3-benzyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 141aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (2- Phenylethyl) -1H-imidazol-3-ium (Compound No. 142aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 143aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (4-fluorobenzyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 144aa),
Bromide 3-benzyl-1- {3- [2-cycloheptyl (hydroxy) phenylacetoxy] propyl} -2-methyl-1H-imidazol-3-ium (compound number 145aa),
Bromide (3- {3- [2-cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 146aa),
Bromide 1- [4-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 147aa),
Bromide 3-benzyl-1- [4-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2-methyl-1H -Imidazole-3-ium (compound no. 148aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound number 149aa),
Chloride 3-benzyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound no. 150aa),
Bromide 1- [4-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 151aa),
Bromide 3-benzyl-1- [4-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2-methyl-1H -Imidazole-3-ium (compound number 152aa),
Bromide 3- (4-tert-butylbenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 153aa),
Bromide 3- (biphenyl-4-ylmethyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] 2-methyl-1H-imidazol-3-ium (Compound No. 154aa),
Bromide 3- (2,5-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 155aa),
Bromide 3- (2,4-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 156aa),
Bromide 3- (3,5-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 157aa),
Bromide 3- (3,4-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 158aa),
Bromide 1- {3- [2-cyclopentyl (hydroxy) phenylacetyl] propyl} -2-methyl-3- (pyridin-4-ylmethyl) -1H-imidazol-3-ium (Compound No. 159aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 160aa),
Bromide 3- (1,3-benzodioxo-5-ylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} Oxy) propyl] -2-methyl-1H-imidazol-3-ium (Compound No. 161aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (Compound No. 162aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isobutyl-2-methyl-1H -Imidazole-3-ium (compound number 163aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 164aa),
Bromide 1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2-methyl-3- (2-phenylethyl) -1H-imidazol-3-ium (Compound No. 165aa),
Bromide 3- (cyclopropylmethyl) -1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 166aa),
Bromide 3-benzyl-1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 167aa),
Bromide 1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 168aa),
Bromide 3- (cyclopropylmethyl) -1- (2- {2-hydroxy [bis (3-methylphenyl)] acetoxy} ethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 169aa),
Bromide 1- (2- {2-hydroxy [bis (3-methylphenyl)] acetoxy} ethyl) -2-methyl-1H-imidazol-3-ium (compound no. 170aa),
Bromide 3-benzyl-1- (2- {2-hydroxy [bis (3-methylphenyl)] acetoxy} ethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 171aa),
Bromide 1- {2- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] ethyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 172aa),
Bromide 3-benzyl-1- {2- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] ethyl} -2-dimethyl-1H-imidazol-3-ium (Compound No. 173aa),
Bromide 1- {2- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] ethyl} -3- (cyclopropylmethyl) -2-dimethyl-1H-imidazol-3-ium (Compound No. 174aa) ,
Bromide 3-benzyl-1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -2-methyl-1H-imidazol-3-ium (Compound No. 175aa),
Bromide 1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -3- (cyclopropylmethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 176aa) ,
Bromide 1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -3-ethyl-2-methyl-1H-imidazol-3-ium (Compound No. 177aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (3- Phenoxypropyl) -1H-imidazol-3-ium (Compound No. 178aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (3- Phenoxypropyl) -1H-imidazol-3-ium (Compound No. 179aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound number 180aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound no. 181aa),
Bromide 3- (cyclopropylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2 -Methyl-1H-imidazol-3-ium (Compound No. 182aa),
Bromide 3- (cyclohexylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2- Methyl-1H-imidazol-3-ium (Compound No. 183aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (2- Phenylethyl) -1H-imidazol-3-ium (Compound No. 184aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 185aa),
Bromide 1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 186aa),
Bromide 3- (4-bromobenzyl) -1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 187aa),
Bromide 3-benzyl-1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 188aa),
Bromide 3- (cyclopropylmethyl) -1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 189aa),
Bromide 3-ethyl-1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 190aa),
Bromide 1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 191aa),
Bromide 3- (4-bromobenzyl) -1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-1H-imidazol-3-ium (Compound No. 192aa),
Bromide 3-benzyl-1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-1H-imidazol-3-ium (Compound No. 193aa),
Bromide 3- (4-bromobenzyl) -1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-1H-imidazol-3-ium (Compound No. 194aa),
Bromide 3-ethyl-1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-methyl-1H-imidazol-3-ium (compound number 195aa),
1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2, 3-dimethyl-1H-imidazol-3-ium (Compound No. 196aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3- (3- Phenoxypropyl) -1H-imidazol-3-ium (Compound No. 197aa),
Bromide 3- (cyclopropylmethyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2 -Methyl-1H-imidazol-3-ium (compound number 198aa),
Bromide 3-butyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound no. 199aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound no. 200aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (Compound No. 201aa),
Bromide 3-benzyl-1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 202aa),
Bromide 3- (cyclopropylmethyl) -1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 203aa),
Bromide 3-ethyl-1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 204aa),
Bromide 1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 205aa),
Bromide 1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-3- (2-phenylethyl) -1H-imidazol-3-ium (Compound No. 206aa),
Bromide 1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-3- (3-phenoxypropyl) -1H-imidazol-3-ium (Compound No. 207aa),
Bromide 3-butyl-1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-1H-imidazol-3-ium (Compound No. 208aa),
Bromide 3-ethyl-1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-1H-imidazol-3-ium (Compound No. 209aa),
Bromide 1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 210aa),
Bromide 1- (3-{[(2R) -2-hydroxy-2-phenyl-2-{(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetyl] oxy} propyl) -2,3-dimethyl -1H-imidazol-3-ium (Compound No. 211aa),
Bromide 3-benzyl-1- (3-{[(2R) -2-hydroxy-2-phenyl-2-{(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetyl] oxy} propyl) -2 -Methyl-1H-imidazol-3-ium (Compound No. 212aa),
Bromide 3- (4-Bromobenzyl) -1- (3-{[(2R) -2-hydroxy-2-phenyl-2-{(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetyl] oxy } Propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 213aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound number 214aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound number 215aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 216aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 217aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound no. 218aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound no. 219aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 220aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound number 221aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 222aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isobutyl-2-methyl-1H -Imidazole-3-ium (compound number 223aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 224aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound number 225aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound no. 226aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 227aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 228aa),
Bromide 3-butyl-1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound number 229aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound number 230aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound number 231aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 232aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 233aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound number 234aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 235aa),
Bromide 3-butyl-1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound no. 236aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound no. 237aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound no. 238aa),
2- (2-methyl-1H-imidazol-1-yl) ethyl (2R)-[(1R) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 239aa),
2- (2-methyl-1H-imidazol-1-yl) propyl (2R)-[(1R) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 240aa),
Cycloheptyl (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 241aa),
2- (2-methyl-1H-imidazol-1-yl) ethyl (2R)-[(1S) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 242aa),
4- (2-methyl-1H-imidazol-1-yl) butyl (2R)-[(1S) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate (Compound No. 243aa),
4- (2-methyl-1H-imidazol-1-yl) butyl (2R)-[(1S) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 244aa),
Hydroxy (phenyl) -2-thienyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 245aa),
Hydroxy [bis (3-methylphenyl)] acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 246aa),
Bis (4-fluorophenyl) (hydroxy) acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 247aa),
3- (2-methyl-1H-imidazol-1-yl) propylbis (4-fluorophenyl) (hydroxy) acetate (Compound No. 248aa),
3- (2-methyl-1H-imidazol-1-yl) propylhydroxy [bis (3-methylphenyl)] acetate (Compound No. 249aa),
Hydroxy (phenyl) 2-thienyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (compound no. 250aa),
Hydroxy (di-2-thienyl) acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 251aa),
Hydroxy (di-2-thienyl) acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 252aa),
3- (2-methyl-1H-imidazol-1-yl) propyl (2R) -hydroxy (phenyl) {(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetate (Compound No. 253aa),
3- (2-methyl-1H-imidazol-1-yl) propyl (2R)-[(1S) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 254aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 255aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 256aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 257aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (2- Methylpropyl) -1H-imidazol-3-ium (Compound No. 258aa),
Bromide 1- (3-{[(3,3-difluorocyclopentyl) (hydroxy) thiophen-2-ylacetyl] oxy} propyl) -3-ethyl-2-methyl-1H-imidazol-3-ium (Compound No. 259aa) ,
Bromide 1- (3-{[(3,3-difluorocyclopentyl) (hydroxy) thiophen-2-ylacetyl] oxy} propyl) -2, 3-dimethyl-1H-imidazol-3-ium (compound number 260aa), and
Bromide 3-benzyl-1- (3-{[(3,3-difluorocyclopentyl) (hydroxy) thiophen-2-ylacetyl] oxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 261aa) ,
You can choose from.

  Suitable anticholinergics are, for example, ipratropium salts, oxitropium salts, salts of compounds known from WO 20/32899, optionally in the form of their hydrates and solvates; tropenol N-methyl -2,2-diphenylpropionate, scopine N-methyl-2,2-diphenylpropionate, scopine N-methyl-2-fluoro-2,2-diphenylacetate and tropenol N-methyl-2-fluoro-2 , 2-diphenylacetate; and salts of compounds known from WO 02/32898; tropenol N-methyl-3,3 ′, 4,4′-tetrafluorobenzilate, scopine N-methyl-3,3 ′, 4 , 4′-tetrafluorobenzylate, scopine N-methyl-4,4′-dichlorobenzylate, scopine Pin N-methyl-4,4′-difluorobenzylate, tropenol N-methyl-3,3′-difluorobenzylate, scopine N-methyl-3,3′-difluorobenzylate, and tropenol N-methyl-4, 4'-difluorobenzilate. The salt means a compound containing a single negatively charged anion selected from chloride, bromide, and methanesulfonate as a counter ion in addition to the cation described above.

  Specific anticholinergics include, for example, tiotropium bromide, ipratropium bromide, oxitropium bromide, tropenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2, 2-diphenylacetate methobromide, tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol 3,3 ′, 4,4′-tetrafluorobenzylate methobromide, scopine 3,3 ′, 4,4′- Tetrafluorobenzilate methobromide; scopine 4,4′-dichlorobenzylate methobromide, scopine 4,4′-difluorobenzylate methobromide, tropenol 3,3′-difluorobenzylate Bromide, including scopine 3,3'-difluoro benzilate methobromide and tropenol 4,4'-difluoro benzilate ethyl bromide.

  Suitable antiallergic agents include, for example, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimethindene, clemastine, bamipine, hexachloropheniramine, phenylamine, doxylamine, chlorophenoxamine, dimenhydrinate , Diphenhydramine, promethazine, ebastine, desloratadine, and meclizine. Special antiallergic agents include, for example, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratadine, and mizolastine, epinastine. Any reference to an antiallergic agent as described above includes any pharmacologically acceptable acid addition salts thereof that may be present.

  Suitable PAF antagonists are, for example, 4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propanon-1-yl] -6H-thieno [3,2-f]. [1,2,4] triazolo [4,3-α] [1,4] diazepine and 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8-[(4-morpholinyl) carbonyl] -4H, 7H-cyclopenta [4.5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine.

  Suitable EGFR kinase inhibitors include, for example, 4-[(3-chloro-4-fluorophenyl) amino] -7- (2- {4-[(S)-(2-oxotetrahydrofuran-5-yl) carbonyl ] Piperazin-1-yl} -ethoxy) -6-[(vinylcarbonyl) amino] quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [4-((S) -6-6 Methyl-2-oxomorpholin-4-yl) butyloxy] -6-[(vinylcarbonyl) amino] quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [4-((R) -6-methyl-2-oxomorpholin-4-yl) butyloxy] -6-[(vinylcarbonyl) amino] quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- 2-((S) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -6-[(vinylcarbonyl) amino] quinazoline, 4-[(3-chloro-4-fluorophenyl) amino]- 6-[(4- {N- [2- (ethoxycarbonyl) ethyl] -N-[(ethoxycarbonyl) methyl] -amino} -1-oxo-2-buten-1-yl) amino] -7-cyclo Propylmethoxyquinazoline, 4-[(R)-(1-phenylethyl) amino] -6-{[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 -Cyclopropyl-methoxyquinazoline, and 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) propyloxy] -7-methoxyquinazoline. Any reference to an EGFR kinase inhibitor described above includes any pharmacologically acceptable acid addition salts thereof that may be present. The physiologically or pharmacologically acceptable acid addition salts thereof that can be formed by EGFR kinase inhibitors are according to the invention hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumarate. It means a pharmaceutically acceptable salt selected from acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid salt. Preferred according to the invention are salts of EGFR kinase inhibitors selected among acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid salts.

  Suitable additional PDE-IV inhibitors include, for example, enprofylline, roflumilast, Aliflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A, Z-15370, and AWD. -12-281. Specific PDE-IV inhibitors include enprofylline, roflumilast, Ariflo, Z15370, and AWD-12-281. Any reference to a PDE-IV inhibitor as described above includes any pharmaceutically acceptable acid addition salt thereof that may be present. According to the present invention, the physiologically acceptable acid addition salts that can be formed by the aforementioned PDE-IV inhibitors are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid. It means a pharmaceutically acceptable salt selected from acid, lactic acid, citric acid, tartaric acid or maleic acid salt. According to the invention, salts selected from acetates, hydrochlorides, hydrobromides, sulfates, phosphates and methanesulfonates are preferred in this connection.

  Leukotriene antagonists are not limited to those described in US Pat. No. 5,565,473, US Pat. No. 5,583,152, US Pat. No. 4,859,692 or US Pat. No. 4,780,469. It can be selected from compounds.

  Examples of leukotriene antagonists include, but are not limited to, montelukast, zafirlukast, pranlukast, and pharmaceutically acceptable salts thereof.

  The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, manganous, potassium, sodium, zinc and the like.

  Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and arginine, betaine, Caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-dibenzylethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucanin , Glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and toluene It includes salts of such basic ion exchange resins as Metamin.

  When the compound of the present invention is basic, the salt is acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, Pharmaceutically acceptable non-organic including inorganic and organic acids such as maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid It can be prepared from toxic acids.

  The pharmaceutical composition of the present invention has the following routes, for example, oral, topical, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, subcutaneous, It can be administered intranasally, by inhalation, rectum or vagina.

  Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, troches, patches, gel caps, plasters, medicinal candy, creams, pastes, plasters, lotions, discs, or ointments. Including. Liquid form preparations include solutions, suspensions, emulsions, syrups, elixirs, aerosols, inhalations, nasal sprays or oral sprays.

  The active compound can be admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.

  The pharmaceutical compositions used in the methods described herein can be prepared by any of the pharmaceutical methods, but all methods include the active ingredient together with a carrier that constitutes one or more necessary ingredients. The process of carrying out is included. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with pharmaceutically acceptable liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired form. Is done.

  Commonly used carriers are corn starch, lactose, talc, calcium phosphate, calcium sulfate, calcium stearate, magnesium stearate, stearic acid, sorbitol, microcrystalline cellulose, mannitol, gelatin, carboxymethylcellulose, methylcellulose, alginate, dextran, acacia Includes one or more of natural or synthetic gums such as gum, karaya gum, locust bean gum. In addition, other excipients such as diluents, binders, lubricants, disintegrants, colorants and fragrances can be used. For example, a tablet can be prepared by compression or molding, optionally with one or more pharmaceutically acceptable excipients. Compressed tablets are compressed with a suitable machine the active ingredients in free-flowing form such as powders or granules, which may be mixed with binders, lubricants, inert diluents, surfactants or dispersants as desired. Can be prepared. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  In addition to the conventional dosage forms described above, the therapeutically active active ingredient is administered by controlled release means and / or delivery devices to provide rate controlled release of the ingredient or any one or more of the active ingredients; The desired therapeutic effect can also be optimized. Suitable dosage forms for sustained release include various disintegration rates or molded into tablet forms or capsules containing a porous polymer matrix impregnated with the active ingredient and so impregnated or encapsulated. A layered tablet containing a layer of a controlled release polymer matrix is included.

  The “polymer matrix” substantially acts to modulate the drug release rate and stabilize the metastable drug. Because of their diversity, polymers represent a selective material for matrix delivery systems. In fact, polymer matrices can be beneficially used in, for example, oral delivery, implantable systems, regenerative medicine, DNA / RNA release, intelligent delivery systems and polymer conjugation.

  The magnitude of the prophylactic or therapeutic dose of one or more compounds described herein in the acute or chronic prevention, treatment or management of a disorder or disease depends on the severity of the disease to be treated and the route of administration. It will change. The dose, and possibly the dose frequency, will also vary according to the age, weight and response of the individual patient. Appropriate total daily dose ranges can be readily determined by one skilled in the art. In general, for the diseases described herein, the total daily dose range for one or more compounds described herein is a single or divided dose, depending on the particular application and efficacy of the active ingredient. It can range from about 1 mg to about a few grams administered. Appropriate dosages can be determined using smaller dosages that are less than the optimum dosage. Such small doses can be increased by small increments until the optimum effect is reached. The dose can be divided and administered as divided doses if desired.

  Formula Ia and Formula Ib type IV phosphodiesterase inhibitors, and muscarinic receptor antagonists (MRAs) should be present in the compositions described herein in a ratio of about 1:10 to 10: 1. Can do. Type IV phosphoesterase inhibitors and muscarinic receptor antagonists (MRAs) are also available in ratios of about 1: 1, 2: 1, 1: 2, 1: 3, 3: 1, 1: 5 and 5: 1. It can be present in the compositions described herein.

  The type IV phosphodiesterase inhibitor of formula Ia and formula Ib, and the β2-agonist can be present in a ratio of about 1:10 to 10: 1. Type IV phosphodiesterase inhibitors and β2-agonists are also described herein in ratios of about 1: 1, 2: 1, 1: 2, 1: 3, 3: 1, 1: 5 and 5: 1. Can be present in different compositions.

  The type IV phosphodiesterase inhibitor of formula Ia and formula Ib, and the p38 MAP kinase inhibitor can be present in the compositions described herein in a ratio of about 1:10 to 10: 1. Type IV phosphodiesterase inhibitors, and p38 MAR kinase inhibitors are also used herein in ratios of about 1: 1, 2: 1, 1: 2, 1: 3, 3: 1, 1: 5 and 5: 1. Can be present in the composition described in.

  Formula Ia and Formula Ib type IV phosphodiesterase inhibitors, and corticosteroids can be present in the compositions described herein in a ratio of about 1:10 to 10: 1. Type IV phosphodiesterase inhibitors and corticosteroids are also described herein in ratios of about 1: 1, 2: 1, 1: 2, 1: 3, 3: 1, 1: 5 and 5: 1. Can be present in different compositions.

  The invention also provides methods for treating or preventing autoimmunity, inflammation, or allergic disorders. The method comprises a therapeutically effective amount of one or more compounds described herein of Formula Ia or Ib, and a therapeutically effective amount of one or more muscarinic receptor antagonists (MRAs), β2-agonists, There is a need for a pharmaceutical dosage form comprising one or more corticosteroids, or at least one other active ingredient, such as one or more p38 MAP kinase inhibitors, and one or more pharmaceutically acceptable excipients. Administration to a mammal.

  The invention also provides methods for treating or preventing autoimmunity, inflammation, or allergic disorders. The method comprises a therapeutically effective amount of one or more compounds described herein of Formula Ia or Formula Ib, and a therapeutically effective amount of one or more anticholinergic agents, one or more muscarinic receptors. At least one other active ingredient such as an antagonist, one or more anti-allergic agents, one or more PAF antagonists, one or more leukotriene antagonists, one or more EGFR kinase inhibitors, or one or more additional PDE-IV inhibitors, And administering a pharmaceutical dosage form comprising one or more pharmaceutically acceptable excipients to a mammal in need thereof.

  Still other methods include: a) a pharmaceutical dosage form comprising a therapeutically effective amount of one or more of the compounds described herein of Formula Ia and Formula Ib, and one or more pharmaceutically acceptable excipients. And b) a therapeutically effective amount of at least one other active ingredient, such as one or more corticosteroids, one or more β2-agonists, or one or more p38 MAP kinase inhibitors, and one or more pharmaceutically One or more dosage forms containing acceptable excipients are administered simultaneously or sequentially to a mammal in need thereof.

  Still other methods include: a) a pharmaceutical dosage form comprising a therapeutically effective amount of one or more compounds described herein of Formula Ia or Formula Ib, and one or more pharmaceutically acceptable excipients; And b) a therapeutically effective amount of one or more muscarinic receptor antagonists, one or more anticholinergics, one or more antiallergic agents, one or more PFA antagonists, one or more leukotriene antagonists, one or more EGFR kinases One or more dosage forms comprising at least one other active ingredient, such as an inhibitor or one or more additional PDE-IV inhibitors, and one or more pharmaceutically acceptable excipients, a mammal in need thereof Including simultaneous or sequential administration to animals.

  In one embodiment, there is provided a method for treating or preventing autoimmunity and / or inflammation / allergic diseases or disorders comprising administering one or more compounds of the pharmaceutical compositions described herein. Is done. Such autoimmune and / or inflammatory / allergic diseases or disorders include, for example, respiratory disorders, asthma, chronic bronchitis, chronic obstructive pulmonary disease, whooping cough, eosinophilic granuloma, psoriasis, and other benign or Malignant proliferative skin disease, eczema, inflammatory bowel disease, endotoxic shock, anaphylactic shock, horseshoe inflammation in horses, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory arthritis Periodontitis, chronic glomerulonephritis, atopic dermatitis, hives, adult respiratory distress syndrome, infant respiratory distress syndrome, transplant rejection, rhinitis, pruritus, diabetes insipidus, ophthalmitis, allergic rhinitis, allergic conjunctivitis , Spring catarrh, arterial restenosis, orcerosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, osteoporosis, osteoarthritis, inflammation, ankylosing spine , Transplant rejection, graft versus host rejection, gastric acid hypersecretion, bacteria, fungus-induced sepsis, virus-induced sepsis, fungus-induced sepsis shock, virus-induced sepsis shock, inflammation-mediated chronic tissue degeneration, cytokine-mediated chronic tissue degeneration, deformation Osteoarthritis, cancer, cachexia, muscle wasting, depressed memory damage, tumor growth, normal tissue cancer invasion, Hashimoto's thyroiditis (low-active thyroid), Grave's disease (overactive thyroid), lupus and acquired immune deficiency Including syndrome.

  Although the invention has been described with reference to specific embodiments thereof, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the invention. The examples are set forth to illustrate particular embodiments of the disclosure and are not intended to limit the scope of the invention as defined by the claims.

  Biological assay method:

In vitro assay to assess the effects of PDE IV inhibitors in combination with p38 MAP kinase inhibitors Cell-based assays for TNF-α release:
Blood was taken from healthy human volunteers in heparin or EDTA vacutainers and peripheral blood mononuclear cells were isolated using a Ficoll Hyperpaque gradient. Cells were resuspended in serum free RPMI 1640 medium at a concentration of 2 million cells / ml. 1 ml of this cell suspension, alone or in combination, was incubated with 20 μl of compound for 10 minutes in a flat bottom 96 well microtiter plate. Compounds were first dissolved in DMSO and diluted in medium for a final concentration of 0.2% DMSO. LPS (1 μg / ml, final concentration) was then added in a volume of 10 μl per well. After 30 minutes, 20 μl of fetal calf serum (10% final concentration) was added to each well. Cultures were incubated overnight at 37 ° C. in an atmosphere of 5% CO ₂ and 95% air. The supernatant was then removed and tested by ELISA for TNF-α release using a commercially available kit (eg, BD Biosciences). The level of TNF-α in the treated wells was compared to the vehicle-treated control, and the inhibitory ability of the compound was expressed as an IC ₅₀ value calculated from the percent inhibition value by using GraphPad Prism.

IC _{50 for} inhibition of TNF-α release:
Compound No. 266 (PDE IV inhibitor) and p38 MAP kinase inhibitor (Compound No. 44a, Compound No. 46a, Compound No. 47a, and Vx-745 disclosed in WO 98/27098) are TNF-α from human PBMC. It exhibits the following IC ₅₀ in inhibiting release.

ＰＤＥ ４阻害剤化合物番号２６６は、７６ｎＭのＩＣ₅₀値にてＴＮＦ−αの放出を阻害した。それは、ヒトＰＢＭＣにおけるＴＮＦ−α放出を阻害する際に、ｐ３８ ＭＡＰキナーゼ阻害剤化合物番号４４ａ、化合物番号４６ａ、化合物番号４７ａ、およびＷＯ ９８／２７０９８に開示されたＶｘ−７４５と共に相乗作用応答を呈した。 Compound No. 266 (PDE IV inhibitor) and p38 MAP kinase inhibitor (Compound No. 44a, Compound No. 46a, Compound No. 47a, and Vx-745 disclosed in WO 98/27098) are TNF-α from human PBMC. The following combination index (CI) is exhibited in inhibiting release.

PDE 4 inhibitor compound number 266 inhibited the release of TNF-α with an IC ₅₀ value of 76 nM. It exhibits a synergistic response in combination with the p38 MAP kinase inhibitor Compound No. 44a, Compound No. 46a, Compound No. 47a, and Vx-745 disclosed in WO 98/27098 in inhibiting TNF-α release in human PBMC. did.

In vitro assay to assess the effect of PDE IV inhibitors in combination with β2-agonists-measurement of intracellular cAMP elevation in U937 cells U937 cells were treated with 10% (v / v) heat-inactivated fetal bovine serum and 1% Grow in endotoxin-free RPMI 1640 + HEPES medium containing (v / v) antibiotic solution (5000 IV / ml penicillin, 5000 ug / ml streptomycin) (human pro-single cell line). Cells were resuspended in Krebs buffer solution ^{(0.25 × 10 6 / 200μl)} , and incubated for 15 min at 37 ° C. in the presence of the test compound or vehicle (20 [mu] l). cAMP development is initiated by adding 50 μl of 10 μM prostaglandin (PGE2). The reaction is stopped after 15 minutes by adding 1N HCl (50 μl) and placed on ice for 30 minutes. Samples are centrifuged (450 g, 3 min) and cAMP levels are measured in the supernatant by using a cAMP enzyme-linked immunosorbent assay kit (Assay Designs). Percent inhibition is calculated according to the following formula, and IC ₅₀ values are calculated with these values using a graph pad prism.

  In vitro functional assay to assess the effects of PDE IV inhibitors in combination with β-agonists

Animals and anesthesia Guinea pigs are obtained (400-600 gm) and the trachea is removed under anesthesia (sodium pentobarbital, 300 mg / kg ip) and stored immediately in ice-cold Krebs Henselite buffer. Indomethacin (10 μM) is present throughout the KH buffer to prevent the formation of bronchoactive prostanoids.

Trachea experiment:
The adhesive fascia tissue is cleaned and cut into equal sized strips (approximately 4-5 tracheal rings in each strip). Carefully remove the epithelium by rubbing to minimize damage to smooth muscle. The trachea is opened along the mid-back surface with the smooth muscle band intact, and a series of transverse cuts are made from the other side so that they do not completely cut the preparation sideways. Tie the opposite ends of the cutting wheel with the help of a thread. The tissue is placed at 1 gm basal tension in an excised tissue bath maintained at 37 ° C. and containing 10 ml of Krebs Henselite buffer aerated with carbogen. The buffer is changed 4 to 5 times over about 1 hour. Tissue is equilibrated for 1 hour with 1 μM carbachol or 10 μM histamine for stabilization. Tissues are washed for 30 minutes followed by precontraction with histamine (10 μM) or carbachol (1 μM). The developed tension is allowed to stabilize for 15-20 minutes, followed by cumulative addition of β-agonist prior to incubation with suboptimal doses of PDE IV inhibitor. Tissue contractile responses are recorded either by the Powerlab data acquisition system or by the Grass polygraph (model 7). The relaxation as a percentage is expressed as the maximum carbachol response. Data are mean ± SEM for observation. E. Expressed as average. The EC ₅₀ is calculated as the concentration that produces 50% of the maximum relaxation for 1 μM carbachol. Percent relaxation is compared between treated and control tissues using a non-parameter unpaired t-test. A p value of <0.05 is considered statistically significant.

  In vivo assay to assess the effect of PDE IV inhibitors in combination with β-agonists

Lipopolysaccharide (LPS) induced airway hypersensitivity (AHR) and neutropenia:

Drug treatment:
A β-agonist (1 ng / kg to 1 mg / kg) and a PDE4 inhibitor (1 ng / kg to 1 mg / kg) are injected into the trachea under anesthesia, either alone or in combination.

Method:
Male Wistar rats weighing 200 ± 20 gm are used in the experiment. Rats should have free access to food and water. On the day of the experiment, animals are exposed to lipopolysaccharide (LPS, 100 μg / ml) for 40 minutes. One group of vehicle-treated rats should be exposed to phosphate buffered saline (PBS) for 40 minutes. 2 hours after LPS / PBS exposure, the animals were placed inside a whole body plethysmograph (Buxco Electronics, USA) and the Penh value (indicator of airway resistance) in rats was observed with PBS alone (PC-100) Exposure to PBS or increasing acetylcholine (1, 6, 12, 24, 48, and 96 mg / ml) aerosol until reaching 2 times. Respiratory system parameters are recorded online using Biosystem XA software (Buxco Electronics, USA). At any selected dose of acetylcholine, Penh is expressed as a percentage of PBS response and PC100 (2 times PBS value) is calculated using nonlinear regression analysis. The percent inhibition is calculated using the following formula:

式中、
ＰＣ１００_LPS＝ＬＰＳを負荷したビークル処理群におけるＰＣ１００
ＰＣ１００_TEST＝与えられた用量のテスト化合物で処理された群におけるＰＣ１００
ＰＣ１００_PBS＝ＰＢＳを負荷したビークル処理群におけるＰＣ１００

Where
PC100 _LPS = PC100 in the vehicle processing group loaded with LPS
PC100 _TEST = PC100 in the group treated with a given dose of test compound
PC100 _PBS = PC100 in vehicle-treated group loaded with PBS

  Immediately after airway hypersensitivity, responses are recorded, animals are euthanized and bronchoalveolar lavage (BAL) is performed. The collected wash fluid is centrifuged at 3000 rpm for 5 minutes at 4 ° C. The pellet is collected and resuspended in 1 ml HBSS. Total leukocyte count is determined in the resuspended sample. A portion of the suspension is centrifuged and stained with Leishmann staining for differential leukocyte count. Total leukocyte and neutrophil counts are expressed as cell counts (million cells per ml of BAL). The percent inhibition I is calculated using the following formula:

式中、
ＮＣ_LPS＝ＬＰＳを負荷されたビークル処理群における好中球のパーセンテージ
ＮＣ_TEST＝与えられた用量のテスト化合物で処理された群における好中球のパーセンテージ
ＮＣ_PBS＝ＰＢＳを負荷されたビークル処理群における好中球のパーセンテージ
ＥＤ₅₀値は、グラフパッドプリズムソフトウエア（Ｇｒａｐｈｐａｄ Ｓｏｆｔｗａｒｅ Ｉｎｃ．，ＵＳＡ）を用いてパーセント阻害データから計算する。

Where
NC _LPS = percentage of neutrophils in vehicle treated group loaded with LPS NC _TEST = percentage of neutrophils in group treated with given dose of test compound NC _PBS = in vehicle treated group loaded with PBS Neutrophil percentage ED ₅₀ values are calculated from percent inhibition data using Graphpad Prism Software (Graphpad Software Inc., USA).

  In vitro assay to evaluate the effects of PDE IV inhibitors in combination with corticosteroids

Cell-based assay for TNF-α release:
Blood is collected from healthy human volunteers in heparin or EDTA vacutainers and peripheral blood mononuclear cells are isolated using a Ficoll Hypacqe gradient. Cells are resuspended in serum free RPMI 1640 medium at a concentration of 2 million cells / ml. 1 ml of this cell suspension is incubated for 10 minutes with 20 μl of compound alone or in combination (PDE IV inhibitor and corticosteroid) in flat bottom 96 well microtiter plates. The aforementioned compounds are first dissolved in DMSO and diluted in medium for a final concentration of 0.2% DMSO. LPS (1 mg / ml, final concentration) is then added in a volume of 10 μl per well. After 30 minutes, 20 μl of fetal calf serum (10% final concentration) is added to each well. Cultures are incubated overnight at 37 ° C. in an atmosphere of 5% CO ₂ and 95% air. The supernatant is then removed and tested for TNF-α release by ELISA using a commercially available kit (eg, BD Biosciences). The level of TNF-α in the treated wells is compared to the vehicle-treated control and the inhibitory ability of the compound is expressed as an IC ₅₀ value calculated by percent inhibition using the graph pad prism. The IC ₅₀ values for the test compounds are found to be in the lower μM to nM concentration range.

・ Ｃ番号２６６とは、化合物番号２６６をいう。
・ 組合せ指標：相乗活性を示す０．２１
・ Ｃ番号２６６は、コルチコステロイドとの相乗効果を示し、これは、用量を低下させる能力を示す。 A synergistic effect was observed with the combination of corticosteroid and PDE IV inhibitor, which can be seen from the graph shown below.

-C number 266 refers to compound number 266.
Combination index: 0.21 indicating synergistic activity
• C # 266 shows a synergistic effect with corticosteroids, which indicates the ability to reduce the dose.

In vivo assay LPS to evaluate the effect of PDE IV inhibitors in combination with corticosteroids induced a rat neutropenia model.

Drug treatment:
PDE-4 inhibitors and corticosteroids were injected intratracheally under anesthesia at different doses, either alone or in combination.
LPS loading: 1 hour after drug injection, (LPS 20 μg / 200 μl of PBS) was dropped into the trachea. One group of vehicle-treated rats was injected with 200 μl phosphate buffered saline (PBS) and served as a negative control.

Bronchoalveolar lavage (BAL): Two hours after LPS challenge, bronchoalveolar lavage was performed; the animals were sacrificed with sodium thiopentone (150 mg / kg ip). The trachea was cannulated and BAL was performed using Hank's buffer salt solution (HBSS) (5 ml × 10 times). The bronchoalveolar lavage fluid was centrifuged at 800 g for 5 minutes at 4 ° C. and the pellet was resuspended in 1 ml HBSS. A total leukocyte count was performed in the resuspended sample by using a hemocytometer. Cell resuspension was performed using resuspended bronchoalveolar lavage fluid on a glass slide, stained with Leishmann staining, and then a fractionated leukocyte count was performed for neutrophil counts. Statistical significance of each parameter in the different treatment groups was determined for the vehicle subject group using a one-sided analysis of deviations followed by Dunnett's “t” test for multiple comparisons. A p level of ≦ 0.05 was considered statistically significant.

  The percent inhibition was calculated using the following formula:

式中、
Ｎｅｕ_LPS＝ビークル処理ＬＰＳ負荷群における好中球カウント
Ｎｅｕ_TEST＝与えられた用量のテスト化合物で処理した群における好中球カウント
Ｎｅｕ_PBS＝ＰＢＳで負荷した群における好中球のパーセンテージ

Where
Neu _LPS = neutrophil count in vehicle-treated LPS-loaded group Neu _TEST = neutrophil count in group treated with given dose of test compound Neu _PBS = percentage of neutrophils in group loaded with PBS

・ Ｃ番号２６６とは、化合物番号２６６をいう。
・ 組合せ指標＝相乗活性を示す０．５８
・ Ｃ番号２６６（ＰＤＥ ＩＶ阻害剤）はコルチコステロイドとで相乗効果を示し、これは、用量を降下させる能力を示す。 A synergistic effect is observed with the combination of PDE IV inhibitor and corticosteroid, which is evident from the graph shown below.

-C number 266 refers to compound number 266.
-Combination index = 0.58 indicating synergistic activity
• C # 266 (PDE IV inhibitor) is synergistic with corticosteroids, indicating its ability to lower the dose.

  In vivo assay to evaluate the effect of PDE-IV inhibitors in combination with muscarinic receptor antagonists (MRA)

Drug treatment:
MRA (1 ng / kg to 1 mg / kg) and PDE-IV inhibitor (1 ng / kg to 1 mg / kg) were injected into the trachea under anesthesia, alone or in combination.

Method:
Wistar rats weighing 200 ± 20 gm were used in this study. Rats had free access to food and water. On the day of the experiment, animals were exposed to lipopolysaccharide (LPS, 100 μg / ml) for 40 minutes. One group of vehicle-treated rats was exposed to phosphate buffered saline (PBS) for 40 minutes. Two hours after LPS / PBS exposure, the animals were placed inside a whole body plethysmograph (Buxco Electronics, USA) and the rat Penh value (an index of oral airway) was the value observed with PBS alone (PC-100). Exposure to PBS or increasing concentrations of acetylcholine (1, 6, 12, 24, 48, and 96 mg / ml) aerosol until doubled. Respiratory system parameters were recorded online using Biosystem XA software (Buxco Electronics, USA). At any selected dose of acetylcholine, Penh was expressed as a percent of the PBS response and PC100 (2 times PBS value) values were calculated using nonlinear regression analysis. Percent inhibition was calculated using the following formula:

式中、
ＰＣ１００_LPS＝ビークル処理およびＬＰＳ負荷群におけるＰＣ１００
ＰＣ１００_TEST＝与えられた用量のテスト化合物で処理した群におけるＰＣ１００
ＰＣ１００_PBS＝ＰＢＳを負荷したビークル処理群におけるＰＣ１００

Where
PC100 _LPS = PC100 in vehicle treatment and LPS load group
PC100 _TEST = PC100 in the group treated with a given dose of test compound
PC100 _PBS = PC100 in vehicle-treated group loaded with PBS

・ 組合せ指標＝相乗活性を示す０．２６
・ Ｃ番号２６６（ＰＤＥ ＩＶ阻害剤）はチオトロピウム（ＭＲＡ）と共に相乗作用を 示し、これは、用量を低下させる能力を示す。 A synergistic effect is observed with the combination of a muscarinic receptor antagonist (MRA) and a PDE4 inhibitor, which can be seen from the graph shown below.

-Combination index = 0.26 indicating synergistic activity
• C # 266 (PDE IV inhibitor) synergizes with tiotropium (MRA), indicating its ability to reduce dose.

In another experiment, MRA case compound number 104aa alone had no effect at a dose of 10 ng / kg, and a synergistic effect was observed when administered with PDE4 case compound number 266 (10 μg / kg). . When a PDE4 inhibitor was combined with MRA Compound No. 104aa, Compound No. 266, which was not individually effective compared to the LPS control group, showed a statistically significant increase in PC100 values. The preventive effect percentage shown by the combination of both drugs is 82%. The combination index is calculated to be 0.19, indicating a synergistic effect.

Claims (12)

One or more type IV phosphodiesterase inhibitors (“PDE-IV”) and at least one other selected from muscarinic receptor antagonists (MRAs), β2-agonists, p38 MAP kinase inhibitors, and corticosteroids. An active ingredient, and one or more pharmaceutically acceptable excipients, wherein the PDE-IV inhibitor is one or more compounds having the structure of Formula Ia or Formula Ib;
here,
a. Formula Ia is:

Formula Ia

And pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides thereof, wherein
When X is oxygen,
R ₁ is hydrogen, alkyl, heterocyclyl, — (CH ₂ ) _m C (═O) R ₃ , or (CH ₂ ) _1-4 OR ′ (where m is an integer from 0 to 2, ₃ is an alkyl, cycloalkyl, heterocyclyl, or optionally substituted R _p or R _q , wherein R _p is a heterocyclyl or heteroaryl ring, wherein the ring is Bonded to (CH ₂ ) _m C (═O), R _q is a heterocyclyl or heteroaryl ring, wherein the ring is bonded to — (CH ₂ ) _m C (═O) via C; Wherein R ′ is alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl);
R ₂ is (CH ₂ ) _m C (═O) R ₃ , — (CH ₂ ) _1-4 OR ′, or C (═O) NR _x R _y {where m, R ₃ and R ′ Is as defined above, wherein R _x and R _y are each independently hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, cycloalkyl, carboxy, —S ( O) _m R ₅ where R ₅ is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl,}, or R ₁ and R ₂ together may be optionally substituted by Shikuroa Forming Kill or heterocyclyl ring, where the substituents of said desired oxo, alkyl, alkenyl, alkynyl, halogen, _{nitro, -NH 2, -NHC (= O} ) OR 6, -C (= O) NR x R _y , cyano, hydroxy, alkoxy, or substituted amino (where R ₆ is alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), provided that R ₁ Is — (CH ₂ ) _1-4 OR ′, R ₂ is also — (CH ₂ ) _1-4 OR ′, provided that if R ₁ is C (═O) NR _x R _y , R ₂ is also C (═O) NR _x R _y ;
R ₄ is hydrogen; alkyl; -OR _5; halogen; -NH _2, substituted amino, cyano, carboxy; or -C (= O) a NR _x R _y (herein, R _5, R _x and R _y is as defined above; or R ₂ and R ₄ are optionally substituted 4- to 12-membered saturated or unsaturated monocyclic ring fused to ring B having 0 to 4 heteroatoms. Or form a bicyclic ring system wherein the substituent is one or more of alkyl, halogen, hydroxy, alkoxy, —NH ₂ or substituted amino (where R ₅ and R _x and R _y Is as defined above) provided that R ₂ and R ₄ together do not form —CH ₂ —O—CH ₂ —O—CH ₂ —;
R ₇ is hydrogen, alkyl, alkenyl, alkynyl, —OR ₅ , halogen, cyano, —NH ₂ , or substituted amino;
X ₁ and X ₂ are each independently hydrogen, alkyl, alkaryl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, — (CH ₂ ) _g C (═O ) NR _x R _y , — (CH ₂ ) _g1 C (═O) OR ₃ or heteroarylalkyl; where g1 is an integer from 1 to 3 (where R _x , R _y , g and R ₃ is as defined above);
Y is each independently an oxygen atom; a sulfur atom; or —NR (where R is hydrogen, acyl, aryl, or alkyl);
Y ₁ and Y ₂ are each independently hydrogen; alkyl; —OR; —SR; or —NHR (where R is as defined above);
Where Y ₁ and X ₂ and either X ₁ and Y ₂ are optionally joined together to form a fused ring with ring A, the ring containing from 3 to 5 carbon atoms in the ring And having 1 to 3 heteroatoms, and X ₁ and X ₂ are optionally combined to form a fused ring with ring A, the ring containing 3 to 5 carbon atoms in the ring Containing and having 2 to 3 heteroatoms and X is NR ₇ or S (where R ₇ can be hydrogen or C _1-6 alkyl)
R ₁ and R ₂ are independently alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, nitro, halogen, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, NH ₂ , substituted amino, carboxy, — (CH ₂ ) _m C (═O) R ₃ , —C (═O) NR _x R _y , or (CH ₂ ) _1-4 OR ′ {where m is an integer from 0 to 2, R ₃ is alkyl, cycloalkyl, heterocyclyl, or optionally substituted R _p or R _q (where R _p is a heterocyclyl or heteroaryl ring, wherein the ring is Te (CH ₂₎ attached to _m C (= O), and R _q is heterocyclyl or heteroaryl ring, where said ring via a C - (CH _{2) m} C ( Bound to O)), herein, R 'is alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl, and wherein the, R _x and R _y are each independently And hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, cycloalkyl, carboxy, —S (O) _m R ₅ (where R ₅ is hydrogen, alkyl, alkenyl, alkynyl). , Aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl}, or R ₁ and R ₂ optionally substituted together Forming a which may cycloalkyl or heterocyclyl ring, wherein the substituents of said desired oxo, alkyl, alkenyl, alkynyl, halogen, nitro, -NH _2, a -NHC (= O) OR ₆ (wherein, R ₆ Is alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), —C (═O) NR _x R _y , cyano, hydroxy, alkoxy, or substituted amino;
R ₄ is hydrogen; alkyl; -OR _5; halogen; -NH _2, substituted amino, cyano, carboxy; or -C (= O) a NR _x R _y (herein, R _5, R _x and R _y is as defined above; or R ₂ and R ₄ are optionally substituted 4- to 12-membered saturated or unsaturated monocyclic ring fused to ring B having 0 to 4 heteroatoms. Or forms a bicyclic ring system, wherein the substituent can be one or more of alkyl, halogen, hydroxy, alkoxy or substituted amino (where R ₃ and R _x and R _y are As defined above) provided that R ₂ and R ₄ together do not form —CH ₂ —O—CH ₂ —O—CH ₂ —;
R ₇ is hydrogen, alkyl, alkenyl, alkynyl, —OR ₅ , halogen, cyano, —NH ₂ , or substituted amino;
X ₁ and X ₂ are each independently alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl;
Y is each independently an oxygen atom; a sulfur atom; or —NR (where R is hydrogen, acyl, aryl, or alkyl);
Y ₁ and Y ₂ are each independently hydrogen, alkyl, —OR, —SR, or —NHR (where R is as defined above);
Wherein Y ₁ and X ₂ , and X ₁ and Y ₂ are optionally joined together to form a ring fused to ring A, the ring containing from 3 to 5 carbon atoms in the ring, and Having 1 to 3 heteroatoms such as N, O and S;
X ₁ and X ₂ can optionally combine to form a cyclic ring fused with the ring A, the ring containing 3 to 5 carbon atoms in the ring and 2 to 3 heteroatoms. And b. Formula Ib is:

Formula Ib

And pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides thereof, wherein
R ₁ and R ₂ together form an optionally substituted cycloalkyl or heterocyclyl ring, wherein one or more desired substituents are oxo, alkyl, alkaryl, alkenyl, alkyne, heterocyclyl Alkyl, cycloalkylalkyl, —SO ₂ NR _x R _y , halogen, —NH ₂ , — (CH ₂ ) _g C (═O) NR _x R _y , —NHC (═O) OR ₆ , —NHC (═O _{) NR x R y, -C (} = O) oR 3, -NHC (= O) R x, -SO 2 R 3, cyano, hydroxy, alkoxy, substituted amino or -C (= O) R _3, Where R _x , R _y , g, R ₆ and R ₃ are as defined above;
R ₄ is hydrogen; alkyl, hydroxyl, halogen, or carboxy;
R ₇ is hydrogen or alkyl;
R ₁ is independently hydrogen or alkyl, and R ₂ and R ₄ are optionally substituted 4 to 12 membered saturated or unsaturated, fused to ring B having 0 to 4 heteroatoms. Forms a monocyclic or bicyclic ring system wherein the substituent is oxo, alkyl, —OC (═O) OR ₃ , —SO ₂ R ₃ , halogen, hydroxy, alkoxy, —NH ₂ or substituted (Wherein R ₃ is as defined below), provided that R ₂ and R ₄ together represent —CH ₂ —O—CH ₂ —O—CH ₂ —. Does not form;
X ₁ and X ₂ are hydrogen, alkyl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, — (CH ₂ ) _g C (═O) NR _x R _y or _{- (CH 2) g1 C (} = O) is oR ₃ (here, g can be a integer of 0 to 3, g1 may be a an integer of 1 to 3, and R _x, R _y and R ₃ Is as defined above);
X ₁ and X ₂ together can optionally form a cyclic ring fused to ring A shown in Formula I, which contains 3 to 5 carbon atoms in the ring, and 2 to Having 3 heteroatoms N, O or S;
Where R ₃ is alkyl, cycloalkyl or heterocyclyl;
Wherein the halogen may be F, Cl, Br, or I; R _x and R _y are each independently hydrogen, alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, carboxy , Cycloalkyl, —S (O) _m R ₅ , aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl; m can be an integer between 0 and 2; R ₆ is Can be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl, or heterocyclylalkyl; and wherein R ₅ is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, hetero Must be arylalkyl, heterocyclyl or heterocyclylalkyl Pharmaceutical compositions characterized. The one or more compounds of Formula Ia or Formula Ib are:
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-6-ol (Compound No. 1),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -N- (4-fluorophenyl) -1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-carboxamide (compound Number 2),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -7- (tetrahydrofuran-3-ylcarbonyl) -1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 3) ),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -N, N-dimethyl-1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-sulfonamide (Compound No. 4 ),
N-butyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-carboxamide (Compound No. 5),
2- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-en-7-yl} acetamide (Compound No. 6),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8-propyl-1-oxa-2,8-diazaspiro [4.5] dec-2-ene hydrochloride (Compound No. 7),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -8- (2-morpholin-4-yl-ethyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene ( Compound No. 8),
N-butyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-8-carboxamide (Compound No. 9),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8- (methylsulfonyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 10),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.4] non-2-ene (Compound No. 11),
3- [3,4-bis (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 12),
3- (3,4-diisopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 13),
3- [3-methoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 14),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-8-one (Compound No. 15),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-8-ol (Compound No. 16),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -7-isopropyl-1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 17),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -7- (cyclopropylcarbonyl) -1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 18),
N-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-ene-7-carboxamide (Compound No. 19),
7-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-ene (Compound No. 20),
Tert-butyl 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene-7-carboxylate (Compound No. 21),
N-butyl-N ′-{3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} urea (Compound No. 22),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} -N ′-(2-methoxyphenyl) ) Urea (compound number 23),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-ol (Compound No. 24),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene hydrochloride (Compound No. 25),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-one (Compound No. 26),
3- [3,4-bis (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 27),
3- [3,4-bis (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 28),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-en-4-ol (Compound No. 29),
(R) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 30),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8- (cyclopropylmethyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 31),
N-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-8-carboxamide (Compound No. 32),
3- [3,4-bis (benzyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 33),
4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) benzene-1,2-diol (Compound No. 34),
7-amino-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-en-6-one (Compound No. 35),
Ethyl 8-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-4-carboxylate (Compound No. 36) ,
3- [3- (cyclopentyloxy) -4- [methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-ene-4-carboxylic acid (Compound No. 37),
8-benzyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 38),
Ethyl 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-ene-4-carboxylate (Compound No. 39);
3- [3- (difluoromethoxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 40),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 41),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.4] non-2-en-6-one (Compound No. 42),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 6a-dimethyl-3aH-cyclopenta [d] isoxazole-4,6 (5H, 6aH) -dione (Compound No. 43),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 4,6,6a-tetrahydrofuro [3,4-d] isoxazole (Compound No. 44),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -6,6a-dihydrofuro [3,4-d] isoxazol-4 (3aH) -one (Compound No. 45),
[({3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} amino) carbonyl] carbamate tert-butyl (Compound No. 46),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} cyclopentanecarboxamide (Compound No. 47),
8-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 48),
8- (cyclopentylcarbonyl) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 49),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -8- (2-piperidin-1-ylethyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 50),
3- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 51),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,8-dioxa-2-azaspiro [4.5] dec-2-ene (Compound No. 52),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3aH-cyclopenta [d] isoxazole-4,6 (5H, 6aH) -dione (Compound No. 53),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8-ethyl-1-oxa-2,8-diazaspiro [4.5] dec-2-ene (Compound No. 54),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -8-vinyl-1-oxa-2-azaspiro [4.5] dec-2-en-8-ol (Compound No. 55),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 4,5,6,7,7a-hexahydro-1,2-benzisoxazole (Compound No. 56),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole (Compound No. 57),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} methanesulfonamide (Compound No. 58),
3- [3- (cyclopentyloxy)]-4-methoxyphenyl] -8-methyl-1-oxa-2-azaspiro [4.5] dec-2-en-8-ol (Compound No. 59),
3- [3- (allyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 60),
3- [3- (2-chloroethoxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 61),
2- (cyclopentyloxy) -4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 62),
3- (4-butoxy-3-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 63),
3- (3-isobutoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 64),
3- [3-butoxy-4- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 65),
3- (3-butoxy-4-ethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 66),
3- [3-butoxy-4- (cyclohexyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 67),
3- [3- (cyclohexylmethoxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 68),
3- [3- (cyclohexylmethoxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 69),
3- [4-butoxy-3- (cyclohexylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 70),
3- (4-isobutoxy-3-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 71),
3- (4-butoxy-3-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 72),
3- [4- (cyclohexylmethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 73),
3- [3-isopropoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 74),
3- [3- (cyclopropylmethoxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 75),
3- [3- (cyclopropylmethoxy) -4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 76),
3- [4-butoxy-3- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 77),
3- [3- (cyclopropylmethoxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 78),
3- (3-isobutoxy-4-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 79),
3- [4- (cyclopropylmethoxy) -3-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 80),
3- [4- (cyclohexyloxy) -3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 81),
3- [4- (cyclohexylmethoxy) -3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 82),
3- [4- (cyclopropylmethoxy) -3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 83),
3- [3- (cyclopentyloxy) -4-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 84),
3- [3- (cyclopentyloxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 85),
3- [3- (cyclopropylmethoxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 86),
3- [4- (cyclopentyloxy) -3-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 87),
3- [3-isopropoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 88),
3- (4-ethoxy-3-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 89),
3- [3- (cyclopentyloxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 90),
3- [4-butoxy-3- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 91),
3- [3- (cyclopentyloxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 92),
3- [3- (cyclopentyloxy) -4- (cycloheptyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 93),
3- [3- (cyclopentyloxy) -4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 94),
3- [4- (cyclohexylmethoxy) -3-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 95),
3- [4- (cyclohexylmethoxy) -3- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 96),
3- [3- (cyclopropylmethoxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 97),
3- [4- (cyclopentyloxy) -3- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 98),
3- [4- (cyclopropylmethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 99),
3- [4- (cyclopentyloxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 100),
3- (3-isopropoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 101),
3- (4-ethoxy-3-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 102),
3- [3-butoxy-4- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 103),
3- [3-butoxy-4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 104),
3- (3-butoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 105),
3- (3-butoxy-4-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 106),
3- [3- (cyclohexylmethoxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 107),
3- [3- (cyclohexylmethoxy) -4-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 108),
3- [3- (cyclohexylmethoxy) -4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 109),
3- [3- (cyclohexylmethoxy) -4- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 110),
3- [4- (cyclohexylmethoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 111),
3- [4- (cyclopropylmethoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 112),
3- [4- (cyclopentyloxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 113),
3- [4- (3-isobutoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 114),
3- [3- (cycloheptyloxy) -4- (cyclopropylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 115),
3- [3- (cycloheptyloxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 116),
3- [4-butoxy-3- (cycloheptyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 117),
3- [3- (cycloheptyloxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 118),
3- [3- (cycloheptyloxy) -4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 119),
3- (3-ethoxy-4-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 120),
3- [4- (cycloheptyloxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 121),
3- [4- (cyclopropylmethoxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 122),
3- [4- (cyclohexylmethoxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 123),
(S) -3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 124),
3- (3-butoxy-4-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 125),
3- (3-ethoxy-4-isopropoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 126),
3- [4- (cyclopentyloxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 127),
3- (4-butoxy-3-ethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 128),
3- (3-ethoxy-4-isobutoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 129),
3- [3- (cycloheptyloxy) -4-isobutoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 130),
3- [3- (cycloheptyloxy) -4- (cyclopentyloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 131),
3- [3- (cycloheptyloxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 132),
3- (4-butoxy-3-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 133),
3- (4-ethoxy-3-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 134),
3- [4- (morpholin-4-ylethoxy) -3-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 135),
3- (4-isopropoxy-3-propoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 136),
2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] cyclopentanol (Compound No. 137),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} -2-fluorobenzamide (Compound No. 138) ),
N- {3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2-azaspiro [4.5] dec-2-en-8-yl} benzamide (Compound No. 139),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] isoxazole (Compound No. 140),
7- (cyclopentylcarbonyl) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene (Compound No. 141),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3a, 4,6,6a-tetrahydro-5H-pyrrolo [3,4-d] isoxazole-5-carboxylate tert-butyl (Compound No. 142 ),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,8-diazaspiro [4.5] dec-2-ene-8-carboxamide (Compound No. 143),
N-butyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene-7-carboxamide (Compound No. 144),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -7- (methylsulfonyl) -1-oxa-2,7-diazaspiro [4.5] dec-2-ene (Compound No. 145),
3- [4-methoxy-3- (pyridin-3-ylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 146),
5-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] isoxazole (Compound No. 147),
3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -5- (methylsulfonyl) -4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] isoxazole (Compound No. 148) ,
4-bromo-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 149),
3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3a, 5,6,7a-tetrahydro-1,2-benzisoxazol-7 (4H) -one (Compound No. 150),
3- [4- (Difluoromethoxy) -3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene ( Compound No. 151),
3- [4- (Cyclopentyloxy) -3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene ( Compound No. 152),
3- [4-Butoxy-3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 153 ),
3- (3-{[3- (benzyloxy) cyclopentyl] oxy} -4-methoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 154),
7-acetyl-3- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxa-2,7-diazaspiro [4.5] dec-2-ene (Compound No. 155),
3- [4-methoxy-3- (pyridin-2-ylmethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 156),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 157 ),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4-propoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 158) ),
3- [4- (Cyclopropylmethoxy) -3- (2,3-dihydro-1H-inden-2-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 159),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 160),
2- (2,3-dihydro-1H-inden-2-yloxy) -4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 161) ),
N-cyclopropyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] acetamide (Compound No. 162),
3- [4-methoxy-3- (piperidin-3-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene hydrochloride (Compound No. 163),
2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] acetamide (Compound No. 164),
[5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] ethyl acetate (Compound No. 165),
[5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2-methoxyphenoxy] acetonitrile (Compound No. 166),
3- {3-[(2,6-dichloropyridin-4-yl) methoxy] -4-methoxyphenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 167 ),
[3- (3-Cyclopentyloxy-4-methoxyphenyl) -5- (4-carboxylic acid tertbutyl ester-piperazin-1-yl-carbonyl) -4,5-dihydroisoxazol-5-yl]-({ 4-carboxylic acid-tertbutyl ester piperazin-1-yl) ethanone (Compound No. 168),
1- {1- [5- (4-acetyl-4-phenyl-piperidine-1-carbonyl) -3- (3-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-isoxazole-5- Yl] -4-acetyl-4-phenyl-piperidin-4-yl} -ethanone (Compound No. 169),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (pyrrolidin-1-carbonyl) -4,5-dihydro-isoxazol-5-yl] -pyrrolidin-1-yl-ethanone (Compound No. 170),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (piperidin-1-carbonyl) -4,5-dihydro-isoxazol-5-yl] -piperidin-1-yl-ethanone (Compound No. 171),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (pyrrolidine-2-carboxylic acid methyl ester-1-carbonyl) -4,5-dihydro-isoxazol-5-yl)-[{pyrrolidine- 2-Carboxylic acid methyl ester-5-yl] ethanone (Compound No. 172),
[5- [4- (4-Chlorophenyl) -4-hydroxy-piperidine-1-carbonyl] -3- (3-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-isoxazol-5-yl ]-[4- (4-Chlorophenyl) -5-hydroxy-piperidin-1-yl] -ethanone (Compound No. 173),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5- (hydroxymethyl-piperidin-1-carbonyl) -4,5-dihydro-isoxazol-5-yl]-(4-hydroxymethyl-piperidine -1-yl) -ethanone (Compound No. 174),
[5- (5-Benzyl-2,5-diazabicyclo [2.2.1] heptane-2- (carbonyl) -3- (3-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-iso Oxazol-5-yl] -5-benzyl-2,5-diazabicyclo- [2.2.1] hept-2-yl-ethanone (Compound No. 175),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -piperzin-1-yl-methanone (Compound No. 176),
4- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (Compound No. 177) ),
1- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-carbonyl] -pyrrolidine-2-carboxylic acid (Compound No. 178),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -pyrrolidine-2-carboxylic acid methyl ester (Compound No. 179),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -pyrrolidin-1-yl-methanone (Compound No. 180),
[1-4] -Bipiperidinyl-1-yl- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] methanone (Compound No. 181 ),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -4-phenyl-piperidin-4-yl} -ethanone (compound Number 182),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-methyl-piperazin-1-yl) -methanone (Compound No. 183),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -piperazin-1-yl-methanone (Compound No. 184),
[4- (4-Chloro-phenyl) -4-hydroxy-piperidin-1-yl]-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydroisoxazole- 5-yl] -methanone (Compound No. 185),
{4- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl]-[1,4] diazepan-1-yl}-[ 3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (Compound No. 186),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-cyclopropylmethyl-piperazin-1-yl) -methanone ( Compound No. 187),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-isobutyl-1-piperazin-1-yl) -methanone ( Compound No. 188),
[3-Hydroxymethyl-piperidin-1-yl]-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (compound Number 189),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-hydroxy-piperidin-1-yl) -methanone (Compound No. 190),
(4-Benzyl-piperidin-1-yl)-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (Compound No. 191),
1- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -piperidin-4-one (Compound No. 192),
[4- (4-Bromophenyl) -4-hydroxy-piperidin-1-yl]-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole- 5-yl] -methanone (Compound No. 193),
(5-Benzyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro -Isoxazol-5-yl] -methanone (Compound No. 194),
(4-Benzyl-piperazin-1-yl)-[3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl] -methanone (Compound No. 195),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -pyrrolidine-2-carboxylic acid methylamide (Compound No. 196),
1- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -pyrrolidine-2-carboxylic acid diethylamide (Compound No. 197),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl]-(2-hydroxymethyl-pyrrolidin-1-yl) -methanone (compound Number 198),
1- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydroisoxazole-5-carbonyl] -piperidine-2-carboxylic acid methyl ester (Compound No. 199),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carboxyl] -pyrrolidine-2-carboxylic acid amide (Compound No. 200),
3- [3- (3-Cyclopentyloxy-4-methyl-phenyl) -5-methyl-4,5-dihydro-isoxazole-5-carbonyl] -bicyclo [2.2.1] heptan-2-one ( Compound No. 201),
3- [3-cyclopentyloxy-4-methoxy-phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-en-6-one (Compound No. 202),
3- [3-Cyclopentyloxy-4-methoxy-phenyl) -7-methyl-1-oxa-2,7-diaza-spiro [4.4] non-2-ene-6,9-dione (Compound No. 203) ),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-yl- (2-methoxymethyl-pyrrolidin-1-yl) -methanone (compound number 204),
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 205),
3- (3-cyclopropylmethoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 206),
3- (4-difluoromethoxy-3-propoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 207),
3- (4-difluoro-3-butoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 208),
3- (4-difluoromethoxy-3-isobutoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 209),
3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 210),
3- (3-benzyloxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 211),
3- (4-difluoromethoxy-3-cyclopentyloxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 212),
3- (3,4-bis-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 213),
3- (3-butoxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 214),
3- [3- (Bicyclo [2.2.1] hept-2-yloxy) -4-difluoromethoxy-phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 215),
3- (4-difluoromethoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 216),
3- (4-benzyloxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 217),
3- (3-cycloheptyloxy-4-difluoromethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 218),
4- (1,7-dioxa-2-aza-spiro [4.4] non-2-en-3-yl) -2-methoxy-phenol (Compound No. 219),
3- [3- (Indan-2-yloxy) -4-methoxy-phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 220),
3- (4-ethoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 221),
3- (3-methoxy-4-propoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 222),
3- (4-Isopropoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 223),
3- (4-butoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 224),
3- (4-cyclopentyloxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 225),
3- (4- (isobutoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 226),
3- (4-cyclohexyloxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 227),
3- (4-cyclopropylmethoxy-3-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 228),
3- (3,4-dimethoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 229),
3- (3-ethoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 230),
3- (4-methoxy-3-propoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 231),
3- (3-isopropoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 232),
3- (3-butoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 233),
3- (3-isobutoxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 234),
3- [4-methoxy-3- (3-methyl-butoxy) -phenyl-1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 235),
3- (3-cyclohexyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 236),
3- (3-cycloheptyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 237),
3- [4-Methoxy-3- (2-morpholin-4-yl-ethoxy) -phenyl] -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 238) ,
3- (3-benzyloxy-4-methoxy-phenyl) -1,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 239),
5- (1,7-dioxa-2-aza-spiro [4.4] non-2-en-3-yl) -2-methoxy-phenol (Compound No. 240),
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carboxylic acid isopropyl ester (Compound No. 241),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene hydrochloride (Compound No. 242),
4-Chloro-N- [3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carbonyl] -benzene Sulfonamide (Compound No. 243),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carboxylic acid- (2,6-difluoro-phenyl ) -Amide (Compound No. 244),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-8-carboxylic acid- (2,4-dichloro-phenyl ) -Amide (Compound No. 245),
[3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-en-8-yl] -carbamic acid isopropyl ester (Compound No. 246) ,
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-en-8-ylamine hydrochloride (Compound No. 247),
2- [3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-en-8-yl] -isoindole-1,3- Dione (Compound No. 248),
7- (3-cyclopentyloxy-4-methoxy-phenyl) -5-oxa-6-aza-spiro [3.4] oct-6-ene (Compound No. 249),
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2-aza-spiro [4.5] dec-2-ene (Compound No. 250),
3- (3-Cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,7-diaza-spiro [4.4] non-2-ene-7-carboxylic acid tert-butyl ester (Compound No. 251) ,
3- (3-cyclopentyloxy-4-methoxy-phenyl) -1-oxa-2,7-diaza-spiro [4.4] non-2-ene hydrochloride (Compound No. 252),
3- [3-{[(3S) -1-benzylpyrrolidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 253),
3- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] propan-1-ol (Compound No. 254),
[2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] acetonitrile (Compound No. 255),
4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 256),
4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 257),
5-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 258),
(5S or 5R) -3- (3,4-dimethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 259),
(5R or 5S) -3- (3,4-dimethoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 260),
2- (benzyloxy) -4- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenol (Compound No. 261),
2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] ethanol (Compound No. 262),
3- [4- (difluoromethoxy) -3-ethoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 263),
3- [3- (cyclohexyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 264),
(5R or 5S) -3- [4- (difluoromethoxy) -3-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 265),
(5S or 5R) -3- [4- (difluoromethoxy) -3-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 266),
[2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] ethyl acetate (Compound No. 267),
3- [4- (difluoromethoxy) -3- (2-morpholin-4-ylethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 268),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylcyclohexanecarboxylate (Compound No. 269),
5- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pentanoic acid (Compound No. 270),
3- [3- (2,2,2-trifluoroethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 271) ,
3- [3- (cyclopentylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 272),
N-cyclopropyl-2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] acetamide (Compound No. 273) ,
2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] acetamide (Compound No. 274),
2- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] -N-methylacetamide (Compound No. 275),
3- [3- (Cyclopentyloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 276) ,
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylcyclopropanecarboxylate (Compound No. 277),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylmorpholine-4-carboxylate (Compound No. 278),
2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenylbenzoate (Compound No. 279),
5- [2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pentanamide (Compound No. 280),
3- [3-propoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 281),
3- [3-isopropoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 282),
3- [3- (Cyclopropylmethoxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 283) ),
3- [3- (2,3-Dihydro-1H-inden-2-yloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4 ] Non-2-ene (Compound No. 284),
5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenol (Compound No. 285),
3- [3-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 286),
3- [3-ethoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 287),
3- [3-butoxy-4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene 10019955 (Compound No. 288),
3- [3- (Cyclohexylmethoxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 289) ,
3-{[2- (difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] methyl} benzonitrile (Compound No. 290),
2- {2- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] ethyl} -1H-isoindole- 1,3 (2H) -dione (Compound No. 291),
3- [3- (Cyclohexyloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 292) ,
[5- (1,7-Dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy] ethyl acetate (Compound No. 293 ),
3- [3- (cyclohexylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 294),
[2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] tert-butyl acetate (Compound No. 295),
N-cyclopropyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy Acetamide (Compound No. 296),
2- (cyclopentyloxy) -4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 297),
2- (cyclopentyloxy) -4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 298),
N-benzyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy] Acetamide (Compound No. 299),
N-cyclopentyl-2- [5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) -2- (2,2,2-trifluoroethoxy) phenoxy] Acetamide (Compound No. 300),
4- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] piperidine-1-carboxylic acid tert-butyl (compound Number 301),
3- [4- (difluoromethoxy) -3- (piperidin-4-yloxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene hydrochloride (Compound No. 302),
3- {3-[(1-Acetylpiperidin-4-yl) oxy] -4- (difluoromethoxy) phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 303),
(3S) -3- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pyrrolidine-1-carboxylic acid tert -Butyl (compound no. 304),
(3R) -3- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] pyrrolidine-1-carboxylic acid tert -Butyl (compound no. 305),
3- [2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] piperidine-1-carboxylic acid tert-butyl (compound Number 306),
(2S) -2-{[2- (Difluoromethoxy) -5- (1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl) phenoxy] methyl} pyrrolidine-1- Tert-butyl carboxylate (Compound No. 307),
(5R or 5S) -3- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 308),
(5S or 5R) -3- (3-isopropoxy-4-methoxyphenyl) -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 309),
(5S or 5R) -3- [3- (Cyclopropylmethoxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 310)
2- (cyclopropylmethoxy) -4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 311),
4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-isopropoxyphenol (Compound No. 312),
(5S or 5R) -3- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 313),
(5S or 5R) -3- [3- (Cyclopropylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 314) ,
(5S or 5R) -3- [4- (difluoromethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 315),
(5R or 5S) -3- [4- (difluoromethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 316),
2- (cyclopropylmethoxy) -4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 317),
4-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-isopropoxyphenol (Compound No. 318),
(5R or 5S) -3- [3- (Cyclopropylmethoxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 319) ,
(5R or 5S) -3- [4- (difluoromethoxy) -3-isopropoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 320),
Hydrochloride of 3- {4- (difluoromethoxy) -3-[(3S) -pyrrolidin-3-yloxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (compound Number 321),
3- {4- (Difluoromethoxy) -3-[(2S) -pyrrolidin-2-ylmethoxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene hydrochloride (compound Number 322),
Hydrochloride of 3- {4- (difluoromethoxy) -3-{(2R) -pyrrolidin-2-ylmethoxy} phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (compound Number 323),
3- [4- (Difluoromethoxy) -3-{[(2R) -1-propionylpyrrolidin-2-yl] methoxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 324),
3- [3-{[(2S) -1-acetylpyrrolidin-2-yl] methoxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 325),
3- [3-{[(3S) -1-Benzoylpyrrolidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 326),
3- [4- (Difluoromethoxy) -3-{[(3S) -1-propionylpyrrolidin-3-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 327),
(5S or 5R) -3- [3- (benzyloxy) -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 328),
2- (benzyloxy) -4-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 329),
(5S or 5R) -3- [3- (Benzyloxy) -4-methoxyphenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 330),
3- {4- (Difluoromethoxy) -3-[(1-propionylpiperidin-4-yl) oxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 331),
3- [4- (Difluoromethoxy) -3-{[1- (4-fluorobenzoyl) piperidin-4-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] nona-2 -Ene (compound number 332),
3- [3-{[1- (Cyclopropylcarbonyl) piperidin-4-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 333),
3- [3-{[1- (Cyclopentylcarbonyl) piperidin-4-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 334),
3- [4- (Difluoromethoxy) -3-({1-[(trifluoromethyl) sulfonyl] piperidin-4-yl} oxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] nona -2-ene (Compound No. 335),
3- {3-[(1-Acetylpiperidin-3-yl) oxy] -4- (difluoromethoxy) phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 336),
3- {4- (Difluoromethoxy) -3-[(1-propionylpiperidin-3-yl) oxy] phenyl} -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 337),
3- [4- (Difluoromethoxy) -3-{[1- (4-fluorobenzoyl) piperidin-3-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] nona-2 -Ene (compound no. 338),
3- [3-{[1- (Cyclopropylcarbonyl) piperidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2- En (Compound No. 339),
3- [3-{[1- (Cyclopentylcarbonyl) piperidin-3-yl] oxy} -4- (difluoromethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 340),
3- [4- (Difluoromethoxy) -3-{[1- (ethylsulfonyl) piperidin-3-yl] oxy} phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 341),
3- [3- (Benzyloxy) -4- (2,2,2-trifluoroethoxy) phenyl] -1,7-dioxa-2-azaspiro [4.4] non-2-ene (Compound No. 342) ,
2- (difluoromethoxy) -5-[(5S or 5R) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] phenol (Compound No. 343),
5-[(5R or 5S) -1,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl] -2-methoxyphenol (Compound No. 344)
A pharmaceutical composition according to claim 1 selected from. The pharmaceutical composition according to claim 1, wherein the one or more muscarinic receptor antagonists (MRAs) are selected from tiotropium salts, methanoserine, ipratropium, propantheline, dicyclomine, scopolamine, telenzepine, benztropine and atropine. The one or more muscarinic receptor antagonist (MRA) is 2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 1aa);
Cyclohexyl (hydroxy) (4-methylphenyl) hydrochloride 1H-imidazol-1-ylmethyl (Compound No. 2aa),
2- (4-fluorophenyl) -2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 3aa),
2-cyclobutyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 4aa),
2-cyclopentyl-2- (4-fluoropentyl) -2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] acetamide (Compound No. 5aa),
2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2, 2-diphenylacetamide (Compound No. 6aa),
2-cyclohexyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 7aa),
2-cyclopentyl-2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 8aa),
2-cyclohexyl-2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2phenylacetamide (Compound No. 9aa),
2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2-phenyl-2-pyridin-3-ylacetamide (Compound No. 10aa),
2- (4-fluorophenyl) -2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (compound 11aa),
2-hydroxy-N- [2- (2-isopropyl-1H-imidazol-1-yl) ethyl] -2, 2-diphenylacetamide (Compound No. 12aa),
Cyclopentyl (hydroxy) phenylacetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 13aa),
(2R) -cyclopentyl (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 14aa),
1-cyclopentyl-1-hydroxy-1- (4-methoxyphenyl) -3- (2-methyl-1H-imidazol-1-yl) acetone (Compound No. 15aa),
(2R) -2-cyclopentyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 16aa),
2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -2-phenyl-2-pyridin-3-ylacetamide (Compound No. 17aa),
2-cyclopentyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 18aa),
2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenyl-2-pyridin-3-ylacetamide (Compound No. 19aa),
2-cyclohexyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 20aa),
2- (4-fluorophenyl) -2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 21aa),
2-cyclopentyl-2- (4-fluoropentyl) -2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] acetamide (Compound No. 22aa),
2-cyclobutyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 23aa),
2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2,2-diphenylacetamide (Compound No. 24aa),
3,3,3-trifluoro-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylphenyl) propanamide (Compound No. 25aa),
N- [2- (2-Methyl-1H-imidazol-1-yl) ethyl] -2,2-diphenylacetamide (Compound No. 26aa),
2-cyclopentyl-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2-phenylacetamide (Compound No. 27aa),
2-cyclopentyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylphenyl) acetamide (Compound No. 28aa),
2-cyclohexyl-2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylpentyl) acetamide (Compound No. 29aa),
2-hydroxy-N- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -2- (4-methylphenyl) -2-phenylacetamide (Compound No. 30aa),
2-cyclopentyl-2-hydroxy-N- [3- (1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 31aa),
2-cyclohexyl-2-hydroxy-N- [3- (1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 32aa),
2-cyclopentyl-2-hydroxy-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 33aa),
2-cyclohexyl-2-hydroxy-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 34aa),
(2R) -2- (3,3-difluorocyclopentyl) -2-hydroxy-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 35aa),
2-cyclopentyl-2-hydroxy-N-methyl-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 36aa),
2-cyclohexyl-2-hydroxy-N-methyl-N- [3- (2-methyl-1H-imidazol-1-yl) propyl] -2-phenylacetamide (Compound No. 37aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -N-methyl-2-phenylacetamide (Compound No. 38aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-4-yl) ethyl] -2-phenylacetamide (Compound No. 39aa),
N- [2- (1-Benzyl-1H-imidazol-4-yl) ethyl] -2-cyclopentyl-2-hydroxy- (4-methylphenyl) acetamide (Compound No. 40aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazole) ethyl] -2- (4-methylphenyl) acetamide (Compound No. 41aa),
2-cyclohexyl-2-hydroxy-N- [2- (1H-imidazol-4-yl) ethyl] -2- (4-methylphenyl) acetamide (Compound No. 42aa),
2-hydroxy-N- [2- (1H-imidazol-4-yl) ethyl] -2, 2-diphenylacetamide (Compound No. 43aa),
N- [2- (1-benzyl-1H-imidazol-4-yl) ethyl] -2-cyclohexyl-2-hydroxy-2- (4-methylphenyl) acetamide (Compound No. 44aa),
N- [2- (1-benzyl-1H-imidazol-4-yl) ethyl] -2-hydroxy-2, 2-diphenylacetamide (Compound No. 45aa),
Cyclopentyl (hydroxy) phenyl acetate 1H-imidazol-1-ylmethyl (Compound No. 46aa),
Cyclohexyl (hydroxy) phenyl acetate 1H-imidazol-1-ylmethyl (Compound No. 47aa),
(2R) -cyclopentyl (hydroxy) phenyl acetate 1H-imidazol-1-ylmethyl (Compound No. 48aa),
Cyclopentyl (hydroxy) (4-methoxyphenyl) acetate 1H-imidazol-1-ylmethyl (Compound No. 49aa),
1-Cyclohexyl-1-hydroxy-3- (1H-imidazol-1-yl) -1-
Phenylacetone (compound no. 50aa),
1-cyclohexyl-1-hydroxy-3- (2-methyl-1H-imidazol-1-yl) -1-phenylacetone (Compound No. 51aa),
1-cyclopentyl-1-hydroxy-3- (2-isopropyl-1H-imidazol-1-yl) -1- (4-methoxyphenyl) acetone (Compound No. 52aa),
1-cyclohexyl-1-hydroxy-3- (2-isopropyl-1H-imidazol-1-yl) -1-phenylacetone (Compound No. 53aa),
1-cyclohexyl-1-hydroxy-3- (2-methyl-4,5-dihydro-1H-imidazol-1-yl) -1-phenylacetone (Compound No. 54aa),
1-cyclopentyl-1-hydroxy-1- (4-methoxyphenyl) -3- (2-methyl-4,5-dihydro-1H-imidazol-1-yl) acetone (Compound No. 55aa),
1-cyclopentyl-1-hydroxy-3- (1H-imidazol-1-yl) -1- (4-methoxyphenyl) acetone (Compound No. 56aa),
2-cyclohexyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -N-methyl-2-phenylacetamide (Compound No. 57aa),
2-cyclopentyl-2-hydroxy-N- [2- (1H-imidazol-1-yl) ethyl] -N-methyl-2-phenylacetamide (Compound No. 58aa),
Cyclopentyl (phenyl) acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 59aa),
Cyclohexyl (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 60aa),
Cyclopentyl (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 61aa),
(2R)-[(1R) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 62aa),
2R-2- (1S or 1R) (3,3-difluorocyclohexyl) (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 63aa),
Cyclohexyl (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 64aa),
Cyclopentyl (hydroxy) phenyl acetate 2- (1H-imidazol-1-yl) ethyl (Compound No. 65aa),
(2R)-[1S] -3,3-difluorocyclopentyl 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 66aa),
Cyclohexyl (hydroxy) phenyl acetate 2- (1H-imidazol-1-yl) ethyl (Compound No. 67aa),
Cyclopentyl (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 68aa),
(2R)-[(1R) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 69aa),
Cycloheptyl (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 70aa),
Cycloheptyl (hydroxy) phenyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 71aa),
Bromide 3-benzyl-1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-isopropyl-1H-imidazol-3-ium (Compound No. 72aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-1H -Imidazole-3-ium (compound no. 73aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-1H -Imidazole-3-ium (compound no. 74aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-isopropyl-1H-imidazol-3-ium (Compound No. 75aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound no. 76aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1R) -3, -3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H-imidazol-3-ium (Compound No. 77aa),
Bromide 3- (4-fluorobenzyl-1- [2-({(2R) -2-[(1R) -3, -3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 78aa),
Bromide 3-benzyl-1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 79aa),
Bromide 3- (4-bromobenzyl) -1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-methyl-1H-imidazol-3-ium (compound no. 80aa),
Iodide 1- [2-({(2R) -2-[(1S) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-3-methyl- 1H-imidazol-3-ium (Compound No. 81aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (4-fluorobenzyl)- 2-isopropyl-1H-imidazol-3-ium (Compound No. 82aa),
1- (2-{[2-cyclohexyl-2-hydroxy-2-phenylacetyl] oxy} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (compound number 83aa),
Iodide 1- (2-{[cyclopentyl (hydroxy) phenylacetyl] oxy} ethyl) -3-methyl-1H-imidazol-3-ium (Compound No. 84aa),
1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H-imidazole- 3-ium (compound number 85aa),
Iodide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H- Imidazol-3-ium (Compound No. 86aa),
Iodide 1- (2-{[cyclohexyl (hydroxy) phenylacetyl] oxy} ethyl) -3-methyl-1H-imidazol-3-ium (Compound No. 87aa),
Iodide 1-({[Cyclopentyl (hydroxy) phenylacetyl] oxy} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (Compound No. 88aa),
1- (2-{[cyclopentyl (hydroxy) phenylacetyl] amino} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 89aa),
1- (2-{[cyclohexyl (hydroxy) phenylacetyl] amino} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (compound no. 90aa),
1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 91aa),
1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-isopropyl-3-methyl-1H-imidazol-3-ium (Compound No. 92aa),
Iodide 1- [2-({(2R) -2-[(1R) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-isopropyl-3-methyl- 1H-imidazol-3-ium (Compound No. 93aa),
Iodide 1- (3-{[(2R) -2- (3,3-Difluorocyclopentyl) -2-hydroxy-2-phenylacetyl] amino} propyl) -2,3-dimethyl-1H-imidazole-3- Ium (compound number 94aa),
1- (3-{[cyclopentyl (hydroxy) phenylacetyl] amino} propyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 95aa),
1- (3-{[cyclohexyl (hydroxy) phenylacetyl] amino} propyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 96aa),
1- (2-{[cyclopentyl (hydroxy) phenylacetyl] (methyl) amino} ethyl) -3-methyl-1H-imidazol-3-ium (compound no. 97aa),
1- (3-{[cyclopentyl (hydroxy) phenylacetyl] (methyl) amino} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 98aa),
1- (3-{[cyclopentyl (hydroxy) phenylacetyl] oxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 99aa),
Iodide 1- [3-({(2R) -2-[(1S) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H- Imidazol-3-ium (Compound No. 100aa),
Bromide 3-benzyl-1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (Compound No. 101aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 102aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 103aa),
Bromide 3-benzyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound no. 104aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 105aa),
Bromide 1- [3-({(2R) -2-[(1S or 1R) -3,3-difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 106aa),
Bromide 3-benzyl-1- [3-({(2R) -2 [(1R or 1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl- 1H-imidazol-3-ium (Compound No. 107aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2 [(1R or 1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H-imidazol-3-ium (Compound No. 108aa),
1- (2-{[cyclopentyl (hydroxy) phenylacetyl] (methyl) amino} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 109aa),
3- (2-methyl-1imidazol-1-yl) propyl (2R)-[(1S) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate (Compound No. 110aa),
1- (2-{[cyclohexyl (hydroxy) phenylacetyl] oxy} ethyl) -2,3-dimethyl-1H-imidazol-3-ium (compound number 111aa),
(2R)-[(1S) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 112aa),
(2R)-[(1R) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate 2- (2-isopropyl-1H-imidazol-1-yl) ethyl (Compound No. 113aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) ethyl] -2- Methyl-1H-imidazol-3-ium (Compound No. 114aa),
Iodide 1- [2-({(2R) -2-[(1R) -3,3-Difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H-imidazole- 3-ium (compound number 115aa),
Bromide 1- (2-{[cycloheptyl (hydroxy) phenylacetyl] oxy} ethyl) -2-methyl-3- (4-methylbenzyl) -1H-imidazol-3-ium (Compound No. 116aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3- (4- Methylbenzyl) -1H-imidazol-3-ium (Compound No. 117aa),
Iodide 1- [3-({(2R) -2-[(1R) -3,3-Difluoro cyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2, 3-dimethyl-1H -Imidazole-3-ium (compound no. 118aa),
1,1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 119aa),
Bromide 1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2-methyl-3- (4-methylbenzyl) -1H-imidazol-3-ium (Compound No. 120aa),
Bromide 3- (4-bromobenzyl) -1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 121aa),
Bromide 3- (4-Bromobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 122aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-phenylacetyl} oxy) ethyl] -2-methyl-3- (4-methylbenzyl) ) -1H-imidazol-3-ium (Compound No. 123aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (4-fluorobenzyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 124aa),
Bromide 3- [2- (1,3-Benzodioxo-5-yl) ethyl] -1- (3- [cycloheptyl (hydroxy) phenylacetyl] oxy) propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 125aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (4-fluorobenzyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 126aa),
Bromide 1- (3-{[cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -3- (4-fluorobenzyl) -2-methyl-1H-imidazol-3-ium (Compound No. 127aa),
Bromide 3- (4-Bromobenzyl) -1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 128aa),
Bromide 3- (4-fluorobenzyl) -1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 129aa),
Chloride 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) ethyl] -2-methyl-1H-imidazol-3-ium (Compound No. 130aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) ethyl] -2-methyl-1H-imidazol-3-ium (compound number) 131aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) ethyl] -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 132aa) ,
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) propyl] -3-isopropyl-2-methyl-1H-imidazol-3-ium (Compound No. 133aa),
Iodide 1- [3-({(2R) -2-[(1R) -3,3-Difluorocyclopentyl]} oxy) propyl] -3-ethyl-2-methyl-1H-imidazol-3-ium (compound Number 134aa),
Bromide 3- (cyclopropylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl]} oxy) propyl] -2-methyl-1H-imidazole-3- Ium (compound number 135aa),
Bromide 3- (cyclohexylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2- Methyl-1H-imidazol-3-ium (Compound No. 136aa),
Chloride 1- [3-({(2R) -2-[(1R) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- [4- (Trifluoromethyl) benzyl] -1H-imidazol-3-ium (Compound No. 137aa),
Chloride 3- (4-Chlorobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 138aa),
Bromide 3- (3-bromobenzyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl]- 2-methyl-1H-imidazol-3-ium (Compound No. 139aa),
Chloride 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H-imidazole-3 -Ium (compound no. 140aa),
Chloride 3-benzyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 141aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (2- Phenylethyl) -1H-imidazol-3-ium (Compound No. 142aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 143aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (4-fluorobenzyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 144aa),
Bromide 3-benzyl-1- {3- [2-cycloheptyl (hydroxy) phenylacetoxy] propyl} -2-methyl-1H-imidazol-3-ium (compound number 145aa),
Bromide (3- {3- [2-cycloheptyl (hydroxy) phenylacetyl] oxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 146aa),
Bromide 1- [4-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 147aa),
Bromide 3-benzyl-1- [4-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2-methyl-1H -Imidazole-3-ium (compound no. 148aa),
Bromide 3-benzyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound number 149aa),
Chloride 3-benzyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound no. 150aa),
Bromide 1- [4-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 151aa),
Bromide 3-benzyl-1- [4-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) butyl] -2-methyl-1H -Imidazole-3-ium (compound number 152aa),
Bromide 3- (4-tert-butylbenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 153aa),
Bromide 3- (biphenyl-4-ylmethyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] 2-methyl-1H-imidazol-3-ium (Compound No. 154aa),
Bromide 3- (2,5-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 155aa),
Bromide 3- (2,4-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 156aa),
Bromide 3- (3,5-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 157aa),
Bromide 3- (3,4-difluorobenzyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl ] -2-Methyl-1H-imidazol-3-ium (Compound No. 158aa),
Bromide 1- {3- [2-cyclopentyl (hydroxy) phenylacetyl] propyl} -2-methyl-3- (pyridin-4-ylmethyl) -1H-imidazol-3-ium (Compound No. 159aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 160aa),
Bromide 3- (1,3-benzodioxo-5-ylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} Oxy) propyl] -2-methyl-1H-imidazol-3-ium (Compound No. 161aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (Compound No. 162aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isobutyl-2-methyl-1H -Imidazole-3-ium (compound number 163aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 164aa),
Bromide 1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2-methyl-3- (2-phenylethyl) -1H-imidazol-3-ium (Compound No. 165aa),
Bromide 3- (cyclopropylmethyl) -1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 166aa),
Bromide 3-benzyl-1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 167aa),
Bromide 1- {2- [2-hydroxy (phenyl) -2-thienylacetoxy] ethyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 168aa),
Bromide 3- (cyclopropylmethyl) -1- (2- {2-hydroxy [bis (3-methylphenyl)] acetoxy} ethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 169aa),
Bromide 1- (2- {2-hydroxy [bis (3-methylphenyl)] acetoxy} ethyl) -2-methyl-1H-imidazol-3-ium (compound no. 170aa),
Bromide 3-benzyl-1- (2- {2-hydroxy [bis (3-methylphenyl)] acetoxy} ethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 171aa),
Bromide 1- {2- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] ethyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 172aa),
Bromide 3-benzyl-1- {2- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] ethyl} -2-dimethyl-1H-imidazol-3-ium (Compound No. 173aa),
Bromide 1- {2- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] ethyl} -3- (cyclopropylmethyl) -2-dimethyl-1H-imidazol-3-ium (Compound No. 174aa) ,
Bromide 3-benzyl-1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -2-methyl-1H-imidazol-3-ium (Compound No. 175aa),
Bromide 1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -3- (cyclopropylmethyl) -2-methyl-1H-imidazol-3-ium (Compound No. 176aa) ,
Bromide 1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -3-ethyl-2-methyl-1H-imidazol-3-ium (Compound No. 177aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (3- Phenoxypropyl) -1H-imidazol-3-ium (Compound No. 178aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (3- Phenoxypropyl) -1H-imidazol-3-ium (Compound No. 179aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound number 180aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound no. 181aa),
Bromide 3- (cyclopropylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2 -Methyl-1H-imidazol-3-ium (Compound No. 182aa),
Bromide 3- (cyclohexylmethyl) -1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2- Methyl-1H-imidazol-3-ium (Compound No. 183aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (2- Phenylethyl) -1H-imidazol-3-ium (Compound No. 184aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 185aa),
Bromide 1- {3- [2,2-bis (4-fluorophenyl) (hydroxy) acetoxy] propyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 186aa),
Bromide 3- (4-bromobenzyl) -1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 187aa),
Bromide 3-benzyl-1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 188aa),
Bromide 3- (cyclopropylmethyl) -1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 189aa),
Bromide 3-ethyl-1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 190aa),
Bromide 1- (3- {2-hydroxy [bis (3-methylphenyl)] acetoxy} propyl) -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 191aa),
Bromide 3- (4-bromobenzyl) -1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-1H-imidazol-3-ium (Compound No. 192aa),
Bromide 3-benzyl-1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-1H-imidazol-3-ium (Compound No. 193aa),
Bromide 3- (4-bromobenzyl) -1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-1H-imidazol-3-ium (Compound No. 194aa),
Bromide 3-ethyl-1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2-methyl-1H-imidazol-3-ium (compound number 195aa),
1- {3- [2-hydroxy (phenyl) -2-thienylacetoxy] propyl} -2, 3-dimethyl-1H-imidazol-3-ium (Compound No. 196aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3- (3- Phenoxypropyl) -1H-imidazol-3-ium (Compound No. 197aa),
Bromide 3- (cyclopropylmethyl) -1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2 -Methyl-1H-imidazol-3-ium (compound number 198aa),
Bromide 3-butyl-1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound no. 199aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound no. 200aa),
Bromide 1- [2-({(2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (Compound No. 201aa),
Bromide 3-benzyl-1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 202aa),
Bromide 3- (cyclopropylmethyl) -1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 203aa),
Bromide 3-ethyl-1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2-methyl-1H-imidazol-3-ium (Compound No. 204aa),
Bromide 1- {2- [2-hydroxy (di-2-thienyl) acetoxy] ethyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 205aa),
Bromide 1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-3- (2-phenylethyl) -1H-imidazol-3-ium (Compound No. 206aa),
Bromide 1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-3- (3-phenoxypropyl) -1H-imidazol-3-ium (Compound No. 207aa),
Bromide 3-butyl-1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-1H-imidazol-3-ium (Compound No. 208aa),
Bromide 3-ethyl-1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2-methyl-1H-imidazol-3-ium (Compound No. 209aa),
Bromide 1- {3- [2-hydroxy (di-2-thienyl) acetoxy] propyl} -2,3-dimethyl-1H-imidazol-3-ium (Compound No. 210aa),
Bromide 1- (3-{[(2R) -2-hydroxy-2-phenyl-2-{(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetyl] oxy} propyl) -2,3-dimethyl -1H-imidazol-3-ium (Compound No. 211aa),
Bromide 3-benzyl-1- (3-{[(2R) -2-hydroxy-2-phenyl-2-{(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetyl] oxy} propyl) -2 -Methyl-1H-imidazol-3-ium (Compound No. 212aa),
Bromide 3- (4-Bromobenzyl) -1- (3-{[(2R) -2-hydroxy-2-phenyl-2-{(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetyl] oxy } Propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 213aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound number 214aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound number 215aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 216aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 217aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound no. 218aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound no. 219aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 220aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound number 221aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 222aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isobutyl-2-methyl-1H -Imidazole-3-ium (compound number 223aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 224aa),
Bromide 1- [3-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound number 225aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound no. 226aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 227aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 228aa),
Bromide 3-butyl-1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound number 229aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound number 230aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound number 231aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2,3-dimethyl-1H-imidazole -3-ium (compound number 232aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 233aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-isopropyl-2-methyl-1H -Imidazole-3-ium (compound number 234aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 235aa),
Bromide 3-butyl-1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-1H -Imidazole-3-ium (compound no. 236aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -2-methyl-3-propyl-1H -Imidazole-3-ium (compound no. 237aa),
Bromide 1- [2-({(2R) -2-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetyl} oxy) ethyl] -3-ethyl-2-methyl-1H -Imidazole-3-ium (compound no. 238aa),
2- (2-methyl-1H-imidazol-1-yl) ethyl (2R)-[(1R) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 239aa),
2- (2-methyl-1H-imidazol-1-yl) propyl (2R)-[(1R) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 240aa),
Cycloheptyl (hydroxy) phenyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 241aa),
2- (2-methyl-1H-imidazol-1-yl) ethyl (2R)-[(1S) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 242aa),
4- (2-methyl-1H-imidazol-1-yl) butyl (2R)-[(1S) -3,3-difluorocyclopentyl] (hydroxy) phenyl acetate (Compound No. 243aa),
4- (2-methyl-1H-imidazol-1-yl) butyl (2R)-[(1S) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 244aa),
Hydroxy (phenyl) -2-thienyl acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 245aa),
Hydroxy [bis (3-methylphenyl)] acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 246aa),
Bis (4-fluorophenyl) (hydroxy) acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 247aa),
3- (2-methyl-1H-imidazol-1-yl) propylbis (4-fluorophenyl) (hydroxy) acetate (Compound No. 248aa),
3- (2-methyl-1H-imidazol-1-yl) propylhydroxy [bis (3-methylphenyl)] acetate (Compound No. 249aa),
Hydroxy (phenyl) 2-thienyl acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (compound no. 250aa),
Hydroxy (di-2-thienyl) acetate 2- (2-methyl-1H-imidazol-1-yl) ethyl (Compound No. 251aa),
Hydroxy (di-2-thienyl) acetate 3- (2-methyl-1H-imidazol-1-yl) propyl (Compound No. 252aa),
3- (2-methyl-1H-imidazol-1-yl) propyl (2R) -hydroxy (phenyl) {(1S) -3-[(phenylsulfonyl) amino] cyclopentyl} acetate (Compound No. 253aa),
3- (2-methyl-1H-imidazol-1-yl) propyl (2R)-[(1S) -3,3-difluorocyclohexyl] (hydroxy) phenyl acetate (Compound No. 254aa),
Bromide 3-butyl-1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-1H -Imidazole-3-ium (compound number 255aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3-pentyl-1H -Imidazole-3-ium (compound no. 256aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -3- (1-ethylpropyl)- 2-methyl-1H-imidazol-3-ium (Compound No. 257aa),
Bromide 1- [3-({(2R) -2-[(1R) -3,3-difluorocyclohexyl] -2-hydroxy-2-phenylacetyl} oxy) propyl] -2-methyl-3- (2- Methylpropyl) -1H-imidazol-3-ium (Compound No. 258aa),
Bromide 1- (3-{[(3,3-difluorocyclopentyl) (hydroxy) thiophen-2-ylacetyl] oxy} propyl) -3-ethyl-2-methyl-1H-imidazol-3-ium (Compound No. 259aa) ,
Bromide 1- (3-{[(3,3-difluorocyclopentyl) (hydroxy) thiophen-2-ylacetyl] oxy} propyl) -2, 3-dimethyl-1H-imidazol-3-ium (compound number 260aa), and Bromide 3-benzyl-1- (3-{[(3,3-difluorocyclopentyl) (hydroxy) thiophen-2-ylacetyl] oxy} propyl) -2-methyl-1H-imidazol-3-ium (Compound No. 261aa) ,
A pharmaceutical composition according to claim 1 selected from. One or more β2-agonists are albuterol, salbutamol, virtuterol, pyrbuterol, levosalbutamol, tubuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, alformoterol, formoterol, or a pharmaceutically acceptable salt thereof The pharmaceutical composition according to claim 1, which is selected from a salt or a solvate thereof. One or more corticosteroids are alclomethasone, amsinonide, amelomethasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, croticazone, cyclomethasone, deflazacort, deprodon, dexbudesonide, diflorazone, diflupredone, fluticadone, fluticadone, fluticasone, fluticasone The pharmaceutical composition according to claim 1 selected from methylprednisolone, mometasone, prednisocarbate, prednisolone, rimisolone, thixcortol, triamcinolone, urobetasol, or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition according to claim 1, wherein the one or more PDE-IV inhibitors and the one or more muscarinic receptor antagonists (MRAs) are present in a ratio of 1:10 to 10: 1. The pharmaceutical composition according to claim 1, wherein the one or more PDE-IV inhibitors and the one or more β2-agonists are present in a ratio of 1:10 to 10: 1. The pharmaceutical composition according to claim 1, wherein the one or more PDE-IV inhibitors and the one or more p38 MAP kinase inhibitors are present in a ratio of 1:10 to 10: 1. The pharmaceutical composition according to claim 1, wherein the one or more PDE-IV inhibitors and the one or more corticosteroids are present in a ratio of 1:10 to 10: 1. 8. A method of treating an autoimmune, inflammatory or allergic disease or disorder comprising administering one or more pharmaceutical compositions of claim 1 or 7. The autoimmune disease, inflammation or allergic disease or disorder is respiratory disorder, asthma, chronic bronchitis, chronic obstructive pulmonary disease, whooping cough, eosinophilic granulomas, psoriasis, and other benign or malignant proliferative skin Disease, eczema, inflammatory bowel disease, endotoxic shock, anaphylactic shock, horseshoe inflammation in horses, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory arthritis, periodontitis Chronic glomerulonephritis, atopic dermatitis, hives, adult respiratory distress syndrome, infant respiratory distress syndrome, transplant rejection, rhinitis, pruritus, diabetes insipidus, ophthalmitis, allergic rhinitis, allergic conjunctivitis, spring catarrh, Arterial restenosis, orcerosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, osteoporosis, osteoarthritis, inflammation, ankylosing spondylitis, transplant rejection Graft-versus-host rejection, gastric acid hypersecretion, bacteria, fungus-induced sepsis, virus-induced sepsis, fungus-induced sepsis shock, virus-induced sepsis shock, inflammation-mediated chronic tissue degeneration, cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, Selected from cachexia, muscle wasting, depression memory damage, tumor growth, normal tissue cancer invasion, Hashimoto's thyroiditis (low activity thyroid), Grave's disease (overactive thyroid), lupus and acquired immune deficiency syndrome The method of claim 11.