JP2009529042A - Phenethanolamine derivatives as β2 adrenergic receptor agonists - Google Patents

Abstract

の化合物、その製造方法、該製造の中間体化合物、および疾患(例えばＡＲＤＳ、肺気腫、気管支炎、気管支拡張症、ＣＯＰＤ、喘息および鼻炎)の処置に使用するための医薬の製造におけるそれらの使用に関する。該化合物は、β２アドレナリン受容体アゴニストである。The present invention provides a compound of formula (I):
[Chemical 1]

Compounds, methods for their preparation, intermediate compounds of their manufacture, and their use in the manufacture of a medicament for use in the treatment of diseases (eg ARDS, emphysema, bronchitis, bronchiectasis, COPD, asthma and rhinitis) . The compound is a β2 adrenergic receptor agonist.

Description

  The present invention relates to phenethanolamine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

  Adrenergic receptors are a group of G-protein coupled receptors and are classified into two major subfamilies α and β. These subfamilies are further divided into subtypes, with the β subfamily having at least three members: β1, β2, and β3. β2 adrenergic receptors (hereinafter referred to as β2 receptors) are mainly expressed in smooth muscle cells.

  The agonistic action of β2 receptors on airway smooth muscle causes relaxation and consequently bronchodilation. By this mechanism, β2 agonists act as functional antagonists for all bronchoconstrictors, such as naturally occurring histamine and acetylcholine, and the experimental reagents methacholine and carbachol. β2 agonists are widely used to treat airway diseases including asthma and chronic obstructive pulmonary disease (COPD), which has been extensively reviewed in the literature and has become a national guide for the treatment of these diseases. (British Guideline on the Management of Asthma, NICE guideline No. 12 on the Management of COPD).

β2 agonists are classified as either short-acting or long-acting. Short-acting β2 agonists (SABA), such as salbutamol, have a duration of action of 2-4 hours. They are suitable for emergency medications during acute bronchoconstriction but are not suitable for continuous medications because the beneficial effects of these medications disappear during the night. Long-acting β2 agonists (LABA) currently have a duration of action of about 12 hours and are administered twice daily to provide continuous bronchodilation. These are particularly effective when administered in combination with inhaled corticosteroids. This advantage is not seen when inhaled corticosteroids are combined with SABA (Kips and Pauwels, Am. J. Respir. Crit. Care Med., 2001, 164 , 923-932). LABA is recommended as an additional treatment to reduce nocturnal arousal and reduce the incidence of exacerbation of the disease in patients who have already received inhaled corticosteroids for asthma. Corticosteroids and LABA are conveniently co-administered with a single inhaler to improve patient compliance.

Existing LABAs have drawbacks and there is a need for new drugs in this class. Salmeterol, a commonly used LABA, has a narrow safety margin and generally has side effects (eg tremor, hypokalemia, tachycardia and hypertension) associated with systemic antagonism of β2 receptors. Salmeterol also has a slow onset of action and is therefore not used for both emergency and maintenance treatments. All existing LABA is administered twice daily and there is a medical need for once daily treatment to improve treatment and patient compliance. Such once-daily compounds that are co-administered with corticosteroids will play a leading role in the treatment of asthma (Barnes, Nature Reviews, 2004, 3 , 831-844). The advantage of once-daily bronchodilator treatment in COPD has been demonstrated with tiotropium, a non-selective muscarinic antagonist (Koumis and Samuel, Clin. Ther. 2005, 27 (4) , 377-92). In order to avoid the side effects of antimuscarinic agents, such as tiotropium, there is a daily requirement for LABA in the treatment of COPD.
A benzothiazolone derivative having the properties of a β2 adrenergic receptor agonist is known from WO 2004/016601.

[式中、
Ａｒは、

であり； According to the invention, the formula (I):

[Where
Ar is

Is;

M is C (O), NR ⁶ , S or CR ⁷ R ⁸ ;
R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S (O) ₂ R ⁹ , NR ¹⁰ S (O) ₂ R ¹¹ , C (O) NR ¹² R ¹³ , NR ¹⁴ C (O) R ¹⁵ , C _1-6 alkyl, C _1-6 alkoxy, C (O) (C _1-6 alkyl) or C (O) ₂ (C _1-6 alkyl);
R ³ may further be CH ₂ OH or NHS (O) ₂ NR ¹⁷ R ¹⁸ ;
X is a bond, CR ²⁷ R ²⁸ or CR ²⁹ R ³⁰ CR ³¹ R ³² ;
Y ^{is, CR 33 R 34 CR 35 R} 36, CR 37 R 38 CR 39 R 40 CR 41 R 42 or ^{CR 43 R 44 CR 45 R 46} CR 47 R 48 CR 49 or a ^{R 50,}
Alternatively, if E is C (O) O—, Y is CR ⁵¹ R ⁵² ;
Z is a bond, CR ⁵¹ R ⁵² , CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R ⁶⁸ CR ⁶⁹ R ⁷⁰ ;

から選択されるシクロアルキル−アミノ基であり、
ここで、該シクロアルキル環は、非置換であるか、あるいはハロゲン、Ｃ_１−４アルキル{所望によりＯＲ^１１６、ＮＲ^１１７Ｒ^１１８またはＮＲ^１１９Ｃ(Ｏ)Ｒ^１２０によって置換されている}、ＯＲ^１９、ＮＲ^２０Ｒ^２１、Ｃ(Ｏ)ＮＲ^２２Ｒ^２３、ＮＲ^２４Ｃ(Ｏ)Ｒ^２５、ＣＮ、Ｓ(Ｏ)_２Ｒ^１６、またはＳ(Ｏ)_２ＮＲ^１１４Ｒ^１１５から独立して選択される１個または２個の置換基によって置換されており；
Ａがシクロアルキル−アミノ基であるとき、ＡはＸに１個の環炭素原子を介して結合しており、かつＹにＮＲ^２６を介して結合しているか、
あるいは、Ａがシクロアルキル−アミノ基であって、かつＸがＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であるとき、Ａは、ＸにＮＲ^２６を介して結合し、かつＹに１個の環炭素原子に結合していてもよく；
Ｘが結合であるとき、ＡはＸにＮＲ^２６を有する環炭素原子を介して結合しておらず；
あるいは
Ａは、

から選択されるヘテロ環式環であり、
ここで、該ヘテロ環式環は、非置換であるか、あるいはハロゲン、Ｃ_１−４アルキル{所望によりＯＲ^１２１、ＮＲ^１２２Ｒ^１２３またはＮＲ^１２４Ｃ(Ｏ)Ｒ^１２５によって置換されている}、ＯＲ^１９、ＮＲ^２０Ｒ^２１、Ｃ(Ｏ)ＮＲ^２２Ｒ^２３、ＮＲ^２４Ｃ(Ｏ)Ｒ^２５、ＣＮ、Ｓ(Ｏ)_２Ｒ^１２６またはＳ(Ｏ)_２ＮＲ^１１４Ｒ^１１５から独立して選択される１個または２個の置換基(例えば１個の置換基がＡがＸまたはＹの何れかに結合している環炭素原子と同一の環炭素原子上にある)によって置換されており；
Ａがヘテロ環式環であるとき、ＡはＹに環窒素原子を介して結合しており；
Ａがヘテロ環式環であるとき、ＡはＸに１個の環炭素原子を介して結合していてもよく、
あるいはＡが２個の環窒素原子を有するヘテロ環であり、かつＸがＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であるとき、ＡはＸに第２の環窒素原子を介して結合していてもよく； A is

A cycloalkyl-amino group selected from
Wherein the cycloalkyl ring is unsubstituted or halogen, C _1-4 alkyl {optionally substituted by OR ¹¹⁶ , NR ¹¹⁷ R ¹¹⁸ or NR ¹¹⁹ C (O) R ¹²⁰ }, OR ¹⁹ , independently selected from NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹⁶ , or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Substituted by one or two substituents as described above;
When A is a cycloalkyl-amino group, A is bonded to X through one ring carbon atom and to Y through NR ²⁶ ;
Alternatively, when A is a cycloalkyl-amino group and X is CR ²⁹ R ³⁰ CR ³¹ R ³² , A is attached to X through NR ²⁶ and Y is a ring carbon atom. May be bound to;
When X is a bond, A is not bonded to X via a ring carbon atom having NR ²⁶ ;
Or A is

A heterocyclic ring selected from
Wherein the heterocyclic ring is unsubstituted or halogen, C _1-4 alkyl {optionally substituted by OR ¹²¹ , NR ¹²² R ¹²³ or NR ¹²⁴ C (O) R ¹²⁵ }, Independently selected from OR ¹⁹ , NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹²⁶ or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Substituted by one or two substituents (eg, one substituent is on the same ring carbon atom as A is bound to either X or Y);
When A is a heterocyclic ring, A is bonded to Y through a ring nitrogen atom;
When A is a heterocyclic ring, A may be bonded to X via one ring carbon atom;
Alternatively, when A is a heterocycle having two ring nitrogen atoms and X is CR ²⁹ R ³⁰ CR ³¹ R ³² , A may be bonded to X via a second ring nitrogen atom. ;

から選択される基(Ｒ^１は所望により置換されている)であるとき、ＥはさらにＣ(Ｏ)であってもよく；
ｎおよびｍは、独立して、１または２であり； E is O, S, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² , NR ⁷³ C (O), C (O) O, S (O) ₂ NR ⁷⁴ or NR ⁷⁵ S (O) ₂ ;
R ¹ is aryl, aryloxy, NR ⁷⁶ aryl, S (O) ₂ aryl, heteroaryl or C _3-10 cycloalkyl {optionally substituted by C _1-6 alkyl, halogen or phenyl}; Here, the aryl and heteroaryl rings are optionally halogen, cyano, trifluoromethyl, phenyl, OCF ₃ , O (CF ₂ ) _n O, O (CH ₂ ) _m O, OR ⁷⁸ , SR ⁷⁹ , NR ⁸⁰ R ⁸¹ , C (O) NR ⁸² R ⁸³ , NR ⁸⁴ S (O) ₂ R ⁸⁵ , C (O) R ⁸⁶ , S (O) ₂ R ⁸⁷ , S (O) ₂ NR ⁸⁸ R ⁸⁹ , NR ⁹⁰ C ^{(O) R 91, C (} O) OR 92, C 1-6 alkyl {optionally fluoro, trifluoromethyl, phenyl, ^{heteroaryl, OR 93, NR 94 R 95} , C (O) NR 9 ^{R 97, NR 98 S (O} ) 2 R 99, S (O) 2 R 100 or S (O) has been replaced by ₂ NR ¹⁰¹ R ^102}, or _{C 1-6} alkoxy {optionally fluoro, trifluoromethyl Methyl, phenyl, heteroaryl, OR ¹⁰³ , NR ¹⁰⁴ R ¹⁰⁵ , C (O) NR ¹⁰⁶ R ¹⁰⁷ , NR ¹⁰⁸ S (O) ₂ R ¹⁰⁹ , S (O) ₂ R ¹¹⁰ or S (O) ₂ NR ¹¹¹ R is substituted by} is substituted by ^112; wherein two substituents on the aryl or heteroaryl ring, taken with R ¹ and the integral, carbocyclic or heterocyclic ring (e.g. O, N and S A 4-membered ring that is selected from 1-, 2-, 3-, or 4-heteroatoms independently selected from Condensed, and Optionally substituted by halogen, C _1-4 alkyl, CF ₃ or C _1-4 alkoxy;
Z is a bond and R ¹ is

E may also be C (O) when R is a group selected from (R ¹ is optionally substituted);
n and m are independently 1 or 2;

R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ^{42, R 43, R 44,} R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56, R 57, R 58, ^R59 , ^R60 , ^R61 , ^R62 , ^R63 , ^R64 , ^R65 , ^R66 , ^R67 , ^R68 , ^R69 , ^R70 , ^R71 , ^R72 , ^R73 , ^R74 , ^{R75 , R 76, R 77, R} 78, R 79, R 80, ^{81, R 82, R 83,} R 84, R 86, R 88, R 89, R 90, R 91, R 92, R 93, R 94, R 95, R 96, R 97, R 98, R 101, ^{R 102, R 103, R 104} , R 105, R 106, R 107, R 108, R 111, R 112, R 113, R 114, R 115, R 116, R 117, R 118, R 119, R 120 , R ¹²¹ , R ¹²² , R ¹²³ , R ¹²⁴ and R ¹²⁵ are independently hydrogen or C _1-6 alkyl;
R ⁵² may further be phenyl;
R ⁷² may further be phenyl (C _1-4 alkyl) (eg benzyl);
R ⁹ , R ¹¹ , R ¹⁶ , R ⁸⁵ , R ⁸⁷ , R ⁹⁹ , R ¹⁰⁰ , R ¹⁰⁹ , R ¹¹⁰ and R ¹²⁶ are independently C _1-6 alkyl;
Provided that R ¹ is aryloxy, NR ⁷⁶ aryl or S (O) ₂ aryl, and E is O, S, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² , S (O) ₂ NR Z is CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R if ⁷⁴ or NR ⁷⁵ S (O) _2. ⁶⁸ CR ⁶⁹ R ⁷⁰ . ]
Or a pharmaceutically acceptable salt thereof.

であり；
Ｍが、Ｃ(Ｏ)、ＮＲ^６、ＳまたはＣＲ^７Ｒ^８であり；
Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５が、独立して、水素、ハロゲン、トリフルオロメチル、シアノ、カルボキシ、ヒドロキシ、ニトロ、Ｓ(Ｏ)_２Ｒ^９、ＮＲ^１０Ｓ(Ｏ)_２Ｒ^１１、Ｃ(Ｏ)ＮＲ^１２Ｒ^１３、ＮＲ^１４Ｃ(Ｏ)Ｒ^１５、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ(Ｏ)(Ｃ_１−６アルキル)またはＣ(Ｏ)_２(Ｃ_１−６アルキル)であり；
Ｒ^３が、さらに、ＣＨ_２ＯＨまたはＮＨＳ(Ｏ)_２ＮＲ^１７Ｒ^１８であってもよく；
Ｘが、結合、ＣＲ^２７Ｒ^２８またはＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であり；
Ｙが、ＣＲ^３３Ｒ^３４ＣＲ^３５Ｒ^３６、ＣＲ^３７Ｒ^３８ＣＲ^３９Ｒ^４０ＣＲ^４１Ｒ^４２またはＣＲ^４３Ｒ^４４ＣＲ^４５Ｒ^４６ＣＲ^４７Ｒ^４８ＣＲ^４９Ｒ^５０であるか、
あるいは、ＥがＣ(Ｏ)Ｏ−であるならば、ＹがＣＲ^５１Ｒ^５２であり；
Ｚが、結合、ＣＲ^５１Ｒ^５２、ＣＲ^５３Ｒ^５４ＣＲ^５５Ｒ^５６、ＣＲ^５７Ｒ^５８ＣＲ^５９Ｒ^６０ＣＲ^６１Ｒ^６２またはＣＲ^６３Ｒ^６４ＣＲ^６５Ｒ^６６ＣＲ^６７Ｒ^６８ＣＲ^６９Ｒ^７０であり； In one particular embodiment, the present invention provides
Ar is

Is;
M is C (O), NR ⁶ , S or CR ⁷ R ⁸ ;
R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S (O) ₂ R ⁹ , NR ¹⁰ S (O) ₂ R ¹¹ , C (O) NR ¹² R ¹³ , NR ¹⁴ C (O) R ¹⁵ , C _1-6 alkyl, C _1-6 alkoxy, C (O) (C _1-6 alkyl) or C (O) ₂ (C _1-6 alkyl);
R ³ may further be CH ₂ OH or NHS (O) ₂ NR ¹⁷ R ¹⁸ ;
X is a bond, CR ²⁷ R ²⁸ or CR ²⁹ R ³⁰ CR ³¹ R ³² ;
Y ^{is, CR 33 R 34 CR 35 R} 36, CR 37 R 38 CR 39 R 40 CR 41 R 42 or ^{CR 43 R 44 CR 45 R 46} CR 47 R 48 CR 49 or a ^{R 50,}
Alternatively, if E is C (O) O—, Y is CR ⁵¹ R ⁵² ;
Z is a bond, CR ⁵¹ R ⁵² , CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R ⁶⁸ CR ⁶⁹ R ⁷⁰ ;

から選択されるシクロアルキル−アミノ基であり、
ここで、該シクロアルキル環が、非置換であるか、あるいはハロゲン、Ｃ_１−４アルキル{所望によりＯＲ^１１６、ＮＲ^１１７Ｒ^１１８またはＮＲ^１１９Ｃ(Ｏ)Ｒ^１２０によって置換されている}、ＯＲ^１９、ＮＲ^２０Ｒ^２１、Ｃ(Ｏ)ＮＲ^２２Ｒ^２３、ＮＲ^２４Ｃ(Ｏ)Ｒ^２５、ＣＮ、Ｓ(Ｏ)_２Ｒ^１６、またはＳ(Ｏ)_２ＮＲ^１１４Ｒ^１１５から独立して選択される、１個または２個の置換基によって置換されており；
Ａがシクロアルキル−アミノ基であるとき、ＡはＸに環炭素原子を介して結合しており、かつＹにＮＲ^２６を介して結合しているか、
あるいは、Ａがシクロアルキル−アミノ基であって、かつＸがＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であるとき、ＡはＸにＮＲ^２６を介して結合し、かつＹに環炭素原子を介して結合していてもよく；
Ｘが結合であるとき、ＡはＸにＮＲ^２６を有する環炭素原子を介して結合しておらず；
あるいは
Ａが、

から選択されるヘテロ環式環であり；
ここで、該ヘテロ環式環が、非置換であるか、あるいはハロゲン、Ｃ_１−４アルキル{所望によりＯＲ^１２１、ＮＲ^１２２Ｒ^１２３またはＮＲ^１２４Ｃ(Ｏ)Ｒ^１２５によって置換されている}、ＯＲ^１９、ＮＲ^２０Ｒ^２１、Ｃ(Ｏ)ＮＲ^２２Ｒ^２３、ＮＲ^２４Ｃ(Ｏ)Ｒ^２５、ＣＮ、Ｓ(Ｏ)_２Ｒ^１２６またはＳ(Ｏ)_２ＮＲ^１１４Ｒ^１１５から独立して選択される１個または２個の置換基によって置換されており(例えば置換基は、ＡがＸまたはＹの何れかに結合している環炭素原子と同一の環炭素原子上にある)；
Ａがヘテロ環式環であるとき、ＡはＹに環窒素原子を介して結合しており；
Ａがヘテロ環式環であるとき、ＡはＸに１個の環炭素原子を介して結合していてもよく、
あるいは、Ａが２個の環窒素原子を有するヘテロ環であり、かつＸがＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であるとき、ＡはＸに第２の環窒素原子を介して結合していてもよく； A is

A cycloalkyl-amino group selected from
Wherein the cycloalkyl ring is unsubstituted or halogen, C _1-4 alkyl {optionally substituted by OR ¹¹⁶ , NR ¹¹⁷ R ¹¹⁸ or NR ¹¹⁹ C (O) R ¹²⁰ }, OR ¹⁹ , independently selected from NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹⁶ , or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Is substituted by one or two substituents;
When A is a cycloalkyl-amino group, A is bonded to X via a ring carbon atom and to Y to NR ²⁶ ;
Alternatively, when A is a cycloalkyl-amino group and X is CR ²⁹ R ³⁰ CR ³¹ R ³² , A is bonded to X through NR ²⁶ and to Y through a ring carbon atom. May be;
When X is a bond, A is not bonded to X via a ring carbon atom having NR ²⁶ ;
Or A is

A heterocyclic ring selected from:
Wherein the heterocyclic ring is unsubstituted or halogen, C _1-4 alkyl {optionally substituted by OR ¹²¹ , NR ¹²² R ¹²³ or NR ¹²⁴ C (O) R ¹²⁵ }, Independently selected from OR ¹⁹ , NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹²⁶ or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Substituted by one or two substituents as defined above (eg, the substituent is on the same ring carbon atom as the ring carbon atom where A is bound to either X or Y);
When A is a heterocyclic ring, A is bonded to Y through a ring nitrogen atom;
When A is a heterocyclic ring, A may be bonded to X via one ring carbon atom;
Alternatively, when A is a heterocycle having two ring nitrogen atoms and X is CR ²⁹ R ³⁰ CR ³¹ R ³² , A may be bonded to X via a second ring nitrogen atom. Often;

から選択される基(Ｒ^１は所望により置換されている)であるとき、ＥはさらにＣ(Ｏ)であってもよく；
ｎおよびｍが、独立して、１または２であり；
Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^１０、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３、Ｒ^３４、Ｒ^３５、Ｒ^３６、Ｒ^３７、Ｒ^３８、Ｒ^３９、Ｒ^４０、Ｒ^４１、Ｒ^４２、Ｒ^４３、Ｒ^４４、Ｒ^４５、Ｒ^４６、Ｒ^４７、Ｒ^４８、Ｒ^４９、Ｒ^５０、Ｒ^５１、Ｒ^５２、Ｒ^５３、Ｒ^５４、Ｒ^５５、Ｒ^５６、Ｒ^５７、Ｒ^５８、Ｒ^５９、Ｒ^６０、Ｒ^６１、Ｒ^６２、Ｒ^６３、Ｒ^６４、Ｒ^６５、Ｒ^６６、Ｒ^６７、Ｒ^６８、Ｒ^６９、Ｒ^７０、Ｒ^７１、Ｒ^７２、Ｒ^７３、Ｒ^７４、Ｒ^７５、Ｒ^７６、Ｒ^７７、Ｒ^７８、Ｒ^７９、Ｒ^８０、Ｒ^８１、Ｒ^８２、Ｒ^８３、Ｒ^８４、Ｒ^８６、Ｒ^８８、Ｒ^８９、Ｒ^９０、Ｒ^９１、Ｒ^９２、Ｒ^９３、Ｒ^９４、Ｒ^９５、Ｒ^９６、Ｒ^９７、Ｒ^９８、Ｒ^１０１、Ｒ^１０２、Ｒ^１０３、Ｒ^１０４、Ｒ^１０５、Ｒ^１０６、Ｒ^１０７、Ｒ^１０８、Ｒ^１１１、Ｒ^１１２、Ｒ^１１３、Ｒ^１１４、Ｒ^１１５、Ｒ^１１６、Ｒ^１１７、Ｒ^１１８、Ｒ^１１９、Ｒ^１２０、Ｒ^１２１、Ｒ^１２２、Ｒ^１２３、Ｒ^１２４およびＲ^１２５が、独立して、水素またはＣ_１−６アルキルであり；
Ｒ^９、Ｒ^１１、Ｒ^１６、Ｒ^８５、Ｒ^８７、Ｒ^９９、Ｒ^１００、Ｒ^１０９、Ｒ^１１０およびＲ^１２６が、独立して、Ｃ_１−６アルキルであり；
ただし、Ｒ^１が、アリールオキシ、ＮＲ^７６アリールまたはＳ(Ｏ)_２アリールであり、かつＥが、Ｏ、Ｓ、Ｓ(Ｏ)_２、ＮＲ^７１、Ｃ(Ｏ)ＮＲ^７２、Ｓ(Ｏ)_２ＮＲ^７４またはＮＲ^７５Ｓ(Ｏ)_２であるならば、Ｚが、ＣＲ^５３Ｒ^５４ＣＲ^５５Ｒ^５６、ＣＲ^５７Ｒ^５８ＣＲ^５９Ｒ^６０ＣＲ^６１Ｒ^６２またはＣＲ^６３Ｒ^６４ＣＲ^６５Ｒ^６６ＣＲ^６７Ｒ^６８ＣＲ^６９Ｒ^７０である、
式（Ｉ）の化合物またはその薬学的に許容される塩を提供する。 E is, O, S, S (O ) 2, NR 71, C (O) NR 72, NR 73 C (O), C (O) O, S (O) 2 NR 74 or ^{NR 75} S (O) ₂ ;
R ¹ is aryl, aryloxy, NR ⁷⁶ aryl, S (O) ₂ aryl, heteroaryl or C _3-10 cycloalkyl {optionally substituted by C _1-6 alkyl, halogen or phenyl}; Where the aryl and heteroaryl rings are optionally halogen, cyano, trifluoromethyl, phenyl, OCF ₃ , O (CF ₂ ) _n O, O (CH ₂ ) _m O, OR ⁷⁸ , SR ⁷⁹ , NR ⁸⁰ R ⁸¹ , C (O) NR ⁸² R ⁸³ , NR ⁸⁴ S (O) ₂ R ⁸⁵ , C (O) R ⁸⁶ , S (O) ₂ R ⁸⁷ , S (O) ₂ NR ⁸⁸ R ⁸⁹ , NR ⁹⁰ C ^{(O) R 91, C (} O) OR 92, C 1-6 alkyl {optionally fluoro, trifluoromethyl, phenyl, ^{heteroaryl, OR 93, NR 94 R 95} , C (O) NR 9 ^{R 97, NR 98 S (O} ) 2 R 99, S (O) 2 R 100 or S (O) has been replaced by ₂ NR ¹⁰¹ R ^102}, or _{C 1-6} alkoxy {optionally fluoro, trifluoromethyl Methyl, phenyl, heteroaryl, OR ¹⁰³ , NR ¹⁰⁴ R ¹⁰⁵ , C (O) NR ¹⁰⁶ R ¹⁰⁷ , NR ¹⁰⁸ S (O) ₂ R ¹⁰⁹ , S (O) ₂ R ¹¹⁰ or S (O) ₂ NR ¹¹¹ R is substituted by} is substituted by ^112; wherein two substituents on the aryl or heteroaryl ring, taken with R ¹ and the integral, carbocyclic or heterocyclic ring (e.g. O, N and S A 4-membered ring that is selected from 1-, 2-, 3-, or 4-heteroatoms independently selected from And as desired More substituted by halogen, C _1-4 alkyl, CF ₃ or C _1-4 alkoxy;
Z is a bond and R ¹ is

E may also be C (O) when R is a group selected from (R ¹ is optionally substituted);
n and m are independently 1 or 2;
R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ^{42, R 43, R 44,} R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56, R 57, R 58, ^R59 , ^R60 , ^R61 , ^R62 , ^R63 , ^R64 , ^R65 , ^R66 , ^R67 , ^R68 , ^R69 , ^R70 , ^R71 , ^R72 , ^R73 , ^R74 , ^{R75 , R 76, R 77, R} 78, R 79, R 80, ^{81, R 82, R 83,} R 84, R 86, R 88, R 89, R 90, R 91, R 92, R 93, R 94, R 95, R 96, R 97, R 98, R 101, ^{R 102, R 103, R 104} , R 105, R 106, R 107, R 108, R 111, R 112, R 113, R 114, R 115, R 116, R 117, R 118, R 119, R 120 , R ¹²¹ , R ¹²² , R ¹²³ , R ¹²⁴ and R ¹²⁵ are independently hydrogen or C _1-6 alkyl;
R ⁹ , R ¹¹ , R ¹⁶ , R ⁸⁵ , R ⁸⁷ , R ⁹⁹ , R ¹⁰⁰ , R ¹⁰⁹ , R ¹¹⁰ and R ¹²⁶ are independently C _1-6 alkyl;
Wherein R ¹ is aryloxy, NR ⁷⁶ aryl or S (O) ₂ aryl, and E is O, S, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² , S (O) _{2 If} NR ⁷⁴ or NR ⁷⁵ S (O) _{2 then} Z is CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R ⁶⁸ CR ⁶⁹ R ⁷⁰ ,
Provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

であり；
Ｍが、Ｃ(Ｏ)、ＮＲ^６またはＣＲ^７Ｒ^８であり；
Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５が、独立して、水素、ハロゲン、トリフルオロメチル、シアノ、カルボキシ、ヒドロキシ、ニトロ、Ｓ(Ｏ)_２Ｒ^９、ＮＲ^１０Ｓ(Ｏ)_２Ｒ^１１、Ｃ(Ｏ)ＮＲ^１２Ｒ^１３、ＮＲ^１４Ｃ(Ｏ)Ｒ^１５、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ(Ｏ)(Ｃ_１−６アルキル)またはＣ(Ｏ)_２(Ｃ_１−６アルキル)であり；
Ｒ^３が、さらに、ＣＨ_２ＯＨまたはＮＨＳ(Ｏ)_２ＮＲ^１７Ｒ^１８であってもよく；
Ｘが、結合、ＣＲ^２７Ｒ^２８またはＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であり；
Ｙが、ＣＲ^３３Ｒ^３４ＣＲ^３５Ｒ^３６、ＣＲ^３７Ｒ^３８ＣＲ^３９Ｒ^４０ＣＲ^４１Ｒ^４２またはＣＲ^４３Ｒ^４４ＣＲ^４５Ｒ^４６ＣＲ^４７Ｒ^４８ＣＲ^４９Ｒ^５０であり；
Ｚが、結合、ＣＲ^５１Ｒ^５２、ＣＲ^５３Ｒ^５４ＣＲ^５５Ｒ^５６、ＣＲ^５７Ｒ^５８ＣＲ^５９Ｒ^６０ＣＲ^６１Ｒ^６２またはＣＲ^６３Ｒ^６４ＣＲ^６５Ｒ^６６ＣＲ^６７Ｒ^６８ＣＲ^６９Ｒ^７０であり； In another aspect, the invention provides:
Ar is

Is;
M is C (O), NR ⁶ or CR ⁷ R ⁸ ;
R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S (O) ₂ R ⁹ , NR ¹⁰ S (O) ₂ R ¹¹ , C (O) NR ¹² R ¹³ , NR ¹⁴ C (O) R ¹⁵ , C _1-6 alkyl, C _1-6 alkoxy, C (O) (C _1-6 alkyl) or C (O) ₂ (C _1-6 alkyl);
R ³ may further be CH ₂ OH or NHS (O) ₂ NR ¹⁷ R ¹⁸ ;
X is a bond, CR ²⁷ R ²⁸ or CR ²⁹ R ³⁰ CR ³¹ R ³² ;
Y ^is, be ^{CR 33 R 34 CR 35 R 36} , CR 37 R 38 CR 39 R 40 CR 41 R 42 or ^{CR 43 R 44 CR 45 R 46} CR 47 R 48 CR 49 R 50;
Z is a bond, CR ⁵¹ R ⁵² , CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R ⁶⁸ CR ⁶⁹ R ⁷⁰ ;

から選択されるシクロアルキル環であり；
ここで、該シクロアルキル環が、非置換であるか、あるいはハロゲン、Ｃ_１−４アルキル{所望によりＯＲ^１１６、ＮＲ^１１７Ｒ^１１８またはＮＲ^１１９Ｃ(Ｏ)Ｒ^１２０によって置換されている}、ＯＲ^１９、ＮＲ^２０Ｒ^２１、Ｃ(Ｏ)ＮＲ^２２Ｒ^２３、ＮＲ^２４Ｃ(Ｏ)Ｒ^２５、ＣＮ、Ｓ(Ｏ)_２Ｒ^１６、またはＳ(Ｏ)_２ＮＲ^１１４Ｒ^１１５から独立して選択される１個または２個の置換基によって置換されており；
Ａがシクロアルキル環であるとき、ＡはＹにＮＲ^２６を介して結合しており；
Ａがシクロアルキル環であるとき、ＡはＸに１個の環炭素原子またはＮＲ^２６を介して結合しており、ただし、ＸがＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であり；
Ｘが結合であるとき、ＡはＸにＮＲ^２６を有する環炭素原子を介して結合しておらず；
あるいは
Ａが、

から選択されるヘテロ環式環であり；
ここで、該ヘテロ環式環が、非置換であるか、あるいはハロゲン、Ｃ_１−４アルキル(所望によりＯＲ^１２１、ＮＲ^１２２Ｒ^１２３またはＮＲ^１２４Ｃ(Ｏ)Ｒ^１２５によって置換されている)、ＯＲ^１９、ＮＲ^２０Ｒ^２１、Ｃ(Ｏ)ＮＲ^２２Ｒ^２３、ＮＲ^２４Ｃ(Ｏ)Ｒ^２５、ＣＮ、Ｓ(Ｏ)_２Ｒ^１２６またはＳ(Ｏ)_２ＮＲ^１１４Ｒ^１１５から独立して選択される１個または２個の置換基によって置換されており；
Ａがヘテロ環式環であるとき、ＡはＹに環窒素原子を介して結合しており；
Ａがヘテロ環式環であるとき、ＡはＸに１個の環炭素原子を介して結合しているか、あるいは、ＸがＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であるならば第２の環窒素原子を介して結合しており； A is

A cycloalkyl ring selected from:
Wherein the cycloalkyl ring is unsubstituted or halogen, C _1-4 alkyl {optionally substituted by OR ¹¹⁶ , NR ¹¹⁷ R ¹¹⁸ or NR ¹¹⁹ C (O) R ¹²⁰ }, OR ¹⁹ , independently selected from NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹⁶ , or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Substituted by one or two substituents as described above;
When A is a cycloalkyl ring, A is attached to Y via NR ²⁶ ;
When A is a cycloalkyl ring, A is attached to X through one ring carbon atom or NR ²⁶ , provided that X is CR ²⁹ R ³⁰ CR ³¹ R ³² ;
When X is a bond, A is not bonded to X via a ring carbon atom having NR ²⁶ ;
Or A is

A heterocyclic ring selected from:
Wherein the heterocyclic ring is unsubstituted or halogen, C _1-4 alkyl (optionally substituted by OR ¹²¹ , NR ¹²² R ¹²³ or NR ¹²⁴ C (O) R ¹²⁵ ), Independently selected from OR ¹⁹ , NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹²⁶ or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Substituted by one or two substituents as described above;
When A is a heterocyclic ring, A is bonded to Y through a ring nitrogen atom;
When A is a heterocyclic ring, A is attached to X through one ring carbon atom, or a second ring nitrogen atom if X is CR ²⁹ R ³⁰ CR ³¹ R ³² Is linked through;

から選択される基(Ｒ^１は所望により置換されている)であるとき、ＥはさらにＣ(Ｏ)であってもよく；
ｎおよびｍは、独立して、１または２であり；
Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^１０、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３、Ｒ^３４、Ｒ^３５、Ｒ^３６、Ｒ^３７、Ｒ^３８、Ｒ^３９、Ｒ^４０、Ｒ^４１、Ｒ^４２、Ｒ^４３、Ｒ^４４、Ｒ^４５、Ｒ^４６、Ｒ^４７、Ｒ^４８、Ｒ^４９、Ｒ^５０、Ｒ^５１、Ｒ^５２、Ｒ^５３、Ｒ^５４、Ｒ^５５、Ｒ^５６、Ｒ^５７、Ｒ^５８、Ｒ^５９、Ｒ^６０、Ｒ^６１、Ｒ^６２、Ｒ^６３、Ｒ^６４、Ｒ^６５、Ｒ^６６、Ｒ^６７、Ｒ^６８、Ｒ^６９、Ｒ^７０、Ｒ^７１、Ｒ^７２、Ｒ^７３、Ｒ^７４、Ｒ^７５、Ｒ^７６、Ｒ^７７、Ｒ^７８、Ｒ^７９、Ｒ^８０、Ｒ^８１、Ｒ^８２、Ｒ^８３、Ｒ^８４、Ｒ^８６、Ｒ^８８、Ｒ^８９、Ｒ^９０、Ｒ^９１、Ｒ^９２、Ｒ^９３、Ｒ^９４、Ｒ^９５、Ｒ^９６、Ｒ^９７、Ｒ^９８、Ｒ^１０１、Ｒ^１０２、Ｒ^１０３、Ｒ^１０４、Ｒ^１０５、Ｒ^１０６、Ｒ^１０７、Ｒ^１０８、Ｒ^１１１、Ｒ^１１２、Ｒ^１１３、Ｒ^１１４、Ｒ^１１５、Ｒ^１１６、Ｒ^１１７、Ｒ^１１８、Ｒ^１１９、Ｒ^１２０、Ｒ^１２１、Ｒ^１２２、Ｒ^１２３、Ｒ^１２４およびＲ^１２５が、独立して、水素またはＣ_１−６アルキルであり；
Ｒ^９、Ｒ^１１、Ｒ^１６、Ｒ^８５、Ｒ^８７、Ｒ^９９、Ｒ^１００、Ｒ^１０９、Ｒ^１１０およびＲ^１２６は、独立して、Ｃ_１−６アルキルであり；
ただし、Ｒ^１がアリールオキシ、ＮＲ^７６アリールまたはＳ(Ｏ)_２アリールであり、かつＥがＯ、Ｓ、Ｓ(Ｏ)_２、ＮＲ^７１、Ｃ(Ｏ)ＮＲ^７２、Ｓ(Ｏ)_２ＮＲ^７４またはＮＲ^７５Ｓ(Ｏ)_２であるとき、Ｚは、ＣＲ^５３Ｒ^５４ＣＲ^５５Ｒ^５６、ＣＲ^５７Ｒ^５８ＣＲ^５９Ｒ^６０ＣＲ^６１Ｒ^６２またはＣＲ^６３Ｒ^６４ＣＲ^６５Ｒ^６６ＣＲ^６７Ｒ^６８ＣＲ^６９Ｒ^７０である、
式(Ｉ)の化合物またはその薬学的に許容される塩を提供する。 E is O, S, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² , NR ⁷³ C (O), S (O) ₂ NR ⁷⁴ or NR ⁷⁵ S (O) ₂ ;
R ¹ is aryl, aryloxy, NR ⁷⁶ aryl, S (O) ₂ aryl, heteroaryl or C _3-7 cycloalkyl; wherein the aryl and heteroaryl rings are optionally halogen, cyano, tri Fluoromethyl, phenyl, O (CF ₂ ) _n O, O (CH ₂ ) _m O, OR ⁷⁸ , SR ⁷⁹ , NR ⁸⁰ R ⁸¹ , C (O) NR ⁸² R ⁸³ , NR ⁸⁴ S (O) ₂ R ⁸⁵ , C (O) R ⁸⁶ , S (O) ₂ R ⁸⁷ , S (O) ₂ NR ⁸⁸ R ⁸⁹ , NR ⁹⁰ C (O) R ⁹¹ , C (O) OR ⁹² , C _1-6 alkyl {optionally Fluoro, trifluoromethyl, phenyl, heteroaryl, OR ⁹³ , NR ⁹⁴ R ⁹⁵ , C (O) NR ⁹⁶ R ⁹⁷ , NR ⁹⁸ S (O) ₂ R ⁹⁹ , S (O) ₂ R ¹⁰⁰ or S (O) ₂ NR ¹⁰¹ R ¹ It is substituted by ^2}, or _{C 1-6} alkoxy {optionally fluoro, trifluoromethyl, phenyl, ^{heteroaryl, OR 103, NR 104 R 105} , C (O) NR 106 R 107, NR 108 S (O ) substituted by} is substituted by ^{_{2 R 109, S (O)}} 2 R 110 or ^{_{S (O) 2 NR 111 R}} 112; wherein two substituents on the aryl or heteroaryl ring , R ¹ together with a 4-membered ring which is a carbocyclic or heterocyclic ring (eg containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S) It may form a 8-membered ring from 8-membered ring from the 4-membered ring, fused and, and substituted _{halogen, C 1-4} alkyl, by CF ₃ or _{C 1-4} alkoxy optionally Cage;
Z is a bond and R ¹ is

E may also be C (O) when R is a group selected from (R ¹ is optionally substituted);
n and m are independently 1 or 2;
R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ^{42, R 43, R 44,} R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56, R 57, R 58, ^R59 , ^R60 , ^R61 , ^R62 , ^R63 , ^R64 , ^R65 , ^R66 , ^R67 , ^R68 , ^R69 , ^R70 , ^R71 , ^R72 , ^R73 , ^R74 , ^{R75 , R 76, R 77, R} 78, R 79, R 80, ^{81, R 82, R 83,} R 84, R 86, R 88, R 89, R 90, R 91, R 92, R 93, R 94, R 95, R 96, R 97, R 98, R 101, ^{R 102, R 103, R 104} , R 105, R 106, R 107, R 108, R 111, R 112, R 113, R 114, R 115, R 116, R 117, R 118, R 119, R 120 , R ¹²¹ , R ¹²² , R ¹²³ , R ¹²⁴ and R ¹²⁵ are independently hydrogen or C _1-6 alkyl;
R ⁹ , R ¹¹ , R ¹⁶ , R ⁸⁵ , R ⁸⁷ , R ⁹⁹ , R ¹⁰⁰ , R ¹⁰⁹ , R ¹¹⁰ and R ¹²⁶ are independently C _1-6 alkyl;
Provided that R ¹ is aryloxy, NR ⁷⁶ aryl or S (O) ₂ aryl, and E is O, S, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² , S (O) ₂ NR Z is CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R ⁶⁸ when ⁷⁴ or NR ⁷⁵ S (O) _2. CR ⁶⁹ R ⁷⁰ ,
Provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

  The compounds of the present invention are selective β2 receptor agonists and have more suitable properties for once daily administration. The compounds were optimized to have the appropriate duration predicted in an in vitro guinea pig trachea model, or a mammalian model (eg histamine-loaded guinea pig). The compound also has a beneficial pharmacokinetic half-life in rat experimental systems. In particular, certain compounds of the invention are at least 10 times more potent against the β2 receptor compared to the α1, β1 or dopamine (D2) receptor. Certain compounds are also noted for their short onset of action, which is the time from administration of a compound of the invention to a patient until the compound develops symptom relief. Guinea pig or human isolated trachea can be used to predict onset of action in vitro.

  Suitable pharmaceutically acceptable salts include, for example, acid addition salts such as hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartaric acid Salt, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, or p-toluenesulfonate. Further examples of acid addition salts are bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, Formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate Napadisylate (naphthalene-1,5-disulfonate or naphthalene-1- (sulfonic acid) -5-sulfonate), edicylate (ethane-1,2-disulfonate or ethane-1- (sulfonic acid) -2-sulfonate) , Isethionic acid (2-hydroxyethyl sulfonate), 2-mesitylene sulfonate and 2-naphthalene sulfonate.

  The present invention includes all possible ratios of pharmaceutically acceptable salts to the compounds of formula (I), such as monohydrobromide, dihydrobromide or hemi salt ( For example, hemifumarate).

  The compounds of formula (I) may exist in the form of stereoisomers. It will be understood that the present invention includes the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. The enantiomerically pure form is particularly desirable.

In this specification, unless otherwise specified, an alkyl substituent or an alkyl moiety in a substituent may be linear or branched. Examples of C _1-6 alkyl groups / moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.

Aryl is, for example, phenyl or naphthyl.
C _3-10 cycloalkyl is optionally bridged by 1, 2, 3 or 4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. In one embodiment of the invention C _3-10 cycloalkyl is for example cyclohexyl or adamantyl.

  Heteroaryl is an aromatic monocyclic or bicyclic ring containing 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen Is done. Examples of heteroaryl are pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxadiazolyl, oxadiazolyl, isothiadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Triazinyl, pyridinonyl, pyrimidinedionyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 4H-chromene- 4-onyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, isoindolinyl and Including the Fuchirijiniru.

Two substituents on the aryl or heteroaryl ring, taken together with R ¹ , are carbocyclic or heterocyclic (eg 1, 2, 3 or 4 independently selected from O, N and S A 4-membered ring that is a heteroatom) is fused, and the resulting R ¹ ring system is, for example, 2, 3 -Dihydro-1,4-benzodioxin, 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin, 1,2,3,4-tetrahydronaphthalene, indane, 1,3 -Benzodioxole, 2,2-dimethyl-1,3-benzodioxole, 2,3-dihydro-1-benzofuran, 2,2-dimethyl-2,3-dihydro-1-benzofuran, indoline, 2 , 3-Dihydro-1-benzothiophene, thiochroman, chroma 1,2,3,4-tetrahydroquinoline, 6,7,8,9-tetrahydro-5H-benzo [7] annulene, 3,4-dihydro-2H-1,5-benzodioxepin, bicyclo [4 .2.0] octa-1,3,5-triene, spiro [1,3-benzodioxole-2,1'-cyclohexane], spiro [1,3-benzodioxole-2,1'- Cyclopentane], 4,5,6,7-tetrahydro-1,3-benzothiazole, 5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole, 5,6-dihydro-4H-cyclopenta [ d] [1,3] oxazole, 4,5,6,7-tetrahydro-1,3-benzoxazole, 4,5,6,7-tetrahydro-1H-benzimidazole, 1,4,5,6-tetrahydro Cyclopenta [d] imidazole, 4,5,6,7-tetrahydro-1-benzofuran, , 5,6,7-tetrahydro-1-benzothiophene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinazoline, indolinyl or isoindolinyl It is.

であり、Ｒ^３がＣＨ_２ＯＨまたはＮＨＣ(Ｏ)Ｈである式(Ｉ)の化合物を提供する。 In a further aspect, the invention provides that Ar is

Wherein R ³ is CH ₂ OH or NHC (O) H.

である、式(Ｉ)の化合物を提供する。 In another embodiment, the invention provides that Ar is

A compound of formula (I) is provided.

である。 In yet another embodiment, Ar is

It is.

である。 In another embodiment, Ar is

It is.

である。 In yet another embodiment, Ar is

It is.

In a further aspect, the invention provides a compound of formula (I), wherein X is a bond or CR ²⁷ R ²⁸ or CR ²⁹ R ³⁰ CR ³¹ R ³² (eg, X is a bond or CR ²⁷ R ²⁸ ). To do. In another embodiment, R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are independently hydrogen or C _1-4 alkyl (eg, methyl). In yet another embodiment, R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are all hydrogen.

In a further aspect, the invention provides a compound of the formula where X is a bond, CH ₂ or C (CH ₃ ) ₂ or (CH ₂ ) ₂ (eg, X is a bond, CH ₂ or C (CH ₃ ) ₂ ). A compound of (I) is provided.

In another aspect, the present invention, X is a bond or CH _2, provides a compound of formula (I).

In yet a further aspect, the invention provides that Y is CR ³³ R ³⁴ CR ³⁵ R ³⁶ , CR ³⁷ R ³⁸ CR ³⁹ R ⁴⁰ CR ⁴¹ R ⁴² or CR ⁴³ R ⁴⁴ CR ⁴⁵ R ⁴⁶ CR ⁴⁷ R ⁴⁸ CR ⁴⁹ R Compounds of formula (I) are provided wherein Y is CR ⁵¹ R ⁵² if E is ⁵⁰ or E is C (O) O. In another aspect, the present invention, Y is the ^CR 33 ^R 34 ^CR 35 ^{R 36} or ^{CR 37 R 38 CR 39 R 40} CR 41 or a ^{R 42,} or if E is C (O) O Y There is provided a compound of formula (I) which is CR ⁵¹ R ⁵² . In yet another ^embodiment, Y is ^{CR 33 R 34} CR 35 R ³⁶ or ^{CR 37 R 38 CR 39 R 40} CR 41 R 42. In a further aspect, R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ and R ⁵⁰ are independently hydrogen or C _1-4 alkyl (eg methyl). In yet a further aspect, R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ and R ⁵⁰ are all hydrogen.

In yet a further aspect, the present invention provides a compound of formula (I), wherein Y is (CH ₂ ) ₂ , (CH ₂ ) ₃ or CH ₂ C (CH ₃ ) ₂ CH ₂ .
In a further aspect, the present invention provides a compound of formula (I) wherein Y is (CH ₂ ) ₂ .

In another embodiment, the present invention provides a compound of formula (I) wherein Z is a bond, CR ⁵¹ R ⁵² , CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ or CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ^62. provide.
In yet another aspect, the present invention provides a compound of formula (I) wherein Z is CR ⁵¹ R ⁵² , CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ or CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² To do.
In a further aspect, the present invention provides a compound of formula (I), wherein Z is a bond, CR ⁵¹ R ⁵² or CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ .

In yet a further aspect, R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , R ⁵⁵ , R ⁵⁶ , R ⁵⁷ , R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ and R ⁶² are independently hydrogen or C _1-4 alkyl (eg methyl). In yet a further aspect, R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , R ⁵⁵ , R ⁵⁶ , R ⁵⁷ , R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ and R ⁶² are all hydrogen.

In another aspect, the present invention provides a compound of formula (I), wherein Z is a bond, CH ₂ , (CH ₂ ) ₂ , (CH ₂ ) ₃ or CH ₂ C (CH ₃ ) ₂ CH _2. To do.
In yet another aspect, the present invention, Z is, CH _2, provides compounds of (CH _{2) 2,} a (CH _{2) 3} or _{CH 2 C (CH 3) 2} CH 2, formula (I) .
In another embodiment, the present invention provides a compound of formula (I), wherein Z is a bond, CH ₂ or (CH ₂ ) ₂ (eg, Z is CH ₂ or (CH ₂ ) ₂ ).

  In a further embodiment, the invention provides that A is azetidine, pyrrolidine, piperidine, morpholine, piperazine, azepan, 1,4-diazepan, 3,8-diazabicyclo [3.2.1] octane, 3-azabicyclo [3.1. Provided is a compound of formula (I) that is a 0.0] hexane, 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, cyclobutane, cyclopentane, cyclohexane or cycloheptane ring. To do.

[式中、＊＊はＸに結合しており、＊＊＊はＹに結合しており；
環Ａは、所望によりヒドロキシ、Ｃ_１−４アルキル(例えばメチル)またはヒドロキシ(Ｃ_１−４アルキル)(例えばＨＯＣＨ_２)によって置換されており；
Ｒ^２６は、水素またはＣ_１−４アルキル(例えばメチル)である。]である。一つの態様において、Ｒ^２６は水素である。 In another embodiment, A is

[Wherein ** is bonded to X and *** is bonded to Y;
Ring A is optionally substituted by hydroxy, C _1-4 alkyl (eg methyl) or hydroxy (C _1-4 alkyl) (eg HOCH ₂ );
R ²⁶ is hydrogen or C _1-4 alkyl (eg methyl). ]. In one embodiment, R ²⁶ is hydrogen.

[式中、＊＊はＸに結合しており、＊＊＊はＹに結合しており；
Ａは、所望により、本明細書に記載している通りに置換されており；
Ｒ^２６は、本明細書で定義している通りである。]である。 In yet another aspect, A is

[Wherein ** is bonded to X and *** is bonded to Y;
A is optionally substituted as described herein;
R ²⁶ is as defined herein. ].

[式中、＊＊はＸに結合しており、＊＊＊はＹに結合しており；
Ａは、所望により本明細書に記載している通りに置換されている。]である。例えば、Ａは、非置換であるか、または、Ｘに結合した環炭素で、ヒドロキシ、Ｃ_１−４アルキル(例えばメチル)またはヒドロキシ(Ｃ_１−４アルキル)(例えばＨＯＣＨ_２)によって置換されている。
本発明の別の態様において、Ａは非置換である。 In a further aspect, A is

[Wherein ** is bonded to X and *** is bonded to Y;
A is optionally substituted as described herein. ]. For example, A is unsubstituted or substituted at the ring carbon attached to X by hydroxy, C _1-4 alkyl (eg methyl) or hydroxy (C _1-4 alkyl) (eg HOCH ₂ ). Yes.
In another aspect of the invention, A is unsubstituted.

Also in a further aspect of the invention, A is halogen, C _1-4 alkyl (optionally substituted by OR ¹²¹ , NR ¹²² R ¹²³ or NR ¹²⁴ C (O) R ¹²⁵ ), OR ¹⁹ , NR ²⁰ One independently selected from R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹²⁶ or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Or a compound of formula (I), which is substituted by two substituents. Here, R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ¹¹⁴ , R ¹¹⁵ , R ¹²¹ , R ¹²² , R ¹²³ , R ¹²⁴ and R ¹²⁵ are, for example, hydrogen or C _1-4 alkyl; R ¹²⁶ is, for example, C _1-4 alkyl.

Also, in a further aspect of the invention, A is independent of halogen, C _1-4 alkyl (optionally substituted by OR ¹²¹ ) or OR ¹⁹ (eg OR ¹⁹ is hydroxy or C _1-4 alkoxy). A compound of formula (I) is provided that is substituted by one selected substituent (eg, on the same ring carbon atom to which A is bonded to X or Y). Here, R ¹⁹ and R ¹²¹ are independently hydrogen or C _1-4 alkyl.

In another embodiment of the invention, A is substituted by hydroxyl, C _1-4 alkyl (optionally substituted by hydroxy), or C _1-4 alkoxy (eg A is attached to X or Y). On the same ring carbon atom as the ring carbon atom being provided).

In yet a further aspect, the present invention provides a compound of formula (I), wherein E is O, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² or NR ⁷³ C (O).
In another aspect, the present invention provides a compound of formula (I), wherein E is O, S (O) ₂ , C (O) NR ⁷² or NR ⁷³ C (O).

In a further aspect, the invention provides that E is O or C (O) NR ⁷² where R ⁷² is hydrogen or C _1-4 alkyl (eg, methyl or ethyl) (eg, R ⁷² is hydrogen). . The compound of formula (I) is provided.

In yet another embodiment, the invention provides that E is C (O) NR ⁷² where R ⁷² is hydrogen or C _1-4 alkyl (eg, methyl or ethyl). The compound of formula (I) is provided. For example, R ⁷² is hydrogen.
In a further aspect, the present invention provides a compound of formula (I), wherein E is O.

In yet a further aspect, the present invention provides a compound of formula (I), wherein E is O and Z is CH ₂ CH ₂ .
In another embodiment, the invention provides that E is C (O) NR ^72, where R ⁷² is hydrogen, for example. A compound of formula (I) is provided wherein Z is CH ₂ .

In yet another embodiment, the invention provides that R ¹ is aryl, aryloxy or heteroaryl, wherein the aryl and heteroaryl rings are optionally halogen, cyano, trifluoromethyl, phenyl, OR ⁷⁸ , Substituted with C (O) NR ⁸² R ⁸³ , S (O) ₂ R ⁸⁷ , S (O) ₂ NR ⁸⁸ R ⁸⁹ , NR ⁹⁰ C (O) R ⁹¹ , C _1-3 alkyl or C _1-3 alkoxy Where the two substituents on the aryl or heteroaryl ring, taken together with R ¹ , are carbocyclic or heterocyclic (eg, one independently selected from O, N and S; 4 to 8 membered rings may be formed, optionally containing halogen, C _1-4 alkyl, CF ₃ or C _{1. -4A} Provided is a compound of formula (I), substituted by lucoxy. The variables R ⁷⁸ , R ⁸² , R ⁸³ , R ⁸⁷ , R ⁸⁸ , R ⁸⁹ , R ⁹⁰ and R ⁹¹ are as defined herein.

In a further aspect, the invention provides that R ¹ is unsubstituted phenyl or halogen (eg, fluoro or chloro), C _1-4 alkyl (eg methyl), C _1-4 alkoxy (eg methoxy), cyano, Provided is a compound of formula (I), which is phenyl, substituted (eg, one, two or three) (which may be the same or different) by OH, CF ₃ , OCF ₃ or phenyl To do.

In another embodiment, the invention provides that R ¹ is unsubstituted phenyl or is substituted (eg, 1 or 2) with halogen (eg, fluoro or chloro) or C _1-4 alkyl (eg, methyl). A compound of formula (I) is phenyl (which may be the same or different).

In yet a further aspect, the present invention provides a compound of formula (I), wherein R ¹ is C _3-10 cycloalkyl (eg cyclopropyl, cyclohexyl or adamantyl) optionally substituted by phenyl.

から選択される基である、式(Ｉ)の化合物を提供する。 In another embodiment, the invention provides that Z is a bond, E is C (O), and R ¹ is

A compound of formula (I) is provided which is a group selected from:

である、式(Ｉ)の化合物を提供する。 In yet another aspect, the invention provides that Z is a bond, E is C (O), and R ¹ is

A compound of formula (I) is provided.

であり；
Ｘが、結合、ＣＲ^２７Ｒ^２８またはＣＲ^２９Ｒ^３０ＣＲ^３１Ｒ^３２であり；
Ｙが、ＣＲ^３３Ｒ^３４ＣＲ^３５Ｒ^３６、ＣＲ^３７Ｒ^３８ＣＲ^３９Ｒ^４０ＣＲ^４１Ｒ^４２またはＣＲ^４３Ｒ^４４ＣＲ^４５Ｒ^４６ＣＲ^４７Ｒ^４８ＣＲ^４９Ｒ^５０であるか、またはＥがＣ(Ｏ)Ｏ−であるならばＹがＣＲ^５１Ｒ^５２であり；
Ｚが、結合、ＣＲ^５１Ｒ^５２またはＣＲ^５３Ｒ^５４ＣＲ^５５Ｒ^５６であり；
Ａが、

から選択されるヘテロ環式環であり、Ｙに環窒素原子を介して結合しており、ここで、該ヘテロ環式環が非置換であるか、またはＣ_１−４アルキル(所望によりＯＲ^１２１によって置換されている)またはＯＲ^１９から独立して選択される１個の置換基(例えば該置換基がＡがＹに結合している環炭素原子と同一の環炭素原子上にある)によって置換されており；
Ｅが、ＯまたはＣ(Ｏ)ＮＲ^７２であり；
Ｒ^１が、アリールまたはＣ_３−１０シクロアルキル(所望によりＣ_１−６アルキル、ハロゲンまたはフェニルによって置換されている)であり；ここで、アリールが、所望によりハロゲン、シアノ、トリフルオロメチル、フェニル、ＯＣＦ_３、ＯＲ^７８、Ｃ_１−６アルキル(所望によりフルオロ、トリフルオロメチル、ＯＲ^９３またはＮＲ^９４Ｒ^９５によって置換されている)またはＣ_１−６アルコキシ(所望によりフルオロ、トリフルオロメチル、ＯＲ^１０３またはＮＲ^１０４Ｒ^１０５によって置換されている)によって置換されており{例えばＲ^１が、フェニル(所望によりハロゲン、Ｃ_１−４アルキルまたはフェニルによって置換されている)またはＣ_３−１０シクロアルキル(所望によりフェニルによって置換されている)である}；
Ｚが結合であって、Ｒ^１が、

であるとき(Ｒ^１は所望により置換されている)、ＥはさらにＣ(Ｏ)であってもよく；
Ｒ^１９、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３、Ｒ^３４、Ｒ^３５、Ｒ^３６、Ｒ^３７、Ｒ^３８、Ｒ^３９、Ｒ^４０、Ｒ^４１、Ｒ^４２、Ｒ^４３、Ｒ^４４、Ｒ^４５、Ｒ^４６、Ｒ^４７、Ｒ^４８、Ｒ^４９、Ｒ^５０、Ｒ^５１、Ｒ^５２、Ｒ^５３、Ｒ^５４、Ｒ^５５、Ｒ^５６、Ｒ^７２、Ｒ^７８、Ｒ^９３、Ｒ^９４、Ｒ^９５、Ｒ^１０３、Ｒ^１０４、Ｒ^１０５およびＲ^１２１が、独立して、水素またはＣ_１−６アルキルである、
式(Ｉ)の化合物またはその薬学的に許容される塩を提供する。 In a further aspect, the invention provides that Ar is

Is;
X is a bond, CR ²⁷ R ²⁸ or CR ²⁹ R ³⁰ CR ³¹ R ³² ;
Y is CR ³³ R ³⁴ CR ³⁵ R ³⁶ , CR ³⁷ R ³⁸ CR ³⁹ R ⁴⁰ CR ⁴¹ R ⁴² or CR ⁴³ R ⁴⁴ CR ⁴⁵ R ⁴⁶ CR ⁴⁷ R ⁴⁸ CR ⁴⁹ R ⁵⁰ or E is C ( If O) O— then Y is CR ⁵¹ R ⁵² ;
Z is a bond, CR ⁵¹ R ⁵² or CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ ;
A is

A heterocyclic ring selected from and attached to Y via a ring nitrogen atom, wherein the heterocyclic ring is unsubstituted or C _1-4 alkyl (optionally OR ¹²¹ Or substituted by one substituent independently selected from OR ¹⁹ (eg, the substituent is on the same ring carbon atom as the ring carbon atom to which A is attached to Y) Has been;
E is O or C (O) NR ⁷² ;
R ¹ is aryl or C _3-10 cycloalkyl (optionally substituted by C _1-6 alkyl, halogen or phenyl); where aryl is optionally halogen, cyano, trifluoromethyl, phenyl , OCF ₃ , OR ⁷⁸ , C _1-6 alkyl (optionally substituted by fluoro, trifluoromethyl, OR ⁹³ or NR ⁹⁴ R ⁹⁵ ) or C _1-6 alkoxy (optionally fluoro, trifluoromethyl, OR ¹⁰³ or substituted by NR ¹⁰⁴ R ¹⁰⁵ (eg R ¹ is phenyl (optionally substituted by halogen, C _1-4 alkyl or phenyl) or C _3-10 cycloalkyl ( Optionally substituted by phenyl)};
Z is a bond and R ¹ is

(R ¹ is optionally substituted), E may also be C (O);
^{R 19, R 27, R 28} , R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R 40, R 41, R 42 , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , R ⁵⁵ , R ⁵⁶ , R ⁷² , R ⁷⁸ , R ⁹³ , R ⁹⁴ , R ⁹⁵ , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ and R ¹²¹ are independently hydrogen or C _1-6 alkyl,
Provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Examples of compounds of the present invention are given below. Each compound or pharmaceutically acceptable salt thereof represents one embodiment of the present invention. Accordingly, the present invention further provides the following compounds:
8-hydroxy-5-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline-2 (1H ) -On;
8-hydroxy-5-{(1R) -1-hydroxy-2-[(trans-4-{[2- (2-phenylethoxy) ethyl] amino} cyclohexyl) amino] ethyl} quinoline-2 (1H)- on;
8-hydroxy-4-[(1R) -1-hydroxy-2-({1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} amino) ethyl] quinolin-2 (1H) -one ;
8-hydroxy-4-[(1R) -1-hydroxy-2-({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} amino) ethyl] quinolin-2 (1H) -one ;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -one;

N-benzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl ) Propanamide;
N-benzyl-3- [4-({[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} methyl) piperidine- 1-yl] propanamide;
5-[(1R) -2-({1- [3- (3,4-dihydroisoquinolin-2 (1H) -yl) -3-oxopropyl] piperidin-4-yl} amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-phenylethyl) propanamide;
N- (2-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-methoxybenzyl) propanamide;
N- (4-cyanobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
N- (2-hydroxybenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -one;
4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} -1,3- Benzothiazol-2 (3H) -one;
4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [3- (2-phenylethoxy) propyl] azetidin-3-yl} methyl) amino] ethyl} -1,3- Benzothiazol-2 (3H) -one;
4-hydroxy-7-{(1R) -1-hydroxy-2-[(2- {1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} ethyl) amino] ethyl} -1, 3-benzothiazol-2 (3H) -one;
4-hydroxy-7- {1-hydroxy-2- [1- (2-phenethyloxy-ethyl) -piperidin-4-ylamino] -ethyl} -3H-benzothiazol-2-one;
4-hydroxy-7-((1R) -1-hydroxy-2-{[(3R) -1- (2-phenethyloxy-ethyl) -piperidin-3-ylmethyl] -amino} -ethyl) -3H-benzo Thiazol-2-one;
4-hydroxy-7-((1R) -1-hydroxy-2-{[(3R) -1- (2-phenethyloxy-ethyl) -piperidin-3-ylmethyl] -amino} -ethyl) -3H-benzo Thiazol-2-one;

5-{(1R) -2-[({1- [3- (benzyloxy) propyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8-hydroxyquinoline-2 (1H) -on;
5-{(1R) -2-[({1- [2- (benzyloxy) ethyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8-hydroxyquinoline-2 (1H) -on;
N- (2,5-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
N- (biphenyl-2-ylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide;
N- (2,6-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
N- (cyclohexylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine- 1-yl) propanamide;
N- (2-chloro-6-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(1R, 2S) -2-phenylcyclopropyl] propanamide;
N- (4-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
N- (3-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
N- (2-chloro-6-fluorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
N- (2,3-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
N- (2-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) -N-methylpropanamide;

5-((1R) -2-{[(1- {2- [2- (3-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl)- 8-hydroxyquinolin-2 (1H) -one;
(4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) benzyl acetate;
8-Hydroxy-5-[(1R) -1-hydroxy-2-({[4-hydroxy-1- (4-phenoxybutyl) piperidin-4-yl] methyl} amino) ethyl] quinoline-2 (1H) -ON;
N-1-adamantyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Yl) propanamide;
N- (3,5-dichlorobenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4- (hydroxymethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] Ethyl} quinolin-2 (1H) -one;
2,6-dichloro-N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) ethyl] benzamide;
8-hydroxy-5-[(1R) -1-hydroxy-2-({[1- (2-{[(2S) -2-phenylpropyl] oxy} ethyl) piperidin-4-yl] methyl} amino) Ethyl] quinolin-2 (1H) -one;
5-((1R) -2-{[(1- {2- [2- (2-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl)- 8-hydroxyquinolin-2 (1H) -one;
N- (2,5-dimethylbenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino) amino } Piperidin-1-yl) propanamide;
N- (adamanta-1-ylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide;
N- (3-chloro-2-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;

3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-trifluoromethoxybenzyl) -propanamide;
N-((3-fluoro-5-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N- [2-Fluoro-3- (trifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N-((2-chloro-5-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N-((5-fluoro-2-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(2-trifluoromethyl) benzyl] propanamide;
N- (5-chloro-2-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
N- (3,5-dimethylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (3-trifluoromethoxybenzyl) propanamide;

N- (3-Chloro-2-fluorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
N-[(2-Fluoro-5-trifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N-[(5-chloro-2-fluoro) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5- Yl) ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (3-trifluoromethyl) benzylpropanamide;
N-benzhydryl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl ) Propanamide;
N, N-dibenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Yl) propanamide;
N-[(3,5-bistrifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5- Yl) ethyl] amino} piperidin-1-yl) propanamide;
N-[(biphenyl-3-yl) methyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(5,6,7,8-tetrahydronaphthalen-1-yl) methyl] propanamide;
5-((1R) -2-{[(1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-hydroxyquinolin-2 (1H) -one;

8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl) amino ] Ethyl} quinolin-2 (1H) -one;
5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl } -8-hydroxyquinolin-2 (1H) -one;
5-((1R) -2-{[(1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-hydroxyquinolin-2 (1H) -one;
5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8- Hydroxyquinolin-2 (1H) -one;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -one;
8-hydroxy-5-{(2R) -1-hydroxy-2-[(4-hydroxy-1- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethyl } Piperidin-4-ylmethyl) amino] ethyl} -1H-quinolin-2-one;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({(2S) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methyl) amino] ethyl} quinoline -2 (1H) -one; or N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] ] Amino} piperidin-1-yl) ethyl] benzenesulfonamide;
Or a pharmaceutically acceptable salt thereof.

  The present invention further provides a process for the preparation of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof. A suitable method is described below.

[式中、Ａｒは式(Ｉ)で定義した通りであり、フェノール基上に適当な保護基(ＰＧ^２)を有していてもいなくてもよく(下記の通り)、かつＰＧ^１は適当な保護基であって、ＰＧ^２と同一であっても異なっていてもよく、可変基は式(Ｉ)で定義した通りである。]の化合物を、式(III)：

の化合物と、適当な還元剤、有機酸および溶媒の存在下、有機合成における還元的アミノ化として知られる条件下で反応させること。本明細書で保護された官能基または保護基と記載しているとき、該保護基は官能基の性質に従って選択されてもよく、例えば“Protective Groups in Organic Synthesis”, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc, 3^rd Edition, 1999 に記載されたものであり、保護基を水素によって置き換える方法も、そこに記載されている。 Method 1
a) Formula (II):

[Wherein Ar is as defined in formula (I), and may or may not have an appropriate protecting group (PG ² ) on the phenol group (as described below), and PG ¹ is appropriate And may be the same as or different from PG ² and the variable groups are as defined in formula (I). A compound of formula (III):

Is reacted in the presence of a suitable reducing agent, organic acid and solvent under conditions known as reductive amination in organic synthesis. When described herein as a protected functional group or protecting group, the protecting group may be selected according to the nature of the functional group, eg, “Protective Groups in Organic Synthesis”, TW Greene and PGM Wuts, John ^{Wiley & Sons Inc, 3 rd Edition} , has been described in 1999, a method of replacing a protecting group by hydrogen is also described therein.

Examples of suitable protecting groups PG ¹ are, tert- butyldimethylsilyl, tert- butyl - including butyldiphenylsilyl, methyl diphenyl silyl, tetrahydropyranyl, trimethylsilyl ethoxymethyl, phenyloxymethyl, methyloxymethyl, a benzyloxymethyl. For example, tert-butyldimethyl-silyl is used. Examples of suitable protecting groups for PG ² include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl. In one embodiment of the invention PG ² is benzyl.

Examples of suitable reducing agents include hydrogen in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride or a suitable catalyst (eg palladium / carbon or palladium oxide) and suitable organic acids (eg C _1-6 aliphatic carboxylic acid) is used in the absence or presence. For example, sodium triacetoxyborohydride is used in the presence of acetic acid.

  Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction can be carried out at a temperature between 0 ° C and 100 ° C. For example, N-methyl-2-pyrrolidinone or tetrahydrofuran is used at ambient temperature (10-30 ° C.).

[式中、Ａｒは式(Ｉ)で定義した通りである。]の化合物を、式(III)の化合物[式中、可変基は式(Ｉ)で定義した通りである。]と、適当な還元剤、有機酸および溶媒の存在下で、反応させること。 b) Formula (IV):

[Wherein Ar is as defined in formula (I). A compound of formula (III) wherein the variable groups are as defined in formula (I). In the presence of a suitable reducing agent, organic acid and solvent.

Examples of suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride and are used in the presence of a suitable organic acid (eg C _1-6 aliphatic carboxylic acid). For example, sodium triacetoxyborohydride is used in the presence of acetic acid.

  Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction can be carried out at a temperature between 0 ° C. and 100 ° C. For example, N-methyl-2-pyrrolidinone is used at ambient temperature (10-30 ° C.).

の化合物と、適当な溶媒中で反応させ、ＡがＯＲ^１９(ここで、Ｒ^１９が水素である。)によって置換されている式(Ｉ)の化合物を得る。 c) Compound of formula (II) or (IV) [wherein Ar is defined by formula (I) and may or may not have a suitable protecting group (PG ² ) on the phenol group. (As above). A compound of formula (XXV):

And a compound of formula (I) in which A is replaced by OR ¹⁹ (where R ¹⁹ is hydrogen).

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme, diglyme Alcohols such as methanol, ethanol, isopropanol, tert-butanol or isobutanol. The method can be performed between 25 ° C and 150 ° C. For example, the method is performed at 50-90 ° C. in methanol or ethanol.

適当な触媒の例は、ヨウ化リチウム、ヨウ化ナトリウム、ヨウ化カリウム、またはヨウ化 トリ−ｎ−ブチルアンモニウムを含む。例えばヨウ化カリウムが所望により用いられる。
Ｌはハロゲンであり、例えば塩素または臭素である。例えば臭素が用いられる。 Method 2
Compound of formula (V) wherein Ar is as defined in formula (I) and has a suitable protecting group (PG ² ) on the phenol group (as described above). A compound of formula (VI) wherein PG ¹ is a suitable protecting group which may be the same as or different from PG ² and the variables are as defined in formula (I) , L is halogen. And in the presence of a suitable base and solvent (optionally a catalyst such as an alkali metal iodide or trialkonium iodide may be used).

Examples of suitable catalysts include lithium iodide, sodium iodide, potassium iodide, or tri-n-butylammonium iodide. For example, potassium iodide is used as desired.
L is a halogen such as chlorine or bromine. For example, bromine is used.

Examples of suitable protecting groups for PG ¹ include tert-butyldimethylsilyl, tert-butyl-diphenylsilyl, methyldiphenylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl or benzyloxymethyl. For example, tert-butyldimethylsilyl is used.
Examples of suitable protecting groups for PG ² include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl. For example, benzyl is used.

  Examples of suitable bases are trialkylamines such as triethylamine or N, N-diisopropylethylamine, 2,6-lutidine, or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or alkali carbonates Metal salts or alkali metal bicarbonate salts (wherein the alkali metal is, for example, Li, Na, K or Cs). For example, sodium bicarbonate is used.

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme. including. The method can be performed between 25 ° C and 150 ° C. For example, the process is performed at 65-145 ° C. in dimethyl sulfoxide.

[式中、Ａｒは、式(Ｉ)で定義した通りであり、フェノール基上に適当な保護基(ＰＧ^２)を有する。]の化合物を、式(VI)の化合物と、適当な塩基および適当な溶媒の存在下で、反応させること。 Method 3
Formula (VII):

[Wherein Ar is as defined in formula (I) and has a suitable protecting group (PG ² ) on the phenol group. And a compound of formula (VI) in the presence of a suitable base and a suitable solvent.

Examples of suitable protecting groups for PG ² include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl. For example, benzyl is used.

  Examples of suitable bases are trialkylamines such as triethylamine or N, N-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or alkali metal carbonates or bicarbonates of bicarbonate ( Here, the alkali metal includes, for example, Li, Na, K, or Cs.

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme. including. The process is performed between 25 ° C and 150 ° C. For example, the process is carried out at 90-145 ° C. in dimethyl sulfoxide.

式(XVII)の化合物[式中、Ａｒは式(Ｉ)で定義した通りであり、フェノール基上に適当な保護基(ＰＧ^２)を有していてもいなくてもよい(上記の通り)。]を、式(XVIII)の化合物と反応させ、ＥがＣ(Ｏ)ＮＲ^７２である式(Ｉ)の化合物を得るか、あるいは、式(XIX)の化合物と反応させ、Ｚが結合であり、ＥがＣ(Ｏ)であり、Ｒ^１が、

から選択される、式(Ｉ)の化合物を得る。ここで、ＰＧ^１は、適当な保護基または水素であって、ＰＧ^２と同一であっても異なっていてもよく、可変基は、式(Ｉ)で定義した通りである。 Method 4

Compound of formula (XVII) wherein Ar is as defined in formula (I) and may or may not have a suitable protecting group (PG ² ) on the phenol group (as described above) . Is reacted with a compound of formula (XVIII) to obtain a compound of formula (I) where E is C (O) NR ⁷² , or reacted with a compound of formula (XIX) , E is C (O), and R ¹ is

To obtain a compound of formula (I) selected from Where PG ¹ is a suitable protecting group or hydrogen and may be the same as or different from PG ² and the variable groups are as defined in formula (I).

The reaction is carried out in the presence of a suitable activated coupling agent, a suitable base and a suitable solvent.
Examples of suitable activated coupling agents are carbonyldiimidazole or O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), Or a mixture of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. For example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) is used.

  Examples of suitable bases include trialkylamines such as triethylamine or N, N-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine). For example, triethylamine is used.

  Examples of suitable solvents are N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme, or chlorine A solvating solvent such as dichloromethane or chloroform. The method can be performed between 0 ° C and 60 ° C. For example, the process is performed in N, N-dimethylformamide at ambient temperature (10-30 ° C.).

Examples of suitable protecting groups for PG ¹ include tert-butyldimethylsilyl, tert-butyl-diphenylsilyl, methyldiphenylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl or benzyloxymethyl. For example, tert-butyldimethylsilyl is used.

Examples of suitable protecting groups for PG ² include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl. For example, benzyl is used.

Preparation of intermediates (II), (III), (IV), (V), (VI), (VII), (XVII), (XX), (XXI), (XXII) and (XXV):
A compound of formula (II) may be prepared by reacting a compound of formula (V) with a suitable nitrogen nucleophile in the presence (or absence) of a suitable base and solvent followed by reduction. . Here, PG ¹ and PG ² are the appropriate protecting groups described above.

  Examples of suitable nucleophiles include metal azide salts such as lithium azide, sodium azide or potassium azide.

  Examples of suitable bases are trialkylamines such as triethylamine or N, N-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine), or alkali metal carbonates or alkali metal bicarbonates. Salt (wherein the alkali metal is, for example, Li, Na, K or Cs).

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylamides, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and Contains diglyme. The reaction can be performed between 25 ° C and 100 ° C. For example, the process is performed at 40-60 ° C. in N, N-dimethylformamide as solvent using sodium azide as the nucleophile.

  Examples of suitable reducing agents include hydrogen gas in the presence of a suitable catalyst and solvent, or triphenylphosphine in the presence of water. For example, hydrogen gas is used at ambient temperature (10-30 ° C.) in a mixture of tetrahydrofuran and ethanol in the presence of 10% palladium / charcoal.

[式中、可変基は式(Ｉ)で定義した通りである。]の化合物を、適当な酸化剤の使用によって、酸化することによって製造され得る。例えばクロロクロム酸ピリジニウムまたはDess-Martin ペルヨージナンを、有機溶媒(例えばジクロロメタン)中、環境温度(１０〜３０℃)で用いる。当業者に既知の他の酸化方法、例えば Synthesis, 1981, 3, 165 に記載されたSwern酸化も用いられ得る。 The compound of formula (III) is represented by formula (VIII):

[Wherein the variable groups are as defined in formula (I). Can be prepared by oxidation by the use of a suitable oxidizing agent. For example, pyridinium chlorochromate or Dess-Martin periodinane is used at ambient temperature (10-30 ° C.) in an organic solvent (eg dichloromethane). Other oxidation methods known to those skilled in the art can also be used, such as the Swern oxidation described in Synthesis, 1981, 3 , 165.

の化合物を、環窒素原子または環外窒素原子を介して、式(Ｘ)：

[式中、可変基は、式(Ｉ)で定義した通りである。]の化合物と、適当な還元剤、有機酸および溶媒の存在下で反応させ、続いてカルボニル保護基(ＰＧ^３)を脱保護することによって製造され得る。 Alternatively, the compound of formula (III) is of formula (IX):

A compound of formula (X): via a ring nitrogen atom or an exocyclic nitrogen atom:

[Wherein the variable groups are as defined in formula (I). And the compound in the presence of a suitable reducing agent, organic acid and solvent followed by deprotection of the carbonyl protecting group (PG ³ ).

Examples of suitable protecting groups (PG ³ ) include alkyl / cyclic acetals or ketals. For example, ketals derived from ethylene glycol are used.
Examples of suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a suitable organic acid (eg C _1-6 aliphatic carboxylic acid). For example, sodium triacetoxyborohydride is used in the presence of acetic acid.

  Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction can be performed between 0 ° C. and 100 ° C. For example, tetrahydrofuran is used at ambient temperature (10-30 ° C.).

[式中、Ｌは、脱離基(例えばヒドロキシルまたはハロゲン、例えば塩素)であり、可変基は式(Ｉ)で定義した通りである。]の化合物と反応させ、次に還元し、そして脱保護することによって製造され得る。Ｌがヒドロキシルであるとき、該反応は、活性化剤(例えばカルボニルジイミダゾールまたはＯ−(７−アザベンゾトリアゾール−１−イル)−Ｎ,Ｎ,Ｎ',Ｎ'−テトラメチルウロニウム ヘキサフルオロホスフェート(ＨＡＴＵ))の存在下、有機溶媒(例えばＮ,Ｎ−ジメチルホルムアミドまたはジクロロメタン)中、例えば０℃から６０℃の範囲の温度で、簡便に行われる。Ｌが塩素であるとき、該反応は、塩基(例えばトリエチルアミンまたはＮ,Ｎ−ジイソプロピルエチルアミン)の存在下、有機溶媒(例えばジクロロメタンまたはテトラヒドロフラン)中、例えば０℃から２５℃の範囲の温度で、簡便に行われる。後続の還元剤の例は、ボラン−ＴＨＦ錯体、水素化リチウムアルミニウムまたは水素化ジイソブチルアルミニウムを含み、適当な溶媒(例えばテトラヒドロフラン、２−メチルテトラヒドロフラン、１,４−ジオキサン、グライムおよびジグライム)中、例えば、０℃から６０℃の範囲の温度で使用される。 Alternatively, the compound of formula (III) is the same as the compound of formula (IX):

[Wherein L is a leaving group (for example, hydroxyl or halogen, for example chlorine), and the variable group is as defined in formula (I)). And then reduced and deprotected. When L is hydroxyl, the reaction is activated by an activator (eg carbonyldiimidazole or O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluoro It is conveniently carried out in an organic solvent (for example N, N-dimethylformamide or dichloromethane) in the presence of phosphate (HATU), for example at a temperature in the range from 0 ° C. to 60 ° C. When L is chlorine, the reaction is conveniently carried out in the presence of a base (eg triethylamine or N, N-diisopropylethylamine) in an organic solvent (eg dichloromethane or tetrahydrofuran), for example at a temperature in the range from 0 ° C. to 25 ° C. To be done. Examples of subsequent reducing agents include borane-THF complex, lithium aluminum hydride or diisobutylaluminum hydride and in a suitable solvent (eg tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme), for example Used at temperatures ranging from 0 ° C to 60 ° C.

の化合物を、環窒素原子または環外窒素原子を介して、式(Ｘ)の化合物と、適当な還元剤、有機酸および溶媒の存在下で反応させ、続いてカルボニル保護基を脱保護することによって製造され得る。ここで、ＸおよびＡは、式(Ｉ)で定義した通りである。 The compound of formula (VIII) is represented by formula (XI):

Reacting a compound of formula (X) with a compound of formula (X) via a ring nitrogen atom or an exocyclic nitrogen atom in the presence of a suitable reducing agent, organic acid and solvent, followed by deprotection of the carbonyl protecting group. Can be manufactured. Here, X and A are as defined in formula (I).

Examples of suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride and are used in the presence of a suitable organic acid (eg C _1-6 aliphatic carboxylic acid). For example, sodium triacetoxyborohydride is used in the presence of acetic acid.

  Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction can be performed between 0 ° C. and 100 ° C. For example, tetrahydrofuran is used at ambient temperature (10-30 ° C.).

  Alternatively, a compound of formula (VIII) can be prepared by reacting a compound of formula (XI) with a compound of formula (XII) followed by reduction and deprotection. Here, L is a leaving group (for example, hydroxyl or halogen, for example chlorine), and the variable group is as defined in formula (I). When L is hydroxyl, the reaction is activated by an activator (eg carbonyldiimidazole or O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluoro It is conveniently carried out in an organic solvent (eg N, N-dimethylformamide or dichloromethane) in the presence of phosphate (HATU), for example at a temperature in the range from 0 ° C. to 60 ° C. When L is chlorine, the reaction is conveniently carried out in the presence of a base (eg triethylamine or N, N-diisopropylethylamine) in an organic solvent (eg dichloromethane or tetrahydrofuran), for example at a temperature ranging from 0 ° C. to 25 ° C. To be done. Examples of subsequent reducing agents include borane-THF complex, lithium aluminum hydride or diisobutylaluminum hydride and in a suitable solvent (eg tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme), for example Used at temperatures ranging from 0 ° C to 60 ° C.

A compound of formula (VI) can be prepared from a compound of formula (III) by reacting with a suitable source of ammonia (eg ammonium chloride) in the presence of a suitable reducing agent, organic acid and solvent. Examples of suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride and are used in the presence of a suitable organic acid (eg C _1-6 aliphatic carboxylic acid). For example, sodium cyanoborohydride is used in the presence of acetic acid. Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of the reaction can be performed between 0 ° C and 100 ° C. For example, tetrahydrofuran is used at ambient temperature (0 ° C. to 30 ° C.).

の化合物を、環窒素原子または環外窒素原子を介して、式(Ｘ)の化合物と、適当な還元剤、有機酸および溶媒の存在下で反応させ、続いてアミン保護基を除去することによって製造され得る。ここで、可変基は、式(Ｉ)で定義した通りである。 Alternatively, the compound of formula (VI) is of formula (XIII):

By reacting a compound of formula (X) via a ring nitrogen atom or an exocyclic nitrogen atom in the presence of a suitable reducing agent, organic acid and solvent, followed by removal of the amine protecting group. Can be manufactured. Here, the variable group is as defined in formula (I).

Examples of suitable amine protecting groups (PG ⁴⁾ comprises tert- butyloxycarbonyl, benzyloxycarbonyl, trifluoromethyl carbonyl or phthalimido. For example, tert-butyloxycarbonyl is used.

Examples of suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride and are used in the presence of a suitable organic acid (eg C _1-6 aliphatic carboxylic acid). For example, sodium triacetoxyborohydride is used in the presence of acetic acid. Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of the reaction can be performed between 0 ° C and 100 ° C. For example, tetrahydrofuran is used at ambient temperature (0 ° C. to 30 ° C.).

  Alternatively, a compound of formula (VI) can be prepared by reacting a compound of formula (XIII) with a compound of formula (XII), followed by reduction and deprotection. Here, L is a leaving group (for example, hydroxyl or halogen, for example chlorine), and the variable group is as defined in formula (I). When L is hydroxyl, the reaction is activated by an activator (eg carbonyldiimidazole or O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluoro It is conveniently carried out in an organic solvent (eg N, N-dimethylformamide or dichloromethane) in the presence of phosphate (HATU), for example at a temperature in the range from 0 ° C. to 60 ° C. When L is chlorine, the reaction is conveniently carried out in the presence of a base (eg triethylamine or N, N-diisopropylethylamine) in an organic solvent (eg dichloromethane or tetrahydrofuran), for example at a temperature ranging from 0 ° C. to 25 ° C. To be done. Examples of subsequent reducing agents include borane-THF complex, lithium aluminum hydride or diisobutylaluminum hydride and in a suitable solvent (eg tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme), for example Used at temperatures ranging from 0 ° C to 60 ° C.

[式中、Ｌは、脱離基(例えばメシレート、トシレート、トリフレートまたはハロゲン、例えば塩素)であり、可変基は式(Ｉ)で定義した通りである。]の化合物と反応させることによって製造され得る。例えば、ここで、Ｌは、トシレートである。該反応は、塩基、例えばトリアルキルアミン類、例えばトリエチルアミンまたはＮ,Ｎ−ジイソプロピルエチルアミンまたはピリジン(所望により触媒、例えば４−ジメチルアミノピリジンの存在下)、または炭酸アルカリ金属塩または重炭酸アルカリ金属塩(ここで、アルカリ金属は、例えば、Ｌｉ、Ｎａ、ＫまたはＣｓである。)および適当な溶媒の存在下で、簡便に行われる。 Alternatively, the compounds of formulas (III), (VIII) and (VI) are converted to the corresponding compounds (IX), (XI) and (XIII) of formula (XIV):

[Wherein L is a leaving group (eg mesylate, tosylate, triflate or halogen, eg chlorine), and the variable group is as defined in formula (I)). It can be produced by reacting with a compound of For example, here, L is tosylate. The reaction may be carried out using a base such as a trialkylamine such as triethylamine or N, N-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine), or an alkali metal carbonate or bicarbonate. (Wherein the alkali metal is, for example, Li, Na, K or Cs) and is conveniently carried out in the presence of a suitable solvent.

  Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of the reaction can be performed between 0 ° C and 100 ° C. For example, triethylamine is used at 85 ° C. in N-methyl-2-pyrrolidinone.

の化合物を、適当な窒素求核剤と、適当な塩基および溶媒の存在下で反応させ、続いて還元することによって製造され得る。ここで、ＰＧ^２は、上記の適当な保護基である。 Compound of formula (IV) [wherein Ar is as defined in formula (I) and has a suitable protecting group (PG ² ) on the phenol group. ] Is the formula (XV):

Can be prepared by reacting with a suitable nitrogen nucleophile in the presence of a suitable base and solvent followed by reduction. Where PG ² is a suitable protecting group as described above.

  Examples of suitable nucleophiles include metal azide salts such as lithium azide, sodium azide or potassium azide. Examples of suitable bases are trialkylamines such as triethylamine or N, N-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or alkali metal carbonates or bicarbonates of bicarbonate ( Here, the alkali metal includes, for example, Li, Na, K, or Cs.

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. including. The temperature of the reaction can be performed between 25 ° C and 100 ° C. For example, the nucleophile is sodium azide and N, N-dimethylformamide is used as a solvent at 50 ° C. (eg, 40 ° C. to 60 ° C.).

  Examples of suitable reducing agents include hydrogen gas in the presence of a suitable catalyst and solvent, or triphenylphosphine in the presence of water. For example, hydrogen gas is used at ambient temperature (10 ° C. to 30 ° C.) in a mixture of tetrahydrofuran and ethanol in the presence of 10% palladium / charcoal.

Compound of formula (V) [wherein Ar is as defined in formula (I) and has a suitable protecting group (PG ² ) on the phenol group. ] In the presence of a compound capable of acting as a suitable protecting group (PG ¹ ) (eg tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl triflate) and a suitable base and solvent It can be produced by reacting under. For example, tert-butyldimethylsilyl triflate is used.

  Examples of suitable bases include trialkylamines such as triethylamine, N, N-diisopropylethylamine, 2,6-lutidine or pyridine (optionally in the presence of a catalyst such as imidazole or 4-dimethylaminopyridine). For example, 2,6-lutidine is used.

  Examples of suitable solvents include N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction may be performed at a temperature between 25 ° C and 100 ° C. For example, N, N-dimethylformamide is used at ambient temperature (10 ° C. to 30 ° C.).

[式中、Ｌはハロゲンである。]の化合物を、適当な還元剤(例えばボラン−ＴＨＦ錯体)と、溶媒中で反応させ、アキラルな化合物を得るか、または、適当なキラル還元剤と、適当な溶媒中で反応させ、単一のエナンチオマー化合物を得ることによって製造され得る。 Compound of formula (XV) wherein Ar is as defined in formula (I) and has a suitable protecting group (PG ² ) on the phenol group. ] Is the formula (XVI):

[Wherein L is halogen. To obtain an achiral compound by reacting with an appropriate reducing agent (for example, borane-THF complex) in a solvent, or reacting with an appropriate chiral reducing agent in an appropriate solvent. Can be prepared by obtaining the enantiomeric compounds of

  Examples of suitable chiral reducing agents include (1R, 2S)-(+)-cis-1-amino-2-indanol or (R)-(+)-2-methyl-CBS-oxaazaborolidine Used in the presence of a reducing agent (eg borane-tetrahydrofuran complex). Suitable solvents include ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction can be carried out at a temperature between −30 ° C. and + 30 ° C. For example, (R)-(+)-2-methyl-CBS-oxaazaborolidine is used as a catalyst together with a reducing agent borane-THF complex in tetrahydrofuran at −10 ° C.

The compound of formula (VII) is obtained from the compound of formula (XV) in the presence of a suitable base and solvent. Where L is a halogen and PG ² is a suitable protecting group as described above. Examples of suitable bases include alkali metal carbonates or bicarbonates such as carbonates of Li, Na, K or Cs. Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylamides, N-methyl-2-pyrrolidinone, butyronitrile, 2-butanone, water, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1, Contains 4-dioxane, glyme and diglyme. The reaction can be carried out at a temperature between 25 ° C and 125 ° C. For example, potassium carbonate is used under reflux in butanone and water as a solvent.

  The compound of formula (XXV) is obtained by converting a compound of formula (III) into a sulfur ylide such as trimethylsulfonium methylide or trimethylsulfoxonium methylide (trimethylsulfonium iodide or trimethylsulfoxonium iodide and a base such as sodium hydride or Prepared by reacting with potassium tert-butoxide or sodium tert-butoxide in a solvent (eg dimethyl sulfoxide and / or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme) Can be done. The reaction can be performed at a temperature in the range of −10 to 100 ° C. For example, trimethylsulfoxonium iodide is used with sodium hydride in a mixture of dimethylsulfoxide and tetrahydrofuran at ambient temperature.

[式中、ＰＧ^５およびＰＧ^１は上記の適当な保護基または水素である。]の化合物から、適当な酸または塩基および適当な溶媒の存在下で製造され得る。 Compound of formula (XVII) wherein Ar is as defined in formula (I) and may or may not have a suitable protecting group (PG ² ) on the phenol group (above Street). ] Is the formula (XX):

[Wherein PG ⁵ and PG ¹ are the above-mentioned suitable protecting groups or hydrogen. Can be prepared from the compound in the presence of a suitable acid or base and a suitable solvent.

Examples of suitable protecting groups for PG ¹ include tert-butyldimethylsilyl, tert-butyl-diphenylsilyl, methyldiphenylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl or benzyloxymethyl. For example, tert-butyldimethylsilyl is used.

Examples of suitable protecting groups for PG ⁵ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl. For example, tert-butyl is used.

Examples of suitable acids and bases include trifluoroacetic acid, hydrochloric acid, alkali metal hydroxide salts. Examples of suitable solvents include dichloromethane, methanol, trifluoroacetic acid, tetrahydrofuran, and water. The reaction can be carried out at a temperature between 0 ° C. and 60 ° C. For example, when PG ⁵ is tert-butyl, trifluoroacetic acid is used in trifluoroacetic acid as a solvent at ambient temperature (10 ° C. to 30 ° C.).

の化合物を、式(II)または(IV)の化合物とを、適当な還元剤、酸および溶媒の存在下で反応させることにより製造され得る。 The compound of formula (XX) is represented by formula (XXI):

Can be prepared by reacting a compound of formula (II) or (IV) in the presence of a suitable reducing agent, acid and solvent.

Examples of suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride, or hydrogen in the presence of a suitable catalyst (eg palladium / carbon or palladium oxide), and suitable organic acids (eg C _1-6 aliphatic carboxylic acid) is used in the absence or presence. For example, sodium triacetoxyborohydride is used in the presence of acetic acid.

  Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction can be carried out at a temperature between 0 ° C. and 100 ° C. For example, N-methyl-2-pyrrolidinone or tetrahydrofuran is used at ambient temperature (10-30 ° C.).

の化合物を、式(Ｖ)の化合物と、適当な塩基および溶媒の存在下(所望により触媒(例えばヨウ化アルカリ金属塩またはヨウ化トリアルコニウム)を用いてもよい)、反応させることにより製造され得る。 Alternatively, the compound of formula (XX) is of formula (XXII):

By reacting the compound of formula (V) with a compound of the formula (V) in the presence of a suitable base and a solvent (optionally using a catalyst (for example, an alkali metal iodide salt or trialkonium iodide)). Can be done.

  Examples of suitable catalysts include lithium iodide, sodium iodide, potassium iodide or tri-n-butylammonium iodide. For example, potassium iodide is used.

  Examples of suitable bases are trialkylamines such as triethylamine or N, N-diisopropylethylamine, 2,6-lutidine, or pyridine (optionally in the presence of a catalyst (eg 4-dimethylaminopyridine)) or alkali carbonates Metal salts or alkali metal bicarbonate salts (wherein the alkali metal is, for example, Li, Na, K or Cs). For example, sodium bicarbonate is used.

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme. including. The method can be performed between 25 ° C and 150 ° C. For example, the process is carried out in dimethyl sulfoxide at 65-145 ° C.

ここで、Ｌは、脱離基(例えばハロゲン、例えばＣｌ、Ｂｒ、Ｉ)である。例えばＬが塩素および臭素である化合物を用いる。 A compound of formula (XXI) can be prepared by reacting a compound of formula (XXIII) with a compound of formula (XXIV) in the presence of a suitable base and solvent.

Here, L is a leaving group (for example, halogen, for example, Cl, Br, I). For example, a compound in which L is chlorine and bromine is used.

  Examples of suitable bases are trialkylamines such as triethylamine or N, N-diisopropylethylamine or pyridine or 1,5-diazabicyclo [5.4.0] undec-5-ene (optionally a catalyst such as 4-dimethyl In the presence of aminopyridine), or alkali metal carbonates or bicarbonates (wherein the alkali metal is, for example, Li, Na, K or Cs). For example, triethylamine is used.

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, chloroform, dichloromethane and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, Contains glyme or diglyme. The method can be performed between 25 ° C and 150 ° C. For example, the process is carried out in chloroform at reflux.

  A compound of formula (XXII) can be prepared by reacting a compound of formula (XIII) with a compound of formula (XXIV) in the presence of a suitable base and solvent followed by removal of the amine protecting group.

  Examples of suitable bases are trialkylamines such as triethylamine or N, N-diisopropylethylamine or pyridine or 1,5-diazabicyclo [5.4.0] undec-5-ene (optionally a catalyst such as 4-dimethyl In the presence of aminopyridine), or alkali metal carbonates or bicarbonates (wherein the alkali metal is, for example, Li, Na, K or Cs). For example, triethylamine is used.

  Examples of suitable solvents are dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, chloroform, dichloromethane and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, Contains glyme or diglyme. The method can be performed between 25 ° C and 150 ° C. For example, the process is carried out in chloroform at reflux.

  Alternatively, a compound of formula (XXII) can be prepared from a compound of formula (XXI) by reacting with a suitable ammonia source in the presence of a suitable reducing agent, acid and solvent.

  Examples of suitable ammonia generating sources include ammonia gas, ammonium chloride and ammonium acetate.

Examples of suitable reducing agents include hydrogen in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride or a suitable catalyst (eg palladium / carbon or palladium oxide) and suitable organic acids (eg C _{1 -6} aliphatic carboxylic acid) in the absence or presence. For example, sodium triacetoxyborohydride is used in the presence of acetic acid.

  Examples of suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme. The reaction can be carried out at a temperature between 0 ° C. and 100 ° C. For example, N-methyl-2-pyrrolidinone or tetrahydrofuran is used at ambient temperature (10-30 ° C.).

Compounds of formula (II) [wherein PG ¹ and PG ² are suitable protecting groups. ], (IX), (X), (XI), (XII), (XIII), (XIV), (XVI), (XVIII), (XIX), (XXIII) and (XXIV) Or can be prepared using methods known in the literature or are commercially available.

[式中、Ａｒは、

である。]の化合物、例えば上で記載した通りに製造した５−[(１Ｒ)−２−アミノ−１−ヒドロキシエチル]−８−ヒドロキシキノリン−２(１Ｈ)−オンに関する。 The present invention further provides novel chiral intermediate compounds such as formula (IV):

[Wherein Ar is

It is. For example, 5-[(1R) -2-amino-1-hydroxyethyl] -8-hydroxyquinolin-2 (1H) -one prepared as described above.

[式中、
Ａｒは、式(Ｉ)で定義した通りであり；
ＰＧ^１は、適当な保護基であり；
Ｘは、結合であり；
Ａは、Ｘに４位で結合し、かつＹにＮ結合しているピペリジニルであり；
Ｙは、(ＣＨ_２)_２であり；
ＰＧ^５は、水素または適当な保護基の何れかである。]
の中間体化合物に関する。 The present invention also further provides formula (XX):

[Where
Ar is as defined in formula (I);
PG ¹ is a suitable protecting group;
X is a bond;
A is piperidinyl bonded to X at the 4-position and N-bonded to Y;
Y is (CH ₂ ) ₂ ;
PG ⁵ is either hydrogen or a suitable protecting group. ]
To an intermediate compound.

PG ¹ is, for example, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl or methyldiphenylsilyl. In one embodiment of the invention, PG ¹ is, for example, tert-butyldimethylsilyl.

PG ⁵ is, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl or benzyl. In one embodiment of the invention PG ⁵ is for example tert-butyl.

Compounds of formula (I) can be converted to other compounds of formula (I) using standard procedures.
It will be appreciated by those skilled in the art that in the methods of the invention certain functional groups in the reaction compound, such as hydroxyl groups or amino groups, may need to be protected by a protecting group. Accordingly, the preparation of compounds of formula (I) may involve the removal of one or more protecting groups at a suitable stage.

Functional group protection and deprotection are described in 'Protective Groups in Organic Chemistry', edited by JWF McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3 ^rd edition, TW Greene and PGM Wuts, Wiley-Interscience ( 1999).

The compounds of formula (I) and their pharmaceutically acceptable salts can be used for the treatment of:
1. Respiratory:
Obstructive airway diseases including: asthma (bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (including aspirin-induced and NSAID-induced), and Including dust-induced asthma) (including both intermittent and persistent, including all severity and including other causes of airway hyperresponsiveness); chronic obstructive pulmonary disease (COPD); bronchitis ( Emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonia; pulmonary fibrosis (including fibrotic alveolitis of unknown cause) , Idiopathic interstitial pneumonia, antineoplastic therapy and fibrosis coexisting with chronic infections (including tuberculosis and aspergillosis and other fungal infections); complications of lung transplantation; vascular and thrombotic pulmonary vasculature Disease and pulmonary hyperemia Antitussive activity (including treatment of chronic and iatrogenic cough with inflammatory and secretory conditions of the respiratory tract); acute and chronic rhinitis (including drug rhinitis and vasomotor rhinitis); perennial and seasonal Allergic rhinitis (including neural rhinitis (hay fever)); nasal polyposis; acute viral infection (including common cold and respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus ); Or eosinophilic esophagitis;

2. Bones and joints:
Arthritis with or including osteoarthritis / both osteoarthritis (including both primary and secondary) (eg congenital pelvic dysplasia); cervical spondylitis and lumbar spondylitis, and back and neck pain; osteoarthritis; rheumatoid arthritis and Still disease; seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and undifferentiated spondyloarthropathy); purulent arthritis, and other infection-related arthropathy and bone abnormalities (eg Tuberculosis) (including Pott disease and Poncet's syndrome); acute and chronic crystal-induced synovitis (including urinary acid gout), calcium pyrophosphate deposition disease, and calcium apatite related tendon Inflammation of the bursa and synovium; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and localized scleroderma; systemic lupus erythematosus , Mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathy (including dermatomyositis and polymyositis); polymyalgia rheumatic; juvenile arthritis (idiopathic inflammatory arthritis (joint location and Rheumatic fever and its systemic complications; vasculitis (giant cell arteritis, Takayasu arteritis, Churg-Strauss syndrome, nodular polyarteritis, microscopic multiple) Arteritis (including microscopic polyarteritis and vasculitis associated with viral infection), hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; familial Mediterranean fever, Muckle-Wells syndrome, and familial Irish fever, Kikuchi disease Drug-induced joint pain, tendonititides and muscle disease;

3. Connective tissue reconstruction of musculoskeletal disorders due to pain and injury (eg sports injury) or disease:
Arthritis (e.g. rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint diseases (e.g. intervertebral disc degeneration or temporomandibular joint degeneration), bone remodeling diseases (e.g. osteoporosis, Paget's disease, or osteonecrosis) ), Polychondritis, scleroderma, mixed connective tissue disease, spondyloarthropathy, or periodontal disease (eg periodontitis);

4. Skin:
Psoriasis, atopic dermatitis, contact dermatitis, or other eczema skin diseases, and delayed type hypersensitivity reactions; plant and photodermatitis; seborrheic dermatitis, herpes dermatitis, lichen planus, sclerosis Atrophic lichen, pyoderma gangrenosum, cutaneous sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, hives, angioedema, vasculitis, toxic erythema, cutaneous eosinophils Alopecia areata, alopecia areata, androgenetic baldness, Sweet syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis (including both infectious and non-infectious); subcutaneous lipohistitis; cutaneous lymphoma, non Melanoma skin cancer and other dysplastic lesions; drug-induced diseases (including specific drug eruptions);

5. Eye:
Conjunctivitis (including perennial and spring allergic conjunctivitis); irisitis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disease affecting the retina; ophthalmitis (sympathetic nerve) Sarcoidosis; infection (including viral, fungal and bacterial infections);

6. Gastroenterology:
Glossitis, gingivitis, periodontal disease; esophagitis (including reflux); eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis (including ulcerative colitis), proctitis, anal pruritus Celiac disease, irritable bowel syndrome, and food-related allergies (eg migraine, rhinitis or eczema) that develop at sites away from the intestine;

7. Abdomen:
Hepatitis (including autoimmunity, alcoholic and viral); liver fibrosis and cirrhosis; cholecystitis; pancreatitis (including both acute and chronic);

8. Urogenital:
Nephritis (including interstitial nephritis and glomerulonephritis); nephrotic syndrome; cystitis (including acute cystitis and chronic (interstitial) cystitis) and Hunner ulcer; acute and chronic urethritis, prostatitis, epididymal Somatitis, ovitis and fallopianitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (including both men and women);

9. Allograft rejection:
For example acute and chronic rejection after transplantation of the kidney, heart, liver, lung, bone marrow, skin or cornea, or after blood transfusion; or chronic graft-versus-host disease;

10. CNS:
Alzheimer's disease and other dementing diseases (including CJD and nvCJD); amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral arteriosclerosis and vasculitis; temporal arteritis; Acute and chronic pain (either acute, intermittent or persistent, central or peripheral) (including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint pain and bone pain), Pain from cancer and tumor invasion, neuropathic pain syndrome (including diabetic, postherpetic, and HIV-related neuropathy); neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune diseases;

11. Other autoimmune and allergic diseases including: Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, high IgE syndrome, Antiphospholipid antibody syndrome;

12. Other diseases with inflammatory or immunological factors, including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes;

13. Cardiology:
Atherosclerosis affecting coronary vessels and peripheral circulation; epicarditis; myocarditis, inflammatory and autoimmune cardiomyopathy (including myocardial sarcoid); ischemic reperfusion injury; endocarditis, valvitis , And aortitis (including infectious (eg syphilis)); vasculitis; proximal and peripheral venous diseases (including phlebitis and thrombosis (including deep vein thrombosis and varicose complications)) );

14. Tumor:
Prostate cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, intestinal and colon cancer, gastric cancer, skin cancer, and brain tumor, and malignant tumors that affect the bone marrow (including leukemia) and lymphoproliferative system (e.g., Hodgkin lymphoma and non-Hodgkin) Treatment of common cancers (including lymphoma), including prevention and treatment of metastatic disease and tumor recurrence and paraneoplastic syndromes;

15. Gastroenterology:
Celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn disease, ulcerative colitis, microscopic colitis, atypical enteritis (indeterminant colitis), irritable bowel disease, irritable bowel syndrome Non-inflammatory diarrhea, food-related allergies (eg migraine, rhinitis and eczema) that develop in areas away from the intestine.

The present invention therefore provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.

  As used herein, the term “treatment” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutic” should be interpreted similarly.

  Prevention is considered to be treatment for humans who have a history of the disease or condition of interest or who are otherwise considered to be at increased risk of suffering from it. A human at risk for a particular disease or condition generally includes a human with a family history of the disease or condition, or a person identified as being particularly susceptible to the disease or condition by genetic testing or screening.

  The present invention also further provides a method of treating or reducing the risk of an inflammatory disease or condition (including reversible obstructive airway disease or condition), in a patient in need of such treatment, in a therapeutically effective amount. There is provided a method comprising administering a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

  In particular, the compounds of the invention may be used for the treatment of adult respiratory distress syndrome (ARDS), emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.

  For the therapeutic uses described above, the dose administered will, of course, vary depending on the compound employed, the mode of administration, the desired treatment and the disease being indicated. For example, a daily dose of a compound of the invention can range from 0.05 μg / kg body weight to 100 μg / kg body weight if inhaled. Alternatively, if the compound is administered orally, the daily dose of the compound of the invention may range from 0.01 μg / kg body weight to 100 mg / kg body weight.

  The compounds of formula (I) and their pharmaceutically acceptable salts can be administered per se, but generally the compounds / salts (active ingredients) of formula (I) are pharmaceutically acceptable adjuvants Administered in the form of a pharmaceutical composition in combination with a diluent or carrier. Conventional procedures for the selection and manufacture of suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals-The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.

  Depending on the method of administration, the pharmaceutical composition has an activity of, for example, 0.05 to 99% w (weight percent), such as 0.05 to 80% w, such as 0.10 to 70% w, such as 0.10 to 50% w. Contains ingredients. All weight percentages are based on the total amount of the composition.

  The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

  The present invention further relates to a process for the preparation of the pharmaceutical composition of the present invention, wherein a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof is converted into a pharmaceutically acceptable adjuvant, diluent. Or a method comprising mixing with a carrier.

  The pharmaceutical compositions are topically (e.g. in the form of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols, and dry powder formulations, e.g. formulations in inhalers known as Turbuhaler®). To the skin, or to the lungs and / or the respiratory tract); or alternatively, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions. Or can be administered systemically, or subcutaneously, or by rectal administration in the form of a suppository.

Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered orally or by nasal inhalation. For inhalation, the compound is desirably finely divided. The comminuted compound has a mass median diameter of less than 10 μm, for example, and is a dispersant, for example a C ₈ -C ₂₀ fatty acid (for example oleic acid) or salts thereof, bile salts, phospholipids, alkyl saccharides, perfluorinated Alternatively, it can be suspended in the propellant mixture with the aid of a polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

  The compounds of the present invention can also be administered by a dry powder inhaler. The inhaler may be a single or multi-dose inhaler or a breath actuated dry powder inhaler.

  Finely divided compounds of the invention can also be admixed with carrier materials such as mono-, di-, or polysaccharides, sugar alcohols, or other polyols. Suitable carriers are sugars such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively, the finely divided compound can be coated with another substance. The powder mixture can also be placed in hard gelatin capsules, each containing the desired dose of the active compound.

  The finely pulverized powder can also be processed into spheres that are crushed during the inhalation process. The spheronized powder may be filled into the drug reservoir of a multi-inhaler known as, for example, Turbuhaler®, where the dosing unit measures the desired dose to be inhaled by the patient. In this system, the active ingredient is delivered to the patient with or without a carrier material.

  For oral administration, the compounds of the present invention can be adjuvanted or carriers such as lactose, sucrose, sorbitol, mannitol, starch, eg potato starch, corn starch, or amylopectin, cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; and / Or can be mixed with lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin and the like and then compressed into tablets. If coated tablets are needed, the core tablets prepared as described above can be coated with a concentrated sugar solution, which can include, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, tablets can be coated with a suitable polymer dissolved in a fast volatile organic solvent.

  For the production of soft gelatin capsules, the compounds of the invention can be mixed, for example, with vegetable oils or polyethylene glycols. Hard gelatin capsules may contain granules of the compound using any of the excipients described above for tablets. In addition, liquid gelatin formulations or semi-solid formulations of the present invention can be filled into hard gelatin capsules.

  Liquid preparations for oral application can be in the form of syrups or suspensions, for example, compounds of the present invention and the balance comprising a mixture of sugar and ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharin and / or carboxymethylcellulose as a thickening agent, or other excipients known to those skilled in the art.

  The compounds of the present invention can also be administered with another compound used to treat the above conditions.

  The invention further relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, and another therapeutic agent (s) that treats one or more of the above conditions. In combination) and is administered simultaneously or sequentially or as a combined preparation.

  In particular, to treat inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease (but not limited thereto) Can be combined with the following drugs: non-selective cyclooxygenase applied locally or systemically non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs), including COX-1 / COX-2 inhibitors (eg piroxicam, Diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen, and ibuprofen, phenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); Selective COX-2 blockage Agents (eg, meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib, and etoroxib); cyclooxygenase-inhibiting nitric oxide donors (CINOD); glucocorticosteroids (local, oral, intramuscular, intravenous, or intraarticular) Methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intraarticular therapy such as hyaluronic acid Derivatives; and nutrients such as glucosamine.

  The present invention further includes cytokines or agonists or antagonists of cytokine function (acting on cytokine signaling pathways) comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and α-, β-, and γ-interferon. Drugs, including SOCS-based modulators); type I insulin-like growth factor (IGF-1); interleukins (IL) including ILs 1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumors Necrosis factor alpha (TNF-α) inhibitors, such as anti-TNF monoclonal antibodies (eg, infliximab; adalimumab, and CDP-870), and TNF receptor antagonists including immunoglobulin molecules (eg, etanercept), and low molecular weight drugs, such as pens Toxifylline and Combination on.

  Furthermore, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof and a monoclonal antibody (eg, CD20 (rituximab), MRA-aILl6R and T lymphocyte, CTLA4-Ig, Regarding combination with HuMax Il-15).

The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof and a modulator of chemokine receptor function, such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9 Antagonists of CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5 (in the CXC family), and CX ₃ CR1 (in the CX ₃ -C family), CCR10, and CCR11 (in the C-C family) Related to the combination.

  The invention further relates to a compound of the invention or a pharmaceutically acceptable salt thereof and a matrix metalloproteinase (MMP), ie stromelysin, collagenase, and gelatinase, and aggrecanase; in particular collagenase-1 (MMP-1 ), Collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP) -11), and combinations with MMP-9 and inhibitors of MMP-12 (including agents such as doxycycline, for example).

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof, a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase activating protein (FLAP) antagonist, For example, zileuton; ABT-761; fenleuton; tepoxaline; Abbott-79175; Abbott-85761; N- (5-substituted) -thiophene-2-alkylsulfonamides; 2,6-di-tert- Butylphenol hydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; compound SB-210661; pyridinyl substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,530; indole or quinoline compounds such as Regarding combination with MK-591, MK-886, and BAY x 1005.

  The present invention further includes leukotriene (LT) B4, LTC4, LTD4, selected from the group consisting of a compound of the present invention or a pharmaceutically acceptable salt thereof and a phenothiazin-3-one, such as L-651,392. And receptor antagonists in LTE4; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast ), Montelukast, Pranlukast, verlukast (MK-679), RG-12525, Ro-245913, Iralukast (CGP 45715A), and BAY x 7195.

  The present invention further includes a phosphodiesterase (PDE) inhibitor comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and theophylline and aminophylline, such as methylxanthanine; PDE4 inhibitor, PDE4D isoform. In combination with inhibitors or selective PDE isoenzyme inhibitors including inhibitors of PDE5.

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acribastine, terfenadine, astemizole, azelastine, levocabastine, Concerning combinations with chlorpheniramine, promethazine, cyclidine, or mizolastine (applied orally, topically, or parenterally).

The invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (eg omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
The invention further relates to the combination of a compound of the invention or a pharmaceutically acceptable salt thereof and a histamine type 4 receptor antagonist.

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof and an α-1 / α-2 adrenergic receptor agonist vasoconstrictive sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine , Ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride, or ethyl norepinephrine hydrochloride.

  The present invention further includes an anticholinergic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a muscarinic receptor (M1, M2 and M3) antagonist such as atropine, hyoscine, glycopyrrolate, bromide It relates to combinations with ipratropium, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The invention further relates to the combination of a compound of the invention or a pharmaceutically acceptable salt thereof and a chromone, such as sodium cromoglycate or nedocromil sodium.
The invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof and a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, or mometasone furanate. .

  The invention further relates to the combination of a compound of the invention or a pharmaceutically acceptable salt thereof and a nuclear hormone receptor modulator, such as PPAR.

  The present invention further includes a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with an immunoglobulin (Ig) or Ig formulation or an antagonist or antibody that modulates Ig function, such as anti-IgE (eg, omalizumab) About.

  The invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and other systemically or topically applied anti-inflammatory agents such as thalidomide or derivatives thereof, retinoids, dithranol, or calcipotriol.

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof, aminosalicylates and sulfapyridines such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulators such as thiopurines, And in combination with corticosteroids such as budesonide.

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof and an antibacterial agent such as penicillin derivatives, tetracyclines, macrolides, β-lactams, fluoroquinolones, metronidazole, inhaled aminoglycosides; Antiviral agents, including famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamivir and oseltamivir; protease inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors such as didanosine, Lamivudine, stavudine, sarcitabine, or zidovudine; or in combination with a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof and a cardiovascular drug such as a calcium channel blocker, a β-adrenergic receptor blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin- 2 Receptor antagonists; antihyperlipidemic drugs such as statins or fibrates; modulators of blood cell morphology such as pentoxyphylline; thrombolytic agents, or anticoagulants such as platelet aggregation inhibitors.

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof and a CNS drug, such as an antidepressant (eg, sertraline), an antiparkinsonian drug (eg, deprenyl, L-dopa, ropinirole, pramipexole, MAOB Inhibitors such as selegiline and rasagiline), comP inhibitors (eg tasmar), A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists, or neuronal nitric oxide It relates to combinations with synthase inhibitors or anti-Alzheimer drugs (eg donepezil, rivastigmine, tacrine), COX-2 inhibitors, propentophilin, or metrifonate.

  The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof and an agent for the treatment of acute or chronic pain, such as a centrally acting or peripherally acting analgesic (eg, an opioid or a derivative thereof), It relates to a combination with carbamazepine, phenytoin, sodium valproate, amitryptiline, or other antidepressants, acetaminophen, or non-steroidal anti-inflammatory agents.

The invention further relates to the combination of a compound of the invention or a pharmaceutically acceptable salt thereof and a parenteral or topical application (including inhalation) local anesthetic such as lignocaine or a derivative thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof can also be used in combination with hormonal agents such as raloxifene, or anti-osteoporosis agents including biphosphonates such as alendronate.

The present invention further includes a compound of the present invention or a pharmaceutically acceptable salt thereof,
(i) a tryptase inhibitor;
(ii) a platelet activating factor (PAF) antagonist;
(iii) an interleukin converting enzyme (ICE) inhibitor;
(iv) an IMPDH inhibitor;
(v) an adhesion molecule inhibitor comprising a VLA-4 antagonist;
(vi) cathepsin;
(vii) kinase inhibitors, eg tyrosine kinase (eg Btk, Itk, Jak3, or MAP) inhibitors (eg gefitinib, imatinib mesylate), serine / threonine kinase inhibitors (MAP kinase (eg p38, JNK, protein kinase A , B or C, or IKK) inhibitors), or inhibitors of kinases related to cell cycle control (eg cyclin dependent kinases);
(viii) a glucose-6 phosphate dehydrogenase inhibitor;
(ix) a kinin-B.sub1- or -B.sub2-receptor antagonist;
(x) anti-gout agents such as colchicine;
(xi) xanthine oxidase inhibitors, such as allopurinol;
(xii) uric acid excretion agents such as probenecid, sulfinpyrazone or benzbromarone;
(xiii) a growth hormone secretagogue;
(xiv) transforming growth factor (TGFβ);
(xv) platelet derived growth factor (PDGF);
(xvi) a fibroblast growth factor, such as basic fibroblast growth factor (bFGF);
(xvii) granulocyte macrophage colony stimulating factor (GM-CSF);
(xviii) capsaicin cream;
(xix) tachykinin NK.sub1 or NK.sub3. receptor antagonists such as NKP-608C, SB-233412 (talnetant) or D-4418;
(xx) Elastase inhibitors, such as UT-77 or ZD-0892;
(xxi) a TNF-α converting enzyme (TACE) inhibitor;
(xxii) an inducible nitric oxide synthase (iNOS) inhibitor;
(xxiii) a chemoattractant receptor homologous molecule expressed in TH2 cells (eg, a CRTH2 antagonist);
(xxiv) a P38 inhibitor;
(xxv) Toll-like receptor (TLR) function modulator;
(xxvi) an activity modulator of purine receptors (eg, P2X7);
(xxvii) a transcription factor activation inhibitor, such as NFkB, API, or STATS; or
(xxviii) a glucocorticoid receptor agonist;
Concerning the combination.

In a further aspect, the invention provides a compound of formula (I) and a non-steroidal glucocorticoid receptor (GR receptor) agonist;
Steroids (eg budesonide or fluticasone);
A PDE4 inhibitor comprising an inhibitor of the PDE4D isoform;
Muscarinic receptor antagonists (eg M1, M2 or M3 antagonists, eg selective M3 antagonists), eg ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
A modulator of chemokine receptor function (eg a CCR1 receptor antagonist); or an inhibitor of p38 kinase function;
A combination comprising one or more drugs selected from the group comprising (for example for the treatment of COPD, asthma or allergic rhinitis) is provided.

The compounds of the present invention or pharmaceutically acceptable salts thereof can also be used in combination with existing therapeutic agents for the treatment of cancer. For example, suitable drugs include the following:
(i) for example alkylating agents (eg cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, or nitrosourea); antimetabolites (eg antifolate antimetabolites, eg fluoropyrimidine Fluorouracil or tegafur)), raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine, or paclitaxel; antitumor antibiotics (eg anthracyclines (eg adriamycin), bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mycin Dactinomycin or mithramycin); mitotic inhibitors (eg vinca alkaloids (eg vincristine), vinci Medical oncology such as lastine, vindesine or vinorelbine, or taxoids (eg taxol or taxotere); or topoisomerase inhibitors (eg epipodophyllotoxin (eg etoposide), teniposide, amsacrine, topotecan or camptothecin) Anti-proliferative / anti-tumor agents or combinations thereof used in

(ii) cytostatics such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene, or iodoxyfene), estrogen receptor downregulators (e.g. fulvestrant), anti Androgenic agents (e.g. bicalutamide, flutamide, nilutamide, or cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin or buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (Eg, as anastrozole, letrozole, vorazole, or exemestane), or a 5α-reductase inhibitor (eg, finasteride);
(iii) an agent that inhibits cancer cell invasion (eg, a metalloproteinase inhibitor (such as marimastat) or a urokinase plasminogen activator receptor function inhibitor);

(iv) inhibitors of growth factor function, eg growth factor antibodies (eg anti-erbb2 antibody trastuzumab, or anti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors, or serine / threonine kinase inhibitors Agents, inhibitors of the epidermal growth factor family (eg EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline-4- Amines (gefitinib, AZD1839), N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI 774), or 6-acrylamide-N- (3-chloro -4-fluorophenyl) -7- (3-morpholinopropoxy) quinazoli 4-amine (CI 1033)), inhibitors of inhibitors or hepatocyte growth factor family, platelet-derived growth factor family;

(v) anti-angiogenic agents (e.g. those that inhibit the effects of vascular endothelial growth factor (e.g. anti-vascular endothelial cell growth factor antibody bevacizumab, WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354) Disclosed compounds), or compounds acting by other mechanisms (eg, linomide, inhibitors of integrin αvβ3 function or angiostatin);

(vi) Vascular damaging agents (for example combretastatin A4, or compounds disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213);
(vii) agents used in antisense therapy (eg, those that are directed to one of the targets listed above (eg, ISIS 2503, anti-ras antisense));

(viii) gene therapy approaches, eg approaches that replace abnormal genes (eg abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy)) (eg cytosine deaminase, thymidine kinase, or microbial nitroreductase) And agents used in approaches that increase patient tolerance to chemotherapy or radiation therapy (eg, multidrug resistance gene therapy); or

(ix) immunotherapy approaches, eg ex vivo and in vivo approaches that increase the immunogenicity of a patient's tumor cells, eg cytokines (eg interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor) Transfection, approaches to reduce T cell anergy, approaches using transfected immune cells (eg, dendritic cells transfected with cytokines), approaches using tumor cell lines transfected with cytokines, and anti Drugs used in approaches using idiotype antibodies.

The invention is further illustrated by the description of the following examples.
General method
¹ H-NMR spectra were measured on a Varian Inova 400 MHz or Varian Mercury-VX 300 MHz instrument. Central peak of chloroform-d (δ _H 7.27 ppm), dimethyl sulfoxide-d ₆ (δ _H 2.50 ppm), acetonitrile-d ₃ (δ _H 1.95 ppm), or methanol-d ₄ (δ _H 3.31 ppm) as internal standard Used as.

The compounds of the examples were named using ACD LABS v8.0 naming software.
Column chromatography was performed using silica gel (0.040-0.063 mm, Merck). Unless otherwise noted, the starting materials were commercially available. All solvents and commercially available reagents were laboratory grade and used as purchased.

  Reversed phase high performance liquid chromatography (HPLC) purification with Waters Micromass LCZ with Waters 600 pump controller, Waters 2487 detector and Gilson FC024 fraction collector, or ACE®, Symmetry®, NovaPak® (Trademark) or Xterra® reverse phase silica column, using either a Waters Delta Prep 4000 or Gilson Auto Purification System.

The following method was used for LC / MS analysis:
Instrument Agilent 1100;
Column Waters Symmetry 2.1 × 30mm;
Mass APCI;
Flow rate 0.7 ml / min;
Wavelength 254 nm;
Solvent A: Water + 0.1% TFA; Solvent B: Acetonitrile + 0.1% TFA;
Concentration gradient 15-95% / B 8 minutes, 95% B 1 minute.

Analytical chromatography was performed on a Symmetry C ₁₈ column, 2.1 × 30 mm, 3.5 μm particle size, acetonitrile / water / 0.1% trifluoroacetic acid as mobile phase, 5% to 95% acetonitrile, with a concentration gradient of 8 minutes. At a flow rate of 0.7 ml / min.

Abbreviations or terms used in the examples have the following meanings.

Example 1
8-hydroxy-5-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline-2 (1H ) -On

i) [1- (2-Phenethyloxy-ethyl) -piperidin-4-yl] -methanol 2-phenethyloxyacetaldehyde (WO 94/27601) (0.72 g) and 4-piperidine-in methanol in methanol (20 ml) A solution of methanol (0.5 g) was treated with AcOH (20 mg) and stirred at room temperature for 30 minutes. Thereafter, sodium cyanoborohydride (103 mg) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was basified by adding aqueous concentrated NH ₃ (1 ml) and the solvent was removed under reduced pressure. The crude product was purified by column chromatography, eluting with 1% concentrated aqueous NH _{3 in} DCM and 5% ethanol to give the subtitle compound. Yield: 0.1 g.
¹ H NMR (CDCl ₃ ) δ 7.30-7.18 (m, 5H), 3.67-3.64 (m, 2H), 3.60-3.57 (m, 2H), 3.49-3.47 (m, 2H), 2.95-2.87 (m, 4H), 2.58-2.55 (m, 2H), 2.02-1.96 (m, 2H), 1.72-1.69 (m, 2H), 1.54-1.43 (m, 1H), 1.33-1.23 (m, 2H).

ii) 1- (2-Phenethyloxy-ethyl) -piperidine-4-carbaldehyde A solution of DMSO (0.136 ml) in DCM (0.5 ml) was added to oxalyl chloride (0.130 ml) in DCM (5 ml). To -78 ° C. The reaction was stirred at −78 ° C. for 15 min and the product of step (i) ([1- (2-phenethyloxy-ethyl) -piperidin-4-yl] -methanol) (0) in DCM (3 ml). .23 g) and stirred at −78 ° C. for a further 15 minutes. Triethylamine (0.53 ml) was added and the reaction was warmed to room temperature over 1 hour. The mixture was then quenched with concentrated aqueous NH ₃ and concentrated in vacuo. The crude product was azeotroped twice with toluene and used in the next step (iii) without further purification.
MS APCI + 262 [M + H] ⁺

iii) (R) -8-hydroxy-5- (1-hydroxy-2-{[1- (2-phenethyloxy-ethyl) -piperidin-4-ylmethyl] -amino} -ethyl) -1H-quinoline-2 The crude product of on- stage (ii) was dissolved in methanol (5 ml). Product of Example 5, Step (ii) [5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinoline-2 (1H)- ON (WO 2004/106333)] (0.25 g) followed by AcOH (0.043 ml). After stirring at room temperature for 2 hours, sodium cyanoborohydride (57 mg) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with concentrated aqueous NH ₃ and concentrated in vacuo. The crude material was redissolved in DCM, filtered, purified by column chromatography, eluting with 1% NH ₃ /9% methanol in DCM. Product fractions were concentrated in vacuo. The product was redissolved in THF (5 ml), treated with triethylamine trihydrofluoride (1.24 ml) and stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue was applied to an Argonaut Technologies MP-TsOH (65) resin column (1 g). The resin was washed with methanol and the product was eluted with 3M methanolic NH ₃ . The methanolic NH ₃ fraction was concentrated in vacuo and the residue was redissolved in methanol, filtered and then purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column, 0.2 Elution with a gradient of acetonitrile in% aqueous 0.880 NH ₃ gave the title compound at 20 ml / min for 6 min. Yield: 55 mg.
MS APCI + 466 [M + H] ^+
1 H NMR (CDCl ₃ , 50 ° C) δ 7.84 (s, 1H), 7.27-7.22 (m, 2H), 7.21-7.14 (m, 3H), 6.94-6.88 (m, 1H), 6.75-6.67 (m , 1H), 6.41-6.32 (m, 1H), 4.88 (s, 1H), 3.66-3.60 (m, 2H), 3.57-3.50 (m, 2H), 2.89-2.76 (m, 4H), 2.75-2.58 (m, 2H), 2.56-2.31 (m, 4H), 1.96-1.84 (m, 3H), 1.66-1.51 (m, 2H), 1.42-1.30 (m, 1H), 1.24-1.09 (m, 2H) .

Example 2
8-hydroxy-5-{(1R) -1-hydroxy-2-[(trans-4-{[2- (2-phenylethoxy) ethyl] amino} cyclohexyl) amino] ethyl} quinoline-2 (1H)- on

i) 8- (Benzyloxy) -5- (bromoacetyl) quinolin-2 (1H) -one 5-acetyl-8- (benzyloxy) quinolin-2 (1H) -one in DCM (200 ml) (WO 2005 / 123684) (18.05 g) at 0 ° C., boron trifluoride ether complex (9.2 ml) was added dropwise over 15 minutes, then the mixture was warmed to room temperature and concentrated yellow suspension A liquid was formed. The mixture was heated at 40 ° C. and a solution of bromine (3.4 ml) in DCM (100 ml) was added slowly over 40 minutes. After an additional 15 minutes, the mixture was allowed to reach room temperature and then removed on a rotary evaporator to remove volatile materials. The residue was triturated with excess 10% aqueous sodium carbonate for 1 hour. The gummy solid was collected by filtration, further washed with H ₂ O, and the solid was dried in vacuo at 40 ° C. overnight. The solid was further purified by washing with 1: 1 DCM / methanol solution and filtered, then dried in vacuo at 40 ° C. to give the subtitle compound as an off-white solid. Yield: 14.5g.
MS APCI + 372/374 [M + H] ⁺

ii) 8- (benzyloxy) -5-[(1R) -2-bromo-1-hydroxyethyl] quinolin-2 (1H) -one product of step (i) (8- (benzyloxy) -5- (Bromoacetyl) quinolin-2 (1H) -one) (5.0 g) was placed in an oven-dried flask and dried under vacuum at 40 ° C. for 2 days, followed by the addition of dry THF (100 ml). (R)-(+)-2-Methyl-CBS-oxazaborolidine (2.20 ml, 1.0 M in toluene) was added and the mixture was cooled to −10 ° C. Borane-THF complex (16.2 ml, 1.0 M) was added using a syringe pump over 3.5 hours. The reaction mixture was stirred at −10 to 0 ° C. for 1 hour. Methanol (100 ml) was added and volatiles were removed in vacuo and then azeotroped with methanol (x3). The residue was dissolved in boiling acetonitrile (140 ml), allowed to cool slowly and filtered to give the subtitle compound as a pale yellow solid. Yield: 3.8g.
MS APCI + 374/376 [M + H] ⁺

iii) 8- (Benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) quinolin-2 (1H) -one in DMF (4 ml) Stir a solution of the product of step (ii) (8- (benzyloxy) -5-[(1R) -2-bromo-1-hydroxyethyl] quinolin-2 (1H) -one) (1.00 g). Cooled to 0 ° C., 2,6-lutidine (0.622 ml) was added dropwise thereto, followed by tert-butyldimethylsilyl triflate (1.23 ml). The reaction mixture was stirred at room temperature overnight and then the volatiles were partially evaporated. The residue was dissolved in EtOAc and washed with H ₂ O, 2M aqueous HCl, H ₂ O, and saturated aqueous NaCl. The organics were collected, dried (Na ₂ SO ₄ ) and volatiles were evaporated. The crude material was purified using a Biotage 40S column and eluted with 1: 1 EtOAc: isohexane to give the subtitle compound as a white solid. Yield: 1.3g.
MS APCI + 488/490 [M + H] ⁺

iv) Tert-Butyl (trans-4-{[2- (2-Phenylethoxy) ethyl] amino} cyclohexyl) carbamate (2-phenylethoxy) acetaldehyde (WO 1994/27601) (0.47 g) in methanol (30 ml) ) To a solution of tert-butyl (trans-4-aminocyclohexyl) carbamate (Bioorg. Med. Chem. Lett. 2004, 14 (20), 5223-5226) (0.61 g), then H ₂ O ( 0.05 ml) and AcOH (0.05 ml) were added followed by sodium cyanoborohydride (0.18 g) and the mixture was stirred at room temperature for 18 hours. Volatiles were evaporated in vacuo and the residue was partitioned between EtOAc and H ₂ O. The organic layer was further washed with saturated aqueous sodium bicarbonate and saturated aqueous NaCl, then collected, dried (MgSO ₄ ) and evaporated to give a yellow gum. Purification by column chromatography, eluting with a step mixture of 0.5% triethylamine to 1% triethylamine in EtOAc, gave the subtitle compound as a white solid. Yield: 0.31 g.
MS APCI + 363 [M + H] ⁺

(v) Trans-N- [2- (2-phenylethoxy) ethyl] cyclohexane-1,4-diamine A solution of the product of the dihydrochloride step (iv) (0.13 g) was added to 4M HCl in dioxane (5 ml). ) For 2 hours. Volatiles were evaporated in vacuo to give the subtitle compound as a white solid. Yield: 0.29g.
MS APCI + 263 [M + H] ⁺
Used in next step (vi) without further purification.

(vi) 8- (benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[(trans-4-{[2- (2-phenylethoxy)) Ethyl] amino} cyclohexyl) amino] ethyl} quinolin-2 (1H) -one product of step (v) (0.1 g), product of step (iii) (0.3 ml) in DMSO (0.3 ml). 15 g), sodium bicarbonate (0.1 g) and sodium iodide (90 mg) were heated at 140 ° C. for 1 hour, then allowed to cool to room temperature and stirred for a further 48 hours. Then partitioned the mixture between EtOAc and _{H 2} O. The organics were further washed with brine, collected, dried (MgSO ₄ ) and evaporated to give a brown gum. Purified by column chromatography eluting with EtOAc: triethylamine (9: 1) mixture followed by EtOAc: methanol (9: 1) to give the subtitle compound as a yellow gum. Yield: 70 mg.
MS APCI + 670 [M + H] ⁺

(vii) 8-hydroxy-5-{(1R) -1-hydroxy-2-[(trans-4-{[2- (2-phenylethoxy) ethyl] amino} cyclohexyl) amino] ethyl} quinoline-2 ( A solution of the product of step (vii) (7 mg) in 1H) -one dry THF (1 ml) was treated with triethylamine trihydrofluoride (0.025 ml) and stirred at room temperature overnight. Volatiles were evaporated and the residue was redissolved in ethanol (10 ml) and 2M aqueous HCl (2 ml) followed by addition of 10% palladium / charcoal (0.05 g), then under 5 bar hydrogen gas overnight. Stir. The mixture was filtered through glass fiber paper and the solvent was evaporated in vacuo to give an orange solid. Purification by silica gel preparative plate chromatography eluting with EtOAc / methanol / aqueous 0.880 NH ₃ (65: 30: 5) gave the title compound as a yellow solid. Yield: 21 mg.
MS APCI + 466 [M + H] ^+
1 H NMR (DMSO) δ 8.20 (d, 1H), 7.20 (m, 5H), 7.10 (d, 1H), 6.94 (d, 1H), 6.53 (d, 1H), 5.13 (m, 1H), 3.61 (t, 2H), 3.51 (m, 2H), 2.82 (m, 5H), 1.91 (m, 5H), 1.11 (m, 4H)

Example 3
8-Hydroxy-5-[(1R) -1-hydroxy-2-({1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} amino) ethyl] quinolin-2 (1H) -one

i) 4 - [(1R) -2- azido-1-hydroxyethyl] -8- (benzyloxy) quinolin -2 (IH) - sodium-one iodide (0.47 g) and sodium azide (0.74 g) Of the product (8- (benzyloxy) -5-[(1R) -2-bromo-1-hydroxyethyl] quinoline-2 (1H) of Example 2 step (ii) in dry DMSO (10 ml). -On) (1.07 g) was added to the solution. The reaction mixture was heated at 65 ° C. for 2 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc and H ₂ O, and the layers were separated. Further aqueous material was extracted with EtOAc (x4), then the combined organic extracts were washed with saturated aqueous NaCl. The organics were collected, dried (Na ₂ SO ₄ ) and volatiles were removed in vacuo to give a yellow solid. The solid residue was purified by trituration with 1: 1 diethyl ether / EtOAc to give the subtitle compound as a white solid. Yield: 0.71g.
MS APCI + 337 [M + H] ⁺

ii) 4-[(1R) -2-amino-1-hydroxyethyl] -8- (benzyloxy) quinolin-2 (1H) -one product of step (i) (4-[(1R) -2- Azido-1-hydroxyethyl] -8- (benzyloxy) quinolin-2 (1H) -one) (0.71 g) was dissolved in ethanol (10 ml) and THF (2 ml) and dissolved in ethanol (5 ml). A suspension of 10% palladium / charcoal (71 mg) was added. The reaction mixture was hydrogenated at 5 bar pressure for 14 hours, then filtered through glass microfiber paper and concentrated in vacuo to give the subtitle compound as a dull yellow solid. Yield: 0.64g.
MS APCI + 311 [M + H] ⁺
Used in the next step (iii) without further purification.

iii) 4-[(1R) -2-amino-1-hydroxyethyl] -8-hydroxyquinolin-2 (1H) -one product of step (ii) (4-[(1R) -2-amino-1 -Hydroxyethyl] -8- (benzyloxy) quinolin-2 (1H) -one) (0.64 g) was dissolved in ethanol (20 ml), methanol (2 ml) and concentrated hydrochloric acid (1.5 ml). A suspension of 10% palladium / charcoal (0.21 g) in (5 ml) was added. The reaction mixture was hydrogenated at 5 bar pressure for 4 hours. A further aliquot of 10% palladium / charcoal (50 mg) was added and the mixture was further hydrogenated at 4 bar pressure for 14 hours, then filtered through glass microfiber paper, further washed with a methanol / water mixture, followed by concentration in vacuo. And a dull yellow solid was obtained. This was purified by trituration with ethanol and filtration to give the subtitle compound as a yellow solid. Yield: 0.3g.
MS APCI + 221 [M + H] ^+
1 H NMR (DMSO) δ 10.45 (m, 2H), 8.15 (d, 1H), 7.98 (s, 2H), 7.14 (d, 1H), 6.98 (d, 1H), 6.58 (d, 1H), 6.05 (m, 1H), 5.20 (m, 1H), 3.0 (m, 2H)

iv) 8- [3- (2-Phenylethoxy) propyl] -1,4-dioxa-8-azaspiro [4.5] decane THF (40 ml) in 3- (2-phenylethoxy) propanal (Sciences A solution of Chimiques; 1968, 266 (18), 1379-1380) (2.5 g) and 1,4-dioxa-8-azaspiro [4.5] decane (2 g) was stirred at room temperature for 10 minutes. Thereafter, sodium triacetoxyborohydride (3 g) was added and the mixture was further stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (30 ml) and then extracted with EtOAc (x2). The organic layer was collected, dried (MgSO ₄ ) and the solvent removed under reduced pressure to give a colorless oil. Purification by column chromatography, eluting with 800: 150: 5 EtOAc / methanol / triethylamine, gave the subtitle compound as a colorless oil. Yield: 3.2g.
¹ H NMR (CDCl ₃ ) δ 7.20 (m, 5H), 3.95 (s, 4H), 3.60 (t, 2H), 3.50 (t, 2H), 2.95 (m, 4H), 2.40 (t, 2H), 1.80 (m, 6H)

v) 1- [3- (2-Phenylethoxy) propyl] piperidin-4-one The product of step (iv) in 8-ml THF (25 ml) (8- [3- (2-phenylethoxy) propyl] -1, A solution of 4-dioxa-8-azaspiro [4.5] decane) (1.88 g) was treated with 2M aqueous HCl (15 ml) and the whole was stirred at 50 ° C. for 48 hours. The cooled mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was collected and the aqueous layer was extracted with EtOAc (x3). The organic layer was collected, dried (MgSO ₄ ) and the solvent removed under reduced pressure to give a colorless oil. The crude oil solution dissolved in acetonitrile was purified by applying to an Argonaut Technologies MP-TsOH (65) resin column (2 g) followed by elution with acetonitrile. The pure product was obtained by eluting with a triethylamine / acetonitrile mixture. Volatiles were evaporated in vacuo to give the subtitle compound as a colorless oil. Yield: 1.65g.
¹ H NMR (CDCl ₃ ) δ 7.20 (m, 5H), 3.65 (t, 2H), 3.45 (t, 2H), 2.95 (t, 2H), 2.80 (t, 4H), 2.50 (m, 6H), 1.90 (m, 2H)

vi) 8-hydroxy-4-[(1R) -1-hydroxy-2-({1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} amino) ethyl] quinoline-2 (1H) The product of step (iii) in 4- one N-methyl-2-pyrrolidinone (25 ml) (4-[(1R) -2-amino-1-hydroxyethyl] -8-hydroxyquinolin-2 (1H) -one ) (0.3 g) was added to the product of step (v) (1- [3- (2-phenylethoxy) propyl] piperidin-4-one) (0.36 g) followed by AcOH (0.3 08 ml) and stirred at room temperature for 3 hours. The mixture was then treated with sodium triacetoxyborohydride (0.58 g) and the whole was stirred for a further 24 hours. Volatiles were evaporated to near dryness in vacuo, then the solution was loaded onto an SCX cartridge and eluted with 1: 1 isopropanol / acetonitrile. The product was eluted with 10% 0.880 NH ₃ in 1: 1 isopropanol / acetonitrile to give the crude product as a yellow oil. Purification by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile, The product was obtained as a yellow oil. This was redissolved in an acetonitrile / water mixture and then its pH was adjusted to pH 1 with trifluoroacetic acid. Purification is carried out using a Symmetry® C8 5 micron 19 × 50 mm column, eluting with a gradient of 95% aqueous trifluoroacetic acid in acetonitrile to 50% aqueous trifluoroacetic acid in acetonitrile, followed by polishing with ether. Trituration gave the title compound as an off-white solid. Yield: 0.1 g.
MS APCI + 466 [M + H] ⁺
1H NMR: (DMSO) δ 10.54-10.46 (m, 2H), 8.15 (d, 1H), 7.32-7.15 (m, 5H), 6.99 (d, 1H), 6.59 (dd, 1H), 6.25-6.21 ( m, 1H), 5.35-5.28 (m, 1H), 3.59 (t, 4H), 3.48-3.29 (m, 4H), 3.16-2.86 (m, 4H), 2.81 (t, 2H), 2.34-2.20 ( m, 2H), 1.92-1.69 (m, 4H)

Example 4
8-hydroxy-5-[(1R) -1-hydroxy-2-({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} amino) ethyl] quinolin-2 (1H) -one

i) 2- (2-Phenylethoxy) ethyl 4- (2-phenylethoxy) ethanol (J. Med. Chem. 1983, 26 (11), 1570-1576) in 4-methylbenzenesulfonate pyridine (5 ml) ( To a solution of 1.13 g) tosyl chloride (1.4 g) and N, N-dimethylaminopyridine (20 mg) were added at room temperature and stirred for another 14 hours. Volatiles were evaporated in vacuo and the residue was partitioned between EtOAc and 2M aqueous HCl. The organic layer was collected and further washed with saturated aqueous sodium bicarbonate and with saturated aqueous NaCl followed by H ₂ O. The organic layer was collected, dried (MgSO ₄ ) and the solvent was evaporated to give the subtitle compound as a pink oil. Yield: 1.4g.
¹ H NMR (CDCl ₃ ) δ 7.80 (d, 2H), 7.20 (m, 7H), 4.10 (m, 2H), 3.60 (m, 4H), 2.81 (t, 2H), 2.44 (s, 3H)
Used in the next step (ii) without further purification.

ii) The product of step (i) in 2- [2- (2-phenylethoxy) ethyl] piperidin-4-one N-methyl-2-pyrrolidinone (15 ml) and triethylamine (4 ml) (2- (2 A solution of -phenylethoxy) ethyl 4-methylbenzenesulfonate) (1.9 g) was treated with piperidin-4-one hydrochloride (1.1 g). The whole was brought to 85 ° C. for 2 hours. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic layer was collected and further washed with saturated aqueous NaCl followed by H ₂ O. The organic layer was collected, dried (MgSO ₄ ) and the solvent was evaporated to give the subtitle compound as a brown oil. Yield: 1.6g.
¹ H NMR (CDCl ₃ ) δ 7.30 (m, 5H), 3.70 (m, 8H), 2.90 (m, 3H), 2.80 (t, 2H), 2.72 (t, 1H), 2.42 (t, 2H).
Used in the next step (iii) without further purification.

iii) 5-[(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} amino) ethyl ] -8-Hydroxyquinolin-2 (1H) -one N-methyl-2-pyrrolidinone (10 ml) product of step (ii) (1- [2- (2-phenylethoxy) ethyl] piperidine-4- (On) (0.22 g) was added to the product of step 5 of Example 5 (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0.28 g) followed by AcOH (0.05 ml) and stirred at room temperature for 2 hours. The mixture was then treated with sodium triacetoxyborohydride (0.36 g) and the whole was stirred for a further 24 hours. The reaction mixture was then treated with 0.880 NH ₃ (10 ml) and volatiles were removed in vacuo. The residue was diluted with isopropanol (5 ml) and loaded onto an Argonaut Technologies MP-TsOH (65) resin column (4.6 g) previously washed with isopropanol. The column was eluted with ˜50 ml isopropanol followed by 1: 3 0.880 NH ₃ : isopropanol. Product containing fractions were concentrated in vacuo to give a dark yellow oil. The residue was purified with a Biotage 40S column, 1% in DCM NH ₃ - methanol (7M), and eluted with increasing amounts of methanol up to 10%. Subsequent flush with 2% NH ₃ -methanol (7M) / 18% methanol / 80% EtOAc, then 2% NH ₃ -methanol (7M) / 48% methanol / 50% EtOAc and subtitle compound as a dark yellow oil Obtained as a thing. Yield: 0.14g.
MS APCI + 566 [M + H] ⁺
Used in next step (iv) without further purification.

iv) 8-hydroxy-4-[(1R) -1-hydroxy-2-({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} amino) ethyl] quinoline-2 (1H) The product of the on- stage (iii) (5-[(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-({1- [2- (2-phenylethoxy) ethyl] piperidine -4-yl} amino) ethyl] -8-hydroxyquinolin-2 (1H) -one) (0.114 g) was suspended in THF (5 ml) and triethylamine trihydrofluoride (0.2 ml). ) Was added. The reaction mixture was stirred at room temperature for 3 days, then diluted with methanol and volatiles were evaporated. The residue was dissolved in methanol and loaded onto an Argonaut Technologies MP-TsOH (65) resin column (1 g) previously washed with isopropanol. The column was eluted with 30 ml isopropanol followed by 1: 3 aqueous NH ₃ : isopropanol. Product containing fractions were concentrated in vacuo to give the crude product as a yellow gum. Purify by reverse phase HPLC using a Symmetry® C8 5 micron 19 × 50 mm column, eluting with a gradient of 5-50% acetonitrile in 0.2% aqueous trifluoroacetic acid to give the title compound as an off-white solid Got as. Yield: 26 mg.
MS APCI (+ ve) 452 [M + H] ^+
1 H NMR (DMSO) δ 10.57 (s, 1H), 10.50 (s, 1H), 9.87 (bs, 1H), 9.26 (bs, 1H), 8.94 (bs, 1H), 8.18 (d, 1H), 7.25 (m, 6H), 7.00 (d, 1H), 6.58 (d, 1H), 6.26 (bs, 1H), 5.35 (d, 1H), 3.70 (m, 4H), 3.30 (m, 5H), 3.10 ( m, 2H), 2.85 (m, 4H), 2.0 (m, 4H)

Example 5
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -ON

i) 5 - ((1R) -2- azido -1 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) -8- (benzyloxy) quinolin -2 (IH) - on sodium iodide (0. 38 g) and sodium azide (0.60 g) were added to the product (8- (benzyloxy) -5-((1R) -2-bromo-) of Example 2, step (iii) in dry DMSO (20 ml). 1-{[tert-Butyl (dimethyl) silyl] oxy} ethyl) quinolin-2 (1H) -one) (1.12 g) was added. The reaction mixture was heated at 65 ° C. for 3 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc and H ₂ O, and the layers were separated. The aqueous material was further extracted with EtOAc (x4), then the combined organic extracts were washed with saturated aqueous NaCl, collected, dried (Na ₂ SO ₄ ) and volatiles removed in vacuo. The residue was purified by Biotage 40S column and eluted with 40% EtOAc in isohexane to give the subtitle compound as a white solid. Yield: 0.94g.
MS APCI + 451 [M + H] ⁺

ii) 5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one product of step (i) (5 -((1R) -2-azido-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8- (benzyloxy) quinolin-2 (1H) -one) (0.94 g) in ethanol ( 33 ml), to which was added a suspension of 10% palladium / charcoal (0.49 g) in ethanol (5 ml). The reaction mixture was hydrogenated at 5 bar for 4 hours, then filtered through glass microfiber paper and concentrated in vacuo to give the subtitle compound as a yellow oil. Yield: 0.65g.
MS APCI + 335 [M + H] ⁺

iii) To 6- [2- (2-phenylethoxy) ethyl] -1-oxa-6-azaspiro [2.5] octane dry DMSO (0.27 g), 60% sodium hydride (65 mg) was added at room temperature. Subsequently trimethylsulfoxonium iodide (0.27 g) was added and the resulting solution was stirred for an additional 2.5 hours. A solution of the product of Example 4 step (ii) (1- [2- (2-phenylethoxy) ethyl] piperidin-4-one) (0.2 g) in dry THF (2 ml) was added to the above mixture. Was then added dropwise, followed by further stirring at ambient temperature for 1.5 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was further washed with saturated aqueous NaCl, collected, dried (MgSO ₄ ) and evaporated in vacuo to give a yellow oil. Yield: 0.14g.
MS APCI + 262 [M + H] ⁺

iv) 5-{(1R) -1-{[tert-Butyl (dimethyl) silyl] oxy} -2-[({4-hydroxy-1- [2- (2-phenylethoxy) ethyl] piperidine-4- (Il} methyl) amino] ethyl} -8-hydroxyquinolin-2 (1H) -one methanol (2 ml) and N, N-diisopropylethylamine (0.092 ml) in step (ii) (1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0.26 g) and the product of step (iii) (0.54 g) of the mixture was refluxed for 3 days. Volatile material was evaporated in vacuo to give a black rubbery material. Purify by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile to give the subtitle compound. Obtained as a yellow foam. Yield: 79 mg.
MS APCI + 596 [M + H] ⁺

v) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl } Quinolin-2 (1H) -one The product of step (iv) (5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[({ 4-hydroxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} -8-hydroxyquinolin-2 (1H) -one) (80 mg) was added to triethylamine trifluoride. Treated with hydride (0.033 ml) and stirred at room temperature for a further 18 hours. Volatiles were evaporated in vacuo to give a yellow foam. Purify by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient of 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile to give the title compound. Obtained as a yellow foam. Yield: 62 mg.
MS APCI + 482 [M + H] ^+
1 H NMR (DMSO) δ 8.20 (d, 1H), 7.20 (m, 5H), 7.10 (d, 1H), 6.90 (d, 1H), 6.50 (d, 1H), 5.00 (m, 1H), 3.55 (t, 2H), 3.50 (m, 2H), 2.70 (m, 2H), 2.40 (m, 2H), 2.40 (m, 9H), 1.50 (m, 4H)

Example 6
N-benzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl Propanamide

i) A solution of piperidin-4-one (1 g) in tert-butyl 3- (4-oxopiperidin-1-yl) propanoate CHCl ₃ (30 ml) was added to tert-butyl 3-bromopropanoate (1.2 ml). ) Followed by triethylamine (1.8 ml). The reaction mixture was refluxed for 18 hours. The mixture was allowed to cool to room temperature then diluted with EtOAc and H ₂ O and the layers separated. The aqueous material was extracted with further EtOAc (× 2), a then the combined organic extracts washed with water, followed by saturated aqueous NaCl, collected, and dried (MgSO _4). Volatiles were removed in vacuo to give the subtitle compound as an orange oil. Yield: 0.92g.
¹ H NMR (CDCl ₃ ) δ 2.81-2.75 (m, 6H), 2.47-2.42 (m, 6H), 1.46 (s, 9H).

ii) 3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) (Ethyl) amino} piperidin-1-yl) propanoate tert-butyl NMP (15 ml) product of step (i) (3- (4-oxopiperidin-1-yl) propanoate tert-butyl) (2. 09 g) was added to the product of step 3 of Example 3 (4-[(1R) -2-amino-1-hydroxyethyl] -8- (benzyloxy) quinolin-2 (1H) -one) (1.53 g) followed by AcOH (0.28 ml) and then with powdered molecular sieves and stirred at room temperature for 7 hours. The mixture was then treated with sodium triacetoxyborohydride (1.95 g) and the whole was stirred for an additional 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting oil was loaded onto a Varian Bond Elut SCX resin column (50 g). The column was eluted with 50 ml of 1: 1 isopropanol: acetonitrile followed by 1: 2: 2 0.880 NH ₃ : isopropanol: acetonitrile. Product containing fractions were concentrated in vacuo to give an oil. This was purified using a Biotage column, eluting with 8% methanol in DCM and increasing the amount of methanol to 20% to give the subtitle compound as a dark orange oil. Yield: 1.66 g.
MS APCI + 546 [M + H] ^+
1 H NMR (DMSO) δ 10.38 (s, 1H), 8.24 (d, 1H), 7.03 (d, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 3.46-1.08 (m, 16H) , 1.39-1.38 (m, 9H), 0.84 (s, 9H), 0.05 (s, 3H), -0.18 (s, 3H).

iii) 3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanoic acid in product (3-) (3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy) in TFA (10 ml) } -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) propanoate tert-butyl) was stirred at room temperature for 2 hours. Then concentrated in vacuo and azeotroped with methanol (x2). The resulting residue was loaded onto a Varian Bond Elut SCX resin column (50 g). The column was eluted with 50 ml of 1: 1 isopropanol: acetonitrile followed by 1: 2: 2 0.880 NH ₃ : isopropanol: acetonitrile. Product containing fractions were concentrated in vacuo to give the subtitle compound as a dark yellow oil. Yield: 1.3g.
MS APCI + 490 [M + H] ⁺

iv) N-benzyl-3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5- (yl) ethyl] amino} piperidin-1-yl) propanamide DMF (8 ml) in step (iii) product (3- (4-{[(2R) -2-{[tert-butyl ( Dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) propanoic acid) (0.25 g), benzylamine A mixture of (0.56 ml), triethylamine (0.21 ml) and HATU (0.35 g) was stirred at room temperature for 48 hours and then the volatiles were removed in vacuo. The resulting residue was loaded onto a Varian Bond Elut SCX resin column (10 g). The column was eluted with 50 ml of 1: 1 isopropanol: acetonitrile followed by 1: 2: 2 0.880 NH ₃ : isopropanol: acetonitrile. Product containing fractions were concentrated in vacuo and further purified using a Biotage column, eluting with 1: 9 methanol: 5% NH ₃ -methanol in DCM (7M) to give the subtitle compound as a dark orange oil. . Yield: 0.2g.
MS APCI + 579 [M + H] ⁺

v) N-benzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Il) propanamide The product of step (iv) (N-benzyl-3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2) in THF (5 ml) -(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) propanamide) (0.20 g), triethylamine trihydrofluoride (0 .28 ml) and stirred at room temperature for 18 hours. Volatiles were evaporated in vacuo and the resulting residue was loaded onto a Varian Bond Elut SCX resin column (10 g). The column was eluted with 50 ml of 1: 1 isopropanol: acetonitrile followed by 1: 2: 2 0.880 NH ₃ : isopropanol: acetonitrile. The product-containing fractions were concentrated in vacuo and further purified using reverse phase HPLC using a Symmetry® C8 5 micron 19 × 50 mm column and a concentration of 0-50% acetonitrile in 0.2% aqueous TFA. Elution with a gradient gave the title compound as an off-white solid. Yield: 0.11 g.
MS APCI + 465 [M + H] ^+
1 H NMR (DMSO) δ 10.55-10.46 (m, 2H), 8.16 (d, 1H), 7.36-7.23 (m, 5H), 7.18 (d, 1H), 6.99 (d, 1H), 6.59 (d, 1H), 6.30-6.20 (m, 1H), 5.36-5.29 (m, 1H), 4.30 (d, 2H), 3.79-3.47 (m, 8H), 3.16-3.07 (m, 2H), 3.02-2.91 ( m, 1H), 2.70-2.62 (m, 2H), 2.35-2.20 (m, 1H), 1.93-1.71 (m, 1H).

Example 7
N-benzyl-3- [4-({[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} methyl) piperidine- 1-yl] propanamide

i) tert-Butyl 4- [4- (hydroxymethyl) piperidin-1-yl] butyrate The subtitle compound was prepared in CHCl ₃ (40 ml) according to the procedure outlined in step (i) of Example 6. Prepared by refluxing with piperidin-4-ylmethanol (2 g), tert-butyl 3-bromopropanoate (3.9 ml), triethylamine (2.8 ml) for 18 hours to give the subtitle compound as an orange oil. It was. Yield: 3g.
¹ H NMR (CDCl ₃ ) δ 3.57-3.47 (m, 2H), 3.03-2.92 (m, 2H), 2.77-2.66 (m, 2H), 2.53-2.42 (m, 2H), 2.13-1.99 (m, 2H), 1.83-1.71 (m, 2H), 1.57-1.24 (m, 12H).

ii) 3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ) Ethyl] amino} methyl) piperidin-1-yl] propanoate tert-butyl oxalyl chloride (0.67 ml) was added dropwise to a cooled (−78 ° C.) solution of DMSO (0.57 ml) in DCM (30 ml). And stirred for 30 minutes. A solution of the product of step (i) in DCM (tert-butyl 4- [4- (hydroxymethyl) piperidin-1-yl] butyrate) (1.5 g) was then added dropwise over 10 minutes, − The mixture was further stirred at 78 ° C. for 1 hour. After the addition of triethylamine (1.9 ml), the reaction mixture was warmed to room temperature and stirred for a further 18 hours, then diluted with DCM and H ₂ O and the layers separated. The aqueous material was further extracted with DCM, then the combined organic extracts were washed with saturated aqueous NaCl, collected and dried (MgSO ₄ ). Volatiles were removed in vacuo to give the intermediate compound (4- (4-formylpiperidin-1-yl) butyrate tert-butyl) as an orange oil. Yield: 1.5g.
The subtitle compound was prepared according to the procedure described in step (ii) of Example 6 above for the intermediate compound (tert-butyl 4- (4-formylpiperidin-1-yl) butyrate) (0.48 g), Example 3 Using the product of step (ii) (4-[(1R) -2-amino-1-hydroxyethyl] -8- (benzyloxy) quinolin-2 (1H) -one) (0.34 g) Subsequently, it was prepared in 2 hours at room temperature using AcOH (0.06 ml) in NMP (15 ml). Sodium triacetoxyborohydride (0.42 g) was subsequently added and stirred for an additional 2 hours to give the subtitle compound as a yellow oil. Yield: 0.53g.
MS APCI + 560 [M + H] ^+
1 H NMR (DMSO) δ 8.24 (d, 1H), 7.02 (d, 1H), 6.90 (d, 1H), 6.50 (d, 1H), 5.13-5.07 (m, 1H), 2.82-0.99 (m, 17H), 1.40 (s, 9H), 0.83 (s, 9H), 0.04 (s, 3H), -0.18 (s, 3H).

iii) 3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ) Ethyl] amino} methyl) piperidin-1-yl] propanoic acid subtitle compound is prepared according to the procedure outlined in Example 6, Step (iii) (3- [4-({[( 2R) -2-{[tert-Butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} methyl) piperidine-1- [Il] tert-butyl propanoate) (0.53 g) in TFA (20 ml) at room temperature for 1 h to give the subtitle compound as a dark yellow oil. Yield: 0.24g.
MS APCI + 504 [M + H] ⁺

iv) N-benzyl-3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline) The -5-yl) ethyl] amino} methyl) piperidin-1-yl] propanamide subtitle compound was prepared according to the procedure outlined in step (iv) of Example 6 in DMF (6 ml) and acetonitrile (3 ml) ( iii) product (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline) A solution of -5-yl) ethyl] amino} methyl) piperidin-1-yl] propanoic acid) (0.17 g), benzylamine (0.37 ml), triethylamine (0.14 ml) and HATU (0.34 g). Used in 30 min at room temperature to give the subtitle compound as a dark yellow oil. Yield: 0.2g.
MS APCI + 593 [M + H] ⁺

v) N-benzyl-3- [4-({[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} methyl) The piperidin-1-yl] propanamide subtitle compound is prepared according to the procedure outlined in step (v) of Example 6 for the product of step (iv) (N-benzyl-3- [4-({[(2R)- 2-{[tert-Butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} methyl) piperidin-1-yl] propane Amide) (0.2 g) was used with triethylamine trihydrofluoride (0.30 ml) in THF (5 ml) at room temperature for 3 hours to give the title compound as an off-white solid. . Yield: 70 mg.
MS APCI + 479 [M + H] ^+
1 H NMR (DMSO) δ 8.17 (d, 1H), 7.37-7.22 (m, 5H), 7.15 (d, 1H), 6.99 (d, 1H), 6.59 (d, 1H), 5.34 (d, 1H) , 4.31 (d, 2H), 3.58-2.85 (m, 11H), 2.71-2.63 (m, 2H), 2.04-1.91 (m, 2H), 1.48-1.34 (m, 2H).

Example 8
5-[(1R) -2-({1- [3- (3,4-dihydroisoquinolin-2 (1H) -yl) -3-oxopropyl] piperidin-4-yl} amino) -1-hydroxyethyl ] -8-Hydroxyquinolin-2 (1H) -one

i) 5-[(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-({1- [3- (3,4-dihydroisoquinolin-2 (1H) -yl) -3 -Oxopropyl] piperidin-4-yl} amino) ethyl] -8-hydroxyquinolin-2 (1H) -one subtitle compound was prepared in DMF (5 ml) according to the procedure outlined in step (iv) of Example 6. The product of step (iii) of Example 6 (3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1) , 2-Dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) propanoic acid) (0.22 g), 1,2,3,4-tetrahydro-isoquinoline (0.12 g), triethylamine (0.15 g). 17 ml) and a solution of HATU (0.31 g) in 10 minutes at room temperature to give the subtitle compound as a dark yellow oil. . Yield: 0.27g.
MS APCI + 605 [M + H] ⁺

ii) 5-[(1R) -2-({1- [3- (3,4-dihydroisoquinolin-2 (1H) -yl) -3-oxopropyl] piperidin-4-yl} amino) -1- The hydroxyethyl] -8-hydroxyquinolin-2 (1H) -one subtitle compound is prepared according to the procedure outlined in Example 6, step (v) and the product of step (i) (5-[(1R) -1- {[tert-Butyl (dimethyl) silyl] oxy} -2-({1- [3- (3,4-dihydroisoquinolin-2 (1H) -yl) -3-oxopropyl] piperidin-4-yl} amino ) Ethyl] -8-hydroxyquinolin-2 (1H) -one) (0.27 g) with triethylamine trihydrofluoride (0.36 ml) in THF (5 ml) at room temperature. Prepared in time to give the title compound as an off-white solid. Yield: 0.14g.
MS APCI + 491 [M + H] ^+
1 H NMR (DMSO) δ 8.16 (1H, d), 7.22-7.15 (5H, m), 6.99 (1H, d), 6.59 (1H, d), 5.36-5.30 (1H, m), 4.64 (2H, d), 3.99-1.73 (19H, m).

Example 9
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-Phenylethyl) propanamide

i) 3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) The ethyl] amino} piperidin-1-yl) -N- (2-phenylethyl) propanamide subtitle compound was prepared according to the procedure outlined in Example 6, step (iv) and the step of Example 6 in DMF (5 ml). The product of (iii) (3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline) -5-yl) ethyl] amino} piperidin-1-yl) propanoic acid) (0.22 g), 2-phenylethanamine (0.11 g), triethylamine (0.17 ml) and HATU (0.31 g) To give the subtitle compound as a dark yellow oil. Yield: 0.27g.
MS APCI + 593 [M + H] ⁺

ii) 3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl)- The N- (2-phenylethyl) propanamide subtitle compound is prepared from the product of step (i) (3- (4-{[(2R) -2- { [tert-Butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2- (Phenylethyl) propanamide) (0.27 g) was used with triethylamine hydrofluoride (0.36 ml) in THF (5 ml) at room temperature for 18 hours to give the title compound as off-white. Obtained as a solid. Yield: 90 mg.
MS APCI + 479 [M + H] ^+
1 H NMR (DMSO) δ 8.16 (d, 1H), 7.35-7.15 (m, 6H), 6.99 (d, 1H), 6.59 (d, 1H), 5.37-5.29 (m, 1H), 3.59-1.68 ( m, 19H).

Example 10
N- (3-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide

i) 3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) The ethyl] amino} piperidin-1-yl) -N- (2-chlorobenzyl) propanamide subtitle compound was prepared according to the procedure outlined in Example 6 step (iv) and the step of Example 6 in DMF (5 ml). The product of (iii) (3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline) -5-yl) ethyl] amino} piperidin-1-yl) propanoic acid) (0.22 g), 1- (2-chlorophenyl) methanamine (0.13 g), triethylamine (0.17 ml) and HATU (0.31 g). ) In 18 hours at room temperature to give the subtitle compound as a dark yellow oil. Yield: 0.28g.
MS APCI + 613 [M + H] ⁺

ii) N- (2-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] The amino} piperidin-1-yl) propanamide subtitle compound is prepared from the product of step (i) according to the procedure outlined in step (v) of Example 6 (3- (4-{[(2R) -2- { [tert-Butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2- (Chlorobenzyl) propanamide) (0.28 g) with triethylamine trihydrofluoride (0.36 ml) in THF (5 ml) at room temperature for 18 hours to give the title compound as off-white Obtained as a solid. Yield: 0.18g.
MS APCI + 499 [M + H] ^+
1 H NMR (DMSO) δ 8.16 (d, 1H), 7.47-7.43 (m, 1H), 7.39-7.28 (m, 3H), 7.17 (d, 1H), 6.99 (d, 1H), 6.58 (d, 1H), 5.36-5.30 (m, 1H), 4.40-1.70 (m, 17H).

Example 11
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-Methoxybenzyl) propanamide

i) 3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) The ethyl] amino} piperidin-1-yl) -N- (2-methoxybenzyl) propanamide subtitle compound was prepared according to the procedure outlined in Example 6 step (iv) and the step of Example 6 in DMF (5 ml). The product of (iii) (3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline) -5-yl) ethyl] amino} piperidin-1-yl) propanoic acid) (0.22 g), 1- (2-methoxyphenyl) methanamine (0.12 g), triethylamine (0.17 ml) and HATU (0.15 g). 31 g) was used for 18 hours at room temperature to give the subtitle compound as a dark yellow oil. Yield: 0.27g.
MS APCI + 609 [M + H] ⁺

ii) 3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl)- The N- (2-methoxybenzyl) propanamide subtitle compound is prepared according to the procedure outlined in step (v) of Example 6 (3- (4-{[(2R) -2- { [tert-Butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2- Methoxybenzyl) propanamide) (0.27 g) was used together with triethylamine hydrofluoride (0.36 ml) in THF (5 ml) at room temperature for 18 hours to give the title compound as an off-white Obtained as a solid. Yield: 0.13g.
MS APCI + 495 [M + H] ^+
1 H NMR (DMSO) δ 8.16 (d, 1H), 7.25 (t, 1H), 7.17 (d, 2H), 6.99 (d, 2H), 6.91 (t, 1H), 6.59 (d, 1H), 5.36 -5.30 (m, 1H), 4.26 (d, 2H), 3.81 (s, 3H), 3.73-1.70 (m, 15H).

Example 12
N- (4-cyanobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide

i) 3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) The ethyl] amino} piperidin-1-yl) -N- (4-cyanobenzyl) propanamide subtitle compound was prepared according to the procedure outlined in Example 6 step (iv) and the step of Example 6 in DMF (5 ml). The product of (iii) (3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline) -5-yl) ethyl] amino} piperidin-1-yl) propanoic acid) (0.22 g), 4- (aminomethyl) benzonitrile (0.12 g), triethylamine (0.17 ml) and HATU (0.31 g). ) In 18 hours at room temperature to give the subtitle compound as a dark yellow oil. Yield: 0.27g.
MS APCI + 604 [M + H] ⁺

ii) N- (4-cyanobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] The amino} piperidin-1-yl) propanamide subtitle compound is prepared according to the procedure outlined in step (v) of Example 6 for the product of step (i) (3- (4-{[(2R) -2- { [tert-Butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (4- (Cyanobenzyl) propanamide) (0.27 g) with triethylamine hydrofluoride (0.36 ml) in THF (5 ml) at room temperature for 18 hours to give the title compound as off-white Obtained as a solid. Yield: 0.1 g.
MS APCI + 490 [M + H] ^+
1 H NMR (DMSO) δ 8.17 (d, 1H), 7.80 (d, 2H), 7.46 (d, 2H), 7.45 (d, 2H), 6.59 (d, 1H), 5.37-5.30 (m, 1H) , 4.38 (d, 2H), 3.71-1.70 (m, 15H).

Example 13
N- (2-hydroxybenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide

i) 3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) The ethyl] amino} piperidin-1-yl) -N- (2-hydroxybenzyl) propanamide subtitle compound was prepared according to the procedure outlined in Example 6 step (iv) and the step of Example 6 in DMF (5 ml). The product of (iii) (3- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline) -5-yl) ethyl] amino} piperidin-1-yl) propanoic acid) (0.22 g), 2- (aminomethyl) phenol (0.12 g), triethylamine (0.17 ml) and HATU (0.31 g) To give the subtitle compound as a dark yellow oil. Yield: 0.27g.
MS APCI + 595 [M + H] ⁺

ii) N- (2-hydroxybenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] The amino} piperidin-1-yl) propanamide subtitle compound is prepared from the product of step (i) (3- (4-{[(2R) -2- { [tert-Butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2- Hydroxybenzyl) propanamide) (0.27 g) was used together with triethylamine hydrofluoride (0.36 ml) in THF (5 ml) at room temperature for 18 hours to give the title compound as off-white Obtained as a solid. Yield: 0.14g.
MS APCI + 481 [M + H] ^+
1 H NMR (DMSO) δ 8.15 (d, 1H), 7.17 (d, 1H), 7.13-7.05 (m, 2H), 6.99 (d, 1H), 6.81 (d, 1H), 6.75 (t, 1H) , 6.60 (d, 1H), 5.35-5.29 (m, 1H), 4.23 (d, 2H), 3.63-1.68 (m, 15H).

Example 14
8-hydroxy-5-{(1R) -1-hydroxy-2-[({(3R) -1- [2- (2-phenylethoxy) ethyl] piperidin-3-yl} methyl) amino] ethyl} quinoline -2 (1H) -ON

i) ( 2-Phenylethoxy) acetic acid (0.6 g) in ethyl DCM (12 ml ) (3S) -1- [2- (2-phenylethoxy) ethyl] piperidine-3-carboxylate (J. Med. Chem) 1983, 26 (11), 1570) was added oxalyl chloride (1.6 ml) followed by 1 drop of DMF and the whole was stirred at room temperature for 3 hours. The volatiles were then evaporated in vacuo and the residue azeotroped with DCM (x3). Dry THF (5 ml) was added and the suspension was then added to a mixture of (3S) -piperidine-3-carboxylic acid ethyl tartrate (1.0 g) in dry THF (12 ml) and triethylamine (2.25 ml). Added all at once at 3 ° C. The mixture was further stirred for 10 minutes, and then the temperature was raised to room temperature and further stirred for 2.5 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic phase was further washed with saturated sodium bicarbonate solution, then with saturated aqueous NaCl, collected, dried (MgSO ₄ ) and the solvent evaporated to give an orange-yellow oil. Purification by column chromatography on silica gel, eluting with 4: 6 EtOAc / isohexane, gave the subtitle compound as a clear oil. Yield: 0.36g.
MS APCI + 320 [M + H] ⁺

ii) {(3S) -1- [2- (2-Phenylethoxy) ethyl] piperidin-3-yl} product of step (i) in methanol dry THF (1.4 ml) ((3S) -1- A solution of [2- (2-phenylethoxy) ethyl] piperidine-3-carboxylate) (0.36 g) was added to lithium aluminum hydride (1.8 ml, 1.0 M in THF) in THF (5.6 ml). ) Was added dropwise under nitrogen. After stirring for 2.5 hours, EtOAc (0.86 ml) was added dropwise followed by water (1.43 ml). The mixture was partitioned between EtOAc and saturated aqueous NaCl. The organic phase was collected and the product was then extracted into 1N HCl followed by basification of the aqueous layer with saturated aqueous sodium bicarbonate and extraction of the product into DCM. The organic phase was collected, dried (MgSO ₄ ) and the solvent was evaporated to give the subtitle compound as a yellow gum. Yield: 0.23g.
MS APCI + 264 [M + H] ⁺

iii) (3S) -1- [2- (2-Phenylethoxy) ethyl] piperidine-3-carbaldehyde To oxalyl chloride (0.086 ml) in DCM (1.5 ml) was added DMSO (0.08 ml) at -78 ° C. 07 ml) was added dropwise. After 35 minutes, the product of step (ii) ({(3S) -1- [2- (2-phenylethoxy) ethyl] piperidin-3-yl} methanol) (0.23 g) in DCM (1.5 ml). ) Was added dropwise at -65 ° C. The mixture was further stirred at -70 ° C for 3 hours, then triethylamine (0.27 ml) was added and the mixture was allowed to reach room temperature with stirring for 18 hours. Volatiles were evaporated in vacuo and the residue azeotroped with toluene (x2) to give the subtitle compound as a clear gum. This was used in step (iv) without further purification. Yield: 0.2g.

iv) 5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[({(3R) -1- [2- (2-phenylethoxy) ethyl] piperidine-3- Yl} methyl) amino] ethyl} -8-hydroxyquinolin-2 (1H) -one The crude product of step (iii) was dissolved in methanol (7 ml). The product of step (ii) of Example 5 (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinoline-2 (1H)- On) (0.2 g) was added along with AcOH (0.037 ml). After stirring at room temperature for 2 hours, sodium cyanoborohydride (41 mg) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with saturated sodium bicarbonate solution, collected, dried (MgSO ₄ ) and the solvent evaporated to give a yellow foam. Purification by chromatography on silica gel, eluting with EtOAc / methanol / ammonia mixture, gave the subtitle compound as a yellow foam. Yield: 0.27g.
MS APCI + 580 [M + H] ⁺

v) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({(3R) -1- [2- (2-phenylethoxy) ethyl] piperidin-3-yl} methyl) amino] ethyl } Quinolin-2 (1H) -one The product of step (iv) in dry THF (10 ml) (5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[( {(3R) -1- [2- (2-phenylethoxy) ethyl] piperidin-3-yl} methyl) amino] ethyl} -8-hydroxyquinolin-2 (1H) -one) (0.27 g) Was treated with triethylamine hydrofluoride (0.76 ml) and the whole was further stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by reverse phase HPLC on an ACE® column eluting with a gradient of 0-50% acetonitrile in 0.2% aqueous TFA and triturated with Et ₂ O. Later, the title compound was obtained as an off-white solid. Yield: 0.19g.
MS APCI + 466 [M + H] ^+
1 H NMR (DMSO) δ 10.50 (bs, 1H), 9.75 (bs, 1H), 8.17 (d, 1H), 7.24 (m, 6H), 6.99 (d, 1H), 6.57 (d, 1H), 6.23 (bs, 1H), 5.34 (bd, 1H), 3.75 (bs, 2H), 3.69 (t, 2H), 3.40 (m, 2H), 3.25 (bs, 2H), 3.10 (bs, 1H), 2.80 ( m, 5H), 2.27 (bs, 1H), 1.80 (m, 2H), 1.67 (m, 1H), 1.10 (m, 1H).

Example 15
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -ON

i) 6- [3- (2-Phenylethoxy) propyl] -1-oxa-6-azaspiro [2.5] octane subtitle compound was prepared according to the procedure outlined in Example 5, step (iii). Product of step (v) (1- [3- (2-phenylethoxy) propyl] piperidin-4-one) (0.5 g), trimethylsulfoxonium iodide (0.63 g), 60% hydrogenation Prepared with a solution of sodium (0.15 g) and DMSO (4 ml) to give the subtitle compound as a colorless oil. Yield: 0.5g.
¹ H NMR (DMSO) δ 7.30 (m, 5H), 3.56 (t, 2H), 3.41 (t, 2H), 2.79 (t, 2H), 2.42 (t, 4H), 2.31 (t, 2H), 1.60 (m, 4H), 1.40 (m, 2H).

ii) 5-{(1R) -1-{[tert-Butyl (dimethyl) silyl] oxy} -2-[({4-hydroxy-1- [3- (2-phenylethoxy) propyl] piperidine-4- The yl} methyl) amino] ethyl} -8-hydroxyquinolin-2 (1H) -one subtitle compound is prepared according to the procedure outlined in step (iv) of Example 5 for methanol (10 ml) and N, N-diisopropylethylamine ( Product (6- [3- (2-phenylethoxy) propyl] -1-oxa-6-azaspiro [2.5] octane) (0.26 g) and 0.092 ml) Product of step 5 (ii) (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) This was prepared using a solution of (0.32 g) at reflux for 24 hours. Volatiles were evaporated in vacuo to give a brown gum. Purification by chromatography on silica gel eluting with 10% methanol in DCM gave the subtitle compound as a yellow foam. Yield: 0.17g.
MS APCI + 610 [M + H] ⁺

iii) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} methyl) amino] ethyl } Quinolin-2 (1H) -one The title compound is prepared according to the procedure outlined in Example 5, step (v) and the product of step (ii) (5-{(1R) -1- {[tert-butyl (dimethyl) silyl] oxy} -2-[({4-hydroxy-1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} methyl) amino] ethyl} -8- Prepared by treating a solution of hydroxyquinolin-2 (1H) -one) (0.17 g) with triethylamine trihydrofluoride (0.23 ml). Purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile followed by Et. Trituration with ₂ O gave the title compound as an off-white solid. Yield: 56 mg.
MS APCI + 496 [M + H] ^+
1 H NMR (DMSO) δ 10.55 (s, 2H), 8.20 (d, 1H), 7.20 (m, 6H), 7.00 (d, 1H), 6.59 (d, 1H), 5.40 (m, 1H), 3.60 (t, 4H), 3.40 (m, 4H), 3.10 (m, 6H), 2.82 (t, 2H), 1.80 (m, 6H).

Example 16
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-methyl-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -ON

i) 4-cyano-4-methylpiperidine hydrochloride 4M HCl in dioxane (9 ml) was added to tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate (WO 03/042174 (A1)) (0.794 g). ). After 1.5 hours, a thick white precipitate formed and the reaction mixture was concentrated in vacuo to give the subtitle compound as a creamy fluffy solid. Yield: 0.569 g.
¹ H NMR (DMSO) δ 9.03 (s, 2H), 3.36-3.30 (m, 2H), 2.96-2.87 (m, 2H), 2.10 (d, 2H), 1.82-1.72 (m, 2H), 1.39 ( s, 3H).

ii) 4-Methyl-1- [2- (2-phenylethoxy) ethyl] piperidine-4-carbonitrile The product of step (i) of Example 4 (2- (2-phenylethoxy) ethyl 4-methylbenzene Sulfonate) (1.344 g) and the product of step (i) (4-cyano-4-methylpiperidine hydrochloride) (0.569 g) were dissolved in NMP (12 ml) and triethylamine (3 ml) was added. It was. The reaction mixture was heated at 85 ° C. for 3 hours, then allowed to cool and partitioned between EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO ₃ , water, and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and concentrated. The residue was diluted with isopropanol and then loaded onto a Varian SCX column (50 g). The column was eluted with isopropanol and then 1: 3 0.880 NH ₃ / isopropanol to give the subtitle compound as a brown oil containing ˜1 molar equivalent of NMP. Yield: 0.691 g.
¹ H NMR (CDCl ₃ ) δ 7.30-7.19 (m, 5H), 3.66 (t, 2H), 3.57 (t, 2H), 2.91-2.87 (m, 4H), 2.61 (t, 2H), 2.35-2.30 (m, 2H), 1.89-1.85 (m, 2H), 1.58 (td, 2H), 1.37 (s, 3H).

iii) 8- (Benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[({4-methyl-1- [2- (2-phenylethoxy) ) Ethyl] piperidin-4-yl} methyl) amino] ethyl} quinolin-2 (1H) -one lithium aluminum hydride (15 ml, 1M in THF) is the product of step (ii) in dry THF (10 ml) Slowly added to a cooled (−78 ° C.) solution of (4-methyl-1- [2- (2-phenylethoxy) ethyl] piperidine-4-carbonitrile) (0.691 g). The reaction mixture was gradually warmed to room temperature and stirred overnight. It was cooled in ice, then EtOAc (5 ml) was added carefully followed by isopropanol. When no further foaming occurred, the reaction mixture was poured onto ice and extracted with EtOAc (x10). The combined organic extracts were washed with 10% aqueous potassium sodium tartrate followed by water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ), volatiles removed in vacuo and the intermediate compound ( 1- {4-Methyl-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methanamine) was obtained as a pale yellow oil (0.455 g). This was used without further purification.

The product of step (iii) of Example 2 (8- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy) in DMSO (1 ml). } Ethyl) quinolin-2 (1H) -one) (0.403 g), intermediate compound prepared above (1- {4-methyl-1- [2- (2-phenylethoxy) ethyl] piperidine-4- Yl} methanamine) (0.228 g), sodium iodide (0.247 g) and sodium bicarbonate (0.277 g) were heated at 100 ° C. for 8 h, then diluted with EtOAc and water to remove the aqueous material. Further extraction with EtOAc (x3). The combined organic extracts were washed with water, saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and concentrated. Purification by Biotage chromatography (concentration gradient = 1: 4: 95 to 3:12:85 NH ₃ -methanol (7M): methanol: EtOAc) gave the subtitle compound as a yellow oil. Yield: 0.311 g.
MS APCI + 684 [M + H] ⁺

iv) 8- (Benzyloxy) -5-{(1R) -1-hydroxy-2-[({4-methyl-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) Amino] ethyl} quinolin-2 (1H) -one product of step (iii) (8- (benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2 -[({4-Methyl-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinolin-2 (1H) -one) (0.311 g) in THF (5 ml) and treated with triethylamine trihydrofluoride (0.25 ml). The reaction mixture was stirred at room temperature overnight, then the volatiles were evaporated to give the subtitle compound as a yellow oil. This was used without further purification. Yield: 0.259g.
MS APCI + 570 [M + H] ⁺

v) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-methyl-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl } Quinolin-2 (1H) -one 1: 1 A suspension of palladium hydroxide (20 wt%, on carbon, wet, 70 mg) in DCM: methanol (5 ml) was added to the product of step (iv) ( 8- (benzyloxy) -5-{(1R) -1-hydroxy-2-[({4-methyl-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] Ethyl} quinolin-2 (1H) -one) (0.259 g) was added and hydrogenated at 4 bar for 3.5 hours. The catalyst was removed and the solvent was evaporated, then the crude material was purified by reverse phase HPLC using a Symmetry® column, eluting with a 10-40% acetonitrile gradient in 0.2% aqueous TFA. The ditrifluoroacetate salt of the title compound was obtained as a pale yellow solid. Yield: 0.150 g.
MS APCI + 480 [M + H] ^+
1 H NMR (90 ° C, DMSO) δ 8.22 (d, 1H), 7.31-7.18 (m, 5H), 7.14 (d, 1H), 7.01 (d, 1H), 6.54 (d, 1H), 5.46-5.42 (m, 1H), 3.77-3.74 (m, 2H), 3.71 (t, 2H), 3.29-3.26 (m, 4H), 3.20-3.17 (m, 4H), 3.12-3.10 (m, 2H), 2.85 (t, 2H), 1.86-1.65 (m, 4H), 1.16 (s, 3H).

Example 17
N-benzyl-4- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl Butaneamide

i) 4- (4- Oxopiperidin -1-yl) butyric acid sodium tert-butyl bicarbonate (1.31 g) and potassium iodide (87 mg) were added to piperidin-4-one hydrochloride in methyl isobutyl ketone (25 ml). To a solution of salt monohydrate (0.80 g) and tert-butyl 4-bromobutyrate (1.0 g) was added. The reaction mixture was refluxed for 4 hours, then allowed to cool and the solvent partially evaporated. The residue is dissolved in DCM and water, the layers are separated, the organic layer is washed with 10% aqueous sodium thiosulfate, water, and saturated aqueous NaCl, dried (Na ₂ SO ₄ ), and the volatiles are removed in vacuo. Removed. Purification by Biotage chromatography (concentration gradient = 0-10% methanol in DCM) afforded the subtitle compound as an orange oil. Yield: 0.697 g.
¹ H NMR (CDCl ₃ ) δ 2.75 (t, 4H), 2.43-2.51 (m, 6H), 2.31 (t, 2H), 1.82 (quintet, 2H), 1.46 (s, 9H).

ii) 4- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) butyric acid tert-Butyl The product of Example 3, step (iii) (4-[(1R) -2-amino-1-hydroxyethyl] -8-hydroxyquinolin-2 (1H) -one) (0.154 g) and The product of step (i) (tert-butyl 4- (4-oxopiperidin-1-yl) butyrate) (0.188 g) was partially dissolved in NMP (5 ml) and AcOH (40 μl) was added. The reaction mixture was stirred at room temperature for 1 hour and more NMP (5 ml) was added. After an additional 2 hours, sodium triacetoxyborohydride (0.254 g) was added. The reaction mixture was stirred overnight at room temperature, then 0.880 aqueous NH ₃ (10 ml) was added and the volatiles removed in vacuo. The residue was diluted with isopropanol and loaded onto a Varian SCX column (10 g), which was eluted with 50 ml isopropanol followed by 1: 3 aqueous NH ₃ : isopropanol. The basic wash was concentrated in vacuo to give the subtitle compound as a dark yellow oil. Yield: 0.27g.
MS APCI + 446 [M + H] ⁺

iii) 4- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) butyric acid TFA (1.5 ml) was added to the product of step (ii) (4- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5 -Yl) ethyl] amino} piperidin-1-yl) tert-butyl butyrate) (0.27 g) and the mixture was stirred for 2 hours. The mixture was concentrated in vacuo, then diluted with isopropanol, neutralized with 0.880 aqueous NH ₃ , concentrated, and then loaded onto a Varian SCX column (10 g). The column was eluted with isopropanol and then 1: 3 0.880 aqueous NH ₃ : isopropanol to give the subtitle compound as a yellow solid. Yield: 0.267 g.
MS APCI + 390 [M + H] ⁺

iv) N-benzyl-4- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Yl) butanamide product of step (iii) (4- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl) Amino} piperidin-1-yl) butyric acid) (0.267 g) was dissolved in DMF (3 ml) and then benzylamine (0.65 ml), triethylamine (0.25 ml) and HATU (0.46 g) were added. It was. After 2 hours, more HATU (0.51 g) was added. The reaction mixture was stirred at room temperature overnight, then the DMF was partially evaporated, the residue was dissolved in 1: 1 isopropanol: water, neutralized with 2M aqueous HCl and filtered. The filtrate was loaded onto a Varian SCX cartridge (10 g), washed with isopropanol and then eluted with 1: 3 0.880 aqueous NH ₃ : isopropanol to give the crude product. This was purified by reverse phase HPLC using a Symmetry® column eluting with a gradient of 10-50% acetonitrile in 0.2% aqueous TFA to give the title compound ditrifluoroacetate as a light tan color. As a solid. Yield: 0.110 g.
MS APCI + 479 [M + H] ^+
1 H NMR (DMSO) δ 10.50 (s, 2H), 9.75 (s, 1H), 9.21 (s, 1H), 8.94 (s, 1H), 8.49 (t, 1H), 8.17 (d, 1H), 7.34 -7.24 (m, 5H), 7.17 (d, 1H), 6.99 (d, 1H), 6.58 (d, 1H), 5.33 (d, 1H), 4.28 (d, 2H), 3.62-3.59 (m, 1H ), 3.40-3.34 (m, 2H), 3.15-2.91 (m, 6H), 2.33-2.25 (m, 4H), 1.92-1.78 (m, 4H).

Example 18
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-methoxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -ON

i) The product of step (iii) of Example 5 in 2- (azidomethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-oldioxane (10 ml) and water (3 ml) (2 0.0 g) (6- [2- (2-phenylethoxy) ethyl] -1-oxa-6-azaspiro [2.5] octane) was treated with sodium azide (1.7 g) and then 85 Heat at 14 ° C. for 14 hours. The cooled mixture was partitioned between water and Et ₂ O. The organic phase was further washed with saturated aqueous NaCl, collected, dried (MgSO ₄ ) and the solvent evaporated in vacuo to give the subtitle compound as a yellow oil. Yield: 2.2g.
¹ H NMR (CDCl ₃ ) δ 7.24 (m, 5H), 3.67 (m, 2H), 3.58 (m, 2H), 3.27 (s, 2H), 2.89 (t, 2H), 2.60 (m, 6H), 2.36 (m, 2H).

ii) 4- (azidomethyl) -4-methoxy-1- [2- (2-phenylethoxy) ethyl] piperidine product in step (i) in dry DMF (2 ml) (4- (azidomethyl) -1- [ A solution of 2- (2-phenylethoxy) ethyl] piperidin-4-ol) (0.5 g) was treated with 60% sodium hydride (70 g) under nitrogen. After stirring for 15 minutes, iodomethane (0.13 ml) was added and the mixture was stirred for an additional 18 hours. The mixture was partitioned between water and EtOAc. The organic phase was further washed with water, collected, dried (MgSO ₄ ) and the solvent evaporated in vacuo to give the subtitle compound as a yellow oil. Yield: 0.25g.
MS APCI + 319 [M + H] ⁺

iii) The product of step (ii) (4- (azidomethyl) -4 in 1- {4-methoxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methanamine ethanol (10 ml) -Methoxy-1- [2- (2-phenylethoxy) ethyl] piperidine) (0.25 g) was treated with 10% palladium / charcoal (20 mg) and then stirred for 3 hours under 4 bar pressure of hydrogen gas. did. The mixture was filtered through glass fiber paper and the filtrate was evaporated in vacuo to give the subtitle compound as a yellow gum. Yield: 0.18g.
MS APCI + 293 [M + H] ⁺

iv) 8- (Benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[({4-methoxy-1- [2- (2-phenylethoxy) ) Ethyl] piperidin-4-yl} methyl) amino] ethyl} quinolin-2 (1H) -one subtitle compound according to the procedure outlined in step (vi) of Example 2, product of step (iii) (1 -{4-methoxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methanamine) (0.18 g) and the product of Example 2 step (iii) (8- (benzyloxy ) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) quinolin-2 (1H) -one) (0.195 g) using DMSO (2 ml) and heated in the presence of sodium iodide (88 mg) and potassium carbonate (0.166 g) at 90 ° C. for 6 hours. Purification by column chromatography eluting with EtOAc / isohexane (8: 4) gave the subtitle compound as a yellow gum. Yield: 60 mg.
MS APCI + 701 [M + H] ⁺

v) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-methoxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl The quinolin-2 (1H) -one title compound is prepared according to the procedure outlined in Example 2, step (vii) and the product of step (iv) (8- (benzyloxy) -5-{(1R) -1 -{[Tert-butyl (dimethyl) silyl] oxy} -2-[({4-methoxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline- Prepared by treatment with 2 (1H) -one) (60 mg) in THF (2 ml) with triethylamine trihydrofluoride (0.14 ml) and stirring at room temperature for 5 hours. Volatiles were evaporated and the residue azeotroped with toluene (x2). The residue was dissolved in ethanol (10 ml) followed by addition of 10% palladium / charcoal (20 mg) and then stirred overnight under 5 bar pressure of hydrogen gas. The mixture was filtered and the solvent evaporated in vacuo to give a yellow gum. Purify by reverse phase HPLC using a Symmetry® C8 5 micron 19 × 50 mm column, eluting with a gradient of 0-50% acetonitrile in 0.2% aqueous TFA to give the title compound as an off-white solid. It was. Yield: 20 mg.
MS APCI + 496 [M + H] ^+
1 H NMR (DMSO) δ 10.54 (bs, 1H), 10.50 (bs, 1H), 8.77 (bs, 1H), 8.23 (d, 1H), 7.20 (m, 5H), 7.0 (d, 1H), 6.60 (d, 1H), 6.20 (bs, 1H), 5.40 (m, 1H), 3.60 (m, 4H), 2.90 (m, 4H), 2.0 (m, 4H), 1.80 (m, 2H), 1.20 ( m, 2H).

Example 19
4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} -1,3- Benzothiazol-2 (3H) -one

i) [1- (2-Phenethyloxy-ethyl) -piperidin-4-yl] -methanol 2-phenethyloxyacetaldehyde (WO 94/27601) (0.72 g) and 4-piperidine-in methanol in methanol (20 ml) A solution of methanol (0.5 g) was treated with acetic acid (20 mg) and stirred at room temperature for 30 minutes. Then sodium cyanoborohydride (103 mg) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was made basic by adding concentrated aqueous ammonia (1 ml) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on a silica column, eluting with 1% concentrated aqueous ammonia and 5% ethanol in dichloromethane to give the subtitle compound. Yield: 0.1 g.
MS APCI + 264 (M + H ⁺ , 100%)
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30-7.18 (m, 5H), 3.67-3.64 (m, 2H), 3.60-3.57 (m, 2H), 3.49-3.47 (m, 2H), 2.95-2.87 (m, 4H), 2.58-2.55 (m, 2H), 2.02-1.96 (m, 2H), 1.72-1.69 (m, 2H), 1.54-1.43 (m, 1H), 1.33-1.23 (m, 2H) .

ii) 1- (2-Phenethyloxy-ethyl) -piperidine-4-carbaldehyde A solution of dimethyl sulfoxide (32 mg) in dichloromethane (3 ml) was cooled to −78 ° C. and oxalyl chloride (53 mg) in dichloromethane (1 ml). ) Solution was added dropwise. The reaction mixture was stirred at −78 ° C. for 15 minutes and then the product of step (i) ([1- (2-phenethyloxy-ethyl) -piperidin-4-yl] -methanol) in dichloromethane (1 ml) ( 100 mg) solution was added dropwise. The reaction mixture was stirred at −78 ° C. for 1 hour, then treated dropwise with triethylamine (77 mg), then the cooling bath was removed and the mixture was allowed to warm to room temperature. The reaction mixture was added to aqueous phosphate buffer (pH 7.2) (10 ml) and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the subtitle compound. Yield: 99 mg.
MS APCI + 262 (M + H) ⁺

iii) 4- (Benzyl in 7-[(1R) -2-azido-1-hydroxyethyl] -4- (benzyloxy) -1,3-benzothiazol-2 (3H) -onedimethylsulfoxide (8 ml) Oxy) -7-[(1R) -2-bromo-1-hydroxyethyl] -1,3-benzothiazol-2 (3H) -one (WO 2004/016578) (340 mg) was added to a solution of sodium azide ( 231 mg) and sodium iodide (147 mg) were added. The reaction mixture was heated at 65 ° C. for 5 hours. The mixture was then partitioned between ethyl acetate and water and the organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography on a silica column, eluting with 20% ethyl acetate in toluene to give the subtitle compound. Yield: 195 mg.
¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.89 (s, 1H), 7.54 (d, 2H), 7.38 (t, 2H), 7.33-7.29 (m, 1H), 7.02 (s, 2H), 6.13 (d, 1H), 5.25 (s, 2H), 4.81-4.77 (m, 1H), 3.40-3.27 (m, 2H).

iv) 7-[(1R) -2-amino-1-hydroxyethyl] -4- (benzyloxy) -1,3-benzothiazol-2 (3H) -one hydrochloride ethanol (8 ml) and tetrahydrofuran (4 ml) A solution of the product of step (iii) (7-((1R) -2-azido-1-hydroxyethyl) -4-benzyloxy-3H-benzothiazol-2-one) (195 mg) in a mixture of Treated with 10% palladium / carbon catalyst (20 mg) and the resulting mixture was stirred vigorously under 3 atmospheres of hydrogen gas for 20 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica column, eluting with 1% concentrated aqueous ammonia and 12% methanol in dichloromethane. The product obtained was dissolved in 1,4-dioxane and treated dropwise with 4M hydrogen chloride solution in 1,4-dioxane (0.5 ml). The solvent was evaporated under reduced pressure to give the subtitle compound. Yield: 160 mg.
MS APCI + 315 (MH) ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 8.01 (s, 2H), 7.55 (d, 2H), 7.39 (t, 2H), 7.31 (t, 1H), 7.04 (q, 2H), 6.39 ( d, 1H), 5.26 (s, 2H), 4.83 (dt, 1H), 2.97-2.83 (m, 2H).

v) 4- (Benzyloxy) -7-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} Product of step (iv) (7-[(1R) -2-amino-1-hydroxyethyl] -4- (benzyl ) in 1,3-benzothiazol-2 (3H) -onemethanol (20 ml) Oxy) -1,3-benzothiazol-2 (3H) -one hydrochloride) (133 mg) and the product of step (ii) (1- (2-phenethyloxy-ethyl) -piperidine-4-carbaldehyde) ( 99 mg) was treated with acetic acid (20 mg) and stirred at room temperature for 2 hours. Then sodium cyanoborohydride (9 mg) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was made basic by adding concentrated aqueous ammonia and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica column, eluting with 1% concentrated aqueous ammonia and 6% methanol in dichloromethane to give the subtitle compound. Yield: 28 mg.
MS APCI + 560 (MH) ⁺

vi) 4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} -1, The product of step (v) (4- (benzyloxy) -7-{(1R) -1-) in 3-benzothiazol-2 (3H) -one ethanol (10 ml) and concentrated hydrochloric acid (0.1 ml). Hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} -1,3-benzothiazol-2 (3H) -one) (28 mg) And a 10% palladium / carbon (25 mg) mixture was stirred vigorously under 4 atmospheres of hydrogen gas for 7 hours. Thereafter, further 10% palladium / carbon (25 mg) and concentrated hydrochloric acid (0.1 ml) were added and stirring under hydrogen continued for 16 hours. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase HPLC, eluting with a gradient of 5% to 50% acetonitrile in 0.2% aqueous ammonia to give the title compound. Yield: 6 mg.
MS APCI + 472 (M + H) ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 7.29-7.16 (m, 5H), 6.85 (d, 1H), 6.68 (d, 1H), 4.58-4.55 (m, 1H), 3.57 (t, 2H ), 3.47 (t, 2H), 2.79 (t, 4H), 2.67-2.54 (m, 2H), 2.42-2.33 (m, 4H), 1.85 (t, 2H), 1.58 (d, 2H), 1.28- 1.25 (m, 1H), 1.10-1.00 (m, 2H).

Example 20
4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [3- (2-phenylethoxy) propyl] azetidin-3-yl} methyl) amino] ethyl} -1,3- Benzothiazol-2 (3H) -one hydrochloride

i) A solution of 3- (2-phenylethoxy) -propanoic acid (718 mg) in {1- [3- (2-phenylethoxy) propanoyl] azetidin-3-yl} methanol dichloromethane (10 ml) was added to oxalyl chloride. After treatment with (940 mg) and stirring at room temperature for 4 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (5 ml) and the resulting solution was a solution of 3-azetidinemethanol (460 mg) and triethylamine (747 mg) in a mixture of dichloromethane (10 ml) and 1-methyl-2-pyrrolidinone (3 ml). It was dripped in. The reaction mixture was stirred for 2 hours, then partitioned between dichloromethane and brine, the aqueous layer was extracted again with additional dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica column, eluting with 6% methanol in dichloromethane to give the subtitle compound. Yield: 560 mg.
MS APCI + 264 (M + H) ⁺

ii) The product of step (i) ({1- [3- (2-phenylethoxy) ) in {1- [3- (2-phenylethoxy) propyl] azetidin-3-yl} methanol tetrahydrofuran (10 ml) A solution of propanoyl] azetidin-3-yl} methanol) (560 mg) was treated with a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (6.3 ml). The mixture was heated at 50 ° C. for 30 minutes and then cooled to room temperature before adding methanol (1 ml) and stirring the solution for 15 minutes. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of methanol (24 ml) and concentrated hydrochloric acid (0.2 ml) and refluxed for 1 hour. The solvent was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate and brine. The aqueous layer was treated with excess solid sodium bicarbonate and the mixture was extracted six times with dichloromethane. The combined dichloromethane washings were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the subtitle compound. Yield: 520 mg.
MS APCI + 250 (M + H) ⁺

iii) 1- [3- (2-Phenylethoxy) propyl] azetidine-3-carbaldehyde subtitle compound is converted to the product of step (ii) ({1- [3- (2-phenylethoxy) propyl] azetidine-3 -Il} methanol) (350 mg) using the method of Example 19, step (ii) to give the subtitle compound. Yield: 280 mg.
MS APCI + 248 (M + H) ⁺

iv) 7-[(1R) -2-Amino-1-hydroxyethyl] -4-hydroxy-1,3-benzothiazol-2 (3H) -one hydrochloride in methanol (60 ml) and concentrated hydrochloric acid (4 ml) The product of Example 19, step (iv) (7-((1R) -2-amino-1-hydroxyethyl) -4-benzyloxy-3H-benzothiazol-2-one hydrochloride) (1.8 g ) Was vigorously stirred in the presence of 10% palladium / carbon catalyst (0.36 g) under 4 atmospheres of hydrogen gas for 2 hours. Further 10% palladium / carbon catalyst (0.24 g) was added and stirring was continued for 1 hour under hydrogen. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give the subtitle compound. Yield: 1.3g.
MS APCI + 227 (M + H) ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 11.70 (s, 1H), 10.21 (s, 1H), 8.04 (s, 3H), 6.92 (d, 1H), 6.79 (d, 1H), 6.32 ( d, 1H), 4.81-4.79 (m, 1H), 2.90-2.81 (m, 2H).

v) 4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [3- (2-phenylethoxy) propyl] azetidin-3-yl} methyl) amino] ethyl} -1, 3-Benzothiazol-2 (3H) -one hydrochloride The product of step (iv) (7-[(1R) -2-amino-1-hydroxyethyl] -4-hydroxy-1 in 5 ml of methanol) , 3-Benzothiazol-2 (3H) -one hydrochloride) (193 mg) and the product of step (iii) (1- (3-phenethyloxy-propyl) -azetidine-3-carbaldehyde) (140 mg) Was treated with acetic acid (140 mg) and stirred at room temperature for 40 minutes. Sodium cyanoborohydride (29 mg) was added and stirring was continued for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml) containing concentrated aqueous ammonia (1 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on a silica column, eluting with 1% concentrated aqueous ammonia in dichloromethane and 20% methanol. The resulting product was converted to the hydrochloride salt by dissolving in methanol and adding excess hydrogen chloride (4M in 1,4-dioxane). The solvent was then removed under reduced pressure to give the title compound. Yield: 280 mg.
MS APCI + 458 (M + H) ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 11.70 (s, 1H), 10.95-10.80 (m, 1H), 10.23 (s, 1H), 9.43 (s, 1H), 8.95 (s, 1H), 7.32-7.17 (m, 5H), 6.95-6.91 (m, 1H), 6.79 (d, 1H), 6.45 (s, 1H), 4.99-4.97 (m, 1H), 4.14-4.11 (m, 1H), 4.03-3.99 (m, 2H), 3.83-3.80 (m, 1H), 3.61-3.57 (m, 4H), 3.44 (t, 2H), 3.22-3.20 (m, 2H), 3.17-3.13 (m, 2H ), 3.00-2.97 (m, 2H), 2.82 (t, 2H), 1.73-1.67 (m, 2H).

Example 21
4-hydroxy-7-{(1R) -1-hydroxy-2-[(2- {1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} ethyl) amino] ethyl} -1, 3-Benzothiazol-2 (3H) -one

i) (2-Phenylethoxy) -acetyl chloride in 1- [4- (2-hydroxy-ethyl) -piperidin-1-yl] -2-phenethyloxy- ethanone tetrahydrofuran (5 ml) (WO 2002/059098) A solution of (1.1 g) was added dropwise to a solution of 4-piperidine-ethanol (0.72 g) and triethylamine (1.7 g) in tetrahydrofuran (20 ml) and added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water and the organic layer was washed with aqueous dilute hydrochloric acid and then brine. The solvent was removed under reduced pressure to give the subtitle compound. Yield: 1.23g.
MS APCI + 292 (M + H ⁺ , 100%)

ii) The product of step (i) (1- [4- (2-hydroxyethyl) in 2- [1- (2-phenethyloxy-ethyl) -piperidin-4-yl] -ethanol tetrahydrofuran (20 ml) A solution of -piperidin-1-yl] -2-phenethyloxy-ethanone) (1.23 g) was treated with a solution of 1M borane-tetrahydrofuran complex in tetrahydrofuran (12.7 ml). The mixture was heated at 50 ° C. for 2 hours and then cooled to room temperature. Methanol (10 ml) was added and the solution was stirred for 15 minutes. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of methanol (30 ml) and concentrated hydrochloric acid (0.5 ml) and refluxed for 1 hour. The solvent was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate and brine. The aqueous layer was treated with excess solid sodium bicarbonate and then extracted three times with dichloromethane. The combined dichloromethane washings were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 1% triethylamine and 2% methanol in dichloromethane to give the subtitle compound. Yield: 0.5g.
MS APCI + 278 (M + H ⁺ , 100%)

iii) [1- (2-Phenethyloxy-ethyl) -piperidin-4-yl] -acetaldehyde product of step (ii) in dichloromethane (3 ml) (2- [1- (2-phenethyloxy-ethyl)- To a solution of piperidin-4-yl] -ethanol) (250 mg) and triethylamine (273 mg) cooled to −10 ° C. was added a solution of sulfur trioxide-pyridine complex (431 mg) in dimethyl sulfoxide (3 ml) in one portion. . The cooling bath was removed and the mixture was stirred vigorously for 10 minutes. The reaction mixture was partitioned between ethyl acetate (50 ml) and aqueous phosphate buffer (50 ml, pH 7.2), the organic layer was washed with brine and the solvent was evaporated under reduced pressure to give the subtitle compound. . Yield: 170 mg.
MS APCI + 276 (M + H ⁺ , 100%)

iv) 4-hydroxy-7-{(1R) -1-hydroxy-2-[(2- {1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} ethyl) amino] ethyl}- 1,3-benzothiazol-2 (3H) -one The title compound is obtained from the product of Example 20, step (iv) (7-[(1R) -2-amino-1-hydroxyethyl] -4-hydroxy- 1,3-benzothiazol-2 (3H) -one hydrochloride) (80 mg) and the product of step (iii) ([1- (2-phenethyloxy-ethyl) -piperidin-4-yl] -acetaldehyde) ( 88 mg) using the method of Example 20, step (v). Purification by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 16% methanol in dichloromethane gave the title compound. Yield: 16 mg.
MS APCI + 486 (M + H ⁺ , 100%)
¹ H NMR (400 MHz, d ₆ -DMSO) δ 7.29-7.16 (m, 5H), 6.85 (d, 1H), 6.68 (d, 1H), 4.57 (q, 1H), 3.57 (t, 2H), 3.46 (t, 2H), 2.80-2.76 (m, 4H), 2.68-2.53 (m, 2H), 2.39 (t, 2H), 1.84 (t, 2H), 1.52 (d, 2H), 1.31-1.26 ( m, 2H), 1.25-1.15 (m, 1H), 1.10-1.03 (m, 2H).

Example 22
4-hydroxy-7-[(1R) -1-hydroxy-2-({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} amino) ethyl] -1,3-benzothiazole- 2 (3H) -on

i) Phenethyloxy- sodium hydride acetate (60% in mineral oil) (3.3 g) was added in portions to a solution of 2-phenyl-ethanol (10.0 g) in dimethylformamide (100 ml) under a nitrogen atmosphere. It was. After 30 minutes, sodium 2-chloroacetate (9.6 g) was added and stirred at ambient temperature for 30 minutes, then warmed to 60 ° C. for 1 hour. The reaction mixture was then cooled, poured into water (500 ml) and extracted with ether (500 ml). The aqueous phase was acidified with concentrated hydrochloric acid to pH ˜1 and extracted with ether (2 × 500 ml). The new ether extracts were combined, dried over magnesium sulfate and evaporated to give the subtitle compound as an oil. Yield: 12.0 g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.38-7.16 (m, 5H), 4.12 (s, 2H), 3.80 (t, 2H), 2.96 (t, 2H).

ii) 2-phenethyloxy-ethanol 1M borane-tetrahydrofuran complex (130 ml) is added over 30 minutes to a solution of the product of step (i) (phenethyloxy-acetic acid) (12.0 g) in tetrahydrofuran (200 ml). At 0 ° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was warmed to ambient temperature for 1.5 hours and then methanol (100 ml) was added dropwise [Note: gas evolution]. The reaction mixture was evaporated to dryness and the residue was redissolved in ether (400 ml), extracted twice with saturated sodium bicarbonate solution, once with brine, dried over magnesium sulfate and evaporated to an oil. (8.5 g). Purification by bulb-bulb distillation under high vacuum on a kugelruhr apparatus gave the subtitle compound as an oil. Yield: 5.0 g.
GC / MS 165 (71%), 104 (100%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33-7.27 (m, 2H), 7.24-7.19 (m, 3H), 3.74-3.68 (m, 4H), 3.57-3.55 (m, 2H), 2.91 (t , 2H), 1.88 (t, 1H).

iii) Toluene-4-sulfonic acid 2-phenethyloxy-ethyl ester / 2-phenethyloxyethyl chloride toluenesulfonyl chloride (1.40 g) at ambient temperature in the product of step (ii) in pyridine (5 ml) ( A solution of 2-phenethyloxy-ethanol) (1.13 g) and 4-dimethylaminopyridine (20 mg) was added to give a purple solution. After 18 hours, the reaction mixture was concentrated by rotary evaporation. The residue is dissolved in ethyl acetate, extracted twice with 2M hydrochloric acid, twice with saturated sodium bicarbonate solution and once with brine, dried over magnesium sulfate, evaporated, subtitle compound and 2-phenethyl chloride. A mixture of oxyethyl (2: 1 by NMR) was obtained as an oil. Yield: 1.4g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.79 (d, 2H), 7.35-7.14 (m, 7H), 4.17-4.12 (m, 2H), 3.66-3.57 (m, 4H), 2.81 (t, 2H ), 2.44 (s, 3H).
(+ Signal of 2-phenethyloxyethyl chloride): δ 7.34-7.14 (m, 7H), 4.16-4.10 (m, 2H), 3.74-3.68 (m, 4H), 2.91 (t, 2H).
This was crude and used in the next step (iv) without further purification.

iv) 1- (2-Phenethyloxy-ethyl) -piperidin-4-one 1-methylpyrrolidin-2-one (15 ml) and triethylamine (4 ml) crude mixture of step (iii) (toluene-4- Sulfonic acid 2-phenethyloxy-ethyl ester / 2-phenethyloxyethyl chloride [2: 1]) (1.9 g) was treated with 4-piperidinone hydrochloride (1.1 g) and heated at 85 ° C. for 2 hours. . Upon cooling, the reaction mixture was diluted with ethyl acetate, extracted twice with saturated sodium bicarbonate solution, once with brine, dried over sodium sulfate and evaporated to give the subtitle compound as an oil. Yield: 1.6g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35-7.17 (m, 5H), 3.76-3.58 (m, 8H), 2.95-2.86 (m, 3H), 2.77 (t, 2H), 2.69 (t, 1H ), 2.42 (t, 2H).

v) 4-hydroxy-7- {1-hydroxy-2- [1- (2-phenethyloxy-ethyl) -piperidin-4-ylamino] -ethyl} -3H-benzothiazol-2-one in methanol (10 ml) The product of step (iv) (1- (2-phenethyloxy-ethyl) -piperidin-4-one) (150 mg) was prepared from the product of step 20 of Example 20 (7- (2-amino- 1-hydroxy-ethyl) -4-hydroxy-3H-benzothiazol-2-one hydrochloride) (100 mg) and stirred at ambient temperature for 30 minutes. Sodium cyanoborohydride (40 mg) was added and stirred at ambient temperature for 18 hours. 8:80 ammonia solution (0.5 ml) was added and evaporated to dryness. Purification by mass directed reverse phase HPLC gave the title product as a white solid. Yield: 20 mg.
MS APCI + 458 (M + H) ^+
1 H NMR (400 MHz, d ₆ -DMSO) [90 ° C] δ 7.32-7.17 (m, 5H), 6.91 (d, 1H), 6.73 (d, 1H), 4.56 (t, 1H), 3.64 (t , 2H), 3.51 (t, 2H), 2.83 (t, 3H), 2.80-2.67 (m, 4H), 2.46 (t, 2H), 2.44-2.35 (m, 1H), 2.03 (t, 2H), 1.72 (t, 2H), 1.26 (t, 1H).

Example 23
4-hydroxy-7-{(1R) -1-hydroxy-2-[({(3R) -1- [2- (2-phenylethoxy) ethyl] piperidin-3-yl} methyl) amino] ethyl}- 1,3-benzothiazol-2 (3H) -one

i) (3R) -1- (2-phenethyloxy-acetyl) -piperidine-3-carboxylic acid ethyl ester ethyl (R) -nipecotate-L-tartrate (2.56 g) in anhydrous tetrahydrofuran (30 ml) and A solution of triethylamine (4.2 g) was treated dropwise at 0 ° C. with a solution of (2-phenylethoxy) -acetyl chloride (1.65 g) in anhydrous tetrahydrofuran (5 ml). The mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with aqueous dilute hydrochloric acid followed by brine. The organic layer was separated and dried, and the solvent was removed under reduced pressure to give the subtitle compound. Yield: 1.27g.
MS APCI + 320 (M + H) ⁺

ii) 1M solution of lithium aluminum hydride (6.3 ml) in (3R)-[1- (2-phenethyloxy-ethyl) -piperidin-3-yl] -methanol tetrahydrofuran was added to anhydrous tetrahydrofuran (20 ml). Added dropwise with stirring under nitrogen. The mixture was then added to the product of step (i) ((3R) -1- (2-phenethyloxy-acetyl) -piperidine-3-carboxylic acid ethyl ester) (1.27 g) in anhydrous tetrahydrofuran (5 ml). Was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched by careful addition of ethyl acetate (3 ml) followed by water (5 ml). Most of the tetrahydrofuran was removed under reduced pressure, the residue was partitioned between brine and ethyl acetate, the aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed with excess dilute aqueous hydrochloric acid. The acidic layer was treated with excess solid sodium bicarbonate and the mixture was extracted twice with dichloromethane. The combined dichloromethane layers were evaporated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 1% triethylamine and 4% methanol in dichloromethane to give the subtitle compound. Yield: 0.42 g.
MS APCI + 264 (M + H) ⁺

iii) The (3R) -1- (2-phenethyloxy-ethyl) -piperidine-3-carbaldehyde subtitle compound is converted to the product of (ii) ((3R)-[1- (2-phenethyloxy-ethyl) -Piperidin-3-yl] -methanol) (420 mg) using the method of step (iii) of Example 21 to give the subtitle compound. Yield: 250 mg.
MS APCI + 262 (M + H) ⁺

iv) 4-hydroxy-7-((1R) -1-hydroxy-2-{[(3R) -1- (2-phenethyloxy-ethyl) -piperidin-3-ylmethyl] -amino} -ethyl) -3H The product of step 20 (iv) of Example 20 (7-[(1R) -2-amino-1-hydroxyethyl] -4-hydroxy- 1,3 in benzothiazol-2- onemethanol (5 ml) -Benzothiazol-2 (3H) -one hydrochloride) (70 mg) and the product of step (iii) ((3R) -1- (2-phenethyloxy-ethyl) -piperidine-3-carbaldehyde) (90 mg) Was treated with acetic acid (32 mg). Sodium cyanoborohydride (10 mg) was added and stirring was continued for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml) containing concentrated aqueous ammonia (1 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on a silica column, eluting with 1% concentrated aqueous ammonia and 11% methanol in dichloromethane, gave the title compound. Yield: 30 mg.
MS APCI + 472 (M + H) ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 7.28-7.15 (m, 5H), 6.85 (d, 1H), 6.69 (d, 1H), 4.57 (q, 1H), 3.57 (t, 2H), 3.47 (t, 2H), 2.78 (t, 3H), 2.71-2.54 (m, 3H), 2.41-2.34 (m, 4H), 1.87 (t, 1H), 1.64-1.51 (m, 4H), 1.42- 1.35 (m, 1H), 0.85-0.78 (m, 1H).

Example 24
4-hydroxy-7-{(1R) -1-hydroxy-2-[({(3S) -1- [2- (2-phenylethoxy) ethyl] piperidin-3-yl} methyl) amino] ethyl}- 1,3-benzothiazol-2 (3H) -one

i) The (3R) -1- (2-phenethyloxy-acetyl) -piperidine-3-carboxylic acid ethyl ester subtitle compound was obtained from ethyl (S) -nipecotate-D-tartrate (2.56 g) as in Example 23. The subtitle compound was obtained using the method of step (i). Yield: 1.37g.
MS APCI + 320 (M + H) ⁺

ii) (3R)-[1- (2-Phenethyloxy-ethyl) -piperidin-3-yl] -methanol subtitle compound is prepared from the product of step (i) ((3R) -1- (2-phenethyloxy- (Acetyl) -piperidine-3-carboxylic acid ethyl ester) (1.37 g) using the method of step (ii) of Example 23 to give the subtitle compound. Yield: 0.6g.
MS APCI + 264 (M + H) ⁺

iii) The (3R) -1- (2-phenethyloxy-ethyl) -piperidine-3-carbaldehyde subtitle compound is converted to the product of (ii) ((3R)-[1- (2-phenethyloxy-ethyl) -Piperidin-3-yl] -methanol) (250 mg) using the method of step (iii) of Example 21 to give the subtitle compound. Yield: 162 mg.
MS APCI + 262 (M + H) ⁺

iv) 4-hydroxy-7-((1R) -1-hydroxy-2-{[(3R) -1- (2-phenethyloxy-ethyl) -piperidin-3-ylmethyl] -amino} -ethyl) -3H The benzothiazol-2-one title compound was prepared by converting the product of step (iii) ((3R) -1- (2-phenethyloxy-ethyl) -piperidine-3-carbaldehyde) (70 mg) and the step of Example 20 From the product of (iv) (7-[(1R) -2-amino-1-hydroxyethyl] -4-hydroxy-1,3-benzothiazol-2 (3H) -one hydrochloride) (60 mg) Prepared using the method of Example 23, step (iv) to give the title compound. Yield: 22 mg.
MS APCI + 472 (M + H) ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 7.28-7.16 (m, 5H), 6.86 (d, 1H), 6.69 (d, 1H), 4.58-4.56 (m, 1H), 3.60-3.56 (m , 2H), 3.49-3.46 (m, 2H), 2.83-2.77 (m, 3H), 2.72-2.54 (m, 3H), 2.40-2.36 (m, 4H), 1.87 (t, 1H), 1.62-1.52 (m, 4H), 1.39-1.36 (m, 1H), 0.83-0.80 (m, 1H).

Example 25
5-{(1R) -2-[({1- [3- (benzyloxy) propyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8-hydroxyquinoline-2 (1H)-ON

i) 1- (3-Benzyloxy-propyl) -piperidin-4-one benzyl 3-bromo-propyl ether (2.29 g), 4-piperidinone hydrochloride hydrate (1.69 g) in dry DMF (40 ml). ), Potassium carbonate (anhydrous) (3.45 g) and potassium iodide (830 mg) were stirred at 85 ° C. for 24 hours. The reaction was poured into water (200 ml + brine 25 ml) and extracted with EtOAc. The organic extract was evaporated and the residue was chromatographed on silica gel eluting with 4: 3 EtOAc / isohexane to give the subtitle compound as a colorless oil. Yield: 1.8g.
¹ H NMR (300Mz, CDCl ₃ ) δ 7.39-7.32 (4H, m), 7.31-7.25 (1H, m), 4.52 (2H, d), 3.60-3.53 (2H, m), 2.79-2.70 (4H, m), 2.61-2.54 (2H, m), 2.48-2.41 (4H, m), 1.89-1.80 (2H, m)

ii) 4-Aminomethyl-1- (3-benzyloxy-propyl) -piperidin-4-ol subtitle compound is prepared according to the method of step (ii) of Example 26 and the product of step (i) (1- ( 3-Benzyloxy-propyl) -piperidin-4-one) (1.8 g). Yield: 2.2g.
¹ H NMR (300Mz, CDCl ₃ ) δ 7.38-7.31 (4H, m), 7.30-7.24 (1H, m), 4.50 (2H, s), 3.52 (2H, t), 2.71-2.63 (2H, m) , 2.60 (2H, s), 2.47 (2H, dd), 2.35 (2H, td), 1.88-1.79 (2H, m), 1.61-1.48 (5H, m)

iii) 8-benzyloxy-5- [2-{[1- (3-benzyloxy-propyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1- (tert-butyl-dimethyl-silanyloxy) -Ethyl] -1H-quinolin-2-one subtitle compound was prepared according to the method of Example 26, step (iii) (4-aminomethyl-1- (3-benzyloxy-propyl) -Piperidin-4-ol) (310 mg) and the product of Example 2 step (iii) (8- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) ) Silyl] oxy} ethyl) quinolin-2 (1H) -one) (122 mg) and obtained as a semi-solid. Yield: 110 mg.
1H NMR (300MHz, d ₆ -DMSO) δ 0.00 (3H, s), 0.23 (3H, s), 1.00 (9H, s), 1.67-1.57 (4H, m), 1.85 (3H, t), 2.54- 2.39 (4H, m), 2.64-2.53 (3H, m), 2.87-2.78 (1H, m), 3.03-2.93 (1H, m), 3.61 (2H, t), 4.14 (1H, s), 4.62 ( 2H, s), 5.35-5.29 (1H, m), 5.45 (2H, s), 6.72 (1H, d), 7.30 (1H, d), 7.37 (1H, d), 7.60-7.43 (8H, m) , 7.75 (2H, d), 8.47 (1H, d), 10.73 (1H, s)

iv) 5- [2-{[1- (3-Benzyloxy-propyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1- (tert-butyl-dimethyl-silanyloxy) -ethyl] -8 The -hydroxy-1H-quinolin-2-one subtitle compound was prepared by the method of Example 26, step (iv), from the product of step (iii) (8-benzyloxy-5- [2-{[1- (3 -Benzyloxy-propyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1- (tert-butyl-dimethyl-silanyloxy) -ethyl] -1H-quinolin-2-one) (100 mg) Produced and obtained as a solid. Yield: 19 mg.
¹ H NMR (300Mz, CDCl ₃ ) δ 8.47 (1H, d), 7.57-7.48 (5H, m), 7.21 (1H, d), 7.15 (1H, d), 6.78 (1H, d), 5.31-5.25 (1H, m), 4.68 (2H, s), 1.06 (9H, s), 0.24 (3H, s), 0.00 (3H, s)

v) 5- (2-{[1- (3-Benzyloxy-propyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1-hydroxy-ethyl) -8-hydroxy-1H-quinoline-2 The one title compound is obtained according to the method of Example 26, step (v), from the product of step (iv) (5- [2-{[1- (3-benzyloxy-propyl) -4-hydroxy-piperidine- 4-ylmethyl] -amino} -1- (tert-butyl-dimethyl-silanyloxy) -ethyl] -8-hydroxy-1H-quinolin-2-one) (19 mg), obtained as a solid. Yield: 9 mg.
MS APCI + 482 (M + H) ⁺
1H NMR (d ₆ -DMSO) δ 8.19 (1H, d), 7.40-7.24 (5H, m), 7.07 (1H, d), 6.91 (1H, d), 6.51 (1H, d), 5.07 (1H, t), 4.45 (2H, s), 3.46-3.43 (10H, m), 2.77-2.45 (153H, m), 2.46-2.29 (68H, m), 1.76-1.68 (1H, m), 1.55-1.46 ( 4H, m), 1.08-0.96 (10H, m)

Example 26
5-{(1R) -2-[({1- [2- (benzyloxy) ethyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8-hydroxyquinoline-2 (1H)-ON

i) 1- (2-Benzyloxy-ethyl) -piperidin- 4 -one 4 -piperidinone hydrochloride hydrate (0.714 g), potassium iodide (50 mg), benzyl 2-bromoethyl ether (0.8 g) Stir in refluxing MeCN (20 ml) in the presence of K ₂ CO ₃ (1.28 g) and reflux. The mixture was poured into water (150 ml) and extracted into EtOAc. Dried (MgSO ₄ ) and evaporated to give an oil (880 mg). This was chromatographed on silica gel eluting with 3: 2 EtOAc-isohexane to give the subtitle compound as a colorless oil. Yield: 550 mg.
1H NMR (300Mz, CDCl ₃ ) δ 7.40-7.32 (4H, m), 7.33-7.28 (1H, m), 4.57 (2H, s), 3.63 (2H, t), 2.82 (4H, t), 2.75 ( 2H, t), 2.47 (4H, t)

ii) 4-aminomethyl-1- (2-benzyloxy-ethyl) -piperidin-4-ol trimethylsilyl cyanide (0.351 g) was cooled to the product of step (i) (1- (2 -Benzyloxy-ethyl) -piperidin-4-one) (550 mg) + zinc iodide (30 mg). After 1 hour at 0 ° C., the mixture was heated at 60 ° C. for an additional 3 hours and then cooled to ambient temperature. All volatiles were evaporated in vacuo at 60 ° C. and the residue was dissolved in ether (10 ml) + dry THF (5 ml) and cooled in ice. Lithium aluminum hydride (1M solution in ether, 4 ml) was added and the mixture was stirred for 2 hours with cooling in an ice bath. After 2 hours, the reaction was warmed to ambient temperature. 1M NaOH (20 ml) was added. Excess ether and EtOAc were added and the resulting biphasic mixture was separated. The aqueous solution was further extracted with EtOAc. The combined organic solution was dried over Na ₂ SO ₄ , filtered and evaporated to give the subtitle compound as an oil. Yield: 0.45g.
1H NMR ((300Mz, CDCl ₃ ) δ 7.38-7.31 (4H, m), 7.30-7.23 (1H, m), 4.54 (2H, s), 3.60 (2H, t), 2.74-2.67 (2H, m) , 2.65 (2H, t), 2.60 (2H, s), 2.46-2.36 (2H, m), 1.77-1.35 (2H, m), 1.60-1.52 (3H, m)

iii) benzyloxy-5- [2-{[1- (2-benzyloxy-ethyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1- (tert-butyl-dimethyl-silanyloxy) -ethyl ] -1H-quinolin-2-one The product of Example 2 step (iii) (8- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl) ] Oxy} ethyl) quinolin-2 (1H) -one) (122 mg) and the product of step (ii) (4-aminomethyl-1- (2-benzyloxy-ethyl) -piperidin-4-ol) (290 mg) ), And N, N-diisopropylethylamine (129 mg) were dissolved in dry NMP (2 ml) and heated in a microwave oven at 100 ° C. for 90 minutes. The reaction was poured into 10% brine (25 ml) and then extracted with EtOAc. Dried (MgSO ₄ ) and evaporated the organic solution to give a brown oil. Purification by chromatography on silica gel eluting with 17: 3 EtOAc / MeOH + 10% Et ₃ N gave the subtitle compound as an amber oil. Yield: 170 mg.
1H NMR (300Mz, CDCl ₃ ) δ 0.24 (3H, s), 1.06 (9H, s), 5.34 (2H, s), 6.85 (1H, d), 7.19 (1H, d), 7.30 (1H, d) , 7.49-7.45 (11H, m), 7.54-7.49 (10H, m), 7.63-7.56 (9H, m), 8.43 (1H, d), 9.39 (1H, s), 5.29-5.24 (1H, m) , 4.71-4.66 (4H, m)

iv) 5- [2-{[1- (2-Benzyloxy-ethyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1- (tert-butyl-dimethyl-silanyloxy) -ethyl] -8 -The product of step (iii) (benzyloxy-5- [2-{[1- (2-benzyloxy--) in hydroxy-1H-quinolin-2-one ethanol (3 ml) + 2M HCl (0.25 ml) Ethyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1- (tert-butyl-dimethyl-silanyloxy) -ethyl] -1H-quinolin-2-one) (170 mg) at 5 bar pressure and 10 Hydrogenated with% Pd / C catalyst (10 mg). After 3 hours, more catalyst (5 mg) was added and hydrogenation was continued for a further 6 hours. The catalyst was filtered off and the solvent was evaporated. The residue was purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile, subtitle. A compound was obtained. Yield: 57 mg.
¹ H NMR (300Mz, d ₆ -DMSO) δ 8.44 (1H, d), 7.57-7.41 (5H, m), 7.20 (1H, d), 7.08 (1H, d), 6.67 (1H, d), 5.32 -5.24 (1H, m), 4.64 (2H, s), 3.69 (3H, t), 3.04-2.93 (1H, m), 2.87-2.76 (2H, m), 1.00 (9H, s), 0.22 (3H , s), 0.18 (3H, s)

v) 5- (2-{[1- (2-Benzyloxy-ethyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1-hydroxy-ethyl) -8-hydroxy-1H-quinoline-2 The product of step (iv) in 5- one dry THF (1 ml) (5- [2-{[1- (2-benzyloxy-ethyl) -4-hydroxy-piperidin-4-ylmethyl] -amino} -1 -(Tert-Butyl-dimethyl-silanyloxy) -ethyl] -8-hydroxy-1H-quinolin-2-one) (50 mg) was treated with triethylamine trihydrofluoride (154 mg) and nitrogen at ambient temperature overnight. Stirred under. Volatiles were evaporated in vacuo at 75 ° C. The residue was dissolved in MeOH, applied to an SCX cartridge, further washed with MeOH and finally eluted with 7N methanolic ammonia. Evaporation gave a rubbery material. This was dried in vacuo to give the title compound as a semi-solid. Yield: 30 mg.
MS APCI + 468 (M + H) ⁺
1H NMR (300Mz, d ₆ -DMSO) δ 8.19 (1H, d), 7.39-7.24 (5H, m), 7.07 (1H, d), 6.91 (1H, d), 6.49 (1H, d), 5.05 ( 1H, t), 4.47 (2H, s), 3.53 (2H, t), 2.75-2.70 (2H, m), 2.64-2.55 (7H, m), 2.55-2.46 (12H, m), 2.42-2.32 ( 2H, m), 1.53-1.43 (4H, m), 1.00 (14H, t)

乾燥ＤＭＦ(２ml)中の、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)の溶液を、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(２,５−ジクロロフェニル)メタンアミン(７２mg)で、環境温度で処理した。１時間後、揮発性物質を真空で蒸発させ、残渣をトリエチルアミン 三フッ化水素酸塩(０.１７５ml)で処理し、さらに４８時間撹拌した。揮発性物質を真空で蒸発させ、残渣をＤＭＳＯ(２ml)に再度溶解した。残渣を Varian SCX カラム(２５ｇ)に負荷した。これを１：１ イソプロパノール／アセトニトリル(２×４０ml)で溶出し、フラクションを取った。生成物のフラクションを１：２：２ 水酸化アンモニウム／イソプロパノール／アセトニトリル(４０ml)で溶出した。揮発性物質を真空で蒸発させ、粗製の表題生成物を得た。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：２８mg。
MS APCI+ 533/535 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.51(t, 1H), 8.17(d, 1H), 7.48(m, 1H), 7.34(m, 2H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.98(t, 1H), 4.30(d, 2H), 2.79(bd, 2H), 2.72(d, 2H), 2.50(m, 2H), 2.43(m, 1H), 2.32(t, 2H), 1.93(m, 2H), 1.75(t, 2H), 1.26(m, 2H) Example 27
N- (2,5-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide

The product of step 6 (iii) of Example 6 (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- () in dry DMF (2 ml). 8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g) was added to HATU (0.14 g), triethylamine ( 0.037 ml) and 1- (2,5-dichlorophenyl) methanamine (72 mg) at ambient temperature After 1 hour, the volatiles were evaporated in vacuo and the residue was triethylamine trihydrofluoride (0 175 ml) and stirred for a further 48 hours The volatiles were evaporated in vacuo and the residue was redissolved in DMSO (2 ml) The residue was loaded onto a Varian SCX column (25 g) which was 1: 1. Elution with isopropanol / acetonitrile (2 x 40 ml) and fractions The product fraction was eluted with 1: 2: 2 ammonium hydroxide / isopropanol / acetonitrile (40 ml) The volatiles were evaporated in vacuo to give the crude title product, which was obtained by reverse phase HPLC. Purify using Xterra® C8 5 micron 19 × 50 mm column, eluting with a gradient of 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile to give the title compound as a pale yellow foam Obtained as material Yield: 28 mg.
MS APCI + 533/535 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.51 (t, 1H), 8.17 (d, 1H), 7.48 (m, 1H), 7.34 (m, 2H), 7.07 (d, 1H), 6.91 (d , 1H), 6.50 (d, 1H), 4.98 (t, 1H), 4.30 (d, 2H), 2.79 (bd, 2H), 2.72 (d, 2H), 2.50 (m, 2H), 2.43 (m, 1H), 2.32 (t, 2H), 1.93 (m, 2H), 1.75 (t, 2H), 1.26 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−ビフェニル−２−イルメタンアミン(７５mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：３１mg。
MS APCI+ 541 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.32(t, 1H), 8.17(d, 1H), 7.38(m, 8H), 7.20(d, 1H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.98(t, 1H), 4.17(d, 2H), 2.76(m, 2H), 2.71(d, 2H), 2.50(m, 2H), 2.40(m, 1H), 2.24(t, 2H), 1.90(m, 2H), 1.73(t, 2H), 1.20(m, 2H). Example 28
N- (biphenyl-2-ylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Prepared according to the procedure described in Example 27 in dry DMF (2 ml) using biphenyl-2-ylmethanamine (75 mg) by reverse phase HPLC Xterra® C8 5 micron 19 × Purification using a 50 mm column, eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile, gave the title compound as a pale yellow foam, yield: 31 mg.
MS APCI + 541 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.32 (t, 1H), 8.17 (d, 1H), 7.38 (m, 8H), 7.20 (d, 1H), 7.07 (d, 1H), 6.91 (d , 1H), 6.50 (d, 1H), 4.98 (t, 1H), 4.17 (d, 2H), 2.76 (m, 2H), 2.71 (d, 2H), 2.50 (m, 2H), 2.40 (m, 1H), 2.24 (t, 2H), 1.90 (m, 2H), 1.73 (t, 2H), 1.20 (m, 2H).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(２,６−ジクロロフェニル)メタンアミン(７２mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：３２mg。
MS APCI+ 532/534/536 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.31(m, 1H), 8.16(d, 1H), 7.48(m, 2H), 7.33(t, 1H), 7.08(d, 1H), 6.92(d, 1H), 6.51(d, 1H), 4.99(t, 1H), 4.47(d, 2H), 2.73(m, 4H), 2.50(m, 3H), 2.23(t, 2H), 1.87(t, 2H), 1.71(t, 2H), 1.15(m, 2H) Example 29
N- (2,6-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Prepared according to the procedure described in Example 27 using (2,6-dichlorophenyl) methanamine (72 mg) in dry DMF (2 ml) by reverse phase HPLC Xterra® C8 5 micron 19 Purification using a x50 mm column, eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile, gave the title compound as a pale yellow foam, yield: 32 mg.
MS APCI + 532/534/536 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.31 (m, 1H), 8.16 (d, 1H), 7.48 (m, 2H), 7.33 (t, 1H), 7.08 (d, 1H), 6.92 (d , 1H), 6.51 (d, 1H), 4.99 (t, 1H), 4.47 (d, 2H), 2.73 (m, 4H), 2.50 (m, 3H), 2.23 (t, 2H), 1.87 (t, 2H), 1.71 (t, 2H), 1.15 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−シクロヘキシルメタンアミン(４６mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：２３mg。
MS APCI+ 471 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.17(d, 1H), 7.92(t, 1H), 7.06(d, 1H), 6.90(d, 1H), 6.49(d, 1H), 4.96(t, 1H), 2.87(m, 2H), 2.75(m, 2H), 2.70(d, 2H), 2.46(m, 2H), 2.38(m, 1H), 2.19(t, 2H), 1.90(m, 2H), 1.68(m, 7H), 1.33(m, 1H), 1.14(m, 5H), 0.84(m, 2H) Example 30
N- (cyclohexylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine- 1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Prepared according to the procedure described in Example 27 using cyclohexylmethanamine (46 mg) in dry DMF (2 ml) using Xterra® C8 5 micron 19 × 50 mm column by reverse phase HPLC. Eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile to give the title compound as a pale yellow foam, yield: 23 mg.
MS APCI + 471 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.17 (d, 1H), 7.92 (t, 1H), 7.06 (d, 1H), 6.90 (d, 1H), 6.49 (d, 1H), 4.96 (t , 1H), 2.87 (m, 2H), 2.75 (m, 2H), 2.70 (d, 2H), 2.46 (m, 2H), 2.38 (m, 1H), 2.19 (t, 2H), 1.90 (m, 2H), 1.68 (m, 7H), 1.33 (m, 1H), 1.14 (m, 5H), 0.84 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(２−クロロ−６−メチルフェニル)メタンアミン(６４mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：３０mg。
MS APCI+ 513/515 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.24(t, 1H), 8.17(d, 1H), 7.26(m, 1H), 7.16(m, 2H), 7.06(d, 1H), 6.91(d, 1H), 6.49(d, 1H), 4.95(t, 1H), 4.37(d, 2H), 2.69(m, 4H), 2.45(t, 2H), 2.35(m, 2H), 2.22(t, 2H), 1.87(m, 2H), 1.67(t, 2H), 1.09(m, 2H) Example 31
N- (2-chloro-6-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Prepared using-(2-chloro-6-methylphenyl) methanamine (64 mg) in dry DMF (2 ml) according to the procedure described in Example 27. By reverse phase HPLC, Xterra® C8 Purification using a 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile gave the title compound as a pale yellow foam. : 30 mg.
MS APCI + 513/515 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.24 (t, 1H), 8.17 (d, 1H), 7.26 (m, 1H), 7.16 (m, 2H), 7.06 (d, 1H), 6.91 (d , 1H), 6.49 (d, 1H), 4.95 (t, 1H), 4.37 (d, 2H), 2.69 (m, 4H), 2.45 (t, 2H), 2.35 (m, 2H), 2.22 (t, 2H), 1.87 (m, 2H), 1.67 (t, 2H), 1.09 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および(１Ｒ,２Ｓ)−２−フェニルシクロプロパンアミン(５５mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：５０mg。
MS APCI+ 491 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.21(m, 1H), 8.17(d, 1H), 7.25(t, 2H), 7.15(t, 1H), 7.08(m, 3H), 6.91(d, 1H), 6.50(d, 1H), 4.98(t, 1H), 2.75(m, 5H), 2.50(m, 2H), 2.37(m, 1H), 2.19(t, 2H), 1.89(m, 3H), 1.74(t, 2H), 1.18(m, 2H), 1.13(m, 2H) Example 32
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(1R, 2S) -2-phenylcyclopropyl] propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and ( Prepared according to the procedure described in Example 27 in dry DMF (2 ml) using 1R, 2S) -2-phenylcyclopropanamine (55 mg) by reverse phase HPLC, Xterra® C8 5 Purification using a micron 19 × 50 mm column, eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile, gave the title compound as a pale yellow foam. 50 mg.
MS APCI + 491 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.21 (m, 1H), 8.17 (d, 1H), 7.25 (t, 2H), 7.15 (t, 1H), 7.08 (m, 3H), 6.91 (d , 1H), 6.50 (d, 1H), 4.98 (t, 1H), 2.75 (m, 5H), 2.50 (m, 2H), 2.37 (m, 1H), 2.19 (t, 2H), 1.89 (m, 3H), 1.74 (t, 2H), 1.18 (m, 2H), 1.13 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(４−クロロフェニル)メタンアミン(５８mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：２７mg。
MS APCI+ 499/501 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.43(t, 1H), 8.17(d, 1H), 7.36(d, 2H), 7.29(d, 2H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.99(t, 1H), 4.25(d, 2H), 2.75(m, 4H), 2.50(m, 2H), 2.43(bs, 1H), 2.27(t, 2H), 1.92(m, 2H), 1.74(t, 2H), 1.21(n, 2H) Example 33
N- (4-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Prepared according to the procedure described in Example 27 using (4-chlorophenyl) methanamine (58 mg) in dry DMF (2 ml) by reverse phase HPLC, Xterra® C8 5 micron 19 × 50 mm. Purification using column, eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile, gave the title compound as a pale yellow foam, yield: 27 mg.
MS APCI + 499/501 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.43 (t, 1H), 8.17 (d, 1H), 7.36 (d, 2H), 7.29 (d, 2H), 7.07 (d, 1H), 6.91 (d , 1H), 6.50 (d, 1H), 4.99 (t, 1H), 4.25 (d, 2H), 2.75 (m, 4H), 2.50 (m, 2H), 2.43 (bs, 1H), 2.27 (t, 2H), 1.92 (m, 2H), 1.74 (t, 2H), 1.21 (n, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(３−クロロフェニル)メタンアミン(５８mg)を用いて精製し、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：４４mg。
MS APCI+ 499/501 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.45(t, 1H), 8.17(d, 1H), 7.28(m, 4H), 7.07(d, 1H), 6.91(d, 1H), 6.60(d, 1H), 4.97(t, 1H), 4.27(t, 1H), 2.76(d, 2H), 2.71(d, 2H), 2.50(m, 2H), 2.38(m 1H), 2.28(t, 2H), 1.91(m, 2H), 1.73(t, 2H), 1.17(m, 2H) Example 34
N- (3-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 -Purified with (3-chlorophenyl) methanamine (58 mg) and prepared in dry DMF (2 ml) according to the procedure described in example 27. Xterra® C8 5 micron 19 by reverse phase HPLC. Purification using a x50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile gave the title compound as a light yellow foam, yield: 44 mg.
MS APCI + 499/501 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.45 (t, 1H), 8.17 (d, 1H), 7.28 (m, 4H), 7.07 (d, 1H), 6.91 (d, 1H), 6.60 (d , 1H), 4.97 (t, 1H), 4.27 (t, 1H), 2.76 (d, 2H), 2.71 (d, 2H), 2.50 (m, 2H), 2.38 (m 1H), 2.28 (t, 2H ), 1.91 (m, 2H), 1.73 (t, 2H), 1.17 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(２−クロロ−６−フルオロフェニル)メタンアミン(６５mg)を用いて精製し、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：５６mg。
MS APCI+ 517/519 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.39(t, 1H), 8.17(d, 1H), 7.35(m, 2H), 7.21(m, 1H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.96(t, 1H), 4.37(m, 2H), 2.69(m, 4H), 2.45(t, 4H), 2.37(m, 1H), 2.21(t, 2H), 1.88(m, 2H), 1.69(t, 2H), 1.14(m, 2H) Example 35
N- (2-chloro-6-fluorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Purified with-(2-chloro-6-fluorophenyl) methanamine (65 mg) and prepared in dry DMF (2 ml) according to the procedure described in example 27. By reverse phase HPLC, Xterra® ) Purified using a C8 5 micron 19 × 50 mm column and eluted with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile to give the title compound as a pale yellow foam. Yield: 56 mg.
MS APCI + 517/519 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.39 (t, 1H), 8.17 (d, 1H), 7.35 (m, 2H), 7.21 (m, 1H), 7.07 (d, 1H), 6.91 (d , 1H), 6.50 (d, 1H), 4.96 (t, 1H), 4.37 (m, 2H), 2.69 (m, 4H), 2.45 (t, 4H), 2.37 (m, 1H), 2.21 (t, 2H), 1.88 (m, 2H), 1.69 (t, 2H), 1.14 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(２,３−ジクロロフェニル)メタンアミン(７２mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：２９mg。
MS APCI+ 647/649/651 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) 8.54(t, 1H), 8.17(d, 1H), 7.53(dd, 1H), 7.40(d, 1H), 7.31(t, 1H), 7.08(d, 1H), 6.92(d, 1H), 6.50(d, 1H), 4.99(t, 1H), 4.34(d, 2H), 2.79(m, 2H), 2.73(d, 2H), 2.50(m, 2H), 2.44(m, 1H), 2.31(t, 2H), 1.91(m, 2H), 1.75(t, 2H), 1.21(m, 2H) Example 36
N- (2,3-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Prepared according to the procedure described in Example 27 using (2,3-dichlorophenyl) methanamine (72 mg) in dry DMF (2 ml) by reverse phase HPLC Xterra® C8 5 micron 19 Purification using a x50 mm column, eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile, gave the title compound as a pale yellow foam, yield: 29 mg.
MS APCI + 647/649/651 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) 8.54 (t, 1H), 8.17 (d, 1H), 7.53 (dd, 1H), 7.40 (d, 1H), 7.31 (t, 1H), 7.08 (d , 1H), 6.92 (d, 1H), 6.50 (d, 1H), 4.99 (t, 1H), 4.34 (d, 2H), 2.79 (m, 2H), 2.73 (d, 2H), 2.50 (m, 2H), 2.44 (m, 1H), 2.31 (t, 2H), 1.91 (m, 2H), 1.75 (t, 2H), 1.21 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１ｇ)から、ＨＡＴＵ(０.１４ｇ)、トリエチルアミン(０.０３７ml)および１−(２−クロロフェニル)−Ｎ−メチルメタンアミン(６４mg)を用いて、乾燥ＤＭＦ(２ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中５０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を薄黄色の泡状物質として得た。収量：２１mg。
MS APCI+ 513/515 [M+H]^+
1H NMR (300 MHz, d₆-DMSO 90℃) 8.16(d, 1H), 7.42(d, 1H), 7.30(bs, 2H), 7.21(bs, 1H), 7.07(d, 1H), 6.93(d, 1H), 6.48(d, 1H), 4.99(t, 1H), 4.60(s, 2H), 2.79(d, 4H), 2.59(bs, 2H), 2.02(bs, 2H), 1.74(m, 2H), 1.26(m, 2H) Example 37
N- (2-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) -N-methylpropanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.1 g), HATU (0.14 g), triethylamine (0.037 ml) and 1 Prepared according to the procedure described in Example 27 in dry DMF (2 ml) using-(2-chlorophenyl) -N-methylmethanamine (64 mg) by reverse phase HPLC, Xterra® C8 Purification using a 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 50% 0.880 NH _{3 in} acetonitrile gave the title compound as a pale yellow foam. : 21 mg.
MS APCI + 513/515 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO 90 ° C) 8.16 (d, 1H), 7.42 (d, 1H), 7.30 (bs, 2H), 7.21 (bs, 1H), 7.07 (d, 1H), 6.93 (d, 1H), 6.48 (d, 1H), 4.99 (t, 1H), 4.60 (s, 2H), 2.79 (d, 4H), 2.59 (bs, 2H), 2.02 (bs, 2H), 1.74 ( m, 2H), 1.26 (m, 2H)

Example 38
5-((1R) -2-{[(1- {2- [2- (3-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl)- 8-Hydroxyquinolin-2 (1H) -one

i) [2- (3-Chlorophenyl) ethoxy] acetic acid 2- (3-Chlorophenyl) ethanol (7.32 g, 6.2 ml) was dissolved in DMF (100 ml) and cooled in ice. Sodium hydride (1.72 g, 60% in mineral oil) was added all at once over 15 minutes. After the reaction mixture was stirred at ambient temperature for 1.75 hours, effervescence ceased and then solid sodium chloroacetate (5.00 g) was added. The mixture was stirred at ambient temperature for 15 minutes and then heated at 60 ° C. for 6 hours. The mixture was left overnight, then poured into water and extracted with ether (x6), then the ether extract was removed. The aqueous material was acidified with concentrated HCl from pH 9 to pH 2, then extracted with EtOAc (x7). The combined EtOAc extracts were washed with water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and concentrated to give the subtitle compound as a colorless oil. Yield: 7.65 g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26-7.11 (m, 4H), 4.11 (s, 2H), 3.78 (t, 2H), 2.93 (t, 2H).

ii) 2- [2- (3-Chlorophenyl) ethoxy] ethanol of the product [2- (3-Chloro-phenyl) -ethoxy] -acetic acid (7.65 g) in dry THF (180 ml) The solution was cooled to 0 ° C. Borane-THF (˜1M, 120 ml) was slowly added while keeping the internal temperature below 4 ° C., then the solution was stirred at ambient temperature for 3 hours, then MeOH (100 ml) keeping the internal temperature below 23 ° C. Was dripped. The mixture was stirred for 15 minutes then concentrated in vacuo and partitioned between ether and saturated aqueous NaHCO ₃ . The layers were separated and the aqueous layer was further extracted with ether and EtOAc. The combined organic layers were washed with water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and the volatiles evaporated. Purification by Biotage column, eluting with 1: 9 to 1: 1 EtOAc: isohexane, gave the subtitle compound as a colorless oil. Yield: 3.16 g.
¹ H NMR (300 MHz, CDCl3) δ 7.25-7.09 (m, 4H), 3.74-3.68 (m, 4H), 3.57-3.54 (m, 2H), 2.88 (t, 2H).

iii) 2- [2- (3-Chlorophenyl) ethoxy] ethyl 4-methylbenzenesulfonate / 1-chloro-3- [2- (2-chloroethoxy) ethyl] benzene chloride p-toluenesulfonyl (1.56 g) The product of step (ii) (2- [2- (3-chloro-phenyl) -ethoxy] -ethanol) (1.52 g) and 4-N, N in pyridine (5.5 ml) at ambient temperature. -Added to a solution of dimethylaminopyridine (22 mg). The reaction mixture was stirred at ambient temperature overnight, then diluted with ethyl acetate (120 ml), washed with 2M aqueous HCl (3 × 10 ml), saturated aqueous NaHCO ₃ , water and saturated aqueous NaCl, dried ( Na ₂ SO ₄ ), volatiles evaporated to give the subtitle compound and 1-chloro-3- [2- (2-chloroethoxy) ethyl] benzene (2: 1 by NMR) as a pale yellow oil. . Yield: 1.63g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.77 (m, 2H), 7.35-7.04 (m, 6H), 4.17-4.13 (m, 2H), 3.65-3.57 (m, 4H), 2.79 (td , 2H), 2.45 (s, 3H).
(Signal of + 1-chloro-3- [2- (2-chloroethoxy) ethyl] benzene): δ 7.35-7.04 (m, 4H), 4.17-4.13 (m, 2H), 3.74-3.69 (m, 4H) , 2.89 (td, 2H).
This was crude and used in the next step (iv) without further purification.

iv) 1- {2- [2- (3-Chlorophenyl) ethoxy] ethyl} piperidin-4-one Product of step (iii) (2- [2- (3-Chlorophenyl) ethoxy] ethyl 4-methylbenzenesulfonate / 1-chloro-3- [2- (2-chloroethoxy) ethyl] benzene) (2: 1 by NMR) (1.6 g) and piperidin-4-one hydrochloride hydrate (1.102 g) , Dissolved in NMP (25 ml) and triethylamine (5.3 ml) was added. The reaction mixture was heated at 85 ° C. for 2.5 hours, then allowed to cool and partitioned between EtOAc and water. The layers were separated and the EtOAc layer was further washed with water, then with saturated aqueous NaHCO ₃ , with water and with saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and concentrated. The residue was diluted with iPrOH and loaded onto a Varian SCX column (3 × 10 g). Neutral / acidic material was washed off with iPrOH and the product was then eluted with 1: 3 aqueous ammonia / iPrOH and then concentrated. The resulting gum was partitioned between EtOAc and water, the layers were separated, the aqueous layer was further extracted with EtOAc, the organic extract was washed with saturated aqueous NaCl, dried (Na ₂ SO ₄ ), Concentration gave the subtitle compound as an orange oil. Yield: 0.27g.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23-7.18 (m, 3H), 7.11-7.09 (m, 1H), 3.67 (t, 2H), 3.60 (t, 2H), 2.87 (t, 2H), 2.77 (t, 4H), 2.69 (t, 2H), 2.43 (t, 4H).

v) 6- {2- [2- (3-Chlorophenyl) ethoxy] ethyl} -1-oxa-6-azaspiro [2.5] octane subtitle compound is added to the product of step (iv) (1- {2- [2- (3-Chlorophenyl) ethoxy] ethyl} piperidin-4-one) (0.27 g) using 60% sodium hydride (82 mg), trimethylsulfoxonium iodide (0.23 g) and DMSO (4 ml) was prepared as a yellow oil by the method of Example 5, step (iii). Yield: 0.28g.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23-7.16 (m, 3H), 7.11-7.09 (m, 1H), 3.66 (t, 2H), 3.58 (t, 2H), 2.86 (t, 2H), 2.66-2.55 (m, 8H), 1.86-1.79 (m, 2H), 1.57-1.51 (m, 2H).

vi) 5-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-{[(1- {2- [2- (3-chlorophenyl) ethoxy] ethyl} -4-hydroxy Piperidin-4-yl) methyl] amino} ethyl) -8-hydroxyquinolin-2 (1H) -one The product of step (ii) of Example 5 (5-((1R)- 2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0.4 g) and the product of step (v) (6- { A solution of 2- [2- (3-chloro-phenyl) -ethoxy] -ethyl} -1-oxa-6-aza-spiro [2.5] octane) (0.28 g) was refluxed for 19 hours. The solvent was evaporated to give the crude material. Purification by Isolute Flash silica gel (20 g) eluting with 1: 4: 95 to 3:12:85 NH ₃ -MeOH (7M): MeOH: DCM gave the subtitle compound as a yellow gum. Yield: 0.39 g.
MS APCI + 630/632 [M + H] ⁺

vii) 5-((1R) -2-{[(1- {2- [2- (3-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-Hydroxyquinolin-2 (1H) -one product of step (vi) (5-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-{[(1- {2- [2- (3-Chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0.39 g) , Dissolved in THF (5 ml), triethylamine trihydrofluoride (0.6 ml) was added thereto. The reaction mixture was stirred at ambient temperature for 3 days, then the volatiles were evaporated to give a yellow oil. Purification by reverse phase HPLC (Symmetry®, 100-50% 0.2% aqueous TFA in MeCN) afforded the title compound as a cream solid. Yield: 87 mg.
MS APCI + 516/518 [M + H] ^+
1 H NMR (300 MHz, DMSO) δ 10.50 (br s, 1H), 8.22 (d, 1H), 7.35-7.22 (m, 4H), 7.16 (d, 1H), 7.00 (d, 1H), 6.58 ( d, 1H), 6.20 (br s, 1H), 5.63 (br s, 1H), 5.44-5.42 (m, 1H), 3.75-3.67 (m, 4H), 3.34-3.26 (m, 2H), 3.17- 3.06 (m, 6H), 2.86 (t, 2H), 1.85-1.79 (m, 4H), 1.18 (t, 2H).

Example 39
(4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) benzyl acetate

i) (4- Oxopiperidin -1-yl) acetic acid benzyl subtitle compound was prepared from 4-piperidinone hydrochloride monohydrate (1.5 g). This was dissolved in DMF (10 ml) followed by the addition of anhydrous potassium carbonate (2.8 g) and benzyl bromoacetate (2.3 g). The mixture was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate (x3), the combined extracts washed with water, collected and dried (Na ₂ SO ₄ ) to give a colorless oil. Obtained. This solidified when left alone. Yield: 2.6g.
MS APCI + 248 (M-18) + H +
¹ H NMR (300Mz, d6-DMSO) δ 7.42-7.31 (5H, m), 5.13 (2H, s), 3.50 (2H, s), 2.89-2.83 (4H, m), 2.34 (4H, t)

ii) (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) acetic acid benzyl subtitle compound was prepared from the product of step 5 of Example 5 (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy) } Ethyl) -8-hydroxyquinolin-2 (1H) -one) (100 mg) and the product of step (i) (benzyl (4-oxopiperidin-1-yl) acetate) (158 mg). These were dissolved in NMP (6 ml) followed by addition of acetic acid (1 drop) and activated 4 活性 molecular sieves (6 pellets). After the mixture was stirred for 14 hours, sodium triacetoxyborohydride (253 mg) was added and stirred for an additional 24 hours. The evaporated mixture was passed through an SCX cartridge to give the crude product using 1: 1 isopropyl alcohol / acetonitrile, then 1: 1 isopropyl alcohol / 10% 0.880 ammonia in acetonitrile as eluent. Purification by flash chromatography on silica gel eluting with 9: 1 dichloromethane / methanol 1% 0.880 ammonia gave the subtitle compound. Yield: 160 mg.
MS APCI + 566 [M + H] ⁺

iii) (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) benzyl acetate The compound is converted into the product of step (ii) ((4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2- Prepared from dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) benzyl acetate) (150 mg). This was dissolved in THF (4 ml) followed by the addition of triethylamine trihydrofluoride (0.3 ml) and the solution stirred at ambient temperature for 3 hours. Volatiles were removed in vacuo and the residue was loaded onto an SCX cartridge and crude using 1: 1 isopropyl alcohol / acetonitrile and then 1: 1 isopropyl alcohol / 10% 0.880 ammonia in acetonitrile as eluent. The product was obtained as a dark orange oil. Purification by reverse phase HPLC using 0.1% aqueous TFA and acetonitrile gave the title compound as a cream solid. Yield: 22 mg.
MS APCI + 452 [M + H] ^+
1 H NMR (300Mz, d6-DMSO) δ 8.15 (1H, d), 7.37-7.28 (5H, m), 7.06 (1H, d), 6.91 (1H, d), 6.48 (1H, d), 5.09 ( 2H, s), 5.02 (1H, t), 3.15 (1H, s), 2.77 (4H, t), 2.52-2.47 (2H, m), 2.21-2.15 (2H, m), 1.75 (2H, t) , 1.34-1.25 (2H, m).

Example 40
8-Hydroxy-5-[(1R) -1-hydroxy-2-({[4-hydroxy-1- (4-phenoxybutyl) piperidin-4-yl] methyl} amino) ethyl] quinoline-2 (1H) -ON

i) 1- (4 -Phenoxybutyl ) piperidin-4-one subtitle compound from (4-bromobutoxy) benzene (3 g), 4-piperidinone hydrochloride hydrate (1.92 g), triethylamine (3.5 ml) Prepared in chloroform (50 ml) using the method of step (i) of Example 7 and obtained as a red oil. Yield: 1.8g.
MS APCI + 248 [M + H] ⁺

ii) 4- (Aminomethyl) -1- (4-phenoxybutyl) piperidin-4-ol subtitle compound is converted to the product of step (i) (1- (4-phenoxybutyl) piperidine- in DMF (2 ml) 4-one) (1.8 g), trimethylsilyl cyanide (1.1 g) and zinc chloride (60 mg), and from lithium aluminum hydride (12 ml, 1M in THF), the method of Example 26, step (ii) Was obtained as a yellow solid. Yield: 2.5g.
MS APCI + 279 [M + H] ⁺

iii) 8- (Benzyloxy) -5-[(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-({[4-hydroxy-1- (4-phenoxybutyl) piperidine- 4-yl] methyl} amino) ethyl] quinolin-2 (1H) -one product of step (ii) (4- (aminomethyl) -1- (4-phenoxybutyl) piperidin-4-ol) (0. 2g) and the product of Example 2 step (iii) (8- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) quinoline -2 (1H) -one) (0.23 g), potassium carbonate (0.19 g), sodium iodide (0.1 g) were heated in DMSO (2 ml) at 90 ° C. for 6 hours. The cooled reaction mixture was partitioned between brine and ethyl acetate. The organic layer was collected, dried (MgSO ₄ ) and evaporated to give a red gum. Purify by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile to give the subtitle compound. Obtained as a pale yellow foam. Yield: 70 mg.
MS APCI + 686 [M + H] ⁺

iv) 8-hydroxy-5-[(1R) -1-hydroxy-2-({[4-hydroxy-1- (4-phenoxybutyl) piperidin-4-yl] methyl} amino) ethyl] quinoline-2 ( 1H) -one The product of step (iii) (8- (benzyloxy) -5-[(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-} in THF (2 ml) ({[4-Hydroxy-1- (4-phenoxybutyl) piperidin-4-yl] methyl} amino) ethyl] quinolin-2 (1H) -one) (70 mg) was added to triethylamine hydrofluoride (0 .15 ml). After stirring at ambient temperature for 18 hours, the volatiles were evaporated in vacuo and the residue azeotroped with toluene (x2) to give a yellow gum. This was dissolved in ethanol (10 ml) and 2M HCl (2 ml) and hydrogenated with 10% palladium / charcoal (10 mg) at 5 bar pressure for 4 hours. The catalyst was filtered and the residue was purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile. To give the title compound as a pale yellow solid. Yield: 21 mg.
MS APCI + 482 [M + H] ^+
1 H NMR (300Mz, d6-DMSO) δ 8.19 (d, 1H), 7.27 (t, 2H), 7.07 (d, 1H), 6.91 (d, 4H), 6.50 (d, 1H), 5.03 (m, 1H), 3.96 (t, 2H), 2.72 (m, 2H), 2.46 (m, 2H), 2.33 (bs, 4H), 1.70 (t, 2H), 2.5 (m, 3H), 1.57 (m, 2H ), 1.48 (bs, 3H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１８ｇ)から、ＨＡＴＵ(０.２９ｇ)、トリエチルアミン(０.１９ml)およびアダマンタン−１−アミン(０.１３ｇ)を用いて、乾燥ＤＭＦ(４.１ml)中で、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中６０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を黄色の泡状物質として得た。収量：５０mg。
MS APCI+ 509 [M+H]^+
1H NMR (300 MHz, d6-DMSO) δ 8.16(d, 1H), 7.69(s, 1H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.99(t, 1H), 2.73(m, 3H), 2.55( m, 2H), 2.43(t, 3H), 2.13(t, 3H), 1.99(bs, 2H), 1.90(bs, 6H), 1.76(t, 2H), 1.61(bs, 6H), 1.20(m, 2H) Example 41
N-1-adamantyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.18 g), HATU (0.29 g), triethylamine (0.19 ml) and adamantane Prepared according to the procedure described in Example 27 in dry DMF (4.1 ml) using -1-amine (0.13 g) Xterra® C8 5 micron 19 × by reverse phase HPLC. Purification using a 50 mm column, eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 60% 0.880 NH _{3 in} acetonitrile, gave the title compound as a yellow foam, yield: 50 mg.
MS APCI + 509 [M + H] ^+
1 H NMR (300 MHz, d6-DMSO) δ 8.16 (d, 1H), 7.69 (s, 1H), 7.07 (d, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 4.99 (t , 1H), 2.73 (m, 3H), 2.55 (m, 2H), 2.43 (t, 3H), 2.13 (t, 3H), 1.99 (bs, 2H), 1.90 (bs, 6H), 1.76 (t, 2H), 1.61 (bs, 6H), 1.20 (m, 2H)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１８ｇ)から、ＨＡＴＵ(０.２５ｇ)、トリエチルアミン(０.０６６ml)および３,５−ジクロロベンジルアミン(０.１３ｇ)を用いて、乾燥ＤＭＦ(３.６ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中５０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を緑色のゴム状物質として得た。収量：１１０mg。
MS APCI+ 533 / 535 / 537 [M+H]^+
1H NMR (300 MHz, d6-DMSO) δ 10.5(s, 2H), 8.15(d, 1H), 7.50(s, 1H), 7.32(s, 2H), 7.17(d, 1H), 6.99(d, 1H), 6.58(d, 1H), 5.32(bm, 1H), 4.30(d, 2H), 3.54 - 3.30(bm, 4H), 3.12(bm, 2H), 2.96( bm, 2H), 2.69(bm, 2H), 2.27(bm, 2H), 1.80(bm, 2H). (4H, 溶媒ピークによって不明瞭). Example 42
N- (3,5-dichlorobenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.18 g), HATU (0.25 g), triethylamine (0.066 ml) and 3 , 5-dichlorobenzylamine (0.13 g) was stirred in dry DMF (3.6 ml) for 18 hours and prepared according to the procedure described in Example 27. By reverse phase HPLC, Xterra® Purified using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 50% (0.2% aqueous NH ₃ ) in acetonitrile. The compound was obtained as a green gum, yield: 110 mg.
MS APCI + 533/535/537 [M + H] ^+
1 H NMR (300 MHz, d6-DMSO) δ 10.5 (s, 2H), 8.15 (d, 1H), 7.50 (s, 1H), 7.32 (s, 2H), 7.17 (d, 1H), 6.99 (d , 1H), 6.58 (d, 1H), 5.32 (bm, 1H), 4.30 (d, 2H), 3.54-3.30 (bm, 4H), 3.12 (bm, 2H), 2.96 (bm, 2H), 2.69 ( bm, 2H), 2.27 (bm, 2H), 1.80 (bm, 2H). (4H, obscured by solvent peak).

Example 43
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4- (hydroxymethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] Ethyl} quinolin-2 (1H) -one

i) 1-tert-butyl 4-methyl 4- (iodomethyl) piperidine-1,4-dicarboxylate n-butyllithium (33.5 ml, 1.6 M solution in hexane) with an internal temperature of 1.0 ° C. While maintaining a temperature between 2.5 ° C., it was added dropwise to a cooled solution of diisopropylamine (8.2 ml) in THF (250 ml). The reaction mixture was stirred at 0 ° C. for 10 minutes, then cooled to −78 ° C. and 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (Eur. J. Org. Chem) in THF (150 ml). 2005, 673) (12.5 g) was added dropwise while maintaining the internal temperature at around -72 ° C. The reaction mixture was stirred at −78 ° C. for 45 minutes and then diiodomethane (7.9 ml) was added. The reaction mixture was stirred at −78 ° C. to room temperature overnight, then quenched with water and concentrated to ¼ volume. EtOAc was added and the layers were separated. The aqueous layer was further extracted with ethyl acetate (× 2), the combined organic extracts were, washed with water and saturated aqueous NaCl, dried (Na ₂ SO _4), and the volatiles evaporated. Purification by flash chromatography, eluting with 1: 9 EtOAc: isohexane, gave the subtitle compound as a colorless oil. Yield: 20.2 g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.87-3.80 (m, 2H), 3.76 (s, 3H), 3.29 (s, 2H), 3.03-2.95 (m, 2H), 2.20-2.16 (m, 2H ), 1.52-1.41 (m, 2H), 1.45 (s, 9H).

ii) 1-Tert-Butyl 4-methyl 4- (azidomethyl) piperidine-1,4-dicarboxylate sodium azide (4.00 g) was added to the product of step (i) in dry DMSO (60 ml) (1 To a solution of -tert-butyl 4-methyl 4- (iodomethyl) piperidine-1,4-dicarboxylate) (6.04 g), the reaction mixture was heated at 95 ° C. for 4 hours. After cooling, the mixture was diluted with EtOAc and water, the layers were separated, and the aqueous layer was further extracted with EtOAc (x5). The combined organic extracts were washed with water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and volatiles evaporated to give the subtitle compound as a pale yellow oil. Yield: 4.35g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.88-3.80 (m, 2H), 3.77 (s, 3H), 3.42 (s, 2H), 3.04-2.96 (m, 2H), 2.09 (d, 2H), 1.45 (s, 9H), 1.50-1.43 (m, 2H).

iii) 4- (azidomethyl) piperidine-4-carboxylic acid 4M HCl in methyldioxane (16 ml) was added to the product of step (ii) (1-tert-butyl 4-methyl 4- (azidomethyl) piperidine-1,4- Dicarboxylate) (1.90 g). After 2 hours at room temperature, the volatiles were removed to give the subtitle compound as a pale yellow solid. Yield: 2.15 g.
¹ H NMR (300 MHz, d ₆ -DMSO) δ 9.13-9.05 (m, 2H), 3.71 (s, 3H), 3.72-3.65 (m, 2H), 3.22-3.17 (m, 2H), 2.94-2.82 (m, 2H), 2.12-2.06 (m, 2H), 1.79-1.69 (m, 2H).

iv) 2- (2-Phenylethoxy) ethyl trifluoromethanesulfonate 2- (2-phenylethoxy) ethanol (J. Med. Chem. 1983, 26, 1570) (1.00 g) was dissolved in DCM (20 ml). , Cooled to -10 ° C. Pyridine (0.6 ml) was added dropwise followed by trifluoromethanesulfonic anhydride (1.2 ml) and the reaction mixture was stirred for 1 hour, then warmed to room temperature and stirred overnight. Volatiles were evaporated, then the residue was triturated with isohexane, filtered and washed with more isohexane. The solid was removed and the residue was concentrated to give the subtitle compound as a colorless oil. Yield: 1.48g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33-7.19 (m, 5H), 4.61-4.58 (m, 2H), 3.76-3.69 (m, 4H), 2.90 (t, 2H).

v) 4- (azidomethyl) -1- [2- (2-phenylethoxy) ethyl] piperidine-4-carboxylate methyl product of step (iii) (4- (azidomethyl) piperidine-4-carboxylate methyl) ( 1.06 g) was added to a solution of the product of step (iv) (2- (2-phenylethoxy) ethyl trifluoromethanesulfonate) (1.48 g) in DCM (55 ml). Huenig's base (1.7 ml) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ , water, and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and the volatiles evaporated. Purified by Biotage chromatography, eluting with 1: 1 to 1: 0 EtOAc: isohexane, then 1% NH ₃ -MeOH in EtOAc (7M) to give the subtitle compound as a colorless oil. Yield: 0.94g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31-7.20 (m, 5H), 3.75 (s, 3H), 3.65 (t, 2H), 3.56 (t, 2H), 3.40 (s, 2H), 2.88 ( t, 2H), 2.74-2.69 (m, 2H), 2.55 (t, 2H), 2.23-2.10 (m, 4H), 1.61-1.51 (m, 2H).

vi) {4- (Aminomethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methanol lithium aluminum hydride (15 ml, 1M in THF) was added in dry THF (10 ml). A cooled (−78 ° C.) solution of the product of step (v) (4- (azidomethyl) -1- [2- (2-phenylethoxy) ethyl] piperidine-4-carboxylate methyl) (0.69 g) Slowly added. The reaction mixture was gradually warmed to room temperature and stirred overnight. It was cooled in ice and then a mixture of celite (3.5 g) and sodium sulfate decahydrate (3.5 g) was added in portions, keeping the temperature below 10 ° C. More THF was added followed by 0.4 ml of 10% aqueous NaOH. The solid was removed by filtration and the volatiles were evaporated to give the subtitle compound as a pale yellow oil. Yield: 0.56g.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30-7.18 (m, 5H), 3.67-3.63 (m, 4H), 3.58 (t, 2H), 2.90-2.81 (m, 4H), 2.58 (t, 2H ), 2.54-2.49 (m, 2H), 2.38-2.32 (m, 2H), 1.61-1.55 (m, 2H), 1.46-1.39 (m, 2H).

vii) 8- (Benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[({4- (hydroxymethyl) -1- [2- (2 -Phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinolin-2 (1H) -one The product of step (iii) of Example 2 in 8- mL DMSO (8- ( Benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) quinolin-2 (1H) -one) (0.85 g), step (vi) ({4- (aminomethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methanol) (0.51 g), potassium iodide (0.58 g) and bicarbonate A mixture of sodium (0.58 g) was heated at 100 ° C. for 12 hours. It was allowed to cool, diluted with EtOAc and water, and the aqueous material was further extracted with EtOAc (x3). The combined organic extracts were washed with water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and concentrated. Purify by reverse phase HPLC using a Symmetry® column eluting with a gradient of 5-95% acetonitrile in 0.2% aqueous TFA to give the subtitle compound ditrifluoroacetate as a yellow oil. It was. Yield: 0.172g.
MS APCI + 700 [M + H] ⁺

viii) 8- (Benzyloxy) -5-{(1R) -1-hydroxy-2-[({4- (hydroxymethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl } Methyl) amino] ethyl} quinolin-2 (1H) -one product of step (vii) (8- (benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy } -2-[({4- (hydroxymethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} -quinolin-2 (1H) -one) ( 0.17 g) was dissolved in THF (3 ml) to which triethylamine trihydrofluoride (0.15 ml) was added. The reaction mixture was stirred at room temperature for 2.5 hours before additional triethylamine trihydrofluoride (0.15 ml) was added. The mixture was stirred overnight and then the volatiles were evaporated to give the subtitle compound as a yellow oil. Yield: 0.14g.
MS APCI + 586 [M + H] ⁺

ix) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({4- (hydroxymethyl) -1- [2- (2-phenylethoxy) -ethyl] piperidin-4-yl} methyl ) Amino] ethyl} quinolin-2 (1H) -one 1: 1 suspension of palladium / carbon (10%, 37 mg) in DCM: MeOH (2 ml) in 1: 1 DCM: MeOH (4 ml). Product of step (viii) (8- (benzyloxy) -5-{(1R) -1-hydroxy-2-[({4- (hydroxymethyl) -1- [2- (2-phenylethoxy)) Ethyl] piperidin-4-yl} methyl) amino] ethyl} quinolin-2 (1H) -one) (0.14 g) was added and hydrogenated at 4 bar for 3.5 hours. The catalyst was removed by filtration and the solvent was evaporated. Purification by reverse phase HPLC using an XBridge® column, eluting with a gradient of 10-40% acetonitrile in 0.2% aqueous TFA, gave the ditrifluoroacetate salt of the title compound as a white solid. . Yield: 35 mg.
MS APCI + 496 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 10.58 (s, 1H), 10.51 (s, 1H), 8.20 (d, 1H), 7.32-7.20 (m, 6H), 7.00 (d, 1H), 6.57 (d, 1H), 6.29 (s, 1H), 5.43-5.36 (m, 1H), 3.75-3.65 (m, 6H), 3.30-3.24 (m, 2H), 3.14-3.06 (m, 6H), 2.84 (t, 2H), 1.70-1.16 (m, 6H)

Example 44
2,6-dichloro-N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) ethyl] benzamide

i) 1- (2-Aminoethyl) piperidin-4-ol (0.312 g ) in 2,6-dichloro-N- [2- (4-hydroxypiperidin-1-yl) ethyl] benzamide DMF (10 ml) ) A solution of 2,6-dichlorobenzoic acid (0.826 g) and triethylamine (0.61 ml) was treated with PyBROP (1.21 g) at ambient temperature. After stirring for 14 hours, the mixture was loaded onto an SCX cartridge and eluted with acetonitrile followed by methanol. The product was then eluted with ammonia / methanol solution to give the subtitle compound as a yellow oil after solvent evaporation. Yield: 0.7g.
MS APCI + 317/319/321 [M + H] ⁺

ii) The product of step (i) (2,6 -dichloro) in 2,6-dichloro-N- [2- (4-oxopiperidin-1-yl) ethyl] benzamidoacetone (2 ml) and water (2 ml). A solution of -N- [2- (4-hydroxypiperidin-1-yl) ethyl] benzamide) (0.1 g) was prepared by the Jones reagent (0.48 ml) [prepared by the following procedure: in water (3 ml). Sodium dichromate dihydrate (1.0 g) was cooled in an ice bath and concentrated sulfuric acid (0.74 ml) was added dropwise. The resulting Jones reagent solution was diluted to a total volume of 5 ml. ] Was processed. The mixture was stirred at ambient temperature for 14 hours, then loaded onto an SCX cartridge and eluted with water followed by methanol. The product was then eluted with ammonia / methanol solution to give the subtitle compound as an orange oil after solvent evaporation. Yield: 0.1 g.
MS APCI + 315/317/319 [M + H] ⁺

iii) 2,6-dichloro-N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) ethyl] benzamide NMP (3 ml), the product of step (ii) (2,6-dichloro-N- [2- (4-oxopiperidin-1-yl) ethyl] benzamide ) (0.1 g) and the product of step 5 of Example 5 (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8- A solution of hydroxyquinolin-2 (1H) -one) (0.053 g) was treated with sodium triacetoxyborohydride (0.068 g) and acetic acid (0.01 ml) at ambient temperature. After stirring for 14 hours, the mixture was loaded onto an SCX cartridge and eluted with isopropanol / acetonitrile (1: 1). The product was then eluted with an ammonia / methanol solution and the solvent was evaporated in vacuo to give a yellow foam. This was then dissolved in THF (3 ml) and treated with triethylamine trihydrofluoride (0.1 ml) and the mixture was stirred at ambient temperature for 14 hours. Volatiles were evaporated in vacuo to give the crude product. This was subjected to reverse phase HPLC using 95% (0.2% aqueous NH ₃ ) in acetonitrile to 60% (0.2% aqueous NH ₃ ) in acetonitrile using an Xterra® C8 5 micron 19 × 50 mm column. To give the title compound as a yellow foam. Yield: 20 mg.
MS APCI + 519 [M + H] ^+
1 H NMR (300 MHz, d6-DMSO) δ 8.88 (t, 1H), 8.17 (d, 1H), 7.50-7.39 (m, 3H), 7.07 (d, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 4.98 (t, 1H), 2.84-2.76 (m, 2H), 2.74-2.65 (m, 2H), 2.57-2.30 (m, 6H), 2.43 (t, 2H), 2.02-1.92 (m, 2H), 1.80-1.68 (m, 2H), 1.30-1.17 (m, 2H)

Example 45
8-hydroxy-5-[(1R) -1-hydroxy-2-({[1- (2-{[(2S) -2-phenylpropyl] oxy} ethyl) piperidin-4-yl] methyl} amino) Ethyl] quinolin-2 (1H) -one

i) 1- (4-Hydroxymethylpiperidin-1-yl) -2-((S) -2-phenylpropoxy) ethanone ((S) -2-phenylpropoxy) acetic acid (0. 0) in dry DMF (30 ml). 7 g) A solution of (WO97 / 10227) was treated with HATU (2.5 g), triethylamine (0.037 ml) and 4-piperidinemethanol (0.85 g) at ambient temperature. After 3 days, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 2M HCl, saturated aqueous sodium bicarbonate, water, brine, and dried over anhydrous magnesium sulfate. The organic solution was filtered and concentrated under reduced pressure to give the subtitle compound (0.97 g). This was used in the next step without further purification.
MS APCI + 292 [M + H] ⁺

ii) A solution of [1- [2-((S) -2-phenylpropoxy) ethyl] piperidin-4-yl] methanol lithium aluminum hydride solution (1.8 ml, 1.0 M in THF) was added to dry THF ( To the product of step (i) (1- (4-hydroxymethylpiperidin-1-yl) -2-((S) -2-phenylpropoxy) ethanone) (0.43 g) in 5 ml) with stirring. And was added dropwise under nitrogen. After stirring for 18 hours, a mixture of celite (2.9 g) and sodium sulfate decahydrate (2.9 g) was added all at once. 1M aqueous sodium hydroxide solution (0.5 ml) was added and the resulting mixture was stirred for 30 minutes (Tetrahedron, 1996., 52, 8517). The solid was filtered and washed with THF. The combined filtrate was concentrated to give a colorless oil. The crude product was loaded onto an SCX cartridge and eluted with 1: 1 isopropanol / acetonitrile. The product was eluted with 20% 0.880 NH ₃ in 1: 1 isopropanol / acetonitrile to give the subtitle product as a colorless gum (0.31 g).
MS APCI + 278 [M + H] ⁺

iii) 1- [2- (S) -2-phenylpropoxy) ethyl] piperidine-4-carbaldehyde 4Å molecular sieve (0.05 mg) followed by N-methylmorpholine N-oxide (0.05 g) and TPAP (0.01 g) was added to the product of step (ii) ([1- [2-((S) -2-phenylpropoxy) ethyl] piperidin-4-yl] methanol) in DCM (3 ml) (0 .10 g) of solution. After 1.5 hours, additional DCM (15 ml), NMO (0.05 g) and TPAP (0.01 g) were added and the mixture was stirred for an additional 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The black gum was purified by column chromatography on deactivated alumina (neutral, Brockman 1), eluting with Et ₂ O and DCM (1: 1) to give the subtitle compound as a clear oil. Yield: 0.04g.
MS APCI + 294 [M + H ₂ O + H] ⁺

iv) 8-hydroxy-5-[(R) -1-hydroxy-2-({1- [2-((S) -2-phenylpropoxy) ethyl] piperidin-4-ylmethyl} amino) ethyl] -1H -The product of step (ii) of Example 5 (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl]) in quinolin-2-one methanol (1.6 ml). Oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0.05 g) and the product of step (iii) (1- [2- (S) -2-phenylpropoxy) ethyl] piperidine-4 A solution of -carbaldehyde) (0.04 g) was treated with acetic acid (0.018 ml). Sodium cyanoborohydride (9.8 mg) was added and stirring was continued for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml) containing concentrated aqueous ammonia (1 ml). The organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was dissolved in THF (4.0 ml), treated with triethylamine trihydrofluoride (0.14 ml) and stirred for a further 5.5 hours. Volatiles were evaporated in vacuo and the residue was purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column, from 95% (0.2% aqueous NH ₃ ) in acetonitrile to acetonitrile. Elution with a medium gradient of 70% (0.2% aqueous NH ₃ ) gave the title compound as a light green solid. Yield: 27 mg.
MS APCI + 480 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.16 (d, 1H), 7.26 (m, 4H), 7.17 (m, 1H), 6.99 (d, 1H), 6.81 (d, 1H), 6.46 ( d, 1H), 4.96 (m, 1H), 3.39-3.49 (m, 4H), 2.95 (m, 1H), 2.77 (bd, 2H), 2.65 (m, 2H), 2.38 (m, 4H), 1.84 (t, 2H), 1.56 (d, 2H), 1.18 (d, 3H), 1.04 (m, 2H). (1 x H, obscured by solvent peak).

Example 46
5-((1R) -2-{[(1- {2- [2- (2-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl)- 8-Hydroxyquinolin-2 (1H) -one

i) [2- (2-Chloro-phenyl) -ethoxy] -acetic acid 2- (2-chlorophenyl) ethanol (10 g) was dissolved in DMF (125 ml) and cooled in an ice bath. Sodium hydride (1.687 g, 60% in mineral oil) was added all at once over 15 minutes. The reaction mixture was stirred at room temperature for 1 hour 45 minutes, then sodium chloroacetate (7.44 g) was added. The mixture was stirred at room temperature for 15 minutes, heated at 60 ° C. for 7 hours, and then stirred at room temperature for 50 hours. The reaction mixture was poured into a large amount of water and washed thoroughly with ether. The aqueous solution was acidified (concentrated HCl) and extracted with ether. This was then washed with water and brine. Dried (Na ₂ SO ₄ ) and evaporated to give the subtitle compound as an amber oil. Yield: 6.9g.
¹ H NMR δ (CDCl ₃ ) 3.09 (2H, t), 3.81 (2H, t), 4.13 (2H, s), 7.23-7.14 (2H, m), 7.35 (1H, dd), 7.29 (1H, dd )

ii) 2- [2- (2-Chloro-phenyl) -ethoxy] -1- (4-hydroxy-piperidin-1-yl) -ethanone product of step (i) ([2- (2-Chloro-phenyl ) -Ethoxy] -acetic acid) (6.9 g) was dissolved in DCM (100 ml) and treated with thionyl chloride (5 ml) containing dry DMF (1 drop) at reflux. After refluxing for 1 hour, all volatiles were evaporated and the residue azeotroped with toluene. This acid chloride solution dissolved in DCM (50 ml) was then added to a solution of 4-hydroxy-piperidine (3.25 g) dissolved in DCM (50 ml) and triethylamine (3.24 g). After stirring at room temperature for 2 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate and the organic solution was evaporated to give an orange oil. Purification by silica gel column chromatography, eluting with ethyl acetate, gave the subtitle compound as an oil. Yield: 6.6g.
¹ H NMR δ (CDCl ₃ ) 7.34 (1H, dd), 7.30-7.25 (1H, m), 7.22-7.12 (2H, m), 4.15 (2H, s), 4.06-3.96 (1H, m), 3.93 -3.85 (1H, m), 3.75 (2H, t), 3.78-3.63 (1H, m), 3.24-3.10 (1H, m), 3.06 (2H, t), 2.04-1.72 (4H, m), 1.55 -1.34 (2H, m)

iii) 1- {2- [2- (2-Chloro-phenyl) -ethoxy] -ethyl} -piperidin-4-ol product from step (ii) in 2-ml (2- [2- (2 -Chloro-phenyl) -ethoxy] -1- (4-hydroxy-piperidin-1-yl) -ethanone) (6.6 g) was treated with lithium aluminum hydride (50 ml, 1M in THF) under nitrogen. It was then refluxed for 4 hours and then left at room temperature for 24 hours. Excess EtOAc was carefully added and the reaction was stirred for 2 hours. 1M NaOH solution (25 ml) was added and the whole was stirred until the solid was broken up. Filtration through Celite gave a two-phase mixture. This was exhaustively extracted with EtOAc and evaporated. Purification by column chromatography on silica gel eluting with EtOAc and then with MeOH + 3% triethylamine gave the subtitle compound as an oil. Yield: 3.5g.
¹ H NMR δ (CDCl ₃ ) 7.34 (1H, dd), 7.28-7.24 (1H, m), 7.20-7.14 (2H, m), 3.70 (2H, t), 3.62 (2H, t), 3.04 (2H , t), 2.78 (4H, t), 2.70 (2H, t), 2.43 (4H, t)

iv) 1- {2- [2- (2-Chloro-phenyl) -ethoxy] -ethyl} -piperidin-4-one product of step (iii) (1- {2- [2- (2-chloro- (Phenyl) -ethoxy] -ethyl} -piperidin-4-ol) (710 mg) was dissolved in dry DCM (6 ml) and N-methylmorpholine-N-oxide (360 mg, 3.12 mmol) and tetrapropyl perruthenate. Ammonium (7.5 mol%, 66 mg) was added. The reaction was stirred at room temperature. After 1 hour, the reaction mixture was diluted with ether and filtered through a bed of alumina deactivated with 6% water. The bed was eluted with ether. Fractions were evaporated to give an oil. This was purified by column chromatography on silica gel eluting with EtOAc and then EtOAc-0.5% triethylamine to give the subtitle compound as an oil. Yield: 330 mg.
¹ H NMR δ (CDCl ₃ ) 7.34 (1H, dd), 7.28-7.24 (1H, m), 7.20-7.14 (2H, m), 3.70 (2H, t), 3.62 (2H, t), 3.04 (2H , t), 2.78 (4H, t), 2.70 (2H, t), 2.43 (4H, t)

v) 5-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-{[(1- {2- [2- (2-chlorophenyl) ethoxy] ethyl} -4-hydroxy Piperidin-4-yl) methyl] amino} ethyl) -8-hydroxyquinolin-2 (1H) -one sodium hydride (56.6 mg, 60% in mineral oil) was added to dry DMSO (2.9 ml) and iodine was added. Trimethylsulfoxonium chloride (390 mg) was added. The mixture is stirred at room temperature under nitrogen for 1.25 hours and then the product of step (iv) (1- {2- [2- (2-chloro-phenyl)-] in dry THF (2.9 ml). Ethoxy] -ethyl} -piperidin-4-one) (330 mg) was added. The reaction mixture was stirred under nitrogen for 16 hours and then poured into water. Extracted with EtOAc, dried (Na ₂ SO ₄ ) and evaporated to give an oil. The oil was dissolved in methanol (0.3 ml) and the product of step 5 of Example 5 (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy) } Ethyl) -8-hydroxyquinolin-2 (1H) -one) (99 mg). The solution was heated at 65 ° C. for 4 hours and then left at room temperature for 16 hours. The mixture was purified by adsorption onto silica gel, followed by chromatography on silica gel, eluting with 7.5% MeOH in DCM, then 10% MeOH in DCM, and finally with 100% MeOH, subtitle compound Got. Further purification by reverse phase HPLC gave the subtitle compound as a yellow glass. Yield: 39 mg.
¹ H NMR δ (DMSO) 8.43 (1H, s), 7.57 (2H, s), 7.42 (2H, s), 7.19 (1H, s), 7.07 (1H, s), 6.66 (1H, s), 5.28 (1H, s), 3.24-3.85 (11H, m), 2.92-3.24 (1H, m), 2.34-2.90 (52H, m), 1.59 (3H, s), 1.00 (9H, s), 0.22 (3H , s), 0.00 (3H, s)

vi) 5-((1R) -2-{[(1- {2- [2- (2-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-hydroxyquinolin-2 (1H) -one product of step (v) (5- {1- (tert-butyl-dimethyl-silanyloxy) -2-[(1- {2- [2- (2 -Chloro-phenyl) -ethoxy] -ethyl} -4-hydroxy-piperidin-4-ylmethyl) -amino] -ethyl} -8-hydroxy-1H-quinolin-2-one) (35 mg) was added to dry THF (1 ml ) And treated with triethylamine trihydrofluoride (0.2 ml) at room temperature for 16 hours. All volatiles were removed in vacuo and the residue azeotroped with acetonitrile (x2). Purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column, 95% in acetonitrile (0.2% aqueous NH ₃ ) to 50% in acetonitrile (0.2% aqueous NH ₃ ). To give the title compound as a yellow powder. Yield: 9 mg.
MS APCI + 516 [M + H] ^+
1 H NMR δ (DMSO) 8.19 (1H, d), 7.43-7.34 (2H, m), 7.29-7.20 (2H, m), 7.06 (1H, d), 6.89 (1H, d), 6.49 (1H, d), 5.03-4.98 (1H, m), 3.59 (2H, t), 3.48 (2H, t), 2.92 (2H, t), 2.72-2.64 (3H, m), 2.60-2.36 (258H, m DMSO Signal under peak), 2.35-2.23 (6H, m), 1.48-1.36 (4H, m)

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および２,５−ジメチルベンジルアミン(０.０７４ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を薄緑色のゴム状物質として得た。収量：３６mg。
MS APCI+ 493 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.27(t, 1H), 8.16(d, 1H), 7.04(m, 3H), 6.91(m, 2H), 6.50(d, 1H), 4.95(t, 1H), 4.18(d, 2H), 2.76(bm, 2H), 2.68(d, 2H), 2.37(m, 2H), 2.27( t, 2H), 2.23(s, 3H), 2.19(s, 3H), 1.90(bm, 2H), 1.71(bm, 2H), 1.16(bm, 2H). (1 x H, 溶媒ピークによって不明瞭). Example 47
N- (2,5-dimethylbenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino) amino } Piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and 2 , 5-dimethylbenzylamine (0.074 g), stirred in dry DMF (3.0 ml) for 18 hours and prepared according to the procedure described in Example 27. By reverse phase HPLC, Xterra® Purified using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. The compound was obtained as a light green gum, yield: 36 mg.
MS APCI + 493 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.27 (t, 1H), 8.16 (d, 1H), 7.04 (m, 3H), 6.91 (m, 2H), 6.50 (d, 1H), 4.95 ( t, 1H), 4.18 (d, 2H), 2.76 (bm, 2H), 2.68 (d, 2H), 2.37 (m, 2H), 2.27 (t, 2H), 2.23 (s, 3H), 2.19 (s , 3H), 1.90 (bm, 2H), 1.71 (bm, 2H), 1.16 (bm, 2H). (1 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および１−アダマンチルメチルアミン(０.１ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中、１８時間撹拌し、実施例２７に記載された手順に従って製造した。質量分離精製(mass directed purification)によって精製し、表題化合物をゴム状物質として得た。収量：８mg。
MS APCI+ 523 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.17(d, 1H), 7.90(t, 1H), 7.05(d, 1H), 6.89(d, 1H), 6.48(d, 1H), 4.94(t, 1H), 2.77(m, 4H), 2.69(m, 3H), 2.22(t, 2H), 1.89(bs, 4H), 1.74( bt, 2H), 1.64(d, 4H), 1.56(d, 4H), 1.41(bs, 4H), 1.22(bm, 2H). (4H, 溶媒ピークによって不明瞭). Example 48
N- (adamanta-1-ylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and 1 -Made with adamantylmethylamine (0.1 g) in dry DMF (3.0 ml) for 18 hours and prepared according to the procedure described in Example 27. Purified by mass directed purification. The title compound was obtained as a gum, yield: 8 mg.
MS APCI + 523 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.17 (d, 1H), 7.90 (t, 1H), 7.05 (d, 1H), 6.89 (d, 1H), 6.48 (d, 1H), 4.94 ( t, 1H), 2.77 (m, 4H), 2.69 (m, 3H), 2.22 (t, 2H), 1.89 (bs, 4H), 1.74 (bt, 2H), 1.64 (d, 4H), 1.56 (d , 4H), 1.41 (bs, 4H), 1.22 (bm, 2H). (4H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および３−クロロ−２−メチルベンジルアミン(０.０８５ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ０.８８０ＮＨ_３からアセトニトリル中７０％ ０.８８０ＮＨ_３の濃度勾配で溶出し、表題化合物を緑色のゴム状物質として得た。さらにゴム状物質を、逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％ ＴＦＡからアセトニトリル中５０％ ＴＦＡの濃度勾配で溶出し、次いでＳＣＸカートリッジに負荷し、アセトニトリルを、次いでアセトニトリル中２０％ ０.８８０アンモニアを溶出液として用いて、表題化合物のビストリフルオロ酢酸塩を薄黄色の固体として得た。収量：５０mg。
MS APCI+ 513 [M+H]^+
1H NMR (400 MHz, d₆-DMSO / ND₄OD) δ 8.26(d, 1H), 7.29(d, 1H), 7.19(m, 3H), 6.99(d, 1H, 6.62(d, 1H), 5.12(t, 1H), 4.29(s, 2H), 2.81(bm, 4H), 2.34(bt, 2H), 2.29(s, 3H), 1.97(bt, 2H), 1.79(bm, 2H), 1.29(bm, 2H). (3 x H, 溶媒ピークによって不明瞭). Example 49
N- (3-chloro-2-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and 3 Prepared according to the procedure described in Example 27 using 18-chloro-2-methylbenzylamine (0.085 g) in dry DMF (3.0 ml) and stirred for 18 hours. Purify using a C8 5 micron 19 × 50 mm column eluting with a gradient from 95% 0.880 NH _{3 in} acetonitrile to 70% 0.880 NH _{3 in} acetonitrile to give the title compound as a green gum In addition, the rubbery material was obtained by reverse phase HP. Purified by LC using an Xterra® C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% TFA in acetonitrile to 50% TFA in acetonitrile, then loaded onto an SCX cartridge and acetonitrile was The bistrifluoroacetate salt of the title compound was obtained as a light yellow solid using 20% 0.880 ammonia in acetonitrile as the eluent, yield: 50 mg.
MS APCI + 513 [M + H] ^+
1 H NMR (400 MHz, d ₆ -DMSO / ND ₄ OD) δ 8.26 (d, 1H), 7.29 (d, 1H), 7.19 (m, 3H), 6.99 (d, 1H, 6.62 (d, 1H) , 5.12 (t, 1H), 4.29 (s, 2H), 2.81 (bm, 4H), 2.34 (bt, 2H), 2.29 (s, 3H), 1.97 (bt, 2H), 1.79 (bm, 2H), 1.29 (bm, 2H). (3 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および２−(トリフルオロメトキシ)ベンジルアミン(０.１２ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中８０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：１５mg。
MS APCI+ 549 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.46(m, 1H), 8.17(d, 1H), 7.50(d, 1H), 7.36(m, 3H), 7.06(d, 1H), 6.90(d, 1H), 6.49(d, 1H), 4.96(t, 1H), 4.32(d, 2H), 2.77(m, 2H), 2.70(d, 2H), 2.39(m, 1H), 2.30( t, 2H), 1.90(m, 2H), 1.73(m, 2H), 1.21(m, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 50
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-Trifluoromethoxybenzyl) -propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and 2 Prepared according to the procedure described in Example 27 using-(trifluoromethoxy) benzylamine (0.12 g) in dry DMF (3.0 ml) and stirring for 18 hours. Purify using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 80% (0.2% aqueous NH ₃ ) in acetonitrile. The title compound was obtained as a cream solid, yield: 15 mg.
MS APCI + 549 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.46 (m, 1H), 8.17 (d, 1H), 7.50 (d, 1H), 7.36 (m, 3H), 7.06 (d, 1H), 6.90 ( d, 1H), 6.49 (d, 1H), 4.96 (t, 1H), 4.32 (d, 2H), 2.77 (m, 2H), 2.70 (d, 2H), 2.39 (m, 1H), 2.30 (t , 2H), 1.90 (m, 2H), 1.73 (m, 2H), 1.21 (m, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(３−フルオロ−５−トリフルオロ)ベンジルアミン(０.１２ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中５０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をベージュ色の固体として得た。収量：１７mg。
MS APCI+ 551 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.54(t, 1H), 8.17(d, 1H), 7.53 - 7.43(m, 3H), 7.04(d, 1H), 6.88(d, 1H), 6.49(d, 1H), 4.95(t, 1H), 4.37(d, 2H), 2.76(m, 2H), 2.69(d, 2H), 2.39(m, 1H), 2.30( t, 2H), 1.93(m, 2H), 1.76(bt, 2H), 1.21(bt, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 51
N-((3-fluoro-5-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 3-fluoro-5-trifluoro) benzylamine (0.12 g), stirring in dry DMF (3.0 ml) for 18 hours. Purified using an Xterra® C8 5 micron 19 × 50 mm column with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 50% (0.2% aqueous NH ₃ ) in acetonitrile. To give the title compound as a beige solid, yield: 17 mg.
MS APCI + 551 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.54 (t, 1H), 8.17 (d, 1H), 7.53-7.43 (m, 3H), 7.04 (d, 1H), 6.88 (d, 1H), 6.49 (d, 1H), 4.95 (t, 1H), 4.37 (d, 2H), 2.76 (m, 2H), 2.69 (d, 2H), 2.39 (m, 1H), 2.30 (t, 2H), 1.93 (m, 2H), 1.76 (bt, 2H), 1.21 (bt, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(２−フルオロ−３−トリフルオロ)ベンジルアミン(０.１２ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２３mg。
MS APCI+ 551 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.53(t, 1H), 8.17(d, 1H), 7.68(m, 2H), 7.35(t, 1H), 7.06(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.97(t, 1H), 4.36(d, 2H), 2.73(m, 4H), 2.50(m, 1H), 2.29(t, 2H), 1.91(bm, 2H), 1.76(bm, 2H), 1.20(bt, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 52
N- [2-Fluoro-3- (trifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 2-fluoro-3-trifluoro) benzylamine (0.12 g), stirring in dry DMF (3.0 ml) for 18 hours. Purified using an Xterra® C8 5 micron 19 × 50 mm column with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. To give the title compound as a cream colored solid, yield: 23 mg.
MS APCI + 551 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.53 (t, 1H), 8.17 (d, 1H), 7.68 (m, 2H), 7.35 (t, 1H), 7.06 (d, 1H), 6.91 ( d, 1H), 6.50 (d, 1H), 4.97 (t, 1H), 4.36 (d, 2H), 2.73 (m, 4H), 2.50 (m, 1H), 2.29 (t, 2H), 1.91 (bm , 2H), 1.76 (bm, 2H), 1.20 (bt, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(２−クロロ−５−トリフルオロメチル)ベンジルアミン(０.１３ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２２mg。
MS APCI+ 567 / 569 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.60(t, 1H), 8.17(d, 1H), 7.68(m, 3H), 7.06(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.96(t, 1H), 4.39(d, 2H), 2.77 - 2.69(m, 4H), 2.34(m, 2H), 1.93(m, 2H), 1.72(m, 2H), 1.20(bt, 2H). (3 x H, 溶媒ピークによって不明瞭). Example 53
N-((2-chloro-5-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 2-chloro-5-trifluoromethyl) benzylamine (0.13 g), stirring in dry DMF (3.0 ml) for 18 hours. Purified by HPLC using an Xterra® C8 5 micron 19 × 50 mm column with a concentration of 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. Elution with a gradient gave the title compound as a cream solid Yield: 22 mg.
MS APCI + 567/569 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.60 (t, 1H), 8.17 (d, 1H), 7.68 (m, 3H), 7.06 (d, 1H), 6.91 (d, 1H), 6.50 ( d, 1H), 4.96 (t, 1H), 4.39 (d, 2H), 2.77-2.69 (m, 4H), 2.34 (m, 2H), 1.93 (m, 2H), 1.72 (m, 2H), 1.20 (bt, 2H). (3 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(５−フルオロ−２−トリフルオロメチル)ベンジルアミン(０.１２ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２３mg。
MS APCI+ 551 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.56(t, 1H), 8.18(d, 1H), 7.78(m, 1H), 7.39(d, 1H), 7.29(t, 1H), 7.06(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.96(t, 1H), 4.43(d, 2H), 2.80(bd, 2H), 2.71(d, 2H), 2.32(m, 2H), 1.93(bm, 2H), 1.74(bm, 2H), 1.23(bm, 2H). (3 x H, 溶媒ピークによって不明瞭). Example 54
N-((5-fluoro-2-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 5-fluoro-2-trifluoromethyl) benzylamine (0.12 g), stirring in dry DMF (3.0 ml) for 18 hours. Purified by HPLC using an Xterra® C8 5 micron 19 × 50 mm column with a concentration of 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. Elution with a gradient gave the title compound as a cream solid Yield: 2 3 mg.
MS APCI + 551 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.56 (t, 1H), 8.18 (d, 1H), 7.78 (m, 1H), 7.39 (d, 1H), 7.29 (t, 1H), 7.06 ( d, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 4.96 (t, 1H), 4.43 (d, 2H), 2.80 (bd, 2H), 2.71 (d, 2H), 2.32 (m , 2H), 1.93 (bm, 2H), 1.74 (bm, 2H), 1.23 (bm, 2H). (3 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(２−トリフルオロメチル)ベンジルアミン(０.１１ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２７mg。
MS APCI+ 533 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.53(t, 1H), 8.18(d, 2H), 7.70(d, 1H), 7.65(s, 1H), 7.46(m, 1H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.97(t, 1H), 4.44(d, 2H), 2.80(bd, 2H), 2.71(d, 2H), 2.40(m, 1H), 2.33(t, 2H), 1.93(bm, 2H), 1.73(bt, 2H), 1.20(bm, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 55
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(2-Trifluoromethyl) benzyl] propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 2-trifluoromethyl) benzylamine (0.11 g) in dry DMF (3.0 ml) and stirring for 18 hours. Purify using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. The title compound was obtained as a cream solid, yield: 27 mg.
MS APCI + 533 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.53 (t, 1H), 8.18 (d, 2H), 7.70 (d, 1H), 7.65 (s, 1H), 7.46 (m, 1H), 7.07 ( d, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 4.97 (t, 1H), 4.44 (d, 2H), 2.80 (bd, 2H), 2.71 (d, 2H), 2.40 (m , 1H), 2.33 (t, 2H), 1.93 (bm, 2H), 1.73 (bt, 2H), 1.20 (bm, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(５−クロロ−２−メチル)ベンジルアミン(０.０９８ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２３mg。
MS APCI+ 513 / 515 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.36(t, 1H), 8.17(d, 1H), 7.21(s, 1H), 7.17(s, 2H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.96(t, 1H), 4.22(d, 2H), 2.76(bd, 2H), 2.70(d, 2H), 2.38(m, 1H), 2.29(t, 2H), 2.23(s, 3H), 1.89(bm, 2H), 1.73(bm, 2H), 1.20(bm, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 56
N- (5-chloro-2-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 5-chloro-2-methyl) benzylamine (0.098 g), stirred in dry DMF (3.0 ml) for 18 hours. , Purified using a Xterra® C8 5 micron 19 × 50 mm column with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. Elution gave the title compound as a cream solid, yield: 23 mg.
MS APCI + 513/515 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.36 (t, 1H), 8.17 (d, 1H), 7.21 (s, 1H), 7.17 (s, 2H), 7.07 (d, 1H), 6.91 ( d, 1H), 6.50 (d, 1H), 4.96 (t, 1H), 4.22 (d, 2H), 2.76 (bd, 2H), 2.70 (d, 2H), 2.38 (m, 1H), 2.29 (t , 2H), 2.23 (s, 3H), 1.89 (bm, 2H), 1.73 (bm, 2H), 1.20 (bm, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(３,５−ジメチル)ベンジルアミン(０.０８５ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：１２mg。
MS APCI+ 493 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.37(t, 1H), 8.17(d, 1H), 7.06(d, 1H), 6.91(d, 1H), 6.84(s, 3H), 6.50(d, 1H), 4.97(t, 1H), 4.18(d, 2H), 2.71(bm, 4H), 2.39(m, 1H), 2.23(s + m, 8H), 1.91(bm, 2H), 1.72(bm, 2H), 1.19(bm, 2H). Example 57
N- (3,5-dimethylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 3,5-dimethyl) benzylamine (0.085 g) in dry DMF (3.0 ml) and stirring for 18 hours. Purify using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. The title compound was obtained as a cream solid, yield: 12 mg.
MS APCI + 493 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.37 (t, 1H), 8.17 (d, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 6.84 (s, 3H), 6.50 ( d, 1H), 4.97 (t, 1H), 4.18 (d, 2H), 2.71 (bm, 4H), 2.39 (m, 1H), 2.23 (s + m, 8H), 1.91 (bm, 2H), 1.72 (bm, 2H), 1.19 (bm, 2H).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および３−トリフルオロメトキシベンジルアミン(０.１２ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：１６mg。
MS APCI+ 549 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.49(t, 1H), 8.17(d, 1H), 7.44(t, 1H), 7.31(d, 1H), 7.22(s, 2H), 7.06(d, 1H), 6.90(d, 1H), 6.49(d, 1H), 4.96(t, 1H), 4.31(d, 2H), 2.71(m, 4H), 2.29(m, 2H), 1.92(bm, 2H), 1.72(bm, 2H), 1.21(bt, 2H). (3 x H, 溶媒ピークによって不明瞭). Example 58
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (3-Trifluoromethoxybenzyl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and 3 Prepared according to the procedure described in Example 27 using trifluoromethoxybenzylamine (0.12 g), stirring in dry DMF (3.0 ml) for 18 hours, by reverse phase HPLC, Xterra® Purified using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. The compound was obtained as a cream solid, yield: 16 mg.
MS APCI + 549 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.49 (t, 1H), 8.17 (d, 1H), 7.44 (t, 1H), 7.31 (d, 1H), 7.22 (s, 2H), 7.06 ( d, 1H), 6.90 (d, 1H), 6.49 (d, 1H), 4.96 (t, 1H), 4.31 (d, 2H), 2.71 (m, 4H), 2.29 (m, 2H), 1.92 (bm , 2H), 1.72 (bm, 2H), 1.21 (bt, 2H). (3 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(３−クロロ−２−フルオロ)ベンジルアミン(０.１０ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２４mg。
MS APCI+ 517 / 519 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.49(bm, 1H), 8.17(d, 1H), 7.45(t, 1H), 7.35(t, 1H), 7.16(t, 1H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 4.96(t, 1H), 4.32(d, 2H), 2.71(m, 4H), 2.30(m, 2H), 1.91(bm, 2H), 1.76(bt, 2H), 1.19(bm, 2H). (3 x H, 溶媒ピークによって不明瞭). Example 59
N- (3-chloro-2-fluorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 3-chloro-2-fluoro) benzylamine (0.10 g), stirring in dry DMF (3.0 ml) for 18 hours. , Purified using a Xterra® C8 5 micron 19 × 50 mm column with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. Elution gave the title compound as a cream solid, yield: 24 mg.
MS APCI + 517/519 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.49 (bm, 1H), 8.17 (d, 1H), 7.45 (t, 1H), 7.35 (t, 1H), 7.16 (t, 1H), 7.07 ( d, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 4.96 (t, 1H), 4.32 (d, 2H), 2.71 (m, 4H), 2.30 (m, 2H), 1.91 (bm , 2H), 1.76 (bt, 2H), 1.19 (bm, 2H). (3 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(２−フルオロ−５−トリフルオロメチル)ベンジルアミン(０.１２ｇ)を用いて精製し、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19x50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を白色の固体として得た。収量：１９mg。
MS APCI+ 551 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.54(m, 1H), 8.17(d, 1H), 7.66(m, 2H), 7.42(t, 1H), 7.06(d, 1H), 6.90(d, 1H), 6.50(d, 1H), 4.96(t, 1H), 2.70(m, 4H), 2.31(m, 2H), 1.91(bm, 2H), 1.71(bm, 2H), 1.18(bm, 2H). (3 x H, 溶媒ピークによって不明瞭). Example 60
N-[(2-Fluoro-5-trifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Purified with 2-fluoro-5-trifluoromethyl) benzylamine (0.12 g), stirred in dry DMF (3.0 ml) for 18 hours and prepared according to the procedure described in Example 27. Purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column with a concentration of 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. Elution with a gradient gave the title compound as a white solid, yield: 1 mg.
MS APCI + 551 [M + H] ^{+
1 H NMR (300 MHz, d} 6 -DMSO) δ 8.54 (m, 1H), 8.17 (d, 1H), 7.66 (m, 2H), 7.42 (t, 1H), 7.06 (d, 1H), 6.90 ( d, 1H), 6.50 (d, 1H), 4.96 (t, 1H), 2.70 (m, 4H), 2.31 (m, 2H), 1.91 (bm, 2H), 1.71 (bm, 2H), 1.18 (bm , 2H). (3 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(５−クロロ−２−フルオロ)ベンジルアミン(０.１０ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２８mg。
MS APCI+ 517 / 519 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.46(t, 1H), 8.17(d, 1H), 7.33(d, 2H), 7.22(t, 1H), 7.07(d, 1H), 6.92(d, 1H), 6.50(d, 1H), 4.97(t, 1H), 4.28(t, 2H), 2.72(m, 1H), 2.41(m, 1H), 2.29(t, 2H), 1.91(bt, 2H), 1.74(bt, 2H), 1.24(bm, 2H).( 2 x H, 溶媒ピークによって不明瞭). Example 61
N-[(5-chloro-2-fluoro) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5- Yl) ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 5-chloro-2-fluoro) benzylamine (0.10 g), stirred in dry DMF (3.0 ml) for 18 hours. , Purified using a Xterra® C8 5 micron 19 × 50 mm column with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. Elution gave the title compound as a cream solid, yield: 28 mg.
MS APCI + 517/519 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.46 (t, 1H), 8.17 (d, 1H), 7.33 (d, 2H), 7.22 (t, 1H), 7.07 (d, 1H), 6.92 ( d, 1H), 6.50 (d, 1H), 4.97 (t, 1H), 4.28 (t, 2H), 2.72 (m, 1H), 2.41 (m, 1H), 2.29 (t, 2H), 1.91 (bt , 2H), 1.74 (bt, 2H), 1.24 (bm, 2H) (2 x H, unclear by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２２ｇ)、トリエチルアミン(０.１１ml)および(３−トリフルオロメチル)ベンジルアミン(０.１１ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中７０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物をクリーム色の固体として得た。収量：２４mg。
MS APCI+ 533 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.51(t, 1H), 8.18(d, 1H), 7.56(m, 4H), 7.07(d, 1H), 6.92(d, 1H), 6.50(d, 1H), 4.98(t, 1H), 4.35(d, 2H), 2.72(m, 4H), 2.41(m, 1H), 2.29(t, 2H), 1.91(bm, 2H), 1.73(bt, 2H), 1.21(bm, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 62
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (3-Trifluoromethyl) benzylpropanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.22 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using 3-trifluoromethyl) benzylamine (0.11 g) in dry DMF (3.0 ml) and stirring for 18 hours. Purify using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 70% (0.2% aqueous NH ₃ ) in acetonitrile. The title compound was obtained as a cream solid, yield: 24 mg.
MS APCI + 533 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.51 (t, 1H), 8.18 (d, 1H), 7.56 (m, 4H), 7.07 (d, 1H), 6.92 (d, 1H), 6.50 ( d, 1H), 4.98 (t, 1H), 4.35 (d, 2H), 2.72 (m, 4H), 2.41 (m, 1H), 2.29 (t, 2H), 1.91 (bm, 2H), 1.73 (bt , 2H), 1.21 (bm, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１３ｇ)から、ＨＡＴＵ(０.２０ｇ)、トリエチルアミン(０.０７ml)およびベンズヒドリルアミン(０.１０ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中８０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を黄色の泡状物質として得た。収量：７７mg。
MS APCI+ 541 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.97(d, 1H), 8.18(d, 1H), 7.27(m, 10H), 7.07(d, 1H), 6.91(d, 1H), 6.50(d, 1H), 6.08(d, 1H), 4.98(t, 1H), 4.35(d, 2H), 2.72(m, 4H), 2.41(m, 1H), 2.29(t, 2H), 1.91(bm, 2H), 1.73(bt, 2H), 1.21(bm, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 63
N-benzhydryl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl Propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.13 g), HATU (0.20 g), triethylamine (0.07 ml) and benz Prepared using hydrylamine (0.10 g) in dry DMF (3.0 mL) for 18 hours and prepared according to the procedure described in Example 27. By reverse phase HPLC, Xterra® C85 Purify using a micron 19 × 50 mm column, eluting with a gradient from 95% in acetonitrile (0.2% aqueous NH ₃ ) to 80% in acetonitrile (0.2% aqueous NH ₃ ) to give the title compound as a yellow Obtained as a foam, yield: 77 mg.
MS APCI + 541 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.97 (d, 1H), 8.18 (d, 1H), 7.27 (m, 10H), 7.07 (d, 1H), 6.91 (d, 1H), 6.50 ( d, 1H), 6.08 (d, 1H), 4.98 (t, 1H), 4.35 (d, 2H), 2.72 (m, 4H), 2.41 (m, 1H), 2.29 (t, 2H), 1.91 (bm , 2H), 1.73 (bt, 2H), 1.21 (bm, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１３ｇ)から、ＨＡＴＵ(０.２０ｇ)、トリエチルアミン(０.０７ml)およびジベンジルアミン(０.１１ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中５０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を黄色のゴム状物質として得た。収量：７０mg。
MS APCI+ 555 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.16(d, 1H), 7.29(m, 10H), 7.05(d, 1H), 6.90(d, 1H), 6.49(d, 1H), 4.95(t, 1H), 4.53(s, 2H), 4.50(s, 2H), 2.68(d, 4H), 2.34(m, 1H), 1.88(m, 2H), 1.69(bt, 2H), 1.16(m, 2H). (4 x H, 溶媒ピークによって不明瞭). Example 64
N, N-dibenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.13 g), HATU (0.20 g), triethylamine (0.07 ml) and di- Prepared using benzylamine (0.11 g) in dry DMF (3.0 mL) for 18 hours and prepared according to the procedure described in Example 27. By reverse phase HPLC, Xterra® C85 Purify using a micron 19 × 50 mm column, eluting with a gradient from 95% in acetonitrile (0.2% aqueous NH ₃ ) to 50% in acetonitrile (0.2% aqueous NH ₃ ) to give the title compound as a yellow Obtained as a gum, yield: 70 mg.
MS APCI + 555 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.16 (d, 1H), 7.29 (m, 10H), 7.05 (d, 1H), 6.90 (d, 1H), 6.49 (d, 1H), 4.95 ( t, 1H), 4.53 (s, 2H), 4.50 (s, 2H), 2.68 (d, 4H), 2.34 (m, 1H), 1.88 (m, 2H), 1.69 (bt, 2H), 1.16 (m , 2H). (4 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１３ｇ)から、ＨＡＴＵ(０.２０ｇ)、トリエチルアミン(０.０７ml)および(３,５−ビストリフルオロメチル)ベンジルアミン(０.１３ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中５０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を黄色の泡状物質として得た。収量：６５mg。
MS APCI+ 601 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.59(t, 1H), 8.16(d, 1H), 7.97(s, 1H), 7.93(s, 2H), 7.06(d, 1H), 6.90(d, 1H), 6.49(d, 1H), 4.95(t, 1H) 4.44(d, 2H), 2.74(m, 4H), 2.37(m, 1H), 2.31(t, 2H), 1.91(m, 2H), 1.70(bt, 2H), 1.16(m, 2H). (2 x H, 溶媒ピークによって不明瞭). Example 65
N-[(3,5-bistrifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5- Yl) ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.13 g), HATU (0.20 g), triethylamine (0.07 ml) and ( Prepared according to the procedure described in Example 27 using 3,5-bistrifluoromethyl) benzylamine (0.13 g), stirring in dry DMF (3.0 ml) for 18 hours. , Purified using a Xterra® C8 5 micron 19 × 50 mm column with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 50% (0.2% aqueous NH ₃ ) in acetonitrile. Elution gave the title compound as a yellow foam, yield: 65 mg.
MS APCI + 601 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.59 (t, 1H), 8.16 (d, 1H), 7.97 (s, 1H), 7.93 (s, 2H), 7.06 (d, 1H), 6.90 ( d, 1H), 6.49 (d, 1H), 4.95 (t, 1H) 4.44 (d, 2H), 2.74 (m, 4H), 2.37 (m, 1H), 2.31 (t, 2H), 1.91 (m, 2H), 1.70 (bt, 2H), 1.16 (m, 2H). (2 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２３ｇ)、トリエチルアミン(０.１１ml)および(ビフェニル−３−イル)メチルアミン(０.１２ｇ)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中５０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を黄色の固体として得た。収量：４０mg。
MS APCI+ 541 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.46(t, 1H), 8.17(d, 1H), 7.62(d, 2H), 7.39(m, 7H), 7.06(d, 1H), 6.91(d, 1H), 6.49(d, 1H), 4.95(t, 1H) 4.34(d, 2H), 2.75(m, 2H), 2.68(d, 2H), 2.31(m, 4H), 1.89(m, 2H), 1.68(bt, 2H), 1.15(m, 2H). (1 x H, 溶媒ピークによって不明瞭). Example 66
N-[(biphenyl-3-yl) methyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.23 g), triethylamine (0.11 ml) and ( Prepared according to the procedure described in Example 27 using biphenyl-3-yl) methylamine (0.12 g), stirred in dry DMF (3.0 ml) for 18 hours, by reverse phase HPLC. Purify using a C8 5 micron 19 × 50 mm column, eluting with a gradient from 95% (0.2% aqueous NH ₃ ) in acetonitrile to 50% (0.2% aqueous NH ₃ ) in acetonitrile. The title compound was obtained as a yellow solid, yield: 40 mg.
MS APCI + 541 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.46 (t, 1H), 8.17 (d, 1H), 7.62 (d, 2H), 7.39 (m, 7H), 7.06 (d, 1H), 6.91 ( d, 1H), 6.49 (d, 1H), 4.95 (t, 1H) 4.34 (d, 2H), 2.75 (m, 2H), 2.68 (d, 2H), 2.31 (m, 4H), 1.89 (m, 2H), 1.68 (bt, 2H), 1.15 (m, 2H). (1 x H, obscured by solvent peak).

表題化合物を、実施例６の段階(iii)の生成物(３−[４−({[(２Ｒ)−２−{[ｔｅｒｔ−ブチル(ジメチル)シリル]オキシ}−２−(８−ヒドロキシ−２−オキソ−１,２−ジヒドロキノリン−５−イル)エチル]アミノ}ピペリジン−１−イル]プロパン酸)(０.１５ｇ)から、ＨＡＴＵ(０.２３ｇ)、トリエチルアミン(０.１１ml)および(５,６,７,８−テトラヒドロナフタレン−１−イル)メチルアミン(０.１２ｇ)(Chem. Ber., 1922, 55 1705)を用いて、乾燥ＤＭＦ(３.０ml)中で、１８時間撹拌し、実施例２７に記載された手順に従って製造した。逆相ＨＰＬＣによって、Xterra(登録商標) C8 5ミクロン 19×50mm カラムを用いて精製し、アセトニトリル中９５％(０.２％水性ＮＨ_３)からアセトニトリル中５０％(０.２％水性ＮＨ_３)の濃度勾配で溶出し、表題化合物を黄色の泡状物質として得た。収量：４５mg。
MS APCI+ 519 [M+H]^+
1H NMR (300 MHz, d₆-DMSO) δ 8.26(m, 1H), 8.17(d, 1H), 7.02(m, 3H), 6.91(m, 2H), 6.49(m, 1H), 4.95(t, 1H), 4.16(d, 2H), 2.72(m, 6H), 2.62(t, 2H), 2.33(m, 2H), 2.27(t, 2H), 1.90(bm, 2H), 1.72(m, 6H), 1.14(bm, 2H). (1 x H, 溶媒ピークによって不明瞭) Example 67
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(5,6,7,8-tetrahydronaphthalen-1-yl) methyl] propanamide

The title compound is obtained from the product of Example 6, step (iii) (3- [4-({[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl] propanoic acid) (0.15 g), HATU (0.23 g), triethylamine (0.11 ml) and ( 5,6,7,8-tetrahydronaphthalen-1-yl) methylamine (0.12 g) (Chem. Ber., 1922, 55 1705) was stirred in dry DMF (3.0 ml) for 18 hours. And purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column and 95% in acetonitrile (0.2% aqueous NH ₃ ). To a gradient of 50% (0.2% aqueous NH ₃ ) in acetonitrile to give the title compound as a yellow foam Yield: 45 mg.
MS APCI + 519 [M + H] ^+
1 H NMR (300 MHz, d ₆ -DMSO) δ 8.26 (m, 1H), 8.17 (d, 1H), 7.02 (m, 3H), 6.91 (m, 2H), 6.49 (m, 1H), 4.95 ( t, 1H), 4.16 (d, 2H), 2.72 (m, 6H), 2.62 (t, 2H), 2.33 (m, 2H), 2.27 (t, 2H), 1.90 (bm, 2H), 1.72 (m , 6H), 1.14 (bm, 2H). (1 x H, obscured by solvent peak)

Example 68
5-((1R) -2-{[(1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-Hydroxyquinolin-2 (1H) -one

i) [2- (2,6-Dichlorophenyl) ethoxy] acetic acid 2- (2,6-dichlorophenyl) ethanol (4.70 g) was dissolved in DMF (53 ml), cooled in an ice bath and then sodium hydride (1.08 g, 60% in mineral oil) was added in small portions. The reaction mixture was stirred at room temperature for 2 hours and then sodium chloroacetate (2.63 g) was added. The mixture was then heated at 60 ° C. for 6 hours, then poured into water and extracted with ether (× 6). The aqueous material was acidified with concentrated HCl from pH 9 to pH 2, then extracted with EtOAc (x7). The combined EtOAc extracts were washed with water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and concentrated to give the subtitle compound as a pale yellow solid. Yield: 3.36 g.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.30 (d, 2H), 7.12 (dd, 1H), 4.14 (s, 2H), 3.80 (t, 2H), 3.33 (t, 2H).

ii) 1-{[2- (2,6-dichlorophenyl) ethoxy] acetyl} piperidin-4-ol product of step (i) ([2- (2,6-dichlorophenyl) ethoxy] acetic acid) (2.06 g ) Was dissolved in DMF (35 ml) to which HATU (3.92 g), triethylamine (2.9 ml) and piperidin-4-ol (3.47 g) were added. The reaction mixture was stirred at room temperature overnight, then the DMF was partially evaporated and the residue was diluted with EtOAc. The mixture was then washed with 2M aqueous HCl, saturated aqueous NaHCO ₃ , water, and saturated aqueous NaCl, the organic layer was dried (Na ₂ SO ₄ ) and evaporated. Purified by Biotage and eluted with EtOAc to give the subtitle compound as a pale yellow oil. Yield: 2.44 g.
MS APCI + 332/334/336 [M + H] ⁺

iii) 1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} piperidin-4-ol lithium aluminum hydride (14 ml, 1M in THF) is added to stage (ii) in dry THF (35 ml). Was slowly added to a cooled (0 ° C.) solution of the product (1-{[2- (2,6-dichlorophenyl) ethoxy] acetyl} piperidin-4-ol) (2.28 g). The reaction mixture was gradually warmed to room temperature and stirred for 2 days. It was cooled in ice and then a mixture of celite (5 g) and sodium sulfate decahydrate (5 g) was added in portions. More THF was added followed by 1 ml of 10% aqueous NaOH. The solid was removed by filtration and the volatiles were evaporated. The residue was dissolved in EtOAc, dried (Na ₂ SO ₄ ) and volatiles were evaporated to give the subtitle compound as a yellow oil. Yield: 2.05g.
MS APCI + 318/320/322 [M + H] ⁺

iv) 1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} piperidin-4-one product of step (iii) (1- {2- [2- (2,6-dichlorophenyl) ethoxy ] Ethyl} piperidin-4-ol) (0.75 g) was dissolved in dry DCM (10 ml) and to it was added powdered 4Å molecular sieve, TPAP (83 mg) and NMO (0.46 g). The reaction mixture was stirred at room temperature for 1 hour. Ether (10 ml) was added and the mixture was filtered. The filter pad was washed with EtOAc and the filtrate was concentrated in vacuo. Purified by Biotage column, eluting with 1: 3 hexane: EtOAc, then EtOAc, then with 0.5% Et ₃ N in EtOAc to give the subtitle compound as a colorless oil. Yield: 0.22g.
MS APCI + 316/318/320 [M + H] ⁺

v) 6- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -1-oxa-6-azaspiro [2.5] octane sodium hydride (54 mg, 60% in mineral oil) was added to dry DMSO (3.5 ml) and the mixture was stirred for 15 minutes, then trimethylsulfoxonium iodide (0.17 g) was added and the mixture was stirred for 2.25 hours. A solution of the product of step (iv) (1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} piperidin-4-one) (0.22 g) in dry THF (3.5 ml) was added. In addition, the reaction mixture was stirred overnight and then diluted with EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (x3). The combined organic extracts were washed with water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and volatiles evaporated to give the subtitle compound as a yellow oil. Yield: 0.23g.
MS APCI + 330/332/334 [M + H] ⁺

vi) 5-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-{[(1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -4 -Hydroxypiperidin-4-yl) methyl] amino} ethyl) -8-hydroxyquinolin-2 (1H) -one methanol (5 ml) in Example 5 step (ii) product (5-((1R ) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0.27 g) and the product of step (v) (6 A solution of-{2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -1-oxa-6-azaspiro [2.5] octane) (0.23 g) was refluxed for 20 hours. The solvent was evaporated in vacuo and purified by flash chromatography, eluting with _NH in DCM 3 -MeOH (0.7M) (2.5 15%) to give the subtitle compound as a yellow gum. Yield: 0.39 g.
MS APCI + 664/666/668 [M + H] ⁺

vii) 5-((1R) -2-{[(1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1- Hydroxyethyl) -8-hydroxyquinolin-2 (1H) -one product of step (vi) (5-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-{[( 1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0 .39 g) was dissolved in THF (9 ml) and to it was added triethylamine hydrofluoride (0.3 ml). The reaction mixture was stirred overnight and then the volatiles were evaporated. Purification by reverse phase HPLC using an XBridge® column, eluting with a gradient of 5-75% acetonitrile in 0.2% aqueous TFA, gave the ditrifluoroacetate salt of the title compound as a yellow solid. . Yield: 0.20 g.
MS APCI + 550/552/554 [M + H] ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 10.51 (s, 2H), 10.06 (s, 1H), 8.68 (s, 1H), 8.42 (s, 1H), 8.20 (d, 1H), 7.48 ( d, 2H), 7.31 (t, 1H), 7.15 (d, 1H), 6.99 (d, 1H), 6.59 (d, 1H), 6.20 (s, 1H), 5.60 (s, 1H), 5.45-5.42 (m, 1H), 3.81-3.07 (m, 16H), 1.88-1.74 (m, 4H).

Example 69
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl) amino ] Ethyl} quinolin-2 (1H) -one

i) (2-Methyl-2-phenylpropoxy) acetic acid subtitle compound was prepared from 2-phenyl-2-methyl-propanol (4.05 g) by the method of Example 46, step (i) and was a clear oil Obtained as a thing. Yield: 4.2g.
¹ H NMR δ (CDCl ₃ ) 1.38 (6H, s), 3.59 (2H, s), 4.03 (2H, s), 7.18-7.27 (2H, m), 7.19-7.24 (1H, m), 7.30-7.35 (2H, m), 7.38-7.42 (2H, m)

ii) 1- (4-Hydroxy-piperidin-1-yl) -2- (2-methyl-2-phenyl-propoxy) -ethanone subtitle compound is prepared from the product of step (i) ((2-methyl-2- (Phenylpropoxy) acetic acid) (2.44 g) was prepared by the method of Example 46, step (ii) and obtained as a clear oil. Yield: 2.5g.
¹ H NMR δ (CDCl ₃ ) 7.40-7.35 (2H, m), 7.33-7.27 (2H, m), 7.22-7.16 (1H, m), 4.06 (2H, s), 4.03-3.94 (1H, m) , 3.88-3.78 (1H, m), 3.64-3.54 (1H, m), 3.52 (2H, s), 3.12 (1H, ddd), 2.99 (1H, ddd), 1.89-1.79 (1H, m), 1.78 -1.74 (1H, m), 1.72-1.62 (1H, m), 1.50-1.38 (1H, m), 1.34 (7H, s)

iii) 1- [2- (2-Methyl-2-phenyl-propoxy) -ethyl] -piperidin-4-ol subtitle compound is prepared from the product of step (ii) (1- (4-hydroxy-piperidine-1- Yl) -2- (2-methyl-2-phenyl-propoxy) -ethanone) (2.5 g) was prepared as a clear rubbery material by the method of Example 46, step (iii). Yield: 1.76 g.
¹ H NMR δ (CDCl ₃ ) 1.32 (6H, s), 1.59-1.47 (3H, m), 1.88-1.78 (2H, m), 2.18-2.09 (2H, m), 2.53 (2H, t), 2.77 -2.68 (2H, m), 3.43 (2H, s), 3.50 (2H, t), 3.68-3.58 (1H, m), 7.18 (1H, t), 7.29 (2H, t), 7.38 (2H, d )

iv) 1- [2- (2-Methyl-2-phenyl-propoxy) -ethyl] -piperidin-4-one subtitle compound was prepared from the product of step (iii) (1- [2- (2-methyl-2 -Phenyl-propoxy) -ethyl] -piperidin-4-ol) (0.9 g) was prepared as a clear rubbery material by the method of Example 46, step (iv). Yield: 0.57g.
¹ H NMR δ (CDCl ₃ ) 1.33 (6H, s), 2.37 (4H, t), 2.65 (2H, t), 2.71 (4H, t), 3.45 (2H, s), 3.54 (2H, t), 7.20-7.15 (1H, m), 7.32-7.26 (2H, m), 7.39-7.35 (2H, m)

v) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl ) Amino] ethyl} quinolin-2 (1H) -one The title compound is converted to the product of step (iv) (1- [2- (2-methyl-2-phenyl-propoxy) -ethyl] -piperidin-4-one ) (150 mg) by the method of Example 46, step (v) and Example 46, step (vi), and the intermediate was obtained without purification as a beige solid. Yield: 58 mg.
MS: APCI + 510 [M + H] ^+
1 H NMR δ (DMSO) 8.19 (1H, d), 7.38 (2H, d), 7.28 (2H, t), 7.16 (1H, t), 7.07 (1H, d), 6.91 (1H, d), 6.50 (1H, d), 5.06-5.01 (1H, m), 3.44 (2H, t), 3.41 (2H, s), 2.76-2.65 (2H, m), 2.47-2.39 (6H, m), 2.35-2.26 (2H, m), 1.49-1.37 (4H, m), 1.24 (6H, s)

Example 70
5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl } -8-Hydroxyquinolin-2 (1H) -one

i) (1,1-Dimethyl-2-phenyl-ethoxy) -acetic acid ethyl ester ethyl diazoacetate (9.13 g) and 2-methyl-1 containing Rh (OAc) ₂ dimer (0.7 mol%) -Phenyl-propan-2-ol (24.35 g) was slowly added dropwise at room temperature over 4 hours. The reaction was stirred at room temperature for 16 hours. Vacuum distillation (boiling point 110-120 ° C./5 mm) gave the subtitle compound as a clear liquid. Yield: 12.5g.
¹ H NMR δ (CDCl ₃ ) 1.15 (6H, s), 1.26 (3H, t), 2.80 (2H, s), 4.05 (2H, s), 4.19 (2H, q), 7.15-7.28 (5H, m )

ii) The product of step (i) ((1,1 -dimethyl-2) in (1,1-dimethyl-2-phenyl-ethoxy) -acetic acid ethanol (100 ml) + water (50 ml) and NaOH (4 g) -Phenyl-ethoxy) -acetic acid ethyl ester) (11.82 g) were refluxed together for 6 hours and then allowed to stand at room temperature for 16 hours. The ethanol was evaporated in vacuo and the aqueous residue was washed well with EtOAc. The aqueous solution was acidified (concentrated HCl) and extracted into EtOAc. Drying and evaporation gave an oil. This was purified by column chromatography on silica gel eluting with 9: 1 isohexane-EtOAc to give the subtitle compound as a clear liquid. Yield: 7g.
¹ H NMR δ (CDCl ₃ ) 1.22 (6H, s), 2.84 (2H, s), 4.07 (2H, s), 7.16-7.35 (5H, m), 9.22-9.65 (1H, m)

iii) 2- (1,1-dimethyl-2-phenyl-ethoxy) -1- (4-hydroxy-piperidin-1-yl) -ethanone product of stage (ii) ((1,1-dimethyl-2- (Phenyl-ethoxy) -acetic acid) (3.124 g), 4-hydroxy-piperidine (4.55 g) and HATU (6.84 g) were dissolved in dry DMF (50 ml) and triethylamine (3.03 g) was added. . The reaction was stirred at room temperature for 60 hours. The reaction was poured into water (600 ml) and acidified (concentrated HCl). The aqueous solution was extracted with ether and the organic phase was washed with saturated aqueous sodium bicarbonate, dried and evaporated to give the subtitle compound as a clear liquid. Yield: 1.6g.
¹ H NMR δ (CDCl ₃ ) 7.17-7.31 (5H, m), 4.11 (2H, s), 4.00-4.09 (1H, m), 3.79-3.95 (2H, m), 3.12-3.27 (2H, m) , 2.81 (2H, s), 2.80 (1H, s), 1.74-1.94 (2H, m), 1.42-1.56 (2H, m), 1.19 (6H, s)

iv) 1- [2- (1,1-Dimethyl-2-phenyl-ethoxy) -ethyl] -piperidin-4-ol subtitle compound is prepared from the product of step (iii) (2- (1,1-dimethyl- 2-Phenyl-ethoxy) -1- (4-hydroxy-piperidin-1-yl) -ethanone) (1.6 g) was prepared as a rubbery material by the method of Example 46, step (iii). Yield: 0.9g.
¹ H NMR δ (CDCl ₃ ) 7.32-7.16 (5H, m), 3.73-3.63 (1H, m), 3.56 (2H, t), 2.86-2.78 (2H, m), 2.78-2.75 (2H, m) , 2.57 (2H, t), 2.27-2.17 (2H, m), 1.94-1.84 (2H, m), 1.72-1.66 (1H, m), 1.65-1.52 (2H, m), 1.14 (6H, s)

v) 1- [2- (1,1-Dimethyl-2-phenyl-ethoxy) -ethyl] -piperidin-4-one subtitle compound is prepared from the product of step (iv) (1- [2- (1,1 -Dimethyl-2-phenyl-ethoxy) -ethyl] -piperidin-4-ol) (0.9 g) as a rubbery material by the method of Example 46, step (iv). Yield: 0.58g.
¹ H NMR δ (CDCl ₃ ) 1.17 (6H, s), 2.45 (4H, t), 2.72 (2H, t), 2.79 (2H, s), 2.84 (4H, t), 3.61 (2H, t), 7.30-7.17 (5H, m)

vi) 5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1- Hydroxyethyl} -8-hydroxyquinolin-2 (1H) -one The title compound is converted into the product of step (v) (1- [2- (1,1-dimethyl-2-phenyl-ethoxy) -ethyl] -piperidine. -4-one) (220 mg) from Example 46, step (v) and Example 46, step (vi), and the intermediate obtained without purification as a beige solid. It was. Yield: 58 mg.
MS APCI + 510 [M + H] ^+
1 H NMR δ (DMSO) 8.19 (1H, d), 7.29-7.14 (5H, m), 7.08 (1H, d), 6.92 (1H, d), 6.50 (1H, d), 5.06 (1H, t) , 3.49 (2H, t), 2.77-2.67 (4H, m), 2.48-2.31 (4H, m), 1.53-1.41 (4H, m), 1.06 (6H, s)

Example 71
5-((1R) -2-{[(1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-Hydroxyquinolin-2 (1H) -one

i) [2- (2,3-dichlorophenyl) ethoxy] acetic acid 2- (2,3-dichlorophenyl) ethanol (5.03 g) was dissolved in DMF (53 ml), cooled in an ice bath. Sodium hydride (1.15 g, 60% in mineral oil) was added in small portions. The reaction mixture was stirred at room temperature for 1.75 hours and then sodium chloroacetate (2.80 g) was added. The mixture was then heated at 60 ° C. for 6 hours, then poured into water and extracted with ether (× 6). The aqueous material was acidified with concentrated HCl from pH 9 to pH 2 and then extracted with EtOAc (x5). The combined EtOAc extracts were washed with water, saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and concentrated to give the subtitle compound as a pale yellow oil. Yield: 1.57g.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (dd, 1H), 7.24 (dd, 1H), 7.14 (t, 1H), 4.11 (s, 2H), 3.82 (t, 2H), 3.13 (t, 2H).

ii) 1-{[2- (2,3-dichlorophenyl) ethoxy] acetyl} piperidin-4-ol product of step (i) ([2- (2,3-dichlorophenyl) ethoxy] acetic acid) (2.41 g ) Was dissolved in DMF (45 ml), to which HATU (4.42 g), triethylamine (4.1 ml) and piperidin-4-ol (2.94 g) were added. The reaction mixture was stirred at room temperature for 28 hours, then the DMF was partially evaporated and the residue was diluted with EtOAc. It is washed with 2M aqueous HCl, saturated aqueous NaHCO ₃ , water, and saturated aqueous NaCl, the organic layer is collected, dried (Na ₂ SO ₄ ), the volatiles are evaporated and the subtitle compound is As an oil. Yield: 2.75 g.
MS APCI + 332/334/336 [M + H] ⁺

iii) 1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} piperidin-4-ol lithium aluminum hydride (16 ml, 1M in THF) is added to stage (ii) in dry THF (40 ml). Was slowly added to a cooled (0 ° C.) solution of the product of (1-{[2- (2,3-dichlorophenyl) ethoxy] acetyl} piperidin-4-ol) (2.59 g). The reaction mixture was gradually warmed to room temperature and stirred for 3 hours. It was cooled in ice and then a mixture of celite (5 g) and sodium sulfate decahydrate (5 g) was added in portions. More THF was added followed by 1 ml of 10% aqueous NaOH. The solid was removed by filtration and the volatiles were evaporated to give the subtitle compound as a yellow oil. Yield: 1.98 g.
MS APCI + 318/320/322 [M + H] ⁺

iv) 1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} piperidin-4-one product of step (iii) (1- {2- [2- (2,3-dichlorophenyl) ethoxy ] Ethyl} piperidin-4-ol) (0.39 g) was dissolved in DCM (8 ml) to which NMO (0.18 g) and powdered 4 粉末 molecular sieves (0.5 g) were added. The reaction mixture was stirred for 30 minutes and then TPAP (83 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes, then additional NMO (0.18 g), TPAP (32 mg) and molecular sieves (0.5 g) were added. After an additional 40 minutes, ether was added and the mixture was filtered. The filter pad was washed with EtOAc and the filtrate was concentrated. Purification by flash chromatography eluting with 10% MeOH in DCM gave the subtitle compound as a black oil. Yield: 0.23g.
MS APCI + 316/318/320 [M + H] ⁺

v) 6- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -1-oxa-6-azaspiro [2.5] octane sodium hydride (80 mg, 60% in mineral oil) was added to dry DMSO (4 ml) followed by trimethylsulfoxonium iodide (0.24 g) and the mixture was stirred for 2 hours. A solution of the product of step (iv) (1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} piperidin-4-one) (0.23 g) in dry THF (5 ml) was added, The reaction mixture was stirred for 3 hours and then diluted with EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (x3). The combined organic extracts were washed with water, saturated aqueous NaCl, dried (MgSO ₄ ) and the volatiles evaporated to give the subtitle compound as a colorless oil. Yield: 0.25g.
MS APCI + 330/332/334 [M + H] ⁺

vi) 5-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-{[(1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -4 -Hydroxypiperidin-4-yl) methyl] amino} ethyl) -8-hydroxyquinolin-2 (1H) -one methanol (5 ml) in Example 5 step (ii) product (5-((1R ) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0.30 g) and the product of step (v) (6 A solution of-{2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -1-oxa-6-azaspiro [2.5] octane) (0.24 g) was refluxed for 20 hours. The solvent was evaporated and purified by flash chromatography, eluting with _NH in DCM 3 -MeOH (1.4M) (2 25%) to afford the product as a yellow foam. Yield: 0.26g.
MS APCI + 664/666/668 [M + H] ⁺

vii) 5-((1R) -2-{[(1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1- Hydroxyethyl) -8-hydroxyquinolin-2 (1H) -one product of step (vi) (5-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-{[( 1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} ethyl) -8-hydroxyquinolin-2 (1H) -one) (0 .26 g) was dissolved in THF (9 ml) and to it was added triethylamine trihydrofluoride (0.4 ml). The reaction mixture was stirred at room temperature for 3 days and then volatiles were evaporated. Purify by reverse phase HPLC using an Ace® column eluting with a gradient of 5-50% acetonitrile in 0.2% aqueous TFA to give the title compound ditrifluoroacetate as a cream solid. It was. Yield: 90 mg.
MS APCI + 550/552/554 [M + H] ^+
1 H NMR (400 MHz, d ₆ -DMSO) δ 10.58 (s, 1H), 10.50 (s, 1H), 9.65 (s, 1H), 8.78 (s, 1H), 8.45 (s, 1H), 8.22 ( d, 1H), 7.52 (d, 1H), 7.40 (d, 1H), 7.31 (t, 1H), 7.16 (d, 1H), 7.00 (d, 1H), 6.58 (d, 1H), 5.45-5.43 (m, 1H), 3.79-3.76 (m, 2H), 3.71 (t, 2H), 3.50-3.10 (m, 12H), 3.05 (t, 2H), 1.88-1.78 (m, 4H)

Example 72
5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8- Hydroxyquinolin-2 (1H) -one

i) 1- [2- (1,1-Dimethyl-2-phenyl-ethoxy) -ethyl] -piperidine-4-carbaldehyde trimethylsilyl-diazomethane (179 mg) was added to lithium diisopropylamide (n-BuLi (0.627 ml, (Prepared from 2.5M in hexane) and diisopropylamine (1.315 g) in THF (3 ml) at −78 ° C. and stirred at −78 ° C. for 30 minutes. Product of Example 70, step (v) (1- [2- (1,1-dimethyl-2-phenyl-ethoxy) -ethyl] -piperidin-4-one) (360 mg) in dry THF (3 ml) Was added dropwise and the reaction was further stirred at −78 ° C. for 1 hour and then refluxed for 3 hours. After quenching with ice water, the reaction was extracted into ether and the ether extract was dried (Na ₂ SO ₄ ) and evaporated to give an orange oil. It was dissolved in EtOAc (25 ml) containing silica gel (4 g) and stirred for 16 h under nitrogen. The silica gel was filtered off, washed with more EtOAc and the combined organic solution was evaporated to give an orange oil. Yield: 230 mg.
¹ H NMR δ (CDCl ₃ ) 9.64 (1H, s), 7.29-7.23 (2H, m), 7.23-7.17 (3H, m), 3.56 (2H, t), 2.92-2.84 (2H, m), 2.77 (2H, s), 2.57 (2H, t), 2.27-2.14 (3H, m), 1.93-1.84 (2H, m), 1.74-1.62 (2H, m), 1.14 (6H, s)

ii) 5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] -1-hydroxyethyl}- 8-hydroxyquinolin-2 (1H) -one product of step (i) (1- [2- (1,1-dimethyl-2-phenyl-ethoxy) -ethyl] -piperidine-4-carbaldehyde) (986 mg ) And the product of step 5 of Example 5 (5-((1R) -2-amino-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinoline-2 (1H ) -One) (100 mg) was dissolved in MeOH (3.2 ml), treated with water (36 μL) and AcOH (36 mg), then sodium cyanoborohydride (19 mg) was added. The reaction was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was partitioned between water and EtOAc. The organic solution was evaporated to give a pink solid. This was dissolved in dry THF (3 ml). The solution was treated with triethylamine hydrofluoride (161 mg) at room temperature and stirred for 16 hours. The reaction mixture was diluted with toluene and evaporated to dryness. Purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column, 95% in acetonitrile (0.2% aqueous NH ₃ ) to 50% in acetonitrile (0.2% aqueous NH ₃ ). To give the title compound as a gum. Yield: 62 mg.
MS: APCI + 494 [M + H] ^+
1 H NMR δ (DMSO) 8.18 (1H, d), 7.14-7.29 (6H, m), 7.06 (1H, d), 6.92 (1H, d), 6.50 (1H, d), 5.04 (1H, dd) , 3.47 (2H, t), 2.85 (2H, d), 2.63-2.76 (6H, m), 2.36-2.47 (4H, m), 1.89-1.96 (2H, m), 1.87 (6H, s), 1.57 -1.67 (2H, m), 1.29-1.42 (1H, m), 1.01-1.15 (9H, m)

Example 73
8-hydroxy-5-{(1R) -1-hydroxy-2-[({1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -ON

i) 1- [2- (2-Methyl-2-phenyl-propoxy) -ethyl] -piperidine-4-carbaldehyde subtitle compound is obtained from the product of Example 69 step (iv) (1- [2- ( 2-Methyl-2-phenyl-propoxy) -ethyl] -piperidin-4-one) (360 mg) as an oil by the method of Example 72, step (i). Yield: 230 mg.
¹ H NMR δ (CDCl ₃ ) 9.62 (1H, s), 7.38 (2H, d), 7.29 (2H, t), 7.18 (1H, t), 3.50 (2H, t), 3.42 (2H, s), 2.82-2.75 (2H, m), 2.53 (2H, t), 2.22-2.06 (3H, m), 1.87-1.78 (2H, m), 1.68-1.56 (2H, m), 1.32 (6H, s)

ii) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl } Quinolin-2 (1H) -one The title compound is converted into the product of step (i) (1- [2- (2-methyl-2-phenyl-propoxy) -ethyl] -piperidine-4-carbaldehyde) (85 6 mg) as a glassy material by the method of Example 72, step (ii). Yield: 44 mg.
MS: APCI + 494 [M + H] ^+
1 H NMR δ (DMSO) 8.17 (1H, d), 7.37 (2H, d), 7.27 (2H, t), 7.16 (1H, t), 7.06 (1H, d), 6.92 (1H, d), 6.49 (1H, d), 5.04 (1H, dd), 3.43 (2H, t), 3.40 (2H, s), 2.63-2.82 (4H, m), 2.36-2.47 (4H, m), 1.78-1.93 (11H , m), 1.53-1.62 (2H, m), 1.27-1.37 (1H, m), 1.24 (6H, s), 0.99-1.11 (2H, m)

Example 74
8-hydroxy-5-{(2R) -1-hydroxy-2-[(4-hydroxy-1- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethyl } Piperidin-4-ylmethyl) amino] ethyl} -1H-quinolin-2-one

i) 2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethanol platinum oxide (0.1 g) into a solution of 2- (naphth-1-yl) ethanol (1.0 g) in acetic acid. added. The reaction mixture was hydrogenated at 2 bar pressure for 2 days. An aliquot of platinum oxide (0.10 g) was added and the mixture was hydrogenated at 5 bar pressure for 18 hours and then filtered through celite. The filtrate was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated sodium chloride, dried and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with 2: 8 ethyl acetate: isohexane, to give the subtitle compound as a clear oil. Yield: 0.7g.
¹ H NMR (CDCl ₃ ) δ 7.05 (m, 3H), 3.82 (m, 3H), 2.87 (t, 2H), 2.76 (m, 4H), 1.78 (m, 4H), 1.40 (t, 1H).

ii) [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] acetic acid subtitle compound is converted to the product of step (i) ([2- (5,6,7,8-tetrahydronaphthalene). -1-yl) ethoxy] acetic acid) (0.65 g) using sodium hydride (0.15 g, 60% in mineral oil) in anhydrous DMF (4.7 ml), step (i) of Example 38 To give a pale yellow oil. Yield: 0.74g.
¹ H NMR (CDCl ₃ ) δ 7.06 (m, 1H), 6.98 (m, 2H), 4.13 (s, 2H), 3.76 (t, 2H), 2.93 (t, 2H), 2.78 (t, 2H), 2.72 (t, 2H), 1.80 (m, 4H).

iii) 1- (4-hydroxypiperidin-1-yl) -2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethanone in DCM (126 ml), step (ii) To a solution of the product of [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] acetic acid (0.74 g) was added thionyl chloride (0.63 ml) followed by 3 drops. Of DMF was added and the whole was stirred at room temperature for 2 hours. The solution was azeotroped twice with toluene. DCM (16 ml) was added to the residue and the suspension was then added dropwise to a solution of 4-piperidinol (0.64 g) and triethylamine (0.44 ml) in DCM (16 ml). The mixture was stirred for an additional 2 days. The mixture was partitioned between EtOAc and water. The organic phase was washed with 2M HCl, saturated sodium bicarbonate solution, then saturated aqueous NaCl. The organic layer was collected, dried (MgSO ₄ ) and the solvent was evaporated to give a colorless gum. Purification by chromatography on silica gel eluting with EtOAc / isohexane (8: 2 to 10: 0) gave the subtitle compound as a clear oil. Yield: 0.60 g.
MS APCI + 318 [M + H] ⁺

iv) 1- {2- [2- (5,6,7,8-Tetrahydronaphthalen-1-yl) ethoxy] ethyl} piperidin-4-ol subtitle compound is added to the product of step (iii) (1- ( 4-hydroxypiperidin-1-yl) -2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethanone) (0.62 g) from lithium aluminum hydride (3.8 ml) , 1M solution in THF) in anhydrous THF (5.7 ml) according to the procedure described in step (ii) of Example 45 and obtained as a gum. Yield: 0.57g.
MS APCI + 304 [M + H] ⁺

v) 1- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethyl} piperidin-4-one hydrate subtitle compound is converted to the product of step (iv) ( 1- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethyl} piperidin-4-ol) (0.62 g) to 4 mol molecular sieve (0.26 g) , NMO (0.13 g) and TPAP (0.023 g) in DCM (4.7 ml) and after 4 h, an additional amount of 4Å molecular sieve (0.13 g), NMO (0.13 g). 06g) and TPAP (0.012 g) were added according to the procedure described in Example 45, step (iii) and obtained as a clear oil. Yield: 0.526g.
MS APCI + 302 [M + H] ⁺ and 320 [M + 18 + H] ⁺

vi) 6- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethyl} -1-oxa-6-azaspiro [2.5] octane subtitle compound Following the procedure outlined in step (iii) of step 5, the product of step (v) (1- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethyl} piperidine- 4-one hydrate) (0.26 g), trimethylsulfoxonium iodide (0.28 g), sodium hydride (0.06 g, 60% in mineral oil) and dry DMSO (2.75 ml) were used. Produced as a yellow oil. Yield: 0.26g.
MS APCI + 316 [M + H] ⁺

vii) 8-hydroxy-5-{(2R) -1-hydroxy-2-[(4-hydroxy-1- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ] Ethyl} piperidin-4-ylmethyl) amino] ethyl} -1H-quinolin-2-one methanol (0.32 ml) in step (vi) product (6- {2- [2- (5,6 , 7,8-Tetrahydronaphthalen-1-yl) ethoxy] ethyl} -1-oxa-6-azaspiro [2.5] octane) (0.12 g) and the product of Example 5 step (ii) (0 .13 g) was refluxed for 4 hours and the solvent was evaporated under reduced pressure. A solution of the residue in THF (10 ml) was treated with triethylamine trihydrofluoride (0.35 ml). After stirring for 18 hours at ambient temperature, the volatiles were evaporated in vacuo and the residue azeotroped with toluene (x2). The residue was purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column and 95% in acetonitrile (0.2% aqueous NH ₃ ) to 50% in acetonitrile (0.2% aqueous NH ₃ ). Elution with a gradient of ₃ ) gave the title compound as a yellow foam. Yield: 56 mg.
MS APCI + 536 [M + H] ^+
1 H NMR (300Mz, d6-DMSO) δ 8.19 (d, 1H), 7.07 (d, 1H), 6.98 (m, 2H), 6.90 (m, 2H), 6.49 (d, 1H), 5.01 (m, 1H), 3.52 (t, 2H), 3.47 (t, 2H), 2.70 (m, 8H), 2.43 (m, 6H), 2.31 (m, 2H), 1.71 (m, 4H), 1.43 (bm, 4H )

Example 75
8-hydroxy-5-{(1R) -1-hydroxy-2-[({(2S) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methyl) amino] ethyl} quinoline -2 (1H) -ON

i) 1- [3- (2-Phenylethoxy) propanoyl] -L-prolinamide L-prolinamide (2.0 g) and Hunig's base (0.40 ml) and 3- (phenylethoxy) in DCM (200 ml) ) A mixture of propanoic acid (3.4 g) was treated with HATU (0.84 g). After stirring at room temperature for 4 hours, the mixture was poured into water and the organic layer was washed with water (x3). The organic layer was collected, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by chromatography on silica gel to give pure product by eluting first with ethyl acetate and then with ethyl acetate / methanol (4: 1) to give the subtitle compound as an oil. Yield: 3.7g.
MS APCI + 291 [M + H] ⁺

ii) 1-{(2S) -1- [3- (2-Phenylethoxy) propyl] pyrrolidin-2-yl} methanamine in THF (30 ml), the product of step (i) (1- [3- ( A solution of 2-phenylethoxy) propanoyl] -L-prolinamide) (3.5 g) was treated with stirring by adding borane-THF complex (140 ml, 1.0 M in THF) in small portions. The mixture was refluxed for 12 hours. The solvent was removed under reduced pressure and methanol was added dropwise to the residue followed by 12M HCl (4 ml). The mixture was refluxed for 2 hours and then concentrated in vacuo to give a viscous oil. This was dissolved in an acetonitrile / isopropanol mixture (1: 1) and loaded onto a 70 g SCX cartridge. After elution of the mixture, the product was eluted with acetonitrile / isopropanol / 0.880 ammonia (2: 2: 1) and the solvent was evaporated to give the subtitle compound as a colorless oil. Yield: 2.1 g.
¹ H NMR (DMSO) δ 7.18-7.29 (m, 5H), 3.55 (t, 2H), 3.40 (t, 2H), 3.00 (t, 1H), 2.77 (t, 2H), 2.70-2.73 (m, 1H), 2.48-2.53 (m, 2H), 2.25-2.37 (m, 1H), 2.06-2.12 (m, 2H), 1.74 (m, 1H), 1.56-1.66 (m, 5H)

iii) 8- (Benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl) silyl] oxy} -2-[({(2S) -1- [3- (2-phenylethoxy ) Propyl] pyrrolidin-2-yl} methyl) amino] ethyl} quinolin-2 (1H) -one product (8- (benzyloxy)-of Example 2 step (iii) in dry DMSO (3 ml) 5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) quinolin-2 (1H) -one) (310 mg), potassium iodide (210 mg) and stage (ii ) Product of 1-{(2S) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methanamine) (281 mg) was heated at 70 ° C. under nitrogen for 12 hours. did. The mixture was diluted with water and extracted with EtOAc (x2) and the combined organics were shaken with water and dried (sodium sulfate) to give a brown gum. Purification by chromatography on silica gel eluting with 3-5% methanol in DCM gave the subtitle compound as an orange gum. Yield: 260 mg.
MS APCI + 670 [M + H] ⁺

iv) 8- (Benzyloxy) -5-{(1R) -1-hydroxy-2-[({(2S) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methyl) Amino] ethyl} quinolin-2 (1H) -one product of step (iii) (8- (benzyloxy) -5-{(1R) -1-{[tert-butyl (dimethyl)) in THF (6 ml) Silyl] oxy} -2-[({(2S) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methyl) amino] ethyl} quinolin-2 (1H) -one) (310 mg ) Was treated with triethylamine trihydrofluoride (0.6 ml) and the mixture was stirred overnight. Volatiles were evaporated under reduced pressure and the residue azeotroped with toluene. Purify by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient of 95% 0.880 NH _{3 in} acetonitrile to 5% 0.880 NH _{3 in} acetonitrile to give the subtitle compound. Obtained as a beige gum. Yield: 86 mg.
MS APCI + 555 [M + H] ⁺

v) 8-hydroxy-5-{(1R) -1-hydroxy-2-[({(2S) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methyl) amino] ethyl } The product of step (iv) (8- (benzyloxy) -5-{(1R) -1-hydroxy-2-[({(2S)) in quinolin-2 (1H) -one EtOH (3 ml) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methyl) amino] ethyl} quinolin-2 (1H) -one) (75 mg), 2M HCl (2 drops), 10% palladium / A mixture of charcoal (10 mg) was hydrogenated at 5 bar for 6 days. The catalyst was filtered and the solvent was evaporated under reduced pressure to give a brown gum. This was purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column, 95% in acetonitrile (0.2% aqueous NH ₃ ) to 50% in acetonitrile (0.2% aqueous). Elution with a gradient of NH ₃ ) gave the title compound as a glassy material. Yield: 19 mg.
MS APCI + 466 [M + H] ^+
1 H NMR (DMSO) δ 8.20 (d, 1H), 7.14-7.27 (m, 5H), 7.06 (d, 1H), 6.93 (d, 1H), 6.47 (d, 1H), 5.08 (t, 1H) , 3.53 (t, 2H), 3.36 (t, 2H)

Example 76
N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) Ethyl] benzenesulfonamide

i) (4-Hydroxypiperidin-1-yl) acetonitrile bromoacetonitrile (5.7 g) is added dropwise to a solution of 4-hydroxypiperidine (5.0 g) in dry THF (20 ml) while the temperature is between 45-50. Maintained between ° C. Thereafter, the mixture was refluxed for 30 minutes and then allowed to cool to room temperature. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel eluting with 19: 1 then 10: 1 ether / methanol to give the subtitle compound as a white solid. Yield: 3.2g.
¹ H NMR (DMSO) δ 4.59 (d, 1H), 3.66 (s, 2H), 3.66-3.32 (m, 1H), 2.71-2.64 (m, 2H), 2.26-2.18 (t, 2H), 1.77- 1.70 (m, 2H), 1.47 -1.35 (m, 2H)

ii) 1- (2-Aminoethyl) piperidin-4-ol Lithium aluminum hydride in THF (43 ml, 1.0 M in THF) was diluted with dry THF (13 ml) and cooled to 0 ° C. under nitrogen. The product of step (i) ((4-hydroxypiperidin-1-yl) acetonitrile) (2.0 g) in THF (5 ml) was slowly added by syringe. The reaction mixture was refluxed for 5 hours and then cooled to room temperature. Excess hydride was destroyed by dropwise addition of 1.6 ml water and 1.6 ml 15% NaOH, and EtOAc was added dropwise until no bubbling was finally seen. The granular precipitate that formed was filtered, washed several times with DCM and with EtOAc. The organic layer was dried (MgSO ₄ ) and the solvent evaporated in vacuo to give the subtitle compound as a yellow oil. Yield: 2.0 g.
This was used in the next step without purification.
¹ H NMR (DMSO) δ 3.44-3.37 (m, 1H), 2.64 (t, 2H), 2.57 (t, 2H), 2.25-2.21 (t, 2H), 1.99-1.94 (m, 2H), 1.70- 1.65 (m, 2H), 1.40 -1.31 (m, 2H).

iii) N- [2- (4-Hydroxypiperidin-1-yl) ethyl] benzenesulfonamide Step (ii) product (1- (2-aminoethyl) piperidin-4-ol) (0.43 g) , Suspended in DCM (40 ml) followed by addition of triethylamine (0.84 ml) and benzenesulfonyl chloride (0.53 g). The mixture was stirred at room temperature for 4 hours, then partitioned between DCM and water, the organics collected, dried (Na ₂ SO ₄ ) and the solvent evaporated to give a beige solid. Purification by silica gel chromatography, eluting with 20: 1 to 10: 1 DCM / MeOH, gave the subtitle compound as a colorless solid. Yield: 0.43g.
MS APCI + 285 [M + H] ^+
1 H NMR (DMSO) δ 7.82-7.79 (m, 2H), 7.66-7.57 (m, 3H), 7.49 (s, 1H), 4.49 (s, 1H), 3.45-3.37 (m, 1H), 2.80 ( t, 2H), 2.26 (t, 2H), 1.93 (t, 2H), 1.63-1.60 (m, 2H), 1.34 -1.25 (m, 2H).

iv) N- [2- (4-Oxopiperidin-1-yl) ethyl] benzenesulfonamide Product of step (iii) (N- [2- (4-hydroxypiperidin-1-yl) ethyl] benzenesulfonamide ) (0.50 g) was dissolved in DCM (200 ml) and pyridinium dichromate (3.9 g) was added in small portions. The mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and water, the aqueous layer was basified to pH 8 with aqueous sodium bicarbonate and extracted with DCM (x3). The organics were collected, dried (MgSO ₄ ) and evaporated to give the subtitle compound as a yellow oil. Yield: 0.21 g.
MS APCI + 283 [M + H] ^+
1 H NMR (DMSO) δ 7.85-7.79 (m, 2H), 7.66-7.57 (m, 3H), 2.94 (q, 2H), 2.59 (t, 4H), 2.43 (t, 2H), 2.26 (t, 4H).

v) N- [2- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5) -Il) ethyl] amino} piperidin-1-yl) ethyl] benzenesulfonamide NMP (3 ml), the product of step (ii) of Example 5 (5-((1R) -2-amino-1- {[tert-Butyl (dimethyl) silyl] oxy} ethyl) -8-hydroxyquinolin-2 (1H) -one) (140 mg), acetic acid (0.027 ml), activated molecular sieves (8 beads), and steps The product of (iv) (N- [2- (4-oxopiperidin-1-yl) ethyl] benzenesulfonamide) (180 mg) was stirred at room temperature overnight. Sodium triacetoxyborohydride (133 mg) was added and stirring was continued for 2 hours. The reaction mixture was loaded onto an SCX resin cartridge and eluted with isopropyl alcohol / acetonitrile (1: 1). The product was eluted with isopropyl alcohol / acetonitrile / 0.880 ammonia (2: 2: 1). After evaporation of the volatiles, the residue was purified by chromatography on silica gel eluting with 20: 1 then 10: 1 DCM / MeOH to give the subtitle compound as a brown gum. Yield: 100 mg.
MS APCI + 601 [M + H] ⁺

vi) N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1- Yl) ethyl] benzenesulfonamide product of stage (v) (N- [2- (4-{[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (8-hydroxy 2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) ethyl] benzenesulfonamide) (100 mg) was dissolved in dry THF (4 ml) and triethylamine trifluoride was dissolved. Treated with hydrogenate (0.2 ml) and then stirred at room temperature for 3 hours under nitrogen. The mixture was evaporated and azeotroped with toluene in vacuo. The residue was purified by reverse phase HPLC using an Xterra® C8 5 micron 19 × 50 mm column eluting with a gradient of 95 to 50% (0.1% ammonium acetate / acetonitrile) to give the title compound. Obtained as a beige solid. Yield: 23 mg.
MS APCI + 501 [M + H] ^+
1 H NMR (DMSO) δ 8.16 (d, 1H), 7.38 -7.34 (m, 5H), 7.07 (d, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 5.02 (t, 1H) , 4.37 (s, 2H), 2.99 (t, 2H), 2.70 (t, 4H) 2.32 (t, 1H), 1.92 (t, 2H), 1.78 (t, 2H), 1.27 (t, 2H).

Biological assay
Experimental procedure
Cell preparation H292 cells were grown in RPMI (Roswell Park Memorial Institute) medium containing 10% (v / v) FBS (fetal bovine serum) and 2 mM L-glutamine. Cells were grown in a 225 cm ² flask containing 25 ml of medium in a humidified incubator at 37 ° C., 5% CO ₂ . Cells were harvested from the flask and diluted 1:10 once a week.

Experimental Method The medium containing H292 cells was removed from the flask, rinsed with 10 ml PBS (phosphate buffered saline) and replaced with 10 ml Accutase ™ cell detachment solution. The flask was incubated for 15 minutes at 37 ° C., 5% CO ₂ in a humidified incubator. The cell suspension was counted and the cells were resuspended at 0.05 × 10 ⁶ cells / ml in RPMI medium (containing 10% (v / v) FBS and 2 mM L-glutamine). 5000 cells in 100 μl were added to each well of a tissue culture treated 96-well plate and the cells were incubated overnight at 37 ° C., 5% CO ₂ in a humidified incubator. The culture medium was removed and washed twice with 100 μl assay buffer and replaced with 50 μl assay buffer. Cells were left for 20 minutes at room temperature. Then 25 μl of rolipram (prepared to 1.2 mM with assay buffer containing 2.4% (v / v) dimethyl sulfoxide) was added. Cells were incubated with rolipram for 10 minutes, after which test compounds (prepared as x4 concentrated stock in assay buffer containing 4% (v / v) dimethyl sulfoxide) were added and the cells were incubated for 10 minutes at room temperature. The final rolipram concentration in the assay was 300 μM and the final vehicle concentration was 1.6% (v / v) dimethyl sulfoxide. The reaction was stopped by removing the supernatant, washed once with 100 μl assay buffer and replaced with 50 μl lysis buffer. The cell monolayer was frozen at −80 ° C. for 30 minutes (or overnight).

The concentration of cAMP (cyclic adenosine monophosphate) in the AlphaScreen ™ cAMP detecting cell lysate was determined using the AlphaScreen ™ method. The frozen cell plate was thawed on a plate shaker for 20 minutes and then 10 μl of cell lysate was transferred to a 96 well white plate. 40 μl of mixed AlphaScreen ™ detection beads (containing an equal volume of donor beads (pre-incubated with biotinylated cAMP for 30 minutes in the dark) and acceptor beads) and each well are added to each well and the plate is For 10 hours in the dark. AlphaScreen ™ signals were measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) with recommended manufacturer settings. Refer to calibration curves determined in the same experiment using standard cAMP concentrations (prepared in lysis buffer in 96 well tissue culture treated plates, freeze / thaw with test sample) and detected using the same protocol The cAMP concentration was determined accordingly. Concentration response curves for agonists were drawn to determine both pEC ₅₀ and intrinsic activity. Intrinsic activity was expressed as a fraction of the maximum activity determined for formoterol in each experiment. The results obtained for the example compounds are shown in Table 1 below.

Alternative adrenaline β2-mediated cAMP production
Cell preparation H292 cells were grown in RPMI medium containing 10% (v / v) FBS (fetal bovine serum) and 2 mM L-glutamine in a 225 cm ² flask incubator at 37 ° C., 5% CO ₂ .

Experimental Method Adherent cells H292 were removed from tissue culture flasks by treatment with Accutase ™ cell detachment solution for 15 minutes. The flask was incubated for 15 minutes at 37 ° C., 5% CO ₂ in a humidified incubator. The detached cells were resuspended at 0.05 × 10 ⁶ cells / mL in RPMI medium (containing 10% (v / v) FBS and 2 mM L-glutamine). 5000 cells in 100 μl were added to each well of a tissue culture treated 96-well plate and the cells were incubated overnight at 37 ° C., 5% CO ₂ in a humidified incubator. The culture medium was removed and the cells were washed twice with 100 μl assay buffer and replaced with 50 μl assay buffer (HBSS solution containing 10 mM HEPES (pH 7.4) and 5 mM glucose). Cells were left for 20 minutes at room temperature. Thereafter, 25 μl of rolipram (prepared to 1.2 mM in assay buffer containing 2.4% (v / v) dimethyl sulfoxide) was added. The cells were incubated with rolipram for 10 minutes after which the test compound was added and the cells were incubated for 60 minutes at room temperature. The final rolipram concentration in the assay was 300 μM and the final vehicle concentration was 1.6% (v / v) dimethyl sulfoxide. The reaction was stopped by removing the supernatant, washed once with 100 μl assay buffer and replaced with 50 μl lysis buffer. The cell monolayer was frozen at −80 ° C. for 30 minutes (or overnight).

The concentration of cAMP (cyclic adenosine monophosphate) in the AlphaScreen ™ cAMP detecting cell lysate was determined using the AlphaScreen ™ method. The frozen cell plate was thawed on a plate shaker for 20 minutes and then 10 μl of cell lysate was transferred to a 96 well white plate. 40 μl of mixed AlphaScreen ™ detection beads (preincubated with biotinylated cAMP) was added to each well and the plates were incubated in the dark for 10 hours at room temperature. AlphaScreen ™ signals were measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) with recommended manufacturer settings. The cAMP concentration was determined by reference to a calibration curve determined in the same experiment with standard cAMP concentration. Concentration response curves for agonists were drawn and the data fit to a 4-variable logistic equation to determine both pEC ₅₀ and intrinsic activity. Intrinsic activity was expressed as a fraction of the maximum activity determined for formoterol in each experiment.

The results obtained for the example compounds are shown in Table 2 below.

Selectivity assay
Adrenaline α1D
Membrane Preparation Membranes were prepared from human fetal kidney 293 (HEK293) cells expressing recombinant human α1 _D receptor. These were diluted in assay buffer (50 mM HEPES, 1 mM EDTA, 0.1% gelatin, pH 7.4) to determine the final concentration of membrane that allowed discrimination between maximum specific binding and minimum specific binding. .

Experimental Method Assays were performed in U-bottom 96-well polypropylene plates. 10 μl [ ³ H] -prazosin (final concentration 0.3 nM) and 10 μl of test compound (10 × final concentration) were added to each test well. In each assay plate, for [ ³ H] -prazosin binding, 10 μl vehicle (10% (v / v) DMSO in assay buffer; maximum binding defined), or 10 μl BMY7378 (final concentration 10 μM; not) Eight replicates were obtained in the presence of specific binding (NSB defined). The membrane was then added to a final volume of 100 μl. The plates were incubated for 2 hours at room temperature and then filtered using a 96 well plate Tomtec cell harvester on PEI coated GF / B filter plates (presoaked in assay buffer for 1 hour). Washing was performed 5 times at 4 ° C. with 250 μl wash buffer (50 mM HEPES, 1 mM EDTA, pH 7.4) to remove unbound radioactivity. The plates were dried and then sealed from below using a Packard plate sealer and MicroScint-O (50 μl) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3 minute counting protocol.

The total amount of specific binding (B ₀ ) was determined by subtracting the average NSB from the average maximum binding. NSB values were also subtracted from values in all other wells. These data were expressed as a percentage of B _0. Compound concentration-titer curves ([ ³ H] -prazosin binding inhibition) were determined using serial dilutions, typically in the range of 0.1 nM to 10 μM. The data was fitted to a 4-variable logistic equation to determine the compound titer. This was expressed as pIC ₅₀ (molar negative logarithm causing 50% inhibition of [ ³ H] -prazosin binding).

Adrenaline β1
Membrane preparation Membranes containing recombinant human β1 receptors were obtained from Euroscreen. These are diluted in assay buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, 0.1% gelatin, pH 7.4) to give a final membrane concentration that allows discrimination between maximum and minimum specific binding. It was determined.

Experimental Method Assays were performed in U-bottom 96-well polypropylene plates. 10 μl of [ ¹²⁵ I] -iodocyanopindolol (final concentration 0.036 nM) and 10 μl of test compound (10 × final concentration) were added to each test well. In each assay plate, 10 [ ^mu ] l vehicle (10% (v / v) DMSO in assay buffer; maximum binding defined) or 10 [ ^mu ] l propranolol (final concentration) for [ ^<125 > I] -iodocyanopindolol binding. 8 replicates were obtained in the presence of 10 μM; non-specific binding (NSB) defined. The membrane was then added to a final volume of 100 μl. The plates were incubated for 2 hours at room temperature and then filtered using a 96 well plate Tomtec cell harvester on PEI coated GF / B filter plates (presoaked in assay buffer for 1 hour). Washing was performed 5 times at 4 ° C. with 250 μl wash buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, pH 7.4) to remove unbound radioactivity. The plates were dried and then sealed from below using a Packard plate sealer and MicroScint-O (50 μl) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3 minute counting protocol.

The total amount of specific binding (B ₀ ) was determined by subtracting the average NSB from the average maximum binding. NSB values were also subtracted from values in all other wells. These data were expressed as a percentage of B _0. Compound concentration-titer curves ([ ¹²⁵ I] -iodocyanopindolol binding inhibition) were determined using serial dilutions, typically in the range of 0.1 nM to 10 μM. The data was fitted to a 4-variable logistic equation to determine the compound titer. This was expressed as pIC ₅₀ (molar negative logarithm that causes 50% inhibition of [ ¹²⁵ I] -iodocyanopindolol binding).

Dopamine D2
Membrane Preparation A membrane containing the recombinant human dopamine subtype D2 receptor was obtained from Perkin Elmer. These are diluted in assay buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, 0.1% gelatin, pH 7.4) to give a final membrane concentration that allows discrimination between maximum and minimum specific binding. It was determined.

Experimental Method Assays were performed in U-bottom 96-well polypropylene plates. 30 μl of [ ³ H] -spiperone (final concentration 0.16 nM) and 30 μl of test compound (10 × final concentration) were added to each test well. In each assay plate, 30 [mu] l vehicle (10% (v / v) DMSO in assay buffer; maximum binding defined) or 30 [mu] l haloperidol (final concentration 10 [mu] M; non-binding) for [< ³ > H] -spiperone binding. Eight replicates were obtained in the presence of specific binding (NSB defined). The membrane was then added to a final volume of 300 μl. The plates were incubated for 2 hours at room temperature and then filtered using a 96 well plate Tomtec cell harvester on PEI coated GF / B filter plates (presoaked in assay buffer for 1 hour). Washing was performed 5 times at 4 ° C. with 250 μl wash buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, pH 7.4) to remove unbound radioactivity. The plates were dried and then sealed from below using a Packard plate sealer and MicroScint-O (50 μl) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3 minute counting protocol.

The total amount of specific binding (B ₀ ) was determined by subtracting the average NSB from the average maximum binding. NSB values were also subtracted from values in all other wells. These data were expressed as a percentage of B _0. Compound concentration-titer curves ([ ³ H] -spiperone binding inhibition) were determined using serial dilutions, typically in the range of 0.1 nM to 10 μM. The data was fitted to a 4-variable logistic equation to determine the compound titer. This was expressed as pIC ₅₀ (molar negative logarithm causing 50% inhibition of [ ³ H] -spiperone binding).

Action expression assay
Dunkin-Hartley guinea pigs (200-300 g, delivery) were supplied by a designated breeding institution. The guinea pig was killed by neck dislocation and the trachea was removed. Excluding the adhesive connective tissue, the trachea was cut into 4 rings each. The tissue ring was then attached to an isometric transducer. The tissue was washed and 1 g force was applied to each ring. In all experiments, a paired curve design was used. The tissue was primed with 1 μM methacholine. The tissue was then washed (3 times, washed for 1 minute), 1 g static tension was applied again, and the tissue was allowed to rest for 1 hour to equilibrate. The tissue was then contracted with 1 μM methacholine and once a steady response was obtained, a cumulative concentration response curve (10 ⁻⁹ M to 10 ⁻⁵ M) against isoprenaline was drawn. The tissue was then washed (3 times, 1 minute wash) and allowed to rest for 1 hour. At the end of rest, the tissue was contracted with 1 μM methacholine and a test compound at a p [A] ₅₀ concentration was added. When the tissue reached maximum relaxation, 30 × p [A] ₅₀ concentrations of test compound were added. When the tissue response reached a plateau, 10 μM sotalol was added to the bath to confirm that the relaxation was β ₂ mediated.
Data was collected using ADInstruments chart4forwindows software and the maximum tension produced by each concentration of agonist was measured.

の４変数ロジスティック関数を用いてフィットさせた。 Responses were calculated as% relaxation of methacholine-induced contraction for each concentration of isoprenaline cumulative concentration curve. The curve was plotted as% inhibition of log ₁₀ [agonist] (M) vs. methacholine-induced contraction. These data were then fitted to a non-linear regression curve fit. In each experiment, E / [A] curve data is

A four-variable logistic function was used for fitting.

E and [A] are the pharmacological effect (% relaxation) and agonist concentration, respectively. α, β, [A] ₅₀ and m are asymptotic, baseline, position and slope variables, respectively. The respective isoprenaline curves for p [A] ₅₀ and IA were determined from this fit to determine if the tissue could be used to measure the onset of action of the test compound.

In each of the p [A] ₅₀ concentration of test compound, the response was calculated as% relaxation of the methacholine-induced contraction. The results are plotted as% relaxation versus time, and the time to reach the 90% relaxation value is calculated and recorded.

By adding 30 × p [A] ₅₀ concentrations, the maximum titer of the compound in an individual tissue can be determined. Therefore, the% of maximum compound titer at p [A] ₅₀ concentration was calculated and recorded.

Administration solutions of pharmacokinetic test compounds in rats were prepared using an appropriate administration vehicle. The concentration of the compound in the dosing solution was assayed by diluting an aliquot to a nominal concentration of 50 μg / ml and calibrated against a duplicate of the standard solution and QC standard at this concentration. A group of three 250-350 g rats received the compound intravenously (approximately 1 ml / kg) as a bolus in the tail vein. For oral administration, another group of 2 or 3 animals were administered by gavage (3 ml / kg). The delivered dose was estimated by weight loss. Although animals were not fasted prior to normal administration, the effects of diet were examined as needed.

A blood sample (0.25 ml) was taken from the tail vein into a 1 ml syringe, transferred to an EDTA tube, and immediately after taking the sample, plasma was prepared by centrifugation (5 min, 13000 rpm) and stored at -20 ° C. Typical sampling times are 2, 4, 8, 15, 30, 60, 120, 180, 240, 300 (minutes) or until the final t _1/2 is accurately described.

  The concentration of the analyte (s) was determined by quantitative mass spectrometry in plasma. Standard solutions and quality control (QC) stock solutions were prepared at a concentration of 1 mg / ml in methanol. A range of standards and QC stock prepared by serial dilutions were added to control rat plasma (50 μl). The concentration range includes the analyte concentration range present in the rat sample. Standards, QCs and samples were liquid extracted with 50 μl organic solvent and 100 μl organic solvent containing an internal standard that was chosen to be very close to the analyte. Samples were then mixed by repeated inversion, stored at −20 ° C. for at least 1 hour, and centrifuged in a centrifuge at 3500 rpm for 20 minutes. An aliquot (120 μl) of each sample was subjected to analysis using LC-MSMS. Standard and quality control samples, including a range of concentrations found in the test samples, had a nominal concentration of 25%.

Pharmacokinetic data analysis was performed using WinNonlin. Using standard non-compartmental analysis, variables such _{Tmax, Cmax, λ_z, t 1/2} _λ_z, AUC _{all, AUC INF} (measured value), Cl (measured value) was estimated Vss (measured value).

Claims (20)

Formula (I):

[Where
Ar is

Is;
M is C (O), NR ⁶ , S or CR ⁷ R ⁸ ;
R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S (O) ₂ R ⁹ , NR ¹⁰ S (O) ₂ R ¹¹ , C (O) NR ¹² R ¹³ , NR ¹⁴ C (O) R ¹⁵ , C _1-6 alkyl, C _1-6 alkoxy, C (O) (C _1-6 alkyl) or C (O) ₂ (C _1-6 alkyl);
R ³ may further be CH ₂ OH or NHS (O) ₂ NR ¹⁷ R ¹⁸ ;
X is a bond, CR ²⁷ R ²⁸ or CR ²⁹ R ³⁰ CR ³¹ R ³² ;
Y ^{is, CR 33 R 34 CR 35 R} 36, CR 37 R 38 CR 39 R 40 CR 41 R 42 or ^{CR 43 R 44 CR 45 R 46} CR 47 R 48 CR 49 or a ^{R 50,}
Alternatively, if E is C (O) O—, Y is CR ⁵¹ R ⁵² ;
Z is a bond, CR ⁵¹ R ⁵² , CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R ⁶⁸ CR ⁶⁹ R ⁷⁰ ;
A is

A cycloalkyl-amino group selected from
Wherein the cycloalkyl ring is unsubstituted or halogen, C _1-4 alkyl {optionally substituted by OR ¹¹⁶ , NR ¹¹⁷ R ¹¹⁸ or NR ¹¹⁹ C (O) R ¹²⁰ }, OR ¹⁹ , independently selected from NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹⁶ , or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Substituted by one or two substituents as described above;
When A is a cycloalkyl-amino group, A is bonded to X through one ring carbon atom and to Y through NR ²⁶ ;
Alternatively, when A is a cycloalkyl-amino group and X is CR ²⁹ R ³⁰ CR ³¹ R ³² , A is attached to X through NR ²⁶ and Y is a ring carbon atom. May be bound to;
When X is a bond, A is not bonded to X via a ring carbon atom having NR ²⁶ ;
Or A is

A heterocyclic ring selected from
Wherein the heterocyclic ring is unsubstituted or halogen, C _1-4 alkyl {optionally substituted by OR ¹²¹ , NR ¹²² R ¹²³ or NR ¹²⁴ C (O) R ¹²⁵ }, Independently selected from OR ¹⁹ , NR ²⁰ R ²¹ , C (O) NR ²² R ²³ , NR ²⁴ C (O) R ²⁵ , CN, S (O) ₂ R ¹²⁶ or S (O) ₂ NR ¹¹⁴ R ¹¹⁵ Substituted by one or two substituents (eg, one substituent is on the same ring carbon atom as A is bound to either X or Y);
When A is a heterocyclic ring, A is bonded to Y through a ring nitrogen atom;
When A is a heterocyclic ring, A may be bonded to X via one ring carbon atom;
Alternatively, when A is a heterocycle having two ring nitrogen atoms and X is CR ²⁹ R ³⁰ CR ³¹ R ³² , A may be bonded to X via a second ring nitrogen atom. ;
E is O, S, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² , NR ⁷³ C (O), C (O) O, S (O) ₂ NR ⁷⁴ or NR ⁷⁵ S (O) ₂ ;
R ¹ is aryl, aryloxy, NR ⁷⁶ aryl, S (O) ₂ aryl, heteroaryl or C _3-10 cycloalkyl {optionally substituted by C _1-6 alkyl, halogen or phenyl}; Here, the aryl and heteroaryl rings are optionally halogen, cyano, trifluoromethyl, phenyl, OCF ₃ , O (CF ₂ ) _n O, O (CH ₂ ) _m O, OR ⁷⁸ , SR ⁷⁹ , NR ⁸⁰ R ⁸¹ , C (O) NR ⁸² R ⁸³ , NR ⁸⁴ S (O) ₂ R ⁸⁵ , C (O) R ⁸⁶ , S (O) ₂ R ⁸⁷ , S (O) ₂ NR ⁸⁸ R ⁸⁹ , NR ⁹⁰ C ^{(O) R 91, C (} O) OR 92, C 1-6 alkyl {optionally fluoro, trifluoromethyl, phenyl, ^{heteroaryl, OR 93, NR 94 R 95} , C (O) NR 9 ^{R 97, NR 98 S (O} ) 2 R 99, S (O) 2 R 100 or S (O) has been replaced by ₂ NR ¹⁰¹ R ^102}, or _{C 1-6} alkoxy {optionally fluoro, trifluoromethyl Methyl, phenyl, heteroaryl, OR ¹⁰³ , NR ¹⁰⁴ R ¹⁰⁵ , C (O) NR ¹⁰⁶ R ¹⁰⁷ , NR ¹⁰⁸ S (O) ₂ R ¹⁰⁹ , S (O) ₂ R ¹¹⁰ or S (O) ₂ NR ¹¹¹ R is substituted by} is substituted by ^112; wherein two substituents on the aryl or heteroaryl ring, taken with R ¹ and the integral, carbocyclic or heterocyclic ring (e.g. O, N and S A 4-membered ring that is selected from 1-, 2-, 3-, or 4-heteroatoms independently selected from Condensed, and Optionally substituted by halogen, C _1-4 alkyl, CF ₃ or C _1-4 alkoxy;
Z is a bond and R ¹ is

E may be C (O) when R is a group selected from (R ¹ is optionally substituted);
n and m are independently 1 or 2;
R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ^{42, R 43, R 44,} R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56, R 57, R 58, ^R59 , ^R60 , ^R61 , ^R62 , ^R63 , ^R64 , ^R65 , ^R66 , ^R67 , ^R68 , ^R69 , ^R70 , ^R71 , ^R72 , ^R73 , ^R74 , ^{R75 , R 76, R 77, R} 78, R 79, R 80, ^{81, R 82, R 83,} R 84, R 86, R 88, R 89, R 90, R 91, R 92, R 93, R 94, R 95, R 96, R 97, R 98, R 101, ^{R 102, R 103, R 104} , R 105, R 106, R 107, R 108, R 111, R 112, R 113, R 114, R 115, R 116, R 117, R 118, R 119, R 120 , R ¹²¹ , R ¹²² , R ¹²³ , R ¹²⁴ and R ¹²⁵ are independently hydrogen or C _1-6 alkyl;
R ⁵² may further be phenyl;
R ⁷² may further be phenyl (C _1-4 alkyl) (eg benzyl);
R ⁹ , R ¹¹ , R ¹⁶ , R ⁸⁵ , R ⁸⁷ , R ⁹⁹ , R ¹⁰⁰ , R ¹⁰⁹ , R ¹¹⁰ and R ¹²⁶ are independently C _1-6 alkyl;
Provided that R ¹ is aryloxy, NR ⁷⁶ aryl or S (O) ₂ aryl, and E is O, S, S (O) ₂ , NR ⁷¹ , C (O) NR ⁷² , S (O) ₂ NR Z is CR ⁵³ R ⁵⁴ CR ⁵⁵ R ⁵⁶ , CR ⁵⁷ R ⁵⁸ CR ⁵⁹ R ⁶⁰ CR ⁶¹ R ⁶² or CR ⁶³ R ⁶⁴ CR ⁶⁵ R ⁶⁶ CR ⁶⁷ R if ⁷⁴ or NR ⁷⁵ S (O) _2. ⁶⁸ CR ⁶⁹ R ⁷⁰ . ]
Or a pharmaceutically acceptable salt thereof. Ar is

The compound of formula (I) according to claim 1, wherein X is a bond, CH ₂ or C (CH _{3) 2} or (CH _{2) 2,} the compound of formula (I) according to claim 1 or 2. Y _{is, (CH 2) 2, (} CH 2) 3 or CH ₂ C (CH ₃₎ a ₂ CH _2, the compound of formula (I) according to claim 1, 2 or 3. E is O or ^{C (O) NR 72, R} 72 is hydrogen or _{C 1-4} alkyl, the compound of formula (I) according to claim 1, 2, 3 or 4. Z is CH ₂ or (CH _{2) 2,} the compound of formula (I) according to claim 1, 2, 3, 4 or 5. A is

{Wherein ** is bound to X and *** is bound to Y; A is optionally substituted as described in claim 1;
R ²⁶ is as defined in claim 1. The compound of formula (I) according to any one of claims 1 to 6, wherein R ¹ is unsubstituted phenyl or by halogen, C _1-4 alkyl, C _1-4 alkoxy, cyano, OH, CF ₃ , OCF ₃ or phenyl (which may be the same or different) 8. A compound of formula (I) according to any one of claims 1 to 7, which is substituted phenyl. 8-hydroxy-5-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline-2 (1H ) -On;
8-hydroxy-5-{(1R) -1-hydroxy-2-[(trans-4-{[2- (2-phenylethoxy) ethyl] amino} cyclohexyl) amino] ethyl} quinoline-2 (1H)- on;
8-hydroxy-4-[(1R) -1-hydroxy-2-({1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} amino) ethyl] quinolin-2 (1H) -one ;
8-hydroxy-4-[(1R) -1-hydroxy-2-({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} amino) ethyl] quinolin-2 (1H) -one ;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -one;
N-benzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl ) Propanamide;
N-benzyl-3- [4-({[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} methyl) piperidine- 1-yl] propanamide;
5-[(1R) -2-({1- [3- (3,4-dihydroisoquinolin-2 (1H) -yl) -3-oxopropyl] piperidin-4-yl} amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-phenylethyl) propanamide;
N- (2-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-methoxybenzyl) propanamide;
N- (4-cyanobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
N- (2-hydroxybenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [3- (2-phenylethoxy) propyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -one;
4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} -1,3- Benzothiazol-2 (3H) -one;
4-hydroxy-7-{(1R) -1-hydroxy-2-[({1- [3- (2-phenylethoxy) propyl] azetidin-3-yl} methyl) amino] ethyl} -1,3- Benzothiazol-2 (3H) -one;
4-hydroxy-7-{(1R) -1-hydroxy-2-[(2- {1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} ethyl) amino] ethyl} -1, 3-benzothiazol-2 (3H) -one;
4-hydroxy-7- {1-hydroxy-2- [1- (2-phenethyloxy-ethyl) -piperidin-4-ylamino] -ethyl} -3H-benzothiazol-2-one;
4-hydroxy-7-((1R) -1-hydroxy-2-{[(3R) -1- (2-phenethyloxy-ethyl) -piperidin-3-ylmethyl] -amino} -ethyl) -3H-benzo Thiazol-2-one;
4-hydroxy-7-((1R) -1-hydroxy-2-{[(3R) -1- (2-phenethyloxy-ethyl) -piperidin-3-ylmethyl] -amino} -ethyl) -3H-benzo Thiazol-2-one;
5-{(1R) -2-[({1- [3- (benzyloxy) propyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8-hydroxyquinoline-2 (1H) -on;
5-{(1R) -2-[({1- [2- (benzyloxy) ethyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8-hydroxyquinoline-2 (1H) -on;
N- (2,5-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
N- (biphenyl-2-ylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide;
N- (2,6-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
N- (cyclohexylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine- 1-yl) propanamide;
N- (2-chloro-6-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(1R, 2S) -2-phenylcyclopropyl] propanamide;
N- (4-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
N- (3-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) propanamide;
N- (2-chloro-6-fluorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
N- (2,3-dichlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
N- (2-chlorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) -N-methylpropanamide;
5-((1R) -2-{[(1- {2- [2- (3-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl)- 8-hydroxyquinolin-2 (1H) -one;
(4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) benzyl acetate;
8-Hydroxy-5-[(1R) -1-hydroxy-2-({[4-hydroxy-1- (4-phenoxybutyl) piperidin-4-yl] methyl} amino) ethyl] quinoline-2 (1H) -ON;
N-1-adamantyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Yl) propanamide;
N- (3,5-dichlorobenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4- (hydroxymethyl) -1- [2- (2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] Ethyl} quinolin-2 (1H) -one;
2,6-dichloro-N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} Piperidin-1-yl) ethyl] benzamide;
8-hydroxy-5-[(1R) -1-hydroxy-2-({[1- (2-{[(2S) -2-phenylpropyl] oxy} ethyl) piperidin-4-yl] methyl} amino) Ethyl] quinolin-2 (1H) -one;
5-((1R) -2-{[(1- {2- [2- (2-chlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl)- 8-hydroxyquinolin-2 (1H) -one;
N- (2,5-dimethylbenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino) amino } Piperidin-1-yl) propanamide;
N- (adamanta-1-ylmethyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino } Piperidin-1-yl) propanamide;
N- (3-chloro-2-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (2-trifluoromethoxybenzyl) -propanamide;
N-((3-fluoro-5-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N- [2-Fluoro-3- (trifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N-((2-chloro-5-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N-((5-fluoro-2-trifluoromethyl) benzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(2-trifluoromethyl) benzyl] propanamide;
N- (5-chloro-2-methylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
N- (3,5-dimethylbenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] Amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (3-trifluoromethoxybenzyl) propanamide;
N- (3-Chloro-2-fluorobenzyl) -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
N-[(2-Fluoro-5-trifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline- 5-yl) ethyl] amino} piperidin-1-yl) propanamide;
N-[(5-chloro-2-fluoro) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5- Yl) ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- (3-trifluoromethyl) benzylpropanamide;
N-benzhydryl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl ) Propanamide;
N, N-dibenzyl-3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidine-1 -Yl) propanamide;
N-[(3,5-bistrifluoromethyl) benzyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinoline-5- Yl) ethyl] amino} piperidin-1-yl) propanamide;
N-[(biphenyl-3-yl) methyl] -3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) Ethyl] amino} piperidin-1-yl) propanamide;
3- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] amino} piperidin-1-yl) -N- [(5,6,7,8-tetrahydronaphthalen-1-yl) methyl] propanamide;
5-((1R) -2-{[(1- {2- [2- (2,6-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-hydroxyquinolin-2 (1H) -one;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({4-hydroxy-1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl) amino ] Ethyl} quinolin-2 (1H) -one;
5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] -4-hydroxypiperidin-4-yl} methyl) amino] -1-hydroxyethyl } -8-hydroxyquinolin-2 (1H) -one;
5-((1R) -2-{[(1- {2- [2- (2,3-dichlorophenyl) ethoxy] ethyl} -4-hydroxypiperidin-4-yl) methyl] amino} -1-hydroxyethyl ) -8-hydroxyquinolin-2 (1H) -one;
5-{(1R) -2-[({1- [2- (1,1-dimethyl-2-phenylethoxy) ethyl] piperidin-4-yl} methyl) amino] -1-hydroxyethyl} -8- Hydroxyquinolin-2 (1H) -one;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({1- [2- (2-methyl-2-phenylpropoxy) ethyl] piperidin-4-yl} methyl) amino] ethyl} quinoline -2 (1H) -one;
8-hydroxy-5-{(2R) -1-hydroxy-2-[(4-hydroxy-1- {2- [2- (5,6,7,8-tetrahydronaphthalen-1-yl) ethoxy] ethyl } Piperidin-4-ylmethyl) amino] ethyl} -1H-quinolin-2-one;
8-hydroxy-5-{(1R) -1-hydroxy-2-[({(2S) -1- [3- (2-phenylethoxy) propyl] pyrrolidin-2-yl} methyl) amino] ethyl} quinoline -2 (1H) -one; or N- [2- (4-{[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl] ] Amino} piperidin-1-yl) ethyl] benzenesulfonamide;
Or a compound that is a pharmaceutically acceptable salt thereof. A process for the preparation of a compound of formula (I) according to claim 1,
a. Formula (II) or (IV):

Wherein Ar is as defined in formula (I) and has or does not have a suitable protecting group on the phenol group;
PG ¹ is a suitable protecting group that is the same or different from the phenol protecting group. ]
A compound of formula (III):

Reacting with a compound in the presence of a suitable reducing agent, organic acid and solvent;
b. Formula (V):

[Wherein having a suitable protecting group (PG ² ) on the phenol group;
PG ¹ is a suitable protecting group identical or different from PG ² ;
L is a halogen. ]
A compound of formula (VI):

Reacting with a compound in the presence of a suitable base and solvent (optionally in the presence of a catalyst);
c. Formula (VII):

[In the formula, a suitable protecting group (PG ² ) is present on the phenol group. ]
Reacting a compound of formula (VI) with a suitable base and a suitable solvent;
d. When E is C (O) NR ⁷² , formula (XVII):

[Wherein Ar has or does not have a suitable protecting group (PG ² ) on the phenol group;
PG ¹ is hydrogen or a suitable protecting group that is the same as or different from PG ² . ]
A compound of formula (XVIII):

Reacting with a compound in the presence of a suitable activated coupling agent, a suitable base and a suitable solvent;
e. Z is a bond, E is C (O), and R ¹ is

When selected from
A compound of formula (XVII), with or without Ar having a suitable protecting group (PG ² ) on the phenol group, is represented by formula (XIX):

Reacting with a compound in the presence of a suitable activated coupling agent, a suitable base and a suitable solvent;
Including methods. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 for use in therapy. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a human disease or condition in which modulation of β2 adrenergic receptor activity is beneficial. Formula (I) according to claim 1 in the manufacture of a medicament for use in the treatment of adult respiratory distress syndrome (ARDS), emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma or rhinitis ) Or a pharmaceutically acceptable salt thereof. A method of treating or reducing the risk of a disease or condition in which modulation of β2 adrenergic receptor activity is beneficial, wherein a patient in need of such treatment is treated with a therapeutically effective amount of formula (I ) Or a pharmaceutically acceptable salt thereof. A method of treating or reducing the risk of an inflammatory disease or condition, wherein a patient in need of such treatment is treated with a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. Administering a salt. 9. The method of claim 7 or 8, wherein the disease or condition is adult respiratory distress syndrome (ARDS), emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma or rhinitis. A compound of formula (I) and a non-steroidal glucocorticoid receptor (GR receptor) agonist;
Steroids (eg budesonide or fluticasone);
● PDE4 inhibitor;
● Muscarinic receptor antagonists;
A modulator of chemokine receptor function; or an inhibitor of p38 kinase function;
A combination comprising one or more drugs selected from a list comprising 5-[(1R) -2-amino-1-hydroxyethyl] -8-hydroxyquinolin-2 (1H) -one, formula (IV):

[Wherein Ar is

It is. ] Chiral intermediate. Formula (XX):

[Where
Ar is as defined in claim 1;
PG ¹ is a suitable protecting group;
X is a bond;
A is piperidinyl bonded to X at the 4-position and N-bonded to Y;
Y is (CH ₂ ) ₂ ;
PG ⁵ is either hydrogen or a suitable protecting group. ]
Intermediate compounds of