HK1124330A

HK1124330A - 7-(2-AMINO-1-HYDROXY-ETHYL)-4-HYDROXYBENZOTHIAZOL-2(3H)-ONE-DERIVATIVES AS β2 ADRENOCEPTOR AGONISTS

Info

Publication number: HK1124330A
Application number: HK09103775.6A
Authority: HK
Inventors: Andrew Bailey; Roger Bonnert; Stephen Connolly; Anthony Ingall; Garry Pairaudeau; Michael Stocks
Original assignee: 阿斯利康(瑞典)有限公司
Priority date: 2005-08-29
Filing date: 2006-08-28
Publication date: 2009-07-10

Description

7- (2-amino-1-hydroxy-ethyl) -4-hydroxybenzothiazol-2 (3H) -one derivatives as beta 2 adrenoreceptor agonists

Technical Field

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

Background

Adrenoceptors are a class of G-protein coupled receptors that fall into two major subfamilies, α and β. These subfamilies are further divided into subtypes, where the β subfamily has at least 3 members: β 1, β 2 and β 3. The β 2 adrenergic receptor (hereinafter referred to as β 2 receptor) is mainly expressed on smooth muscle cells.

Agonize the β 2 receptor on airway smooth muscle, which causes relaxation and thus bronchodilation. By this mechanism, β 2 agonists act as functional antagonists of all bronchoconstrictor (bronchostrictor) substances, such as the naturally occurring histamine and acetylcholine and the experimental substances methacholine and carbachol. β 2 agonists are widely used in the treatment of airway diseases, including Asthma and Chronic Obstructive Pulmonary Disease (COPD), which have been extensively reviewed in the literature and incorporated into the national guidelines (national guidelines for the treatment of these diseases) (British guidelines on the Management of athma, NICE guidelines No.12on the Management of COPD).

Beta 2 agonists are classified as either short-acting or long-acting beta 2 agonists. Short-acting beta 2 agonists (SABAs), such as salbutamol, have a duration of action of 2-4 hours. They are suitable for rescue medication during acute bronchoconstriction, but not for continuous medication, as the beneficial effects of these drugs gradually diminish over the night. Long-acting β 2 agonists (LABAs) currently have a duration of action of about 12 hours, administered twice daily, to provide continuous bronchorelaxing action. They are particularly effective when administered with inhaled corticosteroids. This benefit was not observed when inhaled corticosteroids were used in combination with SABAs (kiss and Pauwels, am.j.respir.crit.care med., 2001, 164, 923 932). For asthma, LABAs is suggested as an additional treatment to patients who have received inhaled corticosteroids to reduce nocturnal arousal and reduce the incidence of exacerbations. Corticosteroids and LABAs are conveniently co-administered in a single inhaler to improve patient compliance.

Existing LABAs have disadvantages and therefore new drugs of this class are needed. Salmeterol, a commonly used LABA, has a narrow safety margin, and side effects associated with systemic agonism of β 2 receptors (e.g., tremor, hypokalemia (hypokalaemia), tachycardia, and hypertension) are common. Salmeterol is also slow acting, which prevents its use in rescue and maintenance therapy. Various existing LABAs are administered twice daily, while medically, once-daily treatments are desirable to improve treatment and improve patient compliance. Such once-daily compounds are administered in combination with corticosteroids and will be the primary means of asthma treatment (Barnes, Nature Reviews, 2004, 3, 831-844). Is already openPerhetobromide, a non-selective muscarinic antagonist, shows the advantages of once daily bronchodilator treatment in COPD (Koumis and Samuel, clin. ther.2005,27(4),377-92). However, once daily LABA for the treatment of COPD is desirable to avoid the side effects of antimuscarinic substances such as tiotropium bromide.

Benzothiazolone derivatives having dual β 2 receptor and dopamine (D2) receptor agonist properties are known from WO 92/08708, WO 93/23385, WO 93/24473, WO 97/10227 and WO 97/23470. In WO 2004/071388 beta 2 receptor agonists are disclosed.

Disclosure of Invention

Accordingly, the present invention provides a compound of formula (I):

wherein

R¹Represents hydrogen;

R²、R³、R⁴、R⁵、R⁴' and R⁵' each independently represents hydrogen or C₁-C₆An alkyl group;

x is 0 or 1;

a represents oxygen, sulfur, S (O) or S (O)₂；

D represents oxygen, sulfur or NR⁶；

W is a bond or CR^6aR^6b；

n is an integer of 0 to 2;

R⁶represents hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxycarbonyl or aryl radicals C₁-C₆An alkyl group;

y is a bond, CR^2eR^2fOr CR^2gR^2hCR^2kR^2m；

R^2a、R^2b、R^2c、R^2d、R^2e、R^2f、R^2g、R^2h、R^2k、R^2m、R^6aAnd R^6bIndependently is hydrogen or C₁-C₆An alkyl group;

R^7ais hydrogen, C₁-C₆Alkyl or NHR^7b；

R^7bIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxycarbonyl or aryl radicals C₁-C₆An alkyl group;

R⁷represents a 5-to 14-membered aromatic or heteroaromatic ring system, said 5-to 14-membered aromatic or heteroaromatic ring system being optionally substituted by: halogen, trifluoromethyl, hydroxy, carboxy, C₁-C₆Alkyl (optionally substituted by-NR)¹⁰R¹¹Substituted), C₁-C₆Alkoxy (optionally substituted by-NR)¹²R¹³Substituted), C₁-C₆Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₆Alkylcarbonylamino, C₁-C₆Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₆alkyl-R¹⁸Or phenyl or a 5-to 6-membered heteroaromatic ring (each of which is optionally substituted by halogen, trifluoromethyl, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or-NR²¹R²²)；

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or C₁-C₆An alkyl group;

R¹⁶represents hydrogen, C₁-C₆Alkyl, phenyl-C₀-C₆Alkyl or C₂-C₆alkylene-NR¹⁹R²⁰；

R¹⁹And R²⁰Each independently represents hydrogen or C₁-C₆Alkyl, or R¹⁹And R²⁰Together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocyclic ring optionally including an additional ring heteroatom selected from nitrogen and oxygen;

R¹⁷represents hydrogen, C₁-C₆Alkyl, phenyl-C₀-C₆Alkyl or C₂-C₆alkylene-NR²³R²⁴；

R²³And R²⁴Each independently represents hydrogen or C₁-C₆Alkyl, or R²³Or R²⁴Together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocyclic ring optionally including an additional ring heteroatom selected from nitrogen and oxygen;

R¹⁸represents a saturated 5 or 6 membered nitrogen containing ring; and

R²¹and R²²Each independently represents hydrogen or C₁-C₆An alkyl group.

Thus, the present invention provides compounds of formula (I) wherein R⁷Is a 5 to 14 membered aromatic or heteroaromatic ring system, optionally substituted with one or more substituents independently selected from: halogen, trifluoromethyl, hydroxy, carboxy, C₁-C₆Alkyl (optionally substituted by-NR)¹⁰R¹¹Substituted), C₁-C₆Alkoxy (optionally substituted by-NR)¹²R¹³Substituted), C₁-C₆Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₆Alkylcarbonylamino, C₁-C₆Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₆alkyl-R¹⁸And phenyl or a 5-to 6-membered heteroaromatic ring (each of which may be optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy and-NR²¹R²²)。

For the avoidance of doubt, when a group is described as "optionally substituted" or "optionally substituted", the group may be unsubstituted or substituted, whether or not such phrase is subject to a number of limitations. When more than one substituent is listed and the group is substituted, the groups may be substituted with the same or different substituents.

In the context of the present specification, unless otherwise indicated, the alkyl substituents or alkyl moieties in a substituent may be straight-chain or branched. C₁-C₆Examples of alkyl/alkyl moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Similarly, the alkylene or alkylene portion of a substituent may be straight or branched. C₁-C₆Examples of alkylene/alkylene moieties include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene, 1, 2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-, 2-or 3-methylpropylene and 1-, 2-or 3-ethylpropylene.

The aryl group or the aryl moiety in the substituent means a monocyclic aromatic ring or a fused bicyclic aromatic ring having 6 to 10 carbon atoms. Monocyclic rings are preferably 6-membered and bicyclic rings preferably have an 8, 9 or 10-membered ring structure. Exemplary aryl/aryl moieties include phenyl and naphthyl.

When R is¹⁹And R²⁰(or R)²³And R²⁴) When taken together to represent a4 to 6 membered saturated heterocyclic ring, it is understood that the ring can contain no more than two ring heteroatoms: r¹⁹And R²⁰(or R)²³And R²⁴) Attached nitrogen ring atom and optionally nitrogenA ring atom or an oxygen ring atom.

The compounds of the present invention are selective β 2 receptor agonists and have properties that make them more suitable for once daily administration. The compounds have been optimized to have a suitable duration in an in vitro guinea pig tracheal model or in a mammalian model such as histamine-challenged guinea pigs. The compounds of the invention also have a favorable pharmacokinetic half-life in the mammalian system. In particular, the compounds of the invention are at least 10 times more potent at the β 2 receptor than at the α 1, β 1 or dopamine (D2) receptors. The compounds of the present invention are also considered to have a rapid onset of action, which refers to the time interval between administration of the compounds of the present invention to a patient and the remission of the symptoms by the compounds. The onset of action can be predicted in vitro using isolated trachea from guinea pig or humans.

In one aspect, the present invention provides a compound of formula (I):

wherein

R¹Represents hydrogen;

x is 0 or 1;

a represents oxygen, sulfur, S (O) or S (O)₂；

D represents oxygen, sulfur or NR⁶；

W is a bond or CR^6aR^6b；

n is an integer of 0 to 2;

y is a bond, CR^2eR^2fOr CR^2gR^2hCR^2kR^2m；

R^2a、R^2b、R^2c、R^2d、R^2e、R^2f、R^2g、R^2h、R^2k、R^2m、R^6aAnd R^6bAre all hydrogen;

R^7ais hydrogen;

R⁷represents a 6 to 14 membered aromatic or heteroaromatic ring system, optionally substituted by one or more substituents independently selected from: halogen, trifluoromethyl, hydroxy, carboxy, C₁-C₆Alkyl (optionally substituted by at least one-NR)¹⁰R¹¹Substituted), C₁-C₆Alkoxy (optionally substituted by at least one-NR)¹²R¹³Substituted), C₁-C₆Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₆Alkylcarbonylamino, C₁-C₆Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₆alkyl-R¹⁸And phenyl or a 5-to 6-membered heteroaromatic ring (each of said phenyl or 5-to 6-membered heteroaromatic ring is optionally substituted with one or more substituents independently selected from halogen, trifluoromethyl, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy and-NR²¹R²²)；

R¹⁹And R²⁰Each independently represents hydrogen or C₁-C₆Alkyl, or R¹⁹Or R²⁰Together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocyclic ring optionally including an additional ring heteroatom selected from nitrogen and oxygen;

R²³And R²⁴Each independently represents hydrogen or C₁-C₆Alkyl, or R²³And R²⁴Together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocyclic ring optionally including an additional ring heteroatom selected from nitrogen and oxygen;

R¹⁸represents a saturated 5 or 6 membered nitrogen containing ring; and

In an embodiment of the invention, R²、R³、R⁴、R⁵And R⁴' and R⁵' (if R is⁴' and R⁵If present) each independently represents hydrogen or C₁-C₆(e.g. C)₁-C₄(such as C)₁-C₂) ) an alkyl group.

In another embodiment, R²、R³、R⁴、R⁵And R⁴' and R⁵' (if R is⁴' and R⁵If present) each represents hydrogen.

The variable n is 0, 1 or 2, for example 1 or 2.

In another embodiment, A is oxygen, sulfur or S (O)₂。

In another embodiment of the present invention, a represents oxygen.

In another embodiment of the present invention, a represents sulfur.

In another embodiment of the present invention, A represents S (O)₂。

In one embodiment of the invention, D represents oxygen.

In another embodiment of the present invention, when W is a bond and n is 0, D is not oxygen.

In another embodiment of the invention, D represents NR⁶。

In another embodiment of the invention, D is NR⁶And A is sulfur, wherein R⁶As defined above (e.g. R)⁶Is hydrogen or C₁-C₆Alkyl groups).

In another embodiment of the invention, both D and A are oxygen.

In one embodiment of the invention, Y is a bond or CR^2eR^2fWherein R is^2eAnd R^2fAre all hydrogen.

In another embodiment of the invention, n is 0 and W is CR^6aR^6bWherein R is^6aAnd R^6bIndependently is hydrogen or C_1-4Alkyl (e.g., methyl). For example R^6aAnd R^6bAre all hydrogen.

In another embodiment of the invention, n is 1 or 2 and W is CR^6aR^6bWherein R is^6aAnd R^6bIndependently is hydrogen or C_1-4Alkyl (e.g., methyl). For example R^6aAnd R^6bAre all hydrogen.

In another embodiment, R⁶Represents hydrogen, C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl radical, C₁-C₆Or C₁-C₄Or C₁-C₂Alkoxycarbonyl or aryl radicals C₁-C₆Or C₁-C₄Or C₁-C₂An alkyl group.

In one embodiment, R⁶Represents hydrogen, C₁-C₄Or C₁-C₂Alkyl radical, C₁-C₄Or C₁-C₂Alkoxycarbonyl, phenyl C₁-C₄Or C₁-C₂Alkyl or naphthyl C₁-C₄Or C₁-C₂An alkyl group.

In another embodiment, R⁶Represents hydrogen, C₁-C₂Alkyl or C₁-C₄An alkoxycarbonyl group.

In another embodiment, R⁷Denotes a 5 to 14 membered (5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered) { e.g. 6 to 14 membered (6, 7, 8, 9, 10, 11, 12, 13 or 14 membered) } aromatic or heteroaromatic ring system, which is optionally substituted by: halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, hydroxy, carboxy, C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl (optionally substituted (e.g. by zero, one or two) -NR¹⁰R¹¹Substituted), C₁-C₆Or C₁-C₄Or C₁-C₂Alkoxy (optionally substituted by (e.g. zero, one or two) -NR¹²R¹³Substituted), C₁-C₆Or C₁-C₄Or C₁-C₂Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₆Or C₁-C₄Or C₁-C₂Alkylcarbonylamino, C₁-C₆Or C₁-C₄Or C₁-C₂Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₆Or C₀-C₄Or C₀-C₂alkyl-R¹⁸Or phenyl or a 5-to 6-membered heteroaromatic ring (each of which is optionally substituted (e.g. mono-, di-, tri-or tetra-) by a substituent independently selected from halogen (such as fluoro, chloro, bromo or iodo), trifluoromethyl, hydroxy, C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl radical, C₁-C₆Or C₁-C₄Or C₁-C₂Alkoxy or-NR²¹R²²)。

Thus, the present invention provides compounds of formula (I) wherein R⁷Denotes a 5 to 14 membered (5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered) { e.g. 6 to 14 membered (6, 7, 8, 9, 10, 11, 12, 13 or 14 membered) } aromatic or heteroaromatic ring system, which aromatic or heteroaromatic ring system is optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from: halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, hydroxy, carboxy, C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl (optionally substituted (e.g. by zero, one or two) -NR¹⁰R¹¹Substituted), C₁-C₆Or C₁-C₄Or C₁-C₂Alkoxy (optionally substituted by (e.g. zero, one or two) -NR¹²R¹³Substituted), C₁-C₆Or C₁-C₄Or C₁-C₂Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₆Or C₁-C₄Or C₁-C₂Alkylcarbonylamino, C₁-C₆Or C₁-C₄Or C₁-C₂Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₆Or C₀-C₄Or C₀-C₂alkyl-R¹⁸And phenyl or a 5-to 6-membered heteroaromatic ring (each of which may be optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen (such as fluoro, chloro, bromo or iodo), trifluoromethyl, hydroxy, C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl radical, C₁-C₆Or C₁-C₄Or C₁-C₂Alkoxy and-NR²¹R²²)。

When R is⁷When an optionally substituted 5 to 14 membered (e.g. 6 to 14 membered) heteroaromatic ring system is indicated, said ring system comprises 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Similarly, if R⁷The substituents in (a) represent an optionally substituted 5-to 6-membered heteroaromatic ring, then said ring comprises 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur.

Examples of 5 to 14 membered (e.g. 6 to 14 membered) aromatic or heteroaromatic ring systems which may be a single ring or two or more ring fused polycyclic (e.g. bicyclic or tricyclic) that may be used include one or more (in any combination) of the following groups: phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1, 2, 4-triazinyl, azaOxa radicals (azepinyl), oxa radicalsRadicals (oxapynyl), thiaA phenyl group (thiepinyl), an indenyl group, a benzofuranyl group, an isobenzofuranyl group, a benzothienyl group, an indolyl group, an isoindolyl group, a benzimidazolyl group, an indazolyl group, a benzisoxazolyl group, a benzoxazolyl group, a benzothiazolyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalinyl group, and a dibenzofuranyl group. Preferred ring systems include phenyl and naphthyl.

Examples of the 5-to 6-membered heteroaromatic ring include pyridyl, triazolyl and tetrazolyl.

In an embodiment of the invention, R⁷Represents a 6-to 10-membered aromatic or heteroaromatic ring system, said 6-to 10-membered aromatic ringIs optionally substituted with: halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, hydroxy, carboxy, C₁-C₄Or C₁-C₂Alkyl (optionally substituted by (e.g. one or two) -NR¹⁰R¹¹Substituted), C₁-C₄Or C₁-C₂Alkoxy (optionally substituted by (e.g. one or two) -NR¹²R¹³Substituted), C₁-C₄Or C₁-C₂Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₄Or C₁-C₂Alkylcarbonylamino, C₁-C₄Or C₁-C₂Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₄Or C₀-C₂alkyl-R¹⁸Phenyl or a 5-to 6-membered heteroaromatic ring.

Thus, the present invention provides compounds of formula (I) wherein R⁷Represents a 6 to 10 membered aromatic or heteroaromatic ring system, said 6 to 10 membered aromatic or heteroaromatic ring system being optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from: halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, hydroxy, carboxy, C₁-C₄Or C₁-C₂Alkyl (optionally substituted by at least one (e.g. one or two) -NR¹⁰R¹¹Substituted), C₁-C₄Or C₁-C₂Alkoxy (optionally substituted by at least one (e.g. one or two) -NR¹²R¹³Substituted), C₁-C₄Or C₁-C₂Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₄Or C₁-C₂Alkylcarbonylamino, C₁-C₄Or C₁-C₂Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₄Or C₀-C₂alkyl-R¹⁸Phenyl and a 5 to 6 membered heteroaromatic ring.

At another placeIn one embodiment, R⁷Represents a 6 to 10 membered aromatic ring system optionally substituted with one or two substituents independently selected from: halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, hydroxy, carboxy, C₁-C₄Or C₁-C₂Alkyl (optionally substituted by (e.g. one or two) -NR¹⁰R¹¹Substituted), C₁-C₄Or C₁-C₂Alkoxy (optionally substituted by (e.g. one or two) -NR¹²R¹³Substituted), C₁-C₄Or C₁-C₂Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₄Or C₁-C₂Alkylcarbonylamino, C₁-C₄Or C₁-C₂Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₄Or C₀-C₂alkyl-R¹⁸Phenyl or a 5-to 6-membered heteroaromatic ring.

Thus, the present invention provides compounds of formula (I) wherein R⁷Represents a 6 to 10 membered aromatic ring system optionally substituted with one or two substituents independently selected from: halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, hydroxy, carboxy, C₁-C₄Or C₁-C₂Alkyl (optionally substituted by at least one (e.g. one or two) -NR¹⁰R¹¹Substituted), C₁-C₄Or C₁-C₂Alkoxy (optionally substituted by at least one (e.g. one or two) -NR¹²R¹³Substituted), C₁-C₄Or C₁-C₂Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₄Or C₁-C₂Alkylcarbonylamino, C₁-C₄Or C₁-C₂Alkylsulfonylamino, phenylsulfonylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₄Or C₀-C₂alkyl-R¹⁸Phenyl and a 5 to 6 membered heteroaromatic ring.

In another embodiment, R⁷Represents a 6 to 10 membered aromatic ring system optionally substituted by (e.g. one, two, three or four) halogen atoms.

Thus, the present invention provides compounds of formula (I) wherein R⁷Denotes a 6 to 10 membered aromatic ring system optionally substituted by one or more (e.g. one, two, three or four) halogen atoms.

In another embodiment, R¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or C₁-C₆Or C₁-C₄Or C₁-C₂An alkyl group. It is understood that if-NR¹⁰R¹¹More than one, then the groups may be the same or different from each other. if-NR¹²R¹³More than one, then the same should be similarly understood.

In another embodiment, R¹⁶Represents hydrogen, C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl, phenyl-C₀-C₆Or C₀-C₄Or C₀-C₂Alkyl (e.g. phenyl or benzyl) or C₂-C₆Or C₂-C₄alkylene-NR¹⁹R²⁰And R is¹⁹And R²⁰Each independently represents hydrogen or C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl, or R¹⁹And R²⁰Together with the nitrogen atom to which they are attached form a4 to 6 membered saturated heterocyclic ring optionally including an additional ring heteroatom selected from nitrogen and oxygen, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In another embodiment, R¹⁷Represents hydrogen, C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl, phenyl-C₀-C₆Or C₀-C₄Or C₀-C₂Alkyl (e.g. phenyl or benzyl) or C₂-C₆Or C₂-C₄alkylene-NR²³R²⁴And R is²³And R²⁴Each independently represents hydrogen or C₁-C₆Or C₁-C₄Or C₁-C₂Alkyl, or R²³And R²⁴Together with the nitrogen atom to which they are attached form a4 to 6 membered saturated heterocyclic ring optionally including an additional ring heteroatom selected from nitrogen and oxygen, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In another embodiment, R¹⁸Denotes a saturated 5 or 6 membered nitrogen containing ring, e.g. a ring containing one or two ring nitrogen atoms, such as hydantoin (hydantoin).

In another embodiment, R²¹And R²²Each independently represents hydrogen or C₁-C₆Or C₁-C₄Or C₁-C₂An alkyl group.

In another embodiment, R^7aIs hydrogen or C₁-C₆An alkyl group.

In another embodiment, R^7aIs NHR^7bWherein R is^7bIs hydrogen, C₁-C₄Alkyl or C₁-C₆Alkoxycarbonyl (e.g. hydrogen or C)₁-C₆Alkoxycarbonyl groups).

In another embodiment of the invention, D is oxygen or sulfur (e.g., oxygen), and R is^7aIs NHR^7bWherein R is^7bAs defined above (e.g. it is hydrogen, C)₁-C₄Alkyl or C₁-C₆Alkoxycarbonyl groups).

In one embodiment, the present invention provides a compound of formula (I), wherein

x is 0 or 1;

a represents oxygen, sulfur or S (O)₂；

D represents oxygen or NR⁶；

Y is a bond or CR^2eR^2f；

W is CR^6aR^6b；

n is 0;

R¹、R²、R³、R⁴、R⁵、R⁴’、R⁵’、R^2a、R^2b、R^2c、R^2d、R^2e、R^2f、R^6a、R^6band R^7aAre all hydrogen;

R⁶represents hydrogen, methyl or C₄An alkoxycarbonyl group;

R⁷represents a 6 to 10 membered aromatic ring system optionally substituted by one or more halogen atoms; for example, the compounds of formula (I) may be in the form of the free base or in the form of a pharmaceutically acceptable salt.

In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof (such as the hydrochloride, hydrobromide or trifluoroacetate salt, e.g. hydrochloride or hydrobromide salt), wherein

x is 0 or 1;

a represents oxygen, sulfur or S (O)₂；

D represents oxygen or NR⁶；

Y is a bond or CH₂；

W is CR^6aR^6b；

n is 0;

R¹、R²、R³、R⁴、R⁵、R⁴’、R⁵’、R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R⁶represents hydrogen, C₁-C₄Alkyl (e.g. methyl) or C₄Alkoxycarbonyl (such as tert-butoxycarbonyl);

R^6aand R^6bIndependently is hydrogen or C₁-C₄Alkyl (e.g., methyl);

R⁷represents a 6 to 10 membered aromatic ring system (such as phenyl or naphthyl) optionally substituted with: halogen (e.g. chlorine or bromine), C₁-C₄Alkyl (e.g. ethyl), C₁-C₄Alkoxy (e.g. ethoxy) or CF₃(ii) a And

R^7ais hydrogen, C₁-C₄Alkyl (e.g. methyl), NH (C)₄Alkoxycarbonyl) (such as NH (tert-butoxycarbonyl)) or NH₂。

x is 0 or 1;

a represents oxygen, sulfur or S (O)₂；

D represents oxygen or NR⁶；

Y is a bond or CH₂；

W is CR^6aR^6b；

n is 0;

R^6aand R^6bIndependently is hydrogen or C₁-C₄Alkyl (e.g., methyl);

x is 0 or 1;

a represents oxygen, sulfur or S (O)₂；

D represents oxygen or NR⁶(e.g. oxygen)

Y is a bond or CH₂；

W is CR^6aR^6b；

n is 0;

R^6aand R^6bIndependently is hydrogen or C₁-C₄Alkyl (e.g., methyl);

R⁷represents a 6 to 10 membered aromatic ring system (such as phenyl or naphthyl) optionally substituted with: halogen (e.g. chlorine or bromine), C₁-C₄Alkyl radical (example)Such as ethyl), C₁-C₄Alkoxy (e.g. ethoxy) or CF₃(ii) a And

R^7ais NH (C)₄Alkoxycarbonyl) (such as NH (tert-butoxycarbonyl)), NH (C)₁-C₄Alkyl) or NH₂。

Another embodiment of the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } sulfonyl) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [2- (2-phenylethoxy) ethoxy ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one;

7- ((1R) -2- { [3- ({3- [2- (4-bromophenyl) ethoxy ] propyl } thio) propyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [3- (2-phenylethoxy) propyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- {2- [2- (1-naphthyl) ethoxy ] ethoxy } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (2- { [3- (2-phenylethoxy) propyl ] thio } ethyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [2- (2-phenylethoxy) ethyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one;

{3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } (2-phenylethyl) carbamic acid tert-butyl ester;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({3- [ (2-phenylethyl) amino ] propyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({3- [ methyl (2-phenylethyl) amino ] propyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one;

tert-butyl [2- (4-ethylphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate;

7- [ (1R) -2- ({2- [ (3- { [2- (4-ethylphenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

tert-butyl [2- (4-ethoxyphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate;

7- [ (1R) -2- ({2- [ (3- { [2- (4-ethoxyphenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

{3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (2- { [3- ({2- [3- (trifluoromethyl) phenyl ] ethyl } amino) propyl ] thio } ethyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one;

[2- (2-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester;

7- [ (1R) -2- ({2- [ (3- { [2- (2-chlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

((1S) -tert-butyl 2- {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamate;

7- ((1R) -2- { [2- ({3- [ (2S) -2-amino-2-phenylethoxy ] propyl } thio) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

((1R) -tert-butyl 2- {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamate;

7- ((1R) -2- { [2- ({3- [ (2R) -2-amino-2-phenylethoxy ] propyl } thio) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

{2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamic acid tert-butyl ester;

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [ (2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one;

{2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamic acid tert-butyl ester;

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [ (2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one;

[2- (2-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester;

7- [ (1R) -2- ({3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } ethyl) thio ] propyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

[2- (3-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester;

7- [ (1R) -2- ({3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } ethyl) thio ] propyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamate;

7- [ (1R) -2- ({2- [ (3- { [2- (2, 3-dichlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

7- ((1R) -2- { [2- (3- { [2- (3-chlorophenyl) ethyl ] amino } propoxy) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate;

[2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester;

7- [ (1R) -2- ({2- [ (3- { [2- (3-chlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

[2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) sulfonyl ] propyl } carbamic acid tert-butyl ester;

7- [ (1R) -2- ({2- [ (3- { [2- (3-chlorophenyl) ethyl ] amino } propyl) sulfonyl ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

(+/-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester;

(+/-) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

(R) - (+) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester;

(R) - (+) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

(S) - (-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester;

(S) - (-) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one;

tert-butyl [ 2-methyl-2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate; or

7- [ (1R) -2- ({2- [ (3- { [ 2-methyl-2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one.

In another embodiment, the present invention provides the following compounds:

4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } sulfonyl) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate;

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [2- (2-phenylethoxy) ethoxy ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one trifluoroacetate salt;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one hydrochloride;

7- ((1R) -2- { [3- ({3- [2- (4-bromophenyl) ethoxy ] propyl } thio) propyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [3- (2-phenylethoxy) propyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (2- { [3- (2-phenylethoxy) propyl ] thio } ethyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride;

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [2- (2-phenylethoxy) ethyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({3- [ (2-phenylethyl) amino ] propyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one hydrochloride;

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({3- [ methyl (2-phenylethyl) amino ] propyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate;

7- [ (1R) -2- ({2- [ (3- { [2- (4-ethylphenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

7- [ (1R) -2- ({2- [ (3- { [2- (4-ethoxyphenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (2- { [3- ({2- [3- (trifluoromethyl) phenyl ] ethyl } amino) propyl ] thio } ethyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

7- [ (1R) -2- ({2- [ (3- { [2- (2-chlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

7- ((1R) -2- { [2- ({3- [ (2S) -2-amino-2-phenylethoxy ] propyl } thio) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

7- ((1R) -2- { [2- ({3- [ (2R) -2-amino-2-phenylethoxy ] propyl } thio) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

7- [ (1R) -2- ({2- [ (3- { [2- (2-chlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrobromide salt;

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [ (2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [ (2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one bis (trifluoroacetate);

7- [ (1R) -2- ({3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } ethyl) thio ] propyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrobromide salt;

7- [ (1R) -2- ({3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } ethyl) thio ] propyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrobromide salt;

7- [ (1R) -2- ({2- [ (3- { [2- (2, 3-dichlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrobromide salt;

7- [ (1R) -2- ({2- [ (3- { [2- (2, 3-dichlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride;

7- [ (1R) -2- ({2- [ (3- { [2- (3-chlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride;

7- [ (1R) -2- ({2- [ (3- { [2- (3-chlorophenyl) ethyl ] amino } propyl) sulfonyl ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride;

(+/-) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride;

(R) - (+) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride;

(S) - (-) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride;

7- [ (1R) -2- ({2- [ (3- { [ 2-methyl-2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride.

Each of the exemplary compounds represents a separate and specific aspect of the present invention.

The present invention also provides a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, which process comprises:

(a) reacting a compound of formula (II) with a compound of formula (III) or a suitable salt thereof (e.g. a hydrobromide or hydrochloride salt) in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine);

the compounds of formula (II) are as follows:

wherein L is¹Represents a leaving group (e.g. chloro, bromo, iodo, mesylate or p-toluenesulfonate), and the other variables are as defined in formula (I);

the compounds of formula (III) are as follows:

wherein R is¹As defined in formula (I); or

(b) When R is²And R³(III) reacting the compound of formula (IV) with a compound of formula (III) or a suitable salt thereof as defined above in (a) in the presence of a suitable reducing agent, for example sodium cyanoborohydride, sodium triacetoxyborohydride or hydrogen in the presence of a palladium on carbon or palladium oxide catalyst, each representing hydrogen;

the compounds of formula (IV) are as follows:

wherein the variables are as defined in formula (I); or

(c) When R is²And R³(iv) contacting the compound of formula (V), each representing hydrogen, with a suitable reducing agent (e.g. lithium aluminium hydride or borane tetrahydrofuran complex);

the compounds of formula (V) are as follows:

wherein the variables are as defined in formula (I);

and optionally after (a), (b) or (c), performing one or more of the following steps:

converting the resulting compound into another compound of the invention;

preparation of a pharmaceutically acceptable salt of the compound.

In the process (a), the reaction may be conveniently carried out in an organic solvent such as N, N-dimethylformamide, ethanol, N-butanol or dimethylsulfoxide at, for example, 25 to 100 ℃.

In process (b), the reaction may conveniently be carried out in an organic solvent such as methanol, ethanol, dichloromethane or N, N-dimethylformamide (containing up to 10% w of water).

In process (c), the reaction may conveniently be carried out in an organic solvent such as tetrahydrofuran or diethyl ether, for example at from 0 to 60 ℃.

A compound of formula (II) (wherein L¹Representing for example bromine) can be prepared by the following method: reacting a compound of formula (X) with N-bromosuccinimide and triphenylphosphine in a solvent (e.g. dichloromethane) at e.g. -10 to 20 ℃; the compounds of formula (X) are as follows:

wherein the variables are as defined in formula (II).

Compounds of formula (X) wherein a represents oxygen or sulphur may be prepared by: reacting a compound of formula (XI) with a compound of formula (XII) under the following conditions: the reaction is carried out in an organic solvent (e.g., tetrahydrofuran or dimethylsulfoxide) in the presence of a suitable base (e.g., potassium carbonate, triethylamine, sodium hydride or diisopropylethylamine) at, for example, 0 to 50 ℃; the compounds of formula (XI) are as follows:

wherein L is²Represents a leaving group (e.g. chloro, bromo, iodo, mesylate or p-toluenesulfonate), and x, R²、R³、R⁴、R⁵、R⁴' and R⁵' as defined in formula (X); the compounds of formula (XII) are as follows:

wherein A' represents oxygen or sulfur, and the other variables are as defined in formula (X).

Compounds of formula (X) wherein a represents sulfinyl or sulfonyl, may be prepared by: the corresponding compound of formula (X) (wherein a represents sulphur) is oxidised using, for example, m-chloroperoxybenzoic acid or hydrogen peroxide in an organic solvent (e.g. methanol, ethanol or dichloromethane) at, for example, 0 to 50 ℃.

The compounds of formula (III) may be prepared by the following process: the compound of formula (XIII) is reduced with a suitable reducing agent, for example hydrogen at a pressure of 1 to 5 atmospheres in the presence of a suitable catalyst, for example 5 to 10% w palladium on carbon or platinum oxide; the compounds of formula (XIII) are as follows:

wherein R is³⁰Represents hydrogen or benzyl. The reaction is conveniently carried out in an organic solvent such as ethanol, methanol, ethyl acetate or tetrahydrofuran.

The compound of formula (XIII) can be prepared by the following method: reacting a compound of formula (XIV) with sodium azide in the presence of, for example, sodium iodide, lithium iodide or tetrabutylammonium iodide; the compounds of formula (XIV) are as follows:

wherein L is³Represents a leaving group (e.g. bromo, iodo, mesylate or p-toluenesulfonate), and R³⁰As defined in formula (XIII).The reaction is conveniently carried out in an organic solvent (e.g. dimethyl sulphoxide or N, N-dimethylformamide) at from 10 to 80 ℃ (especially from 50 to 70 ℃).

A compound of formula (III) (wherein R¹Hydrogen) can be prepared by the following method: reacting the corresponding compound (wherein R¹Substituted with benzyl) with a suitable reducing agent, for example hydrogen at a pressure of 1 to 5 atmospheres in the presence of a suitable catalyst, for example 5 to 10% w palladium on carbon. The reaction is conveniently carried out in an organic solvent such as ethanol or methanol containing 5-10% w concentrated hydrochloric acid.

The compounds of formula (IV) may be prepared by the following process: oxidation of a compound of formula (XV) with an oxidizing agent, such as pyridinium chlorochromate or Dess-martin periodinane, in an organic solvent, such as dichloromethane, at e.g. 25 ℃; the compounds of formula (XV) are as follows:

wherein the variables are as defined in formula (IV). Other oxidation methods known to those skilled in the art, such as the Swern oxidation outlined in Synthesis, 1981, 3, 165, may also be used.

The compounds of formula (XV) can be prepared as described above for the compounds of formula (X).

The compounds of formula (V) may be prepared by the following process: reacting a compound of formula (XVI) with a compound of formula (III) as defined above or a suitable salt thereof; the compounds of formula (XVI) are as follows:

wherein L is⁴Represents a leaving group (e.g. chloro or hydroxy) and the other variables are as defined in formula (V).

When L is⁴When chlorine is represented, the reaction is conveniently carried out under the following conditions: the reaction is carried out in the presence of a base such as triethylamine or diisopropylethylamine in an organic solvent such as dichloromethane at, for example, 0 to 25 ℃.

When L is⁴When representing a hydroxyl group, the reaction is conveniently carried out under the following conditions: the reaction is carried out in the presence of an activating agent, such as carbonyldiimidazole or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylchlorohexafluorophosphate (HATU), in an organic solvent, such as N, N-dimethylformamide or dichloromethane, at, for example, 0 to 60 ℃.

A compound of formula (XVI) (wherein L⁴Representing for example a hydroxyl group) may be prepared by methods analogous to those described for the preparation of compounds of formula (X).

The synthetic route for the compounds (where a is oxygen or sulphur) is shown after the examples. These synthetic routes can be adjusted by alternative intermediates to prepare other compounds of formula (I).

The compounds of formulae (XI), (XII), (XIV) and (XVI) are commercially available or are known in the literature or can be prepared using known techniques.

The invention also relates to novel intermediate compounds, for example compounds of formula (III') (wherein R represents hydrogen or benzyl):

and a compound:

compounds of formula (I) may be converted to other compounds of formula (I) by standard methods. For example, a compound of formula (I) wherein a represents sulphur may be converted to the corresponding compound of formula (I) wherein a represents a sulphonyl group by the following method: the oxidation reaction is carried out in an organic solvent (e.g., methanol, ethanol or dichloromethane) at, for example, 0 to 50 ℃ using, for example, m-chloroperoxybenzoic acid or hydrogen peroxide.

It will be appreciated by those skilled in the art that certain functional groups in the reagents (such as hydroxyl or amino groups) may need to be protected with protecting groups in the process of the invention. Thus, the preparation of a compound of formula (I) may involve removal of one or more protecting groups at a suitable stage.

The protection and deprotection of functional groups is described in the following documents: "Protective Groups in Organic Chemistry", edited by J.W.F.McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3^rd edition，T.W.Greene and P.G.M.Wuts，Wiley-Interscience(1999)。

The compound of formula (I) above may be converted into a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate or p-toluenesulfonate salt.

The compounds of formula (I) can exist in stereoisomeric forms. It will be understood that the invention encompasses the use of the various 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 forms an aspect of the invention. Enantiomerically pure forms are particularly desirable.

In another embodiment, the invention provides the following asterisk (^*) A compound of formula (I) having the absolute configuration (R) at the carbon of the label:

the compounds of formula (I) or a pharmaceutically acceptable salt thereof may exist as solvates (such as hydrates). The present invention encompasses these solvates.

Compounds of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment of the following diseases:

1. respiratory tract: airway obstructive diseases including asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced (including aspirin and NSAID-induced) asthma and dust-induced asthma, intermittent asthma and persistent asthma, and asthma of various severity, and airway hyperresponsiveness due to other causes; chronic Obstructive Pulmonary Disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicated by antineoplastic therapy and chronic infections (including tuberculosis and aspergillosis and other fungal infections); complications of lung transplantation; vasculitis and thrombotic disorders of the pulmonary vessels and pulmonary hypertension; antitussive activity, including treatment of chronic cough and iatrogenic cough associated with airway inflammation and secretion; acute and chronic rhinitis including rhinitis medicamentosa and vasomotor rhinitis; perennial (perennial) allergic rhinitis and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infections, including the common cold and infections caused by respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis (eosinophilic esophageal);

2. bone and joint: arthritis associated with or including osteoarthritis/osteoarthrosis, including primary and secondary arthritis, such as congenital hip dysplasia; cervical and lumbar spondylitis and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infection-related joint and bone diseases, such as tuberculosis, including Potts' disease and fluffy syndrome; crystal-induced acute and chronic synovitis including urate deposition disease, calcium pyrophosphate deposition disease and calcium apatite related tendon, bursal and synovial inflammation; behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies, including dermatomyositis and polymyositis; polymyalgia rheumatica; juvenile arthritis, including idiopathic inflammatory arthritis and associated syndromes distributed in any joint and rheumatic fever and its systemic complications; vasculitis (vasculitis) including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitis associated with viral infections, hypersensitivity, cryoglobulin, and foreign proteins; low back pain; familial mediterranean Fever, Muckle-Wells syndrome (Muckle-Wells syndrome), and Familial Ireland Fever (Familial Hibernian Fever), Kikuchi disease (Kikuchi disease); drug-induced joint pain, tendonitis, and myopathy;

3. pain and connective tissue remodeling musculoskeletal diseases caused by injury (e.g., 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 remodelling diseases (e.g., osteoporosis, Paget's disease, or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease, spondyloarthropathy, or periodontal disease (e.g., periodontitis);

4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed type hypersensitivity; vegetative and solar dermatitis; seborrheic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus atrophicus, pyoderma gangrenosum, dermatosarcoidosis, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, swelt's syndrome, wier-gram syndrome, erythema multiforme; cellulitis, including infectious and non-infectious cellulitis; panniculitis; cutaneous lymphomas, non-melanoma skin cancers and other dysplastic lesions; drug-induced diseases including fixed drug eruptions;

5. eye: blepharitis; conjunctivitis, including perennial allergic conjunctivitis or vernal allergic conjunctivitis; iritis; anterior uveitis and posterior uveitis; choroiditis; autoimmunity; degenerative or inflammatory diseases affecting the retina; ophthalmia, including sympathetic ophthalmia; sarcoidosis; infections, including viral, fungal and bacterial infections;

6. gastrointestinal tract: glossitis, gingivitis, periodontitis; esophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritus ani; abdominal diseases, irritable bowel syndrome, and food-related allergies with off-bowel effects (e.g. migraine, rhinitis or eczema);

7. abdomen: hepatitis, including autoimmune, alcoholic and viral hepatitis; liver fibrosis and cirrhosis; cholecystitis (cholecystitis); pancreatitis, including acute and chronic pancreatitis;

8. genitourinary system: nephritis, including interstitial nephritis and glomerulonephritis; nephrotic syndrome; cystitis, including acute and chronic (interstitial) cystitis and Hanna's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vaginitis of vulva; peyronie's disease; erectile dysfunction (male and female);

9. allograft rejection: acute and chronic allograft rejection after, for example, kidney, heart, liver, lung, bone marrow, skin or cornea transplantation or after blood transfusion; or chronic graft versus host disease;

CNS: alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether central or peripheral) including visceral, headache, migraine, trigeminal neuralgia, atypical facial, joint and bone pain, pain due to cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic and HIV-associated neuropathies; neurogenic sarcoidosis; central and peripheral nervous system complications of malignant, infectious, or autoimmune processes;

11. other autoimmune and allergic diseases, including Hashimoto's thyroiditis, Graves ' disease, Addison's disease, diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, hyper IgE syndrome, antiphospholipid syndrome;

12. other diseases with an inflammatory or immune component, including acquired immunodeficiency syndrome (AIDS), leprosy, Sezary syndrome (Sezary syndrome), and extratumoral syndrome;

13. cardiovascular: atherosclerosis, which affects the coronary and peripheral circulation; pericarditis; myocarditis; inflammatory and autoimmune cardiomyopathies, including myocardial sarcoidosis; ischemic reperfusion injury; endocarditis, valvular inflammation and aortic inflammation, including infectious (e.g., syphilitic); vasculitis; diseases of the proximal and peripheral veins, including phlebitis and complications of thrombosis, including deep vein thrombosis and varicose veins;

14. tumor: treatment of cancers in general, including prostate, breast, lung, ovarian, pancreatic, intestinal and colon, gastric, skin and brain tumors and malignancies affecting the bone marrow (including leukemias) and lymphoproliferative systems (e.g., Hodgkin's and non-Hodgkin's lymphomas); including the prevention and treatment of metastatic disease and tumor recurrence and extratumoral syndromes; and

15. gastrointestinal tract: coeliac disease, proctitis, eosinophilic gastroenteritis, mast cell hyperplasia, crohn's disease, ulcerative colitis, microscopic colitis, indeterminate colitis, irritable bowel disease, irritable bowel syndrome, noninflammatory diarrhea, food-related allergies with off-bowel effects (e.g. migraine, rhinitis or eczema).

Accordingly, the present invention provides a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use in therapy.

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

In another aspect, the 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 the treatment of human diseases or conditions in which modulation of β 2 adrenoreceptor activity is beneficial.

In another aspect, the present invention provides a method of treating, or reducing the risk of, a disease or condition in which modulation of β 2 adrenoreceptor activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof.

In the context of this specification, the term "treatment" also includes "prevention" unless the contrary is specifically indicated. The terms "therapeutic" and "therapeutically" should also be understood accordingly.

Prevention is considered to be of particular relevance to the treatment of persons with a prior onset of the disease or condition, or to the treatment of persons at increased risk of the disease or condition. Persons at risk of developing a particular disease or condition generally include those with a family history of the disease or condition, or those who have been identified by genetic testing or screening as being particularly susceptible to developing the disease or condition.

The present invention also provides a method of treating, or reducing the risk of, inflammatory diseases or conditions, including reversible obstructive airways diseases or conditions, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof.

In particular, the compounds of the present invention may be used in the treatment of Adult Respiratory Distress Syndrome (ARDS), emphysema, bronchitis, bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), asthma or rhinitis.

For the above mentioned therapeutic uses, the dose administered will of course vary with the following conditions: the compound used, the mode of administration, the desired therapeutic effect and the disease to which it is administered. For example, in the case of inhalation, the daily dose of the compound of the present invention may be from 0.05. mu.g/kg body weight (μ g/kg) to 100. mu.g/kg body weight (μ g/kg). Alternatively, if the compounds are administered orally, the daily dose of the compounds of the invention may be from 0.01 micrograms per kilogram of body weight (μ g/kg) to 100 milligrams per kilogram of body weight (mg/kg).

The compounds of formula (I) and their pharmaceutically acceptable salts may be used alone but are generally administered in the form of a pharmaceutical composition in which the compound/salt of formula (I) (the active ingredient) is in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in Pharmaceuticals-The Science of Dosage Form Designs ", m.e. aulton, churchlll Livingstone, 1988.

Based on the mode of administration, the pharmaceutical composition may preferably comprise 0.05 to 99% w (weight percent), more preferably 0.05 to 80% w, still more preferably 0.10 to 70% w, even more preferably 0.10 to 50% w of the active ingredient, all weight percents being based on the total composition.

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

The present invention also provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition may be administered topically (e.g., to the skin or to the lungs and/or airways), for example, in the form of: creams, solutions, suspensions, Heptafluoroalkane (HFA) aerosols and dry powder formulations are known, for exampleThe formulation in an inhaler device of (1); or the pharmaceutical composition may be administered systemically by oral administration, for example in the form of: tablets, capsules, syrups, powders or granules; or the pharmaceutical composition may be administered by parenteral administration in the form of a solution or suspension; or the pharmaceutical composition may be administered by subcutaneous administration; or the pharmaceutical composition may be administered by rectal administration in the form of suppositories; or the pharmaceutical composition may be administered transdermally.

Dry powder formulations of the compounds of the invention and pressurized HFA aerosols may be administered by oral inhalation or nasal inhalation. For inhalation, the compound is finely dispersed as desired. The finely divided compound preferably has a mass median diameter (mass median diameter) of less than 10 μm and can be suspended in the propellant mixture with the aid of a dispersing agent, for example C₈-C₂₀Fatty acids or salts thereof (e.g., oleic acid), bile salts, phospholipids, alkyl sugars, perfluoro or polyethoxylated surfactants, or other pharmaceutically acceptable dispersants.

The compounds of the present invention may also be administered by dry powder inhalers. The inhaler may be a single dose inhaler or a multi-dose inhaler, and may be a breath activated dry powder inhaler.

One possible method is to mix a finely divided compound of the invention with a carrier substance such as a mono-, di-or polysaccharide, a sugar alcohol or another polyol. Suitable carriers are sugars, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch. Alternatively, the finely divided compound may be coated with another substance. The powder mixtures can also be dispensed into hard gelatin capsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into balls, which are broken up during inhalation. Such spheroidized powder can be charged into a container known as a dieIn which the dosing unit doses the desired dose, which is then inhaled by the patient. By means of this system, the active compound is delivered to the patient with or without a carrier substance.

For oral administration, the compounds of the invention may be mixed with excipients or carriers, such as: lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch or amylopectin; a cellulose derivative; binders, such as gelatin or polyvinylpyrrolidone; and/or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, and the like. If coated tablets are desired, the tablet cores prepared as described above may be coated with a concentrated sugar solution which may comprise, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in a volatile organic solvent.

For the preparation of soft gelatin capsules, the compounds of the invention may be mixed, for example, with vegetable oils or polyethylene glycols. Hard gelatin capsules may contain granules of the compounds of the invention using the excipients mentioned above for tablets. Liquid or semisolid formulations of the compounds of the present invention may also be loaded into hard gelatin capsules.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example solutions containing the compounds of the invention in the remainder sugar and a mixture of ethanol, water, glycerol and polypropylene glycol. Optionally, such liquid formulations 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 may also be administered with other compounds useful in the treatment of the above conditions.

Thus, the present invention also relates to combination therapies wherein a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or formulation comprising a compound of the present invention is administered simultaneously or sequentially with another therapeutic agent or agents, or together with another therapeutic agent or agents as a combined preparation for the treatment of one or more of the listed conditions.

In particular, for the treatment of inflammatory diseases such as (but not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), psoriasis and inflammatory bowel disease, the compounds of the invention may be combined with: non-steroidal anti-inflammatory drugs (hereinafter NSAIDs) including non-selective cyclooxygenase COX-1/COX-2 inhibitors (e.g. piroxicam; diclofenac; propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen; fenamic acids such as mefenamic acid, indomethacin, sulindac, apazone (azapropazone), pyrazolones such as phenylbutazone; salicylates such as aspirin), whether applied topically or systemically; selective COX-2 inhibitors (e.g., meloxicam, celecoxib, rofecoxib, valdecoxib, lumiracoxib (lumaroxib), parecoxib, and etoricoxib); nitric Oxide Donors (CINODs) that inhibit cyclooxygenase; glucocorticoids (whether administered by topical, oral, intramuscular, intravenous or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; an analgesic; diacerein (diacerein); intra-articular therapeutic agents such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: agonists or antagonists of cytokines or cytokine function (including drugs acting on cytokine signaling pathways, such as modulators of the SOCS system), including α -, β -and γ -interferons; type I insulin-like growth factor (IGF-1); interleukins (IL), including IL1 to 17 and interleukin antagonists or inhibitors (e.g. anakinra); alpha tumor necrosis factor (TNF-alpha) inhibitors, such as anti-TNF monoclonal antibodies (e.g., infliximab, adalimumab, and CDP-870) and TNF receptor antagonists (including immunoglobulin molecules (e.g., etanercept) and low molecular weight drugs (e.g., pentoxifylline (pentoxyfylline))).

In addition, the present invention relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with: monoclonal antibodies targeting B lymphocytes (e.g., CD20 (rituximab), MRA-aIL16R) and monoclonal antibodies targeting T lymphocytes (CTLA4-Ig, HuMax I1-15).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: modulators of chemokine receptor function, such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (family C-C); antagonists of CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5(C-X-C family); and CX₃CR1(C-X₃-antagonists of family C).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: inhibitors of Matrix Metalloproteinases (MMPs), i.e., stromelysin, collagenase and gelatinase, and aggrecanase (especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), and MMP-9 and MMP-12), including drugs such as doxycycline.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist, such as zileuton; ABT-761; fenton; teposalin; abbott-79175; abbott-85761; n- (5-substituted) -thiophen-2-alkylsulfonamide; 2, 6-di-tert-butylphenol hydrazone; methoxytetrahydropyrans, such as Zeneca ZD-2138; compound SB-210661; pyridyl-substituted 2-cyanonaphthalene compounds, such as L-739,010; 2-cyanoquinoline compounds, such as L-746,530; or indole or quinoline compounds, such as MK-591, MK-886 and BAY x 1005.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: receptor antagonists for Leukotriene (LT) B4, LTC4, LTD4 and LTE4, selected from phenothiazin-3-yl compounds, such as L-651,392; amidino compounds, such as CGS-25019 c; benzoxazines (benzoxamines), such as, for example, ondansetron; benzamidine (benzathine), such as BIIL 284/260; and compounds such as zafirlukast, arlukast, glebrukast, pranlukast, vilukast (MK-679), RG-12525, Ro-245913, ilakast (CGP 45715A), and BAY × 7195.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: phosphodiesterase (PDE) inhibitors, such as methylxanthines (methylxanthines), including theophylline and aminophylline; a selective PDE isozyme inhibitor, comprising a PDE4 inhibitor, an isoform PDE4D inhibitor or a PDE5 inhibitor.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: histamine type 1 receptor antagonists, e.g. cetirizine, loratadine, desloratadine, fexofenadine, avastin, terfenadine, asimidinAzole nitrogenStatin, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; oral, topical or parenteral administration.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: proton pump inhibitors (e.g., omeprazole) or gastroprotective histamine type 2 receptor antagonists.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: a histamine type 4 receptor antagonist.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: alpha 1/alpha 2 adrenoceptor agonists, vasoconstrictors, sympathomimetics such as propylhexedrine (propylhexedrine), phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride, or ethylnorepinephrine hydrochloride.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: anticholinergics, including muscarinic receptor (M1, M2, and M3) antagonists, such as atropine, scopolamine, glycopyrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: chromones, such as cromolyn sodium or nedocromil sodium.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: glucocorticoids, for example flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: drugs that modulate nuclear hormone receptors (e.g., PPARs).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: immunoglobulin (Ig) or Ig preparations; or antagonists or antibodies that modulate Ig function, such as anti-IgE (e.g., omalizumab).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: another antiinflammatory agent for systemic or topical application, for example thalidomide (thalidomide) or a derivative thereof, a retinoid, dithranol (dithranol) or calcipotriol (calcipotriol).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: a combination of an aminosalicylate and a sulfapyridine (e.g., sulfasalazine, mesalamine, balsalazide, and olsalazine); and immunomodulatory drugs such as thiopurines and corticosteroids (e.g., budesonide).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: antibacterial agents, such as penicillin derivatives, tetracycline, macrolides, beta-lactams, fluoroquinolones, metronidazole, inhaled aminoglycosides; antiviral agents including acyclovir, famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir (zanamavir) and oseltamavir (oseltamavir); protease inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors, such as didanosine, lamivudine, stavudine (stavudine), zalcitabine or zidovudine; or non-nucleoside reverse transcriptase inhibitors, such as nevirapine (nevirapine) or efavirenz (efavirenz).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: cardiovascular agents, such as calcium channel blockers, beta-adrenoceptor blockers, Angiotensin Converting Enzyme (ACE) inhibitors, angiotensin 2 receptor antagonists; lipid lowering agents, such as statins or fibrates; blood cell morphology modulators, such as decimphine (pentoxyfylline); thrombolytic or anticoagulant drugs, such as platelet aggregation inhibitors.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: CNS agents, for example antidepressants (e.g. sertraline), anti-Parkinsonian agents (e.g. propinophenylamine, L-dopa, ropinirole, pramipexole, MAOB inhibitors (e.g. selegiline and rasagiline), comp inhibitors (e.g. tolcapone (tasmar)), A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists or neuronal nitric oxide synthase inhibitors) or anti-Alzheimer agents (e.g. donepezil (donepezil), rivastigmine, tacrine, COX-2 inhibitors, propentofylline or metraflate).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: drugs for the treatment of acute or chronic pain, such as centrally or peripherally acting analgesics (e.g. opioids or derivatives thereof), carbamazepine, phenytoin, sodium valproate, amitriptyline or other antidepressants, acetaminophen or non-steroidal anti-inflammatory drugs.

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: parenterally or topically applied (including inhaled) local anesthetics, such as lignocaine or its derivatives.

The compounds of the present invention or pharmaceutically acceptable salts thereof may also be used in combination with: anti-osteoporosis agents, including hormonal agents (e.g. raloxifene) or bisphosphonates (e.g. alendronate).

The present invention also relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with: (i) tryptase (tryptase) inhibitors; (ii) platelet Activating Factor (PAF) antagonists; (iii) interleukin Converting Enzyme (ICE) inhibitors; (iv) an IMPDH inhibitor; (v) an inhibitor of the adhesion molecules is provided,including VLA-4 antagonists; (vi) (ii) a cathepsin; (vii) kinase inhibitors, such as tyrosine kinase (e.g., Btk, Itk, Jak3 or MAP) inhibitors (e.g., gefitinib or imatinib mesylate), serine/threonine kinase inhibitors (e.g., MAP kinase (e.g., p38, JNK, protein kinase A, B or C, or IKK) inhibitors) or inhibitors of kinases involved in cell cycle regulation (e.g., cyclin dependent kinases); (viii) glucose-6 phosphate dehydrogenase inhibitors; (ix) kinins B₁Receptors or kinins B₂A receptor antagonist; (x) Anti-gout agents, such as colchicine; (xi) Xanthine oxidase inhibitors, such as allopurinol; (xii) Uricosuric agents, such as probenecid, sulindac, or benzbromarone; (xiii) Growth hormone secretagogues; (xiv) Transforming growth factor (TGF β); (xv) Platelet Derived Growth Factor (PDGF); (xvi) Fibroblast growth factors, such as basic fibroblast growth factor (bFGF); (xvii) Granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) Capsaicin oil (capsaicin tear); (xix) Tachykinin NK₁Receptor or tachykinin NK₃Receptor antagonists, such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) Elastase inhibitors such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitors (TACE); (xxii) An Induced Nitric Oxide Synthase (iNOS) inhibitor; (xxiii) Chemoattractant receptor-homologous molecules expressed on TH2 cells (e.g., CRTH2 antagonists); (xxiv) Inhibitors of P38; (xxv) Agents that modulate Toll-like receptor (TLR) function; (xxvi) Agents that modulate the activity of purinergic receptors, such as P2X 7; (xxvii) Transcription factor activation inhibitors, such as NFkB, API or STATS; or (xxviii) a non-steroidal glucocorticoid receptor agonist.

Where such a combination is to be administered by inhalation, the one or more agents other than the compound of formula (I) or a pharmaceutically acceptable salt thereof may be selected from the agents listed below:

PDE4 inhibitors, including inhibitors of the isoform PDE 4D;

glucocorticoid receptor agonists { e.g., non-steroidal glucocorticoid receptor agonists or steroidal glucocorticoid receptor agonists (e.g., budesonide) };

muscarinic receptor antagonists (e.g. M1, M2 or M3 antagonists, e.g. selective M3 antagonists), such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine, telenzepine or glycopyrronium bromide (e.g. R, R-glycopyrronium bromide or mixtures of R, S-and S, R-glycopyrronium bromide);

modulators of chemokine receptor function (e.g. CCR1 receptor antagonists); or

Inhibitors of p38 kinase function.

The compounds of the invention or their pharmaceutically acceptable salts may also be used in combination with existing therapeutic agents for the treatment of cancer, suitable agents including, for example:

(i) an anti-proliferative/antineoplastic agent or combination thereof for use in medical oncology, such as an alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, or nitrosourea); an antimetabolite (e.g., an antifolate such as fluoropyrimidine-like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, gemcitabine, or paclitaxel); an anti-tumor antibiotic (e.g., an anthracycline, such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, dactinomycin, or mithramycin); antimitotic agents (e.g. vinca alkaloids such as vincristine, vinblastine, vindesine or vinorelbine; or taxanes such as taxol or taxotere); or a topoisomerase inhibitor (e.g., an epipodophyllotoxin, such as etoposide, teniposide, ansacholine, topotecan, or camptothecin);

(ii) cell growth inhibitory drugs, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, or iodoxyfene); estrogen receptor downregulators (e.g., fulvestrant); anti-androgens (e.g., bicalutamide, flutamide, nilutamide, or cyproterone acetate); LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, or buserelin); progestins (e.g., megestrol acetate); an aromatase (aromatase) inhibitor (e.g. anastrozole, letrozole, vorazole (vorazole) or exemestane); or 5 alpha-reductase inhibitors (e.g., finasteride);

(iii) drugs that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors (e.g., marimastat) or inhibitors of urokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example: growth factor antibodies (e.g., anti-erb b2 antibody trastuzumab or anti-erb b1 antibody cetuximab [ C225 ]); farnesyl transferase inhibitors; tyrosine kinase inhibitors or serine/threonine kinase inhibitors; an epidermal growth factor family inhibitor (e.g. an EGFR family tyrosine kinase inhibitor such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)); platelet derived growth factor family inhibitors; or a hepatocyte growth factor family inhibitor;

(v) anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856, or WO 98/13354); or a compound that acts by another mechanism (e.g., linoxamine, an inhibitor of integrin α v β 3 function, or angiostatin);

(vi) vascular damaging agents, such as 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) drugs used in antisense therapy, such as antisense therapeutic drugs directed to one of the above-listed targets, e.g., ISIS 2503, anti-ras antisense;

(viii) drugs used in, for example, the following gene therapy methods: methods of replacing an aberrant gene (e.g., aberrant p53 or aberrant BRCA1 or BRCA 2); GDEPT (gene-mediated enzyme prodrug therapy) methods, such as GDEPT methods using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and methods of increasing the tolerance of a patient to chemotherapy or radiation therapy, such as multiple drug resistant gene therapy; or

(ix) Drugs used in, for example, the following immunotherapeutic methods: ex vivo and in vivo methods of enhancing the immunogenicity of tumor cells in a patient, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor); methods of reducing T cell anergy; methods using transfected immune cells (e.g., cytokine-transfected dendritic cells); methods of using cytokine-transfected tumor cell lines; and methods of using anti-idiotypic antibodies.

Detailed Description

The invention will now be further explained by reference to the following illustrative examples.

General procedure

¹H NMR spectra were recorded on a Varian Inova 400MHz or Varian Mercury-VX 300MHz instrument. Adding chloroform-d (delta)_H7.27ppm), dimethyl sulfoxide-d₆(δ_H2.50ppm), acetonitrile-d₃(δ_H1.95ppm) or methanol-d₄(δ_H3.31ppm) was used as internal standard. Column chromatography was carried out using silica gel (0.040-0.063mm, Merck). Unless otherwise indicated, the starting materials are commercially available. All solvents and commercial reagents were laboratory grade and used as received.

The following methods were used for LC/MS analysis:

the instrument comprises the following steps: agilent 1100; a chromatographic column: waters Symmetry 2.1 × 30 mm; mass spectrum: APCI; flow rate: 0.7 ml/min; wavelength: 254 nm; solvent A: water + 0.1% TFA; solvent B: acetonitrile + 0.1% TFA; gradient: 15-95%/B8 min, 95% B1 min.

Analytical chromatography in Symmetry C₁₈Column (2.1X 30mm, particle size 3.5 μm) with a mobile phase of acetonitrile/water/0.1% trifluoroacetic acid, gradient from 5% acetonitrile to 95% acetonitrile over 8min, flow rate 0.7 ml/min.

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

HPLC: high performance liquid chromatography

Example 1

4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate

a)3- [2- (2-naphthalen-1-yl-ethoxy) -ethylsulfanyl ] -propan-1-ol

A mixture of 1- (2-vinyloxy-ethyl) -naphthalene (prepared as described in WO 97/23470) (2.04g), 3-mercapto-1-propanol (0.95g) and 2, 2 '-azobisisobutyronitrile (2, 2' -azobisisobutyronitrile) (0.05g) was heated at 60 ℃ for 3 hours. The mixture was then cooled to room temperature and purified by flash chromatography on silica gel eluting with 40% ethyl acetate in isohexane to give the sub-title compound (2.4 g).

¹H NMR(400MHz，D₆-DMSO)δ8.08(d，1H)，7.92(d，1H)，7.80-7.78(m，1H)，7.57-7.49(m，2H)，7.45-7.41(m，2H)，4.45(t，1H)，3.73(t，2H)，3.57(t，2H)，3.44(q，2H)，3.31-3.28(m，2H)，2.62(t，2H)，2.54(t，2H)，1.66-1.60(m，2H)。

b)3- [2- (2-naphthalen-1-yl-ethoxy) -ethylsulfanyl ] -propanal

A stirred solution of oxalyl chloride (482mg) in dichloromethane (15mL) at-78 deg.C under a nitrogen atmosphere was treated dropwise with a solution of dimethyl sulfoxide (593mg) in dichloromethane (2 mL). The mixture was stirred at-78 ℃ for 10 minutes and then treated dropwise with a solution of 3- [2- (2-naphthalen-1-yl-ethoxy) -ethylsulfanyl ] -propan-1-ol (example 1a), 1.0g) in dichloromethane (3 mL). After 15 minutes, triethylamine (1.74g) was added dropwise at-78 ℃ and the mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and the organic phase was washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (0.49 g).

¹H NMR(400MHz，D₆-DMSO)δ9.60(s，1H)，8.09(d，1H)，7.92(d，1H)，7.80-7.78(m，1H)，7.57-7.49(m，2H)，7.45-7.41(m，2H)，3.74(t，2H)，3.58(t，2H)，3.32-3.28(m，2H)，2.76-2.73(m，2H)，2.69-2.63(m，4H)。

c)7- [ (1R) -2-azido-1-hydroxyethyl ] -4- (benzyloxy) -1, 3-benzothiazol-2 (3H) -one

Sodium azide (231mg) and sodium iodide (147mg) were added to a solution of 4- (benzyloxy) -7- [ (1R) -2-bromo-1-hydroxyethyl ] -1, 3-benzothiazol-2 (3H) -one (prepared by the method outlined in WO 2004/016578, 340mg) in dimethyl sulfoxide (8 mL). The reaction mixture was heated at 65 ℃ for 5 hours. After this time, the mixture was partitioned between ethyl acetate and water, and the organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in toluene to give the sub-title compound (195 mg).

¹H NMR(400MHz，D₆-DMSO)δ11.89(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)。

d)7- [ (1R) -2-amino-1-hydroxyethyl ] -4- (benzyloxy) -1, 3-benzothiazol-2 (3H) -one hydrochloride

A solution of 7- ((1R) -2-azido-1-hydroxyethyl) -4-benzyloxy-3H-benzothiazol-2-one (example 1c), 195mg) in a mixture of ethanol (8mL) and tetrahydrofuran (4mL) was treated with 10% w palladium on carbon catalyst (20mg) and the resulting mixture was stirred vigorously under 3 atmospheres of hydrogen for 20 hours. The catalyst was filtered off and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica eluting with 1% concentrated aqueous ammonia and 12% methanol in dichloromethane. The resulting product was dissolved in 1, 4-dioxane and then treated dropwise with a4 molar solution of hydrogen chloride in 1, 4-dioxane (0.5 mL). The solvent was evaporated under reduced pressure to give the sub-title compound (160 mg).

m/e 315(M-H)⁺。

¹H NMR(400MHz，D₆-DMSO)δ8.01(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)。

e)4- (benzyloxy) -7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one

A solution of 7- ((1R) -2-amino-1-hydroxyethyl) -4-benzyloxy-3H-benzothiazol-2-one hydrochloride (example 1d), 157mg) in methanol (6mL) was treated with 3- [2- (2-naphthalen-1-yl-ethoxy) -ethylsulfanyl ] -propionaldehyde (example 1b), 128mg) and acetic acid (30 mg). The mixture was stirred at room temperature for 10 minutes, then treated with sodium cyanoborohydride (17 mg). Stirring was continued at room temperature for 20 hours, after which the solvent was removed under reduced pressure and the resulting residue was partitioned between dilute aqueous ammonia and ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 6% methanol in dichloromethane to give the sub-title compound (94 mg).

m/e 589(M+H⁺，100％)。

f) 4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate

A solution of 4- (benzyloxy) -7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one (example 1e), 94mg) in 98% formic acid (5mL) was treated with palladium black (10mg), and the mixture was stirred vigorously at room temperature under a nitrogen atmosphere. An additional portion of palladium black (10mg) was added at 30 minute intervals for 5 hours. After this time, the mixture was filtered, and the resulting solution was evaporated under reduced pressure. The resulting residue was purified by reverse phase HPLC eluting with a gradient of 5% to 75% acetonitrile in 0.2% trifluoroacetic acid in water to give the title compound (30 mg).

m/e 499(M+H)⁺。

¹H NMR(400MHz，D₆-DMSO)δ11.67(s，1H)，10.22(s，1H)，8.61(s，2H)，8.08(d，1H)，7.92(d，1H)，7.81-7.78(m，1H)，7.58-7.40(m，4H)，6.93(d，1H)，6.77(d，1H)，6.45(d，1H)，4.88-4.85(m，1H)，3.74(t，2H)，3.59(t，2H)，3.05-2.95(m，4H)，2.65(t，2H)，1.91-1.81(m，2H)。

Example 2

4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } sulfonyl) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate

A solution of 4-hydroxy-7- ((1R) -1-hydroxy-2- { [3- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) propyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate (example 1, 83mg) in ethanol (5mL) was treated with 3-chloroperoxybenzoic acid (62mg of 75% grade reagent) and the solution was stirred at room temperature for 2 hours. The solvent was evaporated under a stream of nitrogen and the residue was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane. The resulting product was further purified by reverse phase HPLC eluting with a gradient of 5% to 75% acetonitrile in 0.2% trifluoroacetic acid in water to give the title compound (30 mg).

m/e 531(M+H)⁺。

¹H NMR(400MHz，D₆-DMSO)δ11.68(s，1H)，10.22(s，1H)，8.68(s，2H)，8.08(d，1H)，7.91(d，1H)，7.79(d，1H)，7.57-7.49(m，2H)，7.46-7.40(m，2H)，6.94(d，1H)，6.78(d，1H)，6.47(d，1H)，4.87-4.83(m，1H)，3.81-3.76(m，4H)，3.38(t，2H)，3.11-3.00(m，6H)，2.05-1.99(m，2H)。

Example 3

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [2- (2-phenylethoxy) ethoxy ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one trifluoroacetate salt

a)4- (benzyloxy) -7- [ (1R) -1-hydroxy-2- ({3- [2- (2-phenylethoxy) ethoxy ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one

The sub-title compound was prepared using the method of example 1e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4- (benzyloxy) -1, 3-benzothiazol-2 (3H) -one hydrochloride (example 1d), 250mg) and 3- (2- (2-phenylethoxy) ethoxy) -propionaldehyde (prepared as described in WO 93/24473, 157 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 8% methanol in dichloromethane to give the sub-title compound (160 mg).

m/e 523(M+H)⁺。

b) 4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [2- (2-phenylethoxy) ethoxy ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one trifluoroacetate salt

The title compound was prepared from 4- (benzyloxy) -7- [ (1R) -1-hydroxy-2- ({3- [2- (2-phenylethoxy) ethoxy ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one (example 3a), 160mg) using the method of example 1 f). The crude product was purified by reverse phase HPLC and gradient elution from 5% to 75% acetonitrile in 0.2% trifluoroacetic acid in water to give the title compound (40 mg).

m/e 433(M+H)⁺。

¹H NMR(400MHz，D₆-DMSO)δ11.67(s，1H)，10.26(s，1H)，8.67(s，1H)，8.56(s，1H)，7.30-7.15(m，5H)，6.92(d，1H)，6.77(d，1H)，6.46(s，1H)，4.89-4.86(m，1H)，3.60(t，2H)，3.43(t，2H)，3.03-3.01(m，4H)，2.80(t，2H)，1.93-1.80(m，2H)。

Example 4

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one hydrochloride

a)2- [2- (2-naphthalen-1-yl-ethoxy) -ethylsulfanyl ] -ethanol

1- (2-ethyleneoxy-ethyl) -naphthalene (1.95g) and 2-mercaptoethanol (0.78g, 0.7mL) were mixed together and 2, 2, -azobisisobutyronitrile (40mg) was added. The mixture was heated to 50 ℃ for 2 hours, then cooled and diluted with dichloromethane (5 mL). The resulting solution was purified by silica gel chromatography eluting with ethyl acetate/isohexane (1/9 to 1/1) to give the sub-title compound (2.04g) as an oil.

¹H NMR(400MHz，CDCl₃)δ8.06(d，1H)，7.85(d，1H)，7.74(d，1H)，7.54-7.46(m，2H)，7.43-7.37(m，2H)，3.82(t，2H)，3.71(q，4H)，3.65(t，3H)，3.39(t，2H)，2.73(t，4H)。

b)7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride

A solution of 7- [ (1R) -2-amino-1-hydroxyethyl ] -4- (benzyloxy) -1, 3-benzothiazol-2 (3H) -one hydrochloride (example 1d), 1.8g) in methanol (60mL) and concentrated hydrochloric acid (4mL) was stirred vigorously in the presence of 10% w palladium on carbon catalyst (0.36g) under 4 atmospheres of hydrogen for 2 hours. An additional 10% w palladium on carbon catalyst (0.24g) was added and stirring under hydrogen was continued for 1 hour. The catalyst was filtered off, and then the solvent was evaporated under reduced pressure to give the sub-title compound (1.3 g).

m/e 227(M+H)⁺。

¹H NMR(400MHz，D₆-DMSO)δ11.70(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)。

c) 4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({2- [2- (1-naphthyl) ethoxy ] ethyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one hydrochloride

Pyridine chlorochromate (0.484g) was added to a solution of 2- [2- (2-naphthalen-1-yl-ethoxy) -ethylsulfanyl ] -ethanol (example 4a), 0.21g) in dichloromethane (10mL) and the mixture was stirred for 2 h. The reaction mixture was purified by chromatography on silica gel (10 mm. times.20 mm, column of silica gel rinsed with ethyl acetate/isohexane 1: 1). After evaporation under reduced pressure, the residue was dissolved in methanol (5mL), 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 0.113g) and acetic acid (0.05mL) were added and the mixture was stirred for 1 hour. Sodium cyanoborohydride (0.031g) was added and the reaction mixture was stirred overnight. Concentrated aqueous ammonia (0.1mL) was added and the mixture was concentrated on silica gel, then the residue was purified by silica gel chromatography eluting with 1-10% 0.7N methanolic ammonia in dichloromethane to give the product which was purified again by reverse phase HPLC using 5-95% 0.2M trifluoroacetic acid in acetonitrile. The fractions containing the compound were concentrated, and the residue was dissolved in 4N hydrogen chloride in 1, 4-dioxane (5mL) and then concentrated. The residue was triturated with ether then ether was decanted to give the title compound (0.028g) as a white solid.

m/e 485(M+H)⁺。

¹H NMR(400MHz，D₆-DMSO)δ11.69(s，1H)，10.20(s，1H)，8.90(s，1H)，8.64(s，1H)，8.08(d，1H)，7.91(d，1H)，7.79(dd，1H)，7.57-7.48(m，2H)，7.43(q，2H)，6.91(d，1H)，6.78(d，1H)，6.44(d，1H)，4.93-4.89(m，1H)，3.75(t，2H)，3.60(t，2H)，3.30(t，2H)，3.16-3.09(m，2H)，3.06-2.99(m，2H)，2.85-2.76(m，2H)，2.71(t，2H)。

Example 5

7- ((1R) -2- { [3- ({3- [2- (4-bromophenyl) ethoxy ] propyl } thio) propyl ] amino } -1-hydroxyethyl) -4-hydroxy-13-benzothiazol-2 (3H) -one hydrochloride

a) Toluene-4-sulfonic acid 3-allylthio-propyl ester

A solution of 3- (2-propenylsulfanyl) -1-propanol (3.7g) in dichloromethane (25mL) was treated with triethylamine (3.12g), 4- (dimethylamino) pyridine (0.2g) and toluenesulfonyl chloride (5.87g), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with chloroform, washed with water, and the organic layer was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 40% diethyl ether in isohexane to give the sub-title compound (5.22 g).

¹H NMR(400MHz，CDCl₃)δ7.79(d，2H)，7.35(d，2H)，5.73-5.69(m，1H)，5.08-5.04(m，2H)，4.13(t，2H)，3.06(d，2H)，2.47-2.43(m，5H)，1.91-1.87(m，2H)。

b)1- [2- (3-allylsulfanyl-propoxy) -ethyl ] -4-bromo-benzene

A solution of 4-bromobenzene ethanol (4.12g) in tetrahydrofuran (10mL) was added dropwise to a stirred suspension of sodium hydride (0.8g of 60% grade sodium hydride) in tetrahydrofuran (20mL) at 0 deg.C. The mixture was stirred at room temperature for 1 hour, then cooled to 0 ℃, and a solution of toluene-4-sulfonic acid 3-allylsulfanyl-propyl ester (example 5a), 5.2g) in tetrahydrofuran (10mL) was added dropwise to the resulting mixture. The reaction mixture was heated to reflux for 3 hours and then stirred at room temperature for 18 hours. The reaction mixture was quenched by addition of an excess of dilute aqueous hydrochloric acid. Then, the mixture was basified by adding saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (2.52 g).

¹H NMR(400MHz，CDCl₃)δ7.46-7.05(m，4H)，5.85-5.70(m，1H)，5.14-5.02(m，2H)，3.65-3.56(m，2H)，3.54-3.45(m，2H)，3.15-3.07(m，2H)，2.87-2.77(m，2H)，2.53-2.46(m，2H)，1.88-1.73(m，2H)。

c)3- {3- [2- (4-bromophenyl) -ethoxy ] -propylthio } -propan-1-ol

A0.5 molar solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran (28mL) was added dropwise to a solution of 1- [2- (3-allylsulfanyl-propoxy) -ethyl ] -4-bromo-benzene (example 5b), 2.2g) in tetrahydrofuran (40 mL). The mixture was heated at reflux for 1 hour. The reaction mixture was then cooled to room temperature and treated with 3 molar aqueous sodium hydroxide (2.56mL), followed by 35% aqueous hydrogen peroxide (2.28 mL). The mixture was stirred at room temperature for 1 hour and then treated with solid sodium chloride. The solvent was decanted, dried, and then evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 33% ethyl acetate in isohexane to give the sub-title compound (1.48 g).

¹H NMR(400MHz，D₆-DMSO)δ7.45(d，2H)，7.20(d，2H)，4.45(t，1H)，3.55(t，2H)，3.46-3.41(m，4H)，2.76(t，2H)，2.49-2.42(m，4H)，1.72-1.58(m，4H)。

d)3- {3- [2- (4-bromophenyl) -ethoxy ] -propylthio } -propionaldehyde

The subtitle compound was prepared from 3- {3- [2- (4-bromo-phenyl) -ethoxy ] -propylsulfanyl } -propan-1-ol (example 5c), 620mg) using the method of example 1 b). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (200 mg).

¹H NMR(400MHz，DMSO)δ9.63(s，1H)，7.46(d，2H)，7.19(d，2H)，3.55(t，2H)，3.43(t，2H)，2.77(t，2H)，2.73-2.66(m，4H)，1.73-1.67(m，2H)。

e)7- ((1R) -2- { [3- ({3- [2- (4-bromophenyl) ethoxy ] propyl } thio) propyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride

3- {3- [2- (4-bromo-phenyl) -ethoxy ] -propylsulfanyl } -propionaldehyde (example 5d), 126mg) and acetic acid (20mg) were added to a solution of 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b, 100mg) in methanol (7 mL). The mixture was stirred at room temperature for 40 minutes, then treated with sodium cyanoborohydride (14 mg). The reaction mixture was stirred at room temperature for 18 hours. After this time, the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (50mL) and saturated brine (50mL) containing concentrated aqueous ammonia (1 mL). The organic layer was separated, dried and then evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 9% methanol in dichloromethane. The product was dissolved in methanol and then treated with an excess of hydrogen chloride in dioxane. Then, the solvent was evaporated under reduced pressure to give the title compound (60 mg).

m/e 541(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ11.69(s，1H)，10.20(s，1H)，8.90(s，1H)，8.69(s，1H)，7.47(d，2H)，7.19(d，2H)，6.93(d，1H)，6.78(d，1H)，6.43(d，1H)，4.93-4.90(m，1H)，3.56(t，2H)，3.43(t，2H)，3.02-2.97(m，4H)，2.77(t，2H)，1.92-1.84(m，2H)，1.75-1.68(m，2H)。

Example 6

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [3- (2-phenylethoxy) propyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride

a)3- (3-Phenylethoxy-propylsulfanyl) -propan-1-ol

A mixture of (2-allyloxy-ethyl) -benzene (885mg), 3-mercapto-1-propanol (503mg), and 2, 2' -azobisisobutyronitrile (20mg) was stirred under nitrogen at 60 ℃ for 1 hour. The mixture was cooled to room temperature and then purified by flash chromatography on silica gel eluting with 33% ethyl acetate in isohexane to give the sub-title compound (810 mg).

¹H NMR(400MHz，D₆-DMSO)δ7.29-7.16(m，5H)，4.45(t，1H)，3.56(t，2H)，3.46-3.42(m，4H)，2.79(t，2H)，2.48-2.44(m，4H)，1.74-1.59(m，4H)。

b)3- (3-Phenylethoxy-propylthio) -propionaldehyde

The subtitle compound was prepared from 3- (3-phenethyloxy-propylsulfanyl) -propan-1-ol (800mg) using the method of example 1 b). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (170 mg).

¹H NMR(400MHz，D₆-DMSO)δ9.63(s，1H)，7.30-7.16(m，5H)，3.57(t，2H)，3.44(t，2H)，2.79(t，2H)，2.74-2.67(m，4H)，1.75-1.66(m，2H)。

c) 4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [3- (2-phenylethoxy) propyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride

The title compound was prepared using the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 100mg) and 3- (3-phenethyloxy-propylsulfanyl) -propionaldehyde (example 6b), 96 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane. The product was dissolved in methanol and then treated with an excess of hydrogen chloride in dioxane. Then, the solvent was evaporated under reduced pressure to give the title compound (40 mg).

m/e 463(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ11.69(s，1H)，10.21(s，1H)，8.93(s，1H)，8.70(s，1H)，7.29-7.16(m，5H)，6.93(d，1H)，6.78(d，1H)，6.43(d，1H)，4.94-4.92(m，1H)，3.57(t，2H)，3.45(t，2H)，3.01-2.96(m，4H)，2.79(t，2H)，1.92-1.84(m，2H)，1.76-1.69(m，2H)。

Example 7

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- {2- [2- (1-naphthyl) ethoxy ] ethoxy } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one

a) (2-naphthalen-1-yl-ethoxy) -acetic acid

60% grade sodium hydride (1.33g) was added portionwise to a solution of 1-naphthaleneethanol (2.85g) in N, N-dimethylformamide (40mL), and the resulting mixture was stirred at 60 ℃ for 10 minutes, after which it was cooled to 40 ℃. Chloroacetic acid (1.56g) was added in portions, and then the reaction mixture was heated at 60 ℃ for 30 minutes. After cooling to room temperature, the reaction mixture was quenched by careful addition of water and then partitioned between water and diethyl ether. The aqueous layer was acidified by addition of 2 molar aqueous hydrochloric acid solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried, and then the solvent was removed under reduced pressure to give the subtitle compound (2.9 g).

m/e 229(M-H⁺，100％)。

b)2- (2-naphthalen-1-yl-ethoxy) -ethanol

A solution of (2-naphthalen-1-yl-ethoxy) -acetic acid (example 7a), 2.9g) in tetrahydrofuran (60mL) was treated dropwise with a2 molar solution of borane-dimethylsulfide complex in tetrahydrofuran (12.6mL) and the mixture was stirred at room temperature for 2 hours. Methanol (20mL) was added carefully and stirring was continued for 30 min. After this time, the solvent was removed under reduced pressure, and the residue was partitioned between diethyl ether and saturated aqueous potassium carbonate solution. The organic layer was dried and then evaporated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate in isohexane (1/3) to give the sub-title compound (2.03 g).

¹H NMR(400MHz，D₆-DMSO)δ8.06(d，1H)，7.89(d，1H)，7.80-7.74(m，1H)，7.55-7.44(m，2H)，7.43-7.38(m，2H)，4.55(t，1H)，3.70(t，2H)，3.50-3.42(m，4H)，3.28(t，2H)。

c)3- [2- (2-naphthalen-1-yl-ethoxy) -ethoxy ] -propionitrile

A mixture of 2- (2-naphthalen-1-yl-ethoxy) -ethanol (example 7b), 2.03g), 3-bromopropionitrile (1.09mL), sodium hydroxide (10g) and tetrabutylammonium chloride (0.1g) in dichloromethane (20mL) and water (20mL) was stirred vigorously for 18 h. The reaction mixture was partitioned between water and dichloromethane and the organic layer was washed with dilute aqueous hydrochloric acid, then water, then dried, then evaporated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel eluting with 33% ethyl acetate in isohexane gave the sub-title compound (1.5 g).

¹H NMR(400MHz，D₆-DMSO)δ8.06(d，1H)，7.88(d，1H)，7.77-7.74(m，1H)，7.52-7.46(m，2H)，7.42-7.38(m，2H)，3.71(t，2H)，3.55-3.52(m，6H)，2.67(t，2H)。

d)3- [2- (2-naphthalen-1-yl-ethoxy) -ethoxy ] -propionic acid

A mixture of 3- [2- (2-naphthalen-1-yl-ethoxy) -ethoxy ] -propionitrile (example 7c), 1.5g) in concentrated hydrochloric acid (20mL) and water (10mL) was refluxed for 5 hours with vigorous stirring and then cooled to room temperature. The reaction mixture was partitioned between ether and water, and then the organic layer was extracted with 1 molar aqueous sodium hydroxide solution. The aqueous sodium hydroxide layer was acidified by addition of an excess of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give the subtitle compound (0.87 g).

m/e 287(M-H⁺，100％)。

e)3- [2- (2-naphthalen-1-yl-ethoxy) -ethoxy ] -propan-1-ol

The sub-title compound was prepared from 3- [2- (2-naphthalen-1-yl-ethoxy) -ethoxy ] -propionic acid (example 7d), 0.87g) using the method of example 7b) to give 0.73g of the sub-title compound.

m/e 275(M+H⁺，100％)。

f)3- [2- (2-naphthalen-1-yl-ethoxy) -ethoxy ] -aldehyde

The subtitle compound is prepared from 3- [2- (2-naphthalen-1-yl-ethoxy) -ethoxy ] -propan-1-ol (example 7e), 0.36g) using the method of example 1 b). The crude product was purified by flash chromatography on silica gel eluting with 33% ethyl acetate in isohexane to give the sub-title compound (226 mg).

¹H NMR(400MHz，D₆-DMSO)δ9.62(t，1H)，8.08(d，1H)，7.93-7.90(m，1H)，7.82-7.76(m，1H)，7.58-7.46(m，2H)，7.44-7.39(m，2H)，3.74-3.67(m，4H)，3.55-3.48(m，4H)，2.60-2.55(m，2H)。

g) 4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- {2- [2- (1-naphthyl) ethoxy ] ethoxy } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one

3- [2- (2-Naphthalen-1-yl-ethoxy) -ethoxy ] -propionaldehyde (example 7f), 104mg) and acetic acid (20mg) were added to a solution of 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 100mg) in methanol (7 mL). The mixture was stirred at room temperature for 40 minutes, then treated with sodium cyanoborohydride (14 mg). The reaction mixture was stirred at room temperature for 18 h, after which time the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (50mL) and brine (50mL) containing concentrated aqueous ammonia (1 mL). The organic layer was separated, dried and then evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (40 mg).

m/e 483(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ8.08(d，1H)，7.90(d，1H)，7.78-7.75(m，1H)，7.56-7.45(m，2H)，7.42-7.39(m，2H)，6.85(d，1H)，6.69(d，1H)，4.57(q，1H)，3.73(t，2H)，3.54-3.51(m，2H)，3.47-3.43(m，2H)，3.38(t，2H)，3.29(t，2H)，2.68-2.54(m，2H)，1.63-1.56(m，2H)。

Example 8

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (2- { [3- (2-phenylethoxy) propyl ] thio } ethyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride

a)2- (3-Phenylethoxy-propylsulfanyl) -ethanol

The sub-title compound was prepared according to the method of example 1a) from (2-allyloxy-ethyl) -benzene (647mg) and 2-mercaptoethanol (312 mg). The crude product was purified by flash chromatography on silica gel eluting with 33% ethyl acetate in isohexane to give the sub-title compound (652 mg).

¹H NMR(400MHz，D₆-DMSO)δ7.25-7.12(m，5H)，4.70(t，1H)，3.52(t，2H)，3.45(q，2H)，3.39(t，2H)，2.75(t，2H)，1.70-1.63(m，2H)。

b) (3-Phenylethoxy-propylthio) -acetaldehyde

The subtitle compound is prepared according to the method of example 1b) from 2- (3-phenethyloxy-propylsulfanyl) -ethanol (example 8a), 0.65 g). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (95 mg).

¹H NMR(400MHz，D₆-DMSO)δ9.40(t，1H)，7.30-7.16(m，5H)，3.56(t，2H)，3.43(t，2H)，2.79(t，2H)，2.43(t，2H)，1.74-1.66(m，2H)。

c) 4-hydroxy-7- { (1R) -1-hydroxy-2- [ (2- { [3- (2-phenylethoxy) propyl ] thio } ethyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride

The title compound was prepared from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 100mg) and (3-phenethyloxy-propylsulfanyl) -acetaldehyde (example 8b), 91mg) using the method of example 5 e). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane. The product was dissolved in methanol and then treated with an excess of hydrogen chloride in 1, 4-dioxane. Then, the solvent was evaporated under reduced pressure to give the title compound (40 mg).

m/e 449(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ11.70(s，1H)，10.23(s，1H)，9.12(s，1H)，8.73(s，1H)，7.29-7.16(m，5H)，6.92(d，1H)，6.79(d，1H)，6.44(s，1H)，4.96-4.93(m，1H)，3.57(t，2H)，3.45(t，2H)，3.12-3.05(m，4H)，2.85-2.72(m，4H)，2.53(t，2H)，1.77-1.71(m，2H)。

Example 9

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [2- (2-phenylethoxy) ethyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride

a)3- (2-Phenylethoxy-ethylsulfanyl) -propan-1-ol

The subtitle compound is prepared from 3- [2- (2-phenylethoxy) ethylthio ] propionic acid (1.11g) by the method of example 7 b). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in dichloromethane to give the sub-title compound (0.7 g).

¹H NMR(400MHz，CDCl₃)δ7.32-7.19(m，5H)，3.75-3.68(m，2H)，3.66-3.61(m，4H)，2.92-2.86(m，2H)，2.73-2.62(m，4H)，1.89-1.80(m，2H)。

b)3- (2-Phenylethoxy-ethylthio) -propionaldehyde

A solution of sulfur trioxide-pyridine complex (652mg) in dimethyl sulfoxide (3mL) was added in one portion to a solution of 3- (2-phenethyloxy-ethylsulfanyl) -propan-1-ol (example 9a), 330mg) and triethylamine (417mg) in dichloromethane (3mL) cooled to-10 ℃. The cooling bath was removed and the mixture was then stirred vigorously for 10 minutes. Then, the mixture was partitioned between ethyl acetate and brine, and the organic layer was washed with 10% aqueous citric acid solution, then brine, and then dried, and then evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (165 mg).

¹H NMR(400MHz，D₆-DMSO)δ9.61(s，1H)，7.31-7.17(m，5H)，3.64-3.53(m，4H)，2.83-2.63(m，8H)。

c) 4-hydroxy-7- { (1R) -1-hydroxy-2- [ (3- { [2- (2-phenylethoxy) ethyl ] thio } propyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one hydrochloride

The title compound was prepared using the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 100mg) and 3- (2-phenethyloxy-ethylsulfanyl) -propionaldehyde (example 9b), 91 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane. The product was dissolved in methanol and then treated with an excess of hydrogen chloride in dioxane. The solvent was evaporated under reduced pressure to give the title compound (50 mg).

m/e 449(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ11.69(s，1H)，10.21(s，1H)，8.97(s，1H)，8.71(s，1H)，7.30-7.16(m，5H)，6.93(d，1H)，6.79(d，1H)，6.43(s，1H)，4.95-4.93(m，1H)，3.61(t，2H)，3.55(t，2H)，3.02-2.95(m，4H)，2.80(t，2H)，2.65(t，2H)，2.59(t，2H)，1.95-1.83(m，2H)。

Example 10

{3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } (2-phenylethyl) carbamic acid tert-butyl ester

a) [3- (2-hydroxy-ethylsulfanyl) -propyl ] -phenethyl-carbamic acid tert-butyl ester

A mixture of allyl-phenethyl-carbamic acid tert-butyl ester (520mg), 2-mercaptoethanol (156mg) and 2, 2, -azobis (2-methylpropanenitrile) (20mg) was heated at 60 ℃ under a nitrogen atmosphere for 45 minutes. The crude product was purified by flash chromatography on silica gel eluting with 33% ethyl acetate in isohexane to give the sub-title compound (420 mg).

¹H NMR(400MHz，D₆-DMSO)δ7.31-7.27(m，2H)，7.21-7.18(m，3H)，4.75(t，1H)，3.52(q，2H)，3.16(t，2H)，2.75(t，2H)，2.55(t，2H)，2.45(t，2H)，1.74-1.64(m，2H)，1.35(s，9H)。

b) [3- (2-oxo-ethylsulfanyl) -propyl ] -phenethyl-carbamic acid tert-butyl ester

The subtitle compound is prepared from [3- (2-hydroxy-ethylsulfanyl) -propyl ] -phenethyl-carbamic acid tert-butyl ester (example 10a), 406mg) by the method of example 9 b). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (274 mg).

m/e 336.7(M-H⁺，100％)。

c) {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } (2-phenylethyl) carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 163mg) and [3- (2-oxo-ethylsulfanyl) -propyl ] -phenethyl-carbamic acid tert-butyl ester (example 10b), 209 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (157 mg).

m/e 548(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ11.20-10.80(m，1H)，9.95(s，1H)，7.29-7.26(m，2H)，7.20-7.17(m，3H)，6.85(d，1H)，6.68(d，1H)，5.60-5.40(m，1H)，4.55(q，1H)，3.16-3.14(m，2H)，2.74(t，2H)，2.70-2.54(m，6H)，2.41(t，2H)，1.69-1.62(m，2H)，1.33(s，9H)。

Example 11

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({3- [ (2-phenylethyl) amino ] propyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one hydrochloride

A solution of tert-butyl {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } (2-phenylethyl) carbamate (145mg) prepared as described in example 10 in methanol (7mL) was treated with a4 molar solution of hydrogen chloride in 1, 4-dioxane (2mL) and left at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC eluting with a gradient of 5% to 75% acetonitrile in 0.2% aqueous ammonia. The product was further purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane. The product was dissolved in methanol and then treated with an excess of hydrogen chloride in 1, 4-dioxane. Then, the solvent was evaporated under reduced pressure to give the title compound (44 mg).

m/e 448(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ11.69(s，1H)，10.22(s，1H)，9.25(s，1H)，9.16(s，2H)，8.80(s，1H)，7.35-7.31(m，2H)，7.27-7.23(m，3H)，6.92(d，1H)，6.78(d，1H)，6.44(d，1H)，4.99-4.97(m，1H)，3.15-2.96(m，10H)，2.85-2.83(m，2H)，2.67(t，2H)，1.97-1.92(m，2H)。

Example 12

4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({3- [ methyl (2-phenylethyl) amino ] propyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate

a) [3- (2-hydroxy-ethylsulfanyl) -propyl ] -methyl-carbamic acid tert-butyl ester

The subtitle compound is prepared according to the method of example 1a) using allyl-methyl-carbamic acid tert-butyl ester (5.97g) and 2-mercaptoethanol (2.86 g). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (5.1 g).

¹H NMR(400MHz，D₆-DMSO)δ4.77(t，1H)，3.57-3.50(m，2H)，3.23(t，2H)，2.78(s，3H)，2.56(t，2H)，2.52-2.46(m，2H)，1.76-1.66(m，2H)，1.41(s，9H)。

b)2- (3-methylamino-propylsulfanyl) -ethanol hydrochloride

A solution of [3- (2-hydroxy-ethylsulfanyl) -propyl ] -methyl-carbamic acid tert-butyl ester (example 12a), 5.1g) in methanol (40mL) was treated with a4 molar solution of hydrogen chloride in 1, 4-dioxane (10mL) and the mixture was left at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the residue was triturated with ether to give the sub-title compound (3.8 g).

¹H NMR(400MHz，D₆-DMSO)δ8.90(s，2H)，3.52(t，2H)，2.94-2.84(m，2H)，2.60-2.53(m，4H)，1.89-1.81(m，2H)。

c)2- [3- (methyl-phenethyl-amino) -propylsulfanyl ] -ethanol

2- (3-methylamino-propylsulfanyl) -ethanol hydrochloride (2.5g) prepared as described in example 12b) was converted into the free base by solid-phase extraction with sulfonic acid adsorbent in a yield of 1.68 g. A solution of the free base (800mg) in dichloromethane (20mL) was treated with phenylacetaldehyde (708mg) and acetic acid (483mg), followed by sodium triacetoxyborohydride (2.28g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between dichloromethane and saturated aqueous sodium bicarbonate and the organic layer was extracted with dilute aqueous hydrochloric acid. Excess solid sodium bicarbonate was added to the resulting acid wash and the mixture was extracted with fresh dichloromethane. The organic layer was dried over magnesium sulfate, and then the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 1% triethylamine and 4% methanol in dichloromethane to give the sub-title compound (0.8 g).

m/e 254(M+H⁺，100％)。

d) [3- (methyl-phenethyl-amino) -propylsulfanyl ] -acetaldehyde

A solution of sulfur trioxide-pyridine complex (477mg) in dimethyl sulfoxide (3mL) was added in one portion to a solution of 2- [3- (methyl-phenethyl-amino) -propylsulfanyl ] -ethanol (example 12c), 253mg) and triethylamine (303mg) in dichloromethane (3mL) cooled to-10 ℃. The cooling bath was removed and the mixture was then stirred vigorously for 10 minutes. The reaction mixture was then partitioned between ethyl acetate (50mL) and aqueous phosphate buffer (50mL, pH 7.2), the organic layer was washed with brine, and the solvent was evaporated under reduced pressure to give the sub-title compound (170 mg).

m/e 252(M+H⁺，100％)。

e) 4-hydroxy-7- ((1R) -1-hydroxy-2- { [2- ({3- [ methyl (2-phenylethyl) amino ] propyl } thio) ethyl ] amino } ethyl) -1, 3-benzothiazol-2 (3H) -one trifluoroacetate

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 100mg) and [3- (methyl-phenethyl-amino) -propylsulfanyl ] -acetaldehyde (example 12d), 107 mg). The crude product was purified by reverse phase HPLC eluting with a gradient of 5% to 75% acetonitrile in 0.2% trifluoroacetic acid in water to give the title compound (32 mg).

m/e 462(M+H⁺，100％)。

¹H NMR(400MHz，D₆-DMSO)δ11.64(s，1H)，10.22(s，1H)，9.74(s，1H)，8.83(s，1H)，8.64(s，1H)，7.33-7.22(m，5H)，6.88(d，1H)，6.74(d，1H)，6.46(s，1H)，4.87-4.84(m，1H)，3.40-2.90(m，11H)，2.82(s，3H)，2.80-2.73(m，2H)，2.57(t，2H)，1.91-1.87(m，2H)。

Example 13

[2- (4-ethylphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) Allyl [2- (4-ethylphenyl) ethyl ] carbamic acid tert-butyl ester

60% sodium hydride (0.84g) was added to a solution of tert-butyl [2- (4-ethylphenyl) ethyl ] carbamate (4.77g) in dry THF (40ml) under a nitrogen atmosphere, and the mixture was heated at 50 ℃ for 45 minutes. The solution was cooled to room temperature, allyl bromide (1.82ml) was added, and the mixture was stirred for 3 hours. The reaction mixture was quenched with water, extracted into ethyl acetate, dried over magnesium sulfate, filtered, and then concentrated. The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (3.30 g).

¹H NMR δ(CDCl₃)7.15-7.06(m，4H)，5.85-5.68(m，1H)，5.12(d，2H)，3.87-3.70(m，2H)，3.42-3.31(m，2H)，2.84-2.73(m，2H)，2.62(q，2H)，1.45(s，9H)，1.22(t，3H)。

b) [2- (4-ethylphenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl allyl [2- (4-ethylphenyl) ethyl ] carbamate (example 13a), 3.3g) by the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (3.91 g).

¹H NMR δ(CDCl₃)7.16-7.05(m，4H)，3.71(q，2H)，3.41-3.32(m，2H)，3.31-3.16(m，2H)，2.83-2.74(m，2H)，2.71(t，2H)，2.62(q，2H)，2.50(t，2H)，1.83-1.73(m，2H)，1.44(s，9H)，1.22(t，3H)。

c) [2- (4-ethylphenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 1b) from tert-butyl [2- (4-ethylphenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 13b), 200 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (106 mg).

m/e 266((M-BOC)+H+，100％)。

d) [2- (4-ethylphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 76mg) and tert-butyl [2- (4-ethylphenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 13c), 106 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (95 mg).

m/e 576(M+H+，100％)。

Example 14

7- [ (1R) -2- ({2- [ (3- { [2- (4-ethylphenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the method for example 11 from tert-butyl [2- (4-ethylphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 13d), 95 mg). The residue was purified by reverse phase HPLC eluting with a gradient of 5% to 75% acetonitrile in trifluoroacetic acid in water to give the title compound (28 mg).

m/e 476(M+H+，100％)。

¹H NMR. delta. (DMSO)11.68(s, 1H), 10.24(s, 1H), 8.88-8.76(m, 1H), 8.73-8.55(m, 3H), 7.17(4H, s), 6.92(d, 1H), 6.77(d, 1H), 6.48(s, 1H), 4.93-4.85(m, 1H), 3.21-2.96(m, 8H), 2.90-2.71(m, 4H), 2.66-2.53(m, 4H), 1.86 (quintuple, 2H), 1.16(t, 3H).

Example 15

[2- (4-ethoxyphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) Allyl [2- (4-ethoxyphenyl) ethyl ] carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl [2- (4-ethoxyphenyl) ethyl ] carbamate (5.0g) by the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (3.01 g).

¹H NMRδ(CDCl₃)7.12-7.02(m，2H)，6.81(d，2Hd)，5.81-5.67(m，1H)，5.14-5.04(m，2H)，4.00(q，2H)，3.81-3.64(m，2H)，3.39-3.29(m，2H)，2.79-2.70(m，2H)，1.45(s，9H)，1.40(t，3H)。

b) [2- (4-ethoxyphenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl allyl [2- (4-ethoxyphenyl) ethyl ] carbamate (example 15a), 3.3g) by the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (3.87 g).

¹H NMRδ(CDCl₃)7.13-7.03(m，2H)，6.84-6.79(m，2H)，4.01(q，2H)，3.76-3.66(m，2H)，3.38-3.29(m，2H)，3.28-3.13(m，2H)，2.79-2.69(m，4H)，2.52-2.45(m，2H)，1.81-1.72(m，2H)，1.45(s，9H)，1.40(t，3H)。

c) [2- (4-ethoxyphenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 1b) from tert-butyl [2- (4-ethoxyphenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 15b), 600 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (170 mg).

m/e 282((M-BOC)+H+，100％)。

d) [2- (4-ethoxyphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 117mg) and tert-butyl [2- (4-ethylphenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 15c), 170 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (120 mg).

m/e 592(M+H+，100％)。

Example 16

7- [ (1R) -2- ({2- [ (3- { [2- (4-ethoxyphenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the method for example 11 from tert-butyl [2- (4-ethoxyphenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 15d), 120 mg). The residue was purified by reverse phase HPLC eluting with a gradient of 5% to 75% acetonitrile in trifluoroacetic acid in water to give the title compound (49 mg).

m/e 492(M+H+，100％)。

¹H NMR. delta. (DMSO)11.67(s, 1H), 10.25(s, 1H), 8.89-8.77(m, 1H), 8.72-8.55(m, 3H), 7.16(d, 2H), 6.94-6.86(m, 3H), 6.77(d, 1H), 6.49(s, 1H), 4.92-4.86(m, 1H), 3.99(q, 2H), 3.20-2.98(m, 8H), 2.86-2.73(m, 4H), 2.62(t, 2H), 1.86 (quintuple, 2H), 1.31(t, 3H).

Example 17

{3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

a) Allyl {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

The sub-title compound was prepared from tert-butyl {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (3.11g) according to the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (1.39 g).

¹H NMRδ(CDCl₃)7.50-7.31(m，4H)，5.74(s，1H)，5.12(s，2H)，3.88-3.65(m，2H)，3.46-3.35(m，2H)，2.88(s，2H)，1.46(9H，t)。

b) {3- [ (2-hydroxyethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 10a) from tert-butyl allyl {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (example 17a), 1.39 g). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (1.23 g).

¹H NMRδ(CDCl₃)7.55-7.31(m, 4H), 3.71 (quintuple, 2H), 3.45-3.37(m, 2H), 3.32-3.12(m, 2H), 2.94-2.83(m, 2H), 2.72(t, 2H), 2.54-2.45(m, 2H), 1.85-1.71(m, 2H), 1.43(s, 9H).

c) {3- [ (2-oxoethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

Des-Martin iodophor (624mg) was added to a solution of tert-butyl {3- [ (2-hydroxyethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (example 17b), 600mg) in dichloromethane (12ml) and the mixture was stirred under a nitrogen atmosphere for 1 h. The mixture was washed with dilute sodium hydroxide solution, washed with water, dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (390 mg).

m/e 404(M-H-，100％)。

d) {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 250mg) and tert-butyl {3- [ (2-oxoethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (example 17c), 390 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (223 mg).

m/e 616(M+H+，100％)。

Example 18

4-hydroxy-7- { (1R) -1-hydroxy-2- [ (2- { [3- ({2- [3- (trifluoromethyl) phenyl ] ethyl } amino) propyl ] thio } ethyl) amino ] ethyl } -1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the procedure for example 11 from tert-butyl {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } {2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (example 17d), 223 mg). The residue was purified by reverse phase HPLC eluting with a gradient of 23% to 29% acetonitrile in trifluoroacetic acid in water to give the title compound (63 mg).

m/e 516(M+H+，100％)。

¹H NMR. delta. (DMSO)11.67(s, 1H), 10.25(s, 1H), 8.85(s, 1H), 8.70(s, 3H), 7.68-7.58(m, 4H), 6.92(d, 1H), 6.77(d, 1H), 6.49(s, 1H), 4.93-4.85(m, 1H), 3.30-2.97(m, 10H), 2.84-2.72(m, 2H), 2.63(t, 2H), 1.87 (quintuple, 2H).

Example 19

[2- (2-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) Allyl [2- (2-chlorophenyl) ethyl ] carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl [2- (2-chlorophenyl) ethyl ] carbamate (4.61g) by the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (2.58 g).

¹H NMRδ(CDCl₃)7.38-7.30(m，1H)，7.23-7.13(m，3H)，5.86-5.67(m，1H)，5.19-5.05(m，2H)，3.88-3.66(m，2H)，3.46-3.38(m，2H)，3.04-2.90(m，2H)，1.43(s，9H)。

b) [2- (2-chlorophenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl allyl [2- (2-chlorophenyl) ethyl ] carbamate (example 19a), 2.00g) by the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (2.22 g).

¹H NMRδ(CDCl₃)7.37-7.31(m，1H)，7.22-7.12(m，3H)，3.71(q，2H)，3.41(t，2H)，3.33-3.13(m，2H)，3.03-2.91(m，2H)，2.72(t，2H)，2.55-2.36(m，2H)，1.86-1.71(m，2H)，1.42(s，9H)。

c) [2- (2-chlorophenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl [2- (2-chlorophenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 19b), 600mg) according to the method of example 17 c). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (240 mg).

m/e 272((M-BOC)+H+，100％)。

d) [2- (2-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 170mg) and tert-butyl [2- (2-chlorophenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 19c), 240 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (157 mg).

m/e 582(M+H+，100％)。

Example 20

7- [ (1R) -2- ({2- [ (3- { [2- (2-chlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the procedure for example 11 from tert-butyl [2- (2-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 19d), 157 mg). The residue was purified by reverse phase HPLC eluting with a gradient of 23% to 25% acetonitrile in trifluoroacetic acid in water to give the title compound (150 mg).

m/e 482(M+H+，100％)。

¹H NMR. delta. (DMSO)11.67(s, 1H), 10.27(s, 1H), 8.90-8.63(m, 4H), 7.49-7.46(m, 1H), 7.41-7.30(m, 3H), 6.92(d, 1H), 6.77(d, 1H), 6.49(s, 1H), 4.92-4.87(m, 1H), 3.20-3.02(m, 10H), 2.86-2.72(m, 2H), 2.63(t, 2H), 1.88 (quintuple, 3H).

Example 21

((1S) -tert-butyl 2- {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamate

a) ((1S) -2- {3- [ (2-hydroxyethyl) thio ] propoxy } -1-phenylethyl) carbamic acid tert-butyl ester

The sub-title compound was prepared from tert-butyl [ (1S) -2- (allyloxy) -1-phenylethyl ] carbamate (1.00g) according to the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (1.28 g).

¹H NMRδ(CDCl₃)7.36-7.22(5H, m), 5.32(d, 1H), 4.81(s, 1H), 3.74-3.38(m, 6H), 2.69(t, 2H), 2.56(t, 2H), 1.82 (quintuple, 2H), 1.41(s, 9H).

b) ((1S) -2- {3- [ (2-oxoethyl) thio ] propoxy } -1-phenylethyl) carbamic acid tert-butyl ester

The sub-title compound was prepared from tert-butyl ((1S) -2- {3- [ (2-hydroxyethyl) thio ] propoxy } -1-phenylethyl) carbamate (example 21b), 540mg) according to the method of example 17 c). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (330 mg).

m/e 254((M-BOC)+H+，100％)。

c) ((1S) -tert-butyl 2- {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamate

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 245mg) and tert-butyl ((1S) -2- {3- [ (2-oxoethyl) thio ] propoxy } -1-phenylethyl) carbamate (example 21b), 330 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (207 mg).

m/e 564(M+H+，100％)。

Example 22

7- ((1R) -2- { [2- ({3- [ (2S) -2-amino-2-phenylethoxy ] propyl } thio) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the method for example 11 from tert-butyl ((1S) -2- {3- [ (2- { { (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamate (example 21c), 207 mg). The residue was purified by reverse phase HPLC eluting with a gradient of 9% to 13% acetonitrile in trifluoroacetic acid in water to give the title compound (90 mg).

m/e 464(M+H+，100％)。

¹H NMR. delta. (DMSO)11.69(s, 1H), 10.28(s, 1H), 8.87(s, 1H), 8.68(s, 1H), 8.45(s, 3H), 7.52-7.38(m, 5H), 6.94(d, 1H), 6.79(d, 1H), 6.50(s, 1H), 4.94-4.87(m, 1H), 4.55-4.45(m, 1H), 3.71-3.65(m, 2H), 3.62-3.48(m, 2H), 3.20-3.03(m, 4H), 2.86-2.68(m, 2H), 2.59(t, 2H), 1.80 (quintuple, 2H).

Example 23

((1R) -2- {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamic acid tert-butyl ester

a) ((1R) -2- {3- [ (2-hydroxyethyl) thio ] propoxy } -1-phenylethyl) carbamic acid tert-butyl ester

The sub-title compound was prepared from tert-butyl [ (1R) -2- (allyloxy) -1-phenylethyl ] carbamate (1.00g) according to the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (1.23 g).

¹H NMRδ(CDCl₃)7.36-7.22(m, 5H), 5.32(d, 1H), 4.81(s, 1H), 3.74-3.38(m, 6H), 2.69(t, 2H), 2.56(t, 2H), 1.82 (quintuple, 2H), 1.41(s, 9H).

b) ((1R) -2- {3- [ (2-oxoethyl) thio ] propoxy } -1-phenylethyl) carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 17c) from tert-butyl ((1R) -2- {3- [ (2-hydroxyethyl) thio ] propoxy } -1-phenylethyl) carbamate (example 23b), 500 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (143 mg).

m/e 254((M-BOC)+H+，100％)。

c) ((1R) -2- {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 106mg) and tert-butyl ((1R) -2- {3- [ (2-oxoethyl) thio ] propoxy } -1-phenylethyl) carbamate (example 23b), 143 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (100 mg).

m/e 564(M+H+，100％)。

Example 24

7- ((1R) -2- { [2- ({3- [ (2R) -2-amino-2-phenylethoxy ] propyl } thio) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the method for example 11 from tert-butyl ((1R) -2- {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propoxy } -1-phenylethyl) carbamate (example 23c), 100 mg). The residue was purified by reverse phase HPLC eluting with a gradient of 9% to 13% acetonitrile in trifluoroacetic acid in water to give the title compound (43 mg).

m/e 464(M+H+，100％)。

¹H NMR. delta. (DMSO)11.67(s, 1H), 10.26(s, 1H), 8.85(s, 1H), 8.66(s, 1H), 8.43(s, 3H), 7.50-7.37(m, 5H), 6.92(d, 1H), 6.77(d, 1H), 6.48(s, 1H), 4.92-4.85(m, 1H), 4.48(s, 1H), 3.67(d, 2H), 3.61-3.46(m, 2H), 3.19-3.01(m, 4H), 2.83-2.68(m, 2H), 2.57(t, 2H), 1.78 (quintuple, 2H).

Example 25

The title compound was prepared according to the method for example 11 from tert-butyl [2- (2-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 19d), 5.93 g). The residue was purified by reverse phase HPLC eluting with a gradient of 5% to 50% acetonitrile in ammonium acetate in water. The diacetate obtained is dissolved in water, basified with aqueous ammonia, the supernatant is decanted and the residue is dried under high vacuum. The resulting material was dissolved in ethanol, acidified with 48% HBr, and the resulting solid was collected by filtration to give the title compound (4.53 g).

m/e 482(M+H+，100％)。

¹H NMR. delta. (DMSO)11.67(s, 1H), 10.15(s, 1H), 8.70(s, 4H), 7.50-7.30(m, 4H), 6.94(d, 1H), 6.78(d, 1H), 6.45(s, 1H), 4.96-4.90(m, 1H), 3.22-3.02(m, 10H), 2.86-2.76(m, 2H), 2.66(t, 2H), 1.91 (quintuple, 2H).

Example 26

{2- [ (3- { { (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamic acid tert-butyl ester

a)3- [ (2-oxo-2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propanoic acid methyl ester

Oxalyl chloride (1.14ml) and dimethylformamide (50. mu.l) were added to a solution of [ (3-methoxy-3-oxopropyl) thio ] acetic acid (1.17g) in dichloromethane (25ml), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo then dissolved in dichloromethane (15ml) and added to a solution of [ (2R) -2-phenylpropyl ] amine (0.93ml) and diisopropylethylamine (1.08ml) in dichloromethane (20ml) and the mixture was stirred at room temperature for 18 h. The mixture was washed successively with dilute hydrochloric acid, sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and then concentrated to give the sub-title compound (1.93 g).

m/e 296(M+H+，100％)。

b)3- [ (2-oxo-2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propanoic acid

1M lithium hydroxide solution (14.4ml) was added to a solution of methyl 3- [ (2-oxo-2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propanoate (example 26a), 1.93g) in tetrahydrofuran (40ml) and the reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the resulting residue was diluted with water, acidified with dilute hydrochloric acid and extracted into ethyl acetate. The obtained ethyl acetate extract was washed with water, dried over magnesium sulfate, filtered, and then concentrated to obtain the sub-title compound (1.83 g).

¹H NMRδ(CDCl₃)7.36-7.29(m，2H)，7.27-7.20(m，3H)，6.85-6.78(m，1H)，3.62(d，1Ht)，3.35(ddd，1H)，3.19(s，2H)，3.05-2.95(m，1H)，2.60-2.49(m，4H)，1.29(d，3H)。

c)3- [ (2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propan-1-ol

1M borane tetrahydrofuran complex (26.2ml) was added to a solution of 3- [ (2-oxo-2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propanoic acid (example 26b), 1.83g) in tetrahydrofuran (20ml) and the reaction mixture was heated at reflux for 1.5 h. The mixture was cooled, carefully quenched with methanol, and then concentrated in vacuo. The resulting residue was dissolved in methanol, acidified with concentrated hydrochloric acid (4ml) and then heated at reflux for 15 minutes. It was concentrated in vacuo, then diluted with ethyl acetate and extracted into water. The aqueous extract was basified with sodium hydroxide solution and the product was extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated to give the sub-title compound (1.27 g).

¹H NMRδ(CDCl₃)7.34-7.29(m, 2H), 7.25-7.19(m, 3H), 3.71(t, 2H), 2.94 (hexameric peak, 1H), 2.85-2.72(m, 4H), 2.65-2.55(m, 4H),1.78 (quintuple, 2H), 1.29-1.25(m, 3H).

d) {2- [ (3-hydroxypropyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamic acid tert-butyl ester

Di-tert-butyl dicarbonate (1.09g) was added to a solution of 3- [ (2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propan-1-ol (example 26c), 1.27g) and triethylamine (0.7ml) in tetrahydrofuran (30ml) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo to give the sub-title compound (1.77 g).

m/e 254((M-BOC)+H+，100％)。

¹H NMRδ(CDCl₃)7.33-7.27(m，2H)，7.24-7.15(m，3H)，3.78-3.69(m，2H)，3.60-2.91(m，5H)，2.68-2.31(m，4H)，1.88-1.77(m，2H)，1.43(s，9H)，1.25(d，3H)。

e) {2- [ (3-oxopropyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl {2- [ (3-hydroxypropyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamate (example 26d), 400mg) by the method of example 9 b). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (280 mg).

¹H NMRδ(CDCl₃)9.75(t，1H)，7.34-7.26(m，2H)，7.25-7.15(m，3H)，3.65-2.88(5H，m)，2.82-2.28(m，6H)，1.43(s，9H)，1.25(d，3H)。

f) {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 150mg) and tert-butyl {2- [ (3-oxopropyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamate (example 26e), 201 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (180 mg).

m/e 562(M+H+，100％)。

Example 27

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [ (2- { [ (2R) -2-phenylpropyl ] amino } ethyl) thio ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one

A solution of tert-butyl {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2R) -2-phenylpropyl ] carbamate (example 26f), 180mg) in trifluoroacetic acid (3ml) and dichloromethane (3ml) was stirred at room temperature for 30 minutes. The solution was diluted with toluene (10ml) and then concentrated in vacuo. The residue was purified by reverse phase HPLC eluting with a gradient of 10% to 30% acetonitrile in trifluoroacetic acid in water to give the title compound (44 mg).

m/e 462(M+H+，100％)。

¹H NMR. delta. (DMSO)11.67(s, 1H), 10.25(s, 1H), 8.81-8.60(m, 3H), 8.42(s, 1H), 7.39-7.33(m, 2H), 7.32-7.25(m, 3H), 6.93(d, 1H), 6.77(d, 1H), 6.48(s, 1H), 4.87(dd, 1H), 3.21-2.97(m, 9H), 2.74(t, 2H), 2.59(t, 2H), 1.88 (hexamer, 2H), 1.27(d, 3H).

Example 28

{2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamic acid tert-butyl ester

a)3- [ (2-oxo-2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propanoic acid methyl ester

The sub-title compound was prepared according to the method of example 26a) from [ (3-methoxy-3-oxopropyl) thio ] acetic acid (1.17g) and [ (2S) -2-phenylpropyl ] amine (0.93ml) to give sub-title compound (1.93 g).

m/e 296(M+H+，100％)。

b)3- [ (2-oxo-2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propanoic acid

Prepared according to the method of example 26b) from methyl 3- [ (2-oxo-2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propanoate (example 28a), 1.93g) to give the sub-title compound (1.83 g).

m/e 282(M+H+，100％)。

¹H NMRδ(CDCl₃)7.36-7.30(m，2H)，7.27-7.20(m，3H)，6.82-6.76(m，1H)，3.62(dt，1H)，3.40-3.30(m，1H)，3.19(s，2H)，3.05-2.95(m，1H)，2.60-2.50(m，4H)，1.29(d，3H)。

c)3- [ (2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propan-1-ol

Prepared according to the method of example 26c) from 3- [ (2-oxo-2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propanoic acid (example 28b), 1.83g) to give the sub-title compound (1.19 g).

¹H NMRδ(CDCl₃)7.35-7.28(m, 2H), 7.24-7.19(m, 3H), 3.71(t, 2H), 2.94 (hexameric peak, 1H), 2.85-2.72(m, 4H), 2.65-2.55(m, 4H), 1.82-1.74(m, 2H), 1.27(d, 3H).

d) {2- [ (3-hydroxypropyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 26d) from 3- [ (2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propan-1-ol (example 28c), 1.19g) to give the sub-title compound (1.66 g).

m/e 254((M-BOC)+H+，100％)。

¹H NMRδ(CDCl₃)7.34-7.27(m，2H)，7.24-7.14(m，3H)，3.77-3.69(m，2H)，3.61-2.91(5H，m)，2.68-2.33(m，4H)，1.88-1.77(m，2H)，1.43(s，9H)，1.25(d，3H)。

e) {2- [ (3-oxopropyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl {2- [ (3-hydroxypropyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamate (example 28d), 400mg) by the method of example 9 b). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (280 mg).

¹H NMRδ(CDCl₃)9.75(t，1H)，7.33-7.27(m，2H)，7.24-7.14(m，3H)，3.62-2.90(m，5H)，2.81-2.29(m，6H)，1.43(s，9H)，1.25(d，3H)。

f) {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 150mg) and tert-butyl {2- [ (3-oxopropyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamate (example 28e), 201 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (180 mg).

m/e 562(M+H+，100％)。

Example 29

4-hydroxy-7- [ (1R) -1-hydroxy-2- ({3- [ (2- { [ (2S) -2-phenylpropyl ] amino } ethyl) thio ] propyl } amino) ethyl ] -1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the procedure for example 27 from tert-butyl {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } [ (2S) -2-phenylpropyl ] carbamate (example 28f), 180 mg). The residue was purified by reverse phase HPLC eluting with a gradient of 10% to 30% acetonitrile in trifluoroacetic acid in water to give the title compound (59 mg).

m/e 462(M+H+，100％)。

¹H NMR. delta. (DMSO)11.67(s, 1H), 10.24(s, 1H), 8.78-8.56(m, 3H), 8.39(s, 1H), 7.40-7.33(m, 2H), 7.33-7.25(m, 3H), 6.93(d, 1H), 6.77(d, 1H), 6.47(s, 1H), 4.87(d, 1H), 3.22-2.97(m, 9H), 2.73(t, 2H), 2.59(t, 2H), 1.87 (hexamer, 2H), 1.27(d, 3H).

Example 30

[2- (2-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester

a)3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid methyl ester

The subtitle compound was prepared according to the method of example 26a) from [ (3-methoxy-3-oxopropyl) thio ] acetic acid (1.17g) and [2- (2-chlorophenyl) ethyl ] amine (0.91ml) to give the subtitle compound (2.06 g).

m/e 316(M+H+，100％)。

b)3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid

The sub-title compound was prepared according to the method of example 26b) from methyl 3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoate (example 30a), 2.06g) to give the sub-title compound (1.97 g).

m/e 302(M+H+，100％)。

¹H NMRδ(CDCl₃)7.38-7.34(m，1H)，7.26-7.16(m，3H)，7.03-6.96(m，1H)，3.59(q，2H)，3.25(s，2H)，3.01(t，2H)，2.74(t，2H)，2.63(t，2H)。

c)3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } ethyl) thio ] propan-1-ol

The sub-title compound was prepared according to the method of example 26c) from 3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid (example 30b), 1.97g) to give the sub-title compound (1.00 g).

¹H NMRδ(CDCl₃)7.37-7.32(m，1H)，7.26-7.13(m，3H)，3.75(t，2H)，2.98-2.84(m，6H)，2.72-2.62(m，4H)，1.87-1.79(m，2H)。

d) [2- (2-chlorophenyl) ethyl ] {2- [ (3-hydroxypropyl) thio ] ethyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 26d) from 3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } ethyl) thio ] propan-1-ol (example 30c), 1.00g) to give the sub-title compound (1.37 g).

m/e 274((M-BOC)+H+，100％)。

¹H NMRδ(CDCl₃)7.38-7.31(m，1H)，7.21-7.13(m，3H)，3.79-3.70(m，2H)，3.49-3.20(m，4H)，3.03-2.90(m，2H)，2.73-2.51(m，4H)，1.89-1.80(m，2H)，1.50-1.37(m，9H)。

e) [2- (2-chlorophenyl) ethyl ] {2- [ (3-oxopropyl) thio ] ethyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl [2- (2-chlorophenyl) ethyl ] {2- [ (3-hydroxypropyl) thio ] ethyl } carbamate (example 30d), 420mg) according to the method of example 9 b). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (282 mg).

¹H NMRδ(CDCl₃)9.77(d，1H)，7.35(d，1H)，7.22-7.12(m，3H)，3.46(t，2H)，3.39-3.19(m，2H)，3.04-2.90(m，2H)，2.87-2.53(m，6H)，1.50-1.37(m，9H)。

f) [2- (2-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 150mg) and tert-butyl [2- (2-chlorophenyl) ethyl ] {2- [ (3-oxopropyl) thio ] ethyl } carbamate (example 30e), 212 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (176 mg).

m/e 582(M+H+，100％)。

Example 31

7- [ (1R) -2- ({3- [ (2- { [2- (2-chlorophenyl) ethyl ] amino } ethyl) thio ] propyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the procedure for example 27 from tert-butyl [2- (2-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamate (example 30f), 176 mg). The residue was dissolved in ethanol, acidified with 5% hydrobromic acid and concentrated in vacuo, but not dried. The resulting residue was triturated with acetonitrile and the solid collected by filtration to give the title compound (164 mg).

m/e 482(M+H+，100％)。

¹H NMRδ(DMSO)11.67(s，1H)，10.15(s，1H)，8.81-8.60(m，4H)，7.51-7.29(m，4H)，6.95(d，1H)，6.78(d，1H)，6.44(d，1H)，4.96-4.88(m，1H)，3.26-2.99(m，10H)，2.80(t，2H)，2.65(t，2H)，1.99-1.85(m，2H)。

Example 32

[2- (3-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester

a)3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid methyl ester

The subtitle compound was prepared according to the method of example 26a) from [ (3-methoxy-3-oxopropyl) thio ] acetic acid (1.17g) and [2- (3-chlorophenyl) ethyl ] amine (0.91ml) to give the subtitle compound (2.06 g).

m/e 316(M+H+，100％)。

b)3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid

The sub-title compound was prepared according to the method of example 26b) from methyl 3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoate (example 32a), 2.06g) to give the sub-title compound (1.97 g).

m/e 302(M+H+，100％)。

¹H NMRδ(CDCl₃)7.26-7.18(m，3H)，7.12-7.07(m，1H)，7.04-6.97(m，1H)，3.56(dd，2H)，3.25(s，2H)，2.84(t，2H)，2.75-2.69(m，2H)，2.66-2.60(m，2H)。

c)3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } ethyl) thio ] propan-1-ol

The sub-title compound was prepared according to the method of example 26c) from 3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid (example 32b), 1.97g) to give the sub-title compound (1.33 g).

¹H NMRδ(CDCl₃)7.25-7.17(m，3H)，7.12-7.07(m，1H)，3.75(t，2H)，2.92-2.76(m，6H)，2.70-2.61(m，4H)，1.86-1.79(m，2H)。

d) [ tert-butyl [2- (3-chlorophenyl) ethyl ] {2- [ (3-hydroxypropyl) thio ] ethyl } carbamate

The sub-title compound was prepared according to the method of example 26d) from 3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } ethyl) thio ] propan-1-ol (example 32c), 1.33g) to give the sub-title compound (1.82 g).

m/e 274((M-BOC)+H+，100％)。

¹H NMRδ(CDCl₃)7.25-7.14(m，3H)，7.12-7.00(m，1H)，3.78-3.71(m，2H)，3.47-3.19(m，4H)，2.86-2.75(m，2H)，2.73-2.50(m，4H)，1.88-1.79(m，2H)，1.49-1.40(m，9H)。

e) [2- (3-chlorophenyl) ethyl ] {2- [ (3-oxopropyl) thio ] ethyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl [2- (3-chlorophenyl) ethyl ] {2- [ (3-hydroxypropyl) thio ] ethyl } carbamate (example 32d), 420mg) according to the method of example 9 b). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (292 mg).

¹H NMRδ(CDCl₃)9.78(d，1H)，7.25-7.15(m，3H)，7.12-7.00(m，1H)，3.41(d，2H)，3.37-3.19(m，2H)，2.87-2.71(m，6H)，2.68-2.52(m，2H)，1.50-1.39m，9H)。

f) [2- (3-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 150mg) and tert-butyl [2- (3-chlorophenyl) ethyl ] {2- [ (3-oxopropyl) thio ] ethyl } carbamate (example 32e), 212 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (172 mg).

m/e 582(M+H+，100％)。

Example 33

7- [ (1R) -2- ({3- [ (2- { [2- (3-chlorophenyl) ethyl ] amino } ethyl) thio ] propyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the procedure for example 27 from tert-butyl [2- (3-chlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamate (example 32f), 172 mg). The residue was dissolved in ethanol, acidified with 5% hydrobromic acid and concentrated in vacuo, but not dried. The resulting residue was triturated with acetonitrile and the solid collected by filtration to give the title compound (138 mg).

m/e 482(M+H+，100％)。

¹H NMRδ(DMSO)11.67(s，1H)，10.15(s，1H)，8.74-8.58(m，4H)，7.42-7.31(m，3H)，7.28-7.23(m，1H)，6.95(d，1H)，6.78(d，1H)，6.44(s，1H)，4.96-4.88(m，1H)，3.29-2.93(m，10H)，2.80(t，2H)，2.65(t，2H)，1.98-1.85(m，2H)。

Example 34

[2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester

a)3- [ (2- { [2- (2, 3-dichlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid methyl ester

Prepared according to the method of example 26a) from [ (3-methoxy-3-oxopropyl) thio ] acetic acid (1.17g) and [2- (2, 3-dichlorophenyl) ethyl ] amine (1.25g) to give the sub-title compound (2.29 g).

m/e 350(M+H+，100％)。

b)3- [ (2- { [2- (2, 3-dichlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid

Prepared according to the method of example 26b) from methyl 3- [ (2- { [2- (2, 3-dichlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoate (example 34a), 2.29g) to give the sub-title compound (2.20 g).

m/e 336(M+H+，100％)。

¹H NMRδ(CDCl₃)7.36(dd，1H)，7.18-7.14(m，2H)，7.02-6.96(m，1H)，3.59(q，2H)，3.25(s，2H)，3.05(t，2H)，2.78-2.72(m，2H)，2.67-2.62(m，2H)。

c)3- [ (2- { [2- (2, 3-dichlorophenyl) ethyl ] amino } ethyl) thio ] propan-1-ol

Prepared according to the method of example 26c) from 3- [ (2- { [2- (2, 3-dichlorophenyl) ethyl ] amino } -2-oxoethyl) thio ] propanoic acid (example 34b), 2.20g) to give the sub-title compound (1.16 g).

¹H NMRδ(CDCl₃)7.34(dd，1H)，7.19-7.10(m，2H)，3.76(t，2H)，3.02-2.95(m，2H)，2.93-2.84(m，4H)，2.72-2.62(m，4H)，1.88-1.80(m，2H)。

d) [2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3-hydroxypropyl) thio ] ethyl } carbamic acid tert-butyl ester

Prepared from 3- [ (2- { [2- (2, 3-dichlorophenyl) ethyl ] amino } ethyl) thio ] propan-1-ol (example 34c), 1.16g) according to the method of example 26d) to give the sub-title compound (1.53 g).

m/e 308((M-BOC)+H+，100％)。

¹H NMRδ(CDCl₃)7.38-7.31(m，1H)，7.18-7.04(m，2H)，3.78-3.71(m，2H)，3.46(t，2H)，3.41-3.21(m，2H)，3.07-2.95(m，2H)，2.73-2.51(m，4H)，1.89-1.81(m，2H)，1.49-1.35(m，9H)。

e) [2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3-oxopropyl) thio ] ethyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 9b) from tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3-hydroxypropyl) thio ] ethyl } carbamate (example 34d), 460 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (340 mg).

¹H NMRδ(CDCl₃)9.78(t，1H)，7.38-7.31(m，1H)，7.19-7.03(m，2H)，3.47(t，2H)，3.39-3.21(m，2H)，3.08-2.94(m，2H)，2.88-2.53(6H，m)，1.51-1.33(9H，m)。

f) [2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 150mg) and tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3-oxopropyl) thio ] ethyl } carbamate (example 34e), 232 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane to give the title compound (180 mg).

m/e 616(M+H+，100％)。

Example 35

7- [ (1R) -2- ({2- [ (3- { [2- (2, 3-dichlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

The title compound was prepared according to the procedure for example 27 from tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {2- [ (3- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } propyl) thio ] ethyl } carbamate (example 34f), 180 mg). The residue was dissolved in ethanol, acidified with 5% hydrobromic acid and concentrated in vacuo, but not dried. The resulting residue was triturated with acetonitrile and the solid collected by filtration to give the title compound (158 mg).

m/e 516(M+H+，100％)。

¹H NMRδ(DMSO)11.67(s，1H)，10.15(s，1H)，8.84-8.59(m，4H)，7.63-7.55(m，1H)，7.43-7.34(m，2H)，6.95(d，1H)，6.78(d，1H)，6.44(s，1H)，4.97-4.88(m，1H)，3.28-2.97(m，10H)，2.80(t，2H)，2.65(t，2H)，1.99-1.84(m，2H)。

Example 36

7- ((1R) -2- { [2- (3- { [2- (3-chlorophenyl) ethyl ] amino } propoxy) ethyl ] amino } -1-hydroxyethyl) -4-hydroxy-1, 3-benzothiazol-2 (3H) -one

a) (3-Hydroxypropoxy) acetic acid ethyl ester

Ethyl diazoacetate (5.5g, 5.07ml) was added dropwise to a vigorously stirred solution of rhodium acetate dimer (110mg) in 1, 3-propanediol (55g, 52.2ml) over 1h, stirring for a further 20 h. The mixture was poured into water (1L), extracted with ethyl acetate (× 3), washed with water (× 2) and brine, dried (Na)₂SO₄) Filtered and then evaporated in vacuo to give the sub-title compound (3.9g) as a light brown oil.

m/e 163(M+H⁺，100％)。

¹H NMR(400MHz，CDCl₃) δ 4.23(q, 2H), 4.08(s, 2H), 3.81(q, 2H), 3.70(t, 2H), 2.78(t, 1H), 1.85 (quintuple, 2H), 1.30(t, 3H).

b) (3- { [ (4-methylphenyl) sulfonyl ] oxy } propoxy) acetic acid ethyl ester

Ethyl (3-hydroxypropoxy) acetate (example 36a) (3.8g) was dissolved in DCM (50ml), triethylamine (2.85g, 3.93ml) was added, followed by 4-methylbenzenesulfonyl chloride (4.9g), and the reaction mixture was stirred for 20 h. Quench with water, extract with DCM, wash with water and brine, dry (Na)₂SO₄) Filtered and then evaporated in vacuo. The residue was purified by flash column chromatography eluting with 25% EtOAc/isohexane to give the sub-title compound (5.7g) as a colorless oil.

m/e 317(M+H⁺，100％)。

¹H NMR(400MHz，CDCl₃)δ7.80(d，2H)，7.35(d，2H)，4.20(q，2H)，4.17(t，2H)，3.97(s，2H)，3.57(t，2H)，2.45(s，3H)，1.96(m 2H)，1.28(t，3H)。

c) (3- { (tert-Butoxycarbonyl) [2- (3-chlorophenyl) ethyl ] amino } propoxy) acetic acid ethyl ester

Reacting [2- (3-chlorophenyl) ethyl group]Amine (650mg, 581. mu.l) was dissolved in DMF (10ml), and triethylamine (850mg, 1.171ml) was added followed by (3- { [ (4-methylphenyl) sulfonyl]Oxy } propoxy) acetic acid ethyl ester (example 36b) (880mg) the reaction mixture was stirred at 50 ℃ for 20 h. Cooled to 0 ℃ and di-tert-butyl dicarbonate (1.0g) was added and stirred for 1 h. Quench with water, extract with EtOAc, wash with water and brine, and dry (Na)₂SO₄) Filtered and then evaporated in vacuo. The residue was purified by flash column chromatography eluting with 20% EtOAc/isohexane to give the sub-title compound (700mg) as a colourless gum.

m/e 400(M+H⁺，100％)。

¹H NMR(400MHz，CDCl₃)δ7.19(m，3H)，7.07(m，1H)，4.21(q，2H)，4.05(s，2H)，3.40(t，2H)，3.53(m，2H)，3.25(m，2H)，2.80(m，2H)，1.83(m，2H)，1.43(s，9H)，1.28(t，3H)。

d) [2- (3-chlorophenyl) ethyl ] [3- (2-hydroxyethoxy) propyl ] carbamic acid tert-butyl ester

Reacting (3- { (tert-butoxycarbonyl) [2- (3-chlorophenyl) ethyl ]]Amino } propoxy) acetic acid ethyl ester (example 36c) (650mg) was dissolved in THF (5ml) and lithium borohydride (55mg) was added and stirred for 5 h. Quench with water, extract with ethyl acetate, wash with brine, dry (Na)₂SO₄) Filtered and then evaporated in vacuo. The residue was purified by flash column chromatography eluting with 20% ethyl acetate/isohexane to give the sub-title compound (510mg) as a colorless oil.

m/e 358(M+H⁺，100％)。

¹H NMR(300MHz，CDCl₃)δ7.19(m，3H)，7.05(m，1H)，3.71(m，2H)，3.53(m，2H)，3.45(t，2H)，3.26(m，4H)，2.80(m，2H)，1.77(m，2H)，1.44(s，9H)。

e) 4-Methylbenzenesulfonic acid 2- (3- { (tert-butoxycarbonyl) [2- (3-chlorophenyl) ethyl ] amino } propoxy) ethyl ester

Reacting [2- (3-chlorophenyl) ethyl group][3- (2-Hydroxyethoxy) propyl group]Tert-butyl carbamate (example d) (500mg) was dissolved in DCM (10ml), triethylamine (400. mu.l) was added followed by 4-methylbenzenesulfonyl chloride (300mg), and the reaction mixture was stirred for 20 h. Quench with water, extract with ethyl acetate, and use NaHCO₃Washed with aqueous solution and brine, dried (Na)₂SO₄) Filtered and then evaporated in vacuo. The residue was purified by flash column chromatography eluting with 20% ethyl acetate/isohexane to give the sub-title compound (500mg) as a colorless oil.

m/e 513(M+H⁺，100％)。

¹H NMR(300MHz，CDCl₃)δ7.79(d，2H)，7.33(d，2H)，7.19(m，3H)，7.06(m，1H)，4.15(t，2H)，3.59(t，2H)，3.39(t，2H)，3.36(t，2H)，3.16(m，2H)，2.78(m，2H)，2.43(s，3H)，1.72(m，2H)，1.42(s，9H)。

f)7- [2- (2- {3- [2- (3-chlorophenyl) -ethylamino ] -propoxy } -ethylamino) -1-hydroxy-ethyl ] -4-hydroxy-3H-benzothiazol-2-one

Reacting 7- [ (1R) -2-amino-1-hydroxyethyl]-4-hydroxy-1, 3-benzothiazol-2 (3H) -one (100mg) was dissolved in DMF (2ml), and triethylamine (75.1mg, 103.4. mu.l) was added, followed by addition of 4-methylbenzenesulfonic acid 2- (3- { (tert-butoxycarbonyl) [2- (3-chlorophenyl) ethyl ] ethyl]Amino } propoxy) ethyl ester (example 36e) (190mg) and the reaction mixture was stirred at 50 ℃ for 20 h. Quench with water, extract with ethyl acetate, wash with water and brine, dry (Na)₂SO₄) Filtered and then evaporated in vacuo. The residue was dissolved in DCM (2ml), TFA (2ml) was added and stirred for 1 h. Toluene (5ml) was added, then evaporated in vacuo and the residue was purified by reverse phase HPLC (aqueous TFA/CH)₃CN as eluent). The solvent was evaporated in vacuo, the residue was redissolved in 10% aqueous acetonitrile, aqueous HBr (500 μ l) was added, and then evaporated in vacuo to give the title compound (80mg) as a white solid.

m/e 466(M+H⁺，100％)。

¹H NMR(400MHz，CDCl₃)δ7.18-7.04(m，3H)，6.98(m，1H)，6.79-6.70(m，1H)，6.60-6.50(m，1H)，4.71-4.60(m，1H)，3.53-3.24(m，4H)，2.90-2.55(m，8H)，1.65(m，2H)，1.23(m，2H)。

Example 37

[2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) Allyl [2- (2, 3-dichlorophenyl) ethyl ] carbamic acid tert-butyl ester

The sub-title compound was prepared from tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] carbamate (5.4g) according to the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (3.9 g).

¹H NMRδ(DMSO-d6)7.51(d，1H)，7.32-7.25(m，2H)，5.80-5.70(m，1H)，5.16-5.11(m，2H)，3.81-3.72(m，2H)，3.40(s，2H)，2.94(t，2H)，1.34-1.17(m，9H)。

b) [2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl allyl [2- (2, 3-dichlorophenyl) ethyl ] carbamate (example 37a), 3.9g) by the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (2.1 g).

¹H NMRδ(DMSO-d6)7.50(d，1H)，7.32-7.26(m，2H)，4.75(t，1H)3.52-3.48(m，2H)，3.42(s，2H)，3.22(s，2H)，2.94(t，2H)，2.57-2.50(m，4H)，1.67(t，2H)，1.36-1.22(m，9H)。

c) [2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 17c) from tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 37b), 820 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (540 mg).

m/e 306((M-BOC)+H+，100％)。

d) [2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 350mg) and tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 37c), 540 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane and then recrystallized from acetonitrile to give the title compound (190 mg).

m/e 616(M+H+，100％)。

Example 38

7- [ (1R) -2- ({2- [ (3- { [2- (2, 3-dichlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride

The title compound was prepared from tert-butyl [2- (2, 3-dichlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 37d), 190mg) by the following method: the tert-butyl carbamate was dissolved in dioxane (8ml) and the resulting solution was treated with 4M HCl in dioxane (3ml) and stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration to give the title compound (160 mg).

m/e 516(M+H+，100％)。

¹H NMRδ(DMSO-d6)11.69(s，1H)，10.22(s，1H)，9.22(s，2H)，8.78(s，4H)，7.57(d，1H)，7.43-7.34(m，2H)，6.92(d，1H)，6.77(d，1H)，6.45(s，1H)，4.97(d，1H)，3.18(s，6H)，3.09-3.06(m，4H)，2.87-2.85(m，2H)，2.68(t，2H)，1.98-1.94(m，2H)。

Example 39

[2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) Allyl [2- (3-chlorophenyl) ethyl ] carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl [2- (3-chlorophenyl) ethyl ] carbamate (5.4g) by the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (3.9 g).

¹H NMRδ(DMSO-d6)7.34-7.26(m，3H)，7.14(d，1H)，5.81-5.68(m，1H)，5.15-5.09(m，2H)，3.76(s，2H)，3.34(t，2H)，2.76(t，2H)，1.31(m，9H)。

b) [ tert-butyl [2- (3-chlorophenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate

The subtitle compound is prepared from tert-butyl allyl [2- (3-chlorophenyl) ethyl ] carbamate (example 39a), 3.9g) by the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (3.8 g).

¹H NMRδ(DMSO-d6)7.35-7.25(m，3H)，7.15(d，1H)，4.75(t，1H)3.55-3.51(m，2H)，3.38(t，2H)，3.17(t，2H)，2.76(t，2H)，2.55-2.43(m，4H)，1.70(t，2H)，1.47-1.36(m，9H)。

c) [2- (3-chlorophenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl [2- (3-chlorophenyl) ethyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 39b), 1200mg) according to the method of example 17 c). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (760 mg).

m/e 272((M-BOC)+H+，100％)。

d) [2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b, 540mg) and tert-butyl [2- (3-chlorophenyl) ethyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 39c), 760 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane and then recrystallized from acetonitrile to give the title compound (190 mg).

m/e 582(M+H+，100％)。

Example 40

7- [ (1R) -2- ({2- [ (3- { [2- (3-chlorophenyl) ethyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride

The title compound was prepared from tert-butyl [2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 39d), 150mg) by the following method: the tert-butyl carbamate was dissolved in dioxane (6ml) and the resulting solution was treated with a 4M HCl solution in dioxane (2.5ml) and stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration to give the title compound (114 mg).

m/e 482(M+H+，100％)。

¹H NMRδ(DMSO-d6)11.70(s，1H)，10.24(s，1H)，9.21(s，3H)，8.82(s，1H)，7.42-7.31(m，3H)，7.25(d，1H)，6.93(d，1H)，6.81(d，1H)，6.45(s，1H)，4.99(q，1H)，3.15(t，4H)，3.04-2.87(m，6H)，2.84(t，2H)，2.68(t，2H)，1.94(t，2H)。

EXAMPLE 41

[2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) sulfonyl ] propyl } carbamic acid tert-butyl ester

The title compound was prepared from tert-butyl [2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 39d), 50mg) by the following method: the tert-butyl carbamate was dissolved in acetonitrile (15ml), a solution of oxone (80mg) in water (15ml) was added to the solution, and the mixture was stirred at room temperature overnight. The mixture was concentrated and then extracted with ethyl acetate, the organic layer was shaken with brine, then dried over sodium sulfate and concentrated to a solid which was recrystallized from acetonitrile (21 mg).

m/e 614(M+H+，100％)。

Example 42

7- [ (1R) -2- ({2- [ (3- { [2- (3-chlorophenyl) ethyl ] amino } propyl) sulfonyl ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride

The title compound was prepared from tert-butyl [2- (3-chlorophenyl) ethyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) sulfonyl ] propyl } carbamate (example 41d), 21mg) by the following method: the tert-butyl carbamate was dissolved in dioxane (1ml) and the resulting solution was treated with a 4M HCl solution in dioxane (0.4ml) and stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration and then purified by reverse phase HPLC using a gradient of 5 to 60% acetonitrile in aqueous ammonia to give the title compound (1.3 mg).

m/e 514(M+H+，100％)。

Example 43

(+/-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) (+/-) -allyl [2- (phenyl) propyl ] carbamic acid tert-butyl ester

The subtitle compound was prepared from tert-butyl (+/-) - [2- (phenyl) propyl ] carbamate (5.8g) by the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (3.7 g).

¹H NMRδ(DMSO-d6)7.29(t，3H)，7.20(d，2H)，5.72-5.62(m，1H)，5.06(d，2H)，3.70(s，1H)，3.56(s，1H)，3.23(s，2H)，3.06-3.03(m，1H)，1.33(m，9H)，1.15，(d，3H)。

b) (+/-) - [2- (2-phenyl) propyl ] {3- [ (2-hydroxypropyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from (+/-) -allyl [2- (phenyl) propyl ] carbamic acid tert-butyl ester (example 43a), 3.7g) by the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (3.3 g).

¹H NMRδ(DMSO-d6)7.30-7.26(d，2H)，7.21-7.16(m，3H)，4.74(t，1H)，3.50(q，2H)，3.30(s，4H)，3.08(t，2H)，2.99-2.94(m，1H)，2.53(t，2H)，2.39(t，2H)，1.32(s，9H)，1.16(s，3H)。

c) (+/-) - [2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl (+/-) - [2- (phenyl) propyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 43b), 700mg) by the method of example 17 c). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (300 mg).

m/e 252((M-BOC)+H+，100％)。

d) (+/-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 220mg) and tert-butyl (+/-) - [2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 43c), 300 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane and then recrystallized from acetonitrile to give the title compound (180 mg).

m/e 562(M+H+，100％)。

Example 44

(+/-) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-13-benzothiazol-2 (3H) -one dihydrochloride

The title compound was prepared from tert-butyl (+/-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 43d), 175mg) by the following method: the tert-butyl carbamate was dissolved in dioxane (6ml) and the resulting solution was treated with a 4M HCl solution in dioxane (2.5ml) and stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration to give the title compound (84 mg).

m/e 462(M+H+，100％)。

¹H NMR. delta. (DMSO-d6)11.69(s, 1H), 10.21(s, 1H), 9.18(s, 1H), 8.92(1H, s), 8.76(s, 1H), 8.65(1H, s), 7.37-7.31(m, 3H), 7.29-7.25(m, 2H), 6.91(d, 1H), 6.78(d, 1H), 6.45(s, 1H), 4.96(d, 1H), 3.39-3.22(m, 1H), 3.10(4H, t), 3.05(s, 2H), 2.95 (quintet, 2H), 2.83(q, 2H), 2.62(t, 2H), 1.90 (quintet, 2H)1.28(d, 3H).

Example 45

(R) - (+) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) (R) - (+) -allyl [2- (phenyl) propyl ] carbamic acid tert-butyl ester

The sub-title compound was prepared from tert-butyl (R) - (+) - [2- (phenyl) propyl ] carbamate (5.2g) according to the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (4.2 g).

¹H NMRδ(DMSO-d6)7.29(t，3H)，7.20(d，2H)，5.72-5.62(m，1H)，5.06(d，2H)，3.70(s，1H)，3.56(s，1H)，3.23(s，2H)，3.06-3.03(m，1H)，1.33(9H，m)，1.15，(d，3H)。

b) (R) - (+) - [2- (2-phenyl) propyl ] {3- [ (2-hydroxypropyl) thio ] propyl } carbamic acid tert-butyl ester

The sub-title compound was prepared from tert-butyl (R) - (+) -allyl [2- (phenyl) propyl ] carbamate (example 45a), 4.2g) according to the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (3.3 g).

c) (R) - (+) - [2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 17c) from tert-butyl (R) - (+) - [2- (phenyl) propyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 45b), 1000 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (800 mg).

m/e 252((M-BOC)+H+，100％)。

d) (R) - (+) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 160mg) and tert-butyl (R) - (+) - [2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 45c), 260 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane and then recrystallized from acetonitrile to give the title compound (65 mg).

m/e 562(M+H+，100％)。

Example 46

(R) - (+) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride

The title compound was prepared from tert-butyl (R) - (+) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 45d), 63mg) by the following method: the tert-butyl carbamate was dissolved in dioxane (2ml) and the resulting solution was treated with a 4M HCl solution in dioxane (0.8ml) and stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration to give the title compound (25 mg).

m/e 462(M+H+，100％)。

¹H NMR. delta. (DMSO-d6)11.69(s, 1H), 10.21(s, 1H), 9.18(s, 1H), 8.92(1H, s), 8.76(s, 1H), 8.65(s, 1H), 7.37-7.31(m, 3H), 7.29-7.25(m, 2H), 6.91(d, 1H), 6.78(d, 1H), 6.45(s, 1H), 4.96(d, 1H), 3.39-3.22(m, 1H), 3.10(4H, t), 3.05(s, 2H), 2.95 (quintet, 2H), 2.83(q, 2H), 2.62(t, 2H), 1.90 (quintet, 2H)1.28(d, 3H).

Example 47

(S) - (-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) (S) - (-) -allyl [2- (phenyl) propyl ] carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl (S) - (-) - [2- (phenyl) propyl ] carbamate (4.8g) by the method of example 13 a). The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (4.2 g).

b) (S) - (-) - [2- (2-phenyl) propyl ] {3- [ (2-hydroxypropyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl (S) - (-) -allyl [2- (phenyl) propyl ] carbamate (example 47a), 4.2g) according to the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (3.4 g).

c) (S) - (-) - [2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 17c) from tert-butyl (S) - (-) - [2- (phenyl) propyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 47b), 500 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (350 mg).

m/e 252((M-BOC)+H+，100％)。

d) (S) - (-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 150mg) and tert-butyl (S) - (-) - [2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 47c), 250 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane and then recrystallized from acetonitrile to give the title compound (65 mg).

m/e 562(M+H+，100％)。

Example 48

(S) - (-) -7- [ (1R) -2- ({2- [ (3- { [2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride

The title compound was prepared from tert-butyl (S) - (-) - [2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 47d), 84mg) by the following method: the tert-butyl carbamate was dissolved in dioxane (2.5ml) and the resulting solution was treated with a 4M HCl solution in dioxane (1.0ml) and stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration to give the title compound (47 mg).

m/e 462(M+H+，100％)。

Example 49

[ 2-methyl-2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

a) Allyl [ 2-methyl-2- (phenyl) propyl ] carbamic acid tert-butyl ester

The subtitle compound is prepared by the following method: tert-butyl [ 2-methyl-2- (phenyl) propyl ] carbamate (3.5g) was dissolved in DMF (15 ml). A60% solution of sodium hydride in oil (0.68g) was rinsed with isohexane, then added to the above solution of tert-butyl carbamate in DMF and heated at 50 ℃ for 2 hours to give a brownish red suspension. After cooling, allyl bromide (1.9ml) was added and the mixture was heated for an additional 2 hours to complete the reaction. After cooling, the mixture was quenched with brine, then extracted with ethyl acetate (× 3), and the combined extracts were dried over sodium sulfate and concentrated to give a brown oil. This crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in isohexane to give the sub-title compound (2.80 g).

¹H NMRδ(DMSO-d6)7.27(t，2H)，7.21(t，1H)，7.10(d，2H)，5.54-5.47(m，1H)，4.94-4.87(m，2H)，3.45(d，2H)，3.07(s，2H)，1.45(s，9H)，1.36(s，6H)。

b) [ 2-methyl-2- (2-phenyl) propyl ] {3- [ (2-hydroxypropyl) thio ] propyl } carbamic acid tert-butyl ester

The subtitle compound is prepared from tert-butyl allyl [ 2-methyl-2- (phenyl) propyl ] carbamate (example 49a), 2.80g) by the method of example 10 a). The crude product was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in isohexane to give the sub-title compound (1.9 g).

¹H NMRδ(_DMSO-d6)7.28(t，2H)，7.20(t，1H)，7.10(d，2H)，4.71(t，1H)，3.49-3.42(m，2H)，3.07(t，2H)，2.88(t，2H)，2.44(t，2H)，2.26(t，2H)，1.67(s，2H)，1.47(s，9H)，1.30(s，6H)。

c) [ 2-methyl-2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamic acid tert-butyl ester

The sub-title compound was prepared according to the method of example 17c) from tert-butyl [ 2-methyl-2- (phenyl) propyl ] {3- [ (2-hydroxyethyl) thio ] propyl } carbamate (example 49b), 600 mg). The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in isohexane to give the sub-title compound (300 mg).

m/e 266((M-BOC)+H+，100％)。

d) [ 2-methyl-2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamic acid tert-butyl ester

The title compound was prepared according to the method of example 5e) from 7- [ (1R) -2-amino-1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one hydrochloride (example 4b), 150mg) and tert-butyl [ 2-methyl-2- (phenyl) propyl ] {3- [ (2-oxoethyl) thio ] propyl } carbamate (example 49c), 300 mg). The crude product was purified by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 10% methanol in dichloromethane, followed by recrystallization from acetonitrile to give the title compound (60 mg).

m/e 576(M+H+，100％)。

Example 50

7- [ (1R) -2- ({2- [ (3- { [ 2-methyl-2- (phenyl) propyl ] amino } propyl) thio ] ethyl } amino) -1-hydroxyethyl ] -4-hydroxy-1, 3-benzothiazol-2 (3H) -one dihydrochloride

The title compound was prepared from tert-butyl [ 2-methyl-2- (phenyl) propyl ] {3- [ (2- { [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-2, 3-dihydro-1, 3-benzothiazol-7-yl) ethyl ] amino } ethyl) thio ] propyl } carbamate (example 49d), 60mg) by the following method: the tert-butyl carbamate was dissolved in dioxane (2ml) and the resulting solution was treated with a 4M HCl solution in dioxane (0.8ml) and stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration to give the title compound (15 mg).

m/e 476(M+H+，100％)。

¹H NMRδ(DMSO-d6)11.69(s，1H)，10.21(s，1H)，9.18(s，1H)，8.92(1H，s)，8.76(s，1H)，8.65(s，1H)，7.26(d，1H)，7.20-7.15(m，4H)，6.86(d，1H)，6.68(s，1H)，4.56(s，1H)，3.39-3.22(m，6H)，2.54(s，6H)1.62(s，2H)，0.95(s，6H)。

Biological assay

Procedure of experiment

Cell preparation

H292 cells in containing 10% (v/V) FBS (fetal bovine serum) and 2mM L-glutamine RPMI (Roswell Park mental institute) medium growth. In a humidified incubator (humidified incubator), at 37 ℃ and 5% CO₂Next, cells were grown in 225cm2 flasks containing 25mL of media. Cells were harvested from flasks once a week and passaged at a 1: 10 dilution.

Experimental methods

The medium was removed from the flask containing the H292 cells, washed with 10mL PBS (phosphate buffered saline), and then with 10mL Accutase^TMCell detachment solution (detachment solution) displacement. In a humidified incubator at 37 ℃ and 5% CO₂Next, the flask was incubated for 15 minutes. The cell suspension was counted and then at 0.05X 10⁶cells/mL, cells were resuspended in RPMI medium (containing 10% (v/v) FBS and 2mM L-glutamine). 5000 cells (100. mu.l) were added to each well of a tissue culture-treated 96-well plate in a humidified incubator at 37 ℃ and 5% CO₂Next, the cells were incubated overnight. The medium was removed, washed twice with 100. mu.l of assay buffer and then replaced with 50. mu.l of assay buffer. The cells were left at room temperature for 20 minutes, after which 25. mu.l of rolipram (made up to 1.2mM in assay buffer containing 2.4% (v/v) dimethyl sulfoxide) was added. Cells were incubated with rolipram for 10 minutes, after which time the test compound (included in the solution) was added4% (v/v) assay buffer in dimethyl sulfoxide A.times.4 concentrated stock solution was prepared) and the cells were incubated for 10 min at room temperature. The final rolipram concentration in the assay was 300. mu.M and the final vehicle concentration was 1.6% (v/v) dimethyl sulfoxide. The reaction was stopped by removing the supernatant, washed once with 100. mu.l assay buffer and then replaced with 50. mu.l cell lysis buffer. The cell monolayer was frozen at-80 ℃ for 30 minutes (or overnight).

AlphaScreen^TMcAMP detection

Using AlphaScreen^TMMethodology, the concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined. The frozen cell plates were thawed for 20 minutes on a plate shaker, and then 10. mu.l of the cell lysate was transferred to a 96-well white plate. Mixing 40. mu.l AlphaScreen^TMDetection beads (containing equal volumes of donor beads (preincubated with biotinylated cAMP for 30 minutes in the absence of light) and acceptor beads) were added to each well and the plates were incubated for 10 hours at room temperature in the absence of light. AlphaScreen was measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) according to the manufacturer's recommended settings^TMA signal. The cAMP concentration is determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations (in cell lysis buffer in 96 well tissue culture processing plates, frozen/thawed alongside the test sample) and determined using the same protocol. Concentration response curves for agonists were constructed to determine pEC₅₀And intrinsic activity. In each experiment, the intrinsic activity was expressed as a fraction of the maximal activity determined for formoterol. The results obtained for a representative selection of example compounds are shown in table 1 below.

TABLE 1

Compound (I)	pEC₅₀	Intrinsic activity
Compound (I)	pEC₅₀	Intrinsic activity	Example 2	9.8	1.0
Example 4	10.0	0.9	Example 2	9.8	1.0
Example 4	10.0	0.9	Example 5	10.2	0.7
Example 8	10.0	1.0	Example 5	10.2	0.7
Example 8	10.0	1.0	Example 12	8.3	0.8

Alternative adrenergic beta 2-mediated cAMP production

Cell preparation

In an incubator at 37 ℃ and 5% CO₂Next, H292 cells were grown in 225cm2 flasks in RPMI medium containing 10% (v/v) FBS (fetal bovine serum) and 2mM L-glutamine.

Experimental methods

By using Accutase^TMWhere cells are detached from the solutionFor 15 minutes, adherent H292 cells were detached from the tissue culture flasks. In a humidified incubator at 37 ℃ and 5% CO₂Next, the flask was incubated for 15 minutes. At 0.05X 10⁶cells/mL, the detached cells were resuspended in RPMI medium (containing 10% (v/v) FBS and 2mM L-glutamine). 5000 cells (100. mu.l) were added to each well of a tissue culture-treated 96-well plate in a humidified incubator at 37 ℃ and 5% CO₂Next, the cells were incubated overnight. The medium was removed and the cells were washed twice with 100. mu.l of assay buffer and replaced with 50. mu.l of assay buffer (HBSS solution containing 10mM HEPES pH7.4 and 5mM glucose). The cells were left at room temperature for 20 minutes, after which 25. mu.l of rolipram (made up to 1.2mM in assay buffer containing 2.4% (v/v) dimethyl sulfoxide) was added. Cells were incubated with rolipram for 10 minutes, after which time the test compound was added and cells were incubated for 60 minutes at room temperature. The final rolipram concentration in the assay was 300. mu.M and the final vehicle concentration was 1.6% (v/v) dimethyl sulfoxide. The reaction was stopped by removing the supernatant, washed once with 100. mu.l assay buffer and replaced with 50. mu.l cell lysis buffer. The cell monolayer was frozen at-80 ℃ for 30 minutes (or overnight).

AlphaScreen^TMcAMP detection

Using AlphaScreen^TMMethodology, the concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined. The frozen cell plates were thawed for 20 minutes on a plate shaker, and then 10. mu.l of the cell lysate was transferred to a 96-well white plate. Mu.l of mixed AlphaScreen pre-incubated with biotinylated cAMP^TMDetection beads were added to each well and the plates were incubated for 10 hours at room temperature in the dark. AlphaScreen was measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) according to the manufacturer's recommended settings^TMA signal. cAMP concentrations were determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations. Concentration response curves of agonists were constructed and the data were fitted to a four parameter logistic equation to determine pEC₅₀And intrinsic activity. In each experiment, intrinsic activity was expressed asThe fraction of maximum activity determined for formoterol. The results for the compounds of the invention are shown in table 2.

Selective assay

Adrenergic alpha 1D

Membrane preparation

Membrane expression recombination of human alpha 1_DHuman embryonic kidney 293(HEK293) cells of the recipient. These membranes were diluted in assay buffer (50mM HEPES, 1mM EDTA, 0.1% gelatin, ph7.4) to a final membrane concentration that provided a clear window between maximum and minimum specific binding.

Experimental methods

The assay was performed in a U-bottom 96-well polypropylene plate. Mixing 10 μ l of³H]Prazosin (0.3nM final concentration) and 10. mu.l of test compound (10 Xfinal concentration) were added to each test well. For each assay plate, [2 ] in the presence of 10. mu.l of vector (10% (v/v) DMSO assay buffer; defined maximum binding) or 10. mu.L of BMY7378 (10. mu.M final concentration; defined non-specific binding (NSB)) ]³H]For prazosin binding, 8 replicates were obtained. Then, the membrane was added to make the final volume 100. mu.L. Plates were incubated at room temperature for 2 hours, and then plates were filtered onto PEI coated GF/B filter plates (preimpregnated in assay buffer for 1 hour) using a 96-well plate Tomtec cell harvester. The unbound radioactive material was removed by five washes at 4 ℃ with 250. mu.l of wash buffer (50mM HEPES, 1mM EDTA, pH 7.4). The plates were dried and then sealed from below using a Packard plate sealer (plate sealer), MicroScint-O (50. mu.l) was added to each well. The plates were sealed (TopSeal a) and the filter-bound radioactivity was measured using a scintillation counter (TopCount, Packard BioScience) using a 3 minute counting protocol.

Total specific binding (B) was determined by subtracting the mean NSB from the mean maximal binding₀). NSB values were also subtracted from the values of all other wells. These data are expressed as B₀Percentage of (c). The usual range of 0.1nM to 10. mu.M is usedDetermining the concentration-effect curve of the compound (p.,)³H]-inhibition of prazosin binding). The data were fitted to a four parameter logistic equation to determine the potency of the compounds, which were expressed as pIC₅₀(para 2³H]Negative logarithm of molar concentration at which prazosin binds with 50% inhibition). The results are shown in table 2 below.

Adrenergic beta 1

Membrane preparation

Membranes containing recombinant human adrenergic beta 1 receptors were obtained from Euroscreen. These membranes were diluted in assay buffer (50mM HEPES, 1mM EDTA, 120mM NaCl, 0.1% gelatin, pH7.4) to give a final membrane concentration that provided a clear window between maximum and minimum specific binding.

Experimental methods

The assay was performed in a U-bottom 96-well polypropylene plate. Mixing 10 μ l of¹²⁵I]Iodocyanopindolol (Iodocyanopindolol) (0.036nM final concentration) and 10. mu.l of test compound (10 Xfinal concentration) were added to each test well. For each assay plate, [2 ] in the presence of 10. mu.l of vector (10% (v/v) DMSO assay buffer; defining maximum binding) or 10. mu.l of propranolol (10. mu.M final concentration; defining non-specific binding (NSB))¹²⁵I]Binding of-iodocyanopindolol gave 8 replicates. Then, the membrane was added to make the final volume 100. mu.L. Plates were incubated at room temperature for 2 hours, and then plates were filtered onto PEI coated GF/B filter plates (preimpregnated in assay buffer for 1 hour) using a 96-well plate Tomtec cell harvester. The unbound radioactive material was removed by five washes at 4 ℃ with 250. mu.l of wash buffer (50mM HEPES, 1mM EDTA, 120mM NaCl, pH 7.4). The plates were dried and then sealed from below using a Packard plate sealer, MicroScint-O (50. mu.l) was added to each well. The plates were sealed (TopSeal a) and the filter-bound radioactivity was measured using a scintillation counter (TopCount, packardcio science) using a 3 minute counting protocol.

By averaging the maximum junctionThe average NSB was subtracted and total specific binding (B) was determined₀). NSB values were also subtracted from the values of all other wells. These data are expressed as B₀Percentage of (c). The compound concentration-effect curve (p., [2 ]) was determined using serial dilutions generally ranging from 0.1nM to 10. mu.M¹²⁵I]Inhibition of iodocyanopindolol binding). The data were fitted to a four parameter logistic equation to determine the potency of the compounds, which were expressed as pIC₅₀(para 2¹²⁵I]Negative logarithm of molar concentration at which iodocyanopindolol binds to produce 50% inhibition). The results are shown in table 2 below.

Dopamine D2

Membrane preparation

Membranes containing recombinant human dopamine D2s subtype receptors were obtained from Perkin Elmer. These membranes were diluted in assay buffer (50mM HEPES, 1mM EDTA, 120mM NaCl, 0.1% gelatin, pH7.4) to give a final membrane concentration that provided a clear window between maximum and minimum specific binding.

Experimental methods

The assay was performed in a U-bottom 96-well polypropylene plate. Mixing 30 μ l of³H]Spiperone (0.16nM final concentration) and 30. mu.l of test compound (10 Xfinal concentration) were added to each test well. For each assay plate, [2 ] in the presence of 30. mu.l of vector (10% (v/v) DMSO assay buffer; defining maximum binding) or 30. mu.l of fluoropiperidinol (10. mu.M final concentration; defining non-specific binding (NSB))³H]For spiperone binding, 8 replicates were obtained. Then, the membrane was added to make the final volume 300. mu.L. Plates were incubated at room temperature for 2 hours, and then plates were filtered onto PEI coated GF/B filter plates (preimpregnated in assay buffer for 1 hour) using a 96-well plate Tomtec cell harvester. The unbound radioactive material was removed by five washes at 4 ℃ with 250. mu.l of wash buffer (50mM HEPES, 1mM EDTA, 120mM NaCl, pH 7.4). The plates were dried and then sealed from below using a Packard plate sealer, MicroScint-O (50. mu.l) was added to each well. Plates were sealed (TopSeal A) and scintillation usedThe filter-bound radioactivity was measured in a counter (TopCount, Packard BioScience) using a 3 minute counting protocol.

Total specific binding (B) was determined by subtracting the mean NSB from the mean maximal binding₀). NSB values were also subtracted from the values of all other wells. These data are expressed as B₀Percentage of (c). The compound concentration-effect curve (p 2) was determined using serial dilutions generally ranging from 0.1nM to 10. mu.M³H]Inhibition of spiperone binding). The data were fitted to a four parameter logistic equation to determine the potency of the compounds, which were expressed as pIC₅₀(para 2³H]Negative logarithm of molar concentration at which spiroperone binding produces 50% inhibition).

The results obtained for a representative selection of example compounds are shown in table 2 below.

Seizure measurement (Onsessay)

Dunkin-Hartley guinea pigs (200 g to 300g at delivery) were provided by a designated breeding facility. These guinea pigs were sacrificed by cervical dislocation and the trachea isolated. Adherent connective tissue was removed and each trachea was then cut into four rings. These tissue loops are then connected to isometric sensors. These tissues were washed and then a force of 1g was applied to each ring. In all experiments, a paired curve design (paired curve design) was used. A sensitizing dose of 1 μ M methacholine was applied to these tissues. The tissue was then washed (three times, one minute between washes) and allowed to equilibrate by reapplying a constant 1g tension for 1 hour. Then, the tissues were contracted with 1 μ M methacholine, and once a stable response was obtained, a cumulative concentration response curve of isoproterenol was constructed (10)^-9M-10^-5M). The tissue was then washed (three times, one minute between each wash) and then left to rest for one hour. After this time, the tissue was contracted with 1. mu.M methacholine and p [ A ] was added]₅₀Concentration of test compound. Once the tissue has reached maximum relaxation, 30 XP A is added]₅₀Concentration of test compound. Once the tissue response has been achievedTo plateau, 10 μ M sotalol was added to the bath to confirm that the relaxation was β₂(ii) mediated.

Data was collected using the ADInstructions chart4 trends software, which measures the maximum tonicity produced for each concentration of agonist.

For each concentration of the isoproterenol accumulation concentration curve, the response value was calculated as the percent relaxation of the contraction induced by methacholine. Plotting the curve as log₁₀[ agonists)](M) and percent inhibition of methacholine induced contraction. These data were then fit to a non-linear regression curve fit. For each experiment, E/[ A ] was paired using a 4-parameter logarithmic function of the form]And (3) fitting a curve:

e and [ A ]]Pharmacological effects (percent relaxation) and concentration of agonist, respectively; alpha, beta, [ A ]]₅₀And m is an asymptote parameter, a baseline parameter, a position parameter, and a slope parameter, respectively. P [ A ] of each isoproterenol curve]₅₀And IA were both determined from this fit to determine whether tissue could be used to derive the onset of the test compound.

P [ A ] for each test compound]₅₀Concentration, response values were calculated as the percent relaxation of the contraction induced by methacholine. The results are plotted as percent slack versus time and the time spent to reach 90% slack value is calculated and recorded.

Addition of 30 XP [ A ]]₅₀Concentration, which allows the determination of maximum compound effect in the tissue of the individual. Thus, p [ A ] is calculated and recorded]₅₀Compound effect at concentration is the percentage of compound effect that is maximized.

Pharmacokinetics in rats

Using a suitable administration vehicle, a solution for administration of the test compound is prepared. The concentration of the compound in the dosing solution is determined by the following method: diluting the aliquot to 50. mu.g/ml^-1And (iv) and calibrated by means of double injection of standard solution and QC standard at this concentration. The compound was administered intravenously by bolus injection into the tail vein to multiple groups of rats (each group consisting of three 250-350g rats) (approximately 1 ml. kg)^-1). For oral administration, another group of animals (consisting of 2 or 3 animals) was administered by oral gavage (3 ml. kg)^-1). The delivered dose is estimated by weight loss. Animals are usually not fasted prior to administration, although this is investigated if necessary.

Blood samples (0.25ml) were collected from the tail vein into 1ml syringes, immediately after sample collection, transferred to EDTA tubes, and plasma prepared by centrifugation (5min, 13000rpm) before storage at-20 ℃. Typical sampling times are 2, 4, 8, 15, 30, 60, 120, 180, 240, 300 minutes or until the terminal half-life (terminal t) is accurately described_1/2)。

The concentration of the analyte (or analytes) in the plasma is determined by quantitative mass spectrometry. Standard and quality control stock solutions were prepared at a concentration of 1mg/ml in methanol. A range of standard and QC stocks prepared by serial dilution were added to control rat plasma (50 μ l). This concentration range covers the range of analyte levels in rat samples. Liquid extraction of standards, QC material and samples was performed using 50 μ l organic solvent and 100 μ l organic solvent containing an internal standard (selected to be very similar to the analyte). The samples were then mixed by repeated inversion, stored at-20 ℃ for at least 1 hour, and then centrifuged in a centrifuge at 3500rpm for 20 minutes. An aliquot (120. mu.l) of each sample was transferred for analysis by LC-MSMS. The standards and quality control samples covering the concentration range in the test samples were at 25% of the above nominal concentration.

Pharmacokinetic data analysis was performed using WinNonlin. Estimating parameters, such as T, using standard non-compartmental analysis (non-compartmental analysis)_max、C_max、λ_z、t_1/2_λ_z、AUC_all、AUC_INF(observed), Cl (observed), Vss (observed).

TABLE 2

Example numbering	β2pEC50	Beta 2 intrinsic activity	Alpha 1 binding pIC50	Beta 1 binding pIC50	D2 binding pIC50
Example numbering	β2pEC50	Beta 2 intrinsic activity	Alpha 1 binding pIC50	Beta 1 binding pIC50	D2 binding pIC50	1	10	1		8.1	6.7
2	9.8	1	6	7.8		1	10	1		8.1	6.7
2	9.8	1	6	7.8		3	9.9	0.9		8.4	6.1
4	10	0.9	6.7	6.9	6.1	3	9.9	0.9		8.4	6.1
4	10	0.9	6.7	6.9	6.1	5	10.3	0.9
6	10.1	0.9		8.4	6.2	5	10.3	0.9
6	10.1	0.9		8.4	6.2	7	9.9	1.1	6.2	8.5	6
8	10.2	1		8.1	6	7	9.9	1.1	6.2	8.5	6
8	10.2	1		8.1	6	9	10.1	1		8.1	6
11	9.1	0.9	6.9	6.6	5.4	9	10.1	1		8.1	6
11	9.1	0.9	6.9	6.6	5.4	12	8.5	1
14	8.4	0.9	7	7.3	5.6	12	8.5	1
14	8.4	0.9	7	7.3	5.6	16	7.9	0.7	5.8	6.9	5.4
18	8.5	0.8	6.6	7	6.3	16	7.9	0.7	5.8	6.9	5.4

20	9.2	0.8	7.6	6.9	5.8
20	9.2	0.8	7.6	6.9	5.8	24	9.4	0.8	6.8	7.1	6.2
27	9	1	6.9	7.2	6	24	9.4	0.8	6.8	7.1	6.2
27	9	1	6.9	7.2	6	29	9.5	0.9	7	7.6	5.4
31	9.4	0.8	7.9	7.4	5.8	29	9.5	0.9	7	7.6	5.4
31	9.4	0.8	7.9	7.4	5.8	33	8.9	1.1	7.4	6.9	6
35	8.8	1	6.9	7.1		33	8.9	1.1	7.4	6.9	6
35	8.8	1	6.9	7.1		36	9.3	1	7.3	7	5.5
38	8.8	0.9	6.8	7.1	6.4	36	9.3	1	7.3	7	5.5
38	8.8	0.9	6.8	7.1	6.4	40	9	0.8	7.1	6.8	6.1
42	9.2	1	6.9	6.1	5	40	9	0.8	7.1	6.8	6.1
42	9.2	1	6.9	6.1	5	44	9.2	0.8	6.4	7.1	4.9
46	9.2	0.8	6.6	7.1	5.9	44	9.2	0.8	6.4	7.1	4.9
46	9.2	0.8	6.6	7.1	5.9	48	8.9	0.9	5.8	6.8	5.4
50	8.9	0.6	6.4	6.1	5.5	48	8.9	0.9	5.8	6.8	5.4

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R¹Represents hydrogen;

R²、R³、R⁴、R⁵、R⁴' and R⁵' each independently represents hydrogen or C₁-C₆Alkyl radical；

x is 0 or 1;

a represents oxygen, sulfur, S (O) or S (O)₂；

D represents oxygen, sulfur or NR⁶；

W is a bond or CR^6aR^6b；

n is an integer of 0 to 2;

y is a bond, CR^2eR^2fOr CR^2gR^2hCR^2kR^2m；

R^7ais hydrogen, C₁-C₆Alkyl or NHR^7b；

R¹⁸represents a saturated 5 or 6 membered nitrogen containing ring; and

2. The compound of claim 1, wherein R²、R³、R⁴And R⁵Each represents hydrogen if R⁴' and R⁵' Presence, then R⁴' and R⁵' each represents hydrogen.

3. A compound according to claim 1 or 2, wherein A represents oxygen, sulphur or S (O)₂。

4. A compound according to claim 1, 2 or 3 wherein D represents oxygen or NR⁶。

5. A compound according to claim 1, 2, 3 or 4 wherein D represents NR⁶。

6. A compound according to any one of the preceding claims wherein D is NR⁶And A is sulfur.

7. A compound according to any one of the preceding claims wherein R is⁶Represents hydrogen, C₁-C₄Alkyl or C₁-C₄An alkoxycarbonyl group.

8. A compound according to any one of the preceding claims wherein x is 0.

9. A compound according to any one of the preceding claims wherein Y is a bond or CR^2eR^2fAnd n is 0.

10. A compound according to any one of the preceding claims wherein R is⁷Represents a 6 to 10 membered aromatic or heteroaromatic ring system, said 6 to 10 membered aromatic or heteroaromatic ring system being optionally substituted by: halogen, trifluoromethyl, hydroxy, carboxy, C₁-C₄Alkyl (optionally substituted by-NR)¹⁰R¹¹Substituted), C₁-C₄Alkoxy (optionally substituted by-NR)¹²R¹³Substituted), C₁-C₄Alkoxycarbonyl, -NR¹⁴R¹⁵、C₁-C₄Alkylcarbonylamino, C₁-C₄Alkylsulfonylamino, phenylsulfonylAcylamino, -C (O) NHR¹⁶、-SO₂NHR¹⁷、C₀-C₄alkyl-R¹⁸Phenyl or a 5-to 6-membered heteroaromatic ring.

11. A compound according to any one of claims 1 to 8 or 10 wherein n is 1 or 2 and W is CR^6aR^6bWherein R is^6aAnd R^6bIndependently is hydrogen or C_1-4An alkyl group.

12. A compound according to any one of the preceding claims wherein R is^7aIs NHR^7bWherein R is^7bIs hydrogen, C₁-C₄Alkyl or C₁-C₆An alkoxycarbonyl group.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein x is 0 or 1; a represents oxygen, sulfur or S (O)₂(ii) a D represents oxygen or NR⁶(ii) a Y is a bond or CH₂(ii) a W is CR^6aR^6b(ii) a n is 0; r¹、R²、R³、R⁴、R⁵、R⁴’、R⁵’、R^2a、R^2b、R^2cAnd R^2dAre all hydrogen; r⁶Represents hydrogen, C₁-C₄Alkyl or C₄An alkoxycarbonyl group; r^6aAnd R^6bIndependently is hydrogen or C₁-C₄An alkyl group; r⁷Represents a 6 to 10 membered aromatic ring system, said 6 to 10 membered aromatic ring system being optionally substituted by: halogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy or CF₃；R^7aIs hydrogen, C₁-C₄Alkyl, NH (C)₄Alkoxycarbonyl) or NH₂。

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is:

15. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which comprises:

(a) reacting a compound of formula (II) with a compound of formula (III) or a suitable salt thereof in the presence of a base;

the compound of formula (II) is as follows:

wherein L is¹Represents a leaving group, the other variables being as defined in formula (I);

the compound of formula (III) is as follows:

wherein R is¹As defined in formula (I); or

(b) When R is²And R³(IV) when each represents hydrogen, reacting the compound of formula (IV) with a compound of formula (III) as defined above in (a) or a suitable salt thereof in the presence of a suitable reducing agent;

the compound of formula (IV) is as follows:

wherein the variables are as defined in formula (I); or

(c) When R is²And R³(ii) contacting the compound of formula (V), each representing hydrogen, with a suitable reducing agent;

the compound of formula (V) is as follows:

wherein the variables are as defined in formula (I);

converting the resulting compound into another compound of the invention;

preparing a pharmaceutically acceptable salt of said compound.

16. A compound of formula (III'):

wherein R represents hydrogen or benzyl.

17. A compound of the formula:

18. a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

19. A process for the preparation of a pharmaceutical composition as claimed in claim 18, which process comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14 with a pharmaceutically acceptable adjuvant, diluent or carrier.

20. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, for use in therapy.

21. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of β 2 adrenoreceptor activity is beneficial.

22. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, in the manufacture of a medicament for use in the treatment of Adult Respiratory Distress Syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), asthma or rhinitis.

23. A method of treating, or reducing the risk of, a disease or condition in which modulation of β 2 adrenoreceptor activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14.

24. A method of treating, or reducing the risk of, an inflammatory disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14.

25. The method of claim 23 or 24, wherein the disease or condition is Adult Respiratory Distress Syndrome (ARDS), emphysema, bronchitis, bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), asthma or rhinitis.

26. A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more active agents selected from:

PDE4 inhibitors, including inhibitors of the isoform PDE 4D;

glucocorticoid receptor agonists;

muscarinic receptor antagonists;

modulators of chemokine receptor function; or

Inhibitors of p38 kinase function.