HK1138844A - 8-oxy-quinoline derivatives as bradykinin b2 receptor modulators - Google Patents

Description

8-oxy-quinoline derivatives as bradykinin B2 receptor modulators

The present invention relates to novel 8- (heteroarylmethoxy) quinoline compounds, compositions comprising them and uses of said compounds. These compounds are useful as selective modulators of the Bradykinin (BK) B2 receptor and, therefore, in pharmaceutical compositions for the treatment of diseases responsive to the modulation of the BK B2 receptor. The compounds of the present invention are also useful as probes for the localization of the BK B2 receptor and as standards for BK B2 receptor binding assays.

Bradykinin (BK) is a vasoactive nonapeptide (nonapeptide), H-Arg-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH, formed by the action of various plasma enzymes such as kallikrein on kininogen. In some aspects, it has some histamine-like action and is released from the venules rather than the arterioles as histamine.

Two types of BK receptors are identified in lactation as B1 and B2(Leeb-Lundberg, et al, pharmacol. rev (review in pharmaceutics). 2005, 57, 27-77). BK action mediated by the B2 receptor is an important physiological function, for example, increasing vascular permeability, modulating inflammatory responses and pain, and vasoactive effects (vasodilation, vasoconstriction). These effects at the B2 receptor are responsible for the role of BK in a number of diseases such as inflammation, cardiovascular disease, and pain. Thus, agents that block BK binding to its B2 receptor may inhibit or at least ameliorate pathogenic events.

Many peptide and non-peptide antagonists of the BK B2 receptor have been described in the prior art. For example, WO2006/40004, WO 03/103671, WO 03/87090, WO00/23439, WO 00/50418, WO 99/64039, WO 97/41104, WO 97/28153, WO 97/07115, WO 96/13485, EP 0795547, EP 0796848, EP 0867432, and EP 1213289 disclose quinoline compounds that are BK B2 receptor antagonists.

In view of the severe diseases (both acute and chronic) associated with the pathophysiological levels of bradykinin, there is still a need for highly selective B2 receptor modulators with improved properties.

The present invention therefore relates to the problem of providing highly selective B2 receptor modulators, preferably with improved properties.

The problems to which the invention relates are solved by the subject matter of the appended claims.

In a first aspect, the problem underlying the present invention is solved by a compound of formula (I) or a pharmacologically acceptable salt, solvate, or hydrate thereof:

wherein

A is a 6-membered heteroaryl having 1 to 3 heteroatoms each independently selected from N or O, wherein the 6-membered heteroaryl is substituted with 2 to 4 substituents each independently selected from halogen atoms, oxygen atoms, hydroxyl groups, cyano groups, amino groups, nitro groups, mercapto groups, alkyl groups, alkenyl groups, alkynyl groups, heteroalkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkylcycloalkyl groups, heteroalkylcycloalkyl groups, aryl groups, heteroaryl groups, aralkyl groups, or heteroaralkyl groups;

R⁵is a halogen atom, hydroxyl, cyano, nitro, mercapto, alkyl, alkenyl, alkynyl, or heteroalkyl;

R⁶is an optionally substituted alkyl group; optionally substituted alkenyl; a 5-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O or S, or cycloalkyl, wherein said 5-membered heterocycloalkyl or cycloalkyl is substituted with 0 to 3 substituents each independently selected from halogen atom, oxygen atom, hydroxyl group, cyano group, amino group, nitro group, mercapto group, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, alkylcycloalkyl group, heteroalkylcycloalkyl group, aryl group, heteroaryl group, aralkyl group, or heteroaralkyl group; a 5-membered heteroaryl having 1 to 4 heteroatoms each independently selected from N, O or S, wherein the 5-membered heteroaryl is substituted with 0 to 3 substituents each independently selected from a halogen atom, an oxygen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; or-S-R¹⁰；

R¹⁰Is a 5-membered heterocycloalkyl group having 1 to 3 heteroatoms each independently selected from N, O or S, or a cycloalkyl group, wherein said 5-membered heterocycloalkyl group or cycloalkyl group is substituted with 0 to 4 substituents each independently selected from a halogen atom, an oxygen atom, a hydroxyl group, a cyano,Amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or a 5-membered heteroaryl having 1 to 4 heteroatoms each independently selected from N, O or S, wherein the 5-membered heteroaryl is substituted with 0 to 4 substituents each independently selected from halogen atoms, oxygen atoms, hydroxyl groups, cyano groups, amino groups, nitro groups, mercapto groups, alkyl groups, alkenyl groups, alkynyl groups, heteroalkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkylcycloalkyl groups, heteroalkylcycloalkyl groups, aryl groups, heteroaryl groups, aralkyl groups, or heteroaralkyl groups;

R⁷is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, an alkyl group, or a heteroalkyl group;

R⁸is a hydrogen atom or a halogen atom; and

R¹⁷is a hydrogen atom or a halogen atom.

In an embodiment of the first aspect of the invention, the heteroaryl group a of the compound comprises 1 to 3 nitrogen atoms.

In an embodiment of the first aspect of the invention, A is

Wherein

W is N, NO or CR⁹；

Y is N, NO or CR²；

Z is N, NO or CR³；

Provided that at least one of W, Y or Z is N or NO;

R¹is a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group or a heteroalkyl groupA cycloalkyl group;

R²is hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, mercapto group, alkyl group, alkenyl group, alkynyl group, or heteroalkyl group;

R³is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group;

R⁴is a halogen atom, hydroxyl, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

R⁹is a hydrogen atom, a halogen atom, or C₁-C₆An alkyl group.

In an embodiment of the first aspect of the invention, R⁶Is that

Wherein

A¹、A²、A³、A⁴And A⁵Each independently selected from O, S, N, N-H, NO, C, or C-H; and

R¹¹and R¹²Each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group.

In an embodiment of the first aspect of the invention, R⁶Is that

Wherein

A¹、A²、A³、A⁴And A⁵Each independently selected from O, S, N, N-H, NO, C, or C-H; and

R¹¹and R¹²Each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group.

In an embodiment of the first aspect of the invention,

R⁴selected from heteroalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;

w is CR⁹；

Y is N, NO or CR²；

Z is N, NO or CR³；

Provided that at least one of Y or Z is N or NO;

R¹is a halogen atom, a hydroxy group, a cyano group, -O-C₁-C₆Alkyl or C₁-C₆An alkyl group;

R²is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -O-C₁-C₆Alkyl or C₁-C₆An alkyl group; and

R³is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, -O-alkyl group or an alkyl group.

In an embodiment of the first aspect of the invention, R⁴Selected from the group-S-Y^a-L、-S-Y^a-CO-NR^aR^b、-Y^a-NR^c-CO-NR^aR^b、-Y^a-NR^c-CO-O-R^e、-Y^a-NR^c-CO-R^e、-Y^a-O-CO-NR^aR^b、-Y^a-CO-NR^aR^b、-Y^a-CO-NR^cL、-O-Y^a-CO-NR^aR^b、-Y^a-NR^c-CO-L、-Y^a-L、-Y^a-O-CO-O-R^c、-Y^a-O-CO-R^c、-Y^a-NR^c-SO₂-NR^aR^b、-Y^a-SO₂-NR^aR^bor-Y^a-NR^c-SO₂-R^eWherein

Y^aIs a bond, C₁-C₆Alkylene radical, C₂-C₆Alkenylene or C₂-C₆An alkynylene group;

R^ais a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or linked to R^bTo form a 4-to 10-membered cycloalkyl or heterocycloalkyl group;

R^bis a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, or with R^aTogether form a 4-to 10-membered cycloalkyl or heterocycloalkyl group;

R^cand R^eEach independently selected from a hydrogen atom, an optionally substituted C₁-C₆Alkyl, optionally substituted C₂-C₆Alkenyl, or optionally substituted C₂-C₆An alkynyl group; and

l is cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl.

In the practice of the first aspect of the inventionIn the scheme, R⁴Is that

Wherein

X^aIs N, O or CH;

X^bis C, S or S ═ O;

X^cis N, O or CH;

R¹³if present, is C₁-C₆An alkyl group;

R¹⁴if present, is C₁-C₆Alkyl radical, C₂-C₆Alkenyl or to R¹⁵Forming:

(i) 5-to 10-membered cycloalkyl;

(ii) 5-to 10-membered heterocycloalkyl;

(iii) 5-to 10-membered heteroaryl; or

(iv) 6-to 10-membered aryl;

R¹⁵is alkyl, alkenyl, or is linked to R¹⁴Forming:

(i) 5-to 10-membered cycloalkyl;

(ii) 5-to 10-membered heterocycloalkyl;

(iii) 5-to 10-membered heteroaryl; or

(iv) 6-to 10-membered aryl; and/or

If R is¹⁵And R¹⁶Together form:

(i) 4-to 10-membered cycloalkyl;

(ii) 4-to 10-membered heterocycloalkyl;

(iii) 5-to 10-membered heteroaryl; or

(iv) 6-to 10-membered aryl; and

R¹⁶is hydrogen, alkyl, alkenyl, aryl, heteroaryl or with R¹⁵Together form:

(i) 4-to 10-membered cycloalkyl;

(ii) 4-to 10-membered heterocycloalkyl;

(iii) 5-to 10-membered heteroaryl; or

(iv) 6-to 10-membered aryl.

In an embodiment of the first aspect of the invention, R⁴Is that

Wherein

R¹³Is a hydrogen atom or C₁-C₆An alkyl group;

R¹⁸and R¹⁹Each independently selected from hydrogen atom, halogen atom, hydroxyl, cyano, amino, nitro, C₁-C₆Alkyl, -O-C₁-C₆Alkyl, -CO-NR^aR^bor-SO₂-NR^aR^bWherein

R^aAnd R^bEach independently selected from a hydrogen atom, or C₁-C₆An alkyl group.

In an embodiment of the first aspect of the invention, R⁵Is a halogen atom, cyano, or C₁-C₆An alkyl group.

In an embodiment of the first aspect of the invention, R⁷、R⁸And R¹⁷Each independently selected from H or F.

In an embodiment of the first aspect of the invention, R⁵Is methyl or ethyl.

In an embodiment of the first aspect of the invention, R⁶Selected from the following groups:

in an embodiment of the first aspect of the invention,

R¹is methyl, Cl, F, CN, or O-CH₃；

W is CH;

y is N, NO, CH, C-CH₃C-OH, or C-OCH₃；

Z is N, NO, CH, C-CH₃C-OH, or C-OCH₃(ii) a And

provided that at least one of Y or Z is N or NO.

In an embodiment of the first aspect of the invention, R⁴Is that

Wherein

R¹³Is a hydrogen atom or a methyl group;

R²⁰is Cl, F, cyano, or CF₃(ii) a And

R²¹is a hydrogen atom or F.

In an embodiment of the first aspect of the invention, wherein R is⁷、R⁸And R¹⁷Is H.

In the first aspect of the inventionIn one embodiment, a compound of the invention, or a salt or solvate thereof, exhibits its IC in a standard in vitro BK B2 receptor mediated assay₅₀Is 500nM or less.

In a second aspect, the problem to which the present invention relates is solved by a compound, wherein said compound is preferably a compound according to the first aspect of the present invention, which is:

1- {3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-methyl-3- [ 2-methyl-4- (4-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-chloro-1-methyl-1H-imidazol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 5-chloro-2-methoxy-4- [ 2-methyl-4- (2-methyl-2H- [1, 2, 4] triazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- (3- {4- [4- (2-amino-ethoxy) -1H-pyrazol-3-yl ] -2-methyl-quinolin-8-yloxymethyl } -4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- {3- [4- (4-hydroxymethyl-2H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

n- (3- { 2-methyl-8- [ 4-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -quinolin-4-yl } -1H-pyrazol-4-ylmethyl) -acetamide,

1- {3- [4- (4-aminomethyl-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

n- (5- {8- [ 4-chloro-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1H-pyrazol-4-ylmethyl) -acetamide,

2- {8- [ 4-chloro-6-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -3-methyl-3H-imidazole-4-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (4-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

5- {8- [ 4-chloro-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -3-methyl-3H-imidazole-4-carbonitrile,

1- { 4-chloro-3- [4- (4-chloro-thiazol-5-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-3- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- {3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methoxy-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

5- {8- [ 4-chloro-6-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1-methyl-1H-pyrrole-2-carboxylic acid amide,

5- {8- [ 4-chloro-2- (3-cyano-2-oxo-2H-pyridin-1-ylmethyl) -6-methyl-pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1-methyl-1H-pyrrole-2-carboxylic acid amide,

1- { 4-chloro-3- [4- (4-hydroxymethyl-2H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (4-fluoro-pyrazol-1-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- {3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methoxy-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

2- {8- [ 5-fluoro-2-methoxy-3- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-4-ylmethoxy ] -2-methyl-quinolin-4-yl } -3-methyl-3H-imidazole-4-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (5-methyl-1H-imidazol-4-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- (1- { 4-chloro-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-yl } -ethyl) -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- (1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-yl } -ethyl) -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

5- {8- [ 4-chloro-2- (3-cyano-2-oxo-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1-methyl-1H-pyrrole-2-carboxylic acid amide,

1- { 4-chloro-3- [4- (4-fluoro-pyrazol-1-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- (1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-yl } -ethyl) -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (3-methyl-isoxazol-4-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 5-chloro-4- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -2-hydroxy-pyridin-3-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-methoxy-6-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (4-hydroxymethyl-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-3- [4- (5-fluoro-thiazol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile

In a third aspect, the problem addressed by the present invention is solved by a pharmaceutical composition comprising one or more compounds according to the first and/or second aspect of the present invention and, optionally, at least one carrier substance, excipient and/or adjuvant.

In an embodiment of the third aspect, the pharmaceutical composition is formulated as an aerosol, cream, gel, pill, capsule, syrup, solution, transdermal patch, or drug delivery device.

In a fourth aspect, the problem addressed by the present invention is solved by a method of inhibiting BK binding to the BK B2 receptor in vitro, said method comprising: contacting the BK B2 receptor with at least one compound described in the first and/or second aspects of the invention, or a salt thereof, under conditions and in an amount sufficient to detectably inhibit BK or any other substance binding to the BK B2 receptor.

In a fifth aspect, the problem underlying the present invention is solved by a method for in vitro localization or detection of BK B2 receptors in a tissue, preferably a tissue section, comprising:

(a) contacting a tissue sample comprising a BK B2 receptor with a detectably labeled compound of the first and/or second aspects of the invention under conditions which allow binding of said compound to a BK B2 receptor; and

(b) detecting said bound compound.

In an embodiment of the fifth aspect, the compound is radiolabeled, fluorescently labeled or luminescently labeled, or labeled with an antibody.

In a sixth aspect, the problem addressed by the present invention is solved by the use of a compound of the first and/or second aspect of the present invention or a pharmaceutical composition of the third aspect of the present invention for the preparation of a medicament for the treatment and/or prevention of a disease or condition.

In an embodiment of the sixth aspect of the invention, the condition or disease is responsive to BK B2 receptor modulation.

In an embodiment of the sixth aspect, the disorder is a skin disorder; ocular diseases; ear diseases, mouth, throat and respiratory diseases; gastrointestinal diseases; liver, gall bladder and pancreatic disorders; urinary and renal diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphoid disorders; central nervous system diseases; brain diseases; diseases of the musculoskeletal system; allergic diseases; pain; infectious diseases; inflammatory diseases; (ii) damage; immune diseases; cancer; a genetic disease; or edema.

In a seventh aspect, the problem to which the invention relates is solved by a method of treating a subject in need of such treatment, said method comprising administering a compound of the first and/or second aspect of the invention or a pharmaceutical composition of the third aspect.

The BK B2 receptor modulators provided herein exhibit high activity at the human BK B2 receptor (i.e., competition for binding of labeled BK to the human BK B2 receptor, Inhibition Constant (IC)₅₀) Less than 5 micromolar), or exhibit very high activity at the human BK B2 receptor (i.e., competition for binding of labeled BK to the human BKB2 receptor, IC)₅₀Preferably less than 50 nanomolar). In certain embodiments, the modulator exhibits high activity at the BK B2 receptor in species other than humans, such as rat, mouse, gerbil, guinea pig, rabbit, dog, cat, pig, or macaque (cynomolgus monkey).

The activity and more specifically the pharmacological activity of the B2 receptor modulators of the invention may be assessed using appropriate in vitro assays. For example, the IC of the modulators of the invention for the B2 receptor₅₀Values can be determined by radioligand binding assays, such as those provided in example 754, which are thus embodiments of standard in vitro BK B2 receptor-mediated assays. The inhibitory effect of a B2 receptor modulator provided herein on the B2 receptor can be determined, for example, by calcium mobilization assays, such as those provided in example 755.

IC of preferred compounds of the invention in the above assays₅₀(maximum half inhibitory concentration) is about 5 micromolar or moreSmall, more preferred IC₅₀Is about 500nM or less, or even 50nM or less, even more preferably IC₅₀Is about 10nM or less, or even 1 nanomolar or less.

The present invention further provides, within other aspects, pharmaceutical compositions comprising at least one BK B2 receptor modulator as described herein, in combination with a physiologically acceptable carrier or excipient. Also provided are methods of preparing the pharmaceutical compositions. The compositions are particularly useful for treating B2 receptor mediated diseases, as described below.

These and other aspects of the invention will become apparent with reference to the following detailed description.

Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it is understood (unless specifically indicated otherwise) that all optical isomers and mixtures thereof are included. Compounds having two or more asymmetric elements may also exist as mixtures of diastereomers. Furthermore, compounds having carbon-carbon double bonds may exist in the Z-and E-forms, and the present invention includes all isomeric forms of said compounds unless otherwise specifically indicated. When a compound exists in various tautomeric forms, the compound is not limited to any one particular tautomer, but is intended to include all tautomeric forms. The compounds are intended to further include compounds in which one or more atoms are replaced by an isotope (i.e., an atom having the same atomic number but a different mass number). As a general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include¹¹C、¹³C. And¹⁴C。

a compound according to the formula provided herein, having one or more stereogenic centers, and having more than at least 50% of enantiomers. For example, the compound may have more than at least 60%, 70%, 80%, 85%, 90%, 95%, or 98% of the enantiomer. The compounds of some embodiments have more than at least 99% enantiomer. It will be apparent that: single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemate. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral HPLC column.

Certain compounds are described herein using a formula that includes a variable (e.g., A, R)¹-R¹²W, Y, Z). Unless specifically stated otherwise, each variable within this formula is defined independently of any other variable, and any variable that occurs more than 1 time in a formula is defined independently in each instance. Thus, for example, if a group is shown to be substituted by 0-2R^*When substituted, the radicals may be unsubstituted or substituted by up to 2R^*Is substituted by radicals, and R^*In each case independently selected from R^*The definition of (1). Likewise, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity).

The term "8- (heteroarylmethoxy) quinoline", as used herein, means the compounds of formula (I) as provided herein, and salts and preferably pharmaceutically acceptable salts thereof. It will be apparent that: the compounds may be further substituted as shown.

"pharmaceutically acceptable salts" of the compounds disclosed herein are acid or base salts which are generally recognized in the art as suitable for use in contact with the tissues of humans or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. The salts include inorganic and organic acid salts of basic residues such as amines, and basic or organic salts of acidic residues such as carboxylic acids.

Suitable pharmaceutical salts include, but are not limited to, the salts of the following acids: such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, nitric acid, benzeneFormic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acids such as acetic acid, HOOC- (CH) acetic acid₂)_n-COOH, wherein n is any integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4), and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. One skilled in the art will further recognize pharmaceutically acceptable salts of the compounds provided herein. In general, pharmaceutically acceptable acid or base salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by any of the usual chemical methods. Briefly, the salts may be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. In general, it is preferred to use non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

It will be apparent that: each compound of formula (I) may, but need not, be present as a hydrate, solvate or non-covalent complex. In addition, various crystalline forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.

A "prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after being administered to a subject or patient to produce a compound of formula I provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein a hydroxy, carboxy, amine, or sulfhydryl group is bound to any group that, when administered to a mammalian subject, is cleaved to form the free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein can be prepared by modifying functional groups present in the compounds such that the modifications are cleaved in vivo to yield the parent compound.

"substituent", as used herein, means a moiety of a molecule that is covalently bonded to an atom of the molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl, haloalkyl, hydroxyl, cyano, amino, nitro, mercapto, or other substituent, as described herein, covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of the ring. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a substituent selected from the designated substituents, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity). When the substituent is oxo (i.e., ═ O), then 2 hydrogens on the atom are replaced. Oxo, which is a substituent of an aromatic carbon atom, results in the conversion of-CH-to-C (═ O) -and loss of aromaticity. For example, pyridyl substituted with oxo is pyridone.

The term "alkyl" means a saturated, straight-chain or branched hydrocarbon group comprising from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 2-dimethylbutyl or n-octyl.

The terms "alkenyl" and "alkynyl" mean an at least partially unsaturated, straight or branched chain hydrocarbon radical containing from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms, for example vinyl, allyl, ethynyl, propargyl, isoprenyl or hex-2-enyl. Preferably, alkenyl has 1 or 2 (more preferably 1) double bonds and alkynyl has 1 or 2 (more preferably 1) triple bonds.

Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced each independently by a halogen atom (preferably F or Cl), such as, for example, 2, 2, 2-trichloroethyl or trifluoromethyl.

The term "heteroalkyl" means an alkyl, alkenyl, or alkynyl group (e.g., heteroalkenyl, heteroalkynyl) in which one or more (preferably 1, 2, or 3) carbon atoms have been substituted, each independently, with an oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur atom (preferably oxygen, sulfur, or nitrogen). Furthermore, the term "heteroalkyl" means a carboxylic acid or a group derived from a carboxylic acid, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide, alkylcarbamoylalkyl, alkylcarbamoyloxyalkyl, alkylureidoalkyl, or alkoxycarbonyloxy.

Examples of heteroalkyl groups are groups of the formula:

-S-Y^a-L，-S-Y^a-CO-NR^aR^b，-Y^a-NR^c-CO-NR^aR^b，-Y^a-NR^c-CO-O-R^c，-Y^a-NR^c-CO-R^c，-Y^a-O-CO-NR^aR^b，-Y^a-CO-NR^aR^b，-O-Y^a-CO-NR^aR^b，-Y^a-NR^c-CO-L，-Y^a-L，-Y^a-O-CO-O-R^c，-Y^a-O-CO-R^c，R^c-O-Y^a-，R^c-S-Y^a-，R^a-N(R^b)-Y^a-，R^c-CO-Y^a-，R^c-O-CO-Y^a-，R^c-CO-O-Y^a-，R^c-CO-N(R^b)-Y^a-，R^a-N(R^b)-CO-Y^a-，R^c-SO-Y^a-，R^c-SO₂-Y^a-，-Y^a-NR^c-SO₂-NR^aR^b，-Y^a-SO₂-NR^aR^b，-Y^a-NR^c-SO₂-R^c，R^a-O-CO-N(R^b)-Y^a-，R^a-N(R^b)-C(＝NR^d)-N(R^c)-Y^a-，R^c-S-CO-Y^a-，R^c-CO-S-Y^a-，R^c-S-CO-N(R^b)-Y^a-，R^a-N(R^b)-CO-S-Y^a-，R^c-S-CO-O-Y^a-，R^c-O-CO-S-Y^a-，R^c-S-CO-S-Y^a-；R^ais a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, or linked to R^bTo form a 4-to 10-membered cycloalkyl or heterocycloalkyl group; r^bIs a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆Alkenyl or C₂-C₆Alkynyl, or with R^aTogether form a 4-to 10-membered cycloalkyl or heterocycloalkyl group; r^cIs a hydrogen atom, optionally substituted C₁-C₆Alkyl, optionally substituted C₂-C₆Alkenyl or optionally substituted C₂-C₆An alkynyl group; r^dIs a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆Alkenyl or C₂-C₆An alkynyl group; l is cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl; and Y is^aIs a bond, C₁-C₆Alkylene radical, C₂-C₆Alkenylene or C₂-C₆An alkynylene group; each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may have been replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, N-propoxy, isopropoxy, t-butoxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyroxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, isobutyrylamino-methyl, N-ethyl-N-methylcarbamoyl and N-methylcarbamoyl. Further examples of heteroalkyl radicals are nitrile, isonitrile, cyanate, thiocyanate, isozymeCyanate esters, isothiocyanates, and alkylnitriles. An example of a heteroalkylene group is of the formula-CH₂CH (OH) -or-CONH-.

The term "cycloalkyl" means a saturated or partially unsaturated cyclic group containing one or more rings (preferably 1 or 2) containing from 3 to 14 ring carbon atoms, preferably from 3 to 10 (more preferably 3, 4, 5, 6 or 7) ring carbon atoms. In one embodiment, the partially unsaturated cyclic group has 1, 2, or more double bonds, e.g., cycloalkenyl. Furthermore, the term "cycloalkyl" means a compound in which one or more hydrogen atoms have been replaced independently of one another by a fluorine, chlorine, bromine or iodine atom or by OH, ═ O, SH, ═ S, NH₂Or NH, CN or NO₂Substituted radicals, thus, for example, cyclic ketones, such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, spiro [4, 5 ]]Decyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo [4.3.0]Nonyl, tetrahydronaphthalene, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl.

The term "heterocycloalkyl" means a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms have been replaced, each independently, by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or nitrogen). Heterocycloalkyl preferably has 1 or 2 rings, which include from 3 to 10 (more preferably 3, 4, 5, 6 or 7) ring atoms. Furthermore, the term "heterocycloalkyl" means a compound in which one or more hydrogen atoms have been replaced independently of one another by a fluorine, chlorine, bromine or iodine atom or by OH, ═ O, SH, ═ S, NH₂Or NH, CN or NO₂An alternative group. Examples are piperidinyl, piperazinyl, morpholinyl, hexamethylenetetramino, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuranyl or 2-pyrazolinyl, and also lactams, lactones, cyclic imines and cyclic anhydrides.

The term "alkylcycloalkyl" means a group comprising both cycloalkyl and alkyl, alkenyl or alkynyl groups according to the above definitions, e.g., alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl. Alkylcycloalkyl preferably comprises cycloalkyl comprising 1 or 2 ring systems having 3 to 10 (preferably 3, 4, 5, 6 or 7) carbon atoms, and 1 or 2 alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms, said cyclic groups being optionally substituted.

The term "heteroalkylcycloalkyl" means an alkylcycloalkyl as defined above in which one or more (preferably 1, 2 or 3) carbon atoms have been substituted, each independently, by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or nitrogen). Heteroalkylcycloalkyl preferably comprises 1 or 2 ring systems having 3 to 10, preferably 3, 4, 5, 6 or 7 ring atoms, and 1 or 2 alkyl, alkenyl, alkynyl or heteroalkyl groups having 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being optionally substituted and being saturated or mono-, di-or tri-unsaturated.

The term "aryl or Ar" means an aromatic group containing one or more rings comprising 6 to 14 ring carbon atoms, preferably 6 to 10 (more preferably 6) ring carbon atoms. Furthermore, the term "aryl (or Ar)" means a compound in which one or more hydrogen atoms have been replaced, independently of one another, by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH₂CN or NO₂A group substituted with a group. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilino, 3-nitrophenyl or 4-hydroxyphenyl.

The term "heteroaryl" means an aromatic group which includes one or more rings comprising 5 to 14 ring atoms, preferably 5 to 10 (more preferably 5 or 6) ring atoms, and includes one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Furthermore, the term "heteroaryl" means a compound in which one or more hydrogen atoms have been replaced independently of one another by fluorine, chlorine, bromine or iodine atoms or by OH, ═ O, SH, NH₂Or NH, CN or NO₂Radical (I)An alternative group. Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2, 3' -bifuryl, 3-pyrazolyl and isoquinolinyl.

The term "aralkyl" means a group containing both aryl and alkyl, alkenyl, alkynyl and/or cycloalkyl groups according to the above definitions, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl. Specific examples of aralkyl groups are toluene, xylene, 1, 3, 5-trimethylbenzene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetrahydronaphthalene, dihydronaphthalene, indanone, phenylcyclopentyl, isopropylbenzene, cyclohexylphenyl, fluorene and indane. Aralkyl preferably comprises 1 or 2 aromatic ring systems (1 or 2 rings) containing 6 to 10 carbon atoms, and 1 or 2 alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms, and/or cycloalkyl groups containing 5 or 6 ring carbon atoms.

The term "heteroaralkyl" means an aralkyl group as defined above in which one or more, preferably 1, 2, 3 or 4, carbon atoms have been substituted, each independently, by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom, preferably oxygen, sulfur or nitrogen, that is, a group containing both an aryl or heteroaryl group and an alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl group in accordance with the above definitions. Heteroaralkyl preferably comprises 1 or 2 aromatic ring systems (1 or 2 rings) containing 5 or 6 to 10 ring carbon atoms, and 1 or 2 alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms, and/or cycloalkyl groups containing 5 or 6 ring carbon atoms, 1, 2, 3 or 4 of those ring carbon atoms having been replaced, independently of one another, by oxygen, sulfur or nitrogen atoms.

Examples of heteroarylalkyl are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkyl heterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkyl heterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheteroarylheteroarylheteroarylcycloalkyl, heteroarylheteroalkylcycloalkenyl, heteroarylheteroarylheteroarylalkyl, and heteroarylheteroalkyl, the cyclic groups being saturated or mono-, di-, or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, 2-or 3-ethylindolyl, 4-methylpyridoyl, 2-, 3-or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3-or 4-carboxyphenylalkyl.

The term "cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl" means a compound in which one or more hydrogen atoms have been replaced independently of one another by a fluorine, chlorine, bromine or iodine atom or by OH, ═ O, SH, ═ S, NH₂Or NH, CN or NO₂A group substituted with a group.

The term "optionally substituted" means that one or more hydrogen atoms have each independently been replaced by a hydrogen, fluorine, chlorine, bromine or iodine atom, or by OH, O, SH, S, NH₂Or NH, CN or NO₂A group substituted with a group. Furthermore, this term means C wherein one or more hydrogen atoms have each independently been unsubstituted₁-C₆Alkyl, unsubstituted C₂-C₆Alkenyl, unsubstituted C₂-C₆Alkynyl, unsubstituted C₁-C₆Heteroalkyl, unsubstituted C₃-C₁₀Cycloalkyl, unsubstituted C₂-C₉Heterocycloalkyl, unsubstituted C₆-C₁₀Aryl, unsubstituted C₁-C₉Heteroaryl, unsubstituted C₇-C₁₂Aralkyl or unsubstituted C₂-C₁₁A heteroaralkyl substituted group.

As used herein, a phrase defining a limitation of a length range, e.g., "from 1 to 5" means any integer from 1 to 5, i.e., 1, 2, 3, 4, and 5. In other words, any range defined by an explicit reference to 2 integers is intended to include and disclose any integer defining the stated limit, and any integer included in the range.

The invention also includes all isotopes of atoms of the compounds. The isotopes are of the sameOriginal source Ordinal numberBut is differentQuality ofAn atom of a number. For example, tritium and deuterium are isotopes of hydrogen. Examples of carbon isotopes are¹¹C、¹³C and¹⁴C。

therapeutic uses of the compounds of formula (I), their pharmacologically acceptable salts, solvates or hydrates, and formulations and pharmaceutical compositions containing them, are within the scope of the present invention. The invention also relates to the use of these compounds of formula (I) as active ingredients for the preparation or manufacture of medicaments.

The pharmaceutical compositions of the present invention comprise at least one compound of formula (I), and, optionally, one or more carrier substances, excipients and/or adjuvants. The pharmaceutical composition may additionally include, for example, one or more of water, buffers (e.g., natural buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextran), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, and/or preservatives. In addition, one or more other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein. For example, the compounds of the present invention may be advantageously used in combination with an antibiotic, antifungal, or antiviral agent, an antihistamine, a non-steroidal anti-inflammatory agent, a disease-modifying antirheumatic, a cytostatic agent, a drug with smooth muscle modulating activity, or a mixture of the foregoing.

The pharmaceutical composition may be formulated for any suitable mode of administration: including, for example, topical (e.g., transdermal or ocular), oral, buccal, nasal, vaginal, rectal, or parenteral administration. The term "parenteral" as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial, and intraperitoneal injections, and any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Within other further embodiments, the compositions provided herein can be formulated as a lyophilized product. Formulations for topical application may be preferred for certain diseases (e.g., treating skin disorders such as burns or itch).

Compositions intended for oral use may additionally comprise one or more ingredients such as sweetening agents, flavouring agents, colouring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin, or acacia), and lubricating agents (e.g., magnesium stearate, stearic acid, or talc). The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally occurring phosphatidic acids such as lecithin, condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol alcohols such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate). The aqueous suspension may also include one or more preservatives, for example, ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and/or flavoring agents may be added to provide a palatable oral preparation. The suspension may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil (e.g. olive oil or arachis oil), a mineral oil (e.g. liquid paraffin) or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also include one or more sweeteners and/or flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. The formulation may also include one or more demulcents, preservatives, flavors, and/or colors.

The compounds may be formulated for topical (local or topical) administration, such as topical administration to the skin or mucous membranes, e.g., in the eye. Formulations for topical administration typically include a topical excipient in combination with the active ingredient, with or without additional optional ingredients. Suitable topical excipients and additional ingredients are well known in the art, and the choice of excipient will depend on the particular physical form or mode of delivery, as will be apparent. The topical vehicle comprises water; an organic solvent such as an alcohol (e.g., ethanol or isopropanol) or glycerol; glycols (e.g., butylene glycol, isopropylene glycol, or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents, and organic solvents such as mixtures of alcohols and glycerol; lipid-based materials such as fatty acids, acylglycerols (including oils, e.g., mineral oils, and fats of natural or synthetic origin), phosphoglycerides, sphingomyelin, and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices. The composition may additionally include one or more ingredients suitable for improving the stability or effectiveness of the formulation for use, for example, stabilizers, suspending agents, emulsifiers, viscosity modifiers, gelling agents, preservatives, antioxidants, skin penetration enhancers, humectants and sustained release materials. Examples of such ingredients are described in Martindale-additional Pharmacopoeia (The Extra Pharmacopoeia) (Pharmaceutical Press, London, 1993) and Martin (eds.), Remington's Pharmaceutical Sciences. The formulation may comprise microcapsules, for example, hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

Topical formulations can be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays, and skin patches. The physical appearance and viscosity of these forms can be controlled by the presence and amount of emulsifiers and viscosity modifiers present in the formulation. Solids are generally solid and non-pourable and are usually formulated as sticks or sticks, or in special forms; the solids may be opaque or transparent, and optionally may include solvents, emulsifiers, humectants, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are generally similar to each other, differing primarily in viscosity; both lotions and creams may be opaque, translucent, or transparent and typically contain emulsifiers, solvents, and viscosity modifiers, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared to have a range of viscosities, from viscous or high to thin or low. These formulations, like lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels, and generally do not contain emulsifiers. Liquid topical products typically contain solvents, emulsifiers, humectants, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.

Suitable emulsifiers for topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol (cetearyl alcohol), non-ionic emulsifiers such as polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate. Suitable viscosity modifiers include, but are not limited to, protective colloids or nonionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silicon dioxide, microcrystalline wax, beeswax, paraffin wax, and cetyl palmitate. The gel composition may be formed by adding a gelling agent such as: chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaternium, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carbomer, or aminated glycyrrhetate. Suitable surfactants include, but are not limited to, nonionic, amphiphilic, ionic, and anionic surfactants. For example, one or more of dimethicone polyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimethyl ammonium chloride (dimonium chloride), and ammonium lauryl sulfate may be used in the topical formulation.

Suitable preservatives include, but are not limited to, antimicrobials such as methyl paraben, propyl paraben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid, and propyl gallate. Suitable humectants include, but are not limited to, lactic acid and other hydroxy acids and salts thereof, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohols, lanolin derivatives, cholesterol, petrolatum, iso-stearate pivalate and mineral oil. Suitable fragrances and colorants include, but are not limited to, FD & C Red (Red) No.40 and FD & C Yellow (Yellow) No. 5. Other suitable additional ingredients that may be included in the topical formulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, antistatic agents, astringents (e.g., witch hazel, alcohols, and herbal extracts such as chamomile extract), binders/excipients, buffers, chelating agents, film forming agents, conditioning agents, propellants, opacifiers, pH adjusters, and protectants.

Examples of suitable topical excipients for gel formulations are: hydroxypropyl cellulose (2.1%); 70/30 isopropanol/water (90.9%); propylene glycol (5.1%); and polysorbate 80 (1.9%). Examples of suitable topical excipients for foam formulations are: cetyl alcohol (1.1%); stearyl alcohol (0.5%; quaternary ammonium salt-52 (1.0%); propylene glycol (2.0%); ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). all percentages are by weight.

Typical modes of delivering topical compositions include application with a finger; application using a physical applicator such as a cloth, tissue, gauze, stick, or brush; sprays (including mists, aerosols or foam sprays); drip coating; spraying; soaking; and washing. Controlled release excipients can also be used, and the compositions can be formulated as transdermal patches for transdermal administration.

The pharmaceutical compositions may be formulated as an inhalation formulation, including a spray, mist, or aerosol. The formulations are particularly useful in the treatment of asthma or other respiratory diseases. For inhalation formulations, the compounds provided herein can be delivered by any inhalation method known to those skilled in the art. The inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA, or physiologically and environmentally acceptable propellants. Other suitable devices are breath-operated inhalers, multi-dose dry powder inhalers and aerosol nebulizers. The aerosol formulations used in the method of the present invention typically comprise a propellant, a surfactant and a co-solvent and may be filled into a conventional aerosol container which is closed by a suitable metering valve.

The inhalation composition may comprise a liquid or powder composition comprising an active ingredient suitable for nebulization and intrabronchial use, or an aerosol composition administered by dispensing metered doses through an aerosol unit. Suitable liquid compositions include the active ingredient in an aqueous pharmaceutically acceptable inhalation solvent, for example, isotonic saline, or bacteriostatic water. The solution is administered by a pump or squeeze actuated nebulizing spray dispenser, or by any other conventional means, to cause or enable the necessary dose of the liquid composition to be inhaled into the lungs of the patient. Suitable formulations for administration (e.g. as nasal sprays or nasal drops) include aqueous or oily solutions of the active ingredient, where the carrier is a liquid.

Formulations or compositions suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns, which is administered in a nasal inhalation administration (i.e., rapid inhalation through the nasal passage from a container holding the powder to the nose). For example, suitable powder compositions include powder formulations of the active ingredient in intimate admixture with lactose or other inert powders acceptable for intrabronchial administration. The powder composition may be administered by an aerosol dispenser or may be enclosed in a breakable capsule that may be loaded by the patient into a device that punctures the capsule and blows the powder in a steady flow manner suitable for inhalation.

Pharmaceutical compositions may also be prepared in the form of suppositories (e.g., for rectal administration). The compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore dissolve in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

The pharmaceutical compositions may be formulated as sustained release formulations (i.e., formulations such as capsules that effect slow release of the modulator after administration). The formulations can generally be prepared using well-known techniques and administered, for example, by oral, rectal or subcutaneous implantation, or by implantation at the intended target site. The carrier used in the formulation is biocompatible and may also be biodegradable; preferably, the formulation provides a substantially sustained amount of release of the modulating agent. The amount of modulator contained within the sustained release formulation depends, for example, on the site of implantation, the rate and expected duration of release, and the nature of the disease to be treated or prevented.

With respect to the prevention and/or treatment of diseases mediated by BK or analogues thereof, the dosage of the biologically active compounds of the present invention may be varied within a wide range and may be adjusted to suit individual requirements. The active compounds of the present invention are generally administered in a therapeutically effective amount. Preferred dosages range from about 0.1mg to about 140mg/kg body weight/day (about 0.5mg to about 7g per patient per day). The daily dose may be administered in a single dose or in multiple doses. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain from about 1mg to about 500mg of the active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs used to treat the patient), and the severity of the particular disease undergoing therapy.

Preferred compounds of the invention will have some degree of pharmacological properties. Such properties include, but are not limited to, oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.

The 8- (heteroarylmethoxy) quinolines provided herein are useful as agonists or (preferably) antagonists of the BK B2 receptor in a variety of applications (in vitro and in vivo). The B2 receptor antagonists of the present invention are useful for inhibiting the binding of BK B2 receptor ligands (e.g., BK) to BK B2 receptor in vitro or in vivo. The BK B2 receptor modulators provided herein are preferably administered orally or topically to a subject (e.g., a human), and are present within at least one bodily fluid or tissue of the patient when modulating BK B2 receptor activity.

The BK B2 receptor modulators of the present invention are particularly useful for the treatment and/or prevention of disorders or diseases responsive to BK B2 receptor modulation, including skin disorders; ocular diseases; ear diseases; mouth, throat and respiratory diseases; gastrointestinal diseases; liver, gall bladder and pancreatic disorders; urinary tract and kidney disease; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphoid disorders; central nervous system diseases; brain diseases; diseases of the musculoskeletal system; allergic diseases; pain; infectious diseases; inflammatory diseases; (ii) damage; immune diseases; cancer; genetic disease, edema or capillary leak syndrome. Within the scope of the present invention, the compounds of the invention are used as or for the preparation of diagnostic agents for the diagnosis of diseases and conditions to which the compounds of the invention may be directed for therapeutic purposes as disclosed herein.

In the following, various diseases and conditions responsive to BK B2 receptor modulation, and the use of the compounds of the invention in particular methods and diagnostics are further described.

Skin diseases: within this application, the term "dermatological disorders" includes, but is not limited to, diseases such as skin aging, skin rashes including pressure sores (decubitus ulcers), decubitus ulcers (decubitus ulcers), irritated, sensitive and abnormal (dysestmatic) skin, erythema, rash, skin edema, psoriasis, eczema, skin infections caused by lichen, bacteria, viruses, fungi and parasites including boils, abscesses, cellulitis, erysipelas, folliculitis and impetigo, lice, scabies and herpes simplex, acne, exanthemas, dermatitis including atopic dermatitis, allergic contact dermatitis (R) ((R))Scholzen，T.E.；Luger，T.AExpdermatiol.2004; 13, supplement 4: 22-6) neurodermatitis, radiation injury, sunburn, pruritus, itch, urticaria (EP 0622361; frigas, e.; park, m.immunological.allergy clin.northam.2006, 226, 739-51; luquin, e.; kaplan, a.p.; ferrer, m.clin.exp.allergy2005, 35, 456-60; kaplan, a.p.; great, m.w.j.am.acad.dermatol.2005, 53, 373-88; test (quiz)389-92), psoriasis, mycoses, tissue ulceration, epidermolysis bullosa, wounds including abnormal wound healing, burns (Nwariaku, f.e.; sies, p.j.; lightfoot, e.; mileski, w.j.; baxter, c.burns 1996, 22, 324-7; neely, a.n.; imwalle, a.r.; holder, i.a. burns 1996, 22, 520-3), chilblain, skin inflammation and edema caused by venom, baldness, hair scales, corns, warts and paronychia.

Eye diseases: within this application, the term "ocular disease" includes, but is not limited to, inflammatory diseases such as scleritis, conjunctivitis, conjunctival edema, iritis, iridocyclitis, uveitis, chorioretinitis, and diseases such as retinochoroidal circulatory diseases, bacterial ocular infections, undefined conjunctivitis and ocular irritation, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration and including both wet and dry), corneal diseases including corneal graft rejection, corneal trauma, corneal scarring, corneal ulceration, corneal haze, keratoconus, glaucoma (preferably open angle glaucoma), myopia, ocular hypertension, ocular vessel damage, angiogenesis, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular haze, posterior capsular haze, corneal haze after laser surgery, ocular fibrosis, and ocular fibrosis, Subconjunctival scarring following glaucoma surgery), Proliferative Vitreoretinopathy (PVR), bacterial ocular infections including hordeolum and eyelash exfoliation.

Ear diseases: within this application, the term "otic disorder" includes, but is not limited to, disorders such as Meniere's disease, middle ear inflammation, external auditory canal inflammation, and acute hearing loss.

Mouth, throat and respiratory diseases: within this application, the term "mouth, throat and respiratory tract disorders" includes, but is not limited to, disorders such as inflammation of the oral mucosa and gums including aphtha (aphta) and stomatitis, periodontitis, epiglottitis, pharyngitis, tracheopharyngitis, tonsillitis, common cold, angina, rhinitis including seasonal allergic rhinitis or chronic allergic rhinitis, rhinorrhea, sinusitis of any type of etiology or pathogenesis, or sinusitis selected from purulent or nonpsuppurative sinusitis, acute and chronic sinusitis and ethmoid, frontal, maxillary or sphenoid sinusitis, expectoration, pneumoconiosis of any type or origin including, for example, aluminosis pulmonale, carbonous, asbestos-pigmentation, chalasia-pigmentation, siderosis, silicosis, nicotinoidosis, and particularly cotton flock, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophiliaProliferative lung infiltrates, chronic eosinophilic pneumonia, primary pulmonary fibrosis and other fibrotic lung diseases, treatment-related fibrotic lung diseases such as those associated with radioactivity, methotrexate, chemotherapy, amiodarone or nitrofurantoin, sarcoidosis, Acute Respiratory Distress Syndrome (ARDS), any type (Akbary, a.m.; Wirth, k.j.; Scholkens, b.a.immunopharmacogology (immunopharmacology) 1996, 33, 238-42; WO00/75107 a2), etiologic, or pathogenic asthma, or asthma selected from: allergic asthma, non-allergic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental agents, intrinsic asthma caused by pathophysiological disturbances, bronchial asthma, IgE-mediated asthma, atopic asthma and atopic asthma of unknown or unknown cause, true asthma, emphysema asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, incipient asthma syndrome of asthma (wheezy infarnat syndrome), bronchial hyperreactivity, Chronic Obstructive Pulmonary Disease (COPD), COPD characterized by irreversible, progressive airway obstruction, Acute Respiratory Distress Syndrome (ARDS) and exacerbation of airway hyperreactivity to other drug therapy, dyspnea, hypoxic alveolar trauma, emphysema, pleurisy, Tuberculosis, exposure to high altitude, i.e. acute mountain sickness and preferably High Altitude Pulmonary Edema (HAPE).

Gastrointestinal diseases: within this application, the term "gastrointestinal disorder" includes, but is not limited to, conditions including esophagitis, gastritis, stress stomach, gastric and duodenal ulcers, ileus, colonic stress, inflammatory bowel disease including crohn's disease and ulcerative colitis, enteritis, hypertensive gastro-and colonic disease, colitis, peritonitis, cecum inflammation, proctitis, gastrointestinal bleeding caused by portal hypertension, collateral circulation or congestion, gastrectomy retrograde pour syndrome, digestive discomfort, diarrhea, hemorrhoids, helminthiasis, abdominal colic, and colic in the gastrointestinal system.

Liver, gall bladder and pancreatic disorders: (Cugno, M.; Salern)o，F.；Nussberger，J.；Bottasso， B.；Lorenzano，E.；Agostoni，A.Clin.Sci.(Lond)2001，101，651-7；WO 01/56995 A1；EP0797997 B1；Wirth，K.J.；Bickel，M.；Hropot，M.；Gunzler， V.；Heitsch，H.；Ruppert，D.；Scholkens，B.A.Eur.J.Pharmacol.1997，337， 45-53): within this application, the term "liver and gallbladder diseases" includes, but is not limited to, diseases such as hepatitis, cirrhosis, liver fibrosis (e.g., caused by infection with virus (HBV/HCV), toxins (alcohol), fatty liver, cholestasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatogenic edema, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic.

Diseases of the urethra and kidneys: within this application, the term "urinary and renal diseases" includes, but is not limited to, urinary tract infections such as acute and chronic cystitis, interstitial cystitis (Campbell, D.J. Clin. exp. Pharmacol. physiol.2001, 28, 1060-5; Meini, S.; Patacchini, R.; Giuliani, S.; Lazzeri, M.; Turini, D.; Maggi, C.A.; Lecci, A.Eur.J. Pharmacol.2000, 388, 177-82; Zuraw, B.L.; Sugimoto, S.; Parsons, C.L.; Huglii, T.; Lotz, M.; Koziol, J.J.Urol.152, 874-8; Rosaemia, A; Clmilentr. W.W.; T.; Loll. M.; Koziol, J.J.Urol.152, 874-8; Rosaemmilentia, J.W.J.W.; Kelvol.83, C.J.R.J. Ik.R.J. 29, E.R.R.J. 23, E.R.J. urinary incontinence, E.A., benign urinary incontinence, III. (III.; E.A.R.R.R.R.R.R.R.R.R.R.R.R.; benign urinary incontinenceSrinivasan，D.；Kosaka， A.H.；，Daniels，D.V.；Ford，A.P.；Bhattacharya，AEur J Pharmacol (european journal of drugs) 2004, 504 (3): 155-67), urethritis, inflammatory renal diseases including glomerulonephritis, renal glomerular disease, interstitial nephritis, pyelonephritis, diuresis, proteinuria, natriuresis, calnuria, disorders of water balance, disorders of electrolyte balance, disorders of acid-base balance and renal colic, renal fibrosis, and chronic renal allograft dysfunction.

Diseases of male and female reproductive organs: within this application, the term "diseases of the male and female reproductive organs" includes, but is not limited to, altered sperm motility, male infertility, orchitis, prostatitis, prostate enlargement, mastitis, inflammatory pelvic diseases, vaginal infections and pain, adnexitis, vaginitis, soft ulcers (soft ulcus), syphilis, gonorrhea, and ovarian hyperstimulation syndrome (Ujioka, T.; Matsura, K.; Tanaka, N.; Okamura, H.hum Reprod. (human reproduction) 1998 Nov; 13 (11): 3009-15.).

Diseases of the hormonal system: within this application, the term "diseases of the hormonal system" includes, but is not limited to, menstrual abnormalities and pain, climacteric disorders, vomiting, premature uterine contractions, premature delivery, endometriosis, endometritis, myoma.

Metabolic diseases: within this application, the term "metabolic disease" includes, but is not limited to, disorders such as diabetes, including non-insulin dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema (Speicher, m.a.; Danis, r.p.; cridwell, m.; Pratt, l.expert opin. emerg. drugs2003, 8, 239-50; Gao, b.b.; Clermont, a.; look, s.; Fonda, s.j.; Srinivasan, v.j.; Wojtkowski, m.; Fujimoto, j.g.; Avery, r.l.; arigg, p.g.; Bursell, s.e.; Aiello, l.p.; Feener e.p.nat.2007, 13, 181-8; tra nos. p.g.; burseou s.e.; insulin, s.e., t. diabetes mellitus, p. neuropathy, s.g.; diabetic neuropathy, s.90. diabetic neuropathy, p., insulin resistance, and diabetes mellitus, e.g. c.; diabetic neuropathy, insulin resistance, diabetes mellitus, p. f.

Cardiovascular diseases: within this application, the term "cardiovascular disease" includes, but is not limited to, diseases including vascular permeability, vasodilation, peripheral vascular circulation diseases, arterial circulation diseases including aortic aneurysm, abdominal aortic aneurysm, cerebral aortic aneurysm, hypertension and hypotension associated with sepsis, menstruationRestenosis after percutaneous transluminal angioplasty, atherosclerosis including atherosclerotic plaque rupture (Fernando, A.N.; Fernando, L.P.; Fukuda, Y.; Kaplan, A.P. am J Physiol Heart Circuit physiol.2005 month 7; 289 (1): H251-7) hemangioma, angiofibroma, venous diseases such as thrombosis, varicose veins, phlebitis, thrombophlebitis, venous thrombosis, Heart disease, congestive Heart failure, carcinoid syndrome, angina pectoris, cardiac arrhythmias, inflammatory heart diseases including endocarditis, pericarditis and systolic pericarditis, myocarditis, myocardial infarction, post-myocardial infarction syndrome, left ventricular dilation, post-ischemic reperfusion injury, shock and collapse including sepsis, allergic, post-traumatic and hemodynamic shock, amniotic fluid embolism (Robillard, J.; Gauvin, F.; Molinaro, G.; Leduc, L.; Ad A.; Rivard, G.E.am J. Obstet Gynecol.200510 months; 193 (4): 1508-12.). Systemic Inflammatory Response Syndrome (SIRS) includes SIRS caused by cardiopulmonary bypass during surgery (Heart bypass), sepsis, and internal and external complications during cardiopulmonary bypass surgery (including but not limited to adverse hemodynamic effects following protamine sulfate reversal of heparin (Pretorius, M.; Scholl, F.G.; McFarlane, J.A.; Murphey, L.J.; Brown, N.J.. Clin Pharmacol Ther.2005 Nov; 78 (5): 477-85).

Blood diseases: within this application, the term "hematological disorders" includes, but is not limited to, diseases such as coagulation, disseminated intravascular coagulopathy, hemorrhage, hemorrhagic diathesis, hypercholesterolemia, and hyperlipidemia.

Lymphoid disorders: within this application, the term "lymphoid disease" as used herein includes, but is not limited to, splenomegaly, lymphangitis, lymphadenitis, and adenoids.

Central nervous system diseases: within this application, the term "central nervous system disease" includes, but is not limited to, disorders such as inflammatory diseases of the central nervous system including encephalitis, meningitis, encephalomyelitis, meningoencephalitis; hydrocephalus, amyotrophic lateral sclerosis, spinal cordMarrow trauma, spinal cord edema, demyelinating diseases of the nervous system, multiple sclerosis, acute and chronic neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, neuritis and peripheral neuropathy, depression, anorexia, anxiety and schizophrenia.

Brain diseases: within this application, the term "Brain disease" includes, but is not limited to, diseases including positive inotropic or cognitive enhancement, cerebral amyloid angiopathy, stroke, head and Brain trauma, traumatic Brain Injury (Marmarmarrou, A.; Guy, M.; Murphey, L.; Roy, F.; Layani, L.; Combal, J.P.; Marquer, C.; American Brain implant Consortium J Neurotrauma 200512 month; 22 (12): 1444-55) cerebral thermal Injury, cerebral ischemia, hemorrhage, post-traumatic and post-ischemic cerebral edema, general cerebral edema, acute mountain sickness, and preferably High Altitude Cerebral Edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-surgical cerebral edema, cerebral edema associated with metabolic disease, increased permeability or blood Brain tumor barrier.

Diseases of the musculoskeletal system: within this application, the term "musculoskeletal system disease" includes, but is not limited to, conditions such as inflammatory musculoskeletal disease, joint disease, osteoarthropathy, osteoarthritis, chondromas following joint trauma or longer immobilization of a joint following meniscal injury or patella injury or torn ligaments, rheumatoid arthritis of any type, etiology, or pathogenesis including acute arthritis, acute gout arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, lyme arthritis, proliferative arthritis, spondyloarthritis (vertebral arthritis), septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatism, sjogren's syndrome, low back pain, spondylitis, spondyloarthritis, rheumatoid spondylitis, osteomyelitis, sprains, tenosynovitis, bone resorption fractures caused by inflammation, and the like, osteoporosis, musculoskeletal pain and sclerosis, joint pain and stiffness in joints, acute gout arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, hypertrophic arthritis, and ligament injury, Spinal cord disease syndrome (spinal disksyndrome).

Allergic diseases: within this application, the term "allergic disease" includes, but is not limited to, conditions such as general allergic reactions, food allergies, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis, and seasonal or perennial allergic rhinitis (Summers, c.w.; pumphey, r.s.; Woods, c.n.; McDowell, g.; Pemberton, p.w.; Arkwright, p.d.j Allergy Clin Immunol. (journal of Allergy clinical immunology) 2008).

Pain (due to cold or dampness): within this application, the term "pain" includes, but is not limited to, centrally and peripherally mediated pain, vascular pain, visceral pain, inflammation mediated pain, neuropathic pain, bulk pain, nociceptive pain, reflex pain, psychogenic pain, acute pain such as pain caused by bone, muscle, tissue, soft tissue, organs, insect bites, post-stroke pain syndrome, post-operative pain, acute injury to pain associated with progressive disease, trauma or surgery, chronic pain such as chronic pain caused by neuropathic pain disorders (including, but not limited to, complex regional pain syndrome (WO 00/75107A 2; Yamaguchi-Sase, S.; Hayashi, I.; Okamoto, H.; Najima, Y.; Matsuzaki, S.; Hoka, S.; Majima, M.Inflamm. Res in. inflammation research, 2003, 52, 164-9; Eckesen, M.M.P.E.P.K.; Segut S.; Penct. Scott S., g; heppelmann, b.; klusch, a.; kniffki, k.d. neuroscience (neuroscience) 1998, 83, 949-59; birklein, f.; schmelz, m.; schifter, s.; weber, m.neurology (neurology) 2001, 57, 2179-84; weber, m.; birklein, f.; neundorfer, b.; schmelz, m.pain 2001, 91, 251-7), causalgia, sudeck disease, reflex sympathetic dystrophy), diabetic peripheral neuropathy, post herpetic neuralgia, trigeminal neuralgia, pain associated with cancer, pain associated with rheumatoid arthritis, osteoarthritis (Bond, a.p.; lemon, m.; dieppe, p.a.; bholoa, k.d. immunopharmacology (immunopharmacology) 1997, 36, 209-16; cassim, b.; naiduo, s.; ramsound, r.; bholoa, k.d. immunopharmacology (immunopharmacology)Chem) 1997, 36, 121-5; calixto, j.b.; cabrini, d.a.; ferreira, j.; campos, m.m. pain 2000, 87, 1-5; kaneyama, k.; segami, n.; sato, j.; fujimura, k.; nagao, t.; yoshimura, h.j.oral.maxillofac.surg.2007, 65, 242-7), tenosynovitis, gout, menstruation and cramping, fibromyalgia (fibromyalgia), eye pain, back pain, headache, cluster headache, migraine (Ebersberger, a.; ringkamp, m.; reeh, p.w.; handwerker, h.o.j Neurophysiol (journal of neurophysiology) 19976 months; 77(6): 3122-33.), hyperalgesia, and fever. In addition, the compounds of the present invention act as analgesics used during general and monitoring anesthesia.

Infectious diseases: within this application, the term "infectious disease" includes, but is not limited to, conditions including diseases mediated by bacterial, viral, fungal, parasitic, protozoan, prion or mycobacterial infections. In particular, the invention is useful for treating bacterial infections caused by: streptococcus (Streptococcus), Escherichia (Escherichia), Salmonella (Salmonella), Staphylococcus (Staphylocollus), Klebsiella (Klebsiella), Moraxella (Moracella), Haemophilus (Haemophilus) and Yersinia (Yersinia). Examples of bacterial infections intended to be within the scope of the present invention include, but are not limited to, conditions such as plague, sepsis, epidemic typhus, food poisoning, tetanus, scarlet, pertussis, diphtheria. Examples of viral infections intended to be within the scope of the present invention include, but are not limited to, diseases such as chicken pox and shingles, AIDS, influenza, smallpox, and childhood diseases such as measles, rubella, mumps, acute anterior polio. The invention is useful for treating protozoal and parasitic infections caused by: schistosoma mansoni (Schistosoma mansoni), Dermatophagoides farinae (Dematofagoides farinaceae) and Plasmodium (Plasmodium) including malaria. Examples of prion infections intended to be within the scope of the present invention include, but are not limited to, diseases such as Bovine Spongiform Encephalopathy (BSE), creutzfeldt-jakob disease, and kuru.

Inflammatory diseases: within this application, the term "inflammatory disease" includes, but is not limited to, conditions such as acute phase reactions, local and systemic inflammation and inflammation caused by any other species, etiology or pathogenesis and inflammatory diseases as specified within the scope of the present invention.

Injury of the skin: within this application, the term "injury" includes, but is not limited to, multiple trauma, head trauma, lung trauma, external, internal, and surgical wounds.

Immune diseases: within this application, the term "immune disease" includes, but is not limited to, conditions such as hyperesthesia, autoimmune diseases, graft rejection in transplantation, graft toxicity, granulomatous inflammation/tissue remodeling, myasthenia gravis, immunosuppression, immune complex disease, overproduction and underproduction of antibodies, vasculitis.

Cancer treatment: within this application, the term "cancer" includes, but is not limited to, conditions such as solid tumor cancers including breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral and pharyngeal cancers (lip, tongue, mouth, pharynx), esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, colon cancer, rectal cancer, gall bladder cancer and biliary tract cancer, pancreatic cancer, laryngeal cancer, lung cancer, bone cancer, osteosarcoma, connective tissue cancer, skin cancers including Kaposi's syndrome, melanoma and skin metastases, epidermal cancer, basal cell cancer, cervical cancer, endometrial cancer (corosus metrium), ovarian cancer, testicular cancer, bladder cancer, ureter cancer and urinary tract cancer, kidney cancer, eye cancer, brain cancer and central nervous system cancer, pseudobrain tumors, sarcomas, thyroid cancer and other endocrine adenocarcinomas (including, but not limited to carcinoid tumors), Hodgsonia disease, a cancer, Non-hodgkin's lymphoma, multiple myeloma, hematologic malignancies including leukemia and lymphomas including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, metastasis, ascites, tumor growth and angiogenesis.

Genetic diseases: within this application, the term "genetic diseaseDisorders "include, but are not limited to, conditions such as hereditary angioedema (Davis, a.e. et al, 3rd transfus. apher. sci.2003, 29, 195-.

Edema (edema): within this application, the term "edema" includes, but is not limited to, general edema and edema caused by: inflammation, angioedema caused by other drugs such as drugs (Mathellie-Fusade, P. Clin. Rev. Allergy Immunol.2006, 30, 19-23; Finley, C.J. et al. am. J. Emerg. Med.1992, 10, 550-2; Billory, L. et al Allergy Proc.1992, 13, 85-7), infection, burn, injury, trauma, chilblain, surgery, sprain, fracture, exposure to high altitude (e.g., High Altitude Pulmonary Edema (HAPE) and High Altitude Cerebral Edema (HACE)), genetic, autoimmune and other diseases and conditions, particularly but not limited to the symptoms specified in the present invention.

Capillary leak syndrome: within this application, the term "capillary leak syndrome" includes, but is not limited to, systemic capillary leak syndrome caused by: sepsis (Marx, g.eur J analesthesol.200320 (6): 429-42; Traber, d.l.crit Care med.2000, 28 (3): 882-3), burns (Jonkam, c.c.; Enkhbaatar, p.; Nakano, y.; Boehm, t.; Wang, J.; Nussberger, j.esechenhe, a.; Traber, l.d.; Herndon, d.; Traber, d.l. shock.2007 Dec; 28 (6): 704-9), allergies, drug/toxin-induced disorders, organ transplantation, and IL-2 cytokine therapy.

Methodology and diagnostic methods: the compounds of the invention may be labeled as follows: isotopes, fluorescent or luminescent labels, antibodies or antibody fragments, any other affinity labels such as nanobodies, aptamers, peptides, etc., enzymes or enzyme substrates. The labeled compounds of the invention are useful for mapping bradykinin receptors in vivo, ex vivo, in vitro and in situThe location of the body (e.g., by autoradiography within a tissue slice) and as a radiotracer for Positron Emission Tomography (PET) imaging, Single Photon Emission Computed Tomography (SPECT), and the like to characterize those receptors within a living subject or within other materials.

The invention also relates to a method for altering the signal transduction activity of bradykinin receptors in vitro and in vivo. For example, the compounds of the present invention and labeled derivatives thereof are useful as standards and reagents for determining the ability of a potential drug to bind to the BKB2 receptor.

The present invention also provides a method of locating or detecting the BK B2 receptor in a tissue, preferably a tissue section, comprising contacting a tissue sample comprising the BK B2 receptor with a detectable labelled compound of the invention under conditions which allow binding of the compound to the BK B2 receptor and detection of the bound compound. Such methods and their respective conditions are well known to those skilled in the art and include, for example, the radioligand binding assay disclosed in example 754.

The present invention also provides a method of inhibiting the binding of BK or any other B2 receptor ligand to the BK B2 receptor, said method comprising contacting a solution comprising a BK B2 receptor antagonist compound disclosed herein with cells expressing BK B2 receptor under conditions and in an amount sufficient to detect inhibition of the binding of BK or any other substance to BK B2 receptor. The methods and their individual conditions are known to those skilled in the art and include, for example, the calcium mobilization assay disclosed in example 755.

The present invention further provides methods of treating a patient suffering from a disorder responsive to modulation of the BK B2 receptor, as described above. As used herein, the term "treatment" includes both disease-modifying treatment and symptom treatment, either of which may be prophylactic (i.e., to prevent, delay, or reduce the severity of symptoms prior to the onset of symptoms) or therapeutic (i.e., to reduce the severity and/or persistence of symptoms after the onset of symptoms). A disorder is "responsive to BK B2 receptor modulation" if modulation of BK B2 receptor activity results in alleviation of the disorder or symptoms thereof. Patients may include, but are not limited to, primates (particularly humans), domesticated companion animals (e.g., dogs, cats, horses), and livestock (e.g., cattle, pigs, sheep), at dosages as described herein.

The following are also within the scope of the invention: the compounds of the present invention are useful as or in the preparation of diagnostic agents for the diagnosis of diseases and conditions for which the compounds of the present invention are indicated, for therapeutic purposes as disclosed herein.

The compounds of formula (I) of the present invention have improved properties, in particular increased selectivity, low toxicity, low drug-drug interaction, increased bioavailability (in particular with respect to oral administration), increased metabolic stability, increased stability in microsomal degradation assays, and increased solubility, when compared to BK B2 receptor antagonists known in the art.

The invention is now further illustrated by the following examples from which the features, embodiments and advantages of the invention can be understood.

Examples

Preparation of the compound:

preparation of the compound:

the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the invention may be synthesized using the methods described below, together with syntheses known in the art of synthetic organic chemistry, or in variations understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. Each of the documents cited below is incorporated herein by reference.

The abbreviations used in the following examples are as follows:

ACN is acetonitrile

BK is bradykinin

BSA is bovine serum albumin

cpm is counts per minute

DCM is dichloromethane

DIBAL is diisobutylaluminum hydride

DIPEA is ethyl-diisopropyl-amine

DMF being dimethylformamide

DMSO is dimethyl sulfoxide

EA is ethyl acetate

ELISA is an enzyme-linked immunosorbent assay

HBTU is benzotriazol-1-yl- (bis-dimethylamino-methylene) -oxonium; hexafluorophosphates

HBSS is Hanks balanced salt solution

HOAc is glacial acetic acid

HPLC is high performance liquid chromatography

LDA is lithium diisopropylamide

NMP is 1-methyl-pyrrolidin-2-one

Pd(OAc)₂Is palladium (II) acetate

PBS is phosphate buffered saline

PIPES is piperazine-N, N' -bis (2-ethanesulfonic acid)

p-TsOH is toluene-4-sulfonic acid

RT is room temperature

THF is tetrahydrofuran

THP is tetrahydropyranyl

TFA is trifluoroacetate or trifluoroacetic acid

Is saturated

WSC is (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride

Pd(dppf)Cl₂Is (1, 1' -bis (diphenylphosphino) ferrocene) -dichloropalladium (II) & DCM

The compounds shown in Table 1 below are representative examples of compounds of formula (I) of the present invention.

Table 1:

the following examples provide specific examples for the preparation of compounds of formula (I). Unless otherwise specifically indicated, all starting materials and reagents are of standard commercial grade and are used without further purification or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will appreciate that the starting materials and reaction conditions may be varied, including additional steps for preparing compounds encompassed by the present invention.

Example 1: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline

A.4-Imidazol-1-yl-2-methyl-quinolin-8-ol

A mixture of 4-chloro-2-methyl-quinolin-8-ol (2.0g, 10mmol) and imidazole (3.53g, 51.8mmol) was heated to reflux in dioxane (20mL) for 28 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with DCM/methanol 10: 1) to give the title compound. MS (m/z): 226.3[ M + H⁺].

B. (3, 5-dichloro-pyridin-4-yl) -methanol

Reacting NaBH₄(0.838g, 22.2mmol) was added to a stirred solution of 3, 5-dichloro-pyridine-4-carbaldehyde (3.0g, 17mmol) in ethanol (40 mL). After stirring at room temperature for 35 minutes, the reaction mixture was concentrated in vacuo, the residue was redissolved in ethyl acetate (200mL) and washed with water (50 mL). Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo to afford the title compound. MS (m/z): 178.1[ M + H⁺].

C.3, 5-dichloro-4-chloromethyl-pyridine

Adding SOCl₂(2.3mL, 32mmol) was added dropwise to a stirred solution of (3, 5-dichloro-pyridin-4-yl) -methanol (2.83g, 15.9mmol) in DCM (20mL) over 10 min. After stirring at room temperature for 35 minutes, saturated Na was added₂CO₃Aqueous solution (40mL) and DCM (60mL) were added to the reaction mixture. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo. Passing the residue rapidly over silica gelPurification by chromatography (eluting with EA/hexanes 1: 4) gave the title compound. MS (m/z): 196.0[ M + H ]⁺].

8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline

Mixing Cs₂CO₃(59mg, 0.18mmol) 3, 5-dichloro-4-chloromethyl-pyridine (48mg, 0.25mmol) and a vigorously stirred solution of 4-imidazol-1-yl-2-methyl-quinolin-8-ol (20mg, 89. mu. mol) in DMF (1mL) were added. After stirring at room temperature for 18 hours, the solvent was removed in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 385.5[ M + H⁺].

Example 2: n- [3, 5-dichloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -pyridin-2-yl]Synthesis of (E) -N-methyl-acetamide

A.3, 5-dichloro-4-chloromethyl-pyridine 1-oxide

3-methyl-perbenzoic acid (2.9g, 16.8mmol) was added to a solution of 3, 5-dichloro-4-chloromethyl-pyridine (0.55g, 2.8mmol) in DCM (10 mL). After stirring at room temperature for 50 hours, saturated Na was added₂CO₃Aqueous solution (20mL) and DCM (40mL) were added to the reaction mixture. The organic layer is passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/hexane 1: 2) to give the title compound. MS (m/z): 214.2[ M + H⁺].

N- (3, 5-dichloro-4-chloromethyl-pyridin-2-yl) -N-methyl-acetamide

Oxalyl chloride (45 μ L, 0.47mmol) was added dropwise to a solution of N-methyl-acetamide (36 μ L, 0.47mmol) and 2, 6-dimethyl-pyridine (55 μ L, 0.47mmol) in anhydrous DCM (10mL) at 0 ℃. After stirring for 20 min, 3, 5-dichloro-4-chloromethyl-pyridine 1-oxide (10mg, 0.047mmol) was added and stirring was continued at 45 ℃ overnight. Saturated Na₂CO₃Aqueous solution (20mL) and DCM (40mL) were added to the reaction mixture. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/hexanes 1: 3) to give the title compound. MS (m/z): 267.4[ M + H⁺].

C.N- [3, 5-dichloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -pyridin-2-yl ] -N-methyl-acetamide

According to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, N- (3, 5-dichloro-4-chloromethyl-pyridin-2-yl) -N-methyl-acetamide (48mg, 0.18mmol) was reacted with 4-imidazol-1-yl-2-methyl-quinolin-8-ol (20mg, 89 μmol) to give the title compound as a TFA salt. MS (m/z): 456.6[ M + H⁺].

Example 9: n1- [3, 5-dichloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -pyridin-2-yl]Synthesis of (E) -ethane-1, 2-diamine

4-Imidazol-1-yl-2-methyl-8- (2, 3, 5-trichloro-pyridin-4-ylmethoxy) -quinoline

3, 5-dichloro-4-chloromethyl-pyridine 1-oxide (0.93g, 4.4mmol) in POCl₃The solution in (15mL) was stirred at 100 ℃ overnight. After removal of the solvent in vacuo, saturated Na was added₂CO₃Aqueous solution (20mL) and DCM (40mL) were added to the reaction mixture. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo, and the residue was used in the next step without further purification. According to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 2, 3, 5-trichloro-4-chloromethyl-pyridine (0.15g, 0.67mmol) was reacted with 4-imidazol-1-yl-2-methyl-quinolin-8-ol (0.10g, 0.45mmol) to give the title compound as a TFA salt. MS (m/z): 421.4[ M + H⁺].

N1- [3, 5-dichloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -pyridin-2-yl ] -ethane-1, 2-diamine

4-imidazol-1-yl-2-methyl-8- (2, 3, 5-trichloro-pyridin-4-ylmethoxy) -quinoline (20mg, 48 μ M) was stirred in ethane-1, 2-diamine (1mL) for 1 hour at 100 ℃. At the end of the reaction, the solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give the title compound as a TFA salt. MS (m/z): 443.4[ M + H⁺].

Example 15: synthesis of 8- (3, 5-dichloro-2-methoxy-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline

Sodium methoxide (13mg, 0.24mmol) was added to a solution of 4-imidazol-1-yl-2-methyl-8- (2, 3, 5-trichloro-pyridin-4-ylmethoxy) -quinoline (10mg, 24 μ M) in anhydrous methanol (2 mL). After stirring at 60 ℃ for 2h, the solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give the title compound as a TFA salt. MS (m/z): 415.2[ M + H⁺].

Example 44: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -5-fluoro-4-imidazol-1-yl-2-methyl-quinoline

A.5-fluoro-8-methoxy-2-methyl-quinolin-4-ol

5-fluoro-2-methoxy-aniline (3.3g, 23mmol), 3-oxo-butyric acid ethyl ester (3.0g, 23mmol), acetic acid (120. mu.L), anda suspension of (12.0g) in ethanol (20mL) was heated to reflux for 5 days. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (1: 3 EA/hexane) to give crude ethyl 3- (5-fluoro-2-methoxy-phenylamino) -but-2-enoate.

A solution of ethyl 3- (5-fluoro-2-methoxy-phenylamino) -but-2-enoate (1.8g, 6.7mmol) in diphenyl ether (10.7mL) was heated to 250 ℃ for 25 minutes. Cooling the reaction mixtureTo room temperature, diluted with hexanes and filtered to give the title compound. MS (m/z): 208.1[ M + H⁺].

B.4-chloro-5-fluoro-8-methoxy-2-methyl-quinoline

At 0 ℃ adding POCl₃(3.4mL, 36mmol) was added dropwise to 5-fluoro-8-methoxy-2-methyl-quinolin-4-ol (0.56g, 2.7 mmol). Assembling a reaction vessel containing P₄O₁₀The test tube was dried and heated to 118 ℃ for 2 hours. The reaction mixture was concentrated in vacuo and partitioned between DCM (30mL), water (2mL), and concentrated NH₃(2mL) of aqueous solution. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/DCM 1: 15) to give the title compound. MS (m/z): 226.5[ M + H⁺].

C.4-chloro-5-fluoro-2-methyl-quinolin-8-ol

4-chloro-5-fluoro-8-methoxy-2-methyl-quinoline (0.440g, 1.95mmol) was co-evaporated in dry toluene (2X 15 mL). The residue was dissolved in anhydrous DCM (25mL) and BBr was added dropwise at-75 deg.C₃(1M in DCM, 9.8mL, 9.8 mmol). The reaction mixture was warmed to room temperature over 3.5 hours. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (10mL) and water (7 mL). The pH of the aqueous layer was adjusted by adding saturated NaHCO₃Adjusted to 8 with aqueous solution and the aqueous layer extracted with DCM (2X 30 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo to afford the title compound. MS (m/z): 212.3[ M + H⁺].

8- (3, 5-dichloro-pyridin-4-ylmethoxy) -5-fluoro-4-imidazol-1-yl-2-methyl-quinoline

According to the synthesis of 4-imidazol-1-yl-2-methyl-quinolin-8-ol, 4-chloro-5-fluoro-2-methyl-quinolin-8-ol (100mg, 0.47mmol) was reacted with imidazole. The resulting phenol was alkylated according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinolineTo give the title compound as TFA salt. MS (m/z): 403.6[ M + H⁺].

Example 45: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinoline

A.4-bromo-8-methoxy-2-methyl-quinoline

8-methoxy-2-methyl-quinolin-4-ol (9.0g, 48mmol) and POBr₃(53g, 185mmol) was placed in a column containing P₄O₁₀In a round bottom flask of dry test tubes. After stirring at 120 ℃ for 40 minutes, the reaction mixture was cooled to room temperature and poured onto ice. The mixture was then extracted with DCM (2X 200 mL). The combined organic layers were washed with Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/EA 10: 1) to give the title compound. MS (m/z): 252.4[ M + H ]⁺].

B.4-bromo-2-methyl-quinolin-8-ol

At-80 deg.C, BBr₃(1M in DCM, 108mL, 108mmol) was added dropwise to a stirred solution of 4-bromo-8-methoxy-2-methyl-quinoline (7.8g, 31mmol) and triisopropyl-silane (6.2mL, 31mmol) in anhydrous DCM (300 mL). The reaction mixture was warmed to room temperature over 4 hours. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (300mL), water (50mL), and concentrated NH₃(20mL) of aqueous solution. The aqueous layer was extracted with DCM (2X 300 mL). The combined organic layers were washed with Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/EA 10: 1) to give the title compound. MS (m/z): 238.3[ M + H ]⁺].

C.2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol

N-butyllithium (1.6M in hexane, 6.0mL, 9.7mmol) was added dropwise to 1-methyl-1H-imidazole (0.83mL, 11mmol) at-78 deg.CIn a stirred solution in water THF (60 mL). The reaction mixture was warmed to-40 ℃. Then, ZnCl was added dropwise at-40 deg.C₂(3.9g, 28mmol) in dry THF (28 mL). The reaction mixture was warmed to room temperature and then transferred to Pd (PPh)₄)₄(340mg, 0.29mmol) and 4-bromo-2-methyl-quinolin-8-ol (1.0g, 4.2mmol) in anhydrous dioxane (20 mL). After stirring at 80 ℃ for 90 min, the reaction mixture was cooled to room temperature, MeOH (5mL) was added, and the solvent was removed in vacuo. And the residue was partitioned between DCM (150mL) and water (50 mL). The pH of the aqueous layer was adjusted by adding concentrated NH₃Adjusted to 11 with aqueous solution and the aqueous layer was extracted with DCM (2X 100 mL). The combined organic layers were washed with Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 20: 1) to give the title compound. MS (m/z): 240.2[ M + H⁺].

8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinoline

Upon synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol (16mg, 67 μmol) was alkylated to give the title compound as a TFA salt. MS (m/z): 399.8[ M + H⁺].

Example 50: 8- [ 3-chloro-5- (thiazol-2-ylsulfanyl) -pyridin-4-ylmethoxy]Synthesis of (E) -2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinoline

Mixing Cs₂CO₃(0.22g, 0.68mmol) was added to a solution of 3, 5-dichloro-pyridine-4-carbaldehyde (0.10g, 0.57mmol) and thiazole-2-thiol (0.10g, 0.85mmol) in THF (10 mL). After stirring overnight at room temperature, the solvent was removed in vacuo and a saturated aqueous NaCl solution (20mL) and EA (40mL) were added to the reaction mixture. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo, and the residue was used in the next step without further purification. Such as synthetic (3, 5-dichloro-pyri-dine)Pyridine-4-yl) -methanol by reducing the aldehyde group in 3-chloro-5- (thiazol-2-ylsulfanyl) -pyridine-4-carbaldehyde to give [ 3-chloro-5- (thiazol-2-ylsulfanyl) -pyridin-4-yl]Methanol, which is used in the next step without further purification. According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, [ 3-chloro-5- (thiazol-2-ylsulfanyl) -pyridin-4-yl]-conversion of methanol to 3-chloro-4-chloromethyl-5- (thiazol-2-ylsulfanyl) -pyridine and subsequent reaction with 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound as a TFA salt. MS (m/z): 480.2[ M + H⁺].

Example 69: synthesis of 5-chloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -nicotinic acid methyl ester

A.5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -nicotinic acid methyl ester

3, 5-dichloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine (400mg, 1.533mmol), triethylamine (278. mu.L, 1.993mmol), (1, 1' -bis (diphenylphosphino) ferrocene) -dichloropalladium (II) DCM (PdCl) at 120 ℃ under an atmosphere of carbon monoxide (15 bar)₂(dppf)₂DCM, 63mg, 0.077mmol) anda mixture of molecular sieves (600mg) in MeOH (10mL) was stirred for 5 hours. The reaction was filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a hexane/EA mixture) to give the title compound. MS (m/z): 286.0[ M + H⁺]。

B.5-chloro-4-hydroxymethyl-nicotinic acid methyl ester

P-toluenesulfonic acid monohydrate (26.7mg, 0.140mmol) was added to a stirred solution of 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -nicotinic acid methyl ester (20mg, 0.070mmol) in MeOH (4 mL). After stirring at room temperature for 60 minutes, the reaction mixture was concentrated in vacuo and the residue partitioned between EA (10mL) and saturationNaHCO of₃Solution (10 mL). After the aqueous layer was extracted with DCM (2X 10mL), the combined organic layers were extracted with Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 202.0[ M + H⁺].

C.5-chloro-4-chloromethyl-nicotinic acid methyl ester

The polymer bound to triphenylphosphine (3mmol/g, 234mg, 0.702mmol) and CCl were combined₄(400. mu.L) A stirred solution of 5-chloro-4-hydroxymethyl-nicotinic acid methyl ester (14.2mg, 0.070mmol) in DCM (4mL) was added. After stirring at room temperature for 2 hours, the reaction mixture was filtered and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 220.1[ M + H⁺].

5-chloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -nicotinic acid methyl ester

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 4-imidazol-1-yl-2-methyl-quinolin-8-ol (19mg, 0.084mmol) was alkylated with 5-chloro-4-chloromethyl-nicotinic acid methyl ester (25mg, 0.077mmol) at RT for 3 days. Purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA afforded the title compound as the TFA salt. MS (m/z): 409.1[ M + H⁺]。

Example 70: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-methyl-thiazol-4-yl) -quinoline and 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-methyl-thiazol-2-yl) -quinoline

A.4-bromo-5-methyl-thiazole

At room temperature, adding Br₂(3.4mL, 66mmol) was added dropwise to a stirred solution of 5-methyl-thiazole (3.0g, 30mmol) in acetic acid. After stirring at room temperature for 3.5 hours, the reaction mixture was warmed to 50 ℃. After stirring at 50 ℃ for 2 days, Br was added₂(3.4mL, 66 mmol). After stirring at 35 ℃ for 4 days, the reaction mixture was partitioned between DCM (150mL) and concentratedNaCl (50mL) in water. The aqueous layer was extracted with DCM (150 mL). The combined organic layers were washed with Na₂CO₃(1M, 150mL) aqueous solution, sodium thiosulfate pentahydrate aqueous solution (1.2M, 2X 50mL) and Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/hexane 1: 10) to give the title compound. MS (m/z): 180.1[ M + H⁺].

2-methyl-4- (5-methyl-thiazol-4-yl) -quinolin-8-ol and 2-methyl-4- (5-methyl-thiazol-2-yl) -quinolin-8-ol

A solution of 4-bromo-5-methyl-thiazole (129mg, 0.725mmol) in anhydrous THF (2.0mL) was added dropwise to a stirred solution of tert-butyllithium (1.7M in pentane, 1.28mL, 2.17mmol) in anhydrous THF (2.0mL) at-95 ℃. The reaction mixture was warmed to-40 ℃. Then ZnCl is added dropwise at-40 DEG C₂(0.302g, 2.21mmol) in dry THF (28 mL). The reaction mixture was allowed to reach room temperature and then transferred to Pd (PPh)₄)₄(75mg, 0.32mmol) and 4-bromo-2-methyl-quinolin-8-ol (73mg, 0.063mmol) in anhydrous dioxane (1.5 mL). After stirring at 80 ℃ for 90 minutes, the reaction mixture was cooled to room temperature, MeOH (1mL) was added, and the solvent was removed in vacuo. And the residue was partitioned between DCM (30mL) and water (5 mL). The pH of the aqueous layer was adjusted by adding concentrated NH₃Adjusted to 11 with aqueous solution and the aqueous layer extracted with DCM (2X 20 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 20: 1) to give a mixture of the title compounds. MS (m/z): 257.2[ M + H⁺].

C.8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-methyl-thiazol-4-yl) -quinoline and 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-methyl-thiazol-2-yl) -quinoline

Upon synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 2-methylA mixture of yl-4- (5-methyl-thiazol-4-yl) -quinolin-8-ol and 2-methyl-4- (5-methyl-thiazol-2-yl) -quinolin-8-ol (38mg, 0.15mmol) was alkylated to give the pure title compound as the TFA salt. MS (m/z): 416.1[ M + H⁺]。

Example 79: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (2H-pyrazol-3-yl) -quinoline

A.1-Benzyloxymethyl-1H-pyrazoles

Chloromethyl-methyl-benzene (purity 60%, 2.0mL, 14mmol) was added dropwise to a stirred solution of 1H-pyrazole (1.93g, 28.4mmol) in DMF (10mL) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1.5 hours. After the reaction by adding concentrated NH₃(1mL) aqueous solution was quenched. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 1: 20) to afford the title compound. MS (m/z): 189.0[ M + H ]⁺]。

B.4- (2-Benzyloxymethyl-2H-pyrazol-3-yl) -8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-quinoline

According to the synthesis of 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol, 1-benzyloxymethyl-1H-pyrazole (158mg, 0.84mmol) was reacted with 4-bromo-2-methyl-quinolin-8-ol (80mg, 0.340 mmol). The resulting product was alkylated upon synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound as a TFA salt. MS (m/z): 505.84[ M + H⁺].

C.8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (2H-pyrazol-3-yl) -quinoline

A solution of 4- (2-benzyloxymethyl-2H-pyrazol-3-yl) -8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-quinoline TFA salt (10mg) in TFA (1.35mL) and DCM (0.15mL) was stirred in a sealed reaction flask at 80 ℃ for 2.5H. The solvent was removed in vacuo and the residue was used by reverse phase HPLC in water with 0.1% TFAWas purified with an acetonitrile gradient to give the title compound as TFA salt. MS (m/z): 385.0[ M + H⁺].

Example 85: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (4-methyl-thiazol-5-yl) -quinoline

A.8- ((3, 5-dichloropyridin-4-yl) methoxy) -2-methylquinolin-4-ylboronic acid

Bis (pinacolato) diborane) (0.77g, 3.0mmol), 4-bromo-8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-quinoline (0.40g, 1.0mmol), potassium acetate (0.30g, 3.0mmol), and Pd (dppf) Cl₂A suspension of (82mg, 0.10mmol) in deoxygenated anhydrous DMSO (7mL) was heated to 85 ℃ for 2 hours. The solvent was then removed in vacuo and the residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 362.9[ M + H⁺]。

B.8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (4-methyl-thiazol-5-yl) -quinoline

8- ((3, 5-dichloropyridin-4-yl) methoxy) -2-methylquinolin-4-ylboronic acid TFA salt (14.6mg), 5-bromo-4-methyl-thiazole (Takeda; Minato; Yakugaku Zasshi; 71; 1951; 1242; chem. Abstr.; 1952; 5583) (6.0mg, 24. mu. mol), Pd (PPh)₃)₄(2mg, 2. mu. mol), and Na₂CO₃(12mg, 0.11mmol) in deoxygenated dioxane (0.7mL) and deoxygenated H₂The O (70. mu.L) suspension was in a sealed reaction flask and stirred at 100 ℃ for 22 hours. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 416.4[ M + H ]⁺]。

Example 86: 3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl]Synthesis of-pyridin-3-yl } -propionic acid methyl ester

A. (3-bromo-5-chloro-pyridin-4-yl) -methanol

A solution of LDA (7.94mL, 1.8M in THF/heptane/ethylbenzene, 14.3mmol) in dry THF (30mL) was treated dropwise with a solution of 3-bromo-5-chloro-pyridine (2.5g, 13.0mmol) in dry THF (30mL) at-78 deg.C under Ar. The solution was stirred at-78 ℃ for 30 minutes, after which a solution of ethyl formate (10.46mL, 130mmol) in dry THF (30mL) was added dropwise. The resulting solution was stirred at-78 ℃ for 1.5 hours and then with saturated NaHCO₃The treatment was accompanied by vigorous stirring. The quenched mixture was extracted with EA (2X 25mL) and the combined organic extracts were extracted with saturated NaHCO₃(15mL) washed and passed over Na₂SO₄And (5) drying. The residue was purified by flash chromatography on silica gel with EA/hexane to afford 3-bromo-5-chloro-pyridine-4-carbaldehyde as a yellow solid. Following the synthesis of (3, 5-dichloro-pyridin-4-yl) -methanol, the aldehyde was reduced to give the title compound. MS (m/z): 224.0[ M + H⁺]。

B.8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinoline

Following the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, (3-bromo-5-chloro-pyridin-4-yl) -methanol was converted to the corresponding 3-bromo-5-chloro-4-chloromethyl-pyridine chloride and subsequently reacted with 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound as a TFA salt. MS (m/z): 445.3[ M + H⁺].

3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -acrylic acid methyl ester

Pd (OAc)₂(42mg, 0.18mmol) and tri-p-tolyl-phosphine (110mg, 0.36mmol) were added to a solution of 8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinoline (80mg, 0.18mmol) and methyl acrylate (0.30g, 3.5mmol) in DMF (3 mL). The solution was stirred at 90 ℃ for 10 h and then purified by HPLC to give the title compound as a TFA salt. MS (m/z))：449.3[M+H⁺].

3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -propionic acid methyl ester

Reacting NaBH₄(7mg, 0.08mmol) 3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl]-pyridin-3-yl } -acrylic acid methyl ester (8.8mg, 0.02mmol) in MeOH (1 mL). The solution was stirred at 30 ℃ for 1 hour and then purified by HPLC to give the title compound as a TFA salt. MS (m/z): 451.3[ M + H⁺]。

Example 87: 1- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-yl) -2-methoxy-ethanone

A.3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine

3, 4-dihydro-2H-pyran (1.7mL, 19.1mmol) and p-TsOH monohydrate (2.9g, 15.2mmol) were added to a solution of (3-bromo-5-chloro-pyridin-4-yl) -methanol (2.8g, 12.7mmol) in anhydrous DCM (80mL) and the solution was stirred at RT overnight. The mixture was washed with saturated NaHCO₃The organic layer was washed, separated and the aqueous solution was extracted with DCM. The combined organic extracts were passed over Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography on silica gel with EA/hexane to provide the title compound as a yellow solid. MS (m/z): 308.5[ M + H⁺].

1- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl ] -2-methoxy-ethanone

3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine (0.30g, 0.98mmol) was dissolved in anhydrous THF (15mL) under Ar and the solution was cooled to-78 ℃. n-BuLi (0.62mL, 1.6M in hexanes, 0.98mmol) was added dropwise and the reaction mixture was stirred at-78 ℃ for 0.5 h. Thereafter, a solution of methoxy-methyl acetate (0.97mL, 9.8mmol) in anhydrous THF (10mL) was added dropwise and stirring continued at-78 deg.C for 2 hours. Monitored by TLCWhen the reaction is finished, saturated NaHCO is added₃With vigorous stirring. The quenched mixture was extracted with EA (2X 20mL) and the combined organic extracts were extracted with saturated NaHCO₃(20mL) washed and passed over Na₂SO₄And (5) drying. The residue was purified by flash chromatography on silica gel with EA/hexanes to provide the title compound as a colorless oil. MS (m/z): 300.5[ M + H⁺].

C.1- (5-chloro-4-hydroxymethyl-pyridin-3-yl) -2-methoxy-ethanone

Adding p-TsOH monohydrate to 1- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl]-2-methoxy-ethanone (0.14g, 0.46mmol) in ethanol (15 mL). After stirring overnight at RT, the solvent was evaporated and the residue was purified by flash chromatography on silica gel with EA/hexanes to provide the title compound as a colorless oil. MS (m/z): 216.0[ M + H⁺].

1- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -2-methoxy-ethanone

Following the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, 1- (5-chloro-4-hydroxymethyl-pyridin-3-yl) -2-methoxy-ethanone was converted to the corresponding 1- (5-chloro-4-chloromethyl-pyridin-3-yl) -2-methoxy-ethanone chloride and subsequently reacted with 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, the title compound was produced as a TFA salt. MS (m/z): 437.2[ M + H⁺]。

Example 91: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-fluoromethyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

A.4-bromo-2-fluoromethyl-quinolin-8-ol

Lithium diisopropylamide (1.8M in THF, 0.70mL, 1.3mmol) in anhydrous THF (1.0mL) was added dropwise to a solution of 4-bromo-2-methyl-quinolin-8-ol (100mg, 0.420mmol) in anhydrous THF at-80 deg.CWater THF (1.0mL) in a stirred solution. After stirring at-80 ℃ for 1 hour, a solution of N-fluorobenzenesulfonylimide (331mg, 1.05mmol) in anhydrous THF (1mL) was added dropwise at-100 ℃. The reaction mixture was warmed to-20 ℃ and then concentrated by addition of NH₄Aqueous Cl (0.4mL) was quenched. The mixture was partitioned between DCM (30mL) and water (5 mL). The aqueous layer was extracted with DCM (2X 10mL) and the combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM) to give the title compound. MS (m/z): 258.1[ M + H⁺].

B.8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-fluoromethyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

Following the synthesis of 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol, 1-methyl-1H-pyrazole (27mg, 0.33mmol) was coupled with 4-bromo-2-fluoromethyl-quinolin-8-ol (21mg, 0.082mmol) and then alkylated following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound as a TFA salt. MS (m/z): 417.4[ M + H⁺].

Example 94: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4- (2-fluoromethyl-2H-pyrazol-3-yl) -2-methyl-quinoline

A.1-fluoromethyl-1H-pyrazoles

Diethylaminosulfur trifluoride (4.5mL, 34mmol) was added dropwise to a stirred solution of pyrazol-1-yl-methanol (3.34g, 34.1mmol) in anhydrous THF (67mL) at-80 ℃. The reaction mixture was allowed to warm to room temperature and then concentrated in vacuo. And the residue was partitioned between DCM (100mL) and water (30 mL). The pH of the aqueous layer was adjusted by adding solid NHCO₃And adjusted to 8. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo to afford the title compound. MS (m/z): 101.0[ M + H⁺]。

B.8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4- (2-fluoromethyl-2H-pyrazol-3-yl) -2-methyl-quinoline

Following the synthesis of 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol, 4-bromo-2-fluoromethyl-quinolin-8-ol (75mg, 0.32mmol) was coupled with 1-fluoromethyl-1H-pyrazole (79mg, 0.79mmol) using lithium diisopropylamide (1.8M in THF, 0.74mL, 1.3mmol) as the base, and then alkylated following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound as a TFA salt. MS (m/z): 417.0[ M + H ]⁺]。

Example 110: 8- [3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-pyridin-4-ylmethoxy]Synthesis of (E) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

3-chloro-5- (1H-imidazol-2-ylsulfanyl) -pyridine-4-carbaldehyde

3, 5-dichloro-pyridine-4-carbaldehyde (600mg, 3.41mmol), 1H-imidazole-2-thiol (341mg, 3.41mmol), and Cs₂CO₃(1.33g, 4.09mmol) of the mixture was stirred in THF (10mL) at RT for 8.5 h. The solvent was removed in vacuo, and the residue partitioned between EA (30mL) and brine (30 mL). After extraction of the aqueous layer with EA (2X 30mL), the combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 240.0[ M + H ]⁺].

[ 3-chloro-5- (1H-imidazol-2-ylsulfanyl) -pyridin-4-yl ] -methanol

Reacting NaBH₄(30.8mg, 0.82mmol) was added to a stirred solution of 3-chloro-5- (1H-imidazol-2-ylsulfanyl) -pyridine-4-carbaldehyde (130mg, 0.54mmol) in ethanol (4 mL). After stirring at room temperature for 30 min, the reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 242.0[ M + H⁺].

[3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-pyridin-4-yl ] -methanol

Dibutyl sulfate (37.3 μ L, 0.189mmol) was added to [ 3-chloro-5- (1H-imidazol-2-ylsulfanyl) -pyridin-4-yl under argon]Methanol (65mg, 0.270mmol) and 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (DBU, 40.5. mu.L, 0.270mmol) in a stirred solution of DCM (6mL) and DMF (1 mL). After stirring at room temperature for 2.5 h, the reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 298.2[ M + H⁺].

3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-4-chloromethyl-pyridine

Adding SOCl₂(27 μ L, 0.37mmol) of [3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-pyridin-4-yl]Methanol (22mg, 0.74mmol) in a stirred solution of DCM (4 mL). After stirring at room temperature for 1 hour, saturated Na was added₂CO₃Aqueous solution (5mL) and DCM (5mL) were added to the reaction mixture. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 316.1[ M + H⁺].

E.8- [3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-pyridin-4-ylmethoxy ] -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

Mixing Cs₂CO₃(26.5mg, 0.081mmol) 3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-4-chloromethyl-pyridine (21.5mg, 0.068mmol) and a vigorously stirred solution of 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol (17.6mg, 0.074mmol) in DMF (1mL) were added. After stirring at room temperature for 1 hour, the solvent was removed in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 519.1[ M + H⁺].

Example 122: 3- [ 5-chloro-4- (4-imidazol-1-yl-2-Methyl-quinolin-8-yloxymethyl) -pyridin-3-yl]Synthesis of (E) -N, N-dimethyl-propionamide

A.8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 3-bromo-5-chloro-4-chloromethyl-pyridine was reacted with 4-imidazol-1-yl-2-methyl-quinolin-8-ol to give the title compound as a TFA salt. MS (m/z): 431.3[ M + H⁺].

3- [ 5-chloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -pyridin-3-yl ] -N, N-dimethyl-acrylamide

According to (3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl]Synthesis of-pyridin-3-yl } -acrylic acid methyl ester 8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline (10mg, 0.023mmol) was reacted with N, N-dimethyl-acrylamide (46mg, 0.46mmol) to give the title compound as a TFA salt. MS (m/z): 448.6[ M + H⁺].

3- [ 5-chloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -pyridin-3-yl ] -N, N-dimethyl-propionamide

According to 3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl]Synthesis of methyl-pyridin-3-yl-propionate using NaBH₄(2 teaspoon portions) 3- [ 5-chloro-4- (4-imidazol-1-yl-2-methyl-quinolin-8-yloxymethyl) -pyridin-3-yl]Reduction of the vinyl group in-N, N-dimethyl-acrylamide (7.4mg, 0.017mmol) gave the title compound as the TFA salt. MS (m/z): 450.4[ M + H ]⁺].

Example 126: 8- [ 3-chloro-5- (2-methanesulfonyl-ethyl) -pyridin-4-ylmethoxy]Synthesis of (E) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

A.8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 3-bromo-5-chloro-4-chloromethyl-pyridine was reacted with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol to give the title compound as a TFA salt. MS (m/z): 445.2[ M + H⁺].

B.8- [ 3-chloro-5- (2-methanesulfonyl-vinyl) -pyridin-4-ylmethoxy ] -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

According to (3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl]Synthesis of-pyridin-3-yl } -acrylic acid methyl ester 8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline (15mg, 0.034mmol) was reacted with methanesulfonyl-ethylene (59.2mL, 0.68mmol) to give the title compound as a TFA salt. MS (m/z): 469.2[ M + H⁺].

C.8- [ 3-chloro-5- (2-methanesulfonyl-ethyl) -pyridin-4-ylmethoxy ] -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

According to 3- { 5-chloro-4- [ 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-yloxymethyl]Synthesis of methyl-pyridin-3-yl-propionate using NaBH₄(5.3mg, 0.14mmol) reduction of 8- [ 3-chloro-5- (2-methanesulfonyl-vinyl) -pyridin-4-ylmethoxy-l]Vinyl group in-2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline (6.6mg, 0.014mmol) to give the title compound as a TFA salt. MS (m/z): 471.3[ M + H⁺].

Example 138: synthesis of 8- (3-chloro-5-methoxymethyl-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline

A.5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine-3-carbaldehyde

According to 1- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl]Synthesis of-2-methoxy-ethanone 3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine (0.36g, 1.0mmol) was reacted with ethyl formate (1.6mL, 20mmol) to give the title compound. MS (m/z): 256.0[ M + H⁺].

[ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl ] -methanol

Following the synthesis of (3, 5-dichloro-pyridin-4-yl) -methanol, the aldehyde group in 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine-3-carbaldehyde was reduced to give the title compound. MS (m/z): 258.2[ M + H⁺]。

C. (3-chloro-5-methoxymethyl-pyridin-4-yl) -methanol

Add NaH (7mg, 0.16mmol) and methyl iodide (14.2. mu.L, 0.22mmol) to [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl at 0 deg.C]Methanol (39mg, 0.15mmol) in DMF (1.5mL) and stirring was continued at RT overnight. HPLC purification and subsequent purification by in ACN/H from HPLC₂The tetrahydropyranyl group was deprotected by stirring 3-chloro-5-methoxymethyl-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine in O solution for 3 hours to give the title compound as TFA salt. MS (m/z): 188.3[ M + H⁺].

8- (3-chloro-5-methoxymethyl-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline

Following the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, (3-chloro-5-methoxymethyl-pyridin-4-yl) -methanol was converted to the corresponding 3-chloro-4-chloromethyl-5-methoxymethyl-pyridine chloride and subsequently reacted with 4-imidazol-1-yl-2-methyl-quinolin-8-ol following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinolin-e-l to give the title compound as a TFA salt. MS (m/z): 395.2[ M + H ]⁺].

Example 165: 2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -1-oxy-pyridin-3-sulfinyl } -N, N-dimethyl-acetamide

A. (3-chloro-5-mercapto-pyridin-4-yl) -methanol

3, 5-dichloro-pyridine-4-carbaldehyde (3.00g, 17.05mmol) and sodium hydrosulfide were added under argonThe mixture of hydrates (70% flakes, 1.37g, 17.05mmol) was stirred in DMF (20mL) at 0 ℃ for 15 min. Adding NaBH₄(8.52g, 17.05 mmol). After 30 minutes at 0 ℃, the solution was filtered and the solvent was removed in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 176.0[ M + H⁺].

B.2- (5-chloro-4-hydroxymethyl-pyridin-3-ylsulfanyl) -N, N-dimethyl-acetamide

NaHCO is added₃(944mg, 1.71mmol) was added to a stirred solution of (3-chloro-5-mercapto-pyridin-4-yl) -methanol (300mg, 1.71mmol) and 2-chloro-N, N-dimethyl-acetamide (176. mu.L, 1.71mmol) in DMF (5 mL). After stirring at room temperature for 15 minutes, the solvent was removed in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 260.9[ M + H⁺].

C.2- (5-chloro-4-chloromethyl-pyridin-3-ylsulfanyl) -N, N-dimethyl-acetamide

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, 2- (5-chloro-4-hydroxymethyl-pyridine-3-sulfanyl) -N, N-dimethyl-acetamide (188mg, 0.72mmol) was reacted with SOCl₂Chlorinated, and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 279.3[ M + H⁺].

2- (5-chloro-4-chloromethyl-1-oxy-pyridin-3-sulfinyl) -N, N-dimethyl-acetamide

H is to be₂O₂(30% solution, 576mg, 5.64mmol) was added to a stirred solution of 2- (5-chloro-4-chloromethyl-pyridin-3-ylsulfanyl) -N, N-dimethyl-acetamide (56mg, 0.201mmol) in HOAc (10 mL). After stirring at 50 ℃ for 1 day, the solvent was removed in vacuo. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 310.9[ M + H⁺].

E.2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -1-oxy-pyridin-3-sulfinyl } -N, N-dimethyl-acetamide

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 2- (5-chloro-4-chloromethyl-1-oxy-pyridin-3-sulfinyl) -N, N-dimethyl-acetamide (6.2mg, 0.020mmol) was alkylated with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol (6.2mg, 0.026mmol) to give the title compound as a TFA salt. MS (m/z): 514.0[ M + H⁺].

Example 166: 8- [ 3-chloro-5- (thiazol-2-ylsulfanyl) -pyridin-4-ylmethoxy]Synthesis of (E) -4-isopropyl-2-methyl-quinoline

A.4-isopropyl-2-methyl-quinolin-8-ol

ZnCl is reacted at-92 DEG C₂A solution of (0.29g, 2.1mmol) in dry THF (2.1mL) was added dropwise to a stirred solution of lithium isopropyl (0.7M in pentane, 1.6mL, 1.1 mmol). The reaction mixture was allowed to reach room temperature, then transferred to a suspension of dichloro (1, 2-bis (diphenylphosphino) ethane) palladium (II) (36mg, 0.063mmol) and 4-bromo-2-methyl-quinolin-8-ol (75mg, 0.32mmol) in anhydrous dioxane (1.1 mL). After stirring at 80 ℃ for 2h, the reaction mixture was cooled to room temperature, MeOH (5mL) was added, and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 20: 1) to give the title compound. MS (m/z): 202.2[ M + H⁺].

B.8- [ 3-chloro-5- (thiazol-2-ylsulfanyl) -pyridin-4-ylmethoxy ] -4-isopropyl-2-methyl-quinoline

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 4-isopropyl-2-methyl-quinolin-8-ol (25mg, 0.12mmol) was alkylated with 3-chloro-4-chloromethyl-5- (thiazol-2-ylsulfanyl) -pyridine (24mg, 0.087mmol) to give the title compound as a TFA salt. MS (m/z): 442.1[ M + H⁺].

Example 167: 8- [ 2-chloro-4- (thiazol-2-ylsulfanyl) -pyridin-3-ylmethoxy]Synthesis of (E) -4-imidazol-1-yl-2-methyl-quinoline

A.2-chloro-4- (thiazol-2-ylsulfanyl) -pyridine-3-carbaldehyde

Upon synthesis of 3-bromo-5-chloro-pyridine-4-carbaldehyde, the formyl group was introduced into 2, 4-dichloro-pyridine, and then reacted with thiazole-2-thiol following synthesis of 3-chloro-5- (thiazol-2-ylsulfanyl) -pyridine-4-carbaldehyde to yield the title compound. MS (m/z): 257.2[ M + H⁺].

[ 2-chloro-4- (thiazol-2-ylsulfanyl) -pyridin-3-yl ] -methanol

The aldehyde group in 2-chloro-4- (thiazol-2-ylsulfanyl) -pyridine-3-carbaldehyde was reduced as described for the synthesis of (3, 5-dichloro-pyridin-4-yl) -methanol to give the title compound, which was used in the following step without further purification. MS (m/z): 259.2[ M + H⁺].

C.8- [ 2-chloro-4- (thiazol-2-ylsulfanyl) -pyridin-3-ylmethoxy ] -4-imidazol-1-yl-2-methyl-quinoline

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, [ 2-chloro-4- (thiazol-2-ylsulfanyl) -pyridin-3-yl]-conversion of methanol to the corresponding 2-chloro-3-chloromethyl-4- (thiazol-2-ylsulfanyl) -pyridine chloride, and subsequent reaction with 4-imidazol-1-yl-2-methyl-quinolin-8-ol according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinolin-e, gives the title compound as TFA salt. MS (m/z): 466.0[ M + H⁺].

Example 171: 2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylsulfanyl) -N-isopropyl-N-methyl-acetamide

A. Bromo-acetic acid 2, 4-dinitro-phenyl ester

Bromo-acetyl bromide (2.67mL, 30.66mmol) dissolved in DCM (15mL) under argon at 0 ℃ over 15 minA mixture of 2, 4-dinitro-phenol (5.13g, 27.88mmol) and pyridine (2.92mL, 36.24mmol) in DCM (40mL) was added. After RT1 hours, aqueous citric acid (10%, 30mL) was added to the reaction mixture. Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo. The resulting residue was recrystallized from diethyl ether (75mL) to provide the title compound.

B.2-bromo-N-isopropyl-N-methyl-acetamide

Isopropyl-methyl-amine (154 μ L, 1.48mmol) was added to a stirred solution of 2, 4-dinitro-phenyl bromo-acetate (450mg, 1.48mmol) in DCM (4 mL). After stirring at room temperature for 3 hours, the organic layer was extracted 2 times with 0.1M NaOH solution (30 mL). Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 194.0[ M + H ]⁺]。

C.2- (5-chloro-4-hydroxymethyl-pyridin-3-ylsulfanyl) -N-isopropyl-N-methyl-acetamide

According to the synthesis of 2- (5-chloro-4-hydroxymethyl-pyridin-3-ylsulfanyl) -N, N-dimethyl-acetamide, (3-chloro-5-mercapto-pyridin-4-yl) -methanol (145mg, 0.83mmol) was alkylated with 2-bromo-N-isopropyl-N-methyl-acetamide (160mg, 0.83mmol) to give the title compound as a TFA salt. MS (m/z): 289.0[ M + H⁺].

2- (5-chloro-4-chloromethyl-pyridin-3-ylsulfanyl) -N-isopropyl-N-methyl-acetamide

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, 2- (5-chloro-4-hydroxymethyl-pyridin-3-ylsulfanyl) -N-isopropyl-N-methyl-acetamide (7.5mg, 0.026mmol) was reacted with SOCl₂Chlorinated to give the title compound. MS (m/z): 307.0[ M + H⁺].

E.2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylsulfanyl } -N-isopropyl-N-methyl-acetamide

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol (5.86mg, 0.025mmol) was alkylated with 2- (5-chloro-4-chloromethyl-pyridin-3-ylsulfanyl) -N-isopropyl-N-methyl-acetamide (7.5mg, 0.024mmol) to give the title compound as a TFA salt. MS (m/z): 510.2[ M + H⁺].

Example 193: n- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl) -isobutyramide

3-azidomethyl-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine

Reacting [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl]Methanol (1.3g, 4.9mmol), diphenylphosphoryl azide (1.4mL, 6.4mmol) and 2, 3, 4, 6, 7, 8, 9, 10-octahydro-pyrimido [1, 2-a ]]Aza derivativesA solution of (0.96mL, 6.4mmol) in toluene (0.15mL) was stirred at RT overnight. The solvent was concentrated in vacuo, and the residue was partitioned between DCM (10mL) and saturated NaCl solution (10 mL). After extraction of the aqueous layer with DCM (2X 10mL), the combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with hexane/EA 3: 1) to give the title compound. MS (m/z): 282.9[ M + H⁺].

B.C- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl ] -methylamine

3-azidomethyl-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine (0.46g, 1.6mmol) and triphenylphosphine (0.43g, 1.6mmol) in THF (15mL) and H₂A solution in O (0.15mL) was stirred at RT overnight. The solvent was concentrated in vacuo, and the residue was partitioned between DCM (10mL) and saturated NaHCO₃Solution (10 mL). With DCMAfter extraction of the aqueous layer (2X 10mL), the combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 256.8[ M + H ]⁺].

C.N- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ] -isobutyramide

DIPEA (0.41mL, 2.2mmol) and isobutyryl chloride (0.18mL, 1.6mmol) were added to C- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl]-methylamine (0.37g, 1.4mmol) in DCM (20 mL). Stirring was continued at RT overnight. The solvent was evaporated and the residue was used in the next step without further purification. MS (m/z): 326.9[ M + H⁺].

D.N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -isobutyramide

Based on the synthesis of 1- (5-chloro-4-hydroxymethyl-pyridin-3-yl) -2-methoxy-ethanone, N- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl]Deprotection of the tetrahydropyranyl group in isobutyramide yields the title compound. MS (m/z): 243.0[ M + H⁺].

E: n- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -isobutyramide

Conversion of N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -isobutyramide to the corresponding chlorinated N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -isobutyramide following the synthesis of 3, 5-dichloro-4-chloromethyl-isobutyramide and subsequent reaction with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline yields the title compound, it is a TFA salt. MS (m/z): 464.1[ M + H ]⁺]。

Example 179: 3- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl } -1, 1-dimethyl-urea

C- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -methylamine

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-pyridin-3-yl } -methanol is converted to the corresponding chloride yielding benzoyl chloride, which is used in the next step without further purification. 8- (3-chloro-5-chloromethyl-pyridin-4-ylmethoxy) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline (6.2mg, 0.015mmol) in 2M NH₃Was stirred at 45 ℃ for 2 hours in a solution of ethanol (0.3 mL). The solvent was evaporated to dryness and the residue was used in the next step without further purification. MS (m/z): 394.1[ M + H⁺].

3- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -1, 1-dimethyl-urea

Dimethylcarbamoyl chloride (5.1. mu.L, 0.056mmol) was added to C- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-pyridin-3-yl } -methylamine (11mg, 0.028mmol) and DIPEA (9.4. mu.L, 0.056mmol) in DCM (0.5mL) and stirring was continued at RT for 2 h. Evaporation of the solvent and HPLC purification yielded the title compound as a TFA salt. MS (m/z): 465.0[ M + H⁺].

Example 181: n- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl } -N-methyl-acetamide

A. (3-chloro-5-methylaminomethyl-pyridin-4-yl) -methanol

A solution of 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine-3-carbaldehyde (25mg, 0.098mmol) and methylamine (0.49mL, 0.98mmol) in methanol (1.5mL) and acetic acid (0.25mL) was stirred at RT overnight. Adding NaBH₃CN (6.8mg, 0.1mmol) and stirring was continued for 6 h. The solvent was evaporated and the residue was purified by HPLC. Followed by HPLC on ACN/H₂Stirring in O solution [ 5-chloro-4- (tetrahydro)-pyran-2-yloxymethyl) -pyridin-3-ylmethyl]Methyl-amine for 3 hours to deprotect the tetrahydropyranyl group to yield the title compound as TFA salt. MS (m/z): 187.0[ M + H ]⁺].

N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -N-methyl-acetamide

Acetic anhydride (46mL, 0.49mmol) was added to a solution of (3-chloro-5-methylaminomethyl-pyridin-4-yl) -methanol (15mg, 0.049mmol) in methanol (0.5mL) and stirring was continued at RT for 5 h. The solvent was evaporated and the residue was used in the next step without further purification. MS (m/z): 228.9[ M + H⁺].

C.N- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -N-methyl-acetamide

Following the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -N-methyl-acetamide was converted to the corresponding chlorinated N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -N-methyl-acetamide, and subsequently following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, reacted with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol, the title compound was produced as a TFA salt. MS (m/z): 450.1[ M + H⁺].

Example 183: dimethyl-carbamic acid 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl ester

A. Dimethyl-carbamic acid 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ester

Dimethylcarbamoyl chloride (0.39. mu.L, 2.15mmol) was added to [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl]A solution of methanol (0.11g, 0.43mmol) and NaH (17mg, 0.86mmol) in DMF (3mL) and stirring was continued at RT overnight. The solvent was concentrated in vacuo, and the residue was partitioned between EA (10mL) and saturated NaCl solution (10 mL). After extraction of the aqueous layer with EA (2X 10mL), the combined organic layersThe organic layer passes Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 328.9[ M + H⁺].

B. Dimethyl-carbamic acid 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl ester

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, while deprotecting the tetrahydropyranyl and converting dimethyl-carbamic acid 5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl ester to the corresponding chlorinated dimethyl-carbamic acid 5-chloro-4-chloromethyl-pyridin-3-ylmethyl ester, and subsequent reaction with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, the title compound was produced as a TFA salt. MS (m/z): 466.0[ M + H⁺].

Example 192: acetic acid 1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-yl } -ethyl ester

1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -ethanone

According to { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of-pyridin-3-yl } -acetaldehyde 8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline (0.1g, 0.22mmol) was reacted with ethyl vinyl ether (0.32g, 4.5mmol) to give the title compound as a TFA salt. MS (m/z): 407.2[ M + H⁺].

B.1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -ethanol

Reduction of 1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl-according to the Synthesis of (3, 5-dichloro-pyridin-4-yl) -methanol]-pyridin-3-yl } -ethanone to give the title compound. MS (m/z): 409.0[ M + H⁺].

C. Acetic acid 1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -ethyl ester

1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl according to the synthesis of 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ester]-pyridin-3-yl } -ethanol (5.8mg, 0.014mmol) was reacted with acetic anhydride (6.7 μ L, 0.07mmol) and purified by HPLC to give the title compound as a TFA salt. MS (m/z): 451.0[ M + H⁺].

Example 195: 8- [ 3-chloro-5- (pyridin-2-yloxy) -pyridin-4-ylmethoxy]Synthesis of (E) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

3-chloro-5- (pyridin-2-yloxy) -pyridines

A mixture of 5-chloro-pyridin-3-ol (1000mg, 7.72mmol), potassium tert-butoxide (866mg, 7.72mmol) and 2-chloro-pyridine (730g, 7.72mmol) in DMF (6mL) was stirred at 130 ℃ for 3 h. The solvent was removed in vacuo, and the residue was partitioned between DCM (50mL) and 2N NaOH solution (50 mL). After extraction of the aqueous layer with DCM (6X 50mL), the combined organic layers were passed over MgSO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a mixture of hexane and EA) to give the title compound. MS (m/z): 207.2[ M + H⁺].

3-chloro-5- (pyridin-2-yloxy) -pyridine-4-carbaldehyde

3-chloro-5- (pyridin-2-yloxy) -pyridine (169mg, 0.82mmol) in THF (5mL) was added over 4 minutes to a stirred solution of lithium diisopropylamide (500 μ L of a 2M solution in THF/heptane/ethylbenzene, 0.90mmol) in THF (10mL) under argon and at-90 deg.C. After stirring at-90 ℃ for 30 min, ethyl formate (657. mu.L, 8.18mmol) in THF (5mL) was added immediately. The reaction was stirred at-90 ℃ for 1.6 h and ice-cold saturated NaHCO was poured in₃Aqueous solution (100 mL). EA (100mL) was added and the aqueous layer was washed with EA (2X 50 m)L) extraction and the combined organic layers are washed with saturated NaHCO₃Aqueous (2X 50mL) solution and brine (3X 50 mL). The organic layer was passed over MgSO₄Dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 235.2[ M + H⁺].

[ 3-chloro-5- (pyridin-2-yloxy) -pyridin-4-yl ] -methanol

A mixture of 3-chloro-5- (pyridin-2-yloxy) -pyridine-4-carbaldehyde (83mg, 0.36mmol) and polymer-bound sodium borohydride (184mg, 2.0mmol/g, 0.57mmol) in DMF (1mL) was stirred at RT for 30 min. The reaction was filtered and the solvent was removed in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 237.0[ M + H⁺].

3-chloro-4-chloromethyl-5- (pyridin-2-yloxy) -pyridine

According to the synthesis of 3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-4-chloromethyl-pyridine, [ 3-chloro-5- (pyridin-2-yloxy) -pyridin-4-yl]Methanol (4.24mg, 0.018mmol) with SOCl₂Chlorinated to give the title compound. MS (m/z): 255.0[ M + H⁺].

E.8- [ 3-chloro-5- (pyridin-2-yloxy) -pyridin-4-ylmethoxy ] -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

According to 8- [3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-pyridin-4-ylmethoxy]-Synthesis of 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline, 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol (10.7mg, 0.045mmol) was alkylated with 3-chloro-4-chloromethyl-5- (pyridin-2-yloxy) -pyridine to give the title compound as a TFA salt. MS (m/z): 458.0[ M + H⁺].

Example 196: 2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-pyridin-3-yloxySynthesis of yl } -N, N-dimethyl-acetamide

3, 5-dichloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine

Dihydropyran (3.01mL, 33.2mmol) and p-toluenesulfonic acid monohydrate (5.06g, 26.6mmol) were added to a stirred solution of (3, 5-dichloro-pyridin-4-yl) -methanol (1.97g, 11.06mmol) in DCM (40 mL). After stirring at 40 ℃ for 1 day, the solvent was removed in vacuo and the residue was partitioned between DCM (50mL) and saturated NaHCO₃Solution (50 mL). After extraction of the aqueous layer with DCM (2X 50mL), the combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a mixture of hexane and EA) to give the title compound. MS (m/z): 261.9[ M + H⁺].

B.5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ol

Potassium tert-butoxide (1.77g, 15.80mmol) was added to a stirred solution of 3, 5-dichloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine (825mg, 3.16mmol) in dioxane. After stirring at 100 ℃ for 3 days, the solvent was removed in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 243.8[ M + H⁺].

C.2- (5-chloro-4-hydroxymethyl-pyridin-3-yloxy) -N, N-dimethyl-acetamide

2-chloro-N, N-dimethyl-acetamide (85 μ L, 0.827mmol) was added to 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ol (67mg, 0.276mmol) and Cs₂CO₃(134.7mg, 0.414mmol) in THF (5mL) with stirring. After stirring at 50 ℃ for 1 day, the solution was filtered and the solvent was removed in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA. The THP ether was cleaved after 3h of HPLC fraction storage at RT to give the title compound as a TFA salt. MS (m/z): 243.8[ M + H⁺].

2- (5-chloro-4-chloromethyl-pyridin-3-yloxy) -N, N-dimethyl-acetamide

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, 2- (5-chloro-4-hydroxymethyl-pyridin-3-yloxy) -N, N-dimethyl-acetamide (4mg, 0.016mmol) was reacted with SOCl₂Chlorinated, and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 263.0[ M + H⁺].

E.2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yloxy } -N, N-dimethyl-acetamide

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 4-imidazol-1-yl-2-methyl-quinolin-8-ol (3.6mg, 0.015mmol) was alkylated with 2- (5-chloro-4-chloromethyl-pyridin-3-yloxy) -N, N-dimethyl-acetamide (3mg, 0.011mmol) to give the title compound as a TFA salt. MS (m/z): 466.1[ M + H⁺].

Example 198: 8- [ 3-chloro-5- (tetrahydro-pyran-2-ylmethoxy) -pyridin-4-ylmethoxy-l]Synthesis of (E) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

[ 3-chloro-5- (tetrahydro-pyran-2-ylmethoxy) -pyridin-4-yl ] -methanol

2-bromomethyl-tetrahydro-pyran (98.1 μ L, 0.766mmol) was added to 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ol (23.3mg, 0.096mmol) and Cs₂CO₃(249mg, 0.764mmol) in THF (5mL) with stirring. After stirring at 120 ℃ for 1 day, the solution was filtered and the solvent was removed in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA. The HPLC fractions were stored at RT for 3 hours before cleaving the THP ether to give the title compound as a TFA salt. MS (m/z): 258.1[ M + H⁺].

3-chloro-4-chloromethyl-5- (tetrahydro-pyran-2-ylmethoxy) -pyridine

According toSynthesis of 3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-4-chloromethyl-pyridine by reacting [ 3-chloro-5- (tetrahydro-pyran-2-ylmethoxy) -pyridin-4-yl]Methanol (10mg, 0.039mmol) with SOCl₂And (4) chlorination. The title compound obtained was used in the following reaction without purification. MS (m/z): 276.0[ M + H⁺].

C.8- [ 3-chloro-5- (tetrahydro-pyran-2-ylmethoxy) -pyridin-4-ylmethoxy ] -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline

According to 8- [3- (1-butyl-1H-imidazol-2-ylsulfanyl) -5-chloro-pyridin-4-ylmethoxy]Synthesis of-2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline 4-imidazol-1-yl-2-methyl-quinolin-8-ol (4mg, 0.016mmol) was alkylated with 3-chloro-4-chloromethyl-5- (tetrahydro-pyran-2-ylmethoxy) -pyridine (4mg, 0.015mmol) (40 ℃ C. for 2 hours). Purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA afforded the title compound as the TFA salt. MS (m/z): 479.2[ M + H⁺].

Example 205: 2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ylhydrylmethyl]Synthesis of (E) -pyridin-3-yl } -N, N-dimethyl-acetamide

{ 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -acetaldehyde

A solution of 8- (3-bromo-5-chloro-pyridin-4-ylmethoxy) -2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinoline (0.1g, 0.22mmol), ethyl vinyl ether (0.32g, 4.5mmol), palladium (II) acetate (15mg, 0.067mmol), tri-p-tolyl-phosphine (0.14g, 0.45mmol), and DIPEA (76. mu.L, 0.45mmol) in DMF (3mL) was stirred at 120 ℃ for 2 hours. HPLC purification yielded the title compound as a TFA salt. MS (m/z): 407.2[ M + H⁺].

{ 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -acetic acid

Adding NaClO at 0 deg.C₂(3.6mg, 0.040mmol) was added { 5-chloro-4- [ 2-methyl-4- (2-methyl-2)H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-pyridin-3-yl } -acetaldehyde (3.3mg, 0.0081mmol), 2, 3-dimethyl-2-butene (3.4mg, 0.040mmol) and KH₂PO₄(5.5mg, 0.040mmol) of tert-butanol (2.5mL) and H₂O (0.5mL) and stirring was continued at this temperature for 30 minutes. The solvent was evaporated and the residue was purified by HPLC to give the title compound as a TFA salt. MS (m/z): 423.1[ M + H⁺].

2- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-yl } -N, N-dimethyl-acetamide

N, N' -diisopropylcarbodiimide (0.98mg, 0.0078mmol) was added to { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-pyridin-3-yl } -acetic acid (2.2mg, 0.0052mmol), N-hydroxybenzotriazole (1.0mg, 0.0078mmol) and DIPEA (3.5mg, 0.026mmol) and stirring was continued at RT for 2 h. The solvent was evaporated and the residue purified by HPLC to give the title compound as a TFA salt. MS (m/z): 450.0[ M + H ]⁺].

Example 216: synthesis of 2-chloro-8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4- (2-methyl-imidazol-1-yl) -quinoline

A.2-chloro-8-methoxy-4- (2-methyl-imidazol-1-yl) -quinoline

A mixture of 2, 4-dichloro-8-methoxy-quinoline (0.20g, 0.88mmol) and 2-methyl-1H-imidazole (0.11g, 1.3mmol) was heated to 140 ℃ in NMP (0.20mL) for 20 hours. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 419.0[ M + H⁺].

2-chloro-8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4- (2-methyl-imidazol-1-yl) -quinoline

According to the synthesis of 4-chloro-5-fluoro-2-methyl-quinolin-8-ol, 2-chloro-8-methoxy-4- (2-methyl-imidazol-1-yl) -quinoline TFA salt (50mg) was demethylated, and then according to 8- (2-methyl-imidazol-1-yl) -quinoline TFA saltSynthesis of 3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline proceeds to alkylation to give the title compound as a TFA salt. MS (m/z): 403.6[ M + H⁺].

Example 230: propane-2-sulfonic acid { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl) -methyl-amide

A. Propane-2-sulfonic acid (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -methyl-amide

Isopropylsulfonyl chloride (60mg, 0.42mmol) was added to [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl]A solution of-methyl-amine (57mg, 0.21mmol) in DCM (0.8mL) and pyridine (0.4mL) and stirring was continued at 50 ℃ overnight. Evaporation of the solvent, purification by HPLC, and subsequent purification by addition of ACN/H from HPLC₂Stirring propane-2-sulfonic acid [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl in O solution]Methyl-amide for 3 hours to deprotect the tetrahydropyranyl group to give the title compound as TFA salt. MS (m/z): 292.9[ M + H⁺].

B. Propane-2-sulfonic acid { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -methyl-amide

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, propane-2-sulfonic acid (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -methyl-amide was converted into the corresponding chlorinated propane-2-sulfonic acid (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -methyl-amide and subsequently reacted with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, the title compound was produced as a TFA salt. MS (m/z): 514.1[ M + H⁺]。

Example 240: { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of isopropyl-pyridin-3-ylmethyl } -methyl-carbamate

A. (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -methyl-carbamic acid isopropyl ester

A solution of 1M isopropyl chloride in toluene (0.19mL) was added [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl]-methyl-amine (52mg, 0.19mmol) and DIPEA (65 μ L, 0.38mmol) in DCM (0.5mL) and stirring was continued at RT for 1 h. Evaporation of the solvent, purification by HPLC and subsequent passage through ACN/H from HPLC₂Stirring [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ] in O solution]Isopropyl methyl-carbamate for 3 hours to deprotect the tetrahydropyranyl group to give the title compound as TFA salt. MS (m/z): 272.9[ M + H⁺].

{ 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -methyl-isopropyl carbamate

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -methyl-carbamic acid isopropyl ester is converted into the corresponding chlorinated (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -methyl-carbamic acid isopropyl ester, and subsequently reacted with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, the title compound was produced as a TFA salt. MS (m/z): 494.1[ M + H⁺].

Example 246: 3, 5-dichloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-2-ylamine

3, 5-dichloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine 1-oxide

3-Chloroperbenzoic acid (mCPBA, 1.32g, 7.66mmol) was added to a stirred solution of 3, 5-dichloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine (200mg, 0.766mmol) in DCM (5 mL). After stirring at RT for 3 hours, the solvent was removed in vacuo and the residue was partitioned between DCM (50mL) and 2N NaOH solution (50 mL). After the organic layer was extracted with water (50mL), the organic layer was passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 278.0[ M + H⁺].

(2-amino-3, 5-dichloro-pyridin-4-yl) -methanol

A mixture of 3, 5-dichloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine 1-oxide (133mg, 0.48mmol) and p-toluenesulfonyl chloride (238mg, 1.25mmol) was heated in pyridine (10mL) to 40 ℃ for 1 day. P-toluenesulfonyl chloride (92mg, 0.48mmol) was added and the solution was heated to 56 ℃ for 5 hours. The solvent was removed in vacuo and the residue was dissolved in 2-amino-ethanol (5 mL). After stirring at 40 ℃ for 3 days, the solvent was removed in vacuo and the residue was partitioned between DCM (20mL) and saturated NaHCO₃Aqueous solution (20 mL). After extraction of the aqueous layer with DCM (2X 20mL), the organic layer was passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA. The HPLC fractions were stored at RT for 3 hours before cleaving the THP ether to give the title compound as a TFA salt. MS (m/z): 193.1[ M + H⁺].

C.3, 5-dichloro-4-chloromethyl-pyridin-2-ylamine

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, (2-amino-3, 5-dichloro-pyridin-4-yl) -methanol (7mg, 0.036mmol) was reacted with SOCl₂And (4) chlorination. The title compound obtained was used in the following reaction without purification. MS (m/z): 211.0[ M + H⁺].

3, 5-dichloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylamine

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 4-imidazol-1-yl-2-methyl-quinolin-8-ol (8.7mg, 0.036mmol) was alkylated with 3, 5-dichloro-4-chloromethyl-pyridin-2-ylamine (7.7mg, 0.036mmol) at 50 ℃ for 1 day. Purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA,the title compound was produced as a TFA salt. MS (m/z): 414.0[ M + H⁺].

Examples 247 and 248: dimethyl-carbamic acid 6-amino-5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-pyridin-3-ylmethyl ester and dimethyl-carbamic acid 2-amino-5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ester]Synthesis of (E) -pyridin-3-ylmethyl ester

A. Dimethyl-carbamic acid 6-amino-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ester and dimethyl-carbamic acid 2-amino-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ester

Upon synthesis of 3, 5-dichloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-1-oxide, dimethyl-carbamic acid 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ester was converted to the N-oxide. The resulting residue, according to the synthesis of (2-amino-3, 5-dichloro-pyridin-4-yl) -methanol, was reacted with p-toluenesulfonyl chloride and 2-amino-ethanol (except for the reaction in 2-amino-ethanol) at 40 ℃ for 2.5 hours. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA. The HPLC fractions cleaved the THP ether after 3 hours of storage at RT. This provided 2 of the title compounds as their TFA salts as pure compounds. MS (m/z): 259.9[ M + H⁺]And MS (m/z): 259.9[ M + H⁺].

B. Dimethyl-carbamic acid 6-amino-5-chloro-4-chloromethyl-pyridin-3-ylmethyl ester

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, dimethyl-carbamic acid 6-amino-5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl ester (18.5mg, 0.071mmol) was reacted with SOCl₂The title compound was obtained by chlorination and used in the following reaction without purification. MS (m/z): 278.0[ M + H⁺].

C. Dimethyl-carbamic acid 2-amino-5-chloro-4-chloromethyl-pyridin-3-ylmethyl ester

According to 3, 5-dichloro-4-chloroSynthesis of methyl-pyridine dimethyl-carbamic acid 6-amino-5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl ester (4mg, 0.015mmol) with SOCl₂And (4) chlorination. The title compound obtained was used in the following reaction without purification. MS (m/z): 277.9[ M + H⁺].

D. Dimethyl-carbamic acid 6-amino-5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl ester

According to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 4-imidazol-1-yl-2-methyl-quinolin-8-ol (17.1mg, 0.071mmol) was alkylated with dimethyl-carbamic acid 6-amino-5-chloro-4-chloromethyl-pyridin-3-ylmethyl ester (19.7mg, 0.071 mmol). Purification was performed by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 480.9[ M + H ]⁺].

E. Dimethyl-carbamic acid 2-amino-5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl ester

Following the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 4-imidazol-1-yl-2-methyl-quinolin-8-ol (3.7mg, 0.015mmol) was alkylated with dimethyl-carbamic acid 2-amino-5-chloro-4-chloromethyl-pyridin-3-ylmethyl ester (4.2mg, 0.015 mmol). Purification was performed by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 480.9[ M + H ]⁺].

Example 250: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4- (2-methoxy-thiazol-4-yl) -2-methyl-quinoline

A mixture of 4-bromo-8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-quinoline (15mg, 0.038mmol), 2-methoxy-4-tributylstannyl-thiazole (18.4mg, 0.046mmol), bis (tri-tert-butylphosphine) palladium (0) (1mg, 0.002mmol), and CsF (12.7mg, 0.083mmol) in dioxane (2mL) was heated to 100 ℃ under argon for 1 day. Will be provided withThe solvent was removed in vacuo and the residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 431.9[ M + H ]⁺].

Example 262: 1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl) -3-methyl-pyrrolidine-2, 5-dione

N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -3-methyl-succinamic acid methyl ester

Reacting C- [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl]A mixture of methylamine (15.3mg, 0.060mmol), HBTU (33.9mg, 0.089mmol), (R) - (+) -methylsuccinic acid 4-methyl ester (13.1mg, 0.089mg) and DIPEA (30.4. mu.L, 0.179mmol) in DMF (0.50mL) was stirred at RT for 1 day. The solvent was removed in vacuo and the residue partitioned between DCM (2mL) and aqueous phosphate buffer (pH 7, 2 mL). After extraction of the aqueous layer with DCM (4X 2mL), the organic layer was passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA. The HPLC fractions were stored at RT for 3 hours before cleaving the THP ether to give the title compound as a TFA salt. MS (m/z): 300.9[ M + H⁺].

N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -3-methyl-succinamic acid methyl ester

According to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, methyl N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -3-methyl-succinamate (1.39mg, 0.0046mmol) was dissolved in SOCl₂And (4) chlorination. The title compound obtained was used in the following reaction without purification. MS (m/z): 318.9[ M + H⁺].

1- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -3-methyl-pyrrolidine-2, 5-dione

According to 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-Synthesis of imidazol-1-yl-2-methyl-quinoline 4-imidazol-1-yl-2-methyl-quinolin-8-ol (3.0mg, 0.0125mmol) was alkylated with N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -3-methyl-succinamic acid methyl ester (1.47mg, 0.0046 mmol). After RT1 days, purification was performed by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 490.0[ M + H⁺].

Example 278: synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-trifluoromethyl-pyrazol-1-yl) -quinoline

A.4-hydrazino-2-methyl-quinolin-8-ol

A mixture of 4-chloro-2-methyl-quinolin-8-ol (0.10g, 0.51mmol) and hydrazine monohydrate (0.75mL, 15mmol) in dioxane (10mL) was heated to reflux for 4 days. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (with DCM/methanol/concentrated NH₃Aqueous 5: 1: 0.033) to give the title compound. MS (m/z): 190.1[ M + H⁺].

2-methyl-4- (5-trifluoromethyl-pyrazol-1-yl) -quinolin-8-ol

A mixture of 4-hydrazino-2-methyl-quinolin-8-ol (21mg, 0.11mmol) and 4-ethoxy-1, 1, 1-trifluoro-but-3-en-2-one (16. mu.L, 0.11mmol) in ethanol (0.5mL) was heated to 75 ℃ for 30 minutes. Next, the solvent was removed in vacuo, and the residue was dissolved again in acetic acid (0.5 mL). Adding concentrated H₂SO₄(20 μ L) and after stirring at 100 ℃ for 1 hour, the reaction mixture was cooled to room temperature and Na was added₂CO₃(0.40mg, 3.8mmol) in water (1 mL). The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (10mL) and water (5 mL). The pH of the aqueous layer was adjusted by adding saturated NH₃Adjusted to 10 with aqueous solution and the aqueous layer was extracted with DCM (1X 320 mL). The combined organic layers were washed with Na₂SO₄Dried, filtered, and concentrated in vacuo to afford the title compound. MS (m/z): 294.2[ M + H⁺].

C.8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-trifluoromethyl-pyrazol-1-yl) -quinoline

Upon synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 2-methyl-4- (5-trifluoromethyl-pyrazol-1-yl) -quinolin-8-ol (7.4mg, 25 μmol) was alkylated to give the title compound as a TFA salt. MS (m/z): 453.0[ M + H⁺].

Example 281: n- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl) -N- (2, 3-dihydroxy-propyl) -isobutyramide

[ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl ] - (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl) -amine

Acetic acid (133. mu.L) and NaBH₃CN (14.8mg, 0.235mmol) was added to a stirred solution of 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine-3-carbaldehyde (40mg, 0.157mmol) and 2, 2-dimethyl-1, 3-dioxolane-4-methanamine (203 μ L, 1.57mmol) in MeOH (1 mL). After stirring at room temperature for 2 hours, the solvent was removed in vacuo and the residue was partitioned between DCM (10mL) and saturated NaHCO₃Solution (10 mL). After extraction of the aqueous layer with DCM (2X 10mL), the combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 370.9[ M + H⁺].

N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -N- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl) -isobutyramide and N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -N- (2, 3-dihydroxy-propyl) -isobutyramide

DIPEA (49.5. mu.L, 0.291mmol) and isobutyryl chloride (21.4. mu.L, 0.204mmol) were added to [ 5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-ylmethyl]- (2, 2-dimethyl- [1, 3)]Dioxolan-4-ylmethyl) -amine (54mg, 0.146mmol) at THF (3mL) in a stirred solution. After stirring at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA. The HPLC fraction cleaved the THP ether after 3 hours storage at RT and the dioxolane was partially cleaved. This provided a mixture of 2 title compounds as TFA salts. MS (m/z): 357.0[ M + H⁺]And MS (m/z): 317.0[ M + H⁺]。

C.N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -N- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl) -isobutyramide and N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -N- (2, 3-dihydroxy-propyl) -isobutyramide

According to the reaction of 3, 5-dichloro-4-chloromethyl-pyridine with SOCl₂(16. mu.L, 0.219mmol) N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -N- (2, 2-dimethyl- [1, 3]Dioxolan-4-ylmethyl) -isobutyramide and N- (5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl) -N- (2, 3-di-hydroxy-propyl) -isobutyramide (39mg, 0.110mmol) were mixed with SOCl₂And (4) chlorination. A mixture of 2 of the title compounds was obtained and used in the following reaction without further purification. MS (m/z): 374.9[ M + H⁺]And MS (m/z): 335.0[ M + H⁺].

D.N- { 5-chloro-4- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -N- (2, 3-dihydroxy-propyl) -isobutyramide

According to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 4-imidazol-1-yl-2-methyl-quinolin-8-ol (12mg, 0.050mmol) was reacted with N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -N- (2, 2-dimethyl- [1, 3-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinolin-e]A mixture of dioxolan-4-ylmethyl) -isobutyramide and N- (5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -N- (2, 3-dihydroxy-propyl) -isobutyramide (17mg, 0.045mmol) was alkylated. After RT1 days, the solvent was removed in vacuo and the residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA. The title compound is thus provided as a TFA salt. MS (m/z): 538.1[ M + H⁺].

Example 292: n- { 4-methyl-3- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-2-ylmethyl) -isobutyramide

A.4-bromo-2-chloro-nicotinic acid methyl ester

A solution of 4-bromo-2-chloro-pyridine (4.5mL, 41mmol) in dry THF (60mL) was added dropwise to a stirred solution of lithium diisopropylamide (1.8M in THF, 25mL, 45mmol) in dry THF (60mL) at-85 deg.C. After stirring for 30 minutes at-80 ℃, the reaction mixture was added dropwise via a cannula to a stirred solution of methyl chloroformate (31mL, 400mmol) in anhydrous THF at-80 ℃. After stirring for 50 minutes at-80 ℃ the reaction was quenched by addition of concentrated NaHCO₃Aqueous solution (90mL) was quenched and then diluted with EA (250 mL). Passing the organic layer over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with hexane/EA 4: 1) to give the title compound. MS (m/z): 252.0.1[ M + H⁺].

B.2-chloro-4-methyl-nicotinic acid methyl ester

ZnMe compound₂(2.0M in toluene, 15.5mL, 25mmol) 4-bromo-2-chloro-nicotinic acid methyl ester (9.6g, 38mmol) and Pd (dppf) Cl were added₂(0.50g, 0.61mmol) in anhydrous dioxane (180 mL). After stirring at 70 ℃ for 8 h, the reaction mixture was cooled to room temperature, MeOH (15mL) was added, and the solvent was removed in vacuo. And the residue was partitioned between EA (300mL) and water (50 mL). Concentrated aqueous HCl was then added until the emulsion became homogeneous. The organic layer was washed with Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with hexane/EA 2: 1) to give the title compound. MS (m/z): 186.0[ M + H⁺].

C.2-cyano-4-methyl-nicotinic acid methyl ester

Methyl 2-chloro-4-methyl-nicotinate (2.64g, 14.3mmol) and CuCN (6.4g,71mmol) in NMP (5.3mL) was heated to 180 ℃ for 30 minutes. The reaction mixture was then cooled to room temperature and diluted with water (80 mL). After 16 hours of vigorous stirring, the suspension was centrifuged and the pellet was suspended in FeCl₃·6H₂O (5.8g, 21mmol) was in aqueous HCl (4M, 80 mL). After vigorous stirring for 1 hour, the suspension was extracted with DCM (3X 70 mL). The organic layer was washed with Na₂SO₄/Na₂CO₃Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/DCM 1: 10) to give the title compound. MS (m/z): 177.0[ M + H⁺].

(2-aminomethyl-4-methyl-pyridin-3-yl) -methanol

At-35 deg.C, adding AlCl₃A solution of (0.15g, 1.1mmol) in anhydrous THF (1.1mL) was added dropwise to a stirred solution of 2-cyano-4-methyl-nicotinic acid methyl ester (0.10g, 0.57 mmol). DIBAL (1.5M in toluene, 3.0mL, 4.5mmol) was then added at-95 ℃. The reaction mixture was warmed to 4 ℃ over 5 hours, and then quenched by the addition of water (0.20mL) at-20 ℃. Adding ACN (17mL) and concentrated NH₃An aqueous solution (1.4mL) was added to the mixture. After stirring vigorously for 30 minutes, the suspension was centrifuged and the pellet was suspended in ACN (5mL) and concentrated NH₃(0.5mL) in aqueous solution. After stirring vigorously for 30 minutes, the suspension was centrifuged. The combined supernatants were concentrated in vacuo to afford the title compound. MS (m/z): 153.0[ M + H⁺].

E.N- (3-hydroxymethyl-4-methyl-pyridin-2-ylmethyl) -isobutyramide

A solution of isobutyryl chloride (29. mu.L, 0.276mmol) in DCM (0.20mL) was added (2-aminomethyl-4-methyl-pyridin-3-yl) -methanol (30mg, 0.20mmol) in DCM (1.0mL) and Na at 0 deg.C₂CO₃(1M, 1mL) in a vigorously stirred aqueous solution. After stirring at 0 ℃ for 30 minutes, DCM (10mL) and water (1mL) were added and the aqueous layer was extracted with DCM (1X 10 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue is led throughPurification was performed by flash chromatography on silica gel (eluting with MeOH/DCM 1: 20) to afford the title compound. MS (m/z): 223.0[ M + H⁺].

F.N- { 4-methyl-3- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -isobutyramide

N- (3-hydroxymethyl-4-methyl-pyridin-2-ylmethyl) -isobutyramide (29mg, 0.13mmol) was converted to the corresponding chloride according to the synthesis of 3, 5-dichloro-4-chloromethyl-pyridine, and subsequently reacted with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to yield the title compound as a TFA salt. MS (m/z): 444.1[ M + H⁺].

Example 303: 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-methyl- [1, 3, 4)]Synthesis of thiadiazol-2-ylsulfanyl) -quinolines

2-methyl-4- (5-methyl- [1, 3, 4] thiadiazol-2-ylsulfanyl) -quinolin-8-ol

4-chloro-2-methyl-quinolin-8-ol (10mg, 52. mu. mol) and 5-methyl- [1, 3, 4]A mixture of thiadiazole-2-thiol (6.9mg, 52. mu. mol) in MeOH (0.3mL) was heated to 80 ℃ for 1.5 hours. The solvent was removed in vacuo to afford the title compound. MS (m/z): 289.9[ M + H⁺].

B.8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-4- (5-methyl- [1, 3, 4] thiadiazol-2-ylsulfanyl) -quinoline

2-methyl-4- (5-methyl- [1, 3, 4) according to the synthesis of 8- (3, 5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline]Thiadiazol-2-ylsulfanyl) -quinolin-8-ol (15mg, 52 μmol) was alkylated to give the title compound as a TFA salt. MS (m/z): 448.9[ M + H⁺].

Example 319: synthesis of 4- (5-chloro-thiazol-4-yl) -8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-quinoline

A. (4-bromo-5-chloro-thiazol-2-yl) -carbamic acid tert-butyl ester

Lithium diisopropylamide (1.8M in THF, 19.8mL, 35.6mmol) was added dropwise to a stirred solution of (5-bromo-thiazol-2-yl) -carbamic acid tert-butyl ester (Kuo, Gee-Hong; et al. J.Med.chem. (J.Med. chem.) 2005; 6; 1886-1900) (3.00g, 10.8mmol) in anhydrous THF (75mL) at 0 ℃. After stirring for 30 min at 0 ℃, a solution of 1, 1, 1, 2, 2, 2-hexachloro-ethane (8.43g, 35.6mmol) in anhydrous THF (45mL) was added dropwise at-90 ℃. The reaction mixture was warmed to-10 ℃ and then concentrated NH was added₄Aqueous Cl (15mL) solution was quenched. The mixture was concentrated in vacuo, and the residue was partitioned between DCM (100mL) and water (30 mL). The aqueous layer was extracted with DCM (2X 50mL) and the combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/hexane 2: 1) to give the title compound. MS (m/z): 314.6[ M + H⁺].

B.4-bromo-5-chloro-thiazole

(4-bromo-5-chloro-thiazol-2-yl) -carbamic acid tert-butyl ester (1.28g, 4.06mmol) was dissolved in a 1: 1 mixture of TFA and DCM (10 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (50mL) and concentrated NaHCO₃(15mL) in water. Na for organic layer₂SO₄Dried, filtered, and concentrated in vacuo. The residue was dissolved in anhydrous THF (15mL) and 2-methyl-2-nitrosohydroxy (nitroxoxy) -propane (0.73mL, 6.1mmol) was added dropwise. After stirring at 60 ℃ for 1 hour, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/hexane 1: 2) to give the title compound.

C.4- (5-chloro-thiazol-4-yl) -8- (3, 5-dichloro-pyridin-4-ylmethoxy) -2-methyl-quinoline

According to 8- (3, 5-dichloro-pyridine-4)Synthesis of-ylmethoxy) -2-methyl-4- (4-methyl-thiazol-5-yl) -quinoline coupling of 4-bromo-5-chloro-thiazole (10mg, 50. mu. mol) with 8- ((3, 5-dichloropyridin-4-yl) methoxy) -2-methylquinolin-4-ylboronic acid TFA salt (15mg) gave the title compound as TFA salt. MS (m/z): 437.9[ M + H⁺].

Example 430: n- { 4-chloro-3- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-2-ylmethyl) -isobutyramide

2, 4-dichloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine

Following the procedure described for the preparation of (3.5-dichloro-pyridin-4-yl) -methanol, 2, 4-dichloro-pyridine-3-carbaldehyde (1.565g, 8.89mmol) was reduced to (2.4-dichloro-pyridin-3-yl) -methanol and then protected with a THP-group following the procedure described for the preparation of 3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine to provide the title compound.

4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine-2-carbonitrile

2, 4-dichloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine (455mg, 1.74mmol) was dissolved in a mixture of DMF (3mL) and water (30. mu.L). The following reagents were then added: zinc cyanide (112mg, 0.95mmol), zinc powder (9.1mg, 139. mu. mol), zinc acetate (25.5mg, 139. mu. mol), 1.1' -bis (diphenylphosphino) ferrocene (58mg, 104. mu. mol) and tris (dibenzylideneacetone) palladium (0). The reaction mixture was degassed 2 times and then heated at 95 ℃ for 4 hours. The solvent was removed in vacuo, and the residue was partitioned between water (20mL) and EtOAc (20mL) and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine, over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with hexane/EtOAc 10: 1 → 5: 1) to give the title compound. MS (m/z): 253.0[ M + H⁺].

C.N- [ 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl ] -isobutyramide

4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine-2-carbonitrile (30mg, 0.12mmol) was dissolved in a mixture of MeOH (0.75mL) and THF (1 mL). Adding CoCl₂Hexahydrate (56mg, 0.24mmol) and NaBH₄(45mg, 1.19mmol, dissolved in 1mL MeOH). After stirring for 8 min at RT, saturated NaHCO was added₃Solution (1mL) and isobutyryl chloride (125. mu.L, 1.19 mmol). The solvent was removed in vacuo and the residue partitioned between saturated NH₄Between Cl solution (10mL) and DCM (10mL) and extracted with DCM (3X 10 mL). The combined organic layers were washed with brine, over Na₂SO₄Dried, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluting with hexane/EtOAc 2: 1 → 1: 2) to give the title compound. MS (m/z): 326.8[ M + H⁺].

D.N- { 4-chloro-3- [ 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -isobutyramide

N- [ 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl ] -N- [ 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl-pyridine-2-ylmethyl-amino-acetic acid is prepared according to the procedure described for the synthesis of 1- (3-chloromethyl-4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one]-isobutyramide chlorination. The resulting N- (4-chloro-3-chloromethyl-pyridin-2-ylmethyl) -isobutyramide was coupled with 2-methyl-4- (2-methyl-2H-pyrazol-3-yl) -quinolin-8-ol according to the procedure described for the preparation of 8- (3.5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound as a TFA salt. MS (m/z): 464.1[ M + H ]⁺].

Example 501: 1- { 4-methyl-3- [ 2-methyl-4- (4-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one

A. 4-methyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazole was converted to 2-methyl-4- [ 4-methyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl ] -quinolin-8-ol according to the procedure described for the synthesis of 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol.

2-chloro-4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine

Methyl 2-chloro-4-methyl-nicotinate (1g, 5.4mmol) was dissolved in THF (10mL) and cooled to-78 deg.C, and DIBAL (1M in toluene) was added via syringe (14.4mL, 21.6 mmol). The reaction mixture was allowed to warm to RT over 4 hours. Additional DIBAL (5mL, 5mmol) was added and the reaction stirred at RT for 1 hour before cooling to-20 ℃. Water (2mL), saturated Na was added₂CO₃Solution (1.5mL), aqueous NH₃(3mL) and ACN (70 mL). After stirring vigorously for 30 minutes, the suspension was centrifuged and the pellet was suspended in ACN (100mL) and concentrated NH₃(5mL) in aqueous solution. After stirring vigorously for 30 minutes, the suspension was centrifuged. The combined supernatants were concentrated in vacuo to give crude (2-chloro-4-methyl-pyridin-3-yl) -methanol, which was converted to the title compound according to the procedure described for the preparation of 3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine. MS (m/z): 158.0[ M + H⁺].

C.4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -2-vinyl-pyridine

2-chloro-4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine (500mg, 2.07mmol) was dissolved in a mixture of 1, 2-dimethoxyethane (16.5mL) and water (7 mL). Adding K₂CO₃(286mg, 2.07mmol) and 2, 4, 6-trivinyl-cyclotriboroxane pyridine complex (498mg, 2.07mmol), and Pd ((PPh)₃)₄Before (120mg, 0.10mmol), the reaction mixture was degassed 2 times. The reaction mixture was stirred at 100 ℃ for 18 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with hexane/EtOAc 6: 1) to give the title compound. MS (m/z): 234.1[ M + H⁺]

[ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl ] -methanol

4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -2-vinyl-pyridine (300mg, 1.29mmol) was dissolved in DCM (36mL) and cooled to-50 ℃. Will be mixed and slowly flow intoOzone is bubbled through the reaction mixture until the solution becomes pale blue in color. Add NaBH dissolved in MeOH (15mL)₄(486mg, 12.9mmol) and the reaction was warmed to RT over 1 hour. The solvent was removed in vacuo, and the residue was partitioned between water (20mL) and EtOAc (20 mL). Extract with EtOAc (3X 20 mL). The combined organic fractions were washed with brine, over Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 40: 1 → 20: 1) to give the title compound. MS (m/z): 238.0[ M + H⁺].

E.1- [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl ] -3-trifluoromethyl-1H-pyridin-2-one

Reacting [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl]Methanol (138mg, 0.58mmol) was dissolved in DCM (5mL) and cooled to 0 ℃. Addition of NEt₃(324. mu.L.2.33mmol) and methanesulfonyl chloride (90. mu.L.1.16mmol), and the reaction mixture was stirred at 0 ℃ for 1 hour. After removal of the solvent in vacuo, the residue was dissolved in DMF (10mL) and CsCO was added₃(570mg, 1.75mmol) and 3-trifluoromethyl-pyridin-2-ol (142mg, 0.87 mmol). After stirring at RT for 2 hours, the solvent was removed in vacuo and the residue was partitioned between water (20mL) and DCM (20 mL). Extract with DCM (3X 20mL) and combine the organic fractions with Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with hexane/EtOAc 2: 1 → 1: 1) to give the title compound. MS (m/z): 382.9[ M + H⁺].

1- (3-chloromethyl-4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one

Reacting 1- [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (100mg, 0.26mmol) was dissolved in DCM (5 mL). Adding SOCl₂(97. mu.L, 1.31mmol) and water (25. mu.L), and the reaction mixture was stirred at RT for 1 hour. After removal of the solvent in vacuo, the resulting titled compoundThe compound was used in the following reaction without purification. MS (m/z): 317.0[ M + H⁺].

G.1- (4-methyl-3- { 2-methyl-4- [ 4-methyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl ] -quinolin-8-yloxymethyl } -pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one

2-methyl-4- [ 4-methyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl ] -quinolin-8-ol and 1- (3-chloromethyl-4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one were coupled according to the procedure described for the synthesis of 8- (3.5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound, which was used in the next step without purification.

H.1- { 4-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one

1- (4-methyl-3- { 2-methyl-4- [ 4-methyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl)]-quinolin-8-yloxymethyl } -pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one (2.02g, 3.34mmol) was dissolved in MeOH (25mL) and concentrated HCl (2.5mL) in water was added. After stirring for 30 min, the solvent was removed in vacuo and the residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA to give the title compound as a TFA salt. MS (m/z): 520.1[ M + H⁺].

Example 597: 4-methyl-5- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -6- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -1H-pyridin-2-one

1- [ 4-methyl-1-oxy-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl ] -3-trifluoromethyl-1H-pyridin-2-one

3-Chloroperbenzoic acid (27.1mg, 0.157mmol) was added to 1- [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (20mg, 0.052mmol) in DCM (2mL) with stirring. Stirring at room temperatureAfter 3 hours, the organic layer was washed with saturated NaHCO₃The solution was extracted (3mL) and the aqueous solution was extracted 3 times with DCM (3 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated in vacuo to give the title compound which was used in the following reaction without purification. MS (m/z): 398.8[ M + H ]⁺].

B.5-chloromethyl-4-methyl-6- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -1H-pyridin-2-one

Adding POCl₃(68.6. mu.L.0.735mmol) 1- [ 4-methyl-1-oxy-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (29.3mg, 0.074mmol) in dichloroethane (5mL) was added to a stirred solution. After stirring for 90 minutes at 100 ℃, the organic layer was washed with saturated NaHCO₃The solution (10mL) was extracted, and the aqueous solution was extracted 3 times with DCM (10 mL). The combined organic layers were extracted with brine (10mL) and passed over Na₂SO₄Dried, filtered and concentrated in vacuo. Purification by HPLC yielded the title compound. MS (m/z): 332.9[ M + H⁺].

4-methyl-5- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -6- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -1H-pyridin-2-one

According to the synthesis of 8- (3.5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, 5-chloromethyl-4-methyl-6- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -1H-pyridin-2-one (10.53mg, 0.030mmol) and 2-methyl-4- [ 4-methyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl ] -was reacted]-quinolin-8-ol (9.7mg, 0.030mmol) and then according to 1- { 4-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-Synthesis, deprotection and purification of pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one to yield the title compound as TFA salt. MS (m/z): 536.1[ M + H⁺].

Example 654: 2- {8- [ 4-chloro-6-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy]-2-methyl-quinolineSynthesis of (E) -4-yl } -3-methyl-3H-imidazole-4-carbonitrile

A.2- (8-hydroxy-2-methyl-quinolin-4-yl) -3-methyl-3H-imidazole-4-carbonitrile

Following the synthesis of 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol, 4-bromo-2-methyl-quinolin-8-ol (400mg, 1.68mmol) was coupled with 3-methyl-3H-imidazole-4-carbonitrile (450mg, 4.20mmol) to give the title compound. MS (m/z): 265.2[ M + H⁺].

B.2- {8- [ 4-chloro-6-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -3-methyl-3H-imidazole-4-carbonitrile

Reduction of ethyl 2, 4-dichloro-6-methyl-nicotinate (550mg, 2.35mmol) to the alcohol according to the synthesis of (2-chloro-4-methyl-pyridin-3-yl) -methanol, followed by THP protection according to the synthesis of 3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine, followed by Pd-catalyzed vinylation according to the synthesis of 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -2-vinyl-pyridine, followed by [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl-methanol]-synthesis of methanol with ozonolysis and reduction, followed by ozonolysis according to 1- [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl]-synthesis of 3-trifluoromethyl-1H-pyridin-2-one and mesylation and alkylation, conversion to chloride according to synthesis of 1- (3-chloromethyl-4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one, and subsequent coupling with 2- (8-hydroxy-2-methyl-quinolin-4-yl) -3-methyl-3H-imidazole-4-carbonitrile according to synthesis of 8- (3.5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline to give the title compound, it is a TFA salt. MS (m/z): 579.0[ M + H⁺].

Example 682: 1- { 5-chloro-2-hydroxy-4- [ 2-methyl-4- (4-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one

A.2-Benzyloxy-3-bromo-5-chloro-pyridine

In a microwave test tube, theNaH (60% in paraffin, 56mg, 1.4mmol) was washed with hexane and 3-bromo-2.5-dichloro-pyridine (245mg, 1.08mmol) in anhydrous DMF (2mL) was added. To this suspension BnOH (123. mu.L.1.23mmol) in anhydrous DMF (1mL) was added carefully dropwise. The reaction mixture was stirred for 15 minutes until the formation of hydrogen ceased. The tube was sealed and stirred in a microwave reactor at 100 ℃ for 30 minutes. After removal of the solvent in vacuo, the residue was partitioned between water (10mL) and DCM (10mL) and extracted with DCM (3X 10 mL). The combined organic fractions were washed with brine, over Na₂SO₄Dried, filtered and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. GC-MS (m/z): 297[ M)⁺]。

B.1- { 5-chloro-2-hydroxy-4- [ 2-methyl-4- (4-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one

2-benzyloxy-3-bromo-5-chloro-pyridine (207mg, 0.69mmol) was formylated according to the procedure described for the synthesis of 3-bromo-5-chloro-pyridine-4-carbaldehyde, subsequently reduced according to the procedure described for the synthesis of (3.5-dichloro-pyridin-4-yl) -methanol, and protected with a THP group according to the procedure described for the synthesis of 3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine. The resulting 2-benzyloxy-3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine is vinylated according to the procedure described for the synthesis of 4-chloro-6-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -2-vinyl-pyridine, and subsequently according to the preparation of [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl]-conversion of methanol to alcohol by said procedure. The resulting [ 2-benzyloxy-5-chloro-4- (tetrahydropyran-2-yloxymethyl) -pyridin-3-yl group]Methanol Synthesis of 1- [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one and subsequently to 1- (2-benzyloxy-5-chloro-4-chloromethyl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one according to the procedure described for the preparation of 1- (3-chloromethyl-4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one. According to the synthesis of 8- (3.5-dichloro-pyridin-4-ylmethoxy) -4-imidazoleAzol-1-yl-2-methyl-quinoline, the chloride is reacted with 2-methyl-4- [ 4-methyl-2- (tetrahydro-pyran-2-yl) -2H-pyrazol-3-yl]-quinolin-8-ol for the final coupling and subsequent 1- { 4-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl according to preparation]-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one the procedure described for the deprotection of both the THP group and benzyl ether yielded the title compound as a TFA salt after purification by reverse phase HPLC using a gradient of acetonitrile in water with 0.1% TFA. MS (m/z): 556.0[ M + H⁺].

Example 711: 1- {3- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl]Synthesis of (E) -4-methoxy-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile

A.2-chloro-4-methoxy-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine

Mixing Cs₂CO₃(0.54g, 1.6mmol) was added to a stirred solution of 2-chloro-4-fluoro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine (0.20g, 0.81mmol) prepared according to the synthesis of 3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine in dry MeOH (4 mL). After 20 hours of vigorous stirring at room temperature, acetic acid (92. mu.L, 1.6mmol) was added. The solvent was removed in vacuo, and the residue was partitioned between DCM (20mL) and water (4 mL). The organic layer was washed with Na₂SO₄Dried, filtered and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 257.9[ M + H⁺].

B.5- (8-hydroxy-2-methyl-quinolin-4-yl) -1-methyl-1H-pyrrole-2-carbonitrile

Following the synthesis of 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol, 4-bromo-2-methyl-quinolin-8-ol (75mg, 0.32mmol) was coupled with 1-methyl-1H-pyrrole-2-carbonitrile (84mg, 0.79mmol) using LDA as the base (1.8M in heptane/THF/ethyl crude benzene to give the title compound. MS (m/z): 264.2[ M + H⁺].

1- {3- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methoxy-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile

According to the synthesis of 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -2-vinyl-pyridine, 2-chloro-4-methoxy-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine (0.20g, 0.79mmol) Pd catalyzed vinylation according to [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl]Synthesis of methanol with ozonolysis and reduction, according to 1- [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl]-synthesis of 3-trifluoromethyl-1H-pyridin-2-one mesylation and alkylation with 2-hydroxy-nicotinonitrile, conversion to chloride upon synthesis of 1- (3-chloromethyl-4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one and subsequent coupling with 5- (8-hydroxy-2-methyl-quinolin-4-yl) -1-methyl-1H-pyrrole-2-carbonitrile upon synthesis of 8- (3.5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline, and purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA yielded the title compound as a TFA salt. MS (m/z): 516.5[ M + H⁺].

Example 733: 1- (1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl]Synthesis of (E) -pyridin-2-yl } -ethyl) -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile

A.1H-pyrazol-4-ol

Hydrogen peroxide (30% in H) was added at 0 deg.C₂In O, 379. mu.L, 3.71mmol) and NaOH (2M in H₂O, 1.86mL, 3.71mmol) was added 4- (4.4.5.5-tetramethyl- [ 1.3.2)]Dioxolane-2-yl) -1H-pyrazole in THF (5mL) in a stirred solution. After stirring at 0 ℃ for 3 minutes, the reaction was warmed to room temperature and stirred for another 50 minutes. H for reactants₂O (20mL), acidified with HCl (2N), and extracted 4 times with DCM (50mL) and 4 times with DCM/isopropanol (4: 1, 50 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated in vacuo. The title obtainedThe compound was used in the following reaction without purification. MS (m/z): 85.0[ M + H ]⁺].

2-methyl-4- [1- (tetrahydro-pyran-2-yl) -4- (tetrahydro-pyran-2-yloxy) -1H-pyrazol-3-yl ] -quinolin-8-ol

Following the synthesis of 3-bromo-5-chloro-4- (tetrahydro-pyran-2-yloxymethyl) -pyridine, 1H-pyrazol-4-ol (420mg, 2.06mmol) was THP protected, followed by coupling of 4-bromo-2-methyl-quinolin-8-ol following the synthesis of 2-methyl-4- (1-methyl-1H-imidazol-2-yl) -quinolin-8-ol and flash chromatography purification to yield the title compound. MS (m/z): 410.0[ M + H⁺].

[ 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl ] -methanol

According to the synthesis of 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -2-vinyl-pyridine, 2, 4-dichloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine (1.71g, 6.52mmol) was subjected to Pd-catalyzed ethenylation, followed by a reaction according to [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl]-synthesis of methanol to ozonolysis and reduction, purification by flash chromatography to yield the title compound. MS (m/z): 257.8[ M + H⁺]。

4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine-2-carbaldehyde

Dess-Martin periodinane (370mg, 0.873mmol) was added to [ 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl]Methanol (150mg, 0.582mmol) in THF (5mL) under stirring. After stirring at room temperature for 2 hours, the reaction was concentrated. Saturated NaHCO was added₃The solution (20mL) was extracted 3 times with DCM (50 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated in vacuo. The title compound obtained was used in the following reaction without purification. MS (m/z): 255.7[ M + H⁺].

E.1- [ 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl ] -ethanol

MeMgBr (3.0M in diethyl ether, 582. mu.L, 1.75mmol) was added to a stirred solution of 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridine-2-carbaldehyde (149mg, 0.58mmol) in THF (6 mL). After stirring at room temperature for 10 minutes, saturated NaHCO was added₃The solution (30mL) was extracted 3 times with DCM (50 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a gradient of ethyl acetate and MeOH) to give the title compound. MS (m/z): 271.8[ M + H ]⁺].

1- (1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-yl } -ethyl) -2-oxo-1.2-dihydro-pyridine-3-carbonitrile

According to 1- [ 4-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-ylmethyl]Synthesis of (E) -3-trifluoromethyl-1H-pyridin-2-one from 1- [ 4-chloro-3- (tetrahydro-pyran-2-yloxymethyl) -pyridin-2-yl]Ethanol (120mg, 0.44mmol) was mesylated and alkylated with 2-hydroxy-nicotinonitrile (79.3mg, 0.66mmol), purified by HPLC, converted to the chloride according to the synthesis of 1- (3-chloromethyl-4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one, followed by synthesis according to 8- (3.5-dichloro-pyridin-4-ylmethoxy) -4-imidazol-1-yl-2-methyl-quinoline with 2-methyl-4- [1- (tetrahydro-pyran-2-yl) -4- (tetrahydro-pyran-2-yloxy) -1H-pyrazol-3-yl.]-quinolin-8-ol coupling and subsequent coupling according to 1- { 4-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl]-Synthesis of pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one deprotection and purification yielded the title compound as a TFA salt. MS (m/z): 513.0[ M + H⁺].

Example 754: radioligand binding assays

The following assay is defined herein as a standard in vitro B2 receptor binding assay.

The pharmaceutical utility of the compounds of the present invention is indicated by detecting activity in the following assay for the BK B2 receptor activity. The B2 receptor binding assay was performed using the following experimental setup.

Incubation buffer: consists of the following components: 40mM PIPES, 109mM NaCl, 5mM KCl, 0.1% glucose, 0.05% BSA, 2mM CaCl₂、1mM MgCl₂pH 7.4; having the following inhibitors: 2mM bacitracin, 0.8mM 1, 10-phenanthroline, 100. mu.M captopril. Before starting the experiment, the [ alpha ], [ alpha³H]BK to give a final concentration of 2 nM.

Add test Compounds to incubation buffer and prepare a series of dilutions: a10. mu.L stock solution of 10mM of a single test compound in DMSO was diluted in 90. mu.L DMSO to give a compound concentration of 1mM in 100% DMSO. Next, 7.5. mu.L of the compound solution (1mM) was added to 242.5. mu.L of an incubation buffer (comprising 2nM 2[, ])³H]BK, see above) to give a test compound concentration of 30 μ M. A10 μ M solution of the compound was prepared by adding 2.5 μ L of a 1mM compound solution to 247.5 μ L of incubation buffer. Based on these 30. mu.M and 10. mu.M compound solutions in incubation buffer, additional dilutions were made by incubation with incubation buffer (containing 2nM 2. mu.M.,)³H]BK, supra) to yield 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, and 0.001. mu.M solutions of the compound. For measurement of nonspecific binding, 1.25. mu.L of a 10mM BK solution was added to 248.8. mu.L of an incubation buffer (containing 2nM [2 ], ]³H]BK). For the measurement of total binding, a peptide having³H]BK but no compound incubation buffer. An appropriate control group was prepared in the same manner except for the compound to be tested.

Step (ii) of：

Coating cells: 96-well cell culture plates were treated with 0.01% poly-D-lysine hydrobromide in PBS for at least 1 hour. Thereafter, HEK293 cells stably expressing recombinant human B2R (10pmol/mg protein) were added and cultured for 1-3 days until at least 90% confluence was reached.

Washing step: then, the porous body is putThe discs were stored on ice and the medium was removed using a 12-channel rack ELISA-wash device. Thereafter, ice-cold PBS (10X-stock solution, 1: 10 dilution, pH adjusted to 7.4) was added, starting at the front of the plate (until the wells were half full), and this washing step was repeated 3 times.

Incubation and readout with Compounds: 100 mu L of a composition containing [ [ solution ] ], [ solution ]³H]BK and test/control compound/control serial dilutions of incubation buffer or 50 μ M BK were added separately to the rinsed cells on ice. After 90 minutes incubation on ice, the incubation medium was removed and the cells were washed 4 times with ice-cold PBS. To dissociate surface-bound [ alpha ], [ alpha ]³H]BK followed by addition of 200. mu.L of 0.2M acetic acid/0.5M NaCl (pH 2.7) followed by an additional 10 min incubation on ice. Then, the supernatant was transferred to a 6mL scintillation vial; 0.9mL of scintillation fluid was added separately and [3H ] was measured by analysis in a beta-counter (cpm, count time 1 min)]The amount of BK. To analyze the results, the cpm measured for non-specific binding was subtracted from the total counts and the cpm values for each compound dilution were used for curve fitting and IC₅₀And (4) calculating.

The compounds shown in examples 1-465 have been tested in this assay and found to exhibit an IC of less than or equal to 5 micromolar₅₀The value is obtained. The most preferred compounds of formula (I) exhibit an IC of less than 50 nanomolar₅₀The value is obtained.

Example 755: calcium mobilization assay

The inhibitory effect of test compounds on BK-mediated calcium mobilization was tested on HF-15 primary human fibroblasts.

Preparation of cell-coated plates and Loading of cells with calcium dye: 50.000 HF-15 cells (passage 12) were added to each well of a 96-well plate with a black, transparent bottom. After overnight incubation, cells were washed with HBSS (37 ℃) and 100. mu.L of HBSS was left in each well. Thereafter, 100. mu.L of freshly prepared calcium dye (Ca3, Molecular Devices) solution (containing 2.5mM probe) was added to each well. Subsequently, the cells were incubated at 37 deg.CIncubate for 60 minutes.

A series of dilutions was prepared and incubated with test compounds: based on a 5mM stock solution in 100% DMSO (and pre-diluted in 100% DMSO, if necessary), serial 1: 3 dilutions of test compounds and controls were prepared in 100% DMSO. The concentration range to be used was chosen to be between 2mM and 1nM, depending on the optimal concentration range for each compound. Next, 2.5 μ L of compound/control dilution was added to each well of the cell-coated assay plate, which already contained 200 μ LHBSS/dye solution. Subsequently, cells were preincubated with compound/control for 20 min at 25 ℃.

Calcium mobilization and outcome analysis: after 25 minutes of pre-incubation with compound/control, calcium mobilization was tested in a Flexstation apparatus (Molecular Devices). 20 seconds after the start of the recording of the fluorescence signal, 50. mu.L of a 25nM BK solution in HBSS was added to each well via the liquid-handling system of the device. The resulting peak height above baseline (relative fluorescence units [ RFU ]]Max-min) was used to calculate the inhibitory effect of test compounds on BK-mediated calcium mobilization. Percent inhibition was calculated by comparing RFU max-min values obtained for the blank (BK only, no antagonist) with values obtained for antagonist treated cells. Percent inhibition values (each referring to a certain concentration of antagonist) were used for curve fitting and IC₅₀And (4) calculating.

The most preferred compounds of formula (I) exhibit an IC in this assay of less than 50 nanomolar₅₀The value is obtained.

The features of the invention disclosed in the specification, the claims and/or the drawings may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.

Claims (27)

1. A compound of formula (I):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

A is a 6-membered heteroaryl having 1 to 3 heteroatoms each independently selected from N or O, wherein the 6-membered heteroaryl is substituted with 2 to 4 substituents each independently selected from halogen atoms, oxygen atoms, hydroxyl groups, cyano groups, amino groups, nitro groups, mercapto groups, alkyl groups, alkenyl groups, alkynyl groups, heteroalkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkylcycloalkyl groups, heteroalkylcycloalkyl groups, aryl groups, heteroaryl groups, aralkyl groups, or heteroaralkyl groups;

R⁵is a halogen atom, hydroxyl, cyano, nitro, mercapto, alkyl, alkenyl, alkynyl, or heteroalkyl;

R⁶is an optionally substituted alkyl group; optionally substituted alkenyl; a 5-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O or S, or cycloalkyl, wherein said 5-membered heterocycloalkyl or cycloalkyl is substituted with 0 to 3 substituents each independently selected from halogen atom, oxygen atom, hydroxyl group, cyano group, amino group, nitro group, mercapto group, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, alkylcycloalkyl group, heteroalkylcycloalkyl group, aryl group, heteroaryl group, aralkyl group, or heteroaralkyl group; a 5-membered heteroaryl having 1 to 4 heteroatoms each independently selected from N, O or S, wherein the 5-membered heteroaryl is substituted with 0 to 3 substituents each independently selected from a halogen atom, an oxygen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; or-S-R¹⁰；

R¹⁰Is a 5-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O or S, or cycloalkyl, wherein said 5-membered heterocycloalkyl or cycloalkyl is substituted with 0 to 4 substituents each independently selected from halogen atom, oxygen atom, hydroxyl group, cyano group, amino group, nitro group, mercapto group, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, alkylcycloalkyl group, heteroalkylcycloalkyl group, aryl group, heteroaryl group, aralkyl group, or heteroaralkyl group; or a 5-membered heteroaryl having 1 to 4 heteroatoms each independently selected from N, O or S, wherein the 5-membered heteroaryl is substituted with 0 to 4 substituents each independently selected from halogen atom, oxygen atom, hydroxyl group, cyano group, amino group, nitro group, mercapto group, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, alkylcyclo groupAlkyl, heteroalkyl cycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R⁷is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, an alkyl group, or a heteroalkyl group;

R⁸is a hydrogen atom or a halogen atom; and

R¹⁷is a hydrogen atom or a halogen atom.

2. The compound according to claim 1, wherein heteroaryl a contains 1-3 nitrogen atoms.

3. A compound according to claim 1 or 2, wherein a is

Wherein

W is N, NO or CR⁹；

Y is N, NO or CR²；

Z is N, NO or CR³；

Provided that at least one of W, Y or Z is N or NO;

R¹is a halogen atom, hydroxyl, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, or heteroalkylcycloalkyl;

R²is hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, mercapto group, alkyl group, alkenyl group, alkynyl group, or heteroalkyl group;

R³is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group;

R⁴is a halogen atom, hydroxyl, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroarylAralkyl, or heteroaralkyl; and

R⁹is a hydrogen atom, a halogen atom, or C₁-C₆An alkyl group.

4. A compound according to any one of claims 1-3, wherein R⁶Is that

Wherein

A¹、A²、A³、A⁴And A⁵Each independently selected from O, S, N, N-H, NO, C, or C-H; and

R¹¹and R¹²Each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group.

5. A compound according to any one of claims 1-3, wherein R⁶Is that

Wherein

A¹、A²、A³、A⁴And A⁵Each independently selected from O, S, N, N-H, NO, C, or C-H; and

R¹¹and R¹²Each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, a mercapto group, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group.

6. A compound according to any one of claims 3 to 5, wherein

R⁴Selected from heteroalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;

w is CR⁹；

Y is N, NO or CR²；

Z is N, NO or CR³；

Provided that at least one of Y or Z is N or NO;

R¹is a halogen atom, a hydroxy group, a cyano group, -O-C₁-C₆Alkyl or C₁-C₆An alkyl group;

R²is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -O-C₁-C₆Alkyl or C₁-C₆An alkyl group; and

R³is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, -O-alkyl group or an alkyl group.

7. A compound according to any one of claims 3 to 6, wherein R⁴Selected from the group-S-Y^a-L、-S-Y^a-CO-NR^aR^b、-Y^a-NR^c-CO-NR^aR^b、-Y^a-NR^c-CO-O-R^e、-Y^a-NR^c-CO-R^e、-Y^a-O-CO-NR^aR^b、-Y^a-CO-NR^aR^b、-Y^a-CO-NR^cL、-O-Y^a-CO-NR^aR^b、-Y^a-NR^c-CO-L、-Y^a-L、-Y^a-O-CO-O-R^c、-Y^a-O-CO-R^c、-Y^a-NR^c-SO₂-NR^aR^b、-Y^a-SO₂-NR^aR^bor-Y^a-NR^c-SO₂-R^eWherein

Y^aIs a bond, C₁-C₆Alkylene radical, C₂-C₆Alkenylene or C₂-C₆An alkynylene group;

R^ais a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or linked to R^bTo form a 4-to 10-membered cycloalkyl or heterocycloalkyl group;

R^bis a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, or with R^aTogether form a 4-to 10-membered cycloalkyl or heterocycloalkyl group;

R^cand R^eEach independently selected from a hydrogen atom, an optionally substituted C₁-C₆Alkyl, optionally substituted C₂-C₆Alkenyl, or optionally substituted C₂-C₆An alkynyl group; and

l is cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl.

8. A compound according to any one of claims 3 to 7, wherein R⁴Is that

Wherein

X^aIs N, O or CH;

X^bis C, S or S ═ O;

X^cis N, O or CH;

R¹³if present, is C₁-C₆An alkyl group;

R¹⁴if present, is C₁-C₆Alkyl radical, C₂-C₆Alkenyl or to R¹⁵To form

(v) 5-to 10-membered cycloalkyl;

(vi) 5-to 10-membered heterocycloalkyl;

(vii) 5-to 10-membered heteroaryl; or

(viii) 6-to 10-membered aryl;

R¹⁵is alkyl, alkenyl, or is linked to R¹⁴To form

(v) 5-to 10-membered cycloalkyl;

(vi) 5-to 10-membered heterocycloalkyl;

(vii) 5-to 10-membered heteroaryl; or

(viii) 6-to 10-membered aryl; and/or

If R is¹⁵And R¹⁶Are formed together

(v) 4-to 10-membered cycloalkyl;

(vi) 4-to 10-membered heterocycloalkyl;

(vii) 5-to 10-membered heteroaryl; or

(viii) 6-to 10-membered aryl; and

R¹⁶is hydrogen, alkyl, alkenyl, aryl, heteroaryl or with R¹⁵Are formed together

(v) 4-to 10-membered cycloalkyl;

(vi) 4-to 10-membered heterocycloalkyl;

(vii) 5-to 10-membered heteroaryl; or

(viii) 6-to 10-membered aryl.

9. The compound of any one of claims 3-8, wherein R⁴Is that

Wherein

R¹³Is a hydrogen atom or C₁-C₆An alkyl group;

R¹⁸and R¹⁹Each independently selected from hydrogen atom, halogen atom, hydroxyl, cyano, amino, nitro, C₁-C₆Alkyl, -O-C₁-C₆Alkyl, -CO-NR^aR^bor-SO₂-NR^aR^bWherein

R^aAnd R^bEach independently selected from a hydrogen atom, or C₁-C₆An alkyl group.

10. The compound according to any one of claims 1-9, wherein R⁵Is a halogen atom, cyano or C₁-C₆An alkyl group.

11. The compound according to any one of claims 1-10, wherein R⁷、R⁸And R¹⁷Each independently selected from H or F.

12. The compound according to any one of claims 1-11, wherein R⁵Is methyl or ethyl.

13. The compound according to any one of claims 1-12, wherein R⁶Selected from the following groups:

14. a compound according to any one of claims 3 to 13, wherein

R¹Is methyl, Cl, F, CN, or O-CH₃；

W is CH;

y is N, NO, CH, C-CH₃C-OH, or C-OCH₃；

Z is N, NO, CH, C-CH₃C-OH, or C-OCH₃(ii) a And is

Provided that at least one of Y or Z is N or NO.

15. A compound according to any one of claims 3 to 14, wherein R⁴Is that

Wherein

R¹³Is a hydrogen atom or a methyl group;

R²⁰is Cl, F, cyano, or CF₃(ii) a And is

R²¹Is a hydrogen atom or F.

16. The compound according to any one of claims 1-15, wherein R⁷，R⁸And R¹⁷Is H.

17. A compound or salt thereof according to any one of claims 1-16 wherein the compound exhibits an IC in a standard in vitro BK B2 receptor mediated assay₅₀Is 500nM or less.

18. A compound, preferably according to any one of claims 1 to 17, which is:

1- {3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-methyl-3- [ 2-methyl-4- (4-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-chloro-1-methyl-1H-imidazol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 5-chloro-2-methoxy-4- [ 2-methyl-4- (2-methyl-2H- [1, 2, 4] triazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-3-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- (3- {4- [4- (2-amino-ethoxy) -1H-pyrazol-3-yl ] -2-methyl-quinolin-8-yloxymethyl } -4-methyl-pyridin-2-ylmethyl) -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- {3- [4- (4-hydroxymethyl-2H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

n- (3- { 2-methyl-8- [ 4-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -quinolin-4-yl } -1H-pyrazol-4-ylmethyl) -acetamide,

1- {3- [4- (4-aminomethyl-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

n- (5- {8- [ 4-chloro-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1H-pyrazol-4-ylmethyl) -acetamide,

2- {8- [ 4-chloro-6-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -3-methyl-3H-imidazole-4-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (4-methyl-2H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

5- {8- [ 4-chloro-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -3-methyl-3H-imidazole-4-carbonitrile,

1- { 4-chloro-3- [4- (4-chloro-thiazol-5-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-3- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- {3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methoxy-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

5- {8- [ 4-chloro-6-methyl-2- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1-methyl-1H-pyrrole-2-carboxylic acid amide,

5- {8- [ 4-chloro-2- (3-cyano-2-oxo-2H-pyridin-1-ylmethyl) -6-methyl-pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1-methyl-1H-pyrrole-2-carboxylic acid amide,

1- { 4-chloro-3- [4- (4-hydroxymethyl-2H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (4-fluoro-pyrazol-1-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- {3- [4- (5-chloro-thiazol-4-yl) -2-methyl-quinolin-8-yloxymethyl ] -4-methoxy-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

2- {8- [ 5-fluoro-2-methoxy-3- (2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl) -pyridin-4-ylmethoxy ] -2-methyl-quinolin-4-yl } -3-methyl-3H-imidazole-4-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (5-methyl-1H-imidazol-4-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- (1- { 4-chloro-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-yl } -ethyl) -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- (1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-yl } -ethyl) -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

5- {8- [ 4-chloro-2- (3-cyano-2-oxo-2H-pyridin-1-ylmethyl) -pyridin-3-ylmethoxy ] -2-methyl-quinolin-4-yl } -1-methyl-1H-pyrrole-2-carboxylic acid amide,

1- { 4-chloro-3- [4- (4-fluoro-pyrazol-1-yl) -2-methyl-quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- (1- { 4-chloro-3- [4- (4-hydroxy-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-yl } -ethyl) -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-6-methyl-3- [ 2-methyl-4- (3-methyl-isoxazol-4-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 5-chloro-4- [4- (5-cyano-1-methyl-1H-pyrrol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -2-hydroxy-pyridin-3-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-methoxy-6-methyl-3- [ 2-methyl-4- (4-methyl-1H-pyrazol-3-yl) -quinolin-8-yloxymethyl ] -pyridin-2-ylmethyl } -3-trifluoromethyl-1H-pyridin-2-one,

1- { 4-chloro-3- [4- (4-hydroxymethyl-1H-pyrazol-3-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile,

1- { 4-chloro-3- [4- (5-fluoro-thiazol-2-yl) -2-methyl-quinolin-8-yloxymethyl ] -6-methyl-pyridin-2-ylmethyl } -2-oxo-1, 2-dihydro-pyridine-3-carbonitrile.

19. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 18, and optionally at least one carrier substance, excipient and/or adjuvant.

20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is formulated in the form of an aerosol, cream, gel, pill, capsule, syrup, solution, transdermal patch or drug delivery device.

21. A method of inhibiting BK binding to the BK B2 receptor in vitro, the method comprising: contacting a BK B2 receptor with at least one compound according to any one of claims 1-18, or a salt thereof, under conditions and in an amount sufficient to detectably inhibit binding of BK or any other substance to a BK B2 receptor.

22. An in vitro method for locating or detecting the BK B2 receptor in a tissue, preferably a tissue section, comprising:

(a) contacting a tissue sample containing a BK B2 receptor with a detectably labeled compound according to any one of claims 1-18 under conditions permitting binding of said compound to BK B2 receptor; and

(b) detecting the bound compound.

23. The method according to claim 22, wherein the compound is radiolabeled, fluorescently labeled or luminescently labeled, or labeled with an antibody.

24. Use of a compound or pharmaceutical composition according to any one of claims 1-20 for the manufacture of a medicament for the treatment and/or prevention of a disease or condition.

25. The use according to claim 24 wherein the condition or disease is responsive to BK B2 receptor modulation.

26. Use according to claim 24 or 25, wherein the condition is a skin disease; ocular diseases; ear diseases; mouth, throat and respiratory diseases; gastrointestinal diseases; liver, gall bladder and pancreatic disorders; urinary and renal diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphoid disorders; central nervous system diseases; brain diseases; diseases of the musculoskeletal system; allergic diseases; pain; infectious diseases; inflammatory diseases; (ii) damage; immune diseases; cancer; a genetic disease; or edema.

27. A method for treating a subject in need of such treatment, the method comprising administering a compound according to any one of claims 1-20.