OA16541A - Benzodioxane inhibitors of leukotriene production. - Google Patents

Abstract

The present invention relates to compounds of formula (I) : <img file="OA16541A_A0001.tif"/> wherein R1 to R3 , A, X and n are as defined herein. The compounds of formula (I) are useful as inhibitors of leukotriene A4 hydrolase (LTA4H) and treating LTA4H related disorder. The present invention also relates to pharmaceutical compositions comprising the compounds of formula (I), methods of using these compounds in the treatment of various diseases and disorders, and processes for preparing these compounds.

Description

Boehringer Ingelheim International GmbH

BENZODIOXANE INHIBITORS OF LEUKOTRIENE PRODUCTION

Field of the Invention

This invention relates to benzodioxanes that are useful as inhibitors of leukotriene A₄ hydrolase (LTA₄H) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of ieukotrienes including asthma, allergy and cardiovascular diseases including atherosclerosis, myocardial infarction and stroke. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

Background of the Invention

Leukotrienes (LT) are oxidized lipids that are produced by several cell types including neutrophils, mast cells, eosinophils, basophils, monocytes and macrophages. The first committed step in the intracellular synthesis of LTs involves oxidation of arachidonic acid by 5-lipoxygenase (5-LO) to leukotriene A4 (LTA₄), a process requiring the 5lipoxygenase-activating protein (FLAP). Leukotriene À₄ hydrolase (LTÀ4H) catalyzes the hydrolysis of LTA₄ to produce leukotriene B₄ (LTB₄). Through the engagement of the LTB₄ receptors (BLT1, BLT2), LTB₄ stimulâtes an array of pro-inflammatory responses (leukocyte chemotaxis, cytokine release, etc.). The leukotriene pathway has been implicated in diseases in which inflammation is a critical component of the pathology; these include cancer, asthma, atherosclerosis, colitis, glomerulamephritis, and pain (for a review, see M. Peters-Golden and W.R. Henderson, Jr., M.D., N. Engl. J. Med., 2007, 357, 1841-1854).

Bricf Summary of the Invention

The présent invention provides novel compounds which inhibit leukotriene A4 hydrolase (LTA₄H) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of leukotrienes, including allergie, pulmonary, fibrotic, inflammatory and cardiovascular diseases and cancer.

-l16541

In one embodiment, the invention relates to a compound of formula (1):

(I) or a pharmaceutically acceptable sait thereof, wherein:

X is N or CH;

n is an integer from 0 to 3;

R¹ is selected from halo, -OH, -CN, -(C]-C₆)alkyl, -O(C|-C₆)alkyl, and -(C₃Côjcycloalkyl;

O *1 'î

R and R are each independently selected elected from -H and -(Ci-Cfi)alkyl; wherein R and R may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, -OH, (=0), -(Ci-C₆)alkyl, -OtCrCéjalkyl, -C(O)OH, -C(O)(Ci-C₆)alkyl, and -C(O)NH₂;

A is a group of formula -NR⁴R⁵, wherein

R⁴ and R⁵ are each independently selected from -H, -(Ci-CsJalkyl, -(C₃Côjcycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 11 membered)heteroaryl; wherein each of the foregoing -(CpCôJalkyl, -(C₃Cô)cycloalkyl, -(4- to 11 -membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 11membered)heteroaryl of said R⁴ and R⁵ groups is optionally independently substituted by one to three R⁶ groups; wherein two R⁶ groups when attached to the same carbon atom of said -(Ci-Cô)alkyl may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and further optionally substituted —-216541 with one to three groups selected from halo, -OH, (=0), -(C|-C₆)alkyl, -O(CjC₆)alkyl, -C(O)OH, -C(O)(C]-C₆)alkyl, and -C(O)NH₂;

or A is a (4- to l l-membered)N-heterocyclic ring of formula B:

wherein said ring B may be a non-aromatic 4-8 membered monocyclic radical; a bridged bicyclic radical; a spirocyclic radical; or a 6 to 11-membered fused bicyclic radical which may be non-aromatic or hâve one aromatic ring provided that the aromatic ring of the bicyclic radical, when présent, is not attached to methylene carbon atom 1 of the compound of formula (I);

wherein said ring B may additionally comprise one to three additional ring heteroatoms independently selected from N, O and S;

wherein said ring B may be further optionally substituted by one to three groups selected from halo, -OH, (=O), -C(O)OH, -C(O)O-(C|-C6)alkyl, and -(Ci-Câ)alkyl; and wherein L is absent or a linker selected from -(Ci-Cô)alkylene;

each R⁶ is independently selected from halo, -OR⁷, -CF3, -CN, -(Cj-Cô)alkyl, -C(O)R⁷, -C(O)2R⁷, -C(O)N(R⁷)2j -N(R⁷)2, -NHC(O)R⁷, -NHC(O)N(R⁷)2, -S(O)₂R⁷, -NH-S(O)2-R⁷, -(C3-C6)cycloalkyl, -(4- to 11 -membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 11 membered)heteroaryl; wherein each of said, -(Ci-Cô)alkyl, -O(Ci-Cs)alkyl, -(C3Côjcycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 11membered)heteroaryl of said R⁶ group is optionally substituted where possible with one to three groups selected from halo, -OH, -CF3, -CN, (=0), -(C|-C6)alkyl, -C(O)OH, -C(O)O-(C_t-C₆)alkyl, -NH₂, -NH(Ci-C₆)alkyl, -N((CrC₆)alkyl)₂, -S(O)₂(C,-C₆)alkyl, -(C₃Cô)cycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 11 membered)heteroaryl; and F

-316541 each R⁷ is independently selected from -H, -(C]-C₆)alkyl, -(C|-C&)alkyl, -(Cj-CôJalkyl-OH, -(C_l-C6)alkyl-O-(C|-C₆)alkyl, -(C3-C₆)cycloalkyl, -(C₃-C6)cycloaikyl-OH, -(4- to 11membered)heterocycloaikyl, -(C6-Cio)aryl, and -(5- to l l-membered)heteroaryl.

This invention also relates to pharmaceutical compositions comprising the compounds of formula (I), methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

Dctailcd Description of the Invention

Définitions:

DCE = dichloroethane

DCM = dichloromethane

DEA = diethylamine

DIBAL-H = diisobutylaluminum hydride

DIPEA = diisopropylethylamine

DMA = dimethylacetamide

DMAP = 4-dimethylaminopyridine

DME = dimethyl ether

DMF = dimethylformamide

DMSO = dimethylsulfoxide

Et₂O = ethyl ether

EtOAc = ethyl acetate

EtOH = éthanol

IPA = isopropyl alcohol

KHMDS = potassium bis(trimethylsilyl)amide

MeCN = acetonitrile

MeOH = methanol

TBTU = 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate

TEA = triethylamine

TFA = trifluoroacetic acid /-416541

THF = tetrahydrofuran

TMSCF3 = (trifluoromethyl)trimethylsilane

It will be understood that the terms “compounds of formula (I)” and “compounds of the invention” hâve the same meaning unless indicated otherwise.

In its broadest embodiment (“the first embodiment of the invention”), the invention relates to compounds of formula (I) as described above, and pharmaceutically acceptable salts thereof, as described above in the summary of the invention.

In another embodiment (“the second embodiment of the invention”), the invention relates to a compound of formula (I) as described in the first embodiment immediately of the invention, or a pharmaceutically acceptable sait thereof, wherein group A is a group of formula -NR⁴R⁵.

In another embodiment (“the third embodiment of the invention”), the invention relates to a compound of formula (!) as described in the first embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein group A is a (4- to l l-membered)Nheterocyclic ring of formula B:

In another embodiment, the invention relates to a compound of formula (I) as described in the second embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(Ci-Côjalkyl, and R⁵ is -(C|-Cé)alkyl; wherein each -(Ci-Cô)alkyl of said R⁴ and R^s groups, when présent, is optionally independently substituted by one to three R⁶ groups.

In another embodiment, the invention relates to a compound of formula (I) as described in the embodiment immediately above, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(Ci-Côjalkyl, and R⁵ is -(C|-C₆)alkyl; wherein said -(CrCéjalkyl of said R⁵^—*

-516541 group is substituted by -(CrCôlcycloalkyl, -(4- to 1 l-niembered)heterocycloalkyl, -(CôC[o)aryl, or -(5- to 1 l-membered)heteroaryi; wherein each of said, -(C3-C&)cycloalkyl, -(4to 1 l-membered)heterocycloalkyl, -(Cô-Cio)aryl, and -(5- to 1 l-membered)heteroaryl is optionally substituted with one to three groups independently selected from -(Ci-Côjalkyl, -CFj, and -C(O)OR⁸.

In another embodiment, the invention relates to a compound of formula (I) as described in the second embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(Ci-Cô)alkyl, and R⁵ is -(Ci-Celalkyl; wherein said -(Ci-Cô)alkyl of said R^s group is independently substituted by one to three groups selected from-(C|Cfi)alkyl, -O(C,-C6)alkyl, -C(O)R⁸, -C(O)OR⁸, -S(O)2R⁸, and -NHC(O)R⁸.

In another embodiment, the invention relates to a compound of formula (I) as described in the second embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein R⁴ and R⁵ are each independently selected from -H or -(C]-C6)alkyl.

In another embodiment, the invention relates to a compound of formula (1) as described in the second embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(C|-C6)aikyl, and R^s is -(C3-C6)cycloalkyl, -(4- to 11 membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 1 l-membered)heteroaryl; wherein each of the foregoing -(C3-C6)cycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -((/,Cio)aryl, and -(5- to 1 l-membered)heteroaryl groups of said R⁵ is optionally independently ϋ

substituted by one to three groups selected from -(Ci-C6)alkyl, -O(C]-C6)alkyl, -C(O)R , -C(O)OR⁸, -S(O)₂R⁸, and -NHC(O)R⁸.

In another embodiment, the invention relates to a compound of formula (I) as described in the third embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein said ring B is 4-8 membered monocyclic radical.

In another embodiment, the invention relates to a compound of formula (I) as described in the embodiment immediately above, or a pharmaceutically acceptable sait thereof, wherein said 4-8 membered monocyclic radical is selected from the group consisting of azetidine, tetrahydropyrrole, piperidine, hexamethyleneimine, 1,2-diazetidine, pyrazolîdine, vV'”

-616541 imidazolidine, piperazine, hexahydrodiazepine, isoxazolidine, oxazolidine, tetrahydro-2H-

1,3-oxazine, morpholine, and hexahydro-l,4-oxazepine; wherein said monocyclic ring may be further optionally substituted by one to three groups selected from halo, -OH, (=0), -C(O)OH, -C(O)O-(Ci-C₆)alkyl, and -(C_rC₆)alkyl.

In another embodiment, the invention relates to a compound of formula (I) as described in the third embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein said ring B is a spirocyclic heterocyclic radical.

In another embodiment, the invention relates to a compound of formula (1) as described in the embodiment immediately above, or a pharmaceutically acceptable sait thereof, wherein 10 said spirocyclic heterocyclic radical is selected from:

-716541

In another embodiment, the invention relates to a compound of formula (I) as described in the third embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein said ring B is a bridged bicyciic radical; or a 6 to 11-membered fused bicyclic radical which may be non-aromatic or have one aromatîc ring provided that the aromatîc ring of the bicyclic radical, when présent, is not attached to methylene carbon atom 1 of the compound of formula (I).

In another embodiment, the invention relates to a compound of formula (I) as described in the embodiment immediately above, or a pharmaceutically acceptable sait thereof, wherein said 6 to 11-membered fused bicyclic radical or bridged bicyclic radical is selected from:

-816541

<_/ i \

In another embodiment, the invention relates to a compound of formula (I) as described in the third embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein L is -CH2-.

In another embodiment, the invention relates to a compound of formula (I) as described in the third embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein L is absent.

-916541

In another embodiment, the invention relates to a compound of formula (I) as described in the third embodiment of the invention, or a pharmaceutically acceptable sait thereof, wherein said 4-8-membered heterocyclic ring B is a selected from azetidinyl, pyrrolidinyl, piperidinyl and azepanyl; wherein each of the foregoing azetidinyl, pyrrolidinyl, piperidinyl and azepanyl rings is optionally substituted by one to three groups selected from halo, -OH, (=0), -C(O)OH, C(O)O-(C_rC₆)alkyl, and -(C_rC₆)alkyl; and wherein

L is absent or a linker selected from -(C|-C6)alkylene; and wherein R⁶is elected from halo, -OR⁷, -CF3, -CN, -(CrC6)alkyl, -C(O)R⁷, -C(O)2R⁷, -C(O)N(R⁷)₂, -N(R⁷)2, -NHC(O)R⁷, -NHC(O)N(R⁷)2, -S(O)₂R⁷, -NH-S(O)₂-R⁷, -(Cj-Côjcycloalkyl, -(4- to l l-membered)heterocycloaikyl, -(C&-Cio)aryl, and -(5to l l-membered)heteroaryl; wherein each of said, -(Ci-Cejalkyl, -O(C]-C6)alkyl, -(C3-Cô)cycloalkyl, -(4- to 11-membered)heterocycloalkyl, -(C6-Cjo)aryl, and -(5to 11 -membered)heteroaryl of said R⁶ group is optionally substituted where possible with one to three groups selected from halo, -OH, -CF3, -CN, (=0), -(C|C₆)alkyl, -C(O)OH, -C(O)O-(C,-C₆)alkyl, -NH₂, -NH(C_rC₆)alkyl, -N((C_r C₆)alkyl)₂, -S(O)₂(C]-C₆)alkyl, -(Cj-Cfijcycloalkyl, -(4- to 11 membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 1 l-membered)heteroaryl.

In another embodiment, the invention relates to a compound of formula (I) as described in any of the embodiments above, or a pharmaceutically acceptable sait thereof, wherein X is N.

In another embodiment, the invention relates to a compound of formula (I) as described in any of the embodiments above except the embodiment immediately above, or a pharmaceutically acceptable sait thereof, wherein X is CH.

The following are représentative compounds of the invention which were made by the »

general synthetic schemes, the examples, and known methods in the art. aa/

-1016541

Table l. Exemplary compounds of the invention.

Cpd No.	Structure	Name
1		1-(4-(2,3-dihydro-l,4benzodioxin-2yl)benzyl]pyrrolidine
2	a:Æ°	4-(4-(2,3-dihydro-1,4benzodioxin-2y 1 )b enzy 1 ] morphol ine
3		1 -(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-4,4dimethylpiperidine
4		8-(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-2,8diazaspiro[4.5]decan-l -one
5		1-(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-4fluoropiperidine
6		( 1 s,4s)-7-[4-(2,3-dihydro-l ,4benzodi ox in-2-yl)benzyl] -7azabicyclo[2.2.1 ]heptane
7	α°/τα°	4-(4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]thiomorpholine 1,1dioxide
8		l-(4-[(2S)-2,3-dihydro-1,4benzodîoxin-2-yl]benzyl}-N,Ndi methyl pi peridine-4-carboxam ide
9	o#°-	(3S)-l-[4-(2,3-dihydro-l,4benzodioxin-2yl)benzyl]pyrrolidin-3-ol
10	a:rJ σΛ?	1-((1 -(4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]piperidin-3yl }methyl)pyrrolidin-2-one

-Il16541

11		I - {4-[4-(2,3-dihydro-l ,4benzodioxin-2yl)benzyl]piperazin-1 -yl} ethanone
12		2-{[4-(2,3-dihydro-l,4- b enzodiox ΐη-2-yl )benzyl ] amino} l -(pyrrolidin-l -yl)ethanone
13	W r^N'S^ g:A!	N-{4-[(2S)-2,3-dihydro-l ,4benzodioxin-2-yl]benzyl} -Nmethyl-1- (methylsul fonyl)piperidin-4-ami ne
14	r «A1	1. [4-[ {4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}(methyl)amino]piperidi n-l-yl} ethanone
15	a;A°	3-[4-(pyrrolidin-lylmethyl)phenyl ] -2,3 dihydro[ 1,4]dioxino[2,3bjpyridine
16	πυα	7-[4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-5,6,7,8tetrahydro[ 1,2,4]triazolo[4,3ajpyrazine
17		3- {4-[( 1,1 -dioxidothiomorpholin- 4- y 1 )methyl ] phen yl} -2,3 dihydro[ 1,4]dioxino[2,3bjpyridine
18	nco	3-[4-(morpholin-4ylmethyl)phenyl]-2,3dihydrof 1,4]dioxino[2,3bjpyridine
19	CCA.?.	(3R)- i - {4-[(2S)-2,3-dihydro-l ,4benzodioxin-2- yljbenzyl} piperidi ne-3 -carboxyl ic acid

-1216541

20	p.oJæÇ O^OH	(3 S)-1 - {4-((28)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}piperidine-3-carboxylic acid
21		1 -( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}piperidin-4-yl)-2,2,2trifluoroethanol
22	α^Ύ·	2-( 1 - {4- [(2S)-2,3-dihydro-1,4- benzodioxin-2- yljbenzyl} piperidin-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-ol
23	ζ5-°θΊι—	N-[4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-2methylpropan-2-amine
24		(2R)-N-[4-(2,3-dihydro-l,4benzodioxin-2-yl)benzyl]butan-2amine
25	.^crc^. HN-·.	1 -[4-(2,3-dihydro-1,4benzodioxin-2-yi)benzyl]-Nmethylpiperidine-4-carboxamide
26	Y’A YY ΗθΎ	4-{ 1-(4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]piperidin-4-yl} butanoic acid
27	.-XXO, ô”	{1 -(4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]piperidin-4-yl} methanol
28	;XXO< à’ ‘	2- {1 -(4-(2,3-dihydro-1,4benzodioxin-2- yl )benzyl]piperidin-4-yl} propan- 2-ol
29	cY Y OH	3-{1-(4-(2,3-dihydro-1,4benzodioxin-2- yl )benzy I ] piperid in-4-yl} propanl-ol

-1316541

30	ΟΧ.	1 -(4-(2,3 -dihydro-1,4benzodioxin-2-yl)benzyl]-4methyl-1,4-diazepane
31	ό-	1-{4-[4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-1,4di azepan-1 -y 1} ethanone
32	(Î-^q	4-(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-1,4oxazepane
33	°\	N-[4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-2methoxy-N -methyl ethanami ne
34	OH	(3R)-1-(4-(2,3-dihydro-l,4benzodioxin-2yl)benzyl]pyrrolidin-3-ol
35	ά	8-(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-1,3,8triazaspiro(4.5]decane-2,4-dione
36	ο /	1-(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-3methoxyazetidine
37	,γΟΎν ότ· 0	{1 -(4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]piperidin-4yl} (morpholin-4-yl)methanone
38	ά° Ο	2-{1-(4-(2,3-dihydro-1,4benzodioxin-2- yl )benzyl]piperidin-4-yl} -N,Ndimethylacetamide

-I416541

39	&	1 -(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-4(methylsul fonyl)piperid ine
40		1 -(4-(2,3-dihydro-1,4- benzodioxin-2-yl)benzyl]azepane
41		N-[4-(2,3-dihydro-l ,4benzodioxin-2yl)benzyl]cyclopentanamine
42		N-[4-(2,3-dihydro-l ,4benzodioxin-2-yl)benzyl]-Nmethyl-2-(pyridin-2yl)ethanamine
43		l-cyclopropyl-N-(4-(2,3-dihydro- 1,4-benzodioxin-2- y 1 )b enzyl Jmethanamine
44	Ο-γίΧ'Ο» V O	1 -(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-4phenylpiperidin-4-ol
45		N-[4-(2,3-dihydro-l ,4benzodioxin-2-yl)benzyi]-Nethylethanamine
46	N	1-(4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]azetidine-3-carbonitrile
47	_-0	1-(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-3methoxypyrrolidine
48	ΐΓΎ 1 _?=° ^nh	N-{1-(4-(2,3-dihydro-1,4benzodioxin-2yl )benzyl]piperidin-4yl} methanesulfonamide

-I516541

49		N-[4-(2,3-dihydro-l,4benzodioxin-2-yl)benzyl]-2methyl-1 -(pyrrolidin-1 -yl)propan2-amine
50	..yOXi, ù'	l-({ 1-(4-(2,3-dihydro-1,4- benzodioxin-2yl)benzyl]piperidin-4yl}methyl)pyrrolidin-2-one
51	,-pa,. tr	1 -(4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-N,Ndimethylpiperidine-4-carboxamide
52	0 $ Η HO 0 0 ü	1 -[4-(2,3-dihydro-1,4benzodioxin-2-yl)benzyl]-N-(2hydroxyethyl)piperidine-4carboxamide
53		1- {1-(4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]piperidin-4-yl} urea
54		1 - [4-(2,3-dihydro-1,4benzodîoxin-2-yl)phenyl]-N(pyridin-3-ylmethyl)methanamine
55	σΗΗγ. 1	l -(4-(2,3-dihydro-1,4benzodioxin-2-yl)phenyl]-N-[(lmethyl-1 H-imidazol-4yl)methyl]methanamine
56	Μ}. v_r°	2-{4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl}-l,2,3,4tetrahydroisoquinoline-4carboxylic acid

-I616541

57	cP............αΛθΗ	( l R,38)-3-( (4-[(2S)-2,3-dihydro- l ,4-benzodioxin-2yljbenzyl} amino)cyclopentanecar boxylic acid
58		3-({4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} amino)4,4-dimethylpentanoic acid
59	CP.....°^;P HO%	l -( (4-[(2S)-2,3-dihydro-1,4benzodîoxin-2- yl ]benzyl} amino)cyclopentanecar boxylic acid
60	rO-O-χ vr° /N_^o HO	N-(4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -Nmethylglycine
61	.-yCTQ ô ·	l-(4-[(2S)-2,3-dihydro-l,4benzodioxin-2yl]benzyl}pyrrolidine-3carboxylic acid
62	<5>Ο><Χ	trans-4-( (4-[(2S)-2,3-dihydro-l ,4benzodioxin-2- yljbenzyl} amino)cyclohexanecarb oxylic acid
63	Cp^irCK	cis-4-( (4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}amino)cyclohexanecarb oxylic acid
64		l -[(3 R)-3-( (4-[(2S)-2,3-dihydrol ,4-benzodioxin-2yl]benzyl}amino)pyrrolidin-l yl]ethanone
65		l - [(3 S )-3-( {4-[(2S)-2,3-dihydro- l ,4-benzodioxin-2yljbenzyl} amino)pyrrolidin-1 yljethanone

-1716541

66	^OlH o oo	trans-4-( {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl]benzyl}amino)cyclohexanecarb oxamide
67		N-(4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -Nmethylcyclohexanamine
68	rOOO-° -Q	l - {4-[(2S)-2,3-dihydro-l ,4benzodioxin-2-yl]benzyl}-2methylpiperidine
69	0-0xJ~° '--' OH	(l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2yl]benzyl}piperidin-3-yl)methanol
70	σ°	2-(l - {4-[(2 S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}piperidin-4-yl)ethanol
71	cP.......°O	N- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl)propan2-amine
72	\	N- {4-[(2 S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl} -1 methoxypropan-2-amine
73		N- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl Jpropanl-amine
74	<Ο-Λ	N-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl)-Nm ethyl ethanamine
75	O<d-	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]phenyl} -N,Nd imethylmethanamine
76		trans-4-( (4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yljbenzyl} amino)cyclohexanol

-I816541

77	cP......	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl}-2methylpyrrolidine
78		l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2yl]benzyl}piperidin-3-ol
79		N-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl }Ν,Ν',Ν'-trimethylethane-1,2diamine
80	HO	2-(cyclohexyl {4-[(2S )-2,3dihydro-1,4-benzodioxin-2yljbenzyl} amino)ethanol
81	cP cz-	N- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl} -N,2dimethylpropan-2-amine
82	0 0 ô	N-( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl]benzy 1} pyrrol id in-3 yl)acetamide
83	.-..cr-Q ôr ·<	N-( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yljbenzyl} pyrrolidin-3-yl)-Nmethylacetamide
84		(lR,2R,4S)-N-{4-[(2S)-2,3dihydro-1,4-benzodioxin-2yl]benzyl)bicyclo[2.2.1]heptan-2amine
85	çp-O-gp	(4aR,8aS)-l-{4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2- yl]benzyl }decahydroquinoline

-1916541

86	Gr° λ=Λ^π“Ο	( l S,2R)-2-( {4-[(2S)-2,3-dihydro- l ,4-benzodioxin-2- yl ]benzyi} amino)cyclohexanecarb oxamide
87	& O-= o HO-	[( l S,2R)-2-( {4-[(2S )-2,3-di hydro- 1,4-benzodîoxin-2- yl]benzyl} amino)cyclohexyl]meth anol
88	XA......Q-Λ VjT° Ç OH	(3 R)-1 - (4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}pyrrolidin-3-ol
89	H0-*	[( 1 R,2R)-2-( {4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2- yljbenzyl} amino)cyclohexyl] meth anol
90	.cra, G'	(l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2yl]benzyl}piperidin-4-yl)methanol
91	/-D.....Ch CH0 M OH	( 3 S)-1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl Jbenzyl} pyrrol idin-3 -ο 1
92	rO......O- GH r-i N^O H	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2yl]benzyl}imidazolidin-4-one
93	.-.œq C '	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl)-N,Ndi methyl pyrrol id in-3 -am i ne
94	C --°	r-(4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -1,4'bipiperidin-2-one

-2016541

95		N-(cyclopropylmethyl)-N- {4[(2S)-2,3-dihydro-l,4benzodioxîn-2yl ]benzyl} cyclohexanamine
96	σ x	l-{4-[(2S)-2,3-dihydro-I,4benzodioxin-2-yl]benzyl} -N-(2hydroxyethyl)piperidine-4carboxamide
97	d>°>p HO	( 1 R,2R)-2-( {4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2- yl]benzyl)amino)cyclohexanol
98	pro, ά1 '	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -4methoxypiperidine
99	&·	1 -[( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yljbenzyl }piperidin-4yl)rnethyl]pyrrolidin-2-one
ΙΟΟ		trans-N-{4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yi]benzyl} -4methylcyclohexanamine
ΙΟΙ	cp-οΛ	( 1 S,2R)-2-( {4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2yljbenzyl} amino)cyclopentanol
102	cp-Oid	( 1 S,2S)-2-( {4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2yljbenzyl} amino)cyclopentanol
103	.....	N- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yljbenzyl} tetrahydro-2H-pyran-3amine
104	—N \	N-cyclohexyl-N-{4-[(2S)-2,3dihydro-l,4-benzodioxin-2yl]benzyl}-N',N'-dimethylethane1,2-diamine

-2I16541

105	HO	( 1 S,2S)-2-[ {4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2- yl]benzyl} (methyl)amino]cyclohe xanol
106	d^'^-p HO	( 1 R,2S)-2-[ {4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2yl]benzyl)(methyl)amino]cyclohe xanol
107	7=0.....0 W“°	4-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl}-3methylmorpholine
108	d^d-o»	5-({4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} amino)- 1 -methylpiperidin-2-one
109	d-'d^o	N- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl) -Nethylcyciopentanamine
110	d-^do-	N- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl} -N, 1 dimethylpiperidin-4-amine
111	o'M dp Pd OH d°	4-[( {4-[ (2 S )-2,3-dihydro -1,4benzodioxin-2- yl Jbenzyl} ami no )meth y 1] pheno 1
112		2-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl Jbenzyl )-1,2,3,4tetrahydroisoquinolin-6-ol
113	α:Λχ	1 -[4-(2,3-dihydro-1,4benzodioxin-2yl)benzyl]piperidine-3-carboxylic acid
114	ccÆS..	l-[4-(2,3-dihydro-l,4benzodioxin-2yl)benzyl]piperidine-3carboxamide

-2216541

115	0^9	(3S)-l-[4-(2,3-dihydro-l,4benzodioxin-2-yi)benzyl]-3fluoropyrrolidine
116		9-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl }-2,9diazaspiro[5.5]undecan-l -one
117	ο	7-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl}-l ,7diazaspiro[4.4]nonan-2-one
118	o=f oo	1 -(7- (4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl] benzyl} -1,7di azaspiro [4.4] non-1 -y 1 ) ethanone
119	ΝΗ, <χΑ'*	7-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -1,7diazaspiro[4.4]nonane-1 carboxamide
120	qo^ZTQ	0 A/	9-{4-[(2S)-2,3-dihydro-l ,4benzodioxin-2-yl]benzyl}-2methyl-2,9- diazaspiro[5.5]undecan-1 -one
121		u°	8-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -2methyl-2,8-diazaspiro[4.5]decan1-one
122	O=S^ α/7 œ	7-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -1 (methylsulfonyl)-l,7diazaspiro[4.4]nonane

-2316541

123	-fh 0 N a’./	2-(7- [4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl}-l,7diazaspiro[4.4]non-1 -yl)acetamide
I24	//y N N a/'	(7-{4-[(2S)-2,3-dihydro-I,4benzodioxin-2-yl]benzyl} -1,7diazaspiro[4.4]non-1 yl)acetonitrile
125	o o	Ί 0 Λ	8-{4-[(3S)-2,3- dîhydro[ 1,4]dioxino[2,3b]pyridin-3-yi]benzyl}-2,8diazaspiro[4.5]decan-1 -one
126	Chiral a:?3 0	(3S)-3-[4-(pyrrolidin-l ylmethyl)phenyl]-2,3dihydro[ 1,4]dioxino[2,3b]pyridine
127	cxW 0	7-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}-1,7diazaspiro[4.4]nonan-2-one
128	a/3	1 .(7. {4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl} -1,7diazaspiro[4.4]non-l-yl)-2methoxyethanone
129		o Λ N	8-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}-2-methyl2,8-diazaspiro[4.5]decan-1 -one

-2416541

130		9-[(S)-4-(2,3-Dihydro- benzo[ 1,4]dioxin-2-yl)-benzyl]-2methyl-2,9-diazaspiro[5.5]undecan-1 -one
131	«ÆQ-	l-[4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -1,4diazepan-5-one
132		l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl} -1,4diazepan-5-one
133	Q o o	N-[2-((4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3yl]benzyl}amino)ethyl]acetamide
134	HOy° ό	3-( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yljbenzyl} piperidin-4yl)propanoic acid
135		N-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3yl]benzyl}cyclopentanamine
136		l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl)piperidine3-carboxamide
137		(3 S)-3 - {4-[(4-methylpiperidin-1 yl )methy 1 ] phenyl} -2,3 dihydrofl ,4]dioxino[2,3b]pyridine

-2516541

138	/-ΟΌ- Η—'	N-(4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3- b ] pyri di n-3 - yl ] b enzyl} -N -m ethy 1 2-(pyridin-2-yl)ethanamine
139	/=0-0 Ο~° θ	(3S)-3-[4-(azepan-1 ylmethyl)phenyl]-2,3dihydro[ 1,4]dioxino[2,3b] pyri dîne
140	/=ΡΡ....... 4_ζ°	N-{4-[(3S)-2,3dihydrof 1,4]dioxino[2,3b ] pyri di n-3 - yl] benzyl} -N methylethanamine
141	ο	N-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b] pyridi n-3-y 1 ] b enzyl} -Nethylethanamine
142	Cp......	N-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl] -N methylcyclopentanamine
143	/=0-0 Ο π	(3S)-3-{4-[(4-methyl-l,4diazepan-1 -yl)methyl] phenyl} 2,3-dihydro[ 1,4]dîoxino[2,3b]pyridine
144	/=Ο ο Ο ç OH	(3R)-l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}pyrrolidin3-ol
145	cCO '“N H	(3S)-3-{4-[(ls,4s)-7azabicyclo[2.2.1 ]hept-7ylmethyljphenyl}-2,3dihydrof 1,4]dioxino[2,3bjpyridîne
146	Λ-·	(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl} piperidin-4yl)methanol

-2616541

147	OH	(3S)-l-{4-[(3S)-2,3- dihydro[ 1,4]dioxîno[2,3b]pyridin-3-yl]benzyl}pyrrolidin3-ol
148	.#0 Λ·· r	l-(4-{4-[(3S)-2,3dihydro[ 1,4]dioxino[2,3b ] pyri din-3 - yl] benzyl}-1,4diazepan-l-yl)ethanone
149	.-/τα a- \ ks^N OH	3-(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3- b ] pyri d i n-3 -yl] benzyl} piperidi n-4yl)propan-l-ol
150	cp	(3S)-3-[4-( 1,4-oxazepan-4ylmethyl)phenyl]-2,3dihydro[ 1,4]dioxino[2,3b]pyridine
I5l	α·	4-(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl]piperidin-4yl)butanoic acid
152	2y.O HN...	l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b ] pyridi n-3 - yl] benzyl} -N methylpiperidine-4-carboxamide
153	cp^»os	l-[4-({4-[(3S)-2,3dihydro[l,4]dioxino[2,3b]pyridin-3- yljbenzyl] amino)piperidin-1 yl]ethanone
154	?νΧΟψ I 0 » k0H	l-{4-[(3S)-2,3dihydrof 1,4]dioxîno[2,3b ] pyri din-3-y 1] benzyl} -N-(2hydroxyethyl)piperidine-4carboxamide

-2716541

155	rD-O V?° Q F	(3S)-3- {4-[(4-fluoropiperidin-l yl )methyl ] phenyl} -2,3 dihydro[ 1,4]dioxino[2,3b]pyridine
I56	N. N	(3S)-3-[4-(5,6- dihydro[ 1,2,4]triazolo[4,3a]pyrazin-7(8H)ylmethyl)phenyl]-2,3dihydro[ 1,4]dioxino[2,3bjpyridine
157		N-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3- b ] pyrid i n-3 - yl] b enzyl} -2-meth y 1- 1 -(pyrrolidin-1 -yl)propan-2-amine
158	XXH vr°	(3S)-3- {4-[(3-methoxypiperidin- 1 -yl)m ethyl ] phenyl} -2,3 dihydrof 1,4]dîoxino[2,3b]pyridine
159	Àr°	l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidine4-carbonitri)e
160	.^.cra. rV A	N-(l-(4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)acetamide
161	v?° n i?*0 0	(3S)-3-{4-[(l,ldioxidothiomorpholin-4yl)methyl]phenyl}-2,3dihydro[ 1,4]dioxino[2,3bjpyridine
162	6' 0	(l-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)(morpholin-4-yl)methanone
163	rCXb Q-0 o σ	l-[(l-{4-[(3S)-2,3- dîhydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-3yl)methyl]pyrrolidin-2-one

-2816541

164	<χΝγΝΗ3 0°	4-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyrîdin-3-yl]benzyl}piperazine1-carboxamide
165	?^œQ“>o Jyi θ «	8-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl} -1,3,8triazaspiro[4.5]decane-2,4-dîone
166	/=0--0- V?° 0 /	(3 S )-3 - (4- [(3-methoxyazetidin-1 yl)methyl]phenyl}-2,3dihydro[ 1,4]dioxino[2,3b]pyridine
167	€p~°/o+°	N-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}-l (methylsulfonyl)piperidin-4-amine
168	rO Ο Ο η ^0	(3 S )-3 - {4-[(3-methoxypyrrolidin- 1 -yl)methyl]phenyl}-2,3dihydro[ 1,4]dioxino[2,3bjpyridine
169	4 +° / \ Λί°° '“Ν Ζ ' ' 0	N-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl} -N-methyl1 -(methylsulfonyl)piperidin-4amine
170	ou Ο s	(3S)-3-(4-{[4-(2methoxyethoxy)piperidin-1 yl jmethyl} phenyl )-2,3 dihydro[ 1,4]dioxino[2,3bjpyridine
171	0^χοα ά° ° <	2-(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidîn-4yl)-N,N-dimethylacetamide

-2916541

172	A°	(3S)-3-(4-{[4(methylsulfbnyl)piperidin-l yljmethyl} phenyl)-2,3dîhydro[ 1,4]dioxino[2,3bjpyridine
173	Cp.....	N-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3- yl]benzyl} cyclobutanamine
174	O ?	N- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl}-1 (methylsulfonyl)piperidin-4-amine
175	NH, «A Ô A3	1 -( 1- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yljbenzyl} piperidin-4-yl)urea
176	0 , ,P HN'S' ό Cif'l1	N-( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl]benzyl} piperidin-4yl)methanesulfonamide
177	N II ύ	l-{4-[(2S)-2,3-dihydro-1,4benzodioxin-2yljbenzyl} piperidine-4carbonitrile

-3016541

178	0 «A Ô a;/3	N-( l - {4-[(2S)-2,3-dihydro-l ,4benzodioxin-2yl]benzyl}piperidin-4yl)acetamide
179	I OyNH ύ or	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl} -Nmethylpiperidine-4-carboxamide
180	Q °yN-> ό	(l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2yl]benzyl}piperidin-4yl)(morpholin-4-yl)methanone
I8l	Y a:A	4-( 1 - {4-[(2S)-2,3-dihydro-l ,4benzodioxin-2yl]benzyl}piperidin-4-yl)butanoic acid
182	Γ'χ3 <»> OH co^	[(3 R)-1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- y 1 Jbenzy 1} piperidi n-3 -y 1 ] aceti c acid

-3116541

183	Cf^° α;Ο	[(3 S)-1 -{4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl]benzyl} piperidin-3-yl]acetic acid
184	Q °	[(3 R)-l-{4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}pyrrolidin-3-yl]acetic acid
185	Ύ° C	l-(4-{4-[(3S)-2,3- dihydrof 1,4]dioxîno[2,3b]pyridin-3-yl]benzyl}piperazinl-yl)ethanone
186	< o o >5	l-{4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl} piperidin-4ol
187	z !<X o o «	l-(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)urea

-3216541

188	V Ο*? 0	(3S)-3-(4-{[4(methylsulfonyl)piperazin-1 yl] methyl} phenyl)-2,3 dihydro[ 1,4]dioxino[2,3b]pyridine
189	O OH 0	l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidine4-carboxylic acid
190	=° k o o	N-(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)methanesulfonamide
I9l	α·.χΧ'-	(lS,3R)-3-({4-[(2S)-2,3-dihydro- 1,4-benzodioxin-2- yl]benzyl} amino)cyciopentanecar boxylic acid
192		i - {4-[(2S)-2,3-dihydro-l ,4bcnzodioxin-2yl Jbenzyl} piperidin-4-ol
193	σογχτα„	1 -{4-[(2R)-2,3-dihydro-1,4benzodioxin-2yl]benzyl }piperidin-4-ol
194		8-{4-[(2S)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl} -2,8diazaspiro[4.5]decan-l -one

-3316541

195	σ:/Γ0Λ.	8- {4-[(2R)-2,3-dihydro-1,4benzodioxin-2-yl]benzyl}-2,8diazaspiro[4.5]decan-l-one
196		l-{4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}pyrrolidine
197		l-{4-[(2R)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}pyrrolidine
198	a;Æ°	4-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2yl]benzyl} morphol ine
199	Cj.jJXO	4- {4-[(2R)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}morpholine
200		l-{4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl ] benzyl} piperidine-4-carboxyl i c acid
201	œOXÇ	1 - {4-[(2R)-2,3-dihydro-1,4benzodioxin-2- yl Jbenzyl} p i peridi ne-4-carb oxyli c acid
202		4-[4-(7-tluoro-2,3-dihydro-l,4- benzodioxin-2- yl)benzyl]morpholine
203	'a:A°	1 -[4-(7-fluoro-2,3-dihydro-1,4benzodioxin-2yl)benzyl]pyrrolidine
204	φ,-^χτο	(3S)-3-[4-(morpholin-4ylmethyl)phenyl]-2,3dihydro[ 1,4]dioxino[2,3bjpyridine

-3416541

205	¢¢/3°	(3R)-3-[4-(morpholin-4ylmethyl)phenyl]-2,3dihydro[ l ,4]dioxino[2,3bjpyridine
206		l-{4-[(3S)-2,3dihydrof l ,4]dioxino[2,3b]pyridin-3-yI]benzyl}pîperidine4-carboxamide
207	.N 0 jO^ 0^γΝΗ2 UU °	l-{4-[(3R)-2,3- dihydro[l,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidine4-carboxamide
208	α;/33	l -[4-(2,3-dihydro[ l ,4]dioxino[2,3b]pyridin-3-yl)benzyl]pyrrolidin2-one
209	ο 4 ο ο	3-[4-(2,3-dihydro[ l ,4]dioxino[2,3b]pyridin-3-yl)benzyl]-l,3oxazolidin-2-one
210	<xfx~'	l -[4-(2,3-dihydro[ l ,4]dioxino[2,3b]pyridin-3- y l )phenyl ] methanamine
2ll	^o^rroço	l-{4-[(2S)-2,3-dihydro-l,4“ benzodioxin-2-yl]benzyl} -4methylpiperidine-4-carboxylic acid
212	^.ο^χτφ^ο	(3 R,4R)-1 - (4-[(2S)-2,3-dihydrol,4-benzodioxin-2-yl]benzyl}-3methylpiperidine-4-carboxylîc acid
213	CX° LÂ0J F OH	1-{4-[(2S)-2,3-dihydro-l,4- benzodioxin-2-yl]benzyl }-4fluoropiperidine-4-carboxylic acid

-3516541

214	f αΡ	( 3 R)-1 - {4-[(2 S )-2,3-d ihydro-1,4benzodioxin-2- yl]benzyl}pyrrolidine-3carboxylic acid
215	Z ο ck ο ο ό	(3 S)-1 - (4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl]benzyl}pyrrolidine-3carboxylic acid
216	OCoJ^ îh,n	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl )-4-(1 Htetrazol-5-yl)piperidine
217	ο ο ô	l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2yljbenzyl} piperidin-4-amine
218	0 ΗΝΛ-ϋΗ ô	N-( 1 - {4-[ (2 S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl)piperidin-4-yl)-2hydroxyacetamide
219	ΗΝ^° Ô α;Α	N-( 1 - (4-[(2S)-2,3-dihydro-l ,4benzodioxin-2- yl]benzyl ) piperidin-4-yl)-2methoxyacetamide

-3616541

220	o o P	N-( l - (4-[(2S)-2,3-dihydro-1,4benzodioxin-2yI]benzyl}piperidin-4-yl)-2hydroxy-2-methylpropanamide
221	d’d	N-(l-{4-[(3S)-2,3- dihydro[ l ,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)-2-hydroxy-2- methylpropanamide
222	CL^oh	N-(l-{4-[(3S)-2,3dîhydro[ l ,4]dioxino[2,3b]pyridin-3-yl]benzyl)piperidin-4y l )-2-hydroxy acetami de
223		N-(l-{4-[(3S)-2,3dihydro[ l ,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4- hydroxycyclopropanecarboxamide
224		l-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl }-4-( 1,1 dioxido-1,2-thiazolidin-2yl)piperidine
225	a;dô	1 -( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2yljphenyl} ethyl)pyrrolidine
226		4-(l - {4-[(2S)-2,3-dihydro-l ,4benzodioxin-2yljphenyl} ethyl )morpholine
227		1.( i - (4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yljphenyl} ethyl )piperidine-4carboxylic acid

v—

228		l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl }-4methylpiperidine-4-carboxylic acid
229	a/æ/t	2-( 1 - {4-[(2S)-2,3-dihydro-l ,4benzodioxin-2yl]benzyl)piperidin-4-yl)-2methylpropanoic acid
230	^'cT hcAo	2-(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)-2-methyl propanoic acid
231	HO^O	4-[( 1 - {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl]benzyl} piperidin-4yl)methyl]benzoic acid
232	HOX>	2-{4-[(2S)-2,3-dihydro-l,4benzodioxin-2-yl]benzyl }-l ,2,3,4tetrahydroisoquinoline-7carboxylic acid
233	0	4-( 1 - {4-[(2S)-2,3-dihydro-l ,4benzodioxîn-2yl]benzyl}piperidin-4-yl)benzoic acid
234	aPpj O^OH	4-[(l-{4-[(3S)-2,3- dihydro[ 1,4]dioxîno[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)methyl]benzoic acid
235	OH	4-(l-(4-[(3S)-2,3- dihydrof 1,4]dioxino[2,3b]pyridin-3-yl]benzyl}piperidin-4yl)benzoic acid
236	LX0J OH	4- {[ {4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}(ethyl)amino]methyl}be nzoic acid

-3816541

237	Y kAy0H LA0J k o	4-[(buty 1 {4-[(2S)-2,3-dihydro-1,4benzodioxin-2- yl ]benzy 1} ami no )meth yl ] benzoic acid
238	a:/30/?.	3- {[ {4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}(ethyl)amino]methyl}be nzoic acid
239	a:/3'0! nOyÀJI 0	3-[(4- {4-[(2S)-2,3-dihydro-1,4benzodioxin-2yl]benzyl}piperazin-l yl)methyl]benzoic acid

In one embodiment, the invention relates to any of the compounds depicted in Table 1, and pharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to a compound selected from the group consisting of:

4-( 1 - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} piperidin-4-yi)butanoic acid;

4-(l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)benzoic acid;

(3S)-3- {4-[( 1 s,4s)-7-azabicyclo[2.2.1 ]hept-7-ylmethyl]phenyl} -2,3dihydro[ 1,4]dioxino[2,3-b]pyridine;

N-( 1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4yl)methanesulfonamide;

(3S)-3-[4-(azepan-l-ylmethyl)phenyl]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine;

- {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} -2-methylpiperidine;

7- {4-[(2S)-2,3-dihydro-1,4-benzodîoxin-2-yl]benzyl} -1,7-diazaspiro[4.4]nonane-1 carboxamide;

7-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-l,7-diazaspiro[4.4]nonan-

2-one;

1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxylic acid; yç-—'

-3916541 ( l - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} piperidin-4-yl)(morpholin-4yl)methanone;

8-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridîn-3-yl]benzyl}-l,3,8triazaspiro[4.5]decane-2,4-dione;

(3S)-3-{4-[(3-methoxypiperidin-l-yl)methyl]phenyl}-2,3-dihydro[l,4]dioxino[2,3-

b]pyridine;

N-( 1 - {4-[(2S)-2,3“dihydro-1,4-benzodioxin-2-yl]benzyl} pyrrolidin-3-yl)-Nmethylacetamide;

- {4-[(2S)-2,3-dihydro-l ,4-benzodioxin-2-yl]benzyl }-4-( 1,1 -dioxido-1,2-thiazolidin-210 yl)piperidine;

(3R)-l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}pyirolidin-3-ol;

N-(l-{4'[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-2hydroxyacetamide;

4-[(l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-415 yl)methyl]benzoic acid;

(l-{4“[(3S)-2,3-dîhydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)(morpholin4-yl)methanone;

(3S)-3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine;

8-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-2,8-diazaspiro[4.5]decan-l-one;

l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carbonitrile;

l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N-methylpiperidine-4-carboxamide;

8-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2,8-diazaspiro[4.5]decan1 -one;

N-( 1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-225 hydroxy-2-methylpropanamide;

N-(l-{4-[(3S)-2_J3-dihydro[l,4]dîoxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-lhydroxycyclopropanec arbox ami de;

N-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N-ethylcyclopentanamine;

l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methylpiperidine-4- carboxamide;

-4016541

N- {4-[(3S)-2,3-dihydro[ l ,4]dioxino[2,3-b]pyridin-3-yl]benzyl} -Nmethylcyclopentanamine;

l -[( l - {4-[(3S)-2,3-dihydro[ l ,4]dioxino[2,3-b]pyridin-3-yl]benzyl }piperidin-3yl )methyl Jpyrrol id i n-2-one;

l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-2-methylpynOlidine;

N-{4-[(3S)-2,3-dihydro[ l ,4]dioxino[2,3-b]pyridin-3-yl]benzyl }-2-methyl-1 -(pyrrolidin-1 yl )propan-2- ami ne;

N-cyclohexyl-N-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N',N'dimethylethane-1,2-diamine;

N-( l- {4-[(3S)-2,3-dibydro[ l ,4]dioxino[2,3-b]pyridin-3-yl]benzyl) piperidin-4yl)acetamide;

N-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methyl-2-(pyridin-2yl)ethanamine;

(3S)-3-[4-(pyrrolidin-l-ylmethyl)phenyl]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine;

l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-3-carboxamide;

l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carboxamide;

N-(l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}pyrrc>lidin-3-yl)acetamide; i-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-(2hydroxyethyl)piperidine-4-carboxamide;

(3S)-3-[4-(l,4-oxazepan-4-ylmethyl)phenyl]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine; l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N-(2-hydroxyethyl)piperidine-4carboxamide;

4-( l - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} piperidin-4-yl)benzoic acid;

l -( l - (4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }piperidin-4-yl)urea;

7- {4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-l,7-diazaspiro[4.4]nonan-2-one;

8- {4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl)-2-methyl-2,8diazaspiro[4.5]decan-l -one;

l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-ol;

N-(I-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}piperidin-4yl)methanesulfonamide;

-4l16541

3- (l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)propan-lol;

(3S)-3-{4-[(4-methylpiperidin-l-yl)methyl]pheny!}-2,3-dihydro[l,4]dioxino[2,3-

b]pyridine;

N-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzy!}-N-ethylethanamine;

N- {4-[(3S)-2,3-dihydro[ l ,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1 (methylsulfonyl)pîperidin-4-amine;

(3S)-3- {4-[(4-fluoropiperidin-1 -yl)methyl] phenyl} -2,3-dihydro[ l ,4]dioxino[2,3bjpyridine;

-(4- {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} -1,4-diazepan-1 yl)ethanone;

[(3R)-l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyI}piperidin-3-yl]acetic acid;

(1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl }piperidin-4-yl)methanol;

4- [( 1 - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }piperidin-4-yl)methyl]benzoic acid;

(3S)-3- {4-[(4-methyl-1,4-diazepan-1 -yl)m ethyl] phenyl} -2,3-dihydro[ 1,4]dioxino[2,3-

b]pyridine;

(3S)-3-{4-[(3-methoxypyrrolidin-l-yl)methyl]phenyl}-2,3-dihydro[l,4]dioxino[2,3b]pyridine; and

N-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N,2-dimethylpropan-2-amine; or a pharmaceutically sait thereof of each of the foregoing.

In another embodiment, the invention relates to a compound selected from the group consisting of:

(3S)-3-[4-(azepan-l-ylmethyl)phenyl]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine;

N-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-Nmethyl cyclop entanami ne;

N-( I - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl }piperidin-4yl)methanesulfonamide;

(3 S )-3 - {4-[(3-methoxypiperidin-1 -yl)methyl]phenyl} -2,3-dihydro[ 1,4]dioxino[2,3b]pyridine;

-4216541 (3S)-3- {4-f(4-methylpiperidin- ί -yl)methyl]phenyl }-2,3-dihydrof 1,4]dioxino[2,3bjpyridine;

N-(l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4yl)acetamide;

( 3 S )-3- {4-[( 1 s,4s)-7-azabicyclo[2.2.1 ]hept-7-ylmethyl]phenyl} -2,3 dihydrof 1,4]dioxino[2,3-b]pyridine;

(3S)-3-[4-(pyrrolidin-l-ylmethyl)phenyl]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine;

N- {4-[(3 S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl }-N-ethylethanamine;

N-( 1 - (4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} pyrrolidin-3-yl)-Nmethylacetamide;

N- {4-[(3S)-2,3-dihydrof 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} -2-methyl-1 -(pyrrolidin-1 yl)propan-2-amine;

- {4-[(3S)-2,3-dihydrof 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-ol;

8-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyi}-2,8-diazaspiro[4.5]decan-

1-one;

( 1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl }piperidin-4-yl)(morpholin-

4-yl)methanone;

N-( 1 - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }pyrrolidin-3-yi)acetamide;

1- {4-[(3S)-2,3-dihydrof l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methylpiperidine-4carboxamide;

7- {4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-l,7-diazaspiro[4.4]nonan-

2- one;

(3 S)-3-[4-( 1,4-oxazepan-4-ylmethyl)phenyl]-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridine;

3- (l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)propan-lol;

8- {4-[(3S)-2,3-dihydrof l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2-methyl-2,8diazaspiro[4.5]decan-l-one;

(3S)-3-{4-[(4-methyl-l ,4-diazepan-l-yl)methyl]phenyl}-2,3-dihydrof 1,4]dioxino[2,3b]pyridine;

4- ( 1 - {4-f (2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }piperidin-4-yl)benzoic acid; (3R)-l“{4-[(3S)“2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}pyrrolidin-3-ol;

-4316541

I -(4- {4-[(3 S)-2,3-dihydro [ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} -1,4-diazepan-l yl)ethanone;

l-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carbonitrile; N-(l - {4-[(3 S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-25 hydroxy-2-methylpropanamide; l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-3-carboxamide; ( 1 - (4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} piperidin-4-yl)methanol;

8- {4-[(3 S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,3,8triazaspiro[4.5]decane-2,4-dione;

N-( 1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} piperidin-4-yl)-1 hydroxycyclopropanecarboxamide;

l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N-(2-hydroxyethyl)piperidine-4carboxamide;

N- {4-[(3 S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} -1 15 (methylsulfonyl)piperidin-4-amine; l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carboxamide;

4-(l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)benzoic acid;

l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-2-rnethylpynOlidine;

1 -[(1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-3yl)methyl]pyrrolidin-2-one;

7-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-l,7-diazaspiro[4.4]nonan-2-one;

-( 1 - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }piperidin-4-yl)urea; N-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N-ethylcyclopentanamine;

N-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl)-N-methyl-2-(pyridin-2yl)ethanamine;

- {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} -2-methylpiperidine;

- (4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }piperidine-4-carboxylic acid;

4-[( 1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl }piperidin-430 yl)methyl]benzoic acid;

(3S)-3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridine;

-4416541 (3S)-3-{4-[(4-fluoropiperidin-l-yl)methyl]phenyl}-2,3-dihydro[l,4]dioxino[2,3bjpyridine;

(l - (4-((23)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} piperidin-4-yl)(morpholin-4yl)methanone;

8-{4-[(2S)-2,3-dihydro-l₁4-benzodioxin-2-yl]benzyl}-2,8-diazaspiro[4.5]decan-l-one; N-(l-(4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-2hydroxyacetamide;

4-[(l-(4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)methyl]benzoic acid;

N-( 1 - (4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} piperidin-4yl)methanesulfonamide;

- (4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} -N-methylpiperidine-4-carboxamide; 4-(l-(4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)butanoic acid;

7- (4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} -1,7-diazaspiro[4.4]nonane-l carboxamide;

N-cyclohexyl-N-(4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N',N’dimethylethane-1,2-diamine;

[(3 R)-1 - (4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }piperidin-3-yl]acetic acid;

- (4-((23)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }-4-( 1,1 -dioxido-1,2-thiazolîdin-2yl)piperidine; and

- (4-((3 S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-(2hydroxyethyl)piperidine-4-carboxamide; or a pharmaceutically acceptable sait thereof of each of the foregoing.

In another embodiment, the invention relates a pharmaceutical composition comprising one or more compounds of formula (I) as defined in any of the embodiments above, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient.

-4516541

Ail terms as used herein in this spécification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more spécifie définitions are as follows:

The term “(Ci-Céjalkyl” refers to branched and unbranched alkyl groups having from l to 6 carbon atoms. Examples of -(Ci-Côjalkyls include methyl, ethyl, n-propyl, isopropyl, nbutyl, sec-butyl, isobutyl, tert-butyl, n-pentane, iso-pentyl, neopentyl, n-hexane, isohexanes (e.g., 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl). It will be understood that any chemically feasible carbon atom of the (Ci-Cù)alkyl group can be the point of attachment to another group or moiety.

The term “(C3-C6)cycloalkyl” refers to a nonaromatic 3- to 6-membered monocyclic carbocyclic radical. Examples of “(C3-C₆)cycloalkyls” include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cyclohexyl.

As used herein, the term “(C6-Cio)aryl” refers to an aromatic hydrocarbon rings containing from six to ten carbon ring and includes monocyclic rings and bicyclic rings where at least one of the rings is aromatic. Non-limiting examples of Cô-io aryls include phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl and benzocycloheptenyl.

As used herein, the term “4 to 11-membered heterocycie” includes stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical. The 4 to 11-membered heterocycie consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycie may be either saturated or partially unsaturated. Non-limiting examples of nonaromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, l,l-dioxo-lZ⁶-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl, Non-limiting examples of nonaromatic 6 to 11-membered fused bicyclic radicals include octahydroindolyl, aa/

-4616541 octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting examples of nonaromatic 6 to l l-membered bridged bicycîic radicale include 2azabicyclo[2.2.l]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.l]octanyl. Non-limiting examples of nonaromatic 6 to l l-membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza-spiro[3,4]octanyl.

As used herein, the term “5 to l l-membered heteroaryl” includes aromatic 5 to 6membered monocyclic heteroaryls and aromatic 7 to l l-membered heteroaryl bicycîic rings where at least one of the rings is aromatic, wherein the heteroaryl ring contains l -4 heteroatoms such as N, O and S. Non-limiting examples of 5 to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyranyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of 7 to l l-membered heteroaryl bicycîic rings include benzimidazolyl, l,3-dihydrobenzoimidazol-

2-one, quinolinyl, dihydro-2/7-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzopyranyl, benzodîoxolyl, benzoxazolyl, benzothiazolyl, pyrrolo[2,3-b]pyridinyl, and imidazo[4,5-b]pyridinyl.

It will be understood that when a heterocyclyl or heteroaryl contains a S ring atom, such S ring atom can be présent in the ring in its divalent, tetravalent, or hexavalent form, i.e., -S-, -S(O)- or-S(O)₂-.

Each aryl or heteroaryl unless otherwise specified includes it’s partially or fully hydrogenated dérivatives. For example, quinolinyl may include decahydroquînolinyl and tetrahydroquinolinyl, naphthyl may include its hydrogenated dérivatives such as tetrahydranaphthyl. Other partially or fully hydrogenated dérivatives of the aryl and heteroaryl compounds described herein will be apparent to one of ordinary skill in the art.

The term “heteroatom as used herein shall be understood to mean atoms other than carbon such as O, N, and S. VJ'*

-4716541

The term “halo” or “halogen” refers to fluoro, chloro, bromo or iodo.

The symbol

R means point of attachment of a group R to a moiety.

In ail alkyl groups or carbon chains one or more carbon atoms can be optionally replaced by heteroatoms: O, S or N, it shall be understood that if N is not substituted then it is NH, it shall also be understood that the heteroatoms may replace either terminal carbon atoms or internai carbon atoms within a branched or unbranched carbon chain. Such groups can be substituted as herein above described by groups such as oxo to resuit in définitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.

For ail compounds disclosed in this application, in the event the nomenclature is in conflict with the structure, it shall be understood that the compound is defined by the structure.

The invention also relates to pharmaceutical préparations, containing as active substance one or more compounds of the invention, or the pharmaceutically acceptable dérivatives thereof, optionally combined with conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelled forms. An isotopically-labelled form of an active agent of a combination of the présent invention is identical to said active agent but for the fact that one or more atoms of said active agent hâve been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature. Examples of isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the présent invention in accordance with well established procedures, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, e.g., ²H, ³H, ^l3C, ^l4C, ^t5N, ^l8O, ^t70,^3lP, ³²P, ³⁵S, ^l8F, and ³⁶Cl, respectively. An active agent of a combination of the présent invention, a

-4816541 prodrug thereof, or a pharmaceutically acceptable sait of either which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is contemplated to be within the scope of the présent invention.

The invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. Ail such isomeric forms of these compounds are expressly included in the présent invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.

Some of the compounds of the invention can exist in more than one tautomeric form. The invention includes methods using ail such tautomers.

The compounds of the invention are only those which are contemplated to be ‘chemically stable’ as will be appreciated by those skilled in the art. For example, a compound which would hâve a ‘dangling valency’, or a ‘carbanion’ is not compounds contemplated by the inventive methods disclosed herein.

The invention includes pharmaceutically acceptable dérivatives of compounds of formula (I). A pharmaceutically acceptable dérivative refers to any pharmaceutically acceptable sait or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active métabolite or pharmacologically active residue thereof. A pharmacologically active métabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized dérivative compounds of the invention.

Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolîc, lactic, —-4916541 salicylic, succinic, toluene-p-sulfuric, tartane, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the préparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali métal (e.g., sodium), alkaline earth métal (e.g., magnésium), ammonium and N-(Ci-C4)alkyl)⁴⁺ salts.

In addition, within the scope of the invention is use of prodrugs of compounds of the invention. Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and réduction. Specifically, when a prodrug is adminîstered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.

GENERAL SYNTHETIC METHODS

The compounds of the invention may be prepared by the general methods, examples presented below, and methods known to those of ordinary skill in the art and reported in the chemical literature. In each of the schemes below, the groups R to R. and A are as defined above for the compound of formula (I), unless noted otherwise. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, températures, pressures and other réaction conditions may be readily selected by one of ordinary skill in the art. Spécifie procedures are provided in the Synthetic Examples section.

Scheme 1 below depicts the general synthetic procedure for making the compounds of formula (I) wherein X is CH (“the benzodioxane LTAH4 inhibitors”). —

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Scheme 1: General synthetic scheme for making benzodioxane LTA4H inhibîtors

Scheme 2 below depicts the general synthetic procedure for making the compounds of formula (I) wherein X is N (“the 8-azabenzodioxane LTAH4 inhibîtors”).

Scheme 2: General synthetic scheme for 8-azabenzodioxane LT A4 II inhibîtors

Starting materials and reagents used in Schemes 1 and 2 are commercially available or may 10 be prepared by one of ordinary skill in the art using methods described in the chemical literature and in the Synthetic Examples section below.

The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds 15 without undue expérimentation.

Synthetic Examples

General Methods: Unless noted otherwise, ail reactions are run at room température (about 25°C), under inert atmosphère (e.g., Argon, N₂), and under anhydrous conditions, iv—

-5116541

Ali compounds are characterized by at least one of the following methods: 'H NMR, HPLC, HPLC-MS, and melting point.

Typically, reaction progress is monitored by thin layer chromatography (TLC) or HPLCMS. Intermediates and products are purified using at least one of the following methods:

Flash chromatography on silica gel,

Recrystallization,

Chiral HPLC using a 20 x 500 mm Chiralpak AD-H column, or 20 x 500 mm Chiralpak OD-H column, and eluting with an isocratic mixture of isopropanol in heptanes with 0.1% diethylamine (DEA) at 7.5 mL/min, x 250 mm Chiralcel OD-H column, and eluting with an isocratic mixture of isopropanol in heptanes at 7.5 mL/min,

Super Critical Fluid (SCF) Chiral HPLC using a 3.0 x 25.0 cm RegisPack column, eluting with an isocratic mixture of MeOH, isopropylamine (1PA), and super critical carbon dioxide at I25 bar; 80 mL/min, and/or

Reversed phase HPLC using a Cl8 semi-preparative column eluting with a gradient of MeCN+0.l% TFA /H₂O+0.l% TFA, or MeCN+0.l% formic acid /H₂O+0.1% forrnic acid.

The reported MS data is for observed [M+H]⁺. For bromine containing compounds, the [M+H]⁺ is either reported for one or both of the bromine isotopes (i.e., ⁷⁹Br and ^8lBr).

LC/MS methods used in to characterize and isolate the compounds of the inventions are described in Tables 2a and 2b below.

Table 2a. LC/MS Methods and rétention times (RT),

LC/MS Method	Time (min)	Mobile Phase	Flow (mL/min)	Column
H2O (0.1% FA)	CH3CN (0.1%FA)
l	0	95	5	2.5	Agilent Zorbax Cl8 SB 3.5um 4,6x30mm cartridge
1.7	5	95	2.5

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	2	5	95	2.5
2.1	95	5	2.5
2.3	95	5	2.5
2	0	70	30	2.5	Agilent Zorbax Cl8 SB 3.5um 4.6x30mm cartridge
1.7	5	95	2.5
2	5	95	2.5
2.1	70	30	2.5
2.3	70	30	2.5
3	0	99	1	2.5	Agilent Zorbax Cl 8 SB 3.5um 4.6x30mm cartridge
1.7	50	50	2.5
2	5	95	2.5
2.1	5	95	2.5
2.3	99	1	2.5
4	0	95	5	1.5	Agilent Zorbax Eclipse XDB-C8 5um 4.6x150mm
7	5	95	1.5
9	5	95	1.5
9.3	95	5	1.5
ΙΟ	95	5	1.5
5	0	99	1	2.5	Agilent Zorbax Cl8 SB 3.5um 4.6x30mm cartridge
1.6	80	20	2.5
1.7	5	95	2.5
2	5	95	2.5
2.1	99	1	2.5
2.3	99	1	2.5
6	0	99	1	1.5	Agilent Zorbax Eclipse XDB-C8 5um 4.6x150mm column
2	80	20	1.5
7	5	95	1.5
9	5	95	1.5
9.3	99	1	1.5
10	99	1	1.5
7	0	88	12	1.5	Agilent SB-C18 1.8um 3x50mm column
0.25	70	30	1.5
0.3	60	40	1.5
1.19	5	95	1.5
1.75	0	100	1.5
8	0	60	40	1.5	Agilent Eclipse C8 1.8um 3x50mm column
1.19	15	85	1.5
1.75	0	100	1.5
9	0	95	5	1.5	Agilent SB-AQ 1.8um 3x50mm column
0.25	50	50	1.5
0.3	70	30	1.5
1.3	10	90	1.5

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	1.7	0	100	1.5
10	0	95	5	1.5	Agilent SB-C18 1.8um 3x50mm column
3.8	10	90	1.5
4.5	0	100	1.5

Table 2b. LC/MS	Methods and rétention times (RT).
LC/MS Method	Time (min)	Mobile Phase	Flow (mL/min)	Column
95% H2O 2+ 5% CHjCN (0.05%Formic Acid)	ch3cn (0.05% Formic Acid)
11	0	90	10	0.8	BEH 2.1x50mm Cl8, 1.7um particle diameter
1.19	5	95	0.8
1.7	5	95	0.8
12	0	90	10	0.8	BEH 2.1x50mm Cl8, 1.7um particle diameter
1.19	0	100	0.8
1.7	0	100	0.8
13	0	95	5	0.6	Waters HSS T3 2.1Xl00mm 18 um column
4.45	0	100	0.6
5	0	100	0.6
14	0	100	0	0.6	Waters HSS T3 2.1X100mm 18 um column
1	100	0	0.6
4.45	0	100	0.6
5	0	100
15	0	90	10	0.6	BEH 2.1x50mm Cl8, 1.7um particle diameter
4.45	0	100	0.6
4.58	0	100	0.6

Synthesis of Intermediates

Préparation of (S)-4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzaldehyde (A) w—-5416541

To a stirred solution of pyrocatechol (23.8 g, 216 mmol) in acetone (300mL) is added césium carbonate (84.4 g, 259 mmol) and 2-Bromo-i-(4-bromo-phenyl)-ethanone (60 g, 216 mmol) at room température. The reaction is stirred at room température for 1 hour then water (200 mL) is added. The precipitate is filtered and triturated with EtOAc (150 mL) to give A-l as a solid.

To a solution of A-l (50.0 g, 163 mmol) in anhydrous THF (375 mL) is added acetic anhydride (23.0 mL, 244 mmol), TEA (34.0 mL, 244 mmol), and DMAP (199 mg, 1.63 mmol). The reaction mixture is stirred at 40°C for 45 min, cooled to room température and diluted with EtOAc (250 mL). The organic solution is washed with water (2 x lOOmL), 0.25N HCl (100mL), saturated sodium bicarbonate solution (lOOmL), and brine (lOOmL), and dried over NaîSO^ After removal of volatile solvent, the residue is triturated with 5% EtOAc in heptane (1500 mL). The solid is filtered and air dried to give A-2.

To degassed DMF (500 mL) is added A-2 (41.0 g, 117 mmol), (1 S,2S)-(+)-N-(4Toluenesulfonyl)-l,2-diphenylethylenediarnine (756 mg, 2.10 mmol) and Pentamethylcyclopentadienylrhodium(IIl)dichloride (Cp*RhC12) dimer (319 mg, 0.520 mmol). The resulting mixture is stirred at 0°C for 20 minutes under argon sparging and treated dropwise with formic acid/triethylamine complex (5:2, 31 mL, 72 mmol). The reaction mixture is stirred under argon at 0°C for 2 hours, diluted with EtOAc (600mL),

-5516541 and washed with half-saturated sodium bicarbonate solution, saturated sodium bicarbonate, and brine. The organic layer is dried over Na₂SO4and concentrated. The residue is purified through a pad of silica gel (400mL), eluting with EtOAc/heptane (1:1, 3 L) to give A-3 as a solid.

To a MeOH solution (125 mL) of A-3 (24.6 g, 69.0 mmol) is added a solution of LiOH*H₂O (5.8 g, 137 mmol) in water (125 mL). The mixture is stirred at 60°C for 30 min, cooled to room température and concentrated. The residue is diluted with water and neutralized with IN aqueous HCl to a pH of 6. The resulting mixture is extracted with EtOAc (3x150 mL). The combined organic extracts are washed by saturated sodium bicarbonate solution, brine, dried over Na₂SO4, filtered and concentrated to give A-4 as an oil.

To a 0°C solution of triphenylphosphine (32.7 g, 125 mmol) and diîsopropyl azodicarboxylate (24.7mL, 125 mmol) in THF (anhydrous, 400 mL) is added a solution of A-4 (35 g, 113 mmol) in THF (anhydrous, 200 mL) over 30 min. The resulting solution is warmed to room température, stirred for 1 hour, and concentrated, The residue is vigorously stirred in heptane (1.8 L) for 2 hours. The precipitate îs filtered, and rinsed with heptane. The filtrate is concentrated and purified by flash column chromatography on silica gel (0-10% EtOAc in heptane) to give A-5 as a solid.

To an argon-degassed solution of A-5 (30.7 g, 105 mmol) in DMF (anhydrous, 400 mL) is added Zn(CN)₂ (12.4 g, 105 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)î) (2.9 g, 3.2 mmol), and 1, l'-bis(diphenylphosphino)ferrocene (dppf) (3.5 g, 6.3 mmol). The resulting mixture is sparged with argon and stirred at 80°C overnight. The reaction is cooled to room température and filtered through a pad of Diatomaceous earth, and rinsed with EtOAc. The filtrate is diluted with water (400mL) and extracted with EtOAc (2 x 400mL). The combined organic extracts are washed with brine and stirred with activated carbon (80 g). After 30 min, the mixture is filtered through a pad of Diatomaceous earth and concentrated. The residue is triturated with 2% EtOAc in heptane (IL), and filtered to give A-6 as a solid.

-5616541

A solution of A-6 (l l.l g, 46.7 mmol) in THF (anhydrous, 400 mL) at 0°C is treated dropwise with DIBAL-H (25 wt% in toluene, 77.8 mL, 117 mmol). The reaction is stirred at 0°C for 30 min, warmed to room température and stirred for 2 hours. The reaction is cooled down to 0°C and quenched with EtOAc (250 mL) followed by saturated potassium sodium tartrate solution (400mL). The mixture is diluted with EtOAc (300 mL) and water (300 mL) and stirred for 30 min. The organic layer is separated and washed with water, IN HCl solution, and brine, and dried over Na₂SO4. After filtering through a pad of Diatomaceous earth, the filtrate is concentrated and purified by flash column chromatography on silica gel (0-30% EtOAc in heptane) to give the title product as a solid.

To a stirred solution of A-l (1.2 g, 3.9 mmol) in EtOH (40 mL) is added sodium borohydride (295 mg, 7.80 mmol). The reaction is stirred for 14 h, quenched with IN HCl (10 mL) and concentrated to remove the EtOH. The solid residue is filtered, washed with water and dried in vacuo to give B-l as a solid.

The title product is synthesized from B-l according to the procedure described for the synthesis of A from A-4.

Préparation of (S)-4-(2,3-Dihydro-|l,4]dioxino[2,3-b]pyridin-3-yl)-benzaldehyde (C) yt/

-5716541

To a solution of 2-chloro-3-hydroxy-pyridine (25,0 g, 193 mmol) and 2,4’-dibromoacetophenone (53.6 g, 193 mmol) in acetone (400 mL) is added Cs₂CO₃ (75.4 g, 232 mmol), and the suspension is stirred at room température for l h. The reaction is poured into l L of water with stirring. Filtration of the mixture gives C-1 as a solid.

A solution of C-1 (30.0 g, 91.9 mmol), Cp*RhC12 dimer (0.57 g, 0.92 mmol) and N((lR,2R)-2-Amino-l,2-diphenyl-ethyl)-4-methyl-benzenesulfonamide (1.0 g, 2.8 mmol) in anhydrous DMF (400 mL) is cooled to 0 °C and sparged with argon for 20 minutes before the dropwise addition of formic acid: TEA mixture (5:2 mixture; 28.2 mL). The reaction is stirred at 0 °C with Argon sparging for 1 hr. The reaction mixture is slowly added to 1.5L of vigorously stirred water. Filtration gives C-2 as a solid.

A solution of C-2 (10.0 g, 30.4 mmol) in DME (350 mL) is heated to 60°C, KHMDS (61.5 mL, 0.5M in toluene) is added slowly and the resulting solution is stirred for 30 minutes. The reaction is cooled to room température, quenched with water, concentrated in vacuo and extracted with EtOAc. The combined organics are washed with brine, dried over Na₂SÛ4, filtered and concentrated. The residue is purified by flash column chromatography (0-40% EtOAc in heptanes) to give C-3 as a solid.

To a degassed solution of C-3 (5.50 g, 18.8 mmol) in anhydrous DMF (100 mL) is added Zn(CN)₂ (2.2 g, 18.8 mmol) and dppf (1.0 g, 1.9 mmol) followed by Pd₂(dba)₃ (0.86 g, 0.90 mmol), and the reaction is warmed to 80°C overnight. The reaction is then cooled to room température and stirred for 48h. The mixture is filtered through a bed of Diatomaceous earth, and the filtrate slowly poured into 1 L of vigorously stirred water. y*/

-5816541

The resulting solid is isolated by filtration and purified by flash chromatography on silica gel (0-40% EtOAc in heptanes) to give C-4 as a solid.

A solution of C-4 (3.5 g, 14.7 mmol) in 125 mL of THF is cooled down to 0°C in a ice bath. 25 mL of 1.5M DIBAL-H (36.7 mmol, 2.5 eq) solution in toluene is added dropwise via addition funnel (over 15 min). The reaction is stirred at 0°C for 30 min and then allowed to warm to room température. The reaction mixture is stirred for 2h at room température. The reaction is cooled to 0 °C and carefully quenched with EtOAc (200 mL total), followed by 100 mL of water and 400 mL of saturated aqueous Rochelle's sait solution, and the mixture is stirred for 5 minutes. The entire mixture is transferred to a separatory funnel and the layers are separated. The aqueous layer is extracted with 100 mL of EtOA twice, and the extracts are combined and washed with 0.5 N HCl (lOOmL). Some product is observed in the acid layer. Acid layer is cooled to 0°C, neutralized with saturated NaHCOî, and extracted with EtOAc twice. The organic layers are combined, washed with brine, and dried over anhydrous NaiSO.», and evaporated, The resulting residue is purified by flash chromatography eluting with 0-80 % EtOAc/Heptane to give the title compound as a solid.

Préparation of (±)-4-(2,3-Dihydro-[l,4]dioxino[2,3-b|pyridin-3-yl)-benzaldehyde (D)

Br

D-2

D-1

Compound D-1 is synthesized from C-l according to the procedure described for the synthesis of B-1.

-5916541

The title compound is synthesized from D-l according to the procedure described for the synthesis of C from C-2.

Préparation of 2,2,2-trifluoro-l-piperidin-4-yl-ethanol (E)

H

A solution of E-l (500 mg, 2.00 mmol) and trimethyl(trifluoromethyl)silane (TMSCF3) (863 mg, 6.00 mmol) in dry DMF (2 mL) is cooled to -25 °C and treated with 1,3-bis(l adamantyl)imidazol-2-y!idene (3.4 mg, 0.010 mmol). The mixture is warmed to room température, stirred for 1 h, and treated with 2N HCl (2 mL). Upon completion, the mixture is neutralized with NaOH (5M, 0.7 mL), concentrated, and purified by reversed phase HPLC (10-90% MeCN/H₂O gradient) to provide E-2 (LC/MS Method 1; RT = 0.88 min; ES+ m/z [M+H]⁺ 318.2).

A mixture of E-2 (524 mg, 1.65 mmol) and 10% palladium on carbon (200 mg) in MeOH ( 16 mL) is stirred under an atmosphère of H2 at room température for 15h. The mixture is filtered through Diatomaceous earth, and the filter pad is washed with MeOH. The filtrate is concentrated to provide the title product.

Préparation of l,l,l,3,3,3-Hexafluoro-2-piperidin-4-yl~propan-2-ol (F) ---6016541

A solution of piperidine-l,4-dicarboxylic acid monobenzyl ester (1.0 g, 3.80 mmol), 2,3,4,5,6-pentafluoro-phenol (0.77 g, 4.18 mmol) and dicyclohexyl-carbodiimide (0.86 g, 4.18 mmol) in dioxane (12 mL) is stirred at room température for 16 h. The mixture is filtered and concentrated in vacuo. The residue is purified by flash chromatography (EtOAc/heptane) to give F-2.

To a solution of F-2 (200 mg, 0.47 mmol) in DME (1.0 mL) is added TMSCF3 (139 mg, 0.98 mol) and tétraméthylammonium fluoride (43 mg, 0.47 mmol) at -50°C. The resulting mixture is allowed to warm to room température and stirred for 16h. The mixture is concentrated in vacuo and the residue is purified by reverse HPLC (30-95%, MeCN/Water) to give F-3.

A mixture of F-3 (670 mg, 1.74 mmol) and 10% palladium on carbon (210 mg) in MeOH (17 mL) is stirred under an atmosphère of H₂ at room température for 15h. The mixture is filtered through Diatomaceous earth and the filter pad is washed with MeOH. The filtrate is concentrated to provide the title product (F).

Préparation of 4-methyl-piperidinc-carboxylic acid methyl ester hydrochloride (1-1)

O

-6116541

To a stirred solution of 4-methyl-piperidine-l,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.10 mmol) in MeOH (2 mL) is added HCl (5 ml, 4 M in dioxane). After 18h, the mixture is evaporated to dryness, the residue is dissolved in MeOH (3mL), and the stirred solution is treated with Et₂O (45 ml). The resulting solid is filtered and dried to give the title compound.

The following intermediates are also prepared according to the procedure described for the synthesis of I-1 :

Intermediate #

1-2

Structure

1-3

1-4

1-5

1-6

Synthesis of Compounds of Formula I

General Method A through E (protocols for reductive amination).

Example of General Method A: w'’'

-6216541

Préparation of 8-|(S)-4-(2,3-Dihydro-[l,4]dioxmo[2,3-b]pyridin-3-yl)-benzyl|-2,8diaza-spiro[4.5]dccan-l-one (Example 125)

125

TEA (0.12mL, 0.83 mmol) is added to a mixture of C (100 mg, 0.42 mmol) and 2,8-Dîaza-spiro[4.5]decan-l-one; hydrochloride (158 mg, 0.83 mmol) in 2 mL of DCM. One drop of acetic acid is added, and the mixture is stirred for 10 min, sodiumacetoxyborohydride (132mg, 0.83 mmol) is added, and the resulting mixture is stirred for 24 h. The solvent is evaporated and the crude mixture is dissolved in 2 ml of MeCN/H₂O (1:1). The mixture is purified on a reverse phase Cl 8 semi-preparative HPLC column eluting with a gradient of 0-95% MeCN/H₂O to give the title product.

Example of General Method B:

Préparation of (±)-4-[4-(2,3-Dihydro-benzo| l,4]dioxin-2-yl)-benzyl]-piperazine-lcarboxylic acid tert-butyl ester

To a solution of B (100 mg, 0.420 mmol), and piperazine-1-carboxylic acid tert-butyl ester (93 mg, 0.50 mmol) in DCE (4 mL) is added acetic acid (50 mg, 0.83mmol). The mixture is stirred at room température for 10 min, treated with sodium triacetoxyborohydride (141 mg, 0.67 mmol), and stirred at room température for 16 hours. The reaction is diluted with saturated aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers is washed with brine, dried over Na₂SO4, filtered and concentrated. The residue is purified on a reversed phase C18 semi-preparative HPLC column eluting with a gradient of 5-85% MeCN+0.1%TFA /H₂O+0.1 %TFA). The

-6316541 combined fractions are concentrated and basified by saturated aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases is washed by brine, dried over Na₂SO4, filtered, and concentrated to give the title product.

Example of General Method C:

Préparation of 4-{l-|(S)-4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-piperidin-4ylmethyl}-benzoic acid methyl ester

A solution of A (100 mg, 0.42 mmol), 4-piperidin-4-ylmethyl-benzoic acid methyl ester hydrochloride (146 mg, 0.54 mmol), sodium cyanoborohydride (52 mg, 0.83 mmol), and TEA (0.08 mL, 0.54 mmol) in THF (5 mL) is treated with 2 drops of acetic acid, and stirred at room température for 16 h. The mixture is concentrated, and the residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give the title compound.

Example of General Method D:

Préparation of l-[4-(2,3-Dihydro-benzo(l,4]dioxin-2~yl)-benzyI]-piperidine-4carboxylic acid methylamide (Example 25) :

A solution of B (40mg, 0.17mmol) and piperidine-4-carboxylic acid methylamide (47.2mg,

0.332mmol) is treated with acetic acid (0.0ImL). After shaking for 1 hour, a solution of sodium triacetoxyborohydride (70.6mg, O.33mmol) in DMA (0.5mL) is added and the

-6416541 resulting mixture is shaken overnight. The mixture is concentrated, diluted with DMSO (0.8 mL), filtered and purified on a Cl8 semi-preparative HPLC column eluting with a gradient of 5-85% MeCN+0.1%TFA /H2O+O. I %TFA) to provide the title compound.

Example of General Method E:

Préparation of 4-{[(S)-4-(2,3-Dihydro-benzo|l,4Jdioxin-2-yl)-bcnzylamino]-methyl}bcnzoic acid methyl ester

HCl

A solution of A (310 mg), methyl 4-(aminomethyl)benzoate hydrochloride (338 mg),

ÎO sodium cyanoborohydride (162 mg), and DIPEA (0.3 mL) in MeOH (5 mL) is treated with drops of acetic acid, and the resulting mixture is stirred at room température for 16h. The mixture is concentrated, and the residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give the title compound.

Table 3 provides a summary of the key reagents used to préparé Examples 1-191 according to general methods A, B, C, D, E, or F as depicted in the reaction below.

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Table 3: Examples synthesized by General Method A, B, C, D, E, or F

Ex #	X	Chiralit yat*	—A	Synthesi s Method	LC/MS Metho d	(M+H| 4-	Rt (min )
l	c H	racemic	Ό	B	10	296.2	1.20
2	C H	racemic	'Ci	B	10	312.2	1.20
3	C H	racemic	Q	B	10	338.4	1.20
4	C H	racemic		B	10	379.4	1.10
5	C H	racemic		B	10	328.4	1.11
6	C H	racemic	N P	B	10	322.4	1.13
7	C H	racemic	<,s*° ri 0	B	10	360.4	1.40
8	C H	S	NX ΟγΟ	B	10	381.3	0.67
9	C H	racemic	'nQ-OH	B	10	312.4	1.04
10	C H	racemic	'CTD	B	10	407.4	1.14
11	C H	racemic	NX 0	B	10	353.40	1.47
12	C H	racemic	o	B	10	353.40	1.57

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13	C H	S	/'P °ô	A	10	417.40	1.62
14	C H	S	0	A	10	381.40	1.57
15	N	racemic	O	B	10	297.40	0.97
16	C H	racemic	p n-n	B	10	349.40	2.14
17	N	racemic	'N> O° 0	B	10	361.20	1.66
18	N	racemic	O	B	10	313.40	0.89
19	C H	S	0 όΛοη	C	1	354.52	0.55
20	C H	S	0 ''N^J^OH	C	1	354.24	0.56
21	C H	S	''N^> F OH	C	1	408.26	0.71
22	C H	s	'Όκ, -A	C	1	476.23	0.77
23	C H	racemic	H 'Νγ	D	11	298.2	0.7

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24	C H	racemic	k »	D	11	298.2	0.73
25	C H	racemic	A HNX	D	11	367.3	0.66
26	C H	racemic	(A	D	11	396.3	0.73
27	C H	racemic	'A OH	D	11	340.2	0.66
28	C H	racemic		D	11	368.3	0.72
29	C H	racemic	''N^> kXzAOH	D	11	368.5	0.7
30	C H	racemic	O	D	11	339.2	0.56
31	C H	racemic	Ό ?°	D	11	367.2	0.65
32	C H	racemic	”O V-o	D	11	326.2	0.67
33	C H	racemic	I	D	11	314.2	0.71
34	C H	racemic	Q OH	D	11	312.2	0.65
35	C H	racemic	-Or H 0	D	11	394.2	0.65

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36	C H	racemic	/'7'°'	D	11	312.4	0.68
37	C H	racemic	O/J 0	D	U	423.3	0.69
38	C H	racemic	CU,I	D	11	395.3	0.70
39	C H	racemic	0	D	11	388.2	0.66
40	C H	racemic	Ό	D	11	324.3	0.79
41	C H	racemic		D	11	310.2	0.78
42	C H	racemic		D	U	361.2	0.79
43	C H	racemic		D	11	296.2	0.75
44	C H	racemic	qO OH	D	11	402.3	0.82
45	C H	racemic		D	11	298.2	0.75
46	C H	racemic		D	11	306.8	0.73
47	C H	racemic	€0	D	11	326.2	0.74
48	C H	racemic	Ou? H	D	11	403.2	0.71

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49	C H	racemic	Vo	D	11	367.2	0.68
50	C H	racemic	tXQ 0	D	11	407.3	0.73
51	C H	racemic	Όγί 0	D	11	381.3	0.73
52	C H	racemic	Ό H —'AVN^'OH 0	D	11	397.3	0.67
53	C H	racemic	'Ο-Λ H	D	11	368.2	0.67
54	C H	racemic	œ N	D	11	333.2	0.66
55	C H	racemic		D	11	336.2	0.59
56	C H	S	Ό3 O^OH	D	11	402.3	0.75
57	C H	S	t HN/, 0 o.....< MJ OH	D	11	354.1	0.63
58	C H	S	I I OH	D	11	370.2	0.70
59	C H	S	h^oh	D	11	354.2	0.66
60	C H	S	''N'^y0 1 OH	D	11	314.3	0.63

-7016541

61	C H	S	'û >~OH 0	D	11	340.1	0.61
62	C H	S	OV OH	D	11	367.9	0.61
63	C H	s	1 HN„ Ov OH	D	11	368.2	0.64
64	C H	s	β-ΌΛ	D	11	353.8	0.63
65	C H	s	'βΌΛ	D	11	353.1	0.63
66	C H	s	ΜγΝΗ2 0	D	11	367.1	0.64
67	C H	s	>-O	D	11	337.8	0.78
68	C H	s	Ό	D	11	323.9	0.73
69	C H	s	''θ^°Η	D	11	339.8	0.66
70	C H	s	''N^>	D	11	353.9	0.67
71	C H	s	nV H \	D	11	284.3	0.68
72	C H	s	N—( H Vo \	D	11	313.6	0.70

-7116541

73	C H	S	H \__	D	11	283.8	0.7
74	C H	S	H	D	11	283.9	0.67
75	C H	S	N— /	D	11	269.8	0.65
76	C H	s	'n-O'0H	D	11	340.2	0.65
77	C H	s	f	D	11	310.2	0.70
78	C H	s	\ N—\	D	11	325.9	0.65
79	C H	s	/N_V z \	D	11	327.1	0.61
80	C H	s	HO	D	11	367.9	0.76
81	C H	s	/7\	D	11	311.7	0.71
82	C H	s	N-y \XNH 0^	D	11	352.9	0.64
83	C H	s	H O'N X	D	11	366.9	0.67
84	C H	s	H	D	11	336.2	0.73
85	C H	s	/—\-H N/ > / /W	D	11	363.8	0.76

-7216541

86	C H	S	'ϊγΌ h2n0	D	11	366.9	0.63
87	C H	S	HO-y yo	D	11	354.4	0.68
88	C H	S	V OH	D	11	313.3	0.64
89	C H	S	HO—. 'iriO	D	11	353.9	0.70
90	C H	S	q HO	D	11	340.8	0.59
91	C H	S	9 OH	D	11	3H.8	0.57
92	C H	s	9 0	D	U	3ll.l	0.75
93	C H	s	9	D	11	339.1	0.49
94	C H	s	•ONP 0	D	11	407.2	0.63

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95	C Η	S	‘V	D	11	377.8	0.78
96	C Η	S	0	D	11	397.3	0.56
97	C Η	S	H0, H-Ô	D	11	339.8	0.65
98	C Η	s	-N^OZ	D	11	340.2	0.63
99	C Η	s	Όύο·	D	11	407.4	0.62
10 0	C Η	s	K}......	D	11	338.2	0.76
10 1	C Η	s	HO 'b/	D	11	325.8	0.62
10 2	C Η	s	HO îtÔ	D	11	325.7	0.6
10 3	C Η	s	> /—θ	D	11	326.3	0.61
10 4	C Η	s	y> —N \	D	11	395.2	0.8
10 5	C Η	s	/nhP HO	D	11	353.9	0.66
10 6	C Η	s	HO	D	11	353.9	0.67
10 Ί	C Η	s	^o	D	11	325.9	0.61

-7416541

ΙΟ 8	C H	S	nV ^=0 H V \	D	11	352.9	0.56
ΙΟ 9	C H	S	J-O	D	11	338.4	0.71
11 0	C H	S	>-CN-	D	11	353.1	0.44
11 l	C H	S		D	11	348.1	0.64
11 2	C H	S	'CO,.	D	11	374.1	0,66
11 3	C H	Racemic	o 'N^y^OH	A	13	354.4	1.1
11 4	C H	Racemic	N-\ 0 Cm mm NHî	A	13	353.4	1.0
11 5	C H	Racemic	N—\ Vf	A	13	314.4	1.0
11 6	C H	S	-tb	A	12	393.1	1.3
11 7	C H	S	C' Q o	A	13	365.4	1.3
11 8	C H	s	> °r	A	13	393.4	1.2
U 9	C H	s	N—. I M	A	13	393.4	1.1

-7516541

12 0	C H	S	1	A	7	407.3	0.7
12 l	C H	S		A	13	393.4	1.1
12 2	C H	s	0 N—λ I	A	7	429.5	0.7
12 3	C H	s	o \ Pd M	A	7	408.3	0.6
12 4	C H	s		A	Ί	390.3	0.7
12 5	N	s	-cP	A	11	380.4	0.4
12 6	N	s	O	A	11	297.2	0.4
12 7	N	s		A	11	366.2	0.4
12 8	C H	s		A	11	423.3	0.6
12 9	N	s	-oP	A	11	394.2	0.4

-7616541

13 0	N	S	-Ob'	A	11	408.3	0.5
13 l	C H	S	<Ύ°	A	11	339.2	0.6
13 2	N	S	N—\ Q.	A	13	340.2	0.9
13 3	N	S	H	A	11	328.2	0.4
13 4	C H	S	Onf 0	A	13	382.4	0.6
13 5	N	s		D	11	311.1	0.52
13 6	N	s	N—\ 0 CH,	D	11	354.1	0.42
13 7	N	s	-o	D	11	325.1	0.53
13 8	N	s	;HP	D	11	362.1	0.51
13 9	N	s	-Ό	D	11	325.1	0.52
14 0	N	s	N—\	D	11	285.3	0.43
14 l	N	s	N O	D	11	299.1	0.47
14 2	N	s	>-O	D	11	325.1	0.53

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14 3	N	S	X X N—\ G.	D	11	340.1	0.31
14 4	N	S	........	D	11	313.1	0.41
14 5	N	S	N zG H	D	11	323.1	0.49
14 6	N	s	-CK	D	11	34l.l	0.43
14 7	N	s	••-ZX-OH	D	11	313.1	0.41
14 8	N	s	GG	D	11	368.1	0.41
14 9	N	s	°h	D	11	369.1	0.47
15 0	N	s	'Ό	D	11	327.1	0.44
15 l	N	s	K ÎH	D	11	397.1	0.51
15 2	N	s	-oG	D	11	368.1	0.42
15 3	N	s	h-CH	D	11	368.1	0.42
15 4	N	s	K N—, H \ '“'OH	D	11	398.1	0.40
15 5	N	s	-CC	D	11	329.1	0.47

-7816541

15 6	N	S		D	11	350.1	0.56
15 7	N	S	N--\	D	11	368.1	0.40
15 8	N	S	Ν-λ	D	11	341.1	0.48
15 9	N	s	-θ'”	D	11	336.1	0.44
16 0	N	s	ΛΑ X° -Nv7 H	D	11	368.1	0.41
16 1	N	s	--N S. \—/ 0	D	11	361.0	0.65
16 2	N	s	ΌγΟ 0	D	11	424.1	0.46
16 3	N	s	o CP 0	D	11	408.1	0.47
16 4	N	s	/---\ ,NH2 —N N-< \—< 0	D	11	355.1	0.38
16 5	N	s	0	D	11	395.1	0.41
16 6	N	s	O°x	D	11	313.1	0.45
16 7	N	s	n-{C h \—! 1 o	D	11	404.1	0.45
16 8	N	s	N-1 Po	D	11	327.1	0.46

-7916541

16 9	N	S	/ \—/ / 0	D	11	418.1	0.47
17 0	N	S	—/ 0^__/0	D	11	385.1	0.50
17 l	N	S		D	II	396.1	0.47
17 2	N	s		D	U	389.1	0.43
17 3	N	s	'nY>	D	11	297.1	0.48
17 4	C H	s	' /---\ θ N—( N“S=0	A	15	403.2	0.69
17 5	C H	s	0 /-Λ >ΝΗ 2	A	15	368.4	0.55
17 6	C H	s	O.,O 0 ZZ ••O-!!	A	15	403.2	0.90
17 7	C H	s	—l/ CN	A	15	336.2	0.85
17 8	C H	s	“V/ N	A	15	368.0	0.98
17 9	C H	s	-ΟΓ	A	15	367.2	1.02
18 0	C H	s	ΌγΟ 0	A	15	423.3	1.03
18 l	C H	s	—n 2—\ )r-OH 0	A	15	395.9	1.13
18 2	C H	s	cnr	A	15	368.2	1.04

-8016541

18 3	C H	S	OYH	A	15	368.2	1.05
18 4	C H	S	-γγγ°Η	A	15	354.2	0.99
18 5	N	S	1 1 0 cA	A	14	354.4	2.09
18 6	N	S	^>~QH	A	14	327.1	2,13
18 7	N	S	0 /—\ Ynh2 — N\ 2~N	A	14	369.2	2.09
18 8	N	s	—N7 XN-S=O x—/ 0	A	14	390.4	2.22
18 9	N	s	-ΟΛ	A	14	355.1	2.16
19 0	N	s	OA”	A	14	404.2	2.16
19 1	C H	s		A	14	353.8	0.63

Examples 192 and 193: Préparation of (S)-l-|4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)benzyl]-piperidin-4-ol (192), and (R)-l-[4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)benzyl|-piperidin-4-ol (193).

A racemic mixture of 192 and 193 is prepared from intermediate B and 4hydroxypiperidine according to the General Method B, and resolved by SCF Chiral HPLC using 20% MeOH, 1% IPA, and super critical carbon dioxide to give 192 as the first- νΆ

-8116541 eluting peak, and 193 as the second-eluting peak. 192: LC/MS Method 10; Rt = 0.98 min.;

[M+H]⁺ = 326.4. 193: LC/MS Method I0; Rt = 0.98 min.; [M+H]⁺ = 326.4.

Examples 194 and 195: Préparation of 8-[(S)-4-(2,3-Dihydro-benzo|l,4]dioxin-2-yl)5 benzyl|-2,8~diaza-spiro[4.5]decan-l-one (194) and (8-|(R)-4-(2,3-Dihydrobenzo[l,4]dioxin-2-yl)-benzyl]-2,8-diaza-spiro[4.5]decan-l-one (195)

Compound 4 (racemate) is resolved by SCF Chiral HPLC using 55% methanol, 1 % isopropylamine, and super critical carbon dioxide to give 194 as the first-eluting peak, and

195 as the second-eluting peak. 194: LC/MS Method 10; Rt = 1.10 min,; [M+H]⁺ = 379.4.

195: LC/MS Method 10; Rt = 1.09 min.; [M+H]⁺ = 379.4.

Exemples 196 and 197: Préparation of l-[(S)-4-(2,3-dihydro-benzo[l,4|diox>n-2-yl)benzyl]-pyrrolidine (196) and l-[(R)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl[15 pyrrolidine (197).

Compound 1 (racemate) is resolved by HPLC using a Chiralpak AD-H column, and eluting with 7% IP A in heptanes with 0.1% DEA to give 196 as the first-eluting peak, and 197 as the second-eluting peak. 196: LC/MS Method 10; Rt = 1.21 min.; [M+H]⁺ = 296.2. 197:

LC/MS Method 10; Rt = 1.21 min.; [M+H] ⁺ = 296.2.

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Examples 198 and 199: Préparation of 4-[(S)-4-(2,3-dihydro-benzo|l,4|dioxin-2-yl)benzyl]-morpholine (198) and 4-[(R)-4-(2,3-dihydro-benzo|l,4|dioxin-2-yl)-benzyl]morpholine (199).

Compound 2 (racemate) is resolved by HPLC using a Chiralpak OD-H column and eluting with 7% IPA in heptanes with 0.1% DEA to give 198 as the first-eluting peak and 199 as the second-eluting peak. 198: LC/MS Method 10; Rt= 1.20 min.; [M+H]⁺ = 312.4. 199: LC/MS Method 10; Rt = 1.21 min.; [M+H]⁺ = 312.4.

Examples 200 and 201: Préparation of (S)-l-|4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)benzyl]-piperidine-4-carboxylic acid (200) and (R)-l-[4-(2,3-Dihydro benzo|l,4|dioxin-2-yl)-benzyl|-piperidine-4-carboxylic acid (201). Vv

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1-(4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-piperidine-4-carboxylic acid ethyl ester is prepared from intermediate B and ethyl isonipecotate according to the procedure described in General Method B, and resolved by HPLC using a Chîralpak OD-H column, and eluting with 12% IPA in heptanes with 0.1% DEA to give (S)-1-(4-(2,3-dihydrobenzo[l,4]dioxin-2-yl)-benzyl]-piperidine-4-carboxylic acid ethyl ester as the first-eluting peak, and (R)-l-(4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-piperidine-4-carboxylic acid ethyl ester as the second-eluting peak.

(S)-1 -(4-(2,3-Dihydro-benzo[ 1,4]dioxin-2-yl)-benzyl]-piperidine-4-carboxylic acid ethyl ester (145 mg, 0.380 mmol) and lithium hydroxide monohydrate (48 mg, 1.1 mmol) are heated in 1:1 mixture of MeOH/water (2 mL) at 75°C for 2h. The reaction mixture is acidified with TFA (300 pL). The resulting white precipitate is filtered off, washed with water, and dried to give compound 200. LC/MS Method 10; Rt = 1.14 min.; (M+H]⁺ = 382.4. v/

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Compound 201 is prepared from (R)-l-[4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl]piperidine-4-carboxylic acid ethyl ester according to the procedure described for the synthesis of compound 201. LC/MS Method 10; Rt = 1.13 min.; [M+H]⁺ = 382.4.

Example: 202

Préparation of 4-|4-(7-Fluoro-2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl[-morpholine (202)

G-3 B_r

G-4

A solution of 4-fluoro-2-methoxy-phenol (3.0 g, 21.1 mmol) in acetone (250 mL) is treated with césium carbonate (8.3 g, 25.3 mmol) followed by 2-bromo-1 -(4-bromo-phenyl)ethanone (5.9 g, 21.1 mmol). The resulting mixture is stirred at room température for 2 h. Water (600 mL) is added slowly to the vigorously stirring solution. After stirring for 30 minutes, the precipitate is filtered off and washed with copious water to give l-(4-bromophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-ethanone (G-l ).

G-l (3.0 g, 8.85 mmol) is dissolved in DCM (30 mL) and cooled to 0°C. Aluminum chloride (2.9 g, 22.1 mmol) is added in one portion and the reaction is stirred at 0°C for 10 minutes. Ethanethiol (1.6 mL, 22.1 mmoL) is added and the reaction is stirred at 0°C for 30 minutes. The reaction mixture is poured onto ice and the resulting slurry is stirred for 30 minutes. The product is the extracted with EtOAc (3 x 50 mL). The combined organic extracts are dried over sodium sulfate, concentrated, and purified by flash column ,ς/''”'

-8516541 chromatography on silica gel (0 to 50% EtOAc in heptane) to provide l-(4-bromo-phenyl)2-(4-fluoro-2-hydroxy-phenoxy)-ethanone (G-2).

To a solution of G-2 (l .25g, 3.85 mmol) in EtOH (25 mL) is added sodium borohydride (291 mg, 7.69 mmol), and the mixture is stirred at room température for 2 h. Water (5 mL) is added, and the resulting mixture is stirred at room température for l h. The reaction mixture is concentrated, and the residue is dissolved in IN HCl and extracted with EtOAc. The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by flash column chromatography on silica gel (0 to 40% EtOAc in heptane) to provide 2-[2-(4-bromo-phenyl)-2-hydroxy-ethoxy]-5-fluoro-phenol (G-3).

Triphenylphosphine (918 mg, 3,5 mmol) is dissolved in THF (25 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (0.7 mL, 3.5 mrnoL) is added to the mixture and stirred at 0°C for 20 minutes. The mixture is then treated dropwise over 5 minutes with a solution of G-3(l .1 g, 3.33 mmol) in THF (10 mL), and the resulting mixture is stirred at 0°C for 30 minutes and at room température for 30 minutes . The reaction mixture is concentrated, and the residue is purified by flash column chromatography on silica gel (0 to 40% EtOAc in heptane) to give 2-(4-bromo-phenyl)-7-fluoro-2,3-dihydro-benzo[l,4]dioxine (G-4).

A solution of G-4 (200 mg, 0.65 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (134 mg, 0.65 mmol), paliadium(ll) acetate (4.3 mg, 0.019 mmol), 2dicyclohexylphosphino-2’,4’,6’-tri-isopropyl-l,l’-biphenyl (19 mg, 0.039 mmol), and césium carbonate (632 mg, 1.9 mmol) in 10:1 THF/water (2 mL) is stirred at 95°C for 18 h under an atmosphère of nitrogen. The mixture is taken up in EtOAc, and the organic layer is washed with water, brine, dried over Na₂SO4, and concentrated. The residue is purified by préparative Cl 8 reversed phase HPLC (MeCN/water; 0.1% TFA) to give the title compound. LC/MS Method 10; Rt = 1,09 min.; [M+H]⁺ = 354.4.

Example 203: Préparation of l-J4-(7-Fluoro-2,3“dihydro-benzo[l,4]dioxin-2-yl)benzylj-pyrrolidinc (203)

-8616541

FW°'r	XX·;		xy	Ό
	o	eu
G-4			203

The title compound is prepared from G-4 and Potassium l trifluoroboratomethylpyrrolidine according to the procedure described for the synthesis of compound 202. 203: LC/MS Method 10; Rt = 1.07 min.; [M+H]⁺ = 354.4.

Examples 204 and 205: Préparation of (S)-3-(4-Morpholin-4-yImethyl-phenyl)-2,3dihydro-|l,4|dioxino|2,3-b]pyridine (204) and (R)-3-(4-Morpholin-4-ylmethylphenyl)-2,3-dihydro-|l,4|dioxino[2,3-b]pyridine (205).

Compound 18 (racemate) is resolved by HPLC using a Chiralcel OD-H column eluting with 28% isopropanol in heptane to give compound 204 (LCMS method 15: ES⁺ m/z 313.2 [M+H]⁺, rt = 0.47 min) and compound 205 (LCMS method 15: ES⁺ m/z 313.2 [M+H]⁺, rt = 0.50 min).

Examples 206 and 207: Préparation of l-{4-[(3S)-2,3-dïhydro[l,4]dioxino[2,3b[pyridin-3-yl]benzyl]piperidine-4-carboxamide (206) and l-{4-[(3R)-2,3dihydroj l,4]dioxino|2,3-b|pyridin-3-yl|benzyl}piperidinc-4-carboxamide (207).

-8716541

The racemic form of 1-(4-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]piperidine-4-carboxylic acid amide is prepared from compound 4-(2,3-dihydro5 [l,4]dioxino[2,3-b]pyridin-3-yl)-benzaldehyde and piperidine-4-carboxylic acid amide according to the general method B. Compounds 206 and 207 are resolved from the corresponding racemic compound by chiral HPLC according to the procedure described for Examples 204 and 205:

Table 4. Préparation of compounds 206 and 207.

Ex#	Chirality at *	MS Method	|M+H|+	rt (min)
206	S	15	354.2	0.47
207	R	15	354.2	0.45

Example 208: Préparation of 11-(4-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl)benzyl]-pyrrolidin-2-one (208) —

-8816541

H

D

A solution of D (l ,0g, 4.15 mmol) in THF (50mL) is treated with sodium borohydride (188 mg, 5.00 mmol) at 0C. The resulting mixture is allowed to warm to room température and stirred at room température for lh. The reaction mixture is concentrated and the residue dissolved in EtOAc. The organic solution is washed with water and brine, dried over sodium sulfate, and concentrated. The residue is purified by flash column chromatography (silica gel) with MeOH in DCM (from 2% to 8%) to give [4-(2,3-dihydro-[l,4]dioxino[2,3b]pyridin-3-yl)-phenyl]-methanol H-1.

A solution of H-1 (400 mg, 1.64 mmol) in THF (10 mL) is treated with triphenylphosphine dibromide (1.39g, 3.29 mmol) and imidazole (224 mg, 3.29 mmol) at room température, and the resulting mixture is stirred at room température for 72h. The mixture is diluted with water and extracted with EtOAc (25mL, 3X). The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by flash column chromatography (silica gel) with EtOAc in heptane (from 15% to 50%) to give 3-(4-Bromomethyl-phenyl)-2,3-dihydro-[ 1,4]dioxino[2,3-b]pyridine H-2.

A solution of pyrrolidinone (18 mg, 0.21 mmol) in anhydrous DMF (2 mL) is treated with sodium hydride (60% dispersion in minerai oil, 7.8 mg, 0.2 mmol), and the mixture is stirred at room température for 15 minutes. Intermediate H-2 (50 mg, 0.16 mmol) is added, and the mixture is stirred at 50°C. After 15 minutes, the mixture is quenched with water and extracted with EtOAc. The organic Iayer is concentrated, and the residue is purified by reversed phase HPLC eluting with a gradient of 5-85% of MeCN in H2O w—

-8916541 (+0.l%TFA). The desired fractions are concentrated. The residue is dissolved in EtOAc, washed with saturated aqueous NaHCCh, brine, and dried over NaiSO^ The solution is then filtered and concentrated to give the title compound as a solid (LCMS method 10: ES⁺ m/z 311.4 [M+H]⁺, Rt = 1.84 min).

Example 209: 3-|4-(2,3-dihydro|1,4]dioxino[2,3-b]pyridin-3-yl)benzyl|-l,3-oxazolidin2-onc (209)

Compound 209 is prepared from intermediate H-2 according to the procedure described for the synthesis of 208. (LCMS method 10: ES⁺ m/z 313.4 [M+H]⁺, Rt = 1.72 min)

Example 210: Préparation of 4-(2,3-Dihydro-Jl,4]dioxino|2,3-b]pyridin-3-yl)benzylaminc (210)

nh₂

A solution of H-1 (340 mg, 1.4 mmol), triphenylphosphine (550 mg, 2.1 mmol) and diphenylphosphophyl azide (0.45 mL, 2.1 mmol) in anhydrous THF (30 mL) is treated with diisopropyl azodicarboxylate (0.41 mL, 2.1 mmol). The reaction is stirred at room température for 24 hours, diluted with water (50 mL), and extracted with EtOAc (3 x 50 *

mL). The combined organic solution is washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified by flash chromatography eluting with a gradient of 10-50% EtOAc in Heptane to give H-3 as an oil.

A solution of H-3 (390mg, 78% pure, 1.1 mmol) and triphenylphosphine (446 mg, 1.7 mmol) in THF (20 mL) is treated with water (0.2 mL, 11.3 mmol). The mixture is stirred at

-9016541

40°C for 24 hours, cooled to room température, diluted with water (25 mL), and extracted with EtOAc (3 x 25 mL). The combined organic solution is washed with brine, dried over Na₂SO4, filtered, and concentrated. The residue is purified by reversed phase HPLC eluting with a gradient of 5-85% MeCN in H₂O (+0.l%TFA), The combined fractions is concentrated, basified with saturated aqueous NaHCOj (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic phase is washed with brine, dried over Na₂SO4, and concentrated to give the title compound as a solid (LCMS method 10: ES⁺ m/z 243.4 [M+H]⁺, Rt = 0.57 min).

Example 211: Préparation of l-[(S)-4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-4methyl-piperidine-4-carboxylic acid (211)

A

HCl

Intermediate A (100 mg, 0.42 mmol), methyl-pîperidine-4-carboxylic acid methyl ester hydrochloride (105 mg, 0.54 mmol), and TEA (75 uL, 0.54 mmol) are stirred in dry THF (3 mL) for 10 minutes. Sodium triacetoxyborohydride ( 176 mg) is added and stirred for 4h. The mixture is diluted with saturated NaHCCh and extracted with EtOAc. The organic layer is washed with brine, dried over Na₂SÜ4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-3% MeOH in DCM to give l-[(S)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-4-methyl-piperidine-4-carboxylic acid methyl ester. —

-9116541

A solution of l-((8)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-4-methyl-piperidine-4carboxylic acid methyl ester in MeOH (2 mL) is treated with a solution of LiOH I LO (52 mg, l .23mmol) in water (2 mL). The mixture is heated to 70°C for 2h, concentrated, and treated with TFA (96 uL, l .23 mmol). The mixture is diluted with water and extracted with EtOAc/THF. The organic layer is dried over Na₂SO4, filtered through Diatomaceous earth, and concentrated. The residue is purified by reversed phase HPLC eluting with a gradient of 5-80% MeCN in water (+0.1 %TFA) to provide the title compound as the TFA sait (LC/MS method l : ES⁺ m/z 368.23 [M+H]⁺; Rt = 0.62 min).

Examples 212-215: Préparation of Compounds 212-215

Compounds 212-215 are prepared from intermediates 1-2,1-3,1-5 and 1-6 according to the procedure described for the synthesis of compound 211 and shown in Table 5.

Table 5. Préparation of compounds 212-215.

Ex#	-A	MS Method	[μ+ηΓ	Rt (min)
212	cis -QA '—( OH	1	368.24	0.62
213	'—f OH	1	372.20	0.61
214	'“Q y-oH 0	1	341.20	0.61

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215

’O O

1

341.23

0.58

Examplc 216: Préparation of, l-[(S)-4-(2,3-Dihydro-benzo|l,4]dioxin-2-yl)-benzyl]-4(lH-tetrazol-5-yl)-piperidine (216).

To a solution of 177 (115 mg, 0.34 mmol) in DMF (2 mL) is added NaNî (89.0 mg, 1.38 mmol) and NH4CI (147 mg, 2.75 mmol). The mixture is heated at 120°C for 18 h. Additional NaNî (89.0 mg, 1.38 mmol) is added, and the reaction is stirred at 120°C for an additional 72 h. The reaction is filtered, and the filtrate is purified by reversed phase

HPLC eluting with a gradient of 5-80% MeCN in water (+0.1 %TFA to provide the title compound (LC/MS method 1 : ES⁺ m/z 378.2 [M+H]⁺; Rt = 0.54 min).

Example 217: Préparation of l-[(S)-4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl|piperidin-4-ylamine (217).

NH₂

A solution of intermediate A (300 mg, 1.25 mmol) and piperidin-4-yl-carbamic acid tertbutyl ester (300 mg, 1.5 mmol, 1.2 equiv.) is stirred in dry THF (3 mL) for 10 minutes.

Sodium triacetoxyborohydride (316 mg, 1.49 mmol) is added, and the reaction is stirred for

-9316541

18h. The reaction is concentrated and partitioned between EtOAc and saturated aqueous NaHCOî. The organic layer is dried over NaîSO^ filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-5% MeOH in DCM. The residue is dissolved in MeOH (l mL), treated with HCl (10 mL, 4M in dioxane), and stirred for 18h. The reaction is diluted with Et2Û (40 mL) and filtered to provide the title compound as the HCl sait (LC/MS method 1 : ES+ m/z 325.2 [M+H]⁺, Rt = 0.35 min).

Example 218: Préparation of N-{l-[(S)-4-(2,3-Dihydro-bcnzo|l,4]dioxin-2-yl)benzyl]-piperidin-4-yl}-2-hydroxy-acetamide (218).

O

A^oh

H

A solution of compound 217 (80 mg, 0.22 mmol), TEA (0.09 mL, 0.67 mmol), hydroxyacetic acid (22 mg, 0.29 mmol) and TBTU (93 mg, 0.29 mmol) in DMF(2 mL) is stirred for 2h. The reaction is filtered and purified by reversed phase HPLC eluting with a gradient of 0-80% MeCN in water (+0.1%TFA) to provide the title compound as a TFA sait (LC/MS method 1: ES+ m/z 383.2 [M+H]⁺, Rt = 0.59 min).

Exemple 219-220: Préparation of N-(l-[4-[(2S)-2,3-dihydro-l,4-benzodioxin-2yl]benzyl}pîperidin-4-yl)-2-methoxyacetamide (219) and N-(l-{4-|(2S)-2,3-dihydrol,4-benzodioxin-2-ylJbenzyl}piperidin-4-yi)-2-hydroxy-2-methylpropanamide (220).

Compounds 219 through 223 are prepared and according to the procedure described for compound 218 and shown in Table 6. The products are purified by reversed phase HPLC or flash chromatography eluting with a gradient of 0-10% MeOH in DCM.

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Table 6. Préparation of compounds 219-223.

Ex#	X	—R6	MS Method	|M+H]+	Rt (min)
219	CH		1	397.08	0.61
220	CH	-°k0H	1	411.30	0.55
221	N	'V	1	412.27	0.48
222	N	0	1	384.22	0.43
223	N		1	410.26	0.47

Example 224: Préparation of l-|(S)-4-(2,3-Dihydro-benzoil,4|dioxin-2-yl)-benzyl]-4(l,l-dioxo-lX⁶-isothiazolidin-2-yi)-piperidine (224).

nh₂

To a stirred solution of compound 217 (535 mg, 1.65 mmol) in THF (10 mL) is added 3chloro-propane-l-sulfonyl chloride (0.40 mL, 3.3 mmol) and pyridine (0,27 mL). After 18

-9516541 h, the mixture is diluted with saturated NaHCCb and extracted with EtOAc. The organic layer is dried over Na₂SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to provide 3-chloropropane-1 -sulfonic acid {1 -[(S)-4-(2,3-dihydro-benzo[ 1,4]dioxin-2-yl)-benzyl]-piperidin5 4-yl)-amide. LC/MS method 1 : ES+ m/z 465.2 [M]⁺, Rt = 0.68 min).

To a solution of 3-chloro-propane-l -sulfonic acid {l-[(S)-4-(2,3-dihydrobenzo[l,4]dioxin-2-yl)-benzyl]-piperidin-4-yl}-amide (410 mg, 0.88 mmol) in DMF (5 mL) is added NaH (60% dispersion in minerai oil, 71 mg, 1.8 mmol). The reaction is heated to 80 °C for 1 h, diluted with EtOAc, washed with water and brine, dried over Na₂SO4, filtered, and concentrated. The residue is purified by reversed phase HPLC eluting with a gradient of 0-80% MeCN in water (+0.1%TFA). The desired fractions are lyophilized, partitioned between saturated aqueous NaHCO₃ and EtOAc. The organic layer is dried over Na₂SO4, filtered and concentrated to provide the title compound (LC/MS method 1 : ES+ m/z 429.4 [M+H]⁺, Rt = 0.63 min).

Example 225: Préparation of l-{l-[(S)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-phenyl]cthylj-pyrrolidinc (225).

A solution of A (1.0 g, 4.16 mmol) in THF (1 OmL) is treated with 1.4M méthylmagnésium bromide solution in toluene at 0°C. The resulting mixture is stirred at 0°C for lh. The kM—

-9616541 mixture is then quenched with saturated ammonium chloride solution and extracted with

EtOAc. The organic solution is dried over Na₂SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-30% EtOAc in heptane to give l -[(S)-4-(2,3-dihydro-benzo[ l ,4]dioxin-2-yl)-phenyl]-ethanol (J-l ),

A solution of J-l (500 mg, 1.95 mmol) in THF (10 mL) is treated with triphenylphosphine dibromide (1.65 g, 3.90 mmol) and imidazole (265 mg, 3.90 mmol) at room température, and the resulting mixture is stirred at room température for 72h. The mixture is diluted with water and extracted with EtOAc (25mL, 3X). The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by flash column chromatography (silica gel) with EtOAc in Heptane (from 0% to 30%) to give (S)-2-[4-( 1 -bromo-ethyl)-phenyl]-2,3-dihydro-benzo[ 1,4]dioxine J.

A mixture of intermediate J (560 mg, 90% pure, 1.58 mmol) in pyrrolidine (0.5 mL) is heated at 60°C for 18h. The reaction is diluted with MeOH and purified by reversed phase HPLC eluting with a gradient of 5-80% MeCN in water (+0.1%TFA). The desired fractions are combined, diluted with EtOAc, and washed with saturated aqueous NaHCOj. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is dissolved in Et₂O (2 mL), treated with HCl (2 mL, 2M in Et₂O), and concentrated to provide the title product as the HCl sait (LC/MS method 1 : ES+ m/z 311.2 Rt =

0.63 min).

Example 226: 4-(l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2yl|phenyl}ethyl)morpholinc (226)

Compound 226 is prepared from intermediate J and morpholine according to the procedure described for the synthesis of compound 225.

Ex#

MS Method

[M+H]+

Rt (min)

-9716541

226

1

327.20

0.89

Examplc 227: Préparation of l-{l-|(S)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-phcnyl|ethyI}-piperidine-4-carboxylic acid (227)

A mixture of intermediate J (188 mg, 0.59 mmol) and piperidine-4-carboxylic acid ethyl ester (0.5 mL, 3.24 mmol) is heated at 60°C for 18h. The reaction is diluted with MeOH and purified by reversed phase HPLC eluting with a gradient of 5-80% CH3CN in water (+0.1%TFA). The desired fractions are combined, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer is dried over Na₂SO4, filtered, and concentrated. The residue is dissolved in a mixture of MeOH (4 mL) and water (4 mL) containing K.OH (110 mg, 2 mmol) and heated at 50°C for 18h. The mixture Îs concentrated, treated with TFA (0.15 mL, 2 mmol), and extracted with EtOAc. The organic layer is dried over Na₂SO4, filtered, and concentrated to provide the title compound as the TFA sait (LCMS method 7: ES+ m/z 369.2 [M+H]⁺, Rt = 0.56 min).

Example 228: Préparation of l-[(S)-4-(2,3-Dihydro-|l,4Jdioxino[2,3-b]pyridin-3-yl)benzyll-4-methyI-pipcridine-4-carboxylic acid formate sait (228)

A mixture of l-[(S)-4-(2,3-Dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4-methylpiperidine-4-carboxylic acid methyl ester (prepared according to the General Method A) ¢/—

-9816541 (43 mg, 0,10 mmol), LiOH*H₂O (21 mg, 0.5 mmol), MeOH (3 mL), and water (1 mL) is warmed to 50 °C ovemight. The reaction is concentrated, neutralized with 1 N aqueous HCl, and purified by reversed phase HPLC eluting with a gradient of 0-70% MeCN in water (+0.1% formic acid) to afford the title compound as the formate sait (LCMS method 15: ES+ m/z 382.8 [M+H]⁺, Rt = 0.54 min).

Examplc 229: Préparation of 2-{l-[(S)-4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl]piperidin-4-yl}-2-methyl~propionic acid formate sait (229)

HCl

2-{l-[(S)-4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-piperidin-4-yl}-2-methylpropionic acid ethyl ester (prepared according to General Method A) (226 mg, 0.430 mmol) is treated with HCl (1.5 mL, 4M in dioxane, 6 mmol) and 1 mL of water. The mixture is warmed to 140 °C for 1 hour, concentrated, diluted with water, and neutralized with 2N aqueous Na₂CO3. The aqueous layer is decanted and the remaining residue is purified by reversed phase HPLC eluting with a gradient of 0-70% MeCN in water (+0.1% formic acid) to afford the title compound as the formate sait (LCMS method 15: ES+ m/z 395.8 [M+H]⁺, Rt= 1.25 min).

Example 230: Préparation of 2-{l-[(S)-4-(2,3-Dihydro-[l,4]dioxino[2,3-b]pyrïdin~3yl)-benzyl|-piperidin-4-yl}-2-methyl-propionic acid formate sait (230)

Compound 230 is prepared according to the procedure described for the synthesis of compound 229.

-9916541

Example 231: Préparation of 4-{l-[(S)-4-(2,3-Dihydro-benzo[l,4]dioxin-2-yl)-benzyl|piperidin-4-ylmethyl}-benzoic acid (231).

A mixture of 4- {1 -[(S)-4-(2,3-dihydro-benzo[ 1,4]dioxin-2-yl)-benzyl]-piperidin-4ylmethylj-benzoic acid methyl ester (prepared according to General Method C) (80 mg, 0.17 mmol), LiOH*H2O (15 mg, 0.36 mmol), MeOH (3 mL) and water (0.5 mL) is stirred at room température for 16h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is triturated with water to give the title compound.

Examples 231-235: Préparation of Compounds 231-235

Compounds 231-235 are prepared according to the procedure described for the synthesis of compound 231 as shown in Table 7 below.

Table 7. Préparation of compounds 231 -235.

Ex#	X	—A	MS Method	[μ+ηΓ	Rt (min)
231	CH	'UxA	4	444.30	1.42

-10016541

232	CH	-oy°H	4	402.25	1.28
233	CH		4	430.26	1.21
234	N		4	445.29	0.81
235	N	χ.» 0	3	431.25	1.59

Example 236: Préparation of 4-({|(S)“4-(2,3-Dihydro-benzo[l,4|dioxin-2-yl)-benzyl|ethyl-amino}-methyl)-bcnzoic acid (236).

A mixture of 4-{[(S)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzylamino]-methyl}benzoïc acid methyl ester (prepared according to General Method E) (130 mg, 0.33 mmol), acetaldehyde (0.03 mL, 0.50 mmol), and sodium cyanoborohydride (42 mg, 0.67 mmol) in MeOH (15 mL) is treated with 2 drops of acetic acid. The mixture is stirred at room température for 16h, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give 4-({[(S)-4-(2,3-dihydrobenzo[l,4]dioxin-2-yl)-benzyl]-ethyl-amino}-methyl)-benzoic acid methyl ester .

-10116541

A mixture of 4-({[(S)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-ethyl-amino}methyl)-benzoic acid methyl ester (65 mg, 0.16 mmol), LiOH*H2O (23 mg, 0.55 mmol),

MeOH (5 mL) and water (0.5 mL) is stirred at room température for I6h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is diluted with water and DCM, phases are separated, the organic layer is dried over Na₂SO4, filtered and concentrated. The residue is purified by flash chromatography eluting with a gradient of 010% MeOH in DCM to give the title compound.

Examples 236-238: Préparation of Compounds 236-238

Compounds 236-238 are prepared according to the procedure described for the synthesis of compound 236 and as shown in Table 8 below.

Table 8. Préparation of compounds 236-238.

Ex#	X	—A	MS Method	|M+H|+	Rt (min)
236	CH	0	3	404.40	1.86
237	CH	Y ΥίΑγΟΗ k O	3	432.29	2.29
238	CH		3	404.26	1.98

Example 239: Préparation of 3-{4-|(S)-4-(2,3-Dihydro-benzo|l,4|dioxin-2-yl)-benzyljpiperazin-l-ylmethyl}-benzoic acid (239)

-10216541

Methanol (30mL) is added dropwise to acetyl chloride (1.4 mL) at 0°C. The solution is added to 4-((8)-4-(2,3-dihydro-benzo[ l ,4]dioxin-2-yl)-benzyl]-piperazine-1 -carboxylic acid tert-butyl ester (408 mg, 0.99 mmol) (prepared according to the General Method E). The resulting mixture is stirred at room température for 16 h and concentrated. The residue is suspended in a mixture of heptane and EtOAc, and the precipitate is collected and dried under vacuum to give l-((S)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl]piperazine dihydrochloride.

A solution of 1-((8)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl]-piperazine dihydrochloride (80 mg, 0.21 mmol), 4-formyl-benzoic acid methyl ester (41 mg, 0.25 mmol), sodium cyanoborohydride (26 mg, 0.42 mmol), and DIPEA (0.07 mL, 0.42 mmol) in MeOH (5 mL) is treated with 2 drops of acetic acid. The resulting mixture is stirred at room température for 16 h, concentrated, diluted with water, and extracted with ethyl acetate. The organic Iayer is washed with brine, dried over Na2SO<i, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 010% MeOH in DCM to give 4-(4-((8)-4-(2,3-dihydro-benzo[l,4]dioxin-2-yl)-benzyl]piperazin-l-ylmethyl) -benzoic acid methyl ester.

A mixture of 4-{4-[(S)-4-(2,3-dihydro-benzo(l,4]dioxin-2-yl)-benzyl]-piperazin-lylmethyl}-benzoic acid methyl ester (48 mg, 0.11 mmol), LiOH*H₂O (15 mg, 0.37 mmol),

-10316541 dioxane (5 mL), and water (0.5 mL) is stirred at room température for 16h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is triturated with water to give the title compound (LCMS method 4: ES+ m/z 445.2 [M+H]⁺, Rt = l .31 min).

Assessment of Biological Properties

The compounds of the invention are assessed for the ability to interact with human LTA₄ hydrolase in an enzymatic assay that measures the ability of the enzyme to cleave the peptide bond of arginyl-aminomethylcoumarin (Arg-AMC). LTA₄H Enzyme (lnM final), ÎO Arg-AMC substrate (50 μΜ final), and compound are combined in a reaction buffer (50 mM Tris-HCI (pH 7.5), 100 mM K.CI, 0.5% bovine sérum albumin) at room température for lh. The formation of product is assessed by measuring the fluorescence of aminomethylcoumarin product (excitation wavelength 380nm/emission wavelength 460nm). In general, the preferred potency range (IC50) of compounds in the LTA₄H

Enzyme assay is between O.l nM to 10 μΜ, the more preferred potency range is 0.1 nM to 0.1 μΜ, and the most preferred potency range is 0.1 nM to 10 nM.

Table 9. [C50 values of LTA₄H Enzyme assay.

Example	IC50 (nM)	Example	ic50 (nM)	Example	icso (nM)	Example	IC50 (nM)
1	0.38	61	0.60	121	0.37	181	0.042
2	2.45	62	1.79	122	0.91	182	0.29
3	2.57	63	7.90	123	0.73	183	0.48
4	0.74	64	0.83	124	2.45	184	0.11
5	2.96	65	1.15	125	0.16	185	0.59
6	0.46	66	1.79	126	0.18	186	0.24
7	2.79	67	0.61	127	0.12	187	0.07
8	0.32	68	0.10	128	0.65	188	0.87
9	1.49	69	0.60	129	0.23	189	0.16
10	0.75	70	0.57	130	0.51	190	0.09
11	2.95	71	1.88	131	1.73	191	1.62
12	10.19	72	1.80	132	0.91	192	0.43
13	0.36	73	3.65	133	1.75	193	5.35

-10416541

Example	ICS0 (nM)	Example	IC50 (nM)	Example	IC50 (nM)	Example	IC50 (nM)
14	0,27	74	1.00	134	0.47	194	0.15
15	0.36	75	4.51	135	0.47	195	1.59
16	2.32	76	1,90	136	0.19	196	0.39
17	0.77	77	0.18	137	0.26	197	2.69
18	1.14	78	1.40	138	0.18	198	2.28
19	0.73	79	0.51	139	0.10	199	40.12
20	1.30	80	0.71	140	0.38	200	0.12
21	4.43	81	0.31	141	0.26	201	1.59
22	200.00	82	0.20	142	0.17	202	23.37
23	5.20	83	0.13	143	0.30	203	2,94
24	5.90	84	2.69	144	0.14	204	0.15
25	0.76	85	0.45	145	0.09	205	27.50
26	0.43	86	0.92	146	0.29	206	0.19
27	1.20	87	0.69	147	0.35	207	0.86
28	3.40	88	0.54	148	0.28	208	21.45
29	2.04	89	1.40	149	0.24	209	12.41
30	1.77	90	0.77	150	0.21	210	19.00
31	1.54	91	0.54	151	0.10	211	0.69
32	1.80	92	35.99	152	0.17	212	0.49
33	3.19	93	1.98	153	0.82	213	0.81
34	1.89	94	0.45	154	0.20	214	0.47
35	0.26	95	0.49	155	0.28	215	0.70
36	4.45	96	0.22	156	0,91	216	0.13
37	1.05	97	2.87	157	0.18	217	2.28
38	1.14	98	0.61	158	0.13	218	0.37
39	2.14	99	0.37	159	0.16	219	0.49
40	0.82	100	2.36	160	0.18	220	0.47
41	3.71	101	1.90	161	0.41	221	0.16
42	0.69	102	2.68	162	0.14	222	0.14
43	4.42	103	2.40	163	0.17	223	0.16
44	0.69	104	0.18	164	0.84	224	0.13
45	0.90	105	0.51	165	0.13	225	5.30
46	24.82	106	0.46	166	0.68	226	42.95
47	1.73	107	1.35	167	0.27	227	1.40

μ/

-10516541

Example	IC50 (nM)	Example	IC50 (nM)	Example	IC50 (nM)	Example	ic50 (nM)
48	0.16	108	0.87	168	0.31	228	0.61
49	0.32	109	0.17	169	0.33	229	3.85
50	0.60	110	2.15	170	0.47	230	1.24
51	0.82	111	2.25	171	0.45	231	0.29
52	0.75	112	1.07	172	0.53	232	2.75
53	0.42	113	2.49	173	0.73	233	0.22
54	5.93	114	0.77	174	0.60	234	0.14
55	3.63	115	3.03	175	0.22	235	0.08
56	6.08	116	0.82	176	0.24	236	6.04
57	13.66	117	0.23	177	1,45	237	0.81
58	1.36	118	0.45	178	0.35	238	0.55
59	89.24	119	0.10	179	0.16	239	0.15
60	31.02	120	0.51	180	0.12

The compounds of the invention are additionally tested in a human whole blood (HWB) assay to détermine their ability to inhibit the synthesis of LTB4 in a cellular system. Compounds are combined with heparinized human whole blood and incubated for 15 minutes at 37°C. Calcimycin (20μΜ final, prepared in phosphate-buffered saline, pH 7.4) is then added and the mixture is incubated for another 30 minutes at 37°C. The samples are centrifuged for 5 min at low speed (1500 x g) and the plasma layer is removed. Plasma LTB4 concentrations are then measured using an antibody-based homogenous timeresolved fluorescence method (CisBio, Bedford, MA). In general, the preferred potency range (IC50) of compounds in the HWB assay is between 10 nM to 10 μΜ, the more preferred potency range is 10 nM to 1 μΜ, and the most preferred potency range is 10 nM to 100 nM. The potencies of représentative compounds of the invention in the WHB assays are shown in Table 10.

Table 10. IC50 values of LTB4 production inhibition assay in human whole blood.

Example	IC50 (nM)	Example	IC50 (nM)	Example	IC50 (nM)	Example	ic50 (nM)
139	13.18	175	72.56	52	145.12	61	250.398

-10616541

142	24.37	173	72.75	219	148.90	118	255.61
190	26.03	109	75.52	183	151.13	174	268.33
158	27.50	138	76.03	14	154.92	87	268.33
137	27.64	68	80.65	53	154.92	9	284.85
160	27.98	81	80.74	64	157.95	229	289.83
145	28.39	200	82.95	156	158.75	25	294.12
126	32.30	220	91.13	121	159.37	85	304.96
141	32.81	185	92.28	178	159.61	227	307.44
140	33.44	237	94.53	69	164.89	26	308.47
83	33.49	134	94.60	214	168.70	116	310.32
157	35.00	234	94.77	18	176.14	123	312.41
186	36.46	204	94.98	187	176.77	37	323.66
168	38.99	155	95.39	1	179.33	67	345.74
125	39.18	99	95.39	98	180.00	10	352.40

Methods of Use

The compounds of the invention are effective inhibitors of leukotriene A4 hydrolase (LTA4H) and thus inhibit leukotriene production. Therefore, in one embodiment of the invention, there is provided methods of treating leukotriene-mediated disorders using compounds of the invention. In another embodiment, there is provided methods of treating cardiovascular, inflammatory, allergie, pulmonary and fibrotic diseases, rénal diseases and cancer using compounds of the invention.

Without wishing to be bound by theory, by inhibiting the activity of LTA4H, the compounds of the invention block the production of LTB4 resulting from the oxidation of arachidonic acid by 5-LO and subséquent metabolism. Thus, the inhibition of LTA4H activity is an attractive means for preventing and treating a variety of diseases mediated by LTB4. These include:

Cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, aortic aneurysm, sickle cell crisis, ischemia-reperfusion injury, pulmonary arterial hypertension and sepsis;

Allergie diseases including asthma, allergie rhinitis, rhinosinusitis, atopie dermatitis and urticaria;

-10716541

Fibrotic diseases including airway remodeling in asthma, idiopathic pulmonary fibrosis, scleroderma, asbestosis;

Pulmonary syndromes including adult respiratory distress syndrome, viral bronchiolitis, obstructive sleep apnea, chronic obstructive pulmonary disease, cystic fibrosis, and bronchopulmonary dysplasia;

Inflammatory diseases including rheumatoid arthritis, osteoarthritis, goût, glomerulonephritis, interstitial cystitis, psoriasis, inflammatory bowel disease systemic lupus erythematosus, transplant rejection, inflammatory and allergie ocular diseases;

Cancer including solid tumors, leukemias and lymphomas; and Rénal diseases such as glomerulonephritis.

For treatment of the above-described diseases and conditions, a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about O.l mg to about 20 mg/kg of body weight per dosage. For example, for administration to a 70 kg person, the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optîmization may be required to détermine an optimal dosing level and pattern. The active ingrédient may be administered from l to 6 times a day.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased antagonist activity, provide adjunct therapy, and the like. The compounds according to the invention may be used on their own or in conjunction with other active substances according to the ιλ/^

-10816541 invention, optionally also in conjunction with other pharmacologically active substances.

In general, the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, orally, buccally (e.g., sublingually), nasally, parenterally, topically, transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aérosols, or the like, preferably in unit dosage forms suitable for simple administration of précisé dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other médicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A.H. Kibbe (ed.), American Pharmaceutical Ass’n, 2000; H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger, 1990; each of which is incorporated herein by reference in their entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds of the invention utilized in a particular pharmaceutical formulation will be selected (e.g., salts) that possess suitable physical characteristics (e.g., water solubility) that are required for the formulation to be efficacious.

Claims (26)

1. Clairns

   What is claimed is:

   l. A compound of formula (I):

   or a pharmaceutically acceptable sait thereof, wherein:

   X is N or CH;

   n is an integer from 0 to 3;

   R¹ is selected from halo, -OH, -CN, -(Ci-Cs)alkyl, -OfCi-CûJalkyl, and -(CjC₆)cycloalkyl;

   ni n

   R and R are each independently selected elected from -H and -(Ci-C6)alkyl; wherein R •1 and R may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, -OH, (=0), -(C|-C₆)alkyl, -O(C_rC₆)alkyl, -C(O)OH, -C(O)(C_rC₆)alkyl, and -C(O)NH₂;

   A is a group of formula -NR⁴R⁵, wherein

   R⁴ and R⁵ are each independently selected from -H, -(Ci-Cô)alkyl, -(C3CôJcycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 11 membered)heteroaryl; wherein each of the foregoing -(Ci-Côjalkyl, -(C3Côjcycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5- to 11membered)heteroaryl of said R⁴ and R^s groups is optionally independently substituted by one to three R⁶ groups; wherein two R⁶ groups when attached to the

   -11016541 same carbon atom of said -(Ci-Cô)alkyl may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, -OH, (=O), -(Cj-Cefalkyl, -O(C|C₆)alkyl, -C(O)OH, -C(O)(C|-C₆)alkyl, and -C(O)NH₂;

   or A is a (4- to l l-membered)N-heterocyclic ring of formula B:

   wherein said ring B may be a non-aromatic 4-8 membered monocyclic radical; a bridged bicyclic radical; a spirocyclic radical; or a 6 to 11-membered fused bicyclic radical which may be non-aromatic or hâve one aromatic ring provided that the aromatic ring of the bicyclic radical, when présent, is not attached to methylene carbon atom 1 of the compound of formula (I);

   wherein said ring B may additionally comprise one to three additional ring heteroatoms independently selected from N, O and S;

   wherein said ring B may be further optionally substituted by one to three groups selected from halo, -OH, (=0), -C(O)OH, -C(O)O-(C|-Cft)alkyl, and -(Ci-Cé)alkyl; and wherein L is absent or a linker selected from -(Ci-CôJalkylene;

   each R⁶is independently selected from halo, -OR⁷, -CF3, -CN, -(Ci-Côialkyl, -C(O)R⁷, -C(O)2R⁷, -C(O)N(R⁷)2, -N(R⁷)2, -NHC(O)R⁷, -NHC(O)N(R⁷)2, -S(O)2R⁷, -NH-S(O)2-R⁷, -(C3-C6)cycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(C6-C|o)aryl, and -(5- to 11 membered)heteroaryl; wherein each of said, -(Ci-C6)alkyl, -O(C|-C6)alkyl, -(C3Céjcycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(Cô-Cio)aryl, and -(5- to 11 membered)heteroaryl of said R⁶ group is optionally substituted where possible with one to three groups selected from halo, -OH, -CF3, -CN, (=0), -(Ci-CûJalkyl, -C(O)OH, -C(O)O-(C_rC₆)alkyl, -NH₂, -NHtCrQJalkyl, -N((C,-C₆)alkyl)₂, -S(O)₂(Ci-C₆)alkyl, -(C₃-11116541

   Cô)cycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(Cô-Cio)aryl, and -(5- to 11 membered)heteroaryl; and each R⁷is independently selected from -H, -(Ci-Côjalkyl, -(Ci-Ce)alkyl, -(C[-Ce)alkyl-OH, -(Ci-Ce)alkyl-O-(Ci-C6)alkyl, -(C3-Ce)cycloalkyl, -(Cj-Cejcycloalkyl-OH, -(4- to 11 membered)heterocycloalkyl, -(Ce-Ciojaryl, and -(5- to 1 l-membered)heteroaryi.
2. 2. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein group A is a group of formula -NR⁴R⁵.
3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(Ci-Ce)alkyl, and R⁵ is -(Ci-Ce)alkyl; wherein each -(Ci-Ce)alkyl of said R⁴ and R⁵ groups, when présent, is optionally independently substituted by one to three R⁶ groups.
4. 4. The compound of claim 1 or 3, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(Ci-C&)alkyl, and R^s is -(Ci-Cô)alkyl; wherein said -(Ci-Cù)alkyl of said R⁵ group is substituted by -(Cî-Céicycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(Cô-Cio)aryl, or -(5- to 1 l-membered)heteroaryl; wherein each of said, -(C3-C6)cycloalkyl, -(4- to 1 l-membered)heterocycloalkyl, -(C(,-Cjo)aryl, and -(5- to 11 -membered)heteroaryl is optionally substituted with one to three groups independently selected from -(C>C₆)alkyl, -CF₃, and -C(O)OR⁸.
5. 5. The compound of claim 1 or 2, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(C|-C6)alkyl, and R⁵ is -(CrCô)alkyl; wherein said -(C[-Cû)alkyl of said R⁵ group is independently substituted by one to three groups selected from-(C)C6)alkyl, -O(Ci-C₆)alkyl, -C(O)R⁸, -C(O)OR⁸, -S(O)₂R⁸, and -NHC(O)R^S.
6. 6. The compound of claim 1 or 2, or a pharmaceutically acceptable sait thereof, wherein R⁴ and R⁵ are each independently selected from -H or -(Ci-Côjalkyl.

   -11216541
7. 7. The compound of claim l or 2, or a pharmaceutically acceptable sait thereof, wherein R⁴ is -H or -(Ci-Côjalkyl, and R⁵ is -(Cj-CôJcycloalkyl, -(4- to 11membered)heterocycloalkyl, -(C(j-Cio)aryl, and -(5- to l l-membered)heteroaryl; wherein each of the foregoing -(Cî-CéJcycloalkyl, -(4- to l l-membered)heterocycloalkyl, -(Ce- £

   Cio)aryl, and -(5- to 11 -membered)heteroaryl groups of said R is optionally independently substituted by one to three groups selected from -(Ci-Cftjalkyl, -O(C|-C6)alkyl, -C(O)R⁸, -C(O)OR⁸, -S(O)₂R⁸, and -NHC(O)R⁸.
8. 8. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein group A is a (4- to 1 l-membered)N-heterocyclic ring of formula B:
9. 9. The compound of claim 1 or 8, or a pharmaceutically acceptable sait thereof, wherein said ring B is 4-8 membered monocyclic radical.
10. 10. The compound of claim 9, or a pharmaceutically acceptable sait thereof, wherein said 4-8 membered monocyclic radical is selected from the group consisting of azetidine, tetrahydropyrrole, piperidine, hexamethyleneimine, 1,2-diazetidine, pyrazolidine, imidazolidine, piperazine, hexahydrodiazepine, isoxazolidine, oxazolidine, tetrahydro-2H1,3-oxazine, morpholine, and hexahydro-l,4-oxazepine; wherein said monocyclic ringmay be further optionally substituted by one to three groups selected from halo, -OH, (=O), -C(O)OH, -C(O)O-(C_rC₆)alkyl, and -(C_rC₆)alkyl.
11. 11. The compound of claim i or 8, or a pharmaceutically acceptable sait thereof, wherein said ring B is a spirocyclic heterocyclic radical.
12. 12. The compound of claim 1 or 8, or a pharmaceutically acceptable sait thereof, wherein said ring B is a bridged bicyclic radical; or a 6 to 11-membered fused bicyclic radical which may be non-aroinatic or hâve one aromatic ring provided that the aromatic w

    -11316541 ring of the bicyclic radical, when présent, is not attached to methylene carbon atom l of the compound of formula (I).
13. 13. The compound of claim 1 or 8, or a pharmaceutically acceptable sait thereof, wherein L is -CH₂-.
14. 14. The compound of claim 1 or 8, or a pharmaceutically acceptable sait thereof, wherein L is absent.
15. 15. The compound of claim 1 or 8, or a pharmaceutically acceptable sait thereof, wherein said 4-8-membered heterocyclic ring B is a selected from azetidinyl, pyrrolidinyl, piperidinyl and azepanyl; wherein each of the foregoing azetidinyl, pyrrolidinyl, piperidinyl and azepanyl rings is optionally substituted by one to three groups selected from halo, -OH, (=0), -C(O)OH, C(O)O-(C|-Cô)alkyl, and -(Ci-Cejalkyl; and wherein

    L is absent or a linker selected from -(Ci-Cûjalkylene; and wherein

    R⁶is elected from halo, -OR⁷, -CF3, -CN, -(C|-C6)alkyl, -C(O)R⁷, -C(O)2R⁷, -C(O)N(R⁷)2, -N(R⁷)2, -NHC(O)R⁷, -NHC(O)N(R⁷)2, -S(O)2R⁷, -NH-S(O)2-R⁷, -(Ci-Cejcycloalkyl, -(4- to 1 l-meinbered)heterocycloalkyl, -(Cô-Cio)aryl, and -(5to 1 l-membered)heteroaryl; wherein each of said, -(CrC6)alkyl, -O(CpC6)alkyl, -(Cj-Cfijcycloalkyl, -(4- to 11 -membered)heterocycloalkyl, -(C6-Cio)aryl, and -(5to 1 l-membered)heteroaryl of said R⁶ group is optionally substituted where possible with one to three groups selected from halo, -OH, -CFî, -CN, (=0), -(Cr C6)alkyl, -C(O)OH, -C(O)O-(Ci-C₆)alkyl, -NH₂, -NH(C|-C₆)alkyl, -N((C_r C₆)alkyl)₂, -S(O)₂(Ci-C₆)alkyl, -(C₃-C₆)cycloalkyl, -(4- to 11 membered)heterocycloaikyl, -(Cfi-Cio)aryl, and -(5- to 1 l-membered)heteroaryl.
16. 16. The compound of any of the preceeding claims, or a pharmaceutically acceptable sait thereof, wherein X is N. A

    -11416541
17. 17. The compound of any of claims 1 to 15, or a pharmaceutically acceptable sait thereof, wherein X is CH.
18. 18. A compound selected from the group consisting of:

    4-(l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl)piperidin-4-yl)butanoic acid;

    4-(l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl)piperidin-4-yl)benzoic acid;

    (3S)-3- {4-[( 1 s,4s)-7-azabicyclo[2.2.1 ]hept-7-ylmethyl]phenyl} -2,3dihydro[ 1,4]dioxino[2,3-b]pyridine;

    N-( 1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl) piperidin-4yl)methanesulfonamide;

    (3S)-3-[4-(azepan-1 -ylmethyl)phenyl]-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridine;

    1 - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }-2-methylpiperidine;

    7- {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }-l ,7-diazaspiro[4.4]nonane-1 carboxamide;

    7- {4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl)-l,7-diazaspiro[4.4]nonan-

    2-one;

    1 -{4-[(2S)-2,3-dihydro-l ,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxylic acid; (l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl)piperidin-4-yl)(morpholin-4yl)methanone;

    8- {4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl )-1,3,8triazaspiro[4.5]decane-2,4-dione;

    (3 S )-3- {4-[(3-methoxypiperidin-1 -yl)methyl]phenyl) -2,3-dihydro[ 1,4]dioxino[2,3b]pyridine;

    N-( 1 - (4- [(2S)-2,3 -dihydro-1,4-benzodioxi n-2-yl]benzyl} pyrrolidin-3-yI)-N methylacetamide;

    1 - {4-[(2S)-2,3-dihydro-l ,4-benzodioxin-2-yl]benzyl )-4-( 1,1 -dioxido-1,2-thiazolidin-2yl)piperidine;

    (3 R)-1 - (4-[(3 S)-2,3-dîhydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl }pyrrolidin-3-ol;

    N-(l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl)piperidin-4-yl)-2hydroxyacetamide; --11516541

    4-[( l - {4-[(3 S)-2,3-dihydro[ l ,4]dioxino[2,3-b]pyridin-3-yl]benzyl} piperidin-4yl)methyl]benzoic acid;

    (l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)(morpholin4-yl)methanone;

    (3S)-3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine;

    8- {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }-2,8-diazaspiro[4.5]decan-1 -one; l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carbonitriie; l-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylpiperidine-4-carboxamide;

    8-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2,8-diazaspiro[4.5]decan1 -one;

    N-(l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-2hydroxy-2-methylpropan amide;

    N-( 1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-1 hydroxycyclopropanecarboxamide;

    N-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl)-N-ethylcyclopentanamine; l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methylpiperidine-4carboxamide;

    N-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-Nmethyicyclopentanamine;

    1 -[( 1 - {4-[(3 S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-3yl)methyl]pyrrolîdin-2-one;

    l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-2-methylpyrrolidine;

    N- {4-[(3S)-2,3-dihydro[ l ,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2-methyl-1 -(pyrrolidin-1 y 1 )propan-2- ami ne;

    N-cyclohexyl-N-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-N',N'dimethylethane-1,2-diamine;

    N-( 1 - {4-[ (3 S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} piperidin-4yl)acetamide;

    N-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methyl-2-(pyridin-2yl)ethan amine;

    (3S)-3-[4-(pyrrolidin-1 -ylmethyl)phenyl]-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridine; v\Z—‘

    -11616541 l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-3-carboxamide;

    1 - {4-[(3 S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl }piperidine-4-carboxamide;

    N-(l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-yl)acetamide;

    1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-(2hydroxyethyl)piperidine-4-carboxamide;

    (3S)-3-[4-(l,4-oxazepan-4-ylmethyl)phenyI]-2,3-dihydro[l,4]dioxino[2,3-b]pyridine;

    1 - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl }-N-(2-hydroxyethyl)piperidine-4carboxamide;

    4-(l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)benzoic acid;

    1 -( 1 - {4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl} piperidin-4-yl)urea;

    7- {4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}-l,7-diazaspiro[4.4]nonan-2-one;

    8- {4-[(3S)-2,3-dibydro[l,4]dioxino[2_}3-b]pyridin-3-yl]benzyi}-2-methyl-2,8diazaspiro[4.5]decan-1 -one;

    1 - {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-ol;

    N-(l-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4yl)methanesulfonamide;

    3- (l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)propan-Ιοί;

    (3S)-3-{4-[(4-methylpiperidin-l-yl)methyl]phenyl}-2,3-dihydro[l,4]dioxino[2,3b]pyridine;

    N-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-ethylethanamine;

    N- (4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} -1 (methylsulfonyl)piperidin-4-amine;

    (3S)-3- (4-[(4-fluoropiperidin-1 -yl)methyl]phenyl} -2,3-dihydro[l ,4]dioxino[2,3b]pyridine;

    1 -(4- {4-[(3S)-2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-3-yl]benzyl} -1,4-diazepan-1 yl)ethanone;

    [(3R)-l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]acetic acid; (l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)methanol;

    4- [(l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)methyl]benzoic acid; jy'

    -11716541 (38)-3-{4-[(4-methyl-l,4-diazepan-l-yl)methyl]phenyl}-2,3-dihydro[l,4]dioxino[2,3bjpyridine;

    (3S)-3-{4-[(3-methoxypyrrolidin-l-yl)methyl]phenyl}-2,3-dihydro[l,4]dioxino[2,3bjpyridine; and

    N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,2-dimethylpropan-2-amine; or a pharmaceutically sait thereof of each of the foregoing.
19. 19. The compound 4-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridin-3yl]benzyl}piperazine-l-carboxamide, or a pharmaceutically acceptable sait thereof.
20. 20. The compound 1 -{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4carboxylic acid, or a pharmaceutically acceptable sait thereof.
21. 21. The compound [(3R)-l-{4-[(2S)-2,3-dihydro-l,4-benzodioxin-2yl]benzyl)piperidin-3-yl]acetic acid, or a pharmaceutically acceptable sait thereof.
22. 22. A pharmaceutical composition comprising the compound of any of daims 1 to 21, or a pharmaceutically acceptable sait thereof
23. 23. Use of a compound of any of daims 1 to 21, or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for treating leukotriene-mediated disorders.
24. 24. Use of a compound of any of daims I to 21, or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for treating a cardiovascular disease.
25. 25. The use of daim 24, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, myocardial infarction, stroke, aortic aneurysm, sickle cell crisis, ischemia-reperfusion injury, pulmonary arterial hypertension and sepsis.

    -11816541
26. 26. Use of a compound of any of ciaims l to 21, or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for the treatment of atherosclerosis.