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NZ614109B2 - Benzodioxane inhibitors of leukotriene production - Google Patents

Benzodioxane inhibitors of leukotriene production Download PDF

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Publication number
NZ614109B2
NZ614109B2 NZ614109A NZ61410912A NZ614109B2 NZ 614109 B2 NZ614109 B2 NZ 614109B2 NZ 614109 A NZ614109 A NZ 614109A NZ 61410912 A NZ61410912 A NZ 61410912A NZ 614109 B2 NZ614109 B2 NZ 614109B2
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New Zealand
Prior art keywords
dihydr0
benzy1
alkyl
membered
compound
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NZ614109A
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NZ614109A (en
Inventor
Asitha Abeywardane
Michael J Burke
Thomas Martin Kirrane Jr
Matthew Russell Netherton
Anil Kumar Padyana
Keenan Lana Louise Smith
Hidenori Takahashi
Michael Robert Turner
Qiang Zhang
Qing Zhang
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Boehringer Ingelheim International Gmbh
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Priority claimed from PCT/US2012/028843 external-priority patent/WO2012125598A1/en
Publication of NZ614109A publication Critical patent/NZ614109A/en
Publication of NZ614109B2 publication Critical patent/NZ614109B2/en

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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract

Disclosed are benzodioxane compounds and their pyridodioxinyl derivatives of formula (I) wherein the variables are as defined in the specification. The compounds of formula (I) are useful as inhibitors of leukotriene A hydrolase (LTA4H) enzyme and treating LTA4H related disorders such as asthma, allergy and cardiovascular diseases including atherosclerosis, myocardial infarction and stroke. Also disclosed are processes for preparing compounds of formula (I), pharmaceutical compositions comprising the compounds of formula (I), and methods of using these compounds in the treatment of said diseases and disorders. ergy and cardiovascular diseases including atherosclerosis, myocardial infarction and stroke. Also disclosed are processes for preparing compounds of formula (I), pharmaceutical compositions comprising the compounds of formula (I), and methods of using these compounds in the treatment of said diseases and disorders.

Description

BENZODIOXANE TORS OF LEUKOTRIENE PRODUCTION Field of the Invention This invention relates to ioxanes 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 leukotrienes including asthma, y and cardiovascular diseases including atherosclerosis, myocardial infarction and stroke.
This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these nds in the treatment of s 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, phils, basophils, monocytes and macrophages. The first committed step in the ellular synthesis of LTs es ion of arachidonic acid by 5-lipoxygenase (5-LO) to leukotriene A4 (LTA4), a process requiring the 5-lipoxygenase-activating protein (FLAP). Leukotriene A4 hydrolase (LTA4H) catalyzes the hydrolysis of LTA4 to produce leukotriene B4 (LTB4). Through the engagement of the LTB4 receptors (BLT1, BLT2), LTB4 stimulates 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 ent of the pathology; these include cancer, asthma, atherosclerosis, colitis, glomerularnephritis, and pain (for a review, see M. Peters-Golden and W.R. Henderson, Jr., M.D., N. Engl. J. Med., 2007, 357, 1841-1854).
Brief Summary of the Invention A first aspect of the invention provides for a compound of formula (I): (7804526_1):KZA or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; n is an integer from 0 to 3; R1 is selected from halo, -OH, -CN, -(C1-C6)alkyl, –O(C1-C 6)alkyl, and -(C3-C6)cycloalkyl; R2 and R3 are each independently selected from -H and -(C1-C6)alkyl; wherein R2 and R3 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), -(C1-C6)alkyl, C6)alkyl, -C(O)OH, -C(O)(C1-C6)alkyl, and -C(O)NH2; A is a group of formula -NR4R5, wherein R4 and R5 are each independently selected from -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to 11-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11-membered)heteroaryl; n each of the foregoing -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to 11-membered)heterocycloalkyl, 10)aryl, and -(5- to 11-membered)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 -(C1-C6)alkyl may join to form a 3- to ered ring optionally sing one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, -OH, (=O), -(C1-C6)alkyl, -O(C1-C6)alkyl, -C(O)OH, -C(O)(C1-C6)alkyl, and H2; or A is a (4- to bered)N-heterocyclic ring of formula B: wherein said ring B may be a non-aromatic 4-8 membered monocyclic radical; a bridged ic radical; a spirocyclic radical; or a 6 to 11-membered fused bicyclic radical which may be non-aromatic or have one aromatic ring provided that the aromatic ring of the bicyclic radical, when present, is not attached to methylene carbon atom 1 of the compound of a (I); wherein said ring B may additionally comprise one to three additional ring heteroatoms independently selected from N, O and S; (7804526_1):KZA 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-(C1-C6)alkyl, and -(C1-C6)alkyl; and wherein L is absent or a linker selected from -(C1-C6)alkylene; each R6 is independently selected from halo, -OR7, -CF3, -CN, -(C1-C6)alkyl, -C(O)R7, -C(O) 7, 2R -C(O)N(R7)2, -N(R7)2, -NHC(O)R7, -NHC(O)N(R7)2, -S(O)2R7, -NH-S(O)2-R7, 6)cycloalkyl, -(4- to 11-membered)heterocycloalkyl, 10)aryl, and -(5- to 11-membered)heteroaryl ; wherein each of said, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to 11- membered)heterocycloalkyl, -(C6-C10)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, (=O), -(C1-C6)alkyl, -C(O)OH, -(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -S(O)2(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to bered)heterocycloalkyl, -(C6-C 10)aryl, and -(5- to 11-membered)heteroaryl; and each R7 is independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C3-C6)cycloalkyl, 6)cycloalkyl-OH, -(4- to 11-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11-membered)heteroaryl.
A second aspect of the invention provides for a compound selected from the group consisting of: 4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinyl)butanoic acid; 4-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl)benzoic acid; -{4-[(1s,4s)azabicyclo[2.2.1]heptylmethyl]phenyl}-2,3- o[1,4]dioxino[2,3-b]pyridine; N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidin yl)methanesulfonamide; (3S)[4-(azepanylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine; 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}methylpiperidine; 7-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-1,7-diazaspiro[4.4]nonane carboxamide; 7-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-1,7-diazaspiro[4.4]nonan- 2-one; 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinecarboxylic acid; (1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinyl)(morpholin yl)methanone; (7804526_1):KZA 8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-1,3,8- triazaspiro[4.5]decane-2,4-dione; (3S){4-[(3-methoxypiperidinyl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3- b]pyridine; N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}pyrrolidinyl)-N- methylacetamide; 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}(1,1-dioxido-1,2-thiazolidin yl)piperidine; (3R){4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}pyrrolidinol; 4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl) hydroxyacetamide; 4-[(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidin yl)methyl]benzoic acid; (1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidin yl)(morpholinyl)methanone; (3S)[4-(morpholinylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine; 8-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-2,8-diazaspiro[4.5]decanone; 1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinecarbonitrile; 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-N-methylpiperidine amide; 8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-2,8-diazaspiro[4.5]decan- 1-one; N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl) hydroxymethylpropanamide; N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl) hydroxycyclopropanecarboxamide; N-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-N-ethylcyclopentanamine; 1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-N-methylpiperidine carboxamide; N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-N- methylcyclopentanamine; 1-[(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidin yl)methyl]pyrrolidinone; 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}methylpyrrolidine; (7804526_1):KZA N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}methyl(pyrrolidin yl)propanamine; N-cyclohexyl-N-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-N',N'- dimethylethane-1,2-diamine; N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidin yl)acetamide; N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-N-methyl(pyridin yl)ethanamine; (3S)[4-(pyrrolidinylmethyl)phenyl]-2,3 -dihydro[1,4]dioxino[2,3-b]pyridine; 1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinecarboxamide; 1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinecarboxamide; N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}pyrrolidinyl)acetamide; 1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-N-(2- hydroxyethyl)piperidinecarboxamide; (3S)[4-(1,4-oxazepanylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine; 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-N-(2-hydroxyethyl)piperidine amide; 4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinyl)benzoic acid; 4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinyl)urea; 7-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-1,7-diazaspiro[4.4]nonanone; 8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}methyl-2,8- diazaspiro[4.5]decanone; 1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinol; N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidin yl)methanesulfonamide; 4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl)propan- 1-ol; (3S){4-[(4-methylpiperidinyl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3- b]pyridine; N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-N-ethylethanamine; N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl} (methylsulfonyl)piperidinamine; (3S){4-[(4-fluoropiperidinyl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3- b]pyridine; (7804526_1):KZA 1-(4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}-1,4-diazepan anone; [(3R){4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinyl]acetic acid; (1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl)methanol; 4-[(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinyl)methyl]benzoic acid; (3S){4-[(4-methyl-1,4-diazepanyl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3- b]pyridine; (3S){4-[(3-methoxypyrrolidinyl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3- b]pyridine; and N-{4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}-N,2-dimethylpropanamine; or a pharmaceutically salt thereof of each of the foregoing.
A third aspect of the ion provides for the compound 4-{4-[(3S)-2,3- dihydro[1,4]dioxino[2,3-b]pyridinyl]benzyl}piperazinecarboxamide, or a pharmaceutically able salt f.
A fourth aspect of the invention provides for the compound 1-{4-[(2S)-2,3-dihydro-1,4- benzodioxinyl]benzyl}piperidinecarboxylic acid, or a pharmaceutically acceptable salt f.
A fifth aspect of the invention provides for the compound [(3R){4-[(2S)-2,3-dihydro- 1,4-benzodioxinyl]benzyl}piperidinyl]acetic acid, or a pharmaceutically acceptable salt thereof.
A sixth aspect of the invention provides for a pharmaceutical composition sing the compound of first to fifth aspects of the invention, or a pharmaceutically acceptable salt thereof.
A seventh aspect of the invention provides for use a of a compound of any one of the first to fifth aspects of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating leukotriene mediated disorders. (7804526_1):KZA An eighth aspect of the invention provides for use of a compound of any one of the first to fifth aspects of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cardiovascular disease.
A ninth aspect of the invention provides for use of a compound of any one of the first to fifth aspects of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a ment for treating atherosclerosis.
The t invention provides novel compounds which inhibit leukotriene A4 hydrolase (LTA4H) and are thus useful for treating a y of diseases and disorders that are ed or sustained through the activity of rienes, including allergic, pulmonary, fibrotic, inflammatory and cardiovascular diseases and cancer. (7804526_1):KZA WO 25598 In one embodiment, the invention relates to a compound of formula (I): R2 R3 1 A X 0 (Run—T \ or a pharmaceutically acceptable salt thereof, n: X is N or CH; n is an integer from 0 to 3; R1 is selected from halo, -OH, -CN, -(C1-C6)alkyl, —O(C1-C6)alkyl, and -(C3- C6)cycloalkyl; R2 and R3 are each independently selected elected from -H and -(C1-C6)alkyl; wherein R2 and R3 may join to form a 3- to ered ring optionally comprising one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, -OH, (=0), -(C1-C6)alkyl, -O(C1-C6)alkyl, -C(O)OH, C1-C6)alkyl, and -C(O)NH2; A is a group of formula -NR4R5, wherein R4 and R5 are each independently selected from -H, -(C1-C6)alkyl, -(C3- C6)cycloalkyl, -(4- to bered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11- membered)heteroaryl; wherein each of the foregoing -(C1-C6)alkyl, -(C3- C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11- membered)heteroaryl of said R4 and R5 groups is optionally independently tuted by one to three R6 groups; wherein two R6 groups when attached to the same carbon atom of said -(C1-C6)alkyl may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and further optionally substituted W0 2012/125598 with one to three groups selected from halo, -OH, (=0), -(C1-C6)alkyl, -O(C1- C6)alkyl, -C(O)OH, -C(O)(C1-C6)alkyl, and -C(O)NH2; or A is a (4- to ll-membered)N-heterocyclic ring of formula B: g—NgL-RB wherein said ring B may be a omatic 4-8 membered monocyclic radical; a bridged bicyclic radical; a spirocyclic radical; or a 6 to ll-membered fused bicyclic l which may be non-aromatic or have one ic ring provided that the aromatic ring of the bicyclic radical, when present, is not attached to ene carbon atom l 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-(C1-C6)alkyl, and -(C1-C6)alkyl; and wherein L is absent or a linker selected from -(C1-C6)alkylene; each R6 is ndently selected from halo, -OR7, -CF3, -CN, -(C1-C6)alkyl, 7, -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 bered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11- membered)heteroaryl; wherein each of said, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C3- C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)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), -(C1-C6)alkyl, -C(O)OH, -C(O)O-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -S(O)2(C1-C6)alkyl, -(C3- loalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11- membered)heteroaryl; and each R7 is ndently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C3-C6)cycloalkyl-OH, -(4- to 11- membered)heterocycloalkyl, -(C6-C10)ary1, and -(5- to ll-membered)heteroaryl.
This ion also relates to pharmaceutical itions comprising the compounds of formula (1), methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these pI'OCCSSCS.
Detailed Description of the Invention Definitions: DCE = dichloroethane DCM = dichloromethane DEA = diethylamine DIBAL-H = utylaluminum hydride DIPEA = diisopropylethylamine DMA = dimethylacetamide DMAP = 4-dimethylaminopyridine DME = dimethyl ether DMF = dimethylformamide DMSO = dimethylsulfoxide EtzO = ethylether EtOAc = ethyl acetate EtOH = l IPA = isopropyl alcohol KHMDS = potassium bis(trimethylsilyl)amide MeCN = acetonitrile MeOH = ol TBTU = 2-(lH-benzotriazole-l-yl)-l,1,3,3-tetramethyluronium tetrafluoroborate TEA = triethylamine TFA = trifluoroacetic acid 2012/028843 THF = tetrahydrofuran TMSCF3 = (trifluoromethyl)trimethylsilane It will be understood that the terms "compounds of formula (I)" and "compounds of the invention" have the same meaning unless indicated otherwise.
In its broadest embodiment ("the first ment of the invention"), the invention relates to compounds of formula (I) as described above, and pharmaceutically able salts thereof, as described above in the summary of the invention.
In another embodiment ("the second embodiment of the ion"), the invention relates to a nd of formula (I) as described in the first embodiment immediately of the invention, or a pharmaceutically acceptable salt 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 (I) as described in the first embodiment of the invention, or a ceutically acceptable salt thereof, wherein group A is a (4- to bered)N- heterocyclic ring of formula B: 3—@L-R6 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 salt thereof, n R4 is -H or -(C1-C6)alkyl, and R5 is 6)alkyl; wherein each -(C1-C6)alkyl of said R4 and R5 groups, when present, is optionally ndently 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 salt thereof, wherein R4 is —H or -(C1-C6)alkyl, and R5 is -(C1-C6)alkyl; wherein said -(C1-C6)alkyl of said R5 group is substituted by -(C3-C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6- C10)aryl, or -(5- to ll-membered)heteroaryl; wherein each of said, -(C3-C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to ll-membered)heteroaryl is optionally substituted with one to three groups independently ed from -(C1-C6)alkyl, -CF3, and R8.
In r ment, the invention relates to a compound of formula (I) as described in the second embodiment of the invention, or a pharmaceutically acceptable salt thereof, wherein R4 is -H or -(C1-C6)alkyl, and R5 is -(C1-C6)alkyl; wherein said -(C1-C6)alkyl of said R5 group is independently substituted by one to three groups selected from-(C1- C6)alkyl, -O(C1-C6)alkyl, -C(O)R8, -C(O)OR8, R8, and -NHC(O)R8.
In another embodiment, the ion relates to a compound of formula (I) as bed in the second embodiment of the invention, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently selected from —H or -(C1-C6)alkyl.
In another embodiment, the invention relates to a compound of formula (I) as bed in the second embodiment of the invention, or a pharmaceutically acceptable salt f, wherein R4 is —H or -(C1-C6)alkyl, and R5 is -(C3-C6)cycloalkyl, -(4- to 11- membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to ll-membered)heteroaryl; n each of the foregoing -(C3-C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6- C10)aryl, and -(5- to ll-membered)heteroaryl groups of said R5 is optionally independently substituted by one to three groups selected from -(C1-C6)alkyl, -O(C1-C6)alkyl, 8, -C(O)OR8, -S(O)2R8, and -NHC(O)R8.
In another embodiment, the invention relates to a compound of formula (I) as bed in the third embodiment of the invention, or a pharmaceutically acceptable salt 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 salt thereof, wherein said 4-8 membered monocyclic radical is selected from the group consisting of ine, tetrahydropyrrole, piperidine, hexamethyleneimine, l,2-diazetidine, pyrazolidine, 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 ed from halo, -OH, (=0), H, -C(O)O-(C1-C6)alkyl, and -(C1-C6)alkyl.
In another embodiment, the invention s to a compound of formula (I) as described in the third embodiment of the invention, or a pharmaceutically acceptable salt thereof, wherein said ring B is a spirocyclic cyclic radical.
In another embodiment, the ion relates to a compound of formula (I) as described in the embodiment immediately above, or a pharmaceutically acceptable salt thereof, wherein said spirocyclic heterocyclic radical is selected from: O C \ CH3 H~ 0% N wk, O O /CH3 /H N N §_N E—N E—N M O E—N E—N 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 salt thereof, wherein said ring B is a bridged ic radical; or a 6 to ll-membered fused bicyclic radical which may be non-aromatic or have one aromatic ring provided that the aromatic ring of the ic l, when t, is not attached to methylene carbon atom l of the compound of formula (I).
In another embodiment, the invention s to a compound of formula (I) as described in the embodiment immediately above, or a pharmaceutically acceptable salt thereof, wherein said 6 to ll-membered fused bicyclic radical or bridged bicyclic radical is selected from: O OH ,, EQQfi and Y0 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 salt thereof, wherein L is —CH2-.
In another embodiment, the invention relates to a compound of formula (I) as described in the third ment of the invention, or a pharmaceutically acceptable salt thereof, wherein L is absent.
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 salt thereof, n said 4membered 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 tuted by one to three groups selected from halo, -OH, (=0), -C(O)OH, C(O)O-(C1-C6)alkyl, and -(C1-C6)alkyl; and wherein L is absent or a linker selected from -(C1-C6)alkylene; and wherein R6 is d from halo, -OR7, -CF3, -CN, -(C1-C6)alkyl, -C(O)R7, -C(O) 2R7, (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 ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to bered)heteroaryl; wherein each of said, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to ll-membered)heteroaryl of said R6 group is optionally substituted where possible with one to three groups selected from halo, -OH, -CF3, -CN, (=0), -(C1- C6)alkyl, -C(O)OH, -C(O)O-(C1-C6)alkyl, -NH2, -C6)alkyl, -N((C1- C6)alkyl)2, -S(O)2(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to 11- membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to bered)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 salt thereof, wherein X is In another ment, 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 salt thereof, wherein X is CH.
The following are entative compounds of the invention which were made by the l synthetic schemes, the examples, and known methods in the art.
WO 25598 Table 1. Exemplary compounds of the invention. de N0. Structure Narne 1-[4-(2,3-dihydr0—1,4- 1 benzodioxin-Z- y1)benzy1]pyrr01idine 4-[4-(2,3-dihydr0—1,4- 2 ioxin-Z- y1)benzy1]rn0rph01ine 1-[4-(2,3-dihydr0—1,4- 3 benzodioxin-Z-y1)benzy1]-4,4- dimethylpiperidine 8-[4-(2,3-dihydr0—1,4- 4 benzodioxin-Z-y1)benzy1]-2,8- diazaspir0[4.5]decan0ne 1-[4-(2,3-dihydr0—1,4- benzodioxin-Z-y1)benzyl] fluoropiperidine (1s,4s)[4-(2,3-dihydr0—1,4- 6 " benzodioxin-Z-y1)benzyl] azabicyclo [2.2. ane 4-[4-(2,3-dihydr0—1,4- benzodioxin-Z- y1)benzy1]thi0m0rph01ine 1,1- dioxide N (28)-2,3-dihydr0-1,4- 8 (>0 o benzodioxin-Z-y1]benzy1}-N,N_ dirnethylpiperidineCarboxamide D (3S)[4-(2,3-dihydr0—1,4- 9 (3:00 benzodioxin-Z- OH y1)benzy1]pyrr01idin01 1-({1-[4-(2,3-dihydr0-1,4- @‘jfiGrokN benzodioxin-Z- N§ y1)benzy1]piperidin O yl}methy1)pyrr01idin0ne 4-(2,3-dihydr0—1,4- 11 benzodioxin-Z- y1)benzy1]piperaziny1}ethan0ne 2-{ [4-(2,3-dihydr0—1,4- 12 benzodioxin-Z-y1)benzyl]amino } - 1-(pyrrolidiny1)ethan0ne (2$)-2,3-dihydr0—1,4- benzodioxin-Z-y1]benzy1} -N- methyl (methylsulfony1)piperidinamine 1-{4-[{4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- y1]benzy1}(methy1)amin0]piperidi ny1}ethan0ne 3-[4-(pyrrolidin ylmethy1)pheny1]-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine 2,3-dihydr0—1,4- benzodioxin-Z-y1)benzy1]-5,6,7,8— tetrahydr0[1,2,4]triaz010[4,3- a]pyrazine 3-{4-[(1,1-dioxid0thiom0rpholin- 4-y1)methy1]pheny1}-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine 3-[4-(m0rpholin ylmethy1)pheny1]-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine (3R){4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- y1]benzy1}piperidinecarb0xylic acid (3S){4-[(2S)-2,3-dihydr0—1,4- benzodioxin zy1}piperidinecarb0xylic acid 4-[(2S)-2,3-dihydr0—1,4- benzodioxin y1]benzy1}piperidiny1)-2,2,2- trifluoroethanol 2-(1-{4-[(2S)-2,3-dihydr0—1,4- benzodioxin y1]benzy1}piperidiny1)- 1,1,1,3,3,3-hexaflu0r0pr0pan01 N-[4-(2,3-dihydr0—1,4- 23 benzodioxiny1)benzyl] methylpropanamine -[4-(2,3-dihydr0—1,4- 24 benzodioxiny1)benzyl]butan amine 1-[4-(2,3-dihydr0—1,4- benzodioxiny1)benzy1]-N- methylpiperidineCarboxamide 4-{1-[4-(2,3-dihydr0—1,4- benzodioxin y1)benzy1]piperidiny1}butan0ic acid {1-[4-(2,3-dihydr0—1,4- 27 benzodioxin y1)benzy1]piperidiny1 }methan01 2-{1-[4-(2,3-dihydr0—1,4- benzodioxin y1)benzy1]piperidiny1 }pr0pan- 2-01 3-{1-[4-(2,3-dihydr0—1,4- benzodioxin y1)benzy1]piperidiny1 }pr0pan- 1-01 O ]:[4-(2,3-dihydIO-1,4- C}; Q ‘NV benzodioxin-Z-yl)benzyl] <\/N\ nknhyL1,44fiazepane $0 1-{4-[4-(2,3-dihydr0—1,4- 31 0 ">’ benzodioxin-Z-y1)benzyl] -1 ,4- :Efo o/ diazepan-l-y1}ethan0ne ©o\/ 4-[4-(2,3-dihydr0—1,4- 32 < > NV benzodioxin-Z-y1)benzyl]-1,4- <\/o ane O N-[4-(2,3-dihydr0—1,4- 33 GO) C \Nx benzodioxin-Z-y1)benzy1] 0\ methoxy-N-methylethanamine o3—©—\ (3R)[4-(2,3-dihydr0—1,4- 34 O QN benzodioxin-Z- zyl]pyrrolidin01 fl" H 8-[4-(2,3-dihydr0—1,4- O benzodioxin-Z-y1)benzy1]-1,3,8- (to // f0 O H triazaspir0[4.5]decane-2,4-dione 1-[4-(2,3-dihydr0—1,4- 36 < § 0 "q benzodioxin-Z-y1)benzyl] O methoxyazetidine N {1-[4-(2,3-dihydr0—1,4- 37 o/\T/£::T/\L::l\f0 ioxin-Z- 60 N y1)benzyl]piperidin [O] yH(nKth0hn¢Lyannhan0ne N 2-{1-[4-(2,3-dfl1ydr0—1,4- 38 0w01 benzodioxin-Z- Go 0/ N/ y1)benzy1]piperidiny1}-N,N- ‘ dimethylacetamide 1-[4-(2,3-dihydr0—1,4- 39 ioxin-Z-y1)benzyl] (methylsulfony1)piperidine 1-[4-(2,3-dihydr0—1,4- benzodioxin-Z-y1)benzyl]azepane N-[4-(2,3-dihydr0—1,4- 41 benzodioxin-Z- y1)benzyl]cyclopentanamine N-[4-(2,3-dihydr0—1,4- benzodioxin-Z-y1)benzyl]-N- methyl-Z-(pyridin-Z- y1)ethanamine 1-Cyclopr0py1-N-[4-(2,3-dihydr0— 43 1,4-benz0dioxin y1)benzyl]methanamine 1-[4-(2,3-dihydr0—1,4- 44 benzodioxin-Z-y1)benzyl] phenylpiperidin01 N-[4-(2,3-dihydr0—1,4- 45 ioxin-Z-y1)benzyl]-N- ethylethanamine 1-[4-(2,3-dihydr0—1,4- 46 benzodioxin-Z- y1)benzy1] azetidine-3 -Carb0nitrile 1-[4-(2,3-dihydr0—1,4- 47 ioxin-Z-y1)benzyl] methoxypyrrolidine N-{1-[4-(2,3-dihydr0—1,4- benzodioxin-Z- y1)benzyl]piperidin y1}methanesulf0namide N-[4-(2,3-dihydr0—1,4- benzodioxin-Z-y1)benzyl] - 1 olidiny1)pr0pan- 2-amine 1-({1-[4-(2,3-dihydr0—1,4- benzodioxin-Z- y1)benzy1]piperidin yl}methy1)pyrrolidin0ne 1-[4-(2,3-dihydr0—1,4- 51 benzodioxin-Z-y1)benzy1]-N,N- dimethylpiperidineCarboxamide 1-[4-(2,3-dihydr0—1,4- benzodioxin-Z-y1)benzyl]-N-(2- hydroxyethy1)piperidine carboxamide 1-{1-[4-(2,3-dihydr0—1,4- 53 benzodioxin-Z- y1)benzy1]piperidiny1}urea 1-[4-(2,3-dihydr0—1,4- 54 benzodioxin-Z-y1)pheny1]-N- (pyridin-3 -y1methy1)methanamine 1-[4-(2,3-dihydr0—1,4- benzodioxin-Z-y1)pheny1]-N-[(1- methyl-1H-imidaz01 y1)methy1]methanamine 2-{4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z-y1]benzy1} - 1 ,2,3,4- tetrahydroisoquinoline carboxylic acid (1R,3S)({ )-2,3-dihydr0- 57 @o03.....©_\ AL 1,4-benz0di0xin HO OH yl]benzy1 } amin0)cyc10pentanecar boxylic acid 3-({4-[(2$)-2,3-dihydr0—1,4- 58 benzodioxin-Z-y1]benzy1}amino)- 4,4-dimethylpentan0ic acid 1-({4-[(25)-2,3—dihydro—1,4- benzodioxin-Z- zy1}amin0)cyclopentanecar c acid N-{4-[(2$)-2,3-dihydr0—1,4- 60 benzodioxin-Z-yl]benzy1} -N- methylglycine 1-{4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- yl]benzy1}pyrr01idine carboxylic acid trans({4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- yl]benzy1 } amin0)cyc10hexanecarb oxylic acid cis({4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- yl]benzy1 } amin0)cyc10hexanecarb oxylic acid 1-[(3R)({4-[(ZS)-2,3-dihydr0- 1,4-benz0di0xin y1]benzy1}amin0)pyrr01idin-1 - yl]ethan0ne 1-[(3 S)({ 4- [(ZS)-2,3-dihydr0- O k 1,4-benz0di0xin 65 Qi—c} ---O O y1]benzy1}amin0)pyrr01idin yl]ethan0ne HZNJ’"~O\ trans({4-[(2$)-2,3-dihydr0—1,4- NH benzodioxin-Z- 66 K© zy1}amin0)cyclohexanecarb "(Om oxamide N-{4-[(2$)-2,3-dihydr0—1,4- 67 benzodioxin-Z-y1]benzy1} -N- methylcyclohexanamine 1-{4-[(ZS)-2,3-dihydro-1,4- 68 benzodioxin-Z-y1]benzy1} methylpiperidine (1-{4-[(ZS)-2,3-dihydr0-1,4- 69 benzodioxin-Z- y1]benly1}piperidiny1)methan01 2-(1-{4-[(2$)-2,3-dihydr0—1,4- 70 benzodioxin-Z- y1]benzy1}piperidiny1)ethan01 N'{4-[(28)-2,3-dihydr0-1,4- 71 benzodioxin-Z-yl]benzy1}pr0pan- N-{4-[(2$)-2,3-dihydr0—1,4- 72 benzodioxin-Z-y1]benzy1} - 1- methoxypropan-Z-amine N'{4-[(28)-2,3-dihydr0-1,4- 73 benzodioxin-Z-yl]benzy1}pf0pan' 1-amine N-{4-[(2$)-2,3-dihydr0—1,4- 74 benzodioxin-Z-yflbenlyl}'N' methylethanamine 1-{4-[(2$)-2,3-dihydr0—1,4- 75 ioxin-Z-yl]pheny1}-N,N- dimethylmethanamine trans({4-[(2$)-2,3-dihydr0—1,4- 76 do ------QHON"OH benzodioxin-Z- y1]benzy1 } amino)cyclohexan01 O'">mm<:::>__\ 1-{4~[(2$)-2,3-dfl1ydro-1,4- 77 @O N benzodioxin-Z-y1]benzy1} methylpyrrolidine C}? @NO 1-{4~[(2$)-2,3-dfl1ydro-1,4- IIIIIII 78 benzodioxin-Z- 00H y1]benzy1}piperidin01 N-{4-[(2$)-2,3-dihydr0—1,4- 79 @3-------QO benzodioxin-Z-yl]benzy1}- O /N_\_ N/ N,N',N'—trimethylethane- 1 ,2- \ diamine OXWQj 2-(Cyclohexy1{4-[(2$)-2,3- 80 O NO g dihydro—l,4-benz0dioxin y1]benzy1}amin0)ethan01 N-{4-[(2$)-2,3-dihydr0—1,4- 81 Q>©N+0 benzodioxin-Z-yl]benzy1}-N,2- / dimethylpropan-Z-amine d :LH/LON N-(1-{4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- 82 : /—{ y1]benzy1}pyrrolidin 0: SO y1)acetamide ©/\N N-(1-{4-[(2$)-2,3-dihydr0—1,4- m" ioxin-Z- 83 o o o= / b]pyridiny1]benzy1}piperidin \ 'N OH pan01 o (3 S) [4-(1 ,4-oxazepan 150 Cy?QB! ylmethyl)pheny1]—2,3- \ N/ dihydr0[1,4]dioxin0[2,3- / HN\ b]pyridiny1]benzy1}-N- \ IN methylpiperidineCarboxamide 1-[4-({4-[(3S)-2,3- O dihydr0[1,4]dioxin0[2,3- """"O 153 — > ‘N N b]pyridin \ / O zy1}amin0)piperidin-1 - yl]ethan0ne (3S)-2,3- (DA0Y0N dihydr0[1,4]dioxin0[2,3- 154 O/\Iw 6/ b]pyridinyl]benzy1}-N-(2- O HN \L hydroxyethy1)piperidine OH carboxamide W0 2012/125598 PCT/U82012/028843 O (3 S) { 4- [(4-flu0r0piperidin 155 \—/ j} ©_\N yl)methy1]pheny1}-2,3- N < > dihydr0[1,4]dioxin0[2,3- b]pyridine (3S)[4-(5,6- 7 3@ dihydr0[1,2,4]triaz010[4,3- N zin-7(8H)- 156 @o N ylmethy1)pheny1]-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine O N-{4-[(3S)-2,3- 157 ®>W©N dihydr0[1,4]dioxin0[2,3- \ N/ H b b]pyridiny1]benzy1}methy1— 1-(pyrrolidiny1)pr0panamine (3 S) { 4- [(3 -meth0xypiperidin- IIIIIIIIQ _ 0:} 1-y1)methy1]pheny1}-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine (3S)-2,3- 0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidine- 4-Carb0nitrile N-(1-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidin y1)acetamide (3S){4-[(1,1- dioxidothiomorpholin 161 \ N/ & y1)methy1]pheny1}-2,3- s\ dihydr0[1,4]dioxin0[2,3- O b]pyridine (1-{4-[(3S)-2,3- 162 ON@UYO dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidin y1)(m0rpholiny1)methan0ne -28— 1-[(1-{4-[(3S)-2,3- 0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidin y1)methy1]pyrrolidin0ne 4-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperazine- 1-Carboxamide 8-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}-1,3,8- spir0[4.5]decane-2,4-dione (3 S) { 4- [(3 -meth0xyazetidin y1)methy1]pheny1}-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine N-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- diny1]benzy1} (methylsulfony1)piperidinamine (3 S) { 4- [(3 -meth0xypyrrolidin- 1-y1)methy1]pheny1}-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine N-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- 169 b]pyridiny1]benzy1}-N-methy1— 1-(methylsulfony1)piperidin amine <3S><4-{[4-<2- methoxyethoxy)piperidin 170 y1]methy1}pheny1)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine OWN 2-(1-{4-[(3S)-2,3- 171 ~\ %\ dihydr0[1 ,4]dioxin0 [2,3 - / O N/ I b]pyridin-§-y1]benzy1}piperidin \ N N-dlmethylacetamlde (3S)(4-{ [4- «[OA(13/N (meth n . . . y y1)P P1 endln-l- 172 O 6’ ~‘o y1]methy1}pheny1)-2,3- bro dihydr0[1,4]dioxin0[2,3- \ N b]pyridine O N-{4-[(3S)-2,3- . . . _ —C>------<;>—\r\J d1hydr0[1,4]d10x1n0[2,3- \ N/ H b]pyridin y1]benzy1}Cyclobutanamine o /O HNQsta N-{4-[(2$)-2,3-dihydr0—1,4- 174 benzodioxin-Z-y1]benzy1} (methylsu1f0ny1)piperidinamine CEOO HN*0 1-(1-{4-[(ZS)-2,3-dihydr0-1,4- 175 N benzodioxin-Z- y1]benzy1}piperidiny1)urea o~ ,9 HN;s\ {j N-(l-{4-[(2$)-2,3-dihydro-1,4- benzodioxin-Z- 176 N y1]benzy1}piperidin y1)methanesu1f0namide 1'{4-[(28)-2,3-dihydr0-1,4- 177 N benz0d10X1I1 y1]benzy1}p1per1d1ne. . carbonitrile (10o HNJI\ N-(1-{4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- 178 N y1]benzy1 idin y1)acetamide 83 1'{4-[(28)-2,3-dihydr0-1,4- 179 benzodioxin-Z-y1]benzy1} -N- methylpiperidineCarboxamide 0% "Q(g (1-{4-[(25)-2,3-dihydr0-1,4- benZOdloxln-Z— N y1]benzy1 }piperidin y1)(m0rpholiny1)methan0ne 4-(1-{4-[(25)-2,3-dihydr0-1,4- benZOdiOXin-Z— y1]benzy1}piperidiny1)butanoic acid [(3R){4-[(2$)-2,3-dihydr0—1,4- benzodioxin-Z- yl]benzy1 }piperidiny1]acetic CEo acid mO [(3S){4-[(ZS)-2,3-dihydro-1,4- N benzodioxin-Z- yl]benzy1}piperidin-3 -y1] acetic CEO acid ._<9 O OH 1-{4-[(2$)-2,3-dihydr0—1,4- N benzodioxin-Z- yl]benzy1 }pyrr01idiny1] acetic 0 acid E j 1-(4-{4-[(3S)-2,3- N dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperazin- 1-y1)ethan0ne 1-{4-[(3S)-2,3- N dihydr0[1,4]dioxin0[2,3- diny1]benzy1}piperidin N o 01 HNJLNHz 1-(1-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- 187 N b]pyridiny1]benzy1}piperidin y1)urea <3S><4-{[4- (methylsu1f0ny1)piperazin 188 y1]methy1}pheny1)-2,3- dihydr0[1,4]dioxin0[2,3- dine 1-{4-[(3S)-2,3- 0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidine- 4-Carboxylic acid N-(1-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidin y1)methanesulf0namide (1S,3R)({4-[(2$)-2,3-dihydr0— 1,4-benz0dioxin y1]benzy1}amin0)cyclopentanecar boxylic acid 1'{4-[(28)-2,3-dihydr0-1,4- 192 benzodioxin-Z- y1]benzy1}piperidin01 1-{4-[(2R)-2,3-dihydr0—1,4- 193 benzodioxin-Z- y1]benzy1}piperidin01 8-{4-[(2$)-2,3-dihydr0—1,4- 194 benzodioxin-Z-y1]benzy1}-2,8- diazaspir0[4.5]decan0ne 8-{4-[(2R)-2,3-dihydr0-1,4- 195 benzodioxiny1]benzy1}-2,8- diazaspir0[4.5]decan0ne 1'{4-[(28)-2,3-dihydr0-1,4- 196 ioxin y11benzy1}pyrrolidine 1-{4-[(2R)-2,3-dihydr0-1,4- 197 benzodioxin y1]benzy1}pyrrolidine 4-{4-[(2S)-2,3-dihydr0-1,4- 198 benzodioxin y1]benzy1}m0rpholine 4-{4-[(2R)-2,3-dihydr0-1,4- 199 benzodioxin y1]benzy1}m0rpholine 1-{4-[(2S)-2,3-dihydr0-1,4- benzodioxin zy1}piperidinecarb0xylic acid 1-{4-[(2R)-2,3-dihydr0-1,4- benzodioxin y1]benzy1}piperidinecarb0xylic acid 4-[4-(7-flu0r0-2,3-dihydr0-1,4- 202 benzodioxin y1)benzy1]m0rpholine 7-flu0r0-2,3-dihydr0-1,4- 203 benzodioxin y1)benzy1]pyrrolidine (3 S) [4-(m0rpholin y1methy1)pheny1]—2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine (3R)[4-(m0rph01in ylmethy1)pheny1]-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridine 1-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidine- 4-carb0xamide 1-{4-[(3R)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidine- 4-carb0xamide 2,3-dihydr0[1,4]di0xin0[2,3- 208 b]pyridiny1)benzy1]pyrr01idin- 2-0ne 3-[4-(2,3-dihydr0[1,4]di0Xin0[2,3- 209 b]pyridiny1)benzy1]—1,3- idin0ne 1-[4-(2,3-dihydr0[1,4]di0xin0[2,3- 210 b]pyridin y1)pheny1]methanamine 1-{4-[(2S)-2,3-dihydr0—1,4- benzodioxiny1]benzy1} methylpiperidinecarb0xy1ic acid (3R,4R){4-[(2S)-2,3-dihydr0— 1 ,4-benz0di0xiny1]benzy1} -3 - piperidinecarb0xy1ic acid 1-{4-[(2S)-2,3-dihydr0—1,4- 213 benzodioxiny1]benzy1} fluoropiperidinecarb0xy1ic acid -{4-[(2S)-2,3-dihydr0—1,4- benzodioxin y1]benzy1}pyrrolidine carboxylic acid (3S){4-[(2S)-2,3-dihydr0—1,4- benzodioxin y1]benzy1}pyrrolidine carboxylic acid (2S)-2,3-dihydr0—1,4- 216 benzodioxiny1]benzy1} (1H- tetrazol-S-y1)piperidine 1'{4-[(28)-2,3-dihydr0-1,4- 217 benzodioxin y11benzy1}piperidinamine N-(1-{4-[(2S)-2,3-dihydr0—1,4- benzodioxin y1]benzy1}piperidiny1) hydroxyacetamide N-(1-{4-[(2S)-2,3-dihydr0—1,4- benzodioxin y1]benzy1}piperidiny1) methoxyacetamide HNROH N-(l-{4-[(2S)-2,3-dihydr0—1,4- 220 (I: benzodioxin zy1}piperidiny1) hydroxymethylpropanamide N-(l-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- 221 b]pyridiny1]benzy1}piperidin yl)hydr0xy methylpropanamide N-(l-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidin y1)hydroxyacetamide N-(l-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- 223 b]pyridiny1]benzy1}piperidin y1) hydroxycyclopropanecarboxamide 1-{4-[(2S)-2,3-dihydr0—1,4- benzodioxinyl]benzy1}(1,1- dioxido—1,2-thiazolidin y1)piperidine 1-(1-{4-[(2S)-2,3-dihydr0—1,4- 225 benzodioxin y1]pheny1 }ethy1)pyrrolidine 4-[(2S)-2,3-dihydr0—1,4- 226 benzodioxin y1]pheny1 }ethy1)m0rpholine 1-(1-{4-[(2S)-2,3-dihydr0—1,4- benzodioxin ny1 }ethy1)piperidine carboxylic acid 1-{4-[(3S)-2,3- N dihydr0[1,4]dioxin0[2,3- 228 N\ O b]pyridinyl]benzyl} I o / methylpiperidinecarb0xy1ic acid 2-(1-{4-[(2S)-2,3-dihydr0—1,4- N benzodioxin 229 CEo y1]benzy1}piperidiny1)—2- 0 HO 0 methylpropanoic acid 2-(1-{4-[(3S)-2,3- 230 N O dihyd.r0.[1,4]dioxin0[2,3.- \ .. | d1ny1]benzy1}p1per1d1n O HO O y1)methy1propanoic acid 0 4-[(1-{4-[(25)-2,3-dihydro-1,4- 231 (I benZOdiOXin-Z— O y1]b€nZy1}piperidin y1)methy1]benz0ic acid 2-{4-[(2S)-2,3-dihydr0—1,4- benzodioxinyl]benzy1}-1,2,3,4- ydroisoquinoline carboxylic acid 4-(1-{4-[(2S)-2,3-dihydr0—1,4- benzodioxin y1]benzy1}piperidiny1)benz0ic acid 4-[(1-{4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidin y1)methy1]benz0ic acid 4-[(3S)-2,3- dihydr0[1,4]dioxin0[2,3- b]pyridiny1]benzy1}piperidin y1)benzoic acid 4'{[{4-[(2S)-2,3-dihydro—1,4— benzodioxin 236 o NK 0 ©:O y1]b€nZy1}(ethy1)amin0]methyl}be nzoic acid 4-[(butyl{4-[(ZS)-2,3-dihydro-l,4- ioxin—Z- CEOOJ/QANAQYOH i yllbenzyl } am1no)methyl]benz01c acid 3-{ 2$)-2,3-dihydro-1,4— benzodioxin—Z- o )N G: yllbenzyl}(ethyl)amino]methyl}be O HO o nzoiC acid 3'[(4'{4-[(25)-2,3-dihydro-1,4- 239 CEOoj/QANK/N benZOdioxin-Z— yl]benzyl }piperazin- l - yl)methyl]benzoic acid In one embodiment, the invention relates to any of the compounds ed in Table l, and pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to a compound selected from the group consisting of: 4-(1- { 4-[(ZS)-2,3-dihydro-l ,4-benzodioxinyl]benzyl}piperidinyl)butanoic acid; 4-(1- { 4-[(3 S)-2, 3-dihydro [ l ,4]dioxino [2,3 -b]pyridinyl]benzyl } piperidinyl)benzoic acid; (3S){4-[(ls,4s)azabicyclo[2.2. l]heptylmethyl]phenyl}-2,3- dihydro[l xino [2,3-b]pyridine; N-(l - { 4- [(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridinyl]benzyl}piperidin yl)methanesulfonamide; (3S) [4-(azepan- l -ylmethyl)phenyl] -2,3-dihydro [ l ,4]dioxino [2,3-b]pyridine; l— { 4- [(28)-2, dro-l ,4-benzodioxinyl]benzyl } methylpiperidine; 7- { 4-[(ZS)-2,3-dihydro-l ,4-benzodioxinyl]benzyl } -l ,7-diazaspiro[4.4]nonane- l - carboxamide; 7-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridinyl]benzyl}-l,7-diazaspiro[4.4]nonan- 2-one; l— { 4- [(28)-2, 3-dihydro-l ,4-benzodioxinyl]benzyl } piperidinecarboxylic acid; (1-{4-[(2$)-2,3-dihydr0—1,4-benzodioxiny1]benzy1}piperidiny1)(m0rpholin han0ne; 8-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}- 1 ,3,8- triazaspir0[4.5]decane-2,4-dione; (3S){4-[(3-meth0xypiperidiny1)methy1]pheny1}-2,3 -dihydr0[1,4]dioxin0[2,3 - b]pyridine; N-(1-{4-[(2$)-2,3-dihydr0—1,4-benzodioxiny1]benzy1}pyrrolidiny1)-N- methylacetamide; 1-{4-[(2$)-2,3-dihydr0—1,4-benz0dioxiny1]benzyl}(1,1-dioxid0—1,2-thiazolidin y1)piperidine; (3R) { 4-[(3 S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}pyrrolidin01; N-(1 -{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1) hydroxyacetamide; 4-[(1- { 4-[(3S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin y1)methy1]benzoic acid; (1- { 4- [(3 S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1)(morpholin- 4-y1)methan0ne; (3S) [4-(morpholiny1methy1)phenyl] -2,3 -dihydr0[1,4]dioxin0[2,3 -b]pyridine; 8-{4-[(2$)-2,3-dihydr0—1 ,4-benz0dioxiny1]benzy1}-2,8-diazaspir0[4.5]decan0ne; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 nzy1}piperidinecarb0nitrile; 1-{4-[(2$)-2,3-dihydr0—1,4-benz0dioxiny1]benzy1}-N-methy1piperidineCarboxamide; 8-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-2,8-diazaspir0[4.5]decan- 1-0ne; N-(1 -{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1) hydroxymethy1pr0panamide; N-(1 -{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1) hydroxycyclopropanecarboxamide; N- { 4- [(28)-2,3 -dihydr0— 1 zodioxiny1]benzy1} -N-ethylcyclopentanamine; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 -y1]benzy1}-N-methy1piperidine carboxamide; WO 25598 N- {4-[(3S)-2,3-dihydr0[1 xin0[2,3-b]pyridinyl]benzy1} -N- methylcyclopentanamine; 1-[( 1 - { 4- [(3 S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin y1)methy1]pyrrolidin0ne; 1-{4-[(ZS)-2,3-dihydr0-1,4-benz0dioxiny1]benzy1}methy1pyrrolidine; N-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}methy1—1-(pyrrolidin prropan:2-annne; N-Cyclohexyl-N- { 4-[(ZS)-2,3-dihydr0-1 ,4-benzodioxiny1]benzy1} -N',N'— dimethylethane- 1 ,2-diamine; N-(1 - { 4- [(3 S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin y1)acetamide; N-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-N-methy1(pyridin y1)ethanamine; (3S)[4-(pyrrolidiny1methy1)pheny1]—2,3 -dihydr0[1,4]dioxin0[2,3 -b]pyridine; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 -y1]benzy1}piperidine-3 -Carboxamide; (3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 -y1]benzy1}piperidinecarb0xamide; N-(1-{4-[(2$)-2,3-dihydr0—1,4-benzodioxiny1]benzy1}pyrrolidin-3 -y1)acetamide; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-N-(2- hydroxyethyl)piperidinecarboxamide; -[4-(1,4-oxazepany1methy1)pheny1]-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridine; 1-{4-[(ZS)-2,3-dihydr0-1 ,4-benz0dioxiny1]benzy1}-N-(2-hydroxyethy1)piperidine carboxannde; 4-[(2$)-2,3-dihydr0—1,4-benz0dioxiny1]benzy1}piperidiny1)benzoic acid; 1-(1-{4-[(2$)-2,3-dihydr0—1,4-benz0dioxiny1]benzy1}piperidiny1)urea; 7-{4-[(2$)-2,3-dihydr0—1,4-benz0dioxiny1]benzy1}-1,7-diazaspir0[4.4]n0nan0ne; 8- { 4-[(3S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridiny1]benzy1 } methy1—2,8- diazaspir0[4.5]decan0ne; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin01; N-(1-{4-[(2$)-2,3-dihydr0—1,4-benzodioxiny1]benzy1}piperidin y1)methanesulf0namide; 2012/028843 3-(1- { 4-[(3S)-2,3-dihydro[l ,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl)propan- 1- (3S) { 4-[(4-methylpiperidin- l -yl)methyl]phenyl } -2,3-dihydro[l ,4]dioxino[2,3- b]pyridine; N- { 4- 2,3 -dihydro[l ,4]dioxino[2,3 -b]pyridinyl]benzyl } -N-ethylethanamine; N-{4-[(3S)-2,3-dihydro[l xino[2,3-b]pyridinyl]benzyl} (methylsulfonyl)piperidinamine; (3S) { 4- [(4-fluoropiperidin- l -yl)methyl]phenyl } -2,3 -dihydro [ l ,4]dioxino[2,3 - b]pyridine; 1-(4- { 4- [(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridinyl]benzyl } -1 ,4-diazepan yl)ethanone; [(3R) { 4- [(28)-2,3 -dihydro- l ,4-benzodioxinyl]benzyl }piperidin-3 -yl] acetic acid; (1- { 4- [(3 S)-2, 3-dihydro[l ,4]dioxino[2, 3-b]pyridinyl]benzyl }piperidinyl)methanol; 4- [( l - { 4- [(28)-2,3 -dihydro-l ,4-benzodioxinyl]benzyl } dinyl)methyl]benzoic acid; (3S) { 4-[(4-methyl-l ,4-diazepan- l -yl)methyl]phenyl } -2,3-dihydro[l xino[2,3- b]pyridine; (3S) { 4- thoxypyrrolidin- l -yl)methyl]phenyl } -2,3 -dihydro [ l ,4]dioxino [2,3- b]pyridine; and N- { 4-[(2$)-2,3-dihydro- l ,4-benzodioxinyl]benzyl } -N,2-dimethylpropanamine; or a ceutically salt thereof of each of the foregoing.
In another embodiment, the invention relates to a compound selected from the group consisting of: (3S) [4-(azepan- l -ylmethyl)phenyl] -2,3-dihydro [ l ,4]dioxino [2,3-b]pyridine; N- { 4-[(3S)-2,3-dihydro[l xino[2,3-b]pyridinyl]benzyl } -N- methylcyclopentanamine; N-(l - { 4- [(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridinyl]benzyl}piperidin yl)methanesulfonamide; (3S) { 4- [(3-methoxypiperidin- l -yl)methyl]phenyl } -2,3 -dihydro[l ,4]dioxino[2,3 - b]pyridine; (3S){4-[(4-methy1piperidiny1)methy1]pheny1}-2,3-dihydr0[1,4]dioxin0[2,3- dine; N-(1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin y1)acetamide; (3S){4-[(1s,4s)azabicyclo[2.2.1]hepty1methy1]pheny1}-2,3- dihydr0[1 ,4]dioxin0 [2,3-b]pyridine; (3S)[4-(pyrrolidiny1methy1)pheny1]—2,3 -dihydr0[1,4]dioxin0[2,3 -b]pyridine; N- { 4- [(3S)-2,3 -dihydr0[1,4]dioxin0[2,3 -b]pyridiny1]benzy1} -N-ethylethanamine; N-(1-{4-[(2$)-2,3-dihydr0—1,4-benzodioxiny1]benzy1}pyrrolidiny1)-N- methylacetamide; N-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}methy1—1-(pyrrolidin prropan:2-annne; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin01; 8-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-2,8-diazaspir0[4.5]decan- 1-0ne; (1- { 4- [(3 S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1)(morpholin- 4-y1)methan0ne; N-(1-{4-[(2$)-2,3-dihydr0—1,4-benzodioxiny1]benzy1}pyrrolidin-3 -y1)acetamide; (3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 -y1]benzy1}-N-methy1piperidine carboxannde; 7-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-1,7-diazaspir0[4.4]n0nan- 2-0ne; (3S)[4-(1,4-oxazepany1methy1)pheny1]-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridine; 4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1)pr0pan 0k 8- { 4-[(3S)-2,3-dihydr0[1 xin0[2,3-b]pyridiny1]benzy1 } methy1—2,8- diazaspir0[4.5]decan0ne; (3S){4-[(4-methy1-1,4-diazepany1)methy1]pheny1}-2,3-dihydr0[1,4]dioxin0[2,3- b]pyridine; 4-(1-{4-[(2$)-2,3-dihydr0—1,4-benz0dioxiny1]benzy1}piperidiny1)benzoic acid; (3R){4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}pyrrolidin01; 1-(4-{4-[(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridiny1]benzy1}-1,4-diazepan none; 1-{4-[(3S)-2,3-dihydr0[1,4]di0Xin0[2,3 -b]pyridin-3 nzy1}piperidinecarb0nitrile; N-(1 - { 4- [(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridinyl]benzy1}piperidinyl) hydroxy-24nedndpropanannde; 1-{4-[(3S)-2,3-dihydr0[1,4]di0Xin0[2,3 idin-3 -y1]benzy1}piperidine-3 -carb0xamide; (1- { 4- [(3 S)-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}piperidiny1)methan01; (3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridiny1]benzyl}-1,3,8- triazaspir0[4.5]decane-2,4-di0ne; N-(1 - { 4- [(3 S)-2,3-dihydr0[1 ,4]di0xin0[2,3-b]pyridiny1]benzy1}piperidiny1) hydroxycyclopropanecarboxannde; 1-{4-[(ZS)-2,3-dihydr0-1 ,4-benz0di0xiny1]benzy1}-N-(2-hydroxyethy1)piperidine carboxannde; N-{4-[(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridinyl]benzy1} (methylsulfony1)piperidinamine; 1-{4-[(3S)-2,3-dihydr0[1,4]di0Xin0[2,3 -b]pyridin-3 -y1]benzy1}piperidinecarb0xamide; 4-(1- { 4-[(3 S)-2, 3-dihydr0 [ 1 ,4]di0Xin0 [2,3 -b]pyridiny1]benzy1}piperidiny1)benz0ic acid; 1-{4-[(ZS)-2,3-dihydr0-1,4-benz0di0xiny1]benzy1}methy1pyrr01idine; 1-[(1-{4-[(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridiny1]benzy1}piperidin y1)methy1]pyrr01idin0ne; 7-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}-1,7-diazaspir0[4.4]n0nan0ne; 1-(1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}piperidiny1)urea; N- { 4- [(28)-2,3 -dihydr0— 1 ,4-benz0di0xiny1]benzy1} y1cyc10pentanamine; N-{4-[(3S)-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}-N-methy1(pyridin y1)ethanamine; 1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}methy1piperidine; 1-{ 4-[(ZS)-2,3-dihydr0-1 ,4-benz0di0xiny1]benzy1}piperidinecarb0xy1ic acid; 4-[(1- { 4-[(3S)-2,3-dihydr0[1 ,4]di0xin0[2,3-b]pyridiny1]benzy1}piperidin y1)methy1]benz0ic acid; (3S) [4-(morpholiny1methy1)phenyl] -2,3 -dihydr0[1,4]di0xin0[2,3 -b]pyridine; (3S) { 4- [(4-fluoropiperidin- l thyl]phenyl } -2,3 -dihydro [ l ,4]dioxino[2,3 - b]pyridine; (l— { 4- [(ZS)-2, 3-dihydro- l ,4-benzodioxinyl]benzyl }piperidinyl)(morpholin yl)methanone; 8- { 4-[(ZS)-2,3-dihydro-l ,4-benzodioxinyl]benzyl } -2,8-diazaspiro[4.5]decanone; N-(1-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridinyl]benzyl}piperidinyl) hydroxyacetamide; 4- [( l - { 4- [(28)-2,3 -dihydro-l ,4-benzodioxinyl]benzyl } piperidinyl)methyl]benzoic acid; N-(l - { 4- [(ZS)-2,3-dihydro-l ,4-benzodioxinyl]benzyl}piperidin hanesulfonamide; l— { 4- [(28)-2, 3-dihydro-l ,4-benzodioxinyl]benzyl } -N-methylpiperidinecarboxamide; 4-(1- { 4-[(ZS)-2,3-dihydro-l ,4-benzodioxinyl]benzyl}piperidinyl)butanoic acid; 7- { 4-[(ZS)-2,3-dihydro-l ,4-benzodioxinyl]benzyl } -l ,7-diazaspiro[4.4]nonane- l - carboxamide; N-cyclohexyl-N- { 4- [(28)-2,3-dihydro-l ,4-benzodioxinyl]benzyl } -N',N'- dimethylethane- l ,2-diamine; [(3R) { 4- [(28)-2,3 ro- l ,4-benzodioxinyl]benzyl }piperidin-3 -yl] acetic acid; 1-{4-[(ZS)-2,3-dihydro-l,4-benzodioxinyl]benzyl}(1,l-dioxido-1,2-thiazolidin yl)piperidine; and l-{4-[(3S)-2,3-dihydro[l,4]dioxino[2,3-b]pyridinyl]benzyl}-N-(2- hydroxyethyl)piperidinecarboxamide; or a pharmaceutically acceptable salt f of each of the foregoing.
In another embodiment, the ion relates a pharmaceutical composition comprising one or more compounds of formula (I) as defined in any of the embodiments above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions are as follows: The term "(C1-C6)alkyl" refers to branched and unbranched alkyl groups having from 1 to 6 carbon atoms. Examples of -(C1-C6)alkyls include methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, n-pentane, iso-pentyl, neopentyl, n-hexane, iso- hexanes (e. g., 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl).
It will be understood that any chemically le carbon atom of the (C1-C6)alkyl group can be the point of attachment to another group or moiety.
The term 6)cycloalkyl" refers to a nonaromatic 3- to 6-membered clic carbocyclic radical. Examples of 6)cycloalkyls" include cyclopropyl, cyclobutyl, cyclohexyl, entyl and cyclohexyl.
As used herein, the term "(C6.C10)aryl" refers to an aromatic hydrocarbon rings containing from six to ten carbon ring and es clic rings and ic rings where at least one of the rings is aromatic. Non-limiting examples of C640 aryls include phenyl, indanyl, l, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl and benzocycloheptenyl.
As used herein, the term "4 to ll-membered heterocycle" includes stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable matic 6 to ll-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical. The 4 to ll-membered heterocycle consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and . The heterocycle may be either saturated or partially unsaturated. Non-limiting examples of matic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, l,l-dioxo-lk6-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of nonaromatic 6 to ll-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting es of nonaromatic 6 to ll-membered bridged bicyclic radicals include 2- azabicyclo[2.2.l]heptanyl, 3-azabicyclo[3.l.0]hexanyl, and 3-azabicyclo[3.2.l]octanyl.
Non-limiting examples of nonaromatic 6 to ll-membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, o[3,4]octanyl, and 7-aza-spiro[3,4]octanyl.
As used , the term "5 to ll-membered heteroaryl" includes aromatic 5 to 6- membered monocyclic heteroaryls and aromatic 7 to ll-membered heteroaryl bicyclic rings where at least one of the rings is aromatic, wherein the heteroaryl ring ns 1-4 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 ll-membered heteroaryl bicyclic rings include benzimidazolyl, l,3-dihydrobenzoimidazol- 2-one, quinolinyl, dihydro-2H—quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, olyl, indazolyl, benzotriazolyl, benzofuranyl, yranyl, ioxolyl, benzoxazolyl and , benzothiazolyl, pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl.
It will be understood that when a heterocyclyl or aryl contains a S ring atom, such S ring atom can be present in the ring in its nt, 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 derivatives. For example, quinolinyl may e decahydroquinolinyl and tetrahydroquinolinyl, naphthyl may include its hydrogenated derivatives such as tetrahydranaphthyl. Other partially or fully hydrogenated derivatives of the aryl and heteroaryl compounds described herein will be nt 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.
The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.
The symbol means point of attachment of a group R to a moiety.
In all 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 e either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain. Such groups can be substituted as herein above described by groups such as oxo to result in definitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
For all 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 s to pharmaceutical preparations, containing as active substance one or more compounds of the invention, or the pharmaceutically able derivatives f, optionally ed with tional excipients and/or carriers.
Compounds of the invention also e their isotopically-labelled forms. An isotopically-labelled form of an active agent of a combination of the present invention is identical to said active agent but for the fact that one or more atoms of said active agent have 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 .
Examples of isotopes which are readily available commercially and which can be orated into an active agent of a combination of the present invention in accordance with well established procedures, include isotopes of hydrogen, carbon, nitrogen, oxygen, 35 phosphorous, fluorine and chlorine, e. g., 2H, 3H, 13C, 14C, N, 18O, 17O, 31F, 32F, S, 18F, and 36Cl, respectively. An active agent of a combination of the present invention, a -48— prodrug thereof, or a ceutically acceptable salt 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 present invention.
The invention includes the use of any compounds of bed above ning 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. All such isomeric forms of these compounds are expressly included in the present invention. Each genic 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 eric form. The invention includes methods using all such tautomers.
The compounds of the invention are only those which are contemplated to be ‘chemically ’ as will be appreciated by those skilled in the art. For example, a compound which would have a ‘dangling valency’, or a ‘carbanion’ is not compounds contemplated by the inventive methods disclosed herein.
The invention includes pharmaceutically acceptable derivatives of compounds of formula (I). A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt 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 metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This es, for example, hydroxylated or oxidized derivative compounds of the invention.
Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids e hloric, hydrobromic, sulfuric, nitric, perchloric, c, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, esulfonic, formic, c, malonic, naphthalenesulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in ing the compounds and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e. g., sodium), alkaline earth metal (e. g., magnesium), ammonium and 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 reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, y ing the desired pharmacological effect.
GENERAL SYNTHETIC METHODS The compounds of the ion 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 R1 to R3 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, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific ures are provided in the tic 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").
Scheme 1: l synthetic scheme for making benzodioxane LTA4H inhibitors OH Br (H‘) —>(R1)T©: O O —. (EVE) o o R2 R3 ( R1 )n Oj/Q///N (RUITCE0 Scheme 2 below depicts the general synthetic procedure for making the compounds of formula (I) wherein X is N ("the 8-azabenzodioxane LTAH4 inhibitors").
Scheme 2: l synthetic scheme for 8-azabenzodioxane LTA4H inhibitors £13111.£1211; £10111 m£11 The es 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 without undue experimentation.
Synthetic Examples General Methods: Unless noted otherwise, all reactions are run at room temperature (about 25 0C), under inert atmosphere (e.g., Argon, N2), and under anhydrous conditions.
All compounds are terized by at least one of the following methods: 1H NMR, HPLC, HPLC-MS, and melting point.
Typically, reaction progress is red by thin layer tography (TLC) or HPLC- MS. Intermediates and products are purified using at least one of the following s: Flash chromatography on silica gel, Recrystallization, Chiral HPLC using a 20 X 500 mm Chiralpak AD-H column, or 20 X 500 mm pak 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 tic mixture of MeOH, isopropylamine (IPA), and super critical carbon dioxide at 125 bar; 80 mL/min, and/or Reversed phase HPLC using a C18 semi-preparative column eluting with a gradient of MeCN+0. 1% TFA /HZO+0.1% TFA, or MeCN+0.1% formic acid /HZO+0. 1% formic acid. 2O The reported MS data is for observed [M+H]+. For bromine containing compounds, the [M+H]+ is either ed for one or both of the bromine isotopes (i.e., 79Br and 81Br).
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 retention times (RT).
LC/MS Time Mobile Phase Flow Column Method (min) (mL/min) H20 CH3CN (&1%FA)(&1%FA) 0 95 5 2.5 Agilent Zorbax C18 SB 3.5um 4.6x30mm cartridge 2.1 95 5 2.5 2.3 95 5 2.5 0 70 30 2.5 1‘7 5 95 2‘5 Agilent Zorbax C18 SB 3.5um 2 5 95 2.5 46x30nnncanndge. 2.1 70 30 2.5 2.3 70 30 2.5 0 99 1 2.5 17 50 50 25 AgflngQmaXC18SB35um 2 5 95 25 46x30nnncanfidge 2.1 5 95 2.5 2.3 99 1 2.5 0 95 5 1.5 7 5 95 1.5 Agllent Zorbax Echpse XDB-CS. . 9 5 95 L5 5un146x150nnn 9.3 95 5 1.5 95 5 1.5 0 99 1 2.5 1.6 80 20 2.5 L7 5 95 25 AgflngQmaXC18SB35um 2 5 95 25 46x30nnncanfidge 2.1 99 1 2.5 2.3 99 1 2.5 0 99 1 1.5 2 80 20 1.5 7 5 95 1.5 Agilent Zorbax Eclipse XDB-CS 9 5 95 L5 5un146x150nnncohnnn 9.3 99 1 1.5 99 1 1.5 0 88 12 1.5 025 70 30 L5 AgflentSB-ClS‘L8un13x50nnn 03 60 40 L5 cohnnn 95 1.5 0 100 1.5 0 60 40 1‘5 t Eclipse C8 1.8um L19 15 85 L5 3X50ancohnnn L75 0 100 L5 0 95 5 1.5 8:5 :8 :8 i: Agilent SB-AQ 1.8um 3X50mm cohnnn 1.3 10 90 1.5 1.7 0 100 1.5 0 95 5 1.5 Agilent SB-C18 1.8um 3X50mm 3.8 10 90 1.5 column 4.5 0 100 1.5 Table 2b. LC/MS Methods and retention times (RT).
LC/MS Time Mobile Phase Flow Column Method (min) (mL/min) 95% H20 2+ 5% CH3CN CH3CN (0.05 % (0.05 %F0rmic Formic Acid) Acid) 0 90 10 0‘8 BEH 2.1X50mm C18, 11 1‘19 5 95 0‘8 1 7um particle diameter 1.7 5 95 0.8 ‘ 0 90 10 0‘8 BEH 2.1x50mm C18, 12 1‘19 0 100 0‘8 1 7um particle er 1.7 0 100 0.8 ‘ 0 95 5 0.6 Waters HSS T3 13 4.45 0 100 0.6 2.1X100mm 18 um 0 100 0.6 column 0 100 0 0‘6 Waters HSS T3 1 100 0 0‘6 14 2 1X100mm 18 um 4.45 0 100 0.6 column 0 100 0 90 10 0‘6 BEH 2.1x50mm C18, 4‘45 0 100 0‘6 1 7um particle diameter 4.58 0 100 0.6 ‘ Synthesis of ediates Preparation of (S)(2,3-Dihydro-benzo[1,4]dioxinyl)-benzaldehyde (A) Br Y OH Br OH Br on 0 Br OH o o YO Br 0 Br Br 0 ailOH To a stirred on of pyrocatechol (23.8 g, 216 mmol) in acetone (300mL) is added cesium carbonate (84.4 g, 259 mmol) and 2-Bromo(4-bromo-phenyl)-ethanone (60 g, 216 mmol) at room temperature. The reaction is stirred at room temperature 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 400C for 45 min, cooled to room temperature and diluted with EtOAc (250 mL). The organic solution is washed with water (2 x 100mL), 0.25N HCl (100mL), saturated sodium onate solution (100mL), and brine (100mL), and dried over NaZSO4. After l 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), )-(+)-N-(4- Toluenesulfonyl)-1,2-diphenylethylenediamine (756 mg, 2.10 mmol) and Pentamethylcyclopentadienylrhodium(III)dichloride (Cp*RhClz) dimer (319 mg, 0.520 mmol). The resulting mixture is stirred at 00C for 20 minutes under argon sparging and treated dropwise with formic acid/triethylamine complex (5:2, 31 mL, 72 mmol). The reaction e is stirred under argon at 00C for 2 hours, diluted with EtOAc (600mL), and washed with half-saturated sodium bicarbonate solution, saturated sodium bicarbonate, and brine. The organic layer is dried over NaZSO4and 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 LiOHonO (5.8 g, 137 mmol) in water (125 mL). The mixture is stirred at 600C for 30 min, cooled to room ature and concentrated. The residue is diluted with water and neutralized with 1N aqueous HCl to a pH of 6. The resulting mixture is ted with EtOAc (3 x 150 mL). The combined organic extracts are washed by ted sodium bicarbonate solution, brine, dried over NaZSO4, filtered and concentrated to give A-4 as an oil.
To a 00C on of triphenylphosphine (32.7 g, 125 mmol) and diisopropyl azodicarboxylate (24.7mL, 125 mmol) in THF (anhydrous, 400 mL) is added a solution of A-4 (35 g, 113 mmol) in THF rous, 200 mL) over 30 min. The resulting solution is warmed to room temperature, stirred for 1 hour, and concentrated. The residue is usly stirred in heptane (1.8 L) for 2 hours. The precipitate is filtered, and rinsed with heptane. The filtrate is trated and purified by flash column chromatography on silica 2O gel (0-10% EtOAc in heptane) to give A-5 as a solid.
To an 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)3) (2.9 g, 3.2 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (3.5 g, 6.3 mmol). The ing mixture is sparged with argon and stirred at 800C overnight. The reaction is cooled to room temperature 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 d 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 (1L), and filtered to give A-6 as a solid.
WO 25598 A solution of A-6 (11.1 g, 46.7 mmol) in THF (anhydrous, 400 mL) at 00C is treated dropwise with DIBAL-H (25 wt% in toluene, 77.8 mL, 117 mmol). The on is stirred at 00C for 30 min, warmed to room temperature and stirred for 2 hours. The reaction is cooled down to 00C 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, 1N HCl solution, and brine, and dried over . 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.
Preparation of (i)(2,3-Dihydr0-benz0[1,4]di0xinyl)-benzaldehyde (B) gmfiamfimg ~ agWioth 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 1N 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 t is synthesized from B-l according to the procedure described for the synthesis of A from A-4.
Preparation of (S)(2,3-Dihydr0-[1,4]di0xin0[2,3-b]pyridinyl)-benzaldehyde (C) El W4 Ufl ,, fl UZJ’U * 6;er a 1;;900 c-s c-4 To a solution of 2-chlorohydroxy-pyridine (25.0 g, 193 mmol) and 2,4’-dibromo- acetophenone (53.6 g, 193 mmol) in acetone (400 mL) is added C82CO3 (75.4 g, 232 mmol), and the suspension is d at room temperature for l h. The reaction is poured into 1L of water with stirring. tion of the mixture gives C-l as a solid.
A solution of C-1 (30.0 g, 91.9 mmol), Cp*RhClz dimer (0.57 g, 0.92 mmol) and N- R)Amino-l,2-diphenyl-ethyl)methyl-benzenesulfonamide (1.0 g, 2.8 mmol) in anhydrous DMF (400 mL) is cooled to 0 OC 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 0C with Argon sparging for 1 hr. The reaction mixture is slowly added to 1.5L of usly 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 600C, 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 temperature, quenched with water, concentrated in vacuo and extracted with EtOAc. The combined organics are washed with brine, dried over , filtered and concentrated. The residue is purified by flash column tography (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 800C overnight. The reaction is then cooled to room temperature and stirred for 48h. The e is filtered through a bed of Diatomaceous earth, and the filtrate slowly poured into 1 L of vigorously stirred water.
The resulting solid is isolated by tion 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 00C 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 on is stirred at 00C for 30 min and then allowed to warm to room temperature. The reaction mixture is stirred for 2h at room temperature. The reaction is cooled to 0 OC and carefully quenched with EtOAc (200 mL , followed by 100 mL of water and 400 mL of saturated aqueous Rochelle‘s salt 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 ed and washed with 0.5 N HCl (100mL). Some product is observed in the acid layer. Acid layer is cooled to 0°C, neutralized with saturated NaHCOg, and extracted with EtOAc twice. The organic layers are combined, washed with brine, and dried over anhydrous NaZSO4, and evaporated. The resulting residue is ed by flash chromatography eluting with 0-80 % EtOAc/Heptane to give the title compound as a solid.
Preparation of (i)(2,3-Dihydr0-[1,4]dioxin0[2,3-b]pyridinyl)-benzaldehyde (D) N CI U E" 0 O N\ Cl Br N\ I OH / O C-1 D-1 D-2 //N H _. N\ o —> ENIO D-S D Compound D-l is synthesized from C-l ing to the procedure described for the synthesis of B-l.
The title compound is sized from D-l according to the procedure described for the synthesis of C from C2 Preparation of 2,2,2-triflu0r0piperidinyl-ethanol (E) F OH 3L :>L E1 E2 E A solution of E-l (500 mg, 2.00 mmol) and hyl(trif1uoromethyl)silane (TMSCF3) (863 mg, 6.00 mmol) in dry DMF (2 mL) is cooled to -25 0C and treated with 1,3-bis(1- adamantyl)imidazolylidene (3.4 mg, 0.010 mmol). The mixture is warmed to room temperature, stirred for lb, 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/HZO 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 d under an atmosphere of H2 at room temperature 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.
Preparation of 1,1,1,3,3,3-Hexafluoropiperidinyl-pr0panol (F) F F HO O OH OH CFS CFS CFS CFS F F _’ O O —> —> >_ > GAO/\Ph F-1 F-2 F-3 F A solution of dine-l,4-dicarboxylic acid monobenzyl ester (1.0 g, 3.80 mmol), 2,3,4,5,6-pentaf1uoro-phenol (0.77 g, 4.18 mmol) and ohexyl-carbodiimide (0.86 g, 4.18 mmol) in dioxane (12 mL) is stirred at room temperature for 16 h. The mixture is filtered and trated in vacuo. The residue is purified by flash chromatography (EtOAc/heptane) to give F-2.
To a on of F—2 (200 mg, 0.47 mmol) in DME (1.0 mL) is added TMSCF3 (139 mg, 0.98 mol) and tetramethylammonium fluoride (43 mg, 0.47 mmol) at -50°C. The resulting mixture is allowed to warm to room temperature 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 atmosphere of H2 at room temperature 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).
Preparation of 4-methyl-piperidine-carboxylic acid methyl ester hydrochloride (I-1) HCI o #06» 4 9% 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 e is dissolved in MeOH (3mL), and the stirred solution is treated with EtzO (45 ml). The resulting solid is ed and dried to give the title compound.
The following intermediates are also prepared according to the procedure described for the synthesis of I-l: Intermediate Structure 1-2 HCI HNCZ—(oo/ 1-3 HCI "CWF 0 I-4 HCI 1-5 HCI HN\%o I-6 HCI oro\ Synthesis of Compounds of Formula I General Method A throu h E rotocols for reductive amination .
Example of General Method A: Preparation of (2,3-Dihydro-[1,4]dioxino[2,3-b]pyridinyl)-benzyl]-2,8- diaza-spiro[4.5]decanone (Example 125) H—CI O CMmI O CMmI H N N o + —> N\0 N |\ ' o / /o o TEA (0.12mL, 0.83 mmol) is added to a mixture of C (100 mg, 0.42 mmol) and 2,8-Diaza-spiro[4.5]decanone; 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/HZO (1:1). The mixture is purified on a reverse phase C18 semi-preparative HPLC column eluting with a gradient of 0-95% MeCN/HZO to give the title product.
Example of l Method B: Preparation of (i)[4-(2,3-Dihydro-benzo[1,4]dioxinyl)-benzyl]-piperazine carboxylic acid tert-butyl ester GiffO0 O N/A\L O _, aggrfl To a on of B (100 mg, 0.420 mmol), and piperazine-l-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 temperature for 10 min, d with sodium triacetoxyborohydride (141 mg, 0.67 mmol), and stirred at room temperature for 16 hours. The reaction is diluted with saturated aqueous sodium onate (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers is washed with brine, dried over NaZSO4, filtered and concentrated. The residue is purified on a reversed phase C18 reparative HPLC column eluting with a gradient of 5-85% MeCN+0.1%TFA /HZO+0.1%TFA). The combined fractions are concentrated and basified by saturated aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (5 mL x 3). The ed organic phases is washed by brine, dried over NaZSO4, filtered, and concentrated to give the title product.
Example of General Method C: Preparation of 4-{1-[(S)(2,3-Dihydro-benzo[1,4]dioxinyl)-benzyl]-piperidin ylmethyl}-benzoic acid methyl ester H / CCo + (Io A HCI A solution of A (100 mg, 0.42 mmol), 4-piperidinylmethyl-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 temperature 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: ation of 1-[4-(2,3-Dihydro-benzo[1,4]dioxinyl)-benzyl]-piperidine ylic acid methylamide le 25) : offlogVol A solution of B (40mg, 0.l7mmol) and piperidinecarboxylic acid methylamide (47.2mg, mol) is treated with acetic acid (0.01mL). After shaking for 1 hour, a solution of sodium triacetoxyborohydride (70.6mg, 0.33mmol) in DMA (0.5mL) is added and the WO 25598 ing mixture is shaken overnight. The mixture is concentrated, diluted with DMSO (0.8 mL), ed and purified on a C18 semi-preparative HPLC column eluting with a gradient of 5-85% MeCN+0. l %TFA /HZO+0. l %TFA) to provide the title compound.
Example of General Method E: Preparation of 4-{[(S)(2,3-Dihydr0-benz0[1,4]di0xinyl)-benzylamin0]-methyl}- benzoic acid methyl ester H O O O n o O O —’ + (Io O\ HQN HCI A solution of A (310 mg), methyl 4-(aminomethyl)benzoate hydrochloride (338 mg), sodium cyanoborohydride (162 mg), and DIPEA (0.3 mL) in MeOH (5 mL) is treated with 2 drops of acetic acid, and the ing mixture is stirred at room temperature 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 prepare Examples 1-191 according to general methods A, B, C, D, E, or F as depicted in the reaction below.
X0 H'A_> \ /O O where H-A is. R4\ /R5 N or H B Table 3: Exam less nthesizedb General MethodA B C D E orF Chirality Synthesis + Rt [Mm] at * Method (min) c 296.2 1.20 racemic 312.2 1.20 racemic 33 8.4 1.20 racenfic 379u4 1.10 racenfic 328u4 1.11 racemic 322.4 1.13 racenfic 36(14 1.40 381.3 0.67 racemic 312.4 1.04 racemic 407.4 1.14 racenfic 353.40 1.47 12 C11 racenfic \‘N #;::> m: B 10 353.40 1.57 417.40 1.62 381.40 1.57 racemic 297.40 0.97 racemic 349.40 2.14 c 361.20 1.66 racemic 313.40 0.89 354 52 (155 354 24 (156 408.26 0.71 476.23 0.77 23 CH racemic /’HW< 11 298.2 0.7 24 CH racemic 11 298.2 0.73 racemic 367.3 0.66 racemic 396.3 0.73 racemic 340.2 0.66 racemic 368.3 0.72 racemic 368.5 0.7 CH ' racemlc K/NS 11 339.2 0.56 31 CH racemic /N 11 367.2 0.65 32 CH racemic k0S 11 326.2 0.67 .\lTl/VO\ 33 CH racemic 11 314.2 0.71 34 CH racemic 11 312.2 0.65 "_ "NH CH racemic 11 394.2 0.65 36 CH . racemlc N/:// 11 312.4 0.68 \N (\O 37 CH racemic My 11 423.3 0.69 \‘N O 38 CH racemic 11 395.3 0.70 racemic 388.2 0.66 racenfic 324 3 0X79 racemic 310.2 0.78 racenfic 361.2 0X79 CH racemic 296.2 0.75 racemic 402.3 0.82 racemic 298.2 0.75 racemic 306.8 0.73 c 326.2 0.74 racenfic 403.2 0371 2012/028843 " VD 49 CH racemic 11 367.2 0.68 50 CH racemic Q 11 407.3 0.73 51 CH racemic N\ 11 381.3 0.73 52 CH racemic N\/\OH 11 397.3 0.67 53 CH racemic 368.2 0.67 54 CH . racemlc H | 11 333.2 0.66 55 racemic 336.2 0.59 56 4023 (175 57 3541, (163 58 370.2 0.70 59 354.2 0.66 60 314.3 0.63 WO 25598 340.1 0.61 367.9 0.61 368.2 0.64 353.8 0.63 353.1 0.63 367.1 0.64 337.8 0.78 323.9 0.73 339.8 0.66 353.9 0.67 284.3 0.68 313.6 0.70 WO 25598 283.8 0.7 283.9 0.67 269.8 0.65 340.2 0.65 310.2 0.70 325.9 0.65 327.1 0.61 367.9 0.76 311.7 0.71 352.9 0.64 366.9 0.67 336.2 0.73 85 CH 11 363.8 0.76 WO 25598 366.9 0.63 354.4 0.68 313.3 0.64 353.9 0.70 340.8 0.59 311.8 0.57 311.1 0.75 339.1 0.49 -- 39 94 CH 11 407.2 0.63 WO 25598 95 CH *N/3 11 377.8 0.78 "‘N HfOH 96 CH 11 397.3 0.56 97 CH NO 11 339.8 0.65 98 CH mgo/ 11 340.2 0.63 99 CH "(DVD 11 407.4 0.62 338.2 0.76 325.8 0.62 325.7 0.6 326.3 0.61 395.2 0.8 353.9 0.66 353.9 0.67 325.9 0.61 WO 25598 108 CH 5 Hfio 11 352.9 0.56 109 CH 5 NO 11 338.4 0.71 110 CH 5 ‘NCN— 11 353.1 0.44 348.1 0.64 112 374.1 0.66 113 CH Racemic 354.4 1.1 114 CH Racemic 353.4 1.0 115 CH Racemic 314.4 1.0 393.1 1.3 365.4 1.3 393.4 1.2 393.4 1.1 WO 25598 O / 120 CH "N: >2 N) 7 407.3 0.7 121 CH ""NOéN/ 13 393.4 1.1 \ (32:3... 122 CH 7 429.5 0.7 408.3 0.6 390.3 0.7 380.4 0.4 297.2 0.4 366.2 0.4 128 CH 11 423.3 0.6 129 N 11 394.2 0.4 WO 25598 130 N "Now 11 408.3 0.5 131 CH "NW0 RN 11 3392‘ 06‘ 132 N :1 13 340.2 0.9 N o 133 N .. 11 328.2 0.4 134 CH "who" 13 382.4 0.6 135 N ‘N 11 311.1 0.52 354.1 0.42 325.1 0.53 362.1 0.51 325.1 0.52 285.3 0.43 299.1 0.47 142 N )NC 11 325.1 0.53 2012/028843 143 N O 11 340.1 0.31 ‘N "'0" 144 N 11 313.1 0.41 145 N (1 11 323.1 0.49 146 N --N::>—/ 11 341.1 0.43 313.1 0.41 368.1 0.41 369.1 0.47 327.1 0.44 397.1 0.51 368.1 0.42 368.1 0.42 398.1 0.40 155 N ---NC>*F 11 329.1 0.47 WO 25598 \\ /N\ 156 N "(EL/N 11 350.1 0.56 157 N H ‘N 11 368.1 0.40 341.1 0.48 336.1 0.44 368.1 0.41 361.0 0.65 424.1 0.46 163 N {VD—filo 11 408.1 0.47 164 N __N N—O\ 11 313.1 0.45 \ [p 167 N NON—s, 11 404.1 0.45 H lo 168 N 11 327.1 0.46 WO 25598 169 11 418.1 0.47 385.1 0.50 396.1 0.47 389.1 0.43 297.1 0.48 403.2 0.69 368.4 0.55 403.2 0.90 336.2 0.85 368.0 0.98 367.2 1.02 423.3 1.03 395.9 1.13 \N OH 182 CH m 15 368.2 1.04 368.2 1.05 354.2 0.99 354.4 2.09 327.1 2.13 369.2 2.09 390.4 2.22 355.1 2.16 404.2 2.16 191 CH 5 HNWOH A 14 353.8 0.63 Examples 192 and 193: Preparation of (S)[4-(2,3-Dihydr0-benz0[1,4]di0xinyl)- benzyl]-piperidinol (192), and (R)[4-(2,3-Dihydr0-benz0[1,4]di0xinyl)- benzyl]-piperidinol (193). 192 193 A racemic mixture of 192 and 193 is ed from intermediate B and 4- hydroxypiperidine 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- g 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 10; Rt = 0.98 min.; [M+H] + = 326.4.
Examples 194 and 195: Preparation of 8-[(S)(2,3-Dihydr0-benz0[1,4]di0xinyl)- benzyl]-2,8-diaza-spir0[4.5]decanone (194) and (8-[(R)(2,3-Dihydro- 1,4]di0xinyl)-benzyl]-2,8-diaza-spir0[4.5]decan0ne (195) N 0 0 oO ~H ~H O O 194 195 Compound 4 (racemate) is ed 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.
Examples 196 and 197: Preparation of 1-[(S)(2,3-dihydr0-benz0[1,4]di0xinyl)- benzyl]-pyrrolidine (196) and 1-[(R)(2,3-dihydr0-benz0[1,4]di0xinyl)-benzyl]- pyrrolidine (197). (130NO @jrgb Compound 1 (racemate) is resolved by HPLC using a Chiralpak AD-H column, and eluting with 7% IPA 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: 2O LC/MS Method 10; Rt = 1.21 min.; [M+H] + = 296.2.
WO 25598 Examples 198 and 199: Preparation of 4-[(S)(2,3-dihydro-benzo[1,4]dioxinyl)- ]—m0rpholine (198) and 4-[(R)(2,3-dihydr0-benz0[1,4]di0xinyl)-benzyl]- morpholine (199). (101/0o K/o (I Jo K/o 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: Preparation of (S)[4-(2,3-dihydr0-benz0[1,4]di0xinyl)- benzyl]-piperidinecarb0xylic acid (200) and (R)[4-(2,3-Dihydr0- benz0[1,4]di0xinyl)-benzyl]-piperidinecarb0xylic acid (201). (if: H0fi~<1§rgofi ~ (mono? + muggy; l 1 who? mono? 1-[4-(2,3-Dihydro-benzo[1,4]dioxinyl)-benzyl]-piperidinecarboxylic acid ethyl ester is prepared from ediate B and ethyl isonipecotate ing to the procedure described in General Method B, and resolved by HPLC using a pak OD-H column, and eluting with 12% IPA in heptanes with 0.1% DEA to give (S)[4-(2,3-dihydro- benzo[1,4]dioxinyl)-benzyl]-piperidinecarboxylic acid ethyl ester as the first-eluting peak, and (R)[4-(2,3-dihydro-benzo[1,4]dioxinyl)-benzyl]-piperidinecarboxylic acid ethyl ester as the second-eluting peak.
(S)[4-(2,3-Dihydro-benzo[1,4]dioxinyl)-benzyl]-piperidinecarboxylic 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 750C for 2h. The reaction mixture is acidified with TFA (300 uL). 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.
WO 25598 Compound 201 is prepared from (R)[4-(2,3-Dihydro-benzo[1,4]dioxinyl)-benzyl]— piperidinecarboxylic 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 ation of 4-[4-(7-Flu0r0-2,3-dihydr0-benz0[1,4]di0xinyl)-benzyl]-m0rpholine (202) F O \Q: \o Br + _ —> F. : :OH O (Ema/G?" a";fag" G-3 Br A on of 4-f1uoromethoxy-phenol (3.0 g, 21.1 mmol) in acetone (250 mL) is treated with cesium carbonate (8.3 g, 25.3 mmol) followed by o(4-bromo-phenyl)- ethanone (5.9 g, 21.1 mmol). The resulting mixture is stirred at room temperature for 2 h.
Water (600 mL) is added slowly to the vigorously stirring solution. After ng for 30 minutes, the precipitate is filtered off and washed with copious water to give 1-(4-bromo- phenyl)(4-f1uoromethoxy-phenoxy)-ethanone (G- 1).
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 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, trated, and purified by flash column chromatography on silica gel (0 to 50% EtOAc in heptane) to provide 1-(4-bromo-phenyl)- 2-(4-fluorohydroxy-phenoxy)-ethanone (G-2).
To a solution of G—2 (1.25g, 3.85 mmol) in EtOH (25 mL) is added sodium borohydride (291 mg, 7.69 mmol), and the mixture is stirred at room temperature for 2 h. Water (5 mL) is added, and the resulting e is stirred at room ature for 1 h. The reaction mixture is concentrated, and the residue is dissolved in 1N HCl and extracted with EtOAc.
The organic layer is washed with brine, dried over sodium e, and concentrated. The e is purified by flash column chromatography on silica gel (0 to 40% EtOAc in heptane) to provide 2-[2-(4-bromo-phenyl)hydroxy-ethoxy]f1uoro-phenol (G-3). nylphosphine (918 mg, 3.5 mmol) is dissolved in THF (25 mL) and cooled to 0°C.
Diisopropyl azodicarboxylate (0.7 mL, 3.5 mmoL) is added to the mixture and d at 0°C for 20 minutes. The mixture is then treated dropwise over 5 minutes with a solution of G—3(1.1 g, 3.33 mmol) in THF (10 mL), and the resulting mixture is stirred at 0°C for 30 minutes and at room temperature 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)f1uoro-2,3-dihydro-benzo[1,4]dioxine (G-4). 2O A solution of G-4 (200 mg, 0.65 mmol), ium (morpholinyl)methyltrif1uoroborate (134 mg, 0.65 mmol), palladium(II) acetate (4.3 mg, 0.019 mmol), 2- dicyclohexylphosphino-2’,4’,6’-tri-isopropyl-1,1’-biphenyl (19 mg, 0.039 mmol), and cesium carbonate (632 mg, 1.9 mmol) in 10:1 THF/water (2 mL) is d at 95°C for 18 h under an atmosphere of nitrogen. The mixture is taken up in EtOAc, and the organic layer is washed with water, brine, dried over NaZSO4, and concentrated. The residue is purified by preparative C18 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: Preparation of 1-[4-(7-Flu0r0-2,3-dihydro-benz0[1,4]di0xinyl)- benzyl]-pyrrolidine (203) F o (BFBK U.) N F o + a —’ UOTOAD 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: Preparation of (S)(4-Morpholinylmethyl-phenyl)-2,3- o-[1,4]di0Xin0[2,3-b]pyridine (204) and (R)(4-Morpholinylmethyl- phenyl)-2,3-dihydr0-[1,4]di0xin0[2,3-b]pyridine (205). '/o pon/QANQONOANQOfigo (10]. 18 204 Compound 18 (racemate) is resolved by HPLC using a cel 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: Preparation of 1-{4-[(3S)-2,3-dihydr0[1,4]di0xin0[2,3- dinyl]benzyl}piperidinecarb0xamide (206) and 1-{4-[(3R)-2,3- dihydro[1,4]di0xin0[2,3-b]pyridinyl]benzyl}piperidinecarboxamide (207).
The racemic form of 1-[4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl)-benzyl]- piperidinecarboxylic acid amide is prepared from compound 4-(2,3-dihydro- [1,4]dioxino[2,3-b]pyridinyl)-benzaldehyde and dinecarboxylic acid amide according to the general method B. Compounds 206 and 207 are resolved from the corresponding racemic compound by chiral HPLC ing to the procedure described for Examples 204 and 205: N O NH Table 4. Preparation of compounds 206 and 207.
Chirality at MS Ex # [M+H]+ rt (min) * Method 206 S 15 354.2 0.47 207 R 15 354.2 0.45 Example 208: Preparation of 11-[4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl)- benzyl]-pyrrolidinone (208) (7804526_1):KZA O OH N o N o \ \ I _> —> /’ / o o D H-1 N o N o ‘ ‘ | | /’ /’ o o H-2 208 A solution of D (1.0g, 4.15 mmol) in THF (50mL) is treated with sodium borohydride (188 mg, 5.00 mmol) at 0°C. The resulting mixture is allowed to warm to room ature and stirred at room temperature for 1h. The reaction mixture is concentrated and the residue dissolved in EtOAc. The c 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-[1,4]dioxino[2,3- b]pyridinyl)-phenyl] -methanol H- 1.
A solution of H-l (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 temperature, and the resulting mixture is stirred at room temperature 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 e (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 e (60% dispersion in mineral oil, 7.8 mg, 0.2 mmol), and the mixture is stirred at room temperature for 15 minutes. Intermediate H-2 (50 mg, 0.16 mmol) is added, and the mixture is d at 500C. After 15 minutes, the mixture is quenched with water and extracted with EtOAc. The organic layer is concentrated, and the residue is ed by reversed phase HPLC g with a gradient of 5-85% of MeCN in H20 2012/028843 (+0.1%TFA). The desired fractions are concentrated. The residue is dissolved in EtOAc, washed with saturated aqueous NaHCOg, brine, and dried over NaZSO4. 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-dihydr0[1,4]di0xin0[2,3-b]pyridinyl)benzyl]-1,3-0xazolidin- 2-0ne (209) EX,N\ org \\/ 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: Preparation of 4-(2,3-Dihydr0-[1,4]di0xin0[2,3-b]pyridinyl)- benzylamine (210) N3 NH2 N 0 \ _> N o _, N o O / / O O H-1 H-3 210 A solution of H-l (340 mg, 1.4 mmol), triphenylphosphine (550 mg, 2.1 mmol) and diphenylphosphophyl azide (0.45 mL, 2.1 mmol) in ous THF (30 mL) is treated with diisopropyl azodicarboxylate (0.41 mL, 2.1 mmol). The reaction is stirred at room temperature for 24 hours, diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined c on is washed with brine, dried over NaZSO4, filtered and concentrated. The e is purified by flash chromatography eluting with a gradient of -50% EtOAc in Heptane to give H-3 as an oil.
A on 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 40C for 24 hours, cooled to room temperature, diluted with water (25 mL), and extracted with EtOAc (3 x 25 mL). The combined organic on is washed with brine, dried over NaZSO4, filtered, and concentrated. The e is purified by reversed phase HPLC eluting with a gradient of 5-85% MeCN in H20 TFA). The combined fractions is concentrated, basified with saturated aqueous NaHC03 (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic phase is washed with brine, dried over NaZSO4, 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: Preparation of 1-[(S)(2,3-Dihydr0-benz0[1,4]di0xinyl)-benzyl] methyl-piperidinecarb0xylic acid (211) H HN O N : O + :o O/—>©:O O/ N o (10 O" o 211 Intermediate A (100 mg, 0.42 mmol), methyl-piperidinecarboxylic 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 d for 4h. The mixture is diluted with saturated NaHC03 and extracted with EtOAc. The organic layer is washed with brine, dried over NaZSO4, filtered, and concentrated. The e is purified by flash chromatography eluting with a gradient of 0-3% MeOH in DCM to give 1- [(S)(2, 3-dihydro-benzo [ l ,4]dioxinyl)-benzyl] methyl-piperidinecarboxylic acid methyl ester.
A solution of 1-[(S)(2,3-dihydro-benzo[1,4]dioxinyl)-benzyl]methyl-piperidine carboxylic acid methyl ester in MeOH (2 mL) is treated with a solution of LiOH-HZO (52 mg, 1.23mmol) in water (2 mL). The mixture is heated to 70°C for 2h, concentrated, and treated with TFA (96 uL, 1.23 mmol). The e is d with water and extracted with EtOAc/THF. The c layer is dried over NaZSO4, 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 salt (LC/MS method 1: ES+ m/z 368.23 [M+H]+; Rt = 0.62 min).
Examples 212-215: Preparation 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. (100 Table 5. Preparation of compounds 212-215.
Ex # MS Method Rt (min) 212 0.62 213 0.61 214 0.61 215 1 341.23 0.58 Example 216: Preparation of, 1-[(S)(2,3-Dihydr0-benzo[1,4]di0xinyl)-benzyl]—4- (1H-tetrazolyl)-piperidine (216). @130O\ * armor/"N~N’ 177 216 To a solution of 177 (115 mg, 0.34 mmol) in DMF (2 mL) is added NaN3 (89.0 mg, 1.38 mmol) and NH4Cl (147 mg, 2.75 mmol). The mixture is heated at 120°C for 18 h.
Additional NaN3 (89.0 mg, 1.38 mmol) is added, and the reaction is d 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 e the title compound (LC/MS method 1: ES+ m/z 378.2 [M+H]+; Rt = 0.54 min).
Example 217: Preparation of 1-[(S)(2,3-Dihydr0-benz0[1,4]di0xinyl)-benzyl]— dinylamine (217). air/Ad)H 2(1quQ A solution of intermediate A (300 mg, 1.25 mmol) and piperidinyl-carbamic acid tert- butyl 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 18h. The reaction is concentrated and partitioned between EtOAc and saturated aqueous NaHCOg. The organic layer is dried over , 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 (1 mL), d with HCl (10 mL, 4M in dioxane), and stirred for 18h. The reaction is diluted with EtzO (40 mL) and filtered to provide the title nd as the HCl salt (LC/MS method 1: ES+ m/z 325.2 [M+H]+, Rt = 0.35 min).
Example 218: Preparation of N-{1-[(S)(2,3-Dihydr0-benz0[1,4]di0xinyl)- benzyl]-piperidinyl}hydroxy-acetamide (218).
We.UNH —’ N O o OH 2 MW 218 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 on is filtered and purified by reversed phase HPLC eluting with a gradient of 0-80% MeCN in water (+0.1%TFA) to e the title compound as a TFA salt (LC/MS method 1: ES+ m/z 383.2 [M+H]+, Rt = 0.59 min).
Example 219-220: Preparation of N-(1-{4-[(ZS)-2,3-dihydr0-1,4-benz0di0xin yl]benzyl}piperidinyl)meth0xyacetamide (219) and N-(l-{4-[(ZS)-2,3-dihydr0- nz0di0xinyl]benzyl}piperidinyl)hydr0xymethylpr0panamide (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.
MS Rt EX # X ---R [M+H]+ Method (min) 219 CH ",LJ\/O\ 1 397.08 0.61 220 CH "’ROH 1 411.30 0.55 222 N [,U\/OH 1 384.22 0.43 223 N ,/ ESOH 1 410.26 0.47 e 224: Preparation of 1-[(S)(2,3-Dihydr0-benz0[1,4]di0xinyl)-benzyl] (1,1-di0x0isothiazolidinyl)-piperidine (224). avg @630 0 $0 O O p 217 l jAO\TI\s}ON o To a stirred solution of compound 217 (535 mg, 1.65 mmol) in THF (10 mL) is added 3- chloro-propane-l-sulfonyl de (0.40 mL, 3.3 mmol) and pyridine (0.27 mL). After 18 h, the mixture is diluted with saturated NaHC03 and extracted with EtOAc. The organic layer is dried over NaZSO4, filtered, and trated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to e 3-chloro- propane- l -sulfonic acid { l- [(S)(2,3 -dihydro-benzo [l ,4]dioxinyl)-benzyl] -piperidin- 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)(2,3-dihydro- benzo[l,4]dioxinyl)-benzyl]-piperidinyl}-amide (410 mg, 0.88 mmol) in DMF (5 mL) is added NaH (60% dispersion in mineral oil, 71 mg, 1.8 mmol). The reaction is heated to 80 0C for lh, diluted with EtOAc, washed with water and brine, dried over NaZSO4, 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 NaHC03 and EtOAc. The organic layer is dried over NaZSO4, filtered and trated to provide the title compound (LC/MS method 1: ES+ m/z 429.4 [M+H] +, Rt = 0.63 min). 2O Example 225: Preparation of (S)(2,3-dihydr0-benz0[1,4]di0xinyl)-phenyl]- ethyl}-pyrrolidine (225).
(I,0 (10 —> (1,30 Br_. "Q (I,0 A solution of A (1.0 g, 4.16 mmol) in THF (10mL) is treated with 1.4M methylmagnesium bromide solution in toluene at 0°C. The resulting mixture is stirred at 0°C for 1h. The mixture is then quenched with saturated ammonium de solution and extracted with EtOAc. The organic solution is dried over NaZSO4, filtered, and concentrated. The e is purified by flash tography eluting with a nt of 0-30% EtOAc in heptane to give 1-[(S)(2,3-dihydro-benzo[1,4]dioxinyl)-phenyl]-ethanol (J- 1).
A solution of J-1 (500 mg, 1.95 mmol) in THF (10 mL) is treated with nylphosphine ide (1.65 g, 3.90 mmol) and imidazole (265 mg, 3.90 mmol) at room temperature, and the resulting mixture is stirred at room temperature 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)[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 600C 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 NaHCOg.
The organic layer is dried over NaZSO4, filtered, and trated. The residue is dissolved in EtzO (2 mL), treated with HCl (2 mL, 2M in EtzO), and concentrated to 2012/028843 provide the title product as the HCl salt (LC/MS method 1: ES+ m/z 311.2 [M+H]+, Rt = 0.63 min).
Example 226: 4-(1-{4-[(2S)-2,3-dihydr0-1,4-benz0di0xin yl]phenyl}ethyl)m0rpholine (226) Compound 226 is prepared from intermediate J and morpholine according to the procedure described for the sis of compound 225. o K/o Ex # MS Method [M+H]Jr Rt (min) 226 1 327.20 0.89 Example 227: Preparation of 1-{1-[(S)(2,3-dihydr0-benz0[1,4]di0xinyl)-phenyl]- ethyl}-piperidinecarb0xylic acid (227) (10 a O Ow J 227 A mixture of intermediate J (188 mg, 0.59 mmol) and piperidinecarboxylic acid ethyl ester (0.5 mL, 3.24 mmol) is heated at 600C 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 NaHCOg. The organic layer is dried over NaZSO4, ed, and trated. The residue is dissolved in a mixture of MeOH (4 mL) and water (4 mL) ning KOH (110 mg, 2 mmol) and heated at 500C for 18h. The mixture is concentrated, treated with TFA (0.15 mL, 2 mmol), and extracted with EtOAc. The organic layer is dried over NaZSO4, filtered, and concentrated to provide the title compound as the TFA salt (LCMS method 7: ES+ m/z 369.2 [M+H]+, Rt = 0.56 min).
Example 228: Preparation of (2,3-Dihydr0-[1,4]di0xin0[2,3-b]pyridinyl)- benzyl]methyl-piperidinecarb0xylic acid formate salt (228) N N N\ o LiOH-HZO N o / o o o\ / i H0 o 228 H OH A mixture of 1-[(S)(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridinyl)-benzyl]—4-methyl- piperidinecarboxylic acid methyl ester red according to the General Method A) (43 mg, 0.10 mmol), LiOHonO (21 mg, 0.5 mmol), MeOH (3 mL), and water (1 mL) is warmed to 50 OC overnight. The reaction is concentrated, neutralized with 1 N aqueous HCl, and purified by reversed phase HPLC g with a gradient of 0-70% MeCN in water (+0.1% formic acid) to afford the title compound as the formate salt (LCMS method : ES+ m/z 382.8 , Rt = 0.54 min).
Example 229: Preparation of 2-{1-[(S)(2,3-Dihydr0-benz0[1,4]di0xinyl)-benzyl]- piperidinyl}methyl-propionic acid e salt (229) @6ng ~ @0911 229 HJLOH 2-{ 1- [(S)(2,3 -Dihydro-benzo[1,4]dioxinyl)-benzyl]-piperidinyl}methyl- propionic 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 0C for 1 hour, concentrated, diluted with water, and neutralized with 2N aqueous N32CO3. The aqueous layer is decanted and the remaining residue is purified by reversed phase HPLC g with a gradient of 0-70% MeCN in water (+0. 1 % formic acid) to afford the title compound as the e salt (LCMS method 15: ES+ m/z 395.8 [M+H]+, Rt = 1.25 min).
Example 230: Preparation of 2-{1-[(S)(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin yl)-benzyl]-piperidinyl}methyl-propionic acid formate salt (230) {I/o O'Hook 230 OH Compound 230 is prepared according to the procedure described for the synthesis of compound 229.
Example 231: Preparation of (S)(2,3-Dihydro-benzo[1,4]dioxinyl)-benzyl]- piperidinylmethyl}-benzoic acid (231). (150% ~ orjrCflO§ A mixture of 4-{ l-[(S)(2,3-dihydro-benzo[l ,4]dioxinyl)-benzyl]-piperidin ylmethyl}-benzoic acid methyl ester red according to General Method C) (80 mg, 0.17 mmol), LiOHonO (15 mg, 0.36 mmol), MeOH (3 mL) and water (0.5 mL) is stirred at room temperature for 16h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is triturated with water to give the title compound. 2O Examples 231-235: Preparation of Compounds 231-235 Compounds 231-235 are prepared according to the procedure described for the synthesis of nd 231 as shown in Table 7 below.
X 0 Table 7. Preparation of compounds 231-235.
MS Rt EX # X ---A [M+H]+ Method (min) 231 CH "WOH 4 444.30 1.42 233 CH ---NW0 4 430.26 1.21 234 N ‘WOH 4 445.29 0.81 235 N 0mm 3 431.25 1.59 Example 236: Preparation of 4-({[(S)(2,3-Dihydr0-benzo[1,4]di0xinyl)-benzyl]- ethyl-amino}-methyl)-benz0ic acid (236). (1:er + To ~ CCWW e ccrgmgr A mixture of 4-{ [(S)(2,3-dihydro-benzo[l ,4]dioxinyl)-benzylamino]-methyl}- c 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 temperature 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)(2,3-dihydrobenzo ioxinyl)-benzyl]-ethyl-amino } -methyl)-benzoic acid methyl ester .
A mixture of 4-({ [(S)(2,3-dihydro-benzo[l ,4]dioxinyl)-benzyl]-ethyl-amino}- methyl)-benzoic acid methyl ester (65 mg, 0.16 mmol), LiOHonO (23 mg, 0.55 mmol), MeOH (5 mL) and water (0.5 mL) is stirred at room temperature for 16h. The reaction mixture is neutralized with acetic acid and concentrated. The e is diluted with water and DCM, phases are separated, the organic layer is dried over NaZSO4, filtered and concentrated. The residue is purified by flash tography eluting with a nt of 0- % MeOH in DCM to give the title compound.
Examples 236-238: Preparation 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. Preparation of compounds 236-238.
MS Rt Ex # X ---A [M+H]+ Method (min) e 239: Preparation of (S)(2,3-Dihydr0-benz0[1,4]di0xinyl)-benzyl]- piperazin-l-ylmethyl}-benzoic acid (239) K/N N/fi $\ ©:o0 0 Y o K/NH + O\'< (3:0 2 HCI Nfi Nfi (10o K/N 0 K/N § —’ (IO 239 0 (I) Methanol (30mL) is added dropwise to acetyl chloride (1.4 mL) at 00C. The solution is added to 4- [(S)(2, 3-dihydro-benzo [ l ,4]dioxinyl)-benzyl] -piperazine- l xylic acid tert-butyl ester (408 mg, 0.99 mmol) (prepared according to the General Method E).
The resulting mixture is stirred at room temperature 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 1-[(S)(2,3-dihydro-benzo[1,4]dioxinyl)-benzyl]— piperazine dihydrochloride.
A solution of 1-[(S)(2,3-dihydro-benzo[1,4]dioxinyl)-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 temperature for 16 h, trated, diluted with water, and extracted with ethyl e. The organic layer is washed with brine, dried over , filtered, and concentrated. The residue is purified by flash chromatography eluting with a nt of 0- % MeOH in DCM to give 4-{4-[(S)(2,3-dihydro-benzo[1,4]dioxinyl)-benzyl]— piperazinylmethyl } -benzoic acid methyl ester.
A mixture of 4-{4-[(S)(2,3-dihydro-benzo[1,4]dioxinyl)-benzyl]-piperazin yl}-benzoic acid methyl ester (48 mg, 0.11 mmol), LiOHonO (15 mg, 0.37 mmol), dioxane (5 mL), and water (0.5 mL) is stirred at room temperature 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 = 1.31 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 (1nM , Arg-AMC substrate (50 11M final), and compound are combined in a reaction buffer (50 mM Tris-HCl (pH 7.5), 100 mM KCl, 0.5% bovine serum albumin) at room temperature for 1h. The formation of t is assessed by measuring the fluorescence of ethylcoumarin product (excitation wavelength 380nm/emission wavelength 460nm). In general, the preferred potency range (ICso) of nds in the LTA4H Enzyme assay is between 0.1 nM to 10 11M, the more preferred potency range is 0.1 nM to 0.1 11M, and the most preferred potency range is 0.1 nM to 10 nM. —104— Table 9. IC50 values of LTA4H Enzyme assay.
E E ).4.5.7.....4.7.9..3.23............2..... 574 6666 2345 @0000 )2981 67 1701100 7.9.81.7.6.1. 9035910 MM24.1...... 3 000 9559676 009 7777777777 01234567009 2 2 3 88888 12345 mx000200000010100000000000M3.9.7.4.1.1.1.6.25.7.9.7.4.4.1.21.1.3.21.3.1.)713568253131577968086704 111111111111111111122222 888888888999999999900000 789012345678901234 56 01131410100000200 5886.0.59.1.4.57.321.6.4.9. 78050108011103952 11111111111111111111111111111111 22222222233333333334444444444555 12345678901234567890123456789012 1 0 009 8 00 22222 00001 67890 002ml 99 12 0100%5.4.7.5..4074% 0000000 23.2221.1. 9584107 2 1 2 0 18449619 Example ICso Example ICso Example IC50 Example IC50 (HM) (HM) ’3Z) (HM) -kl) kl) 3.1 \O 93 .H \O 00 O 00 [\J 213 -U) 4; 1.89 94 .0 -l> kl] O [\DO 214 0.47 -kl) kl] 0.26 95 .0 -l> \O O [\D 00 215 0.70 -kl) O\ 4.45 .0 [\D[\D O\ O \0 ,_] 216 0.13 -UJUJUJ \OOO\] 1.05 N 00\1 O fi—‘ 00 217 2.28 -1.14 .0 C\ ,_] O ,_1 U3 218 0.37 -2.14 .0 U) \] \O O ,_i 0 219 0.49 -4;O 0.82 100 N U3 O\ O\ O ,_i 00 220 0.47 -4; p—k 3.71 101 .H \0O O\ O 4; l—* 221 0.16 -4;to 102 NO\00 O\ O fi—l -l> 222 0.14 -4; U) . 103 N-l>O C\ O ,_] \] 223 0.16 -4;4; 104 .0 l—* 00 O\ O 00 -l> 224 0.13 105 O kl] ]_] O ]_] kl) 225 5.30 -4;O\ 24.82 106 226 42.95 -4;\1 107 Iim4;U]O\ II0]O\\1 $3.0. we] \]oo 1.40 . 227 -4; 00 .09? UJl—tfl [0an 108 .0 00 \l O kl) p—k 228 0.61 -4; \o 109 O fi—k\] HIO\ \o U) U) 229 3.85 -kl] O 110 [\J fi—k kl] n J>\l 230 1.24 -kl]]_] 0.82 111 2.2U] C 4; U] 231 0.29 -kl] [\D 0.75 112 ]_] U) 2.75 232 -kl] kl) 0.42 113 I! kl] [\D #0\O\] \] \] U) 233 0.22 -U] 4; 5.93 114 0. \l \l 234 0.14 -kl] kl] 3.63 115 \] [\J 235 0.08 [\J -kl] C\ 6.08 116 ii000NU) [\JJ> 236 6.04 -kl] \] 13.66 117 O.2kl) p—k 4; kl] 237 0.81 -kl] 00 1.36 118 4;CU] 238 0.55 -kl] \O 89.24 119 CO ,_i 0.0. fi—kkl) O\U] 239 0.15 m31.02 120 O kl] ]_] .0 ]_] [\D The compounds of the ion are additionally tested in a human whole blood (HWB) assay to determine their y 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 (20uM 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 time- resolved fluorescence method (CisBio, Bedford, MA). In general, the preferred potency range (IC50) of nds in the HWB assay is between 10 nM to 10 uM, the more preferred y range is 10 nM to 1 uM, and the most preferred potency range is 10 nM to 100 nM. The potencies of representative 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 Example IC50 Example IC50 Example ICSO [\DNfi—KA9.4.035OLDHZL»)Q00\./ QQQALAWN:UIQUIZ[UL/10v (HM) (HM) LI] [\3 4;p] ,_t [\3 61 250.398 118 255.61 174 68.33 [\DQ LI] 0 QC\ OL») p—k 4; 87 [QQ O\J> EH LII L») 84.85 NQ \0 00 p—k Hi00 C\ U] 00 QJ> C\4; fi—kfi—kfi—kfi—kfi—kfi—k LIILIILIILIIJ> $99300 \O\O\Ol—*\O LIINNLDO 229 [\D 00 L») \O 00 [\D \0 LI] p—l LII 00 Q LII. 25 94.12 "--p—l LII .0 L») Q 85 04.96 --—-15961 227 07.44 "-1!h—Kh—kh—k Q00 900:". l—‘QOO #00 26 08.47 00m m P3 4;\o \o 4; O\O l 16 10.32 L»)L») 0U] #00C) \00 49> \OQ OOQ p—k 00 123 12.41 ,_i QQ QQ 37 23.66 L») 00 \O \O \0 LI] L») \O p—l Q \0 . L») L») 67 45.74 L») \O p—l 00 \0 LI] L») \0 p—l 00.0 OO 10 mmwmmmmwmmwmw 00 00m 0 Methods of Use The compounds of the invention are effective inhibitors of riene A4 hydrolase (LTA4H) and thus inhibit leukotriene production. Therefore, in one ment of the invention, there is provided methods of treating leukotriene-mediated disorders using compounds of the invention. In r embodiment, there is provided methods of treating cardiovascular, inflammatory, allergic, pulmonary and fibrotic diseases, renal 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 ion of arachidonic acid by 5-LO and subsequent 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; ic diseases including asthma, allergic rhinitis, rhinosinusitis, atopic dermatitis and urticaria; Fibrotic diseases including airway ling in , idiopathic pulmonary fibrosis, scleroderma, asbestosis; ary syndromes ing adult respiratory distress me, Viral bronchiolitis, obstructive sleep apnea, chronic obstructive pulmonary disease, cystic fibrosis, and bronchopulmonary dysplasia; Inflammatory diseases including rheumatoid tis, osteoarthritis, gout, glomerulonephritis, interstitial cystitis, psoriasis, inflammatory bowel e systemic lupus erythematosus, transplant ion, inflammatory and ic ocular diseases; Cancer including solid tumors, leukemias and lymphomas; and Renal diseases such as glomerulonephritis.
For treatment of the above-described diseases and conditions, a eutically 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 0.1 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 optimization may be required to determine an optimal dosing level and pattern. The active ingredient may be administered from 1 to 6 times a day.
General Administration and ceutical Compositions When used as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be ed 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 ments, provide increased ution or dispersion, increased antagonist activity, e 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 invention, optionally also in conjunction with other pharmacologically active substances.
In general, the compounds of this ion are administered in a therapeutically or ceutically 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 d out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, , 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 aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or ent and a compound of the invention as the/an active agent, and, in addition, may include other nal agents, pharmaceutical agents, carriers, adjuvants, diluents, es, 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 ofPharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & s, 2000; Handbook maceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook ofPharmaceutical Excipients, A.H.
Kibbe (ed.), American Pharmaceutical Ass’n, 2000; H.C. Ansel and N.G. Popovish, ceutical 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 teristics (e. g., water solubility) that are required for the formulation to be efficacious.

Claims (29)

1. A compound of formula (I): 5 or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; n is an integer from 0 to 3; R1 is selected from halo, -OH, -CN, 6)alkyl, –O(C1-C 6)alkyl, and -(C3-C6)cycloalkyl; 10 R2 and R3 are each independently selected from -H and 6)alkyl; wherein R2 and R3 may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and r optionally substituted with one to three groups selected from halo, -OH, (=O), -(C1-C6)alkyl, -O(C1-C6)alkyl, -C(O)OH, -C(O)(C1-C6)alkyl, and -C(O)NH2; 15 A is a group of formula -NR4R5, wherein R4 and R5 are each independently selected from -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to 11-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11-membered)heteroaryl; wherein each of the foregoing -(C1-C6)alkyl, 6)cycloalkyl, -(4- to bered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 20 11-membered)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 (7804526_1):KZA same carbon atom of said -(C1-C6)alkyl may join to form a 3- to 6-membered ring ally comprising one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, -OH, (=0), -(C1-C6)alkyl, -O(C1- C6)alkyl, -C(O)OH, -C(O)(C1-C6)alkyl, and -C(O)NH2; orAis a (4- to ll-membered)N-heterocyclic ring of formula B: g—N:3}L-R6 wherein said ring B may be a non-aromatic 4-8 membered monocyclic l; a bridged ic l; a spirocyclic radical; or a 6 to ll-membered fused bicyclic 10 l which may be non-aromatic or have one aromatic ring provided that the aromatic ring of the bicyclic radical, when present, is not attached to methylene carbon atom l 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; 15 wherein said ring B may be further optionally substituted by one to three groups selected from halo, -OH, (=0), H, -C(O)O-(C1-C6)alkyl, and -(C1-C6)alkyl; wherein L is absent or a linker selected from -(C1-C6)alkylene; each R6 is independently selected from halo, -OR7, -CF3, -CN, -(C1-C6)alkyl, -C(O)R7, 20 -C(O) 2R7, (R7)2, -N(R7)2, -NHC(O)R7, -NHC(O)N(R7)2, -S(O)2R7, -NH-S(O)2-R7, 6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11- membered)heteroaryl; wherein each of said, -(C1-C6)alkyl, C6)alkyl, -(C3- C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11- membered)heteroaryl of said R6 group is optionally substituted where possible with one to 25 three groups selected from halo, -OH, -CF3, -CN, (=0), -(C1-C6)alkyl, -C(O)OH, -C(O)O-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -S(O)2(C1-C6)alkyl, -(C3- C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11- membered)heteroaryl; and each R7 is independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C3-C6)cycloalkyl-OH, -(4- to 11- membered)heterocycloalkyl, -(C6-C10)ary1, and -(5- to ll-membered)heteroaryl.
2. The compound of claim 1, or a pharmaceutically acceptable salt f, wherein group A is a group of formula . 10
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 is -H or -(C1-C6)alkyl, and R5 is 6)alkyl; wherein each -(C1-C6)alkyl of said R4 and R5 groups, when present, is optionally independently substituted by one to three R6 . 15
4. The compound of claim 1 or 3, or a ceutically acceptable salt thereof, wherein R4 is —H or -(C1-C6)alkyl, and R5 is -(C1-C6)alkyl; wherein said -(C1-C6)alkyl of said R5 group is substituted by -(C3-C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C1o)aryl, or -(5- to ll-membered)heteroaryl; wherein each of said, -(C3-C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6-C10)ary1, and -(5- to ll-membered)heteroaryl 20 is optionally substituted with one to three groups independently selected from -(C1- C6)alkyl, -CF3, and -C(O)OR8.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 is -H or -(C1-C6)alkyl, and R5 is -(C1-C6)alkyl; wherein said 6)alkyl of 25 said R5 group is ndently substituted by one to three groups selected from-(C1- C6)alkyl, -O(C1-C6)alkyl, -C(O)R8, -C(O)OR8, -S(O)2R8, and -NHC(O)R8.
6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently selected from —H or -(C1-C6)alkyl. -ll3-
7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 is —H or -(C1-C6)alkyl, and R5 is -(C3-C6)cycloalkyl, -(4- to 11- membered)heterocycloalkyl, -(C6-C10)ary1, and -(5- to ll-membered)heteroaryl; wherein each of the ing -(C3-C6)cycloalkyl, -(4- to ll-membered)heterocycloalkyl, -(C6- C10)aryl, and -(5- to ll-membered)heteroaryl groups of said R5 is optionally ndently substituted by one to three groups selected from -(C1-C6)alkyl, -O(C1-C6)alkyl, -C(O)R8, -C(O)OR8, R8, and -NHC(O)R8.
8. The compound of claim 1, or a pharmaceutically acceptable salt f, wherein 10 group A is a (4- to ll-membered)N-heterocyclic ring of formula B:
9. The compound of claim 1 or 8, or a pharmaceutically acceptable salt thereof, wherein said ring B is 4-8 membered monocyclic radical.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein 15 said 4-8 membered monocyclic radical is selected from the group consisting of azetidine, tetrahydropyrrole, piperidine, hexamethyleneimine, 1,2-diazetidine, pyrazolidine, olidine, piperazine, hexahydrodiazepine, isoxazolidine, oxazolidine, tetrahydro-2H- azine, 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), 2O -C(O)OH, -C(O)O-(C1-C6)alkyl, and -(C1-C6)alkyl.
11. The compound of claim 1 or 8, or a pharmaceutically acceptable salt thereof, wherein said ring B is a yclic cyclic radical.
12. The compound of claim 1 or 8, or a pharmaceutically acceptable salt thereof, wherein said ring B is a bridged bicyclic radical; or a 6 to ll-membered fused bicyclic 25 radical which may be non-aromatic or have one aromatic ring provided that the ic ring of the bicyclic radical, when present, is not attached to methylene carbon atom l of the nd of formula (I). —114—
13. The compound of claim 1 or 8, or a pharmaceutically acceptable salt thereof, wherein L is –CH2-.
14. The compound of claim 1 or 8, or a ceutically acceptable salt thereof, wherein L is absent. 5 15. The compound of claim 1 or 8, or a ceutically acceptable salt thereof, wherein said 4membered heterocyclic ring B is a selected from azetidinyl, pyrrolidinyl, piperidinyl and yl; n each of the foregoing azetidinyl, pyrrolidinyl, piperidinyl and azepanyl rings is optionally substituted by one to three groups selected from halo, -OH, (=O), -C(O)OH, C(O)O-(C1-C6)alkyl, and -(C1-C6)alkyl; 10 and wherein L is absent or a linker selected from -(C1-C6)alkylene; and wherein R6 is elected from halo, -OR7, -CF3, -CN, 6)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, -(C3-C6)cycloalkyl, -(4- to 11-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to
15. 15 11-membered)heteroaryl; wherein each of said, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4- to 11-membered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11-membered)heteroaryl of said R6 group is optionally tuted where possible with one to three groups selected from halo, -OH, -CF3, -CN, (=O), -(C1-C6)alkyl, -C(O)OH, -C(O)O-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -S(O)2(C1-C6)alkyl, 20 -(C3-C6)cycloalkyl, -(4- to bered)heterocycloalkyl, -(C6-C10)aryl, and -(5- to 11-membered)heteroaryl.
16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, n X is N.
17. The compound of any one of claims 1 to 15, or a pharmaceutically 25 acceptable salt thereof, wherein X is CH.
18. A compound of Formula (I) according to claim 1, selected from the group consisting of: 4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidinyl)butanoic acid; (9394501_1):JJP 4-(1- { 4-[(3 S)-2, 3-dihydr0 [ 1 ,4]di0Xin0 [2,3 -b]pyridiny1]benzy1}piperidiny1)benz0ic acid; (3S){4-[(1s,4s)azabicyc10[2.2.1]hepty1methy1]pheny1}-2,3- dihydr0[1 Xin0 [2,3-b]pyridine; N-(1-{4-[(3S)-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}piperidin y1)methanesulf0namide; (3S)[4-(azepany1methy1)pheny1]-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridine; 1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}methy1piperidine; 7-{4-[(ZS)-2,3-dihydr0-1,4-benz0di0xiny1]benzy1}-1,7-diazaspir0[4.4]n0nane 10 carboxamide; (3S)-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}-1,7-diazaspir0[4.4]n0nan- 2-0ne; 1-{ 4-[(ZS)-2,3-dihydr0-1 ,4-benz0di0xiny1]benzy1}piperidinecarb0xy1ic acid; (1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}piperidiny1)(m0rph01in 15 y1)methan0ne; 8-{4-[(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridiny1]benzyl}-1,3,8- triazaspir0[4.5]decane-2,4-di0ne; (3S){4-[(3-meth0xypiperidiny1)methy1]pheny1}-2,3 -dihydr0[1,4]di0xin0[2,3 - b]pyridine; 20 N-(1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}pyrr01idiny1)-N- methylacetamide; 1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzyl}(1,1-di0xid0—1,2-thiaz01idin eridine; (3R){4-[(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridiny1]benzy1}pyrr01idin01; 25 N-(1 - { 4- [(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridinyl]benzy1}piperidinyl) hydroxyacetamide; 4-[(1- { 4-[(3S)-2,3-dihydr0[1 ,4]di0xin0[2,3-b]pyridiny1]benzy1}piperidin hy1]benz0ic acid; (1- { 4- [(3 S)-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}piperidiny1)(morpholin- 30 4-y1)methan0ne; (3S) [4-(morpholiny1methy1)phenyl] -2,3 -dihydr0[1,4]di0xin0[2,3 -b]pyridine; 8-{4-[(2$)-2,3-dihydr0—1 ,4-benz0dioxiny1]benzy1}-2,8-diazaspir0[4.5]decan0ne; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 -y1]benzy1}piperidinecarb0nitrile; 1-{4-[(2$)-2,3-dihydr0—1,4-benz0dioxiny1]benzy1}-N-methy1piperidineCarboxamide; 8-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-2,8-diazaspir0[4.5]decan- 1-0ne; N-(1 -{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1) hydroxy-24nedndpropanannde; N-(1 -{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidiny1) hydroxycyclopropanecarboxannde; 10 N- { 4- 2,3 r0— 1 ,4-benzodioxiny1]benzy1} -N-ethylcyclopentanamine; (3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 nzy1}-N-methy1piperidine carboxannde; N- {4-[(3S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridinyl]benzy1} -N- methylcyclopentanamine; 15 1-[(1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin y1)methy1]pyrrolidin0ne; 1-{4-[(ZS)-2,3-dihydr0-1,4-benz0dioxiny1]benzy1}methy1pyrrolidine; N-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}methy1—1-(pyrrolidin prropan:2-annne; 20 N-Cyclohexyl-N- { 4-[(ZS)-2,3-dihydr0-1 ,4-benzodioxiny1]benzy1} -N',N'— dimethylethane- 1 ,2-diamine; N-(1 - { 4- [(3 S)-2,3-dihydr0[1 ,4]dioxin0[2,3-b]pyridiny1]benzy1}piperidin y1)acetamide; N-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-N-methy1(pyridin 25 y1)ethanamine; (3S)[4-(pyrrolidiny1methy1)pheny1]—2,3 -dihydr0[1,4]dioxin0[2,3 -b]pyridine; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 -y1]benzy1}piperidine-3 -Carboxamide; 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3 -b]pyridin-3 -y1]benzy1}piperidinecarb0xamide; 4-[(2$)-2,3-dihydr0—1,4-benzodioxiny1]benzy1}pyrrolidin-3 -y1)acetamide; 30 1-{4-[(3S)-2,3-dihydr0[1,4]dioxin0[2,3-b]pyridiny1]benzy1}-N-(2- hydroxyethyl)piperidinecarboxamide; (3S)[4-(1,4-oxazepany1methy1)pheny1]-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridine; 1-{4-[(ZS)-2,3-dihydr0-1 ,4-benz0di0xiny1]benzy1}-N-(2-hydroxyethy1)piperidine carboxannde; 4-(1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}piperidiny1)benz0ic acid; 1-(1-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}piperidiny1)urea; 7-{4-[(2$)-2,3-dihydr0—1,4-benz0di0xiny1]benzy1}-1,7-diazaspir0[4.4]n0nan0ne; 8- { 4-[(3S)-2,3-dihydr0[1 ,4]di0xin0[2,3-b]pyridiny1]benzy1 } methy1—2,8- diazaspir0[4.5]decan0ne; 1-{4-[(3S)-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}piperidin01; 10 N-(1-{4-[(2$)-2,3-dihydr0—1,4-benzodi0xiny1]benzy1}piperidin yDnufihanesqunanflde; 3-(1-{4-[(3S)-2,3-dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}piperidiny1)pr0pan (3S){4-[(4-methy1piperidiny1)methy1]pheny1}-2,3-dihydr0[1,4]di0Xin0[2,3- 15 b]pyridine; N- { 4- [(3S)-2,3 -dihydr0[1,4]di0xin0[2,3 -b]pyridiny1]benzy1} ylethanamine; (3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridinyl]benzy1} (methylsulfony1)piperidinamine; -{4-[(4-flu0r0piperidiny1)methy1]pheny1}-2,3 -dihydr0[1,4]di0xin0[2,3 - 20 b]pyridine; 1-(4-{4-[(3S)-2,3-dihydr0[1,4]di0xin0[2,3-b]pyridiny1]benzy1}-1,4-diazepan yDeflnanone; [(3R){4-[(2$)-2,3 -dihydr0— 1 ,4-benz0di0xiny1]benzy1}piperidin-3 -y1] acetic acid; (1- { 4- [(3 -dihydr0[1,4]di0Xin0[2,3-b]pyridiny1]benzy1}piperidiny1)methan01; 25 4-[(1- { 4-[(ZS)-2,3 -dihydr0—1,4-benzodi0xiny1]benzy1}piperidiny1)methy1]benz0ic acid; (3S){4-[(4-methy1-1,4-diazepany1)methy1]pheny1}-2,3-dihydr0[1,4]di0Xin0[2,3- b]pyridine; (3S){4-[(3-meth0xypyrr01idiny1)methy1]pheny1}-2,3 -dihydr0[1,4]di0Xin0[2,3- 30 b]pyrkfine;and N-{4-[(2$)-2,3-dihydr0—1,4-benzodi0xiny1]benzy1}-N,2-dimethy1pr0panamine; or a pharmaceutically salt thereof of each of the foregoing.
19. The compound 4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin yl]benzyl}piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.
20. 4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin 5 yl]benzyl}piperazinecarboxamide.
21. The compound 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin yl]benzyl}piperidinecarboxylic acid, or a pharmaceutically acceptable salt thereof.
22. (2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidine carboxylic acid. 10
23. The compound [(3R){4-[(2S)-2,3-dihydro-1,4-benzodioxin yl]benzyl}piperidinyl]acetic acid, or a pharmaceutically acceptable salt thereof.
24. [(3R){4-[(2S)-2,3-dihydro-1,4-benzodioxinyl]benzyl}piperidin yl]acetic acid.
25. A pharmaceutical ition comprising the compound of any one of 15 claims 1 to 24, or a pharmaceutically acceptable salt thereof.
26. Use of a compound of any one of claims 1 to 24, or a ceutically acceptable salt f, for the manufacture of a medicament for treating leukotriene mediated disorders.
27. Use of a compound of any one of claims 1 to 24, or a pharmaceutically 20 acceptable salt thereof, for the manufacture of a medicament for treating a cardiovascular disease.
28. The use of claim 27, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, myocardial infarction, stroke, aortic sm, sickle cell crisis, ischemia-reperfusion injury, pulmonary arterial hypertension and sepsis. 25
29. Use of a compound of any one of claims 1 to 24, or a ceutically able salt thereof, for the manufacture of a medicament for treating atherosclerosis.
NZ614109A 2011-03-14 2012-03-13 Benzodioxane inhibitors of leukotriene production NZ614109B2 (en)

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