US2017298022A1PendingUtilityA1
Diamino-Pyridine, Pyrimidine, and Pyridazine Modulators of the Histamine H4 Receptor
Est. expiryJun 12, 2028(~1.9 yrs left)· nominal 20-yr term from priority
Inventors:Hui CaiFrank ChavezPaul J. DunfordAndrew J. GreenspanSteven P. MedunaJorge A. QuirozBrad M. SavallKevin L. TaysRobin ThurmondJianmei WeiRonald L. WolinXiaohu Zhang
A61P 7/06A61P 37/08A61P 37/02A61P 9/10A61P 3/10A61P 37/00A61P 7/04A61P 37/06A61P 43/00A61P 37/04A61P 27/14A61P 25/04A61P 27/04A61P 25/22A61P 25/00A61P 25/24A61P 27/02A61P 29/00A61P 25/18A61P 17/04A61P 17/00A61P 11/00A61P 1/16A61P 11/06A61P 1/04A61P 17/06A61P 15/00A61P 21/00A61P 21/04A61P 13/12A61P 1/00A61P 11/02C07D 213/74C07D 403/04C07D 401/04C07D 237/20A61K 31/50C07D 405/12C07D 401/14C07D 405/14C07D 487/04A61K 31/44A61K 31/4439
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Claims
Abstract
Diamino-pyridine, pyrimidine and pyridazine compounds which may be used as H 4 receptor modulators, and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by H 4 receptor activity, such as allergy, asthma, autoimmune diseases, and pruritis.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A chemical entity selected from the compounds of Formula (I)
wherein
Z is CH;
Y is CH;
R 1 is:
a) —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 SCH 3, or C 1-8 alkyl, each independently unsubstituted or substituted with —OH or —CF 3 ;
b) —(CH 2 ) 0-2 —Ar 1 , —CHR 2 —Ar 1 , or —(CH 2 ) 0-2 —Ar 2 , each of said Ar 1 and Ar 2 independently unsubstituted or substituted with halo, —CH 3, or —OCH 3,
Ar 1 is a 6-membered aromatic carbocyclic ring,
Ar 2 is a 5 to 6-membered heteroaromatic ring containing N, S or O; or
c) cycloalkyl, —(CH 2 )-(monocyclic cycloalkyl), —(CH 2 )-(bridged polycyclic cycloalkyl), —(CHR 2 )-(monocyclic cycloalkyl), —(CH 2 )-(fused cycloalkyl), —(CH 2 )-(bridged monocyclic cycloalkyl), —(CH 2 ) 0-1 -tetrahydrofuranyl, or —(CH 2 ) 0-1 -tetrahydropyranyl, each of said cycloalkyl independently unsubstituted or substituted with one, two, or three C 1-4 alkyl substituents;
R 2 is —C 1-4 alkyl;
is
where R a , R b , and R c are each independently H or C 1-3 alkyl;
provided that:
when R 1 is isopropyl, then R c is methyl;
when R 1 is 4-methylphenyl, then R c is methyl; and
pharmaceutically acceptable salts of compounds of Formula (1).
2 - 5 . (canceled)
6 . A chemical entity of claim 1 , wherein R 1 is selected from the group consisting of:
and
7 . A chemical entity of claim 1 , wherein
is selected from the group consisting of:
8 . A chemical entity of claim 1 , wherein
is
9 . A chemical entity of claim 1 , wherein
is
10 . A chemical entity of claim 1 , wherein
is
11 . A chemical entity of claim 1 , wherein
is
12 . A chemical entity of claim 1 , wherein
is
13 . A chemical entity of claim 1 , wherein R a is H.
14 . A chemical entity of claim 1 , wherein R b is H or methyl.
15 . A chemical entity of claim 1 , wherein R c is H or methyl.
16 . A chemical entity of claim 1 , wherein R 2 is methyl.
17 - 32 . (canceled)
33 . A chemical entity selected from the group consisting of:
Bicyclo[2.2.1]hept-2-yl-[4-((3R)-3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine dihydrochloride; N-Cyclopentyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-propylpyridin-2-amine dihydrochloride; N-(Cyclopropylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine ditrifluoroacetate; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyridin-2-amine dihydrochloride; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[tetrahydrofuran-2-ylmethyl]pyridin-2-amine dihydrochloride; N-(4-Fluorobenzyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine dihydrochloride; N-Cyclopropyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine dihydrochloride; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; N-Benzyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(1-methylethyl)pyridin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(1-methylethyl)pyridin-2-amine; 4-[(3S)-3-Am inopyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine; 4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine; N-Cyclopentyl-4-piperazin-1-ylpyridin-2-amine; 4-Piperazin-1-yl-N-propylpyridin-2-amine dihydrochloride; N-Benzyl-4-piperazin-1-ylpyridin-2-amine; N-(2-Methylpropyl)-4-piperazin-1-ylpyridin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine; 4-(4-Methylpiperazin-1-yl)-N-(2-methylpropyl)pyridin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-phenylpyridin-2-amine; 4[3-(Methylamino)azetidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine; N-(Cyclopropylmethyl)-4-piperazin-1-ylpyridin-2-amine; N-Butyl-4-piperazin-1-ylpyridin-2-amine; N-(2-Methoxyethyl)-4-piperazin-1-ylpyridin-2-amine; N-Phenyl-4-piperazin-1-ylpyridin-2-amine; 4-Piperazin-1-yl-N-(tetrahydrofuran-2-ylmethyl)pyridin-2-amine; N-(4-Fluorobenzyl)-4-piperazin-1-ylpyridin-2-amine; N-(2,2-Dimethylpropyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(2-Methoxyethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine; Adamantan-2-yl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine; Adamantan-2-yl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine; N-[(1R)-1-Cyclohexylethyl]-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; Adamantan-1-yl-[4-(3S)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine; N-(Cyclohexylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(Cyclohexylmethyl)-4-(4-methylpiperazin-1-Opyridin-2-amine; N-[(1R)-1-Cyclohexylethyl]-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-[(1R)-1-Cyclohexylethyl]-4-(4-methylpiperazin-1-Opyridin-2-amine; Adamantan-2-yl-[4-(3S)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine; 3-{[4-(4-Methylpiperazin-1-yl)pyridin-2-yl]aminolpropan-1-ol; N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; Adamantan-1-yl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine; Adamantan-1-yl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine; Adamantan-1-ylmethyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine; N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-(4-methylpiperazin-1-yl)pyridin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine; 4-(4-Methylpiperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine; N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(Cyclohexylmethyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(Cyclopentylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(Cyclopentylmethyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-Cyclopentyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyridin-2-amine; 4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; N-Bicyclo[2.2.1]hept-2-yl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 4-(4-Methylpiperazin-1-yl)-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; N-tert-Butyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 3-({4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-1-ol; N-Cyclopropyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(Cyclopentylmethyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine; N-Benzyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(2-Methoxyethyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; N-(2-Methoxyethyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine; 2-Methyl-1-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-2-ol; 2-Methyl-1-{[4-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}propan-2-ol; 2-Methyl-1-({4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-2-ol; N-Butyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 4-(4-Methylpiperazin-1-yl)-N-(pyridin-2-ylmethyl)pyridin-2-amine; 4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-phenylethyl)pyridin-2-amine; N-(4-Fluorobenzyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-am ine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1 R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine; N-Cyclopentyl-4-(4-methylpiperazin-1-yl)pyridin-2-amine; N-(4-Fluorobenzyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine; 4-(4-Methylpiperazin-1-yl)-N-(2-phenylethyl)pyridin-2-amine; Adamantan-1-ylmethyl-[4-(3S)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine; 4-(4-Methylpiperazin-1-yl)-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-am ine; N-(Bicyclo[2.2.1]hept-2-ylmethyl)-4-[(3R)-3-(methylam ino)pyrrolidin-1-yl]pyridin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-butylpyridin-2-amine; Adamantan-1-ylmethyl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine; N-(Cyclohexylmethyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-am ine; 4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(2-methylpropyl)pyridin-2-am ine; 4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyridin-2-amine; N-Cyclopentyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-am ine; 4-P iperazin-1-yl-N-(pyridin-2-ylmethyl)pyridin-2-amine; N-(Cyclopentylmethyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-am ine; N-Cyclopentyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine; 4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyl)pyridin-2-amine; 4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyl)pyridin-2-amine; N-Bicyclo[2.2.1]hept-2-yl-4-(1,4-diazepan-1-yl)pyridin-2-amine; Adamantan-2-yl-[4-(3aR,6aR)-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyridin-2-yl]-amine; 4-[(3S)-3-Aminopyrrolidin-1-yl]-N-benzylpyridin-2-amine; 4-[(3S)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyridin-2-amine; 4-Piperazin-1-yl-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-bicyclo[2.2.1]hept-2-ylpyridin-2-amine; N-[(1R)-1-Cyclohexylethyl]-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine; 4-[(3S)-3-Aminopyrrolidin-1-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; 1-({4-[(3S)-3-Aminopyrrolidin-1-yl]pyridin-2-yl}amino)-2-methylpropan-2-ol; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyridin-2-amine; N-(Cyclopentylmethyl)-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine; 4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2-phenylethyl)pyridin-2-amine; 4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyl)pyridin-2-amine; 1-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyridin-2-yl}amino)-2-methylpropan-2-ol; N-tert-Butyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine; N-Cyclopropyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine; 2-Methyl-1-({4-[3-(methylamino)azetidin-1-yl]pyridin-2-yl}amino)propan-2-ol; 3-({4-[3-(Methylamino)azetidin-1-yl]pyridin-2-yl}amino)propan-1-ol; 4-[3-(Methylamino)azetidin-1-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; N-Benzyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine; N-(2-Methoxyethyl)-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine; 4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine; N-tert-Butyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyl)pyridin-2-amine; 2-Methyl-1-[(4-piperazin-1-ylpyridin-2-yl)amino]propan-2-ol; N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1 H)-yl]pyridin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyridin-2-amine; N-(2,2-Dimethylpropyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine; 4-[3-(Methylamino)azetidin-1-yl]-N-(2-phenylethyl)pyridin-2-amine; N-(4-FluorobenzyI)-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine; Adamantan-1-yl-[4-(3aR,6aR)-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyridin-2-yl]-amine; 4-[3-(Methylamino)azetidin-1-yl]-N-(pyridin-2-ylmethyl)pyridin-2-amine; N-(Cyclopentylmethyl)-4-piperazin-1-ylpyridin-2-amine; and pharmaceutically acceptable salts thereof.
34 . (canceled)
35 . A pharmaceutical composition comprising an effective amount of at least one chemical entity selected from the compounds of Formula (I)
wherein
Z is CH;
Y is CH;
R 1 is:
a) —(CH 2 ) 2 OCH 3, —(CH 2 ) 2 SCH 3, or C 1-8 alkyl, each independently unsubstituted or substituted with —OH or —CF 3 ;
b) —(CH 2 ) 0-2 -Ar 1 , —CHR 2 -Ar 1 , or —(CH 2 ) 0-2 -Ar 2 , each of said Ar 1 and Ar 2 independently unsubstituted or substituted with halo, —CH 3, or —OCH ,
Ar 1 is a 6-membered aromatic carbocyclic ring,
Ar 2 is a 5 to 6-membered heteroaromatic ring containing N, S or O; or
c) cycloalkyl, —(CH2)-(monocyclic cycloalkyl), —(CH2)-(bridged polycyclic cycloalkyl), —(CHR 2 )-(monocyclic cycloalkyl), —(CH 2 )-(fused cycloalkyl), —(CH2)-(bridged monocyclic cycloalkyl), —(CH 2 ) 0-1 -tetrahydrofuranyl, or —(CH 2 ) 0-1 -tetrahydropyranyl, each of said cycloalkyl independently unsubstituted or substituted with one, two, or three C 1-4 alkyl substituents;
R 2 is —C 1-4 alkyl;
is
where R a , R b , and R c are each independently H or C 1-3 alkyl;
provided that:
when R 1 is isopropyl, then R c is methyl;
when R 1 is 4-methylphenyl, then R c is methyl; and
pharmaceutically acceptable salts of compounds of Formula (I).
36 . (canceled)
37 . (canceled)
38 . A pharmaceutical composition comprising and effective amount of at least one chemical entity of claim 33 .
39 . (canceled)
40 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by histamine H 4 receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one chemical entity selected from compounds of Formula (I)
wherein
Z is CH;
Y is CH;
R 1 is:
a) —(CH 2 ) 2 OCH 3, —(CH 2 ) 2 SCH 3, or C 1-8 alkyl, each independently unsubstituted or substituted with —OH or —CF 3 ;
b) —(CH 2 ) 0-2 -Ar 1 , —CHR 2 -Ar 1 , or —(CH 2 ) 0-2 -Ar 2 , each of said Ar 1 and Ar 2 independently unsubstituted or substituted with halo, —CH 3, or —OCH 3,
Ar 1 is a 6-membered aromatic carbocyclic ring,
Ar 2 is a 5 to 6-membered heteroaromatic ring containing N, S or O; or
c) cycloalkyl, —(CH 2 )-(monocyclic cycloalkyl), —(CH 2 )-(bridged polycyclic cycloalkyl), —(CHR 2 )-(monocyclic cycloalkyl), —(CH 2 )-(fused cycloalkyl), —(CH 2 )-(bridged monocyclic cycloalkyl), —(CH 2 ) 0-1 -tetrahydrofuranyl, or —(CH 2 ) 0-1 -tetrahydropyranyl, each of said cycloalkyl independently unsubstituted or substituted with one, two, or three C 1-4 alkyl substituents;
R 2 is —C 1-4 alkyl;
is
where R a , R b , and R c are each independently H or C 1-3 alkyl;
provided that:
when R 1 is isopropyl, then R c is methyl;
when R 1 is 4-methylphenyl, then R c is methyl; and
pharmaceutically acceptable salts of compounds of Formula (I).
41 . (canceled)
42 . (canceled)
43 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by histamine H 4 receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one chemical entity of claim 33 .
44 . (canceled)
45 . A method as in claim 40 , wherein the disease, disorder or medical condition is inflammation.
46 . A method as in claim 40 , wherein the disease, disorder, or medical condition is selected from the group consisting of: inflammatory disorders, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders.
47 . A method as in claim 40 , wherein the disease, disorder, or medical condition is selected from: allergy, asthma, dry eye, chronic obstructed pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, colitis, Crohn's disease, ulcerative colitis, psoriasis, pruritus, itchy skin, atopic dermatitis, urticaria, hives, ocular inflammation, conjunctivitis, dry eye, nasal polyps, allergic rhinitis, nasal itch, scleroderma, autoimmune thyroid diseases, post-operative adhesion, immune-mediated diabetes mellitus (type 1), type 2 diabetes, chronic renal failure, hepatic cholestasis, lupus, Myasthenia gravis, autoimmune neuropathies, Guillain-Barr, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides, Wegener's granulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliary cirrhosis, autoimmune hepatitis, autoimmune oophoritis, autoimmune orchitis, autoimmune disease of the adrenal gland, polymyositis, dermatomyositis, spondyloarthropathies, ankylosing spondylitis, Sjogren's syndrome, major depression disorder, bipolar disorder, treatment-resistant major depression disorder, treatment-resistant bipolar disorder, generalized anxiety disorder, social phobia, post traumatic stress disorder, and pain.
48 . A method as in claim 40 , wherein the disease, disorder, or medical condition is selected from the group consisting of: allergy, asthma, rheumatoid arthritis, autoimmune diseases, and pruritus.
49 . A method for modulating histamine H 4 receptor activity, comprising exposing histamine H 4 receptor to an effective amount of at least one chemical entity selected from compounds of Formula (I)
wherein
Z is CH;
Y is CH;
R 1 is:
a) —(CH 2 ) 2 OCH 3, —(CH 2 ) 2 SCH 3, or C 1-8 alkyl, each independently unsubstituted or substituted with —OH or —CF 3 ;
b) —(CH 2 ) 0-2 -Ar 1 , —CHR 2 -Ar 1 , or —(CH 2 ) 0-2 -Ar 2 , each of said Ar 1 and Ar 2 independently unsubstituted or substituted with halo, —CH 3, or —OCH 3,
Ar 1 is a 6-membered aromatic carbocyclic ring,
Ar 2 is a 5 to 6-membered heteroaromatic ring containing N, S or O; or
c) cycloalkyl, —(CH 2 )-(monocyclic cycloalkyl), —(CH 2 )-(bridged polycyclic cycloalkyl), —(CHR 2 )-(monocyclic cycloalkyl), —(CH 2 )-(fused cycloalkyl), —(CH 2 )-(bridged monocyclic cycloalkyl), —(CH 2 ) 0-1 -tetrahydrofuranyl, or —(CH 2 ) 0-1 -tetrahydropyranyl, each of said cycloalkyl independently unsubstituted or substituted with one, two, or three C 1-4 alkyl substituents;
R 2 is —C 1-4 alkyl;
is
where R a , R b , and R c are each independently H or C 1-3 alkyl;
provided that:
when R 1 is isopropyl, then R c is methyl;
when R 1 is 4-methylphenyl, then R c is methyl; and
pharmaceutically acceptable salts of compounds of Formula (I).
50 . (canceled)
51 . (canceled)
52 . A method for modulating histamine H 4 receptor activity, comprising exposing histamine H 4 receptor to an effective amount of at least one chemical entity of claim 33 .
53 . (canceled)
54 . A method as in claim 49 , wherein said histamine H 4 receptor is in a human subject.
55 . A method as in claim 54 , wherein said human subject is suffering from or is diagnosed with a disease, disorder, or medical condition mediated by histamine H 4 receptor activity.
56 . A method as in claim 55 , wherein said disease, disorder, or medical condition is allergy, rheumatoid arthritis, asthma, autoimmune diseases, or pruritus.
57 . A method as in claim 40 , wherein said administration comprises a topical application.
58 . A method as in claim 57 , wherein said disorder or medical condition is inflammation.
59 . A method as in claim 57 , wherein said disorder or medical condition is at least one of pruritus, urticaria and atopic dermatitis.Cited by (0)
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