1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin d synthase inhibitors

A compound according to Formula (I)

• wherein:
• X is selected from:
• carbon and nitrogen;
• Y is selected from:
• hydrogen and CH3;
• Y1 is absent or CH3;
• Z is NH or O;
• a is 0 or 1;
• R is selected from:
• O, NH, CH2 and C1alkyl substituted by halogen;
• R1 is selected from:
• aryl,
• aryl substituted from 1 to 4 times by Ra,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Ra,
• bicycloheteroaryl, and
• bicycloheteroaryl substituted from 1 to 4 times by Ra;
• R2 is selected from:
• O and S;
• R3 is selected from:
• aryl,
• aryl substituted from 1 to 4 times by Rb,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rb,
• heterocycle,
• heterocycle substituted from 1 to 4 times by Rb,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Rb,
• bicycloheteroaryl, and
• bicycloheteroaryl substituted from 1 to 4 times by Rb;
• each Ra is independently selected from:
• fluoro,
• chloro,
• bromo,
• iodo,
• —OH,
• C1-6alkyl,
• C1-6alkyl substituted with from 1 to 5 substituents independently selected from:
• fluoro, chloro, bromo, iodo, C1-lalkyloxy, —OH, C1-4alkyl, oxo, —COOH, —NO2, —NH2 and —CN, cyano,
• —OC1-6alkyl,
• —OC1-6alkyl substituted with from 1 to 5 substituents independently selected from:
• fluoro, chloro, bromo, iodo, C1-4aalkyloxy, —OH, C1-4alkyl, oxo, —COOH, —NO2, —NH2 and —CN,
• cyano,
• —C(O)OC1-6alkyl, and
• —C(O)OC1-6alkyl substituted 1 to 5 times by fluoro;
• each Rb is independently selected from:
• cyano,
• fluoro,
• chloro,
• bromo,
• iodo,
• C1-6alkyl,
• Re,
• —OC1-6alkyl,
• —ORe,
• oxo,
• hydroxyl,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rf,
• amino,
• —NHRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —OC1-6alkyl, —OC1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, and —OH, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —OC1-6alkyl, —COOH, —NH2, —NHcycloalkyl, and —CN,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Rf,
• heterocycle,
• heterocycle substituted from 1 to 4 times by Rf,
• —SO2H, and
• —SO2C1-6alkyl;
• each Rf is independently selected from:
• fluoro,
• chloro,
• bromo,
• iodo,
• C1-6alkyl,
• Re,
• oxo,
• —OH,
• amino,
• —NHRx1,
• where Rx1 is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —OC1-6alkyl, —COOH, —NH2, and —CN,
• −NRx2Rx3,
• where Rx2 and Rx3 are each independently selected from:
• aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• nitro, and
• cyano, and
• each Re is independently selected from:
• C1-6alkyl substituted with from 1 to 9 substituents independently selected from:
• fluoro,
• chloro,
• bromo,
• iodo,
• C1-6alkyl,
• —OC1-6alkyl,
• —OC1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, —CN, and phenyl,
• oxo,
• ═N,
• hydroxyl,
• amino,
• —NHRxx, or ═NRxx,
• where Rxx is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —OC1-5alkyl, —OC1-5alkyl substituted from 1 to 6 times by fluoro,
• —NRxx1,Rxx2,
• where Rxx1 and Rxx2 are each independently selected from:
• aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• aryl,
• aryl substituted from 1 to 4 times by Rxx3,
• where Rxx3 is selected from:
• fluoro, chloro, bromo, iodo, C1-6alkyl, C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN, —OC1-5alkyl, and —OC1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rxx4,
• where Rxx4 is selected from:
• fluoro, chloro, bromo, iodo, C1-6alkyl, C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN, —OC1-5alkyl, and —OC1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• nitro, and
• cyano;
• or a pharmaceutically acceptable salt thereof.