发明名称 IP Receptor Agonist Heterocyclic Compounds
摘要 The present invention provides heterocyclic derivatives which activate the IP receptor. Activating the IP receptor signaling pathway is useful to treat many forms of PAH, pulmonary fibrosis and exert beneficial effects in fibrotic conditions of various organs in animal models and in patients. Pharmaceutical compositions comprising such derivatives are also encompassed.
申请公布号 US2015376183(A1) 申请公布日期 2015.12.31
申请号 US201414767500 申请日期 2014.02.11
申请人 BUTLER Rebecca;LEBLANC Catherine;MICKEOWN Stephen Carl;CHARLTON Steven John 发明人 Butler Rebecca;LEBLANC Catherine;McKeown Stephen Carl;Charlton Steven John
分类号 C07D471/04;A61K31/4375 主分类号 C07D471/04
代理机构 代理人
主权项 1. A compound represented by Formula Ia or a pharmaceutically acceptable salt thereof, wherein R′ is H, C1-C8 alkyl optionally substituted by one or more halogen atoms;R1 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, OR′, —NR19R21, CN or C3-C7 cycloalkyl; orR1 is —X—Y; orR1 is —W—R7—X—Y; orR1 is —S(O)2—W—X—Y; orR1 is —S(O)2—W—R7—X—Y;R2 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, OR′, —NR19R21, CN or C3-C7 cycloalkyl; orR2 is —X—Y; orR2 is —W—R7—X—Y; orR2 is —S(O)2—W—X—Y;R2 is —S(O)2—W—R7—X—Y;wherein either R1 or R2 is —X—Y, —S(O)2—W—X—Y; or —S(O)2—W—R7—X—Y;R2a is hydrogen;R2 and R2a taken together are oxo;R3 is H, C1-C4 alkoxy, OH, —NR19R21, CN, halogen, C3-C7 cycloalkyl or C1-C8 alkyl optionally substituted by one or more halogen atoms;R4 is H, C1-C4 alkoxy, OH, —NR19R21, CN, halogen, C3-C7 cycloalkyl or C1-C8 alkyl optionally substituted by one or more halogen atoms;R5 is C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, OR′, —NR19R21, CN or C3-C7 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; C6-C14 aryl; —(C0-C4 alkyl)-4 to 14 membered heteroaryl, or —(C0-C4 alkyl)-3 to 14 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents;R6 is C8-C14 aryl; —(C0-C4 alkyl)-4 to 14 membered heteroaryl, —(C0-C4 alkyl)-3 to 14 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents;W is C1-C8 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;X is C1-C8 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;Y is carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or —CONH—S(O)q—Rx, wherein Rx is —C1-C4 alkyl or —NR19R21;q is 0, 1 or 2;R7 is a divalent moiety represented by —O—, —NHC(O)—, —CH2═CH2—, —C8-C14 aryl-D-; -3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O, S, NH or not present;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups, C1-C6 alkoxy optionally substituted by one or more halogen, C1-C6 alkoxy R21, (SO2)R21, optionally substituted by C1-C4 alkoxy, NR18(SO2)R21, (SO2)NR19R21, (SO2)R21, NR18C(O)R21, C(O)NR19R21, NR18C(O)NR19R21, NR18C(O)OR19, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S;R18 is independently H or C1-C6 alkyl;R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2; orR19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclyl, the heterocyclyl including one or more further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclyl including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclyl substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.
地址 Horsham Sussex GB