发明名称 Substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
摘要 The present invention relates to compounds of the formula I,; wherein A, D, E, L, G, R10, R30, R40, R50 and R60 have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. They are inhibitors of the protease cathepsin A, and are useful for the treatment of diseases such as atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.
申请公布号 US9029559(B2) 申请公布日期 2015.05.12
申请号 US201414157703 申请日期 2014.01.17
申请人 SANOFI 发明人 Ruf Sven;Sadowski Thorsten;Wirth Klaus;Schreuder Herman;Buning Christian
分类号 A61K31/44;C07D213/46;C07D413/06;C07D213/81;C07D213/82;C07D217/22;C07D401/04;C07D401/12;C07D405/12;C07D413/04;C07D471/04;C07D487/04;C07D239/28;C07D241/24 主分类号 A61K31/44
代理机构 Morrison & Foerster LLP 代理人 Morrison & Foerster LLP
主权项 1. A compound of formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein A is selected from the group consisting of C(R1) and N; D is selected from the group consisting of C(R2) and N; E is selected from the group consisting of C(R3) and N; L is selected from the group consisting of C(R4) and N; wherein two of A, D, E, and L are N; G is selected from the group consisting of R71—O—C(O)—, R72—N(R73)—C(O)— and tetrazol-5-yl; R1 is selected from the group consisting of hydrogen, halogen, (C1-C6)-alkyl, HO, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m— and NC—; R2 is selected from the group consisting of hydrogen, halogen, (C1-C7)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-CO—, (C1-C6)-alkyl-CO—HN—, —NR12R13, Het2′ (C3-C7)-cycloalkyl-CsH2s— and Ar—CsH2s—; R3 is selected from the group consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-S(O)m—, Het4-(O)t—, —NR12R13, Het2, R11—O—, R12—N(R13)—C(O)—O—, Het2-C(O)—O— and NC—; or R1 and R2 or R2 and R3 form pyridyl; or R1 and R2 are —C((C1-C3)-alkyl)═N—N((C1-C3)-alkyl)-; or R2 and R3 are —NH—CH═N—; R4 is selected from the group consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, HO—, NR12R13, and Het2; R10 is selected from the group consisting hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, HO—, —NR12R13, Het2, phenyl-CsH2s—(O)t—; with the proviso that one of R1, R2, R3, R4 or R10 is a cyclic substituent; s is 0, 1, 2 or 3; t is 0 or 1; R11 is selected from the group consisting of hydrogen, R14, (C3-C7)-cycloalkyl, Ar and Het3; R12 and R13 are independently selected from hydrogen and R15; R14 is (C1-C10)-alkyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Ar, Het1, Het3, NC—, H2N—C(O)—, (C1-C4)-alkyl-NH—C(O)—, di((C1-C4)-alkyl)N—C(O)—, Het1-C(O)—, (C1-C4)-alkyl-C(O)—NH—, and (C1-C4)-alkyl-S(O)m—; R15 is (C1-C6)-alkyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting halogen, HO—, and (C1-C6)-alkyl-O—; R16 is (C1-C6)-alkyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting of HO—, (C1-C4)-alkyl-O—, and NC—; R30 is selected from the group consisting of R31, (C3-C7)-cycloalkyl, R32—CuH2u— and Het3-CuH2u—, wherein u is an integer selected from the group consisting of 0, 1, 2 and 3; R31 is (C1-C10)-alkyl, which is optionally substituted by one or two identical or different substituents selected from the group consisting of halogen, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, and NC—; R32 is selected from the group consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle containing one, two or three identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C6)-alkyl, HO—, (C1-C6)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, (C1-C4)-alkyl-NH—S(O)2—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, (C1-C6)-alkyl-NH—, di((C1-C6)-alkyl)N—, (C1-C4)-alkyl-C(O)—NH—, (C1-C4)-alkyl-S(O)2—NH— and NC—, or substituted once by a phenyl ring or (C3-C7)-cycloalkyl ring; R40 is selected from the group consisting of hydrogen and (C1-C4)-alkyl; or R30 and R40 together are (CH2)x, which is optionally substituted by one or more identical or different (C1-C4)-alkyl substituents, wherein x is 2, 3, 4, or 5; R50 is selected from the group consisting of hydrogen, (C1-C6)-alkyl, HO— and (C1-C6)-alkyl-O—; R60 is selected from hydrogen and (C1-C6)-alkyl; or R50 and R60 together are (CH2)y, which is optionally substituted by one or more identical or different (C1-C4)-alkyl substituents, wherein y is 2, 3, 4, or 5; R71 is selected from hydrogen and (C1-C8)-alkyl, R72 is selected from the group consisting of hydrogen, (C1-C6)-alkyl, wherein alkyl is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, HO—, HOOC—, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—, NC—, and N((C1-C4)-alkyl)2, and b is 0, 1 or 2; R73 is selected from hydrogen and (C1-C6)-alkyl; or R72 and R73, together with the nitrogen atom to which they are bonded, form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—; Ar, independently of each other group Ar, is selected from the group consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle containing one, two, or three identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C6)-alkyl, HO—(C1-C6)-alkyl, (CH16)-alkyl-O—, CF3, —CO—(C1-C6)-alkyl, —NR12R13, —CO—NR12R13, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2— and NC—; Het1, independently of each other group Het1, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle containing a ring nitrogen atom via which Het1 is bonded, and optionally, one or two identical or different further ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O—, oxo, and NC—; Het2 is a saturated 4-membered to 7-membered monocyclic heterocycle containing a ring nitrogen atom via which Het2 is bonded and optionally one further ring heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C4)-alkyl, HO—, and (C1-C4)-alkyl-O—; Het3, independently of each other group Het3, is a saturated 4-membered to 7-membered monocyclic heterocycle containing one or two identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a ring carbon atom and optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine, (C1-C4)-alkyl and oxo; m is independently 0, 1, or 2; wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents selected from fluorine and (C1-C4)-alkyl; wherein all alkyl, CsH2s, CuH2u, (CH2)x, and (CH2)y groups, independently of each other, and independently of any other substituents, are optionally substituted by one or more fluorine substituents.
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