发明名称 Pyrimidine-substituted pyrrolidine derivatives, pharmaceutical compositions and uses thereof
摘要 The invention relates to new pyrrolidine derivatives of the formula; wherein R1 to R3, Ar, L T and n are as defined in the description and claims, to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.
申请公布号 US8962641(B2) 申请公布日期 2015.02.24
申请号 US201414246526 申请日期 2014.04.07
申请人 Boehringer Ingelheim International GmbH 发明人 Fleck Martin;Heimann Annekatrin;Heine Niklas;Nosse Bernd;Roth Gerald Juergen
分类号 C07D405/14;A61K31/506;C07D413/14;A61K31/5377;C07D417/14;C07D403/04;C07D491/08;C07D403/14;C07D491/04;C07D498/04 主分类号 C07D405/14
代理机构 代理人 Morris Michael P.;Stempel Alan R.
主权项 1. A compound of formula I wherein Ar is selected from the group consisting of phenylene and pyridinylene, which are each optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, —O—CH3 and CH3; R1 independently of one another are selected from the group consisting of halogen, CN, C1-6-alkyl, C3-6-cycloalkyl, aryl, —O—(C1-6-alkyl), —S—(C1-3-alkyl), —O—(C3-6-cycloalkyl), —O—(C5-6-cycloalkenyl), —O—(CH2)1-2—(C3-6-cycloalkyl), —O—(C1-3-alkyl)-aryl, —O—CH2—(C2-4-alkenyl), —O—CH2—(C2-4-alkinyl), —O—CH2-heterocyclyl, —O—CH2-heteroaryl, —O-heterocyclyl, —O-aryl, —O-heteroaryl, —(C═O)—NH-aryl, —NRN1RN2, wherein RN1 is H, —CD3, or C1-3-alkyl, andRN2 is H, —CD3, C1-6-alkyl, C3-6-cycloalkyl, —(CH2)1-2—(C3-6-cycloalkyl), heterocyclyl, —CH2-heterocyclyl, or aryl,or wherein RN1 and RN2 are connected and together with the N-atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, 2,5-dihydro-1H-pyrrolyl, morpholinyl, thiomorpholinyl, or [1,4]oxazepanyl ring, wherein each of said rings is optionally substituted with one to four F, or one or two CN, OH, C1-3-alkyl, —O—C1-3-alkyl or —(C1-3-alkyl)-O—(C1-3-alkyl), said substituents being the same or different, wherein heterocyclyl is tetrahydrofuranyl or tetrahydropyranyl,wherein heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl,wherein aryl is selected from the group consisting of phenyl, indanyl and naphthyl,wherein each alkyl is linear or branched and is optionally substituted with 1 to 6 F or with one or two CN, —OH, —O—(C1-4-alkyl) or phenyl,wherein each cycloalkyl is optionally substituted with 1 to 4 F or with one CN, OH, CH3, CF3 or —SO2—(C1-3-alkyl), andwherein each aryl or heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, C1-3-alkyl and —O—(C1-3-alkyl); n is 1, 2 or 3; R2 is H, F, Cl, CN or —O—(C1-3-alkyl); R3 is H or C1-3-alkyl; L is straight-chain C1-3-alkylene, which is optionally substituted with one or two C1-3-alkyl groups; and T is selected from the group consisting of: H, linear or branched C1-6-alkyl which is optionally substituted with one to six F, with one CN, OH, —O—CH3 or —O—C(═O)—CH3, or with a heteroaryl group selected from the group consisting of oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidinyl and pyrazinyl, wherein each of said heteroaryl groups is optionally substituted with one or two substituents, which are independently of each other selected from the group consisting of C1-3-alkyl, —(C1-3-alkyl)-O—CH3 and —NH—(C═O)—(C1-3-alkyl);C3-6-cycloalkyl which is optionally substituted with one or two F, CN, C1-3-alkyl, CF3, OH, —O—(C1-3-alkyl), —NH2, —NH—(C═O)—(C1-3-alkyl), —NH—(C═O)—(C1-3-alkyl)-O—(C1-3-alkyl), —NH—(C═O)—O—(C1-6-alkyl), —C(═O)—NH2, —C(═O)—NH(C1-3-alkyl) or —C(═O)—N(C1-3-alkyl)2, wherein the substituents are identical or different;—O—(Cl1-4-alkyl) which is optionally substituted with C3-7-cycloalkyl;—NR4R5, wherein R4 is H or C1-3-alkyl, and R5 is H, C1-3-alkyl, —(C1-3-alkyl)-O—CH3 or a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected independently from O, S, N and NH, wherein said heteroaryl group is optionally substituted with C1-3-alkyl; or wherein R4 and R5 are connected and together with the N to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring that is optionally substituted with one or two C1-3-alkyl or with one —NH—(C═O)—CH3; anda 5-membered heteroaryl group containing one to three heteroatoms selected independently from O, S, N and NH, which is optionally substituted with one or two substituents selected independently from the group consisting of C1-3-alkyl, —NH2, —NH—C(═O)—C1-3-alkyl, —NH—C(═O)—(C1-3-alkyl)-O—(C1-3-alkyl), —NH—C(═O)—(C1-3-alkyl)-OH, —NH—C(═O)—O—(C1-6-alkyl) and —O—(C1-2-alkyl), wherein each alkyl group is optionally substituted with one to three F or with one OH;or a tautomer or salt thereof.
地址 Ingelheim am Rhein DE