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US 9,540,349 B2Granted
Substituted pyrimidine compounds
AssigneeGruenenthal GmbH
InventorsAntonio Nardi, Florian Jakob, Ingo Konetzki, Tobias Craan, Christian Hesslinger
Life of this patent
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Abstract
The invention relates to novel substituted pyrimidine compounds of general formula (I) in which the chemical groupings, substituents, variables and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.
Claims26
A compound of formula (I)
- wherein
- A, B and C independently represent CH or N;
- R1 and R2 independently represent
- hydrogen or (C1-C6)-alkyl, whereby said (C1-C6)-alkyl is unsubstituted or substituted with at least one substituent X1, or
- a group U, which is a 3- to 12-membered mono- or bi-cycloaliphatic ring, which is unsubstituted or substituted with at least one substituent X2, whereby said group U may be connected to the nitrogen atom via a C1-6-alkylene group, which in turn is unsubstituted or substituted with at least one substituent independently selected from the group consisting of F, Cl, CF3, ═O, OCF3 and OH, or
- a group V, which is a 3- to 12-membered mono-or bi-cyclic heterocycloaliphatic ring comprising at least one heteroatom selected from the group consisting of O, S and N as a ring member, and which mono- or bicyclic heterocycloaliphatic ring is unsubstituted or substituted with at least one substituent X3, whereby said group V may be connected to the nitrogen atom via a C1-6-alkylene group, which in turn may be unsubstituted or substituted with at least one substituent independently selected from the group consisting of F, Cl, CF3, ═O, OCF3 and OH, or
- a group W which is phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said heteroaryl is unsubstituted or substituted with at least one substituent X4 and may be condensed with a 4-, 5-, 6- or 7-membered ring, being carbocyclic or heterocyclic, wherein said condensed ring may be saturated, partially unsaturated or aromatic and may be substituted with at least on substituent X5, and whereby group W may be connected to the nitrogen atom via a C1-6-alkylene group, which in turn may be unsubstituted or substituted with at least one substituent independently selected from the group consisting of F, Cl, CF3, ═O, OCF3 and OH, or
- R1 and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered monocyclic or bicyclic non-aromatic or aromatic ring wherein said ring may contain at least one additional heteroatom selected from the group consisting of O,S and N and wherein said ring is unsubstituted or substituted with at least one substituent X6;
- R3 and R4,
- independently represent hydrogen, (C1-C6)-alkyl or (C3-C6)-cycloalkyl, wherein said (C1-C6)-alkyl and (C3-C6)-cycloalkyl are each unsubstituted or substituted with at least one substituent Y1, or
- together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring, which is unsubstituted or substituted with at least one substituent Y2;
- L represents a bond, O, S, (C1-C6)-alkylene or (C2-C6)-alkenylene, whereby the aforementioned alkylenes or alkenylenes are in each case unsubstituted or substituted with at least one substituent selected from the group consisting of F, Cl, CF3, ═O,OCF3 and OH;
- G represents a phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said heteroaryl may be substituted with at least one substituent Z;
- X1, X2, X3, X5 and X6, at each occurrence are independently from one another selected from the group consisting of OH, ═O,CN, nitro, halogen, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, S(C1-C6)-alkyl, S(O)—(C1-C6)-alkyl, S(O)2—(C1-C6)-alkyl, (C1-C6)-haloalkyl, S(C1-C6)-haloalkyl, (C1-C6)-haloalkoxy, (C1-C6)-cyanoalkyl, (C3-C8)-cycloalkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH—CO—(C1-C6)-alkyl, NH—SO—(C1-C6)-alkyl, NH—S(O)2—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-SO—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-SO—(C1-C6)-alkyl, NHCONH2, NH—CO—NH—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-CO—N((C1-C6)-alkyl)2, CO—(C1-C6)-alkyl, CO2H, CO—O—(C1-C6)-alkyl, CONH2, CO—NH(C1-C6)alkyl and CO—N((C1-C6)-alkyl)2;
- X4 at each occurrence are independently from one another selected from the group consisting of OH, CN, nitro, halogen, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, S(C1-C6)-alkyl, S(O)—(C1-C6)-alkyl, S(O)2—(C1-C6)-alkyl, (C1-C6)-haloalkyl, S(C1-C6)-haloalkyl, (C1-C6)-haloalkoxy, (C1-C6)-cyanoalkyl, (C3-C8)-cycloalkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH—CO—(C1-C6)-alkyl, NH—SO—(C1-C6)-alkyl, NH—S(O)2—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-CO—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-SO—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-SO2—(C1-C6)-alkyl, NHCONH2, NH—CO—NH—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-CO—N((C1-C6)-alkyl)2, CO2H, CO—O—(C1-C6)-alkyl, CONH2, CO—NH(C1-C6)alkyl and CO—N((C1-C6)-alkyl)2;
- Y1 and Y2, at each occurrence are independently from one another selected from the group consisting of OH, ═O CN, nitro, halogen, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, S(C1-C6)-alkyl, S(O)—(C1-C6)-alkyl, S(O)2—(C1-C6)-alkyl, (C1-C6)-haloalkyl, S(C1-C6)-haloalkyl, (C1-C6)-haloalkoxy, (C1-C6)-cyanoalkyl, (C3-C8)-cycloalkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH—CO—(C1-C6)-alkyl, NH—SO—(C1-C6)-alkyl, NH—S(O)2—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-CO—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-SO—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-SO2—(C1-C6)-alkyl, NHCONH2, NH—CO—NH—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-CO—N((C1-C6)-alkyl)2, CO2H, CO—O—(C1-C6)-alkyl, CONH2, CO—NH(C1-C6)alkyl and CO—N((C1-C6)-alkyl)2;
- Z at each occurrence is independently selected from the group consisting of halogen, OH, CN, SH, nitro, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, (C1-C6)-hydroxyalkyl, (C1-C6)-cyanoalkyl, (C1-C6)-alkoxy, (C1-C6)-thioalkyl, (C1-C6)-haloalkyl, (C1-C6)-thiohaloalkyl, (C1-C6)-haloalkoxy, (C1-C6)-alkylen-S—(C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C3)-alkylenyl, (C3-C8)-heterocycloalkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH—CO—(C1-C6)-alkyl, NH—CO—O—(C1-C6)-alkyl, NH—C(O)NH2, NH—CO—NH—(C1-C6)-alkyl, NH—CO—N((C1-C6)-alkyl)2, NH((C1-C6)-alkylen)-CO—O—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-CONH2, NH((C1-C6)-alkylen)-CO—NH—(C1-C6)-alkyl, NH((C1-C6)-alkylen)-CO—N((C1-C6)-alkyl)2, NH—S(O)2OH, NH—S(O)2(C1-C6)-alkyl, NH—S(O)2O(C1-C6)-alkyl, NH—S(O)2NH2, NH—S(O)2NH(C1-C6)-alkyl, NH—S(O)2N((C1-C6)-alkyl)2, NH((C1-C6)-alkylen)-S(O)2OH, NH((C1-C6)-alkylen)-S(O)2(C1-C6)-alkyl, NH((C1-C6)-alkylen)-S(O)2O(C1-C6)-alkyl, NH((C1-C6)-alkylen)-S(O)2NH2, NH((C1-C6)-alkylen)-S(O)2NH(C1-C6)-alkyl, CO2H, CO(C1-C6)-alkyl, CO—O(C1-C6)-alkyl, O—CO(C1-C6)-alkyl, O—CO—O(C1-C6)-alkyl, CONH2, CO—NH(C1-C6)-alkyl, CO—N((C1-C6)-alkyl)2,O—CO—NH(C1-C6)-alkyl, O—CO—N((C1-C6)-alkyl)2, O—S(O)2—(C1-C6)-alkyl, O—S(O)2OH, O—S(O)2—(C1-C6)-alkoxy, O—S(O)2NH2,O—S(O)2—NH(C1-C6)-alkyl, O—S(O)2—N((C1-C6)-alkyl)2, S(O)(C1-C6)-alkyl, S(O)2(C1-C6)-alkyl, S(O)2OH, S(O)2O(C1-C6)-alkyl, S(O)2NH2, S(O)2NH(C1-C6)-alkyl, and S(O)2N((C1-C6)-alkyl)2;
- optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof.
15 more elements
Dependencies are inferred from the claim text.