US 2020/0347079 A1 · NOVEL PTEFB INHIBITING MACROCYCLIC COMPOUNDS

1:

A compound of formula (I)
wherein
A represents a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O)2—, —S(═O)(═NR5)—, and —S(═NR6)(═NR7)—;
G, E represent, independently from each other, a bivalent moiety selected from the group consisting of —O—, —N(RA)—, —CH2—, —CH(C1-C6-alkyl)-, —C(C1-C6-alkyl)2-, and —S—, with the proviso that at least one of said bivalent moieties G and E is different from —O—;
Z represents a hydrogen atom or a fluorine atom;
L represents a C3-C8-alkylene moiety,
wherein said moiety is optionally substituted with
(i) one substituent selected from the group consisting of hydroxy, —NR8R9, C2-C3-alkenyl-, C2-C3-alkynyl-, C3-C4-cycloalkyl-, hydroxy-C1-C3-alkyl, and —(CH2)NR8R9;
and/or
(ii) one or two or three or four substituents, identically or differently, selected from the group consisting of halogen and C1-C3-alkyl-,
or wherein
one carbon atom of said C3-C8-alkylene moiety forms a three- or four-membered ring together with a bivalent moiety to which it is attached, wherein said bivalent moiety is selected from the group consisting of —CH2CH2—, —CH2CH2CH2—, and —CH2OCH2—;
X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1 represents a group selected from the group consisting of C1-C6-alkyl-, C3-C6-alkenyl-, C3-C7-cycloalkyl-, and heterocyclyl-,
wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C1—C-alkyl-, halo-C1-C3-alkyl-, C1—C-alkoxy-, C1-C3-fluoroalkoxy-, —NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, a cyclic amine, —OP(═O)(OH)2, —C(═O)OH, and —C(═O)NH2;
R2 represents a group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkyl-, and C1-C3-fluoroalkoxy-;
R3, R4 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkyl-, and C1-C3-fluoroalkoxy-;
R5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R10, —C(═O)OR10, —S(═O2) R10, —C(═O)NR8R9, C1-C6-alkyl-, C3-C7-cycloalkyl-, and heterocyclyl-,
wherein said C1-C6-alkyl-, C3-C7-cycloalkyl- and heterocyclyl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, a cyclic amine, halo-C1-C3-alkyl-, and C1-C3-fluoroalkoxy-;
R6, R7 represent, independently from each other, a group selected from a hydrogen atom, cyano, —C(═O)R10, —C(═O)OR10, —S(═O)2R10, —C(═O)NR8R9, C1-C6-alkyl-, C3-C7-cycloalkyl-, and heterocyclyl-,
wherein said C1-C6-alkyl-, C3-C7-cycloalkyl- or heterocyclyl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, a cyclic amine, halo-C1-C3-alkyl-, and C1-C3-fluoroalkoxy-;
R8, R9 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and heteroaryl-,
wherein said C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- or heteroaryl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, a cyclic amine, halo-C1-C3-alkyl-, and C1-C3-fluoroalkoxy-, or
R8 and R9, together with the nitrogen atom they are attached to, form a cyclic amine;
R10 represents a group selected from the group consisting of C1-C6-alkyl-, halo-C1-C3-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-2 and heteroaryl-,
wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, a cyclic amine, halo-C1-C3-alkyl-, and C1-C3-fluoroalkoxy-;
RA represents a hydrogen atom or a C1-C6-alkyl-group;
or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

25 more elements

2:

The compound of formula (I) according to claim 1, wherein
A represents a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O)2—, —S(═O)(═NR5)—, and —S(═NR6)(═NR7)—;
G, E each represent, independently from each other, a bivalent moiety selected from the group consisting of —O—, —N(RA)—, —CH2—, —CH(C1-C3-alkyl)-, and —S—,
with the proviso that at least one of said bivalent moieties G and E is different from —O—;
Z represents a hydrogen atom or a fluorine atom;
L represents a C3-C5-alkylene moiety,
wherein said moiety is optionally substituted with
i) one substituent selected from the group consisting of hydroxy, C3-C4-cycloalkyl-, hydroxy-C1-C3-alkyl-, and —(CH2)NR8R9;
and/or
ii) one or two or three substituents, identically or differently, selected from the group consisting of halogen and C1-C3-alkyl-;
X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1 represents a group selected from the group consisting of C1-C6-alkyl- and C3-C5-cycloalkyl-,
wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C1-C3-alkyl-, fluoro-C1-C2-alkyl-, C1-C3-alkoxy-, C1-C2-fluoroalkoxy-, —NH2, alkylamino-, dialkylamino-, a cyclic amine, —OP(═O)(OH)2, —C(═O)OH, and —C(═O)NH2;
R2 represents a group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, cyano, C1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C2-alkyl-, and C1-C2-fluoroalkoxy-;
R3, R4 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, cyano, C1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C2-alkyl-, ad C1-C2-fluoroalkoxy-;
R5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R10, —C(═O)OR10, —S(═O)2R10, —C(═O)NR8R9, C1-C6-alkyl-, and C3-C5-cycloalkyl-,
wherein said C1-C6-alkyl- and C3-C5-cycloalkyl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, a cyclic amine, fluoro-C1-C2-alkyl-, and C1-C2-fluoroalkoxy-;
R6, R7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R10, —C(═O)OR10, —S(═O)2R10, —C(═O)NR8R9, C1-C6-alkyl-, and C3-C5-cycloalkyl-,
wherein said C1-C6-alkyl- or C3-C5-cycloalkyl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, a cyclic amine, fluoro-C1-C2-alkyl-, and C1-C2-fluoroalkoxy-;
R8, R9 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, C1-C6-alkyl-, C3-C5-cycloalkyl-, phenyl-2 and benzyl-,
wherein said C1-C6-alkyl-, C3-C5-cycloalkyl-, phenyl- or benzyl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, a cyclic amine, fluoro-C1-C2-alkyl-, and C1-C2-fluoroalkoxy-, or
R8 and R9, together with the nitrogen atom they are attached to, form a cyclic amine;
R10 represents a group selected from the group consisting of C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-cycloalkyl-, phenyl-, and benzyl-,
wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, a cyclic amine, fluoro-C1-C2-alkyl-, and C1-C2-fluoroalkoxy-;
RA represents a hydrogen atom or a C1-C3-alkyl-group;
or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

23 more elements

3:

The compound of formula (I) according to claim 1, wherein
A represents a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O)2—, —S(═O)(═NR5)—, and —S(═NR6)(═NR7)—;
E represents a bivalent moiety selected from the group consisting of —O—, —N(RA)—, —CH2—, —CH(C1-C3-alkyl)-, and —S—;
G represents a bivalent moiety selected from the group consisting of —O—, —N(RA)—, —CH2—, —CH(C1-C3-alkyl)-, and —S—;
with the proviso that at least one of said bivalent moieties G and E is different from —O—;
Z represents a hydrogen atom or a fluorine atom;
L represents a C3-C5-alkylene moiety,
wherein said moiety is optionally substituted with
(i) one substituent selected from the group consisting of C3-C4-cycloalkyl- and hydroxymethyl, and/or
(ii) one or two or three C1-C2-alkyl-group substituents, identically or differently;
X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1 represents a group selected from the group consisting of C1-C4-alkyl- and C3-C5-cycloalkyl-,
wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C1-C2-alkyl-, C1-C2-alkoxy-, —NH2, and —C(═O)OH;
R2 represents a group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-, and trifluoromethoxy-;
R3 represents a group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-, and trifluoromethoxy-;
R4 represents a hydrogen atom or a fluorine atom;
R5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R10, —C(═O)OR10, —S(═O)2R10, —C(═O)NR8R9, and C1-C4-alkyl-,
wherein said C1-C4-alkyl-group is optionally substituted with one substituent selected from the group consisting of a fluorine atom, hydroxy, cyano, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, and a cyclic amine;
R6, R7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R10, —C(═O)OR10, —S(═O)2R10, —C(═O)NR8R9, and C1-C4-alkyl-,
wherein said C1-C4-alkyl-group is optionally substituted with one substituent selected from the group consisting of a fluorine atom, hydroxy, cyano, C1-C3-alkoxy-, —NH2, alkylamino-, dialkylamino-, and a cyclic amine;
R8, R9 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, C1-C4-alkyl-2 and C3-C5-cycloalkyl-;
wherein said C1-C4-alkyl- or C3-C5-cycloalkyl-group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, —NH2, alkylamino-, dialkylamino-, and a cyclic amine, or
R8 and R9, together with the nitrogen atom they are attached to, form a cyclic amine;
R10 represents a group selected from the group consisting of C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-cycloalkyl-, and benzyl-,
wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, and —NH2;
RA represents a hydrogen atom or a C1-C3-alkyl-group;
or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

24 more elements

4:

The compound of formula (I) according to claim 1, wherein
A represents a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O)2—, —S(═O)(═NR5)—, and —S(═NR6)(═NR7)—;
E represents a bivalent moiety selected from the group consisting of —O—, —N(RA), and —CH2—;
G represents a bivalent moiety selected from the group consisting of —O—, —N(RA)—, —CH2—, and —S—;
with the proviso that at least one of said bivalent moieties G and E is different from —O—;
Z represents a hydrogen atom or a fluorine atom;
L represents a C3-C5-alkylene moiety;
X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1 represents a C1-C4-alkyl-group,
wherein said group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C1-C2-alkoxy-, —NH2, and —C(═O)OH;
R2 represents a hydrogen atom or a fluorine atom;
R3 represents a group selected from the group consisting of a hydrogen atom, a fluorine atom, and a methoxy-group;
R4 represents a hydrogen atom;
R5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R10, —C(═O)OR10, —C(═O)NR8R9, and C1-C4-alkyl-,
wherein said C1-C4-alkyl-group is optionally substituted with one substituent selected from the group consisting of hydroxy, cyano, C1-C3-alkoxy-, —NH2, alkylamino-, and dialkylamino-;
R6, R7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, cyano, and C1-C4-alkyl-,
wherein said C1-C4-alkyl-group is optionally substituted with one hydroxy group;
R8, R9 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, C1-C4-alkyl-, and C3-C5-cycloalkyl-, or
R8 and R9, together with the nitrogen atom they are attached to, form a cyclic amine;
R10 represents a group selected from the group consisting of C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-cycloalkyl-, and benzyl-,
wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, and —NH2;
RA represents a hydrogen atom, a methyl- or an ethyl-group;
or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

20 more elements

Novel ptefb inhibiting macrocyclic compounds

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Novel ptefb inhibiting macrocyclic compounds

Life of this patent

Abstract

Claims25