US 2021/0277022 A1 · MACROCYCLIC CHLORINE SUBSTITUTED INDOLE DERIVATIVES

Abstract

The present invention relates to macrocyclic indole derivatives of general formula (I): in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

A compound of general formula (I):

wherein
A is
wherein R6 and R7, together with two carbon atoms of the pyrazole ring, two carbon atoms of the indole moiety and the nitrogen atom to which R6 is attached, form a 9- to 16-membered ring and * is the point of attachment of these moieties to the indole carbon atom bearing the A substituent,
or
A is
wherein optionally one or two of the groups selected from CR11, CR12 and CR13 are replaced by a nitrogen atom,
wherein R6 and R10, together with three carbon atoms of the phenyl ring, two carbon atoms of the indole moiety and the nitrogen atom to which R6 is attached, form a 9- to 16-membered ring and * is the point of attachment of these moieties to the indole carbon atom bearing the A substituent;
R1 is a chlorine atom;
R2 and R3 are each a hydrogen atom;
R4 is selected from an aryl group and a heteroaryl group, each of which is unsubstituted or substituted with one, two, three, four or five substituents and each substituent is independently selected from a halogen atom, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-alkoxy group, a C1-C3-thioalkyl group, a C1-C3-haloalkoxy group, a (C1-C3)-haloalkyl-S-group, and a C3-C5-cycloalkyl group;
L is a group —(CH2)m-E- wherein any CH2 group is unsubstituted or substituted with one or two substituents and each substituent is independently selected from a halogen atom, a cyano group, a hydroxyl group, a C1-C3-alkyl group, and a C1-C3-alkoxy group, or two substituents are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 3-6-membered cycloalkyl ring or a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from an oxygen atom, a sulfur atom, a —S(O)— group, a —S(O)2— group, and a —NR14— group;
E is a bond, an oxygen atom, a sulfur atom, a —S(O)— group, a —S(O)2— group or a —NR14— group and constitutes the connecting element to R4;
m is 2, 3, or 4;
R5 is selected from a COOH group, a
group, a —C(O)—NHS(O)2(C1-C6-alkyl) group, a —C(O)—NHS(O)2(C3-C6-cycloalkyl) group, a —C(O)—NHS(O)2(aryl) group, a —C(O)—NHS(O)2(CH2)sNHCO(C1-C6-alkyl) group, a —C(O)—NHS(O)2(CH2)sNHCO(C3-C6-cycloalkyl) group, and a —C(O)—NHS(O)2(CH2)sNHCO(aryl) group;
—R6-R7— is selected from #—(CH2)n—(B)t—(CH2)p—X—##, #—(C2-C6-alkenylene)-(B)t—(CH2)p—X—##, #—(CH2)n—(B)t—(C2-C5-alkenylene)-X—##, and #—(CH2)q—(B)—(CH2)r—(B)—(CH2)v—X—##,
wherein # is the point of attachment with the indole nitrogen atom and ## is the point of attachment with the pyrazole carbon atom bearing the R7 substituent;
and
wherein one or more —CH2— groups may be unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group, a NR16R17 group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group, a C3-C6-cycloalkyl group, and a (heterocycloalkyl)-(C1-C3-alkylene)- group, and where a —CH═CH— group in any alkenylene can be replaced by a 1,2-(C3-C5)cycloalkylene group which is unsubstituted or substituted one or two times with a halogen atom or a C1-C2-alkyl group;
and
where X is —O— or a —NR22— group
where R22 is hydrogen or a C1-C6-alkyl group which is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxy group, a NR16R17 group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-hydroxy alkyl group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group, a C3-C6-cycloalkyl group, a heterocycloalkyl group, an aryl group, a (R18)-(heterocycloalkylene)-(arylene)-O-group, a (heterocycloalkyl)-(arylene)-O— group, an aryl-O— group, an aryl-(C1-C3-alkylene)-O— group, a (R19)—S(O)2-arylene-O— group, a (R19)S(O)2-heterocycloalkylene-arylene-O-group, an aryl-heteroarylene-O— group, an aryl-heteroarylene-O—(C1-C3-alkylene)- group, a heterocycloalkyl-(C1-C3-alkylene)-C(O)— group, a heterocycloalkyl-NH—C(O) group, an aryl-(C1-C3-alkylene)-NH—C(O)— group, a heterocycloalkylene-(C1-C3-alkylene)-S(O)2— group, and a heterocycloalkylene-heteroarylene-S(O)2— group;
—R6-R10— is selected from #—(CH2)n—(B)t—(CH2)p—X—##, #—(C2-C6-alkenylene)-(B)t—(CH2)p—X—##, #—(CH2)n—(B)t—(C2-C5-alkenylene)-X—##, and #—(CH2)q—(B)—(CH2)r—(B)—(CH2)v—X—##, wherein # is the point of attachment with the indole nitrogen atom and ## is the point of attachment with the carbon atom of the phenyl moiety bearing the R10 substituent, one or more —CH2— groups may be unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group, a NR16R17 group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group, a C3-C6-cycloalkyl group, and a (heterocycloalkyl)-(C1-C3-alkylene)- group,
where a —CH═CH— group in any alkenylene can be replaced by a 1,2-(C3-C5)cycloalkylene group which is unsubstituted or substituted one or two times with a halogen atom or a C1-C2-alkyl group, and
where X is —O— or a —NR22— group
where R22 is hydrogen or a C1-C6-alkyl group which is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxy group, a NR16R17 group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-hydroxy alkyl group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group, a C3-C6-cycloalkyl group, a heterocycloalkyl group, an aryl group, a (R18)-(heterocycloalkylene)-(arylene)-O-group, a (heterocycloalkyl)-(arylene)-O— group, an aryl-O— group, an aryl-(C1-C3-alkylene)-O— group, a (R19)—S(O)2-arylene-O— group, a (R19)S(O)2-heterocycloalkylene-arylene-O-group, an aryl-heteroarylene-O— group, an aryl-heteroarylene-O—(C1-C3-alkylene)- group, a heterocycloalkyl-(C1-C3-alkylene)-C(O)— group, a heterocycloalkyl-NH—C(O) group, an aryl-(C1-C3-alkylene)-NH—C(O)— group, a heterocycloalkylene-(C1-C3-alkylene)-S(O)2— group, and a heterocycloalkylene-heteroarylene-S(O)2— group;
n is 2, 3, 4, 5, 6, 7, 8, or 9;
t is 0 or 1;
p is 1, 2, 3, 4, or 5;
q is 2, 3, 4, 5, or 6;
r is 2, 3, 4, 5, or 6;
v is 1;
s is 0, 1, 2, or 3;
where the integers selected for variables n, t, p, q, r, and v result in forming a 9- to 16-membered ring independently from the selection of variable A1, A2 or A3;
B is independently selected from a —C(O)NR15— group, a —NR15C(O)— group, a —N(R15)— group, a —N(R15)—C(═O)—N(R15)— group, a —O—C(═O)—N(R15)— group, a —N(R15)—C(═O)—O— group, —O—, —S—, —S(O)—, and —S(O)2—;
R8 is selected from a hydrogen atom,
a C1-C6-alkyl group, which is unsubstituted or substituted with one or more substituents independently selected from
a halogen atom, a hydroxyl group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group, a C3-C6-cycloalkyl group, a heterocycloalkyl group, and a NR20R21 group;
and
a C3-C6-cycloalkyl group and
R9 is selected from a hydrogen atom,
a C1-C4-alkyl group,
a C1-C3-hydroxyalkyl group,
a C1-C4-haloalkyl group,
a C1-C4-haloalkyl-NH—C(O)—O—(C1-C3-alkylene)- group,
a C2-C6-haloalkenyl group,
a C1-C6-alkyl-O— group,
a C1-C4-haloalkoxy group,
a C1-C6-alkyl-O—(C1-C3-alkylene)- group,
a (C3-C7)-cycloalkyl group,
a (C3-C7)-cycloalkyl-O—(C1-C3-alkylene)- group,
a phenyl-O—(C1-C3-alkylene)- group,
a phenyl-(C1-C3-alkylene)-O—(C1-C3-alkylene)- group,
a R18-(phenylene)-(C1-C3-alkylene)-O—(C1-C3-alkylene)- group,
a R18-(phenylene)-O—(C1-C3-alkylene)- group,
a R18-(phenylene)-(heteroarylene)-O—(C1-C3-alkylene)- group,
a (R18)-(heterocycloalkylene)-(C1-C3-alkylene)- group,
a (R18)-(heterocycloalkylene)-(phenylene)-O—(C1-C3-alkylene)- group,
a (heterocycloalkenyl)-(phenylene)-O—(C1-C3-alkylene)- group,
a (R18)-(heteroarylene)-(C1-C3-alkylene)-O—(C1-C3-alkylene)- group,
a (R18)-(heteroarylene)-(phenylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2-(phenylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2—NH-(phenylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2—NH-(phenylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2—N(C1-C6-alkyl)-(phenylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2-(heterocycloalkylene)-(phenylene)-O—(C1-C3-alkylene)- group,
a (R18)-(heterocycloalkylene)-(heteroarylene)-O—(C1-C3-alkylene)- group,
a (R19)-(heteroarylene)-O—(C1-C3-alkylene)- group,
a (R18)-(heteroarylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2-(heteroarylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2-(heterocycloalkylene)-(heteroarylene)-O—(C1-C3-alkylene)- group,
a NR20R21—(C1-C3-alkylene)- group,
a (C1-C3-alkyl-NH—C1-C3-alkylene)- group,
a (C1-C3-haloalkyl)-(C1-C3-alkylene)-NH—(C1-C3-alkylene)- group,
a (C1-C3-haloalkyl-NH(C1-C3-alkylene)- group,
a (C1-C3-alkyl)-NH—C(O)—(C1-C3-alkylene)- group,
a (C1-C3-alkyl)-NR15—C(O)—(C1-C3-alkylene)- group,
a (C1-C3-alkyl)-C(O)—NH—(C1-C3-alkylene)- group,
a (C1-C3-alkyl)-C(O)—NR15—(C1-C3-alkylene)- group,
a
group, and a
group, where the phenyl ring is unsubstituted or substituted with a halogen atom, a hydroxyl group, or a C1-C3-alkoxy group and
the heterocycloalkyl group is unsubstituted or substituted with an oxo (═O) group or is unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group, a C1-C3-alkyl group, and a C1-C3-alkoxy group,
or R8 and R9 together form a 5- or 6-membered ring optionally comprising one or two heteroatoms selected from —O— and —NR14—;
R11 and R13 are each independently selected from a hydrogen atom, a halogen atom, a C1-C3-alkyl group, and a C1-C3-alkoxy group;
R12 is selected from a hydrogen atom, a C1-C3-alkoxy group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-haloalkoxy group, and a NR16R17 group;
R14 is a hydrogen atom or a C1-C3-alkyl group;
R15 is independently selected from a hydrogen atom,
a C1-C6-alkyl group
which is unsubstituted or substituted with one or more substituents selected from a halogen atom, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-hydroxyalkyl group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group, a heterocycloalkyl group, an aryl group, a (R18)-(heterocycloalkylene)-(arylene)-O-group, a (heterocycloalkyl)-(arylene)-O— group, an aryl-O— group, an aryl-(C1-C3-alkylene)-O— group, a (R19)—S(O)2-arylene-O— group, a (R19)S(O)2-(heterocycloalkylene)-(arylene)-O— group, an (aryl)-(heteroarylene)-O— group, and an (aryl)-(heteroarylene)-O—(C1-C3-alkylene)- group, a phenyl group,
a group,
a group
and
a group
where $ is the point of attachment to the nitrogen atom, to which R15 is attached;
R16 and R17 are each independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-haloalkyl group, a C3-C5-cycloalkyl group, a C1-C3-alkyl-C(O)— group, a C1-C3-alkylS(O)2— group, and a C1-C3-alkyl-O—C(═O)— group;
R18 is selected from a hydrogen atom, a hydroxyl group, a cyano group, a C1-C3-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C3-alkoxy group, a R21OC(O)—(C1-C3-alkylene)- group, a —C(O)OR21 group, a —C(O)NR20R21 group, a (C1-C3-alkyl)-O—(C1-C3-alkylene)-C(O)— group, a (C1-C6-alkyl)-C(O)— group, and a C3-C6-cycloalkyl-C(O)— group;
R19 is selected from a C1-C3-alkyl group, a C3-C6-cycloalkyl group, and a NR20R21 group;
and
R20 and R21 are each independently selected from a hydrogen atom and a C1-C6-alkyl group;
or a tautomer, an N-oxide, or a salt thereof, or a salt of a tautomer, or a salt of an N-oxide, or a mixture of same.

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Macrocyclic chlorine substituted indole derivatives

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Macrocyclic chlorine substituted indole derivatives

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Abstract

Claims18