US 11,440,923 B2 · Substituted macrocyclic indole derivatives

Abstract

The present invention relates to substituted 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-membered 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-membered to 16-membered ring and * is the point of attachment of these moieties to the indole carbon atom bearing the A substituent;
R1 and R2 are each independently selected from a hydrogen atom, a halogen atom, a cyano group, a C1-C3-alkyl group and a C1-C3-alkoxy group;
R3 is selected from a hydrogen atom, a halogen atom, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-alkoxy group, a C1-C3-alkylthio group, a (C1-C3-alkyl)-S(O)— group, a (C1-C3-alkyl)-S(O)2— group, a C1-C3-haloalkoxy group, a C1-C3-haloalkylthio group and a C3-C5-cycloalkyl group;
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 hydroxy 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-membered to 6-membered cycloalkyl ring, or a 3-membered to 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;
s is 0, 1 or 2;
—R6-R7— is #—(CH2)n—(B)t—CR22R23—## or #—(C2-C9-alkenylene)-(B)t—CR22R23—##,
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 hydroxy 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;
—R6-R10— is #—(CH2)n—(B)t—CR22R23—## or #—(C2-C9-alkenylene)-(B)t—CR22R23—##, where one or more —CH2— groups are substituted with one or more substituents independently selected from a halogen atom, a hydroxy group, a NR16R17 group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-alkoxy group and a C1-C3-haloalkoxy group, wherein # is the point of attachment with the indole nitrogen atom and ## is the point of attachment with the carbon atom of the aromatic moiety bearing the R10 substituent;
n is 2, 3, 4, 5, 6, 7, 8, or 9, if B is selected from —O—, —S—, —S(O)—, —S(O)2— and —N(R15)— and
n is 1, 2, 3, 4, 5, 6, 7 or 8 if B is selected from —C(O)NR15— group and a —NR15C(O)— group and
n is 0, 1, 2, 3, 4, 5, 6, or 7 if B is selected from a —N(R15)—C(═O)—N(R15)— group, a —O—C(═O)—N(R15)— group and a —N(R15)—C(═O)—O— group;
t is 1;
where the integers selected for variables n and t, together with the methylene group CR22R23 and the other non-variable atoms of the pyrazole and the indole moiety result in forming a 9-membered 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 —NR 15C(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 hydroxy group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group,
a C3-C6-cycloalkyl group, a heterocycloalkyl group and a NR21R22 group;
a C1-C3-haloalkyl group,
a C3-C6-cycloalkyl group and
a C1-C6-alkyl group in which one or two not directly adjacent carbon atoms are independently replaced by a heteroatom selected from —O— and —NH— 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 hydroxy 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 hydroxy group, a C1-C3-alkyl group and a C1-C3-alkoxy group,
or R8 and R9 together form a 5-membered or 6-membered ring optionally comprising one or two heteroatoms independently 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, 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,
a C1-C3-alkylene-C(O)— group,
a heterocycloalkyl-(C1-C3-alkylene)-C(O)— group,
a heterocycloalkyl-(C1-C3-alkylene)-S(O)2— group,
a heterocyclyl-NH—C(O)— group,
a heterocycloalkyl-(C1-C3-alkylene)-NH—C(O)— group,
an aryl-(C1-C3-alkylene)-NH—C(O)— group, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from a halogen atom, a C1-C3-alkyl group and a C1-C3-alkoxy group,
a heterocycloalkyl-heteroarylene-S(O)2— 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,
or R15 and R22 together, including the atoms to which they are attached, may form a 5- or 6-membered ring optionally comprising one or two additional heteroatoms independently selected from —O— and —NR14—;
R16 and R17 are each independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy 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 hydroxy 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;
R20 and R21 are each independently selected from a hydrogen atom and a C1-C6-alkyl group;
and
R22 is independently selected from
a halogen atom,
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-hydroxyalkyl 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,
a C1-C3-alkyl-C(O)— group,
a C3-C6-cycloalkyl group,
an aryl group,
a heterocycloalkyl group and
a heteroaryl group;
wherein any heterocycloalkyl group of R22 may optionally be itself further substituted with a C1-C3-alkyl group or one or two halogen atoms and
R23 is independently selected from a hydrogen atom, a halogen atom, a hydroxy group, a C1-C6-alkyl group and a C1-C6-haloalkyl group,
or
R22 and R23 together with the carbon atom to which they are attached form a 3-membered to 6-membered carbocyclic ring or a 3-membered to 6-membered heterocyclic ring comprising one or two heteroatoms selected from nitrogen, oxygen or sulfur;
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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Substituted macrocyclic indole derivatives

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Substituted macrocyclic indole derivatives

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Abstract

Claims15