# US 2021/0277022 A1 · Macrocyclic chlorine substituted indole derivatives

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- Number: US 2021/0277022 A1
- Document ID: US20210277022A1
- Status: Published application
- Kind: A1
- Application number: 16/764,675
- Filed: 2018-11-15
- Published: 2021-09-09
- Earliest claimed: 2017-11-17
- Assignees: Bayer Aktiengesellschaft; Bayer Pharma Aktiengesellschaft; The Broad Institute, Inc.
- Applicants: Bayer Aktiengesellschaft; Bayer Pharma Aktiengesellschaft; The Broad Institute, Inc.
- Inventors: Kai Thede; Anne Mengel; Clara Christ; Joachim Kuhnke; Sarah Anna Liesa Johannes; Philipp Buchgraber; Ulrich Klar; Ulrike Sack; Stefan Kaulfuss; Amaury Ernesto Fernandez-Montalvan; Nicolas Werbeck; Ursula Mönning; Katrin Nowak-Reppel; Jeremie Xavier Mortier; Patrick Ryan McCarren; Michael H. Serrano-Wu; Christopher Lemke; David McKinney; Mark Fitzgerald; Christopher Nasveschuk; Kiel Lazarski; Steven James Ferrara; Laura Furst; Guo Wei; Rebecca Ann Flarvey; Daniel Payne; Thomas Pesnot; Craig Wilson
- Web page: https://patentgrep.com/patent/US20210277022A1

## CPC

- C07D 487/04: Ortho-condensed systems
- C07D 498/14: Ortho-condensed systems
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 487/14: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 498/20: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of general formula (I) according to claim 1, 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;
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, or three, 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;
m is 2, 3 or 4;
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;
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, and a C1-C3-haloalkoxy 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 C1-C3-alkyl group, a C3-C6-cycloalkyl group, a heterocycloalkyl group and an aryl group;
n is 2, 3, 4, 5, 6, 7, 8, or 9;
p is 1, 2, 3, 4, or 5;
t is 0 or 1;
s is 0, 1, 2, or 3;
where the integers selected for variables n, t, and p result in forming a 9- to 16-membered ring independently from the selection of variable A1 or A2;
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 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;
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)-O—(C1-C3-alkylene)- group,
a (R18)-(phenylene)-(C1-C3-alkylene)-O—(C1-C3-alkylene)- group,
a (R18)-(phenylene)-(heteroarylene)-O—(C1-C3-alkylene)- group,
a (R18)-(heterocycloalkylene)-(C1-C6-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 (R18)-(phenylene)-(C1-C3-alkylene)-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—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 (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 optionally substituted with a halogen atom, a hydroxyl group, or a C1-C3-alkoxy group and
the heterocycloalkyl group is optionally substituted with an oxo (═O) group or is optionally substituted with one or more substituents independently selected from a halogen atom and a C1-C3-alkyl group;
or R8 and R9 together form a 5- or 6-membered ring optionally comprising one or two heteroatoms selected from —O—, and —NR14—;
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 optionally 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, 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 and an aryl-heteroarylene-O— 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 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; 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.

### Claim 3 (depends on 1)

The compound of general formula (I) according to claim 1, 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 10- to 12-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, or three, substituents and each substituent is independently selected from a halogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group;
L is a group —(CH2)m-E-;
E is a bond or an oxygen atom and constitutes the connecting element to R4;
m is 2, 3, or 4;
R5 is a COOH group;
—R6-R7— is selected from #—(CH2)n—(B)t—(CH2)p—X—## and #—(C2-C6-alkenylene)-(B)t—(CH2)p—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, and a C1-C3-alkoxy 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 a heterocycloalkyl group;
n is 3, 4, 5, or 6;
t is 0 or 1;
P is 1;
where the integers selected for variables n, t, and p result in forming a 10- to 12-membered ring independently from the selection of variable A1 or A2;
B is independently selected from a —N(R15)— group and —O— group;
R8 is selected from a hydrogen atom and
a C1-C4-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 NR20R21 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 C2-C6-haloalkenyl group,
a C1-C6-alkyl-O—(C1-C3-alkylene)- group,
a (C3-C7-cycloalkyl)- group,
a phenyl-O—(C1-C3-alkylene)- group,
a (R18)-(phenylene)-O—(C1-C3-alkylene)- group,
a (R18)-(heterocycloalkylene)-(C1-C3-alkylene)- group,
a (R18)-(heteroarylene)-O—(C1-C3-alkylene)- group,
a (R19)—S(O)2-(heteroarylene)-O—(C1-C3-alkylene)- group,
a NR20R21—(C1-C3-alkylene)- group, and
a (C1-C3-alkyl)-NH—(C1-C3-alkylene)- group,
where the phenyl group is unsubstituted or substituted with a halogen atom, a hydroxyl group, or a C1-C3-alkoxy group and
the heterocycloalkylene group is unsubstituted or substituted with a substituent independently selected from an oxo (═O) group and a C1-C3-alkyl group;
or
R8 and R9 together form a 6-membered ring optionally comprising one or two oxygen atoms;
R15 is selected from a hydrogen atom, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a phenyl group, a benzyl group, a group
a group
and a group
R16 and R17 are each independently selected from a hydrogen atom, a C1-C6-alkyl group, and a C1-C6-haloalkyl group;
R18 is selected from a hydrogen atom, a hydroxy group, a cyano group, a C1-C3-alkyl group, a C1-C6-hydroxy alkyl 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-C3-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-C3-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.

### Claim 4 (depends on 1)

The compound of general formula (I) according to claim 1, 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 10- or 11-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 an aryl group, which is unsubstituted or substituted with a halogen atom;
L is a group —(CH2)m-E-;
E is an oxygen atom and constitutes the connecting element to R4;
m is 3;
R5 is a COOH group;
—R6-R7— is selected from #—(CH2)n—(B)t—(CH2)p—X—## and #—(C2-C6-alkenylene)-(B)t—(CH2)p—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, and a C1-C3-alkoxy group, and
where a —CH═CH— group in any alkenylene can be replaced by a 1,2-(C3-C5)cycloalkylene 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 a heterocycloalkyl group;
n is 3 or 4;
t is 0;
P is 1;
where the integers selected for variables n, t, and p result in forming a 10- to 11-membered ring independently from the selection of variable A1 or A2;
B is independently selected from —O— and —N(R15)—;
R8 is selected from a hydrogen atom and
a C1-C4-alkyl group, which is unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxy group, a C3-C6-cycloalkyl group and a heterocycloalkyl group;
R9 is selected from a C1-C4-alkyl group,
a C1-C3-hydroxyalkyl group,
a C1-C3-haloalkyl group,
a C1-C3-alkyl-O— group,
a C1-C3-haloalkoxy group,
a C1-C3-alkyl-O—(C1-C3-alkylene)- group,
a (C3-C6)-cycloalkyl group,
a R18-(phenylene)-O—(C1-C3-alkylene)- group,
a NR20R21—(C1-C3-alkylene)- group, and
a (C1-C3-alkyl-NH—(C1-C3-alkylene)- group;
R15 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl 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 —C(O)OR21 group, a —C(O)NR20R21 group and a (C1-C6-alkyl)-C(O)-group; and
R20 and R21 are each independently selected from a hydrogen atom and a C1-C3-alkyl group;
or a tautomer, or a salt thereof, or a salt of a tautomer, or a mixture of same.

### Claim 5 (depends on 1)

The compound of general formula (I) according to claim 1, 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 an 11-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 a naphthyl group, which is unsubstituted or substituted with a halogen atom;
L is a group —(CH2)3—O—;
R5 is a COOH group;
—R6-R7— is #—(CH2)n—(B)t—(CH2)p—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
where X is —O— or a —NR22— group where R22 is hydrogen or a C1-C3-alkyl group which is unsubstituted or substituted with a heterocycloalkyl group;
n is 4;
t is 0;
P is 1;
where the integers selected for variables n, t, and p result in forming an 11-membered ring independently from the selection of variable A1 or A2;
R8 is selected from a hydrogen atom and
a C1-C4-alkyl group, which is unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxy group, a C3-C6-cycloalkyl group and a heterocycloalkyl group;
R9 is selected from a C1-C4-alkyl group,
a C1-C3-hydroxyalkyl group,
a C1-C3-haloalkyl group,
a C1-C3-alkyl-O— group,
a C1-C3-haloalkoxy group,
a C1-C3-alkyl-O—(C1-C3-alkylene)- group,
a (C3-C6)-cycloalkyl group,
a R18-(phenylene)-O—(C1-C3-alkylene)- group,
a NR20R21—(C1-C3-alkylene)- group, and
a (C1-C3-alkyl-NH—C1-C3-alkylene)- 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 —C(O)OR21 group, a —C(O)NR20R21 group and a (C1-C6-alkyl)-C(O)-group; and
R20 and R21 are each independently selected from a hydrogen atom and a C1-C3-alkyl group;
or a tautomer, or a salt thereof, or a salt of a tautomer, or a mixture of same.

### Claim 6 (depends on 1)

The compound of general formula (I) according to claim 1, which is selected from,
(rac)-4-chloro-2,3,15-trimethyl-7-{3-[(naphthalen-1-yl)oxy]propyl}-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2-hi]indole-8-carboxylic acid,
(+)-4-chloro-2,3,15-trimethyl-7-{3-[(naphthalen-1-yl)oxy]propyl}-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid (enantiomer 1),
(−)-4-chloro-2,3,15-trimethyl-7-{3-[(naphthalen-1-yl)oxy]propyl}-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid (enantiomer 2),
(rac)-4-chloro-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,3,15-trimethyl- 10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid,
(+)-4-chloro-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,3,15-trimethyl- 10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid-N-ethylethanamine salt (enantiomer 1),
(−)-4-chloro-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,3,15-trimethyl-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid-N-ethylethanamine salt (enantiomer 2),
(rac)-4-chloro-3-ethyl-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,15-dimethyl-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid,
(+)-4-chloro-3-ethyl-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,15-dimethyl-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid-N-ethylethanamine salt (enantiomer 1),
(−)-4-chloro-3-ethyl-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,15-dimethyl-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid N-ethylethanamine salt (enantiomer 2),
(rac)-4-chloro-3-ethyl-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2-methyl-15-[2-(oxan-4-yl)ethyl]-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid,
(+)-4-chloro-3-ethyl-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2-methyl-15-[2-(oxan-4-yl)ethyl]-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid N-ethylethanamine salt (enantiomer 1),
(−)-4-chloro-3-ethyl-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2-methyl-15-[2-(oxan-4-yl)ethyl]-10,11,12,13,14,15-hexahydro-2H-pyrazolo[4′,3′:4,5][1,6]diazacycloundecino[3,2,1-hi]indole-8-carboxylic acid N-ethylethanamine salt (enantiomer 2),
(rac)-4-chloro-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,3-dimethyl-11,12,13,14-tetrahydro-2H, 10H-pyrazolo[3′,4′:2,3][1,6]oxazacycloundecino[4,5,6-hi]indole-8-carboxylic acid,
4-chloro-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,3-dimethyl-11,12,13,14- tetrahydro-2H, 10H-pyrazolo[3′,4′:2,3][1,6]oxazacycloundecino[4,5,6-hi]indole-8-carboxylic acid (enantiomer 1) and
4-chloro-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2,3-dimethyl-11,12,13,14- tetrahydro-2H, 10H-pyrazolo[3′,4′:2,3][1,6]oxazacycloundecino[4,5,6-hi]indole-8-carboxylic acid (enantiomer 2);
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.

### Claim 7 (depends on 1)

A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of reacting an intermediate compound of general formula (II):
wherein R1, R2, R3, R4, R6, A and L are as defined for the compound of general formula (I) according to claim 1, and R5E represents a carboxylic ester group or a benzyl ester group,
with an alkali hydroxide in a mixture of water and THF and/or an aliphatic alcohol of formula C1-C3-alkyl-OH, at a temperature from 0° C. to 100° C.,
to transform the group R5E into a group R5 as defined for the compounds of general formula (I), and subsequently optionally converting the free acid group R5 into a pharmaceutically acceptable salt thereof to obtain a compound of general formula (I)
wherein R1, R2, R3, R4, R5, R6, A and L are as defined for the compound of general formula (I) according to claim 1 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same and
optionally separating enantiomers by means of preparative HPLC on a chiral stationary phase.

### Claim 8 (depends on 1)

A method of inhibiting proliferation of a cell and/or the inducing apoptosis in a cell, comprising contacting the cell with a compound of general formula (I) according to claim 1.

### Claim 9 (depends on 1)

A method of treating a disease, comprising administering a compound of general formula (I) according to claim 1, wherein the disease is a hyperproliferative disease.

### Claim 10

(canceled)

### Claim 11 (depends on 9)

The method according to claim 9, wherein the hyperproliferative disease is cancer.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the cancer is selected from breast cancer, esophageal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, and multiple myeloma.

### Claim 13

(canceled)

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 and one or more pharmaceutically acceptable excipients.

### Claim at position 15

15-16. (canceled)

### Claim 17 (depends on 1)

A pharmaceutical combination comprising:
one or more compounds of general formula (I) according to claim 1, and
one or more further anti-cancer agents.

### Claim 18 (depends on 1)

An intermediate compound of general formula (II):
wherein R1, R2, R3, R4, R6, A and L are as defined for the compound of general formula (I) according to claim 1, and R5E represents a carboxylic ester group.

### Claim 19

(canceled)