Substituted pyrazolopyrimidinylamino-indazoles

Patent metadata

Field	Value
Publication number	US-2016002245-A1
Application number	US-201414765373-A
Country	US
Kind code	A1
Filing date	Jan 29, 2014
Priority date	Feb 1, 2013
Publication date	Jan 7, 2016
Grant date	—

Abstract

The present invention relates to substituted pyrazolopyrimidinylamino-indazole compounds of general formula I as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

First claim

1 . A compound of formula I:

in which:
R 1a , R 1b , R 1c , R 1d are the same or different and are independently selected from R 1 ;
R 1 represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, C 3 -C 6 -cycloalkyl-, C 3 -C 6 -cycloalkyloxy-,
3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-O—, —NR 5a R 5b , —SCF 3 or —SF 5 group;
wherein said C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, C 1 -C 6 -alkoxy-, C 3 -C 6 -cycloalkyl-, C 3 -C 6 -cycloalkyloxy-, (3- to 10-membered heterocycloalkyl)-, and (3- to 10-membered heterocycloalkyl)-O— group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 4 groups;

R 2 represents a hydrogen atom or a halogen atom or a group selected from: C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C 1 -C 3 -alkyl-, cyano-, —(CH 2 ) q —X—(CH 2 ) p —R 3 ;
wherein said C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, aryl-, and heteroaryl- group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 4 groups;

X represents a bond or a bivalent group selected from: —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O)—(NR 3a )—, —(NR 3a )—S(═O)—, —S(═O) 2 —(NR 3a )—, —(NR 3a )—S(═O) 2 —, —C(═O)—, —(NR 3a )—, —C(═O)—O—, —O—C(═O)—, —C(═S)—O—, —O—C(═S)—, —C(═O)—(NR 3a )—, —(NR 3a )—C(═)—, —(NR 3a )—C(═)—(NR 3b )—, —O—C(═O)—(NR 3a )—, —(NR 3a )—C(═O)—O—;
R 3a , R 3b are the same or different and are independently selected from R 3 ;
R 3 represents a hydrogen atom or a group selected from C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, halo-C 1 -C 3 -alkyl-;
wherein said C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, and heteroaryl- group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 4 groups;

or
R 3 together with R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- or a 4- to 10-membered heterocycloalkenyl- group, which is optionally substituted, one or more times, identically or differently, with halo-, hydroxyl-, cyano-;
R 4 represents halo-, hydroxy-, oxo-(O═), cyano-, nitro-, C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, hydroxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, R 5 —O—, —C(═O)—R 5 , —C(═O)—O—R 5 , —O—C(═O)—R 5 , —N(R 5a )—C(═O)—R 5b , —N(R 5a )—C(═O)—NR 5b R 5c , —NR 5a R 5b , —C(═O)—NR 5a R 5b , R 5 —S—, R 5 —S(═O)—, R 5 —S(═) 2 —, —N(R 5a )—S(═O)—R 5b , —S(═O)—NR 5a R 5b , —N(R 5a )—S(═O) 2 —R 5b , —S(═O) 2 —NR 5a R 5b , —S(═O)(═NR 5a )R 5b , —S(═O)(═NR 5a )R 5b or —N═S(═O)(R 5a )R 5b ;
R 5a , R 5b , R 5c are the same or different and are independently selected from R 5 ;
R 5 represents a hydrogen atom, a C 1 -C 6 -alkyl- or a C 3 -C 6 -cycloalkyl- group;
or
R 5a and R 5b ,
or R 5a and R 5c ,
or R 5b and R 5c together may form a C 2 -C 6 -alkylene group, in which one methylene is optionally replaced by —O—, —C(═O)—, —NH—, or —N(C 1 -C 4 -alkyl)-;
p represents an integer of 0, 1, 2 or 3;
q represents an integer of 0, 1, 2 or 3;
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2 . A compound according to claim 1 , wherein
R 2 represents a hydrogen atom or a halogen atom or group selected from:
aryl, heteroaryl, —(CH 2 ) q —X—(CH 2 ) p —R 3 , C 3 -C 6 -cycloalkyl-,
3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-;
wherein said aryl, heteroaryl, C 3 -C 6 -cycloalkyl-,
3- to 10-membered heterocycloalkyl-, and
4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1, 2 or 3 R 4 groups;
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3 . A compound according to claim 1 , wherein
R 1a represents a halogen atom or a hydroxy-, cyano-, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, or halo-C 1 -C 3 -alkoxy- group; R 1b represents a hydrogen atom or a halogen atom; R 1c represents a hydrogen atom or a halogen atom; and R 1d represents a hydrogen atom or a halogen atom or a C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or halo-C 1 -C 3 -alkoxy- group; or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4 . A compound according to claim 1 , wherein
X represents a bond or a bivalent group selected from:
—C(═O)—, —C(═O)—O—, —C(═O)—(NR 3a )—, —(NR 3a )—C(═O)—, —(NR 3a )—C(═O)—(NR 3b )—, —O—C(═O)—(NR 3a )—, —(NR 3a )—C(═)—;
R 3 represents a hydrogen atom or a group selected from:
C 1 -C 3 -alkyl-, 4- to 6-membered heterocycloalkyl-;
wherein said C 1 -C 3 -alkyl- and 4- to 6-membered heterocycloalkyl- group is optionally substituted with one R 4 group;
R 3a represents a hydrogen atom or a C 1 -C 3 -alkyl- group; wherein said C 1 -C 3 -alkyl- group is optionally substituted with one R 4 group; R 3a represents a hydrogen atom or a C 1 -C 3 -alkyl- group; p represents an integer of 0 or 1; and q represents an integer of 0 or 1; or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

5 . A compound according to claim 1 , wherein
R 1a represents a hydrogen atom or a halogen atom or a C 1 -C 3 -alkoxy- group; R 1b represents a hydrogen atom; R 1c represents a hydrogen atom; R 1d represents a hydrogen atom; R 2 represents a hydrogen atom or a halogen atom or group selected from:
aryl, heteroaryl; wherein said aryl and heteroaryl group is optionally substituted, identically or differently, with 1, 2 or 3 R 4 groups;
R 4 represents a group selected from:
halo-, hydroxy-, cyano-, nitro-, C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, hydroxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, R 5 —O—, —C(═O)—R 5 , —C(═O)—O—R 5 , —O—C(═O)—R 5 , —N(R 5a )—C(═O)—R 5b , —N(R 5a )—C(═O)—NR 5b R 5c , —NR 5a R 5b , —C(═O)—NR 5a R 5b , R 5 —S—, R 5 —S(═O)—, R 5 —S(═O) 2 —, —N(R 5a )—S(═O)—R 5b , —S(═O)—NR 5a R 5b , —N(R 5a )—S(═O) 2 —R 5b , —S(═O) 2 —NR 5a R 5b , —S(═O)(═NR 5a )R 5b , —S(═O)(═NR 5a )R 5b or —N═S(═O)(R 5a )R 5b ;
R 5 represents a hydrogen atom or a C 1 -C 6 -alkyl- group; R 5a represents a hydrogen atom or a C 1 -C 6 -alkyl- group; R 5b represents a hydrogen atom or a C 1 -C 6 -alkyl- group; R 5c represents a hydrogen atom or a C 1 -C 6 -alkyl- group; or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6 . A compound according to claim 1 , which is selected from the group consisting of:
N-(1H-Indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, N-(6-Methoxy-1H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, N-[6-(Propan-2-yloxy)-1H-indazol-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 3-Bromo-N-(6-methoxy-1H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 3-Bromo-N-(6-fluoro-1H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 3-Bromo-N-(1H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Assignees

• Bayer Pharma AG

Inventors

• Klar Ulrich
• Wortmann Lars
• Kettschau Georg
• Pühler Florian
• Lienau Philip
• Sülzle Detlev

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title