SUBSTITUTED 4,5,6,7-TETRAHYDRO-PYRAZOLO[1,5-a]PYRAZINE DERIVATIVES AND 5,6,7,8-TETRAHYDRO-4H-PYRAZOLO[1,5-a][1,4]DIAZEPINE DERIVATIVES AS ROS1 INHIBITORS

Patent metadata

Field	Value
Publication number	US-2017174690-A1
Application number	US-201515129582-A
Country	US
Kind code	A1
Filing date	Mar 26, 2015
Priority date	Mar 27, 2014
Publication date	Jun 22, 2017
Grant date	—

Abstract

The present invention relates to substituted 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine derivatives and 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine derivatives of formula (I)

wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as ROS1 inhibitors. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

First claim

1 . A compound of Formula (I)

a tautomer or a stereoisomeric form thereof, wherein
y 1 is CR 7a or N;
y 2 is CH or N;
R 7a is hydrogen, halo, trifluoromethyl or cyano;
R 7 is hydrogen, —NH 2 , —NHCH 3 , —NH(CH 2 CH 3 ), methyl, —CH 2 OH, halo or cyano;
or when y 1 represents CR 7a , this R 7a can be taken together with a R 7 on an adjacent carbon atom to form —CH═CH—NH— or —N═CH—NH—;
X is —CR 1 R 1a —, —CH 2 —CHR 1 —;
R 1 is hydrogen or C 1-6 alkyl;
R 1a is hydrogen; C 1-6 alkyl; mono- or polyhaloC 1-6 alkyl; C 1-6 alkyl substituted with one or two hydroxyl groups; C 1-6 alkyl substituted with one —NR 9a R 9b ; or —C(═O)—NR 9a R 9b ;
R 2a is hydrogen; C 1-6 alkyl; mono- or polyhaloC 1-6 alkyl; C 1-6 alkyl substituted with one or two hydroxyl groups; or C 1-6 alkyl substituted with one substituent selected from the group consisting of —NR 9a R 9b , cyano and C 1-4 alkyloxy;
R 2b is hydrogen or C 1-6 alkyl; or
R 2a and R 2b are taken together to form —CH 2 —CH 2 —, —CH 2 —NR 2c —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —O—CH 2 —, —CH 2 —CH 2 —CH 2 CH 2 —, —CH 2 —CH 2 —NR 2c —CH 2 — or ═O;
R 2c is hydrogen; C 1-4 alkyl optionally substituted with one or two hydroxyl groups; mono- or polyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkyl substituted with one cyano group; or C 1-6 alkyl substituted with one —NR 9a R 9b ;
R 3 is hydrogen; C 1-6 alkyl; mono- or polyhaloC 1-6 alkyl; C 1-6 alkyl substituted with one or two hydroxyl groups; C 1-6 alkyl substituted with one or two hydroxyl groups and one C 1-6 alkyloxy; C 1-6 alkylcarbonyl- optionally substituted with one or two hydroxyl groups; mono- or polyhaloC 1-6 alkylcarbonyl-; R 10a R 10b N—C 1-6 alkylcarbonyl-; C 1-6 alkyl-O-carbonyl-; C 1-6 alkylcarbonyloxy-; C 1-6 alkyl substituted with one R 11 ; C 1-6 alkyloxy optionally substituted with one —NR 10a R 10b ; C 2-6 alkenyl; C 2-6 alkynyl;
hydroxyC 2-6 alkenyl; hydroxyC 2-6 alkynyl; C 1-6 alkyloxyC 2-6 alkenyl;
C 1-6 alkyloxyC 2-6 alkynyl; C 2-6 alkenyl substituted with one —NR 10a R 10b ; C 2-6 alkynyl substituted with one —NR 10a R 10b ; C 1-6 alkyl substituted with one or two hydroxyl groups and one —NR 10 R 10b ; —C 1-6 alkyl-C(R 13 )═N—O—R 13 ; —S(═O) 2 —C 1-6 -alkyl; —S(═O) 2 —NR 9a R 9b ; C 1-6 -alkyl substituted with one —(C═O)—R 14 ; C 1-6 alkyl substituted with one or two hydroxyl groups and one R 14 ; C 1-6 alkyl substituted with one R 14 ; C 2-6 alkenyl substituted with one R 14 ; C 2-6 alkynyl substituted with one R 14 ; or R 14 ;
R 4a is hydrogen;
R 4b is hydrogen; or
R 4a and R 4b are taken together to form ═O;
Y is —O— or —C(═O)—;
Z is —CHR 6 — or —CH 2 —CH 2 —C≡C—;
R 6 is hydrogen; C 1-4 alkyl-O-carbonyl-; C 1-4 alkyl; C 1-4 alkyl substituted with one or two hydroxyl groups; C 1-4 alkyl substituted with one —NR 9a R 9b ; or —C(═O)—NR 9a R 9b ;
Ring A is phenyl or a 6-membered saturated, partially saturated or aromatic heterocyclyl, said heterocyclyl containing one or two nitrogen atoms; wherein the phenyl or the heterocyclyl is optionally substituted with one or two R 8 substituents;
each R 8 is independently hydrogen; C 1-4 alkyloxy; hydroxyl; cyano; C 1-4 alkyl or halo;
or a R 8 substituent on an atom adjacent to the atom carrying the Y—Z substituent may be taken together with the R 6 substituent of Z, by which ring A together with Y—Z forms a bicycle of formula (a-1), (a-2), (a-3) or (a-4):

R 9a and R 9b each independently represent hydrogen; mono- or polyhaloC 1-4 alkyl; C 1-4 alkylcarbonyl-; C 1-4 alkyl-O-carbonyl-; C 1-4 alkyl substituted with one or two hydroxyl groups; or C 1-4 alkyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkyloxy, cyano, amino and mono- or di(C 1-4 alkyl)amino;
R 10a and R 10b each independently represent hydrogen; C 1-4 alkyl; cyanoC 1-6 alkyl;
C 1-6 alkyl substituted with one NR 9a R 9b ; C 1-6 alkyl substituted with one —C(═O)—NR 9a R 9b ; C 1-6 alkyloxy optionally substituted with one or two hydroxyl groups;
C 1-6 alkyloxyC 1-6 alkyl wherein each C 1-6 alkyl is optionally substituted with one or two hydroxyl groups; R 14 ; C 1-6 alkyl substituted with one R 14 ; —(C═O)—R 14 ;
C 1-6 alkylcarbonyl-; C 1-6 alkyl-O-carbonyl-; mono- or polyhaloC 1-6 alkylcarbonyl- substituted with one or two hydroxyl groups; mono- or polyhaloC 1-6 alkyl substituted with one or two hydroxyl groups; mono- or polyhaloC 1-6 alkylcarbonyl-; C 1-6 alkyl substituted with one —Si(CH 3 ) 3 ; —S(═O) 2 —C 1-6 alkyl optionally substituted with one or more halo substituents; —S(═O) 2 —NR 9a R 9b ;
C 1-6 alkyl substituted with one —S(═O) 2 —C 1-6 alkyl wherein —S(═O) 2 —C 1-6 alkyl is optionally substituted with one or more halo substituents;
C 1-6 alkyl substituted with one —S(═O) 2 —NR 9a R 9b ;
C 1-6 alkyl substituted with one —NH—S(═O) 2 —C 1-6 alkyl wherein —NH—S(═O) 2 —C 1-6 alkyl is optionally substituted on a carbon atom with one or more halo substituents;
C 1-6 alkyl substituted with one —NH—S(═O) 2 —NR 9a R 9b ;
mono- or polyhaloC 1-4 alkyl; or C 1-4 alkyl substituted with one or two hydroxyl groups;
R 11 is cyano; —NR 10a R 10b ; C 1-6 alkyloxy optionally substituted with one or two hydroxyl groups; —S(═O) 2 —C 1-6 alkyl; —S(═O) 2 —NR 9a R 9b ; —NR 13 —S(═O) 2 —C 1-6 alkyl; —NR 13 —S(═O) 2 —NR 9a R 9b ; C 1-6 alkylcarbonyloxy-; —C(═O)—NR 10a R 10b ; —O—C(═O)—NR 10a R 10b ; —COOH; —P(═O)OH) 2 ; or —P(═O)(O—C 1-4 alkyl) 2 ;
R 12 is —NR 9a R 9b , C 1-6 alkyloxy, or cyano;
R 13 is hydrogen or C 1-4 alkyl;
R 14 is a C 3-8 cycloalkyl; or a 4, 5 or 6 membered saturated heterocyclyl which is optionally substituted with one, two or three substituents selected from the group consisting of oxo, C 1-4 alkyl, halogen, cyano, hydroxyl, C 1-6 alkyloxy and NR 9a R 9b ;
x 1 is CR 5a or N;
x 2 is CR 5b or N;
x 3 is CR 5c or N;
each R 15 is independently selected from the group consisting of hydrogen, methyl, halo, C 1-4 alkyloxy and hydroxyl;
R 5a and R 5c each independently are selected from the group consisting of hydrogen; hydroxyl; cyano; halo; C 1-6 alkyl; C 1-6 alkyl substituted with one or two hydroxyl groups; mono- or polyhaloC 1-6 alkyl; mono- or polyhaloC 1-6 alkyloxy; C 1-6 alkyl substituted with one —NR 9a R 9b ;
C 1-6 alkyl substituted with one cyano; C 1-6 alkyloxy, C 1-6 alkyl wherein each of the C 1-6 alkyl groups are optionally substituted with one or two hydroxyl groups; C 2-6 alkenyl; C 1-6 alkyl-O-carbonyl-; C 1-6 alkyloxy; C 1-6 alkyloxy substituted with one or two hydroxyl groups; C 1-6 alkyloxyC 1-6 alkyloxy wherein each of the C 1-6 alkyl groups are optionally substituted with one or two hydroxyl groups; C 1-6 alkyloxy substituted with one cyano; and C 1-6 alkyloxy substituted with one —NR 9a R 9b ;
R 5b is hydrogen; C 1-6 alkyl; C 3-6 cycloalkyl optionally substituted with one cyano; hydroxyl; cyano; mono- or polyhaloC 1-6 alkyloxy; mono- or polyhaloC 1-6 alkyl; C 1-4 alkyl substituted with one or two hydroxyl groups; C 2-6 alkenyl; C 1-4 alkyloxy; —Si(CH 3 ) 3 ;
C 1-6 alkyl substituted with one R 12 ; C 1-6 alkyl-O-carbonyl-; or C 1-6 alkyloxy substituted with one R 12 ;
or a N-oxide, a pharmaceutically acceptable addition salt or a solvate thereof.

2 . The compound according to claim 1 , wherein
y 1 is CR 7a or N; y 2 is CH; R 7a is h

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Mevellec Laurence Anne
• Pasquier Elisabeth Therese Jeanne
• Descamps Sophie
• Mercey Guillaume Jean Maurice
• Wroblowski Berthold
• Vialard Jorge Eduardo
• Mrrtpoel Lieven
• Jeanty Matthieu Ludovic
• Jousseaume Thierry Francois Alain Jean

Classifications

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D487/20

  Spiro-condensed systems · CPC title