Tricyclic heterocyclic derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-11028064-B2
Application number	US-201716347420-A
Country	US
Kind code	B2
Filing date	Nov 3, 2017
Priority date	Nov 4, 2016
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

Abstract

Disclosed are tricyclic heterocyclic compounds having kinase inhibitory activity, pharmaceutical compositions and kits comprising the compounds, and use of the compounds in the treatment of or in medicaments for the treatment of various diseases and conditions. In particular, disclosed are tricyclic heterocyclic compounds of the formula (I) having CSF-1R (c-FMS kinase) inhibitory activity and their use in the treatment of various diseases and conditions, such as those mediated by CSF-1R, including proliferative or neoplastic diseases and conditions, including cancers, and bone, inflammatory, and autoimmune diseases and conditions.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
X is NR 4 , O, S, SO, SO 2 , Se or Te and R 2 is G at any one of positions 2 to 4; or
X is NG 1 and R 2 is H, D, NR 6 R 7 , OR 6 , SR 8 , halogen, CF 3 , OCF 3 , CN, NR 6 COR 8 , NR 6 S 2 R 8 , or C 1-4 alkyl optionally substituted with one or more independently selected R a ;
Y is CHR 6 , CO, CHR 6 NR 5 , CHR 6 O, CHR 6 S, CHR 6 SO 2 , CONR 5 , NR 5 , NR 5 CO, NR 5 SO 2 , O, OCHR 6 , S, SO, SO 2 , SCHR 6 , SO 2 CHR 6 , or SO 2 NR 5 ;
Z is W or —W 1 —Y 1 —W 2 ;
R 1 and R 3 are each independently H, D, NR 6 R 7 , OR 6 , SR 8 , halogen, CF 3 , OCF 3 , CN, NR 6 COR 8 , NR 6 SO 2 R 8 , or C 1-4 alkyl optionally substituted with one or more independently selected R a ;
R 4 is H or C 1-6 alkyl optionally substituted with one or more independently selected R b ;
R 5 is H or C 1-4 alkyl optionally substituted with one or more independently selected R c ;
R 6 and R 7 at each instance are each independently H or unsubstituted C 1-4 alkyl;
R 8 at each instance is independently unsubstituted C 1-4 alkyl;
G is -J 1 -L 1 -NR 9a R 10a , -J 1 -L 2 -NR 9b R 10b , -J 1 -L 3 CR 11 R 12 R 13 , -L 10 -NR 9a R 10a , -L 20 -NR 9b R 10b , or -L 30 -CR 11 R 12 R 13 ;
G 1 is -L 1 -NR 9a R 10a , -L 2 -NR 9b R 10b , or -L 3 -cR 11 R 12 R 13 ;
J 1 is O, NR 6 S, —(C 1-3 alkylene)O—*, —(C 1-3 alkylene)NR 6 —*, or —(C 1-3 alkylene)S—*, wherein each alkylene is unsubstituted and wherein * denotes the bond to L 1 , L 2 , or L 3 ;
L 1 and L 2 are each independently C 2-6 alkylene, —C 2-3 alkylene-J 2 -C 2-3 alkylene-*, —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, —C 2-3 alkylene-J 2 -(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, or —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -J 2 C 2-3 alkylene-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to NR 9a R 10a or NR 9b R 10b ;
L 3 is a bond, C 1-6 alkylene, —C 2-6 alkylene-J 2 -*, —C 2-3 alkylene-J 2 -C 1-3 alkylene-*, —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, —C 2-3 alkylene-J 2 -(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, or —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -J 2 -(C 1-3 alkylene)-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to CR 11 R 12 R 13 ;
L 10 and L 20 are each independently C 1-6 alkylene, —C 1-3 alkylene-J 2 -C 2-3 alkylene-*, —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, —C 1-3 alkylene-J 2 -(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, or —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -J 2 -C 2-3 alkylene-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to NR 9a R 10a or NR 9b R 10b ;
L 30 is C 1-6 alkylene, —C 1-6 alkylene-J 2 -*, —C 1-3 alkylene-J 2 -C 1-3 alkylene-*, —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, —C 1-3 alkylene-J 2 -(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -*, or —(C 1-3 alkylene) a -A-(C 1-3 alkylene) b -J 2 -(C 1-3 alkylene) c -*, wherein each alkylene is unsubstituted and wherein * denotes the bond to CR 11 R 12 R 13 ;
A is 3 to 7-membered cycloalkylene optionally substituted with one or more independently selected R d ;
J 2 is O, NR 6 , or S;
a, b, and c are each independently 0 or 1;
R 9a and R 10a are each independently H, unsubstituted C 1-6 alkyl, or unsubstituted 3 to 10-membered cycloalkyl;
R 9b and R 10b together with the nitrogen atom to which they are attached form a 4 to 10-membered heterocyclyl or 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected R g ;
R 11 and R 12 together with the carbon atom to which they are attached form a 4 to 10-membered heterocyclyl comprising at least one ring nitrogen atom, optionally substituted with one or more independently selected R g ; and R 13 is H, C 1-4 alkyl optionally substituted with one or more independently selected R h , or the second bond of a double bond between R 11 or R 12 and the carbon atom to which they are attached; or
R 11 and R 12 together with the carbon atom to which they are attached form a 5 to 10-membered heteroaryl comprising at least one ring nitrogen atom, optionally substituted with one or more independently selected R g ; and R 13 is the second bond of a double bond between R 11 or R 12 and the carbon atom to which they are attached;
W is 6 to 10-membered aryl or 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected R i ;
W 1 is phenylene or 5 or 6-membered hetereoarylene, optionally substituted with one or more independently selected R x ;
Y 1 is C 1-6 alkylene-J 4 -*, —(C 1-3 alkylene)-J 4 -*, —(C 1-3 alkylene)-J 5 -(C 1-3 alkylene)-*, -J 5 -(C 1-3 alkylene)-*, or -J 6 -C 1-3 alkylene-J 7 -*, wherein each alkylene is unsubstituted and wherein * denotes the bond to W 2 ;
J 4 is O, NR 14 , S, NR 15 CO, CONR 14 , NR 15 CONR 14 , OCONR 14 , or NR 15 COO;
J 5 is O, NR 15 , S, NR 15 CO, CONR 15 , NR 15 CONR 15 , OCONR 15 , or NR 15 COO;
J 6 is O, NR 15 , or S;
J 7 is O, NR 14 , S, NR 15 CO, or CONR 14 ;
R 14 and R 15 at each instance are each independently H or C 1-3 alkyl optionally substituted with one or more independently selected R j ;
W 2 is:
(a) 3 to 10-membered cycloalkyl or 4 to 10-membered heterocyclyl, optionally substituted with one or more independently selected R m , or
(b) 6 to 10-membered aryl or 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected R n ;
or R 14 and W 2 together with the nitrogen atom to which they are attached form:
(a) a 4 to 10-membered heterocyclyl, optionally substituted with one or more independently selected R m , or
(b) a 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected R n ;
R a , R b , R c , and R h at each instance are each independently selected from F, OCF 3 , and O(unsubstituted C 1-4 alkyl);
R d and R g at each instance are each independently selected from D, NR 6 R 7 , OR 6 , SR 8 , halogen, CF 3 , OCF 3 , CN, SO 2 R 8 , NR 6 COR 8 , NR 6 SO 2 R 8 , and C 1-4 alkyl optionally substituted with one or more substituents independently selected from F, OCF 3 , and O(unsubstituted C 1-4 alkyl);
R i , R x , and R n at each instance are each independently selected from D, NR 6 R 7 , OR 6 , SR 8 , halogen, CF 3 , OCF 3 , CN, SO 2 R 8 , and C 1-4 alkyl optionally substituted with one or more substituents independently selected from F, OCF 3 , and O(unsubstituted C 1-4 alkyl);
R j at each instance is independently selected from F and D;
R m at each instance is independently selected from D, NR 6 R 7 , OR 6 , SR 8 , F, CF 3 , OCF 3 , CN, SO 2 R 8 , and C 1-4 alkyl optionally substituted with one or more substituents independently selected from F, OCF 3 , and O(unsubstituted C 1-4 alkyl);
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (I-1), (I-2), or (I-3):

3. The compound of claim 1 , wherein X is NR 4 , O, S, SO, or SO 2 .

4. The compound of claim 1 , wherein X is O or S.

5. The compound of claim 1 , wherein the compound of formula (I) is a compound of the formula (I-4):

6

Assignees

• Auckland Uniservices Ltd

Inventors

• Gamage Swarnalatha Akuratiya
• Shepherd Peter Robin
• Flanagan Jack Urquhart
• Rewcastle Gordon William
• Marshall Andrew James
• Buchanan Christina Maree
• Lu Guo-Liang
• Bonnet Muriel
• Jamieson Stephen Michael Frazer
• Denny William Alexander

Classifications

• C07D335/18

  Nitrogen atoms · CPC title

• C07D221/04

  Ortho- or peri-condensed ring systems · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

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