Heterocyclic compounds as RET kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10844067-B2
Application number	US-201716093858-A
Country	US
Kind code	B2
Filing date	Apr 18, 2017
Priority date	Apr 15, 2016
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

The present invention relates to compounds of formula I that function as inhibitors of RET (rearranged during transfection) kinase enzyme activity:

wherein HET, X 1 , X 2 , X 3 , X 4 , integer a and R 3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which RET kinase activity is implicated.

First claim

The invention claimed is:

1. A compound having the structural formula (Id) shown below:

wherein:
HET is one of the following:

wherein

denotes me point of attachment;

R 1 is hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, or a group of the formula:
-L-Y-Q
wherein:
L is absent or is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;
Y is absent or is O, S, SO, SO 2 , N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R a )C(O)N(R b ), N(R a )C(O)O, OC(O)N(R a ), S(O) 2 N(R a ), or N(R a )SO 2 ,
wherein R a and R b are each independently hydrogen or (1-4C)alkyl; and

Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl, or heterocyclyl,
wherein Q is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c where p is 0, 1 or 2, SO 2 N(R d )R c , N(R d )SO 2 R c , Si(R e )(R d )R c , and (CH 2 ) q NR c R d where q is 1, 2, or 3,
wherein R e , R d , and R e are each independently hydrogen, (1-6C)alkyl, or (3-6C)cycloalkyl, or R e and R d are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, and hydroxy; or

Q is optionally substituted by a group of the formula:
-L 1 -L Q1 -W 1
wherein:
L 1 is absent or is (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;
L Q1 is absent or is O, S, SO, SO 2 , N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O), N(R f )C(O)N(R g ), N(R f )C(O)O, OC(O)N(R f ), S(O) 2 N(R f ), or N(R f )SO 2 ,
wherein R f and R g are each independently hydrogen or (1-2C)alkyl; and
W 1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclyl,
 wherein W 1 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h where r is 0, 1 or 2, SO 2 N(R i )R h , N(R i )SO 2 R h , and (CH 2 ) s NR i R h where s is 1, 2, or 3,
 wherein R h and R i are each independently hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

R 1a and R 1b are each independently H, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, or mercapto;
W is O, S, or NR W1 ,
wherein R W1 is H or (1-2C)alkyl;

X 1 , X 2 , X 3 and X 4 are each independently CH, CR 2 , or N,
wherein each R 2 is independently hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, nitro, aryl, heteroaryl, heterocyclyl, cycloalkyl, (2-4C)alkynyl, NR j R k , OR j , C(O)R j , C(O)OR j , OC(O)R j , C(O)N(R k )R j , N(R k )C(O)R j , N(R k )C(O)N(R j ), S(O) r1 R k where r 1 is 0, 1, or 2, SO 2 N(R j )R k , N(R j )SO 2 R k , or (CH 2 ) v NR j R k where v is 1, 2, or 3,
wherein R j and R k are each independently hydrogen or (1-4C)alkyl, and
wherein each (1-4C)alkyl, aryl, heteroaryl, heterocycyl, or cycloalkyl is optionally substituted by one or more substituents selected from halo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, nitro, phenyl, (2-4C)alkynyl, NR j1 R k1 , OR j1 , C(O)R j1 , C(O)OR j1 , OC(O)R j1 , C(O)N(R k1 )R j1 , N(R k1 )C(O)R j1 , S(O) r2 R h where r 2 is 0, 1 or 2, SO 2 N(R j1 )R k1 , N(R j1 )SO 2 R k1 and (CH 2 ) v1 NR j1 R k1 (where v 1 is 1, 2 or 3),
wherein R j1 and R k1 are each independently hydrogen or (1-4C)alkyl; and

R 3 is halo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, nitro, (2-4C)alkynyl, NR l R m , OR l , C(O)R l , C(O)OR l , OC(O)R l , C(O)N(R m )R l , N(R m )C(O)R l , or (CH 2 ) y NR l R m where y is 1, 2, or 3,
wherein the (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy, and halo, and
wherein R l and R m are each independently hydrogen or (1-4C)alkyl;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 , wherein the compound has the structural formula If shown below:

wherein HET, X 1 , R 2 , and R 3 are each as defined in claim 1 ; and
b is an integer selected from 0 and 1;
or a pharmaceutically acceptable salt or a solvate thereof.

3. The compound of claim 1 , wherein X 1 is nitrogen.

4. The compound of claim 1 , wherein HET is one of the following:

and wherein R 1 , R 1a , and R 1b are each as defined in claim 1 .

5. The compound of claim 1 , wherein R 1a and R 1b are each independently H, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, amino, cyano, or hydroxy.

6. The compound of claim 1 , wherein:
R i is hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, or a group of the formula:
-L-Y-Q
wherein:
L is absent or is (1-3C)alkylene;
Y is absent or is O, N(R a ), C(O), C(O)O, or C(O)N(R a ),
wherein R a is hydrogen or (1-4C)alkyl; and

Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl, or heterocyclyl,
wherein Q is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c where p is 0, 1 or 2, SO 2 N(R d )R c , N(R d )SO 2 R c , Si(R e )(R d )R c , and (CH 2 ) q NR c R d where q is 1, 2, or 3,
wherein R e , R d , and R e are each independently hydrogen, (1-6C)alkyl, or (3-6C)cycloalkyl, or R e and R d are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, and hydroxy; or

Q is optionally substituted by a group of the formula:
-L 1 -L Q1 -W 1
wherein:
L 1 is absent or is (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;
L Q1 is absent or is O, N(R f ), C(O), C(O)O, C(O)N(R f ), N(R f )C(O), N(R f )C(O)O, or SO 2 ,
 wherein R f is hydrogen or (1-2C)alkyl; and
W 1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclyl,
 wherein W 1 is optionally

Assignees

• Cancer Research Tech Ltd

Inventors

• Jordan Allan Michael
• Newton Rebecca
• Waszkowycz Bohdan
• Sutton Jonathan Mark
• Hynd George
• Paoletta Silvia
• Fordyce Euan Alexander Fraser

Classifications

• 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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title