Heterobicyclic inhibitors of MAT2A and methods of use for treating cancer

Patent metadata

Field	Value
Publication number	US-11524960-B2
Application number	US-201917040614-A
Country	US
Kind code	B2
Filing date	Mar 28, 2019
Priority date	Mar 30, 2018
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

Abstract

The present disclosure provides for compounds according to Formula I or Formula II and their pharmaceutically acceptable salts, stereoisomers, and/or tautomers thereof. Also provided are pharmaceutical compositions and the compounds of formulae I and II for use in methods of treating cancers, via inhibition of MAT2A, including some cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and/or not fully functioning.

First claim

We claim:

1. A compound of Formula I:

wherein:
X is N or CR 6 ;
L is O, S, NR, or a bond;
R is H or C 1 -C 6 -alkyl;
R 1 is selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 6 -carbocyclyl, —(C 1 -C 6 -alkyl)(C 3 -C 6 -carbocyclyl), and —(C 1 -C 6 -alkyl)(C 3 -C 6 -cycloalkenyl), wherein
any alkyl in R 1 is straight or branched, and
R 1 is optionally substituted by 1-6 halo;

or when L is NR, then R and R 1 in combination with L is a 3- to 6 membered heterocycloalkyl (wherein 1-4 ring members are independently N, O, or S) optionally substituted by one or more R A ;
R 2 and R 3 are independently selected from the group consisting of C 6 -C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently N, O, or S), and 3- to 14-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently N, O, or S),
wherein R 2 and R 3 are independently and optionally substituted by one or more substituents that are selected from the group consisting of R A , OR A , halo, —N═N—R A , NR A R B , —(C 1 -C 6 -alkyl)NR A R B , —C(O)OR A , —C(O)NR A R B , —OC(O)R A , and —CN;

R 2a is absent or present and, if present, it is taken together with R 2 and the carbon atom to which they are attached to form a spiro-fused 5- to 6-membered carbocyclyl or heterocycloalkyl (wherein 1-4 carbocyclyl or heterocycloalkyl members are independently N, O, or S), and each bond (a) is a single bond and each bond (b) is a double bond;
wherein the spiro-fused 5- to 6-membered carbocyclyl or heterocycloalkyl is optionally substituted by one or more R A ;
and if R 2a is absent, then each bond (a) is a double bond and each bond (b) is a single bond;

R 4 , R 5 , and R 6 are independently selected from the group consisting of R A , OR A , halo, NR A R B , —(C 1 -C 6 -alkyl)NR A R B , —C(O)OR A , —C(O)NR A R B , and —OC(O)R A ;
R A and R B are independently selected from the group consisting of H, —CN, -hydroxy, oxo, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, NH 2 , —S(O) 0-2 —(C 1 -C 6 -alkyl), —S(O) 0-2 —(C 6 -C 10 -aryl), —C(O)(C 1 -C 6 -alkyl), —C(O)(C 3 -C 14 -carbocyclyl), —C 3 -C 14 -carbocyclyl, —(C 1 -C 6 -alkyl)(C 3 -C 14 -carbocyclyl), C 6 -C 10 -aryl, 3- to 14-membered heterocycloalkyl, —(C 1 -C 6 -alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently N, O, or S), and 5- to 10 membered heteroaryl (wherein 1-4 heteroaryl members are independently N, O, or S);
wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl moiety of R A and R B is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR′ 2 (wherein each R′ is independently selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 6 -C 10 -aryl, 3- to 14-membered heterocycloalkyl, —(C 1 -C 6 -alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently N, O, or S), and 5- to 10 membered heteroaryl (wherein 1-4 heteroaryl members are independently N, O, or S)), —NHC(O)(OC 1 -C 6 -alkyl), —NO 2 , —CN, oxo, —C(O)OH, —C(O)O(C 1 -C 6 -alkyl), —C 1 -C 6 -alkyl(C 1 -C 6 -alkoxy), —C(O)NH 2 , C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -alkyl, —OC 1 -C 6 -alkyl, —Si(C 1 -C 6 -alkyl) 3 , —S(O) 0-2 —(C 1 -C 6 -alkyl), C 6 -C 10 -aryl, —(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl), 3-to 14-membered heterocycloalkyl, —(C 1 -C 6 -alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently N, O, or S), and —O(C 6 -C 14 -aryl),
wherein each alkyl, alkenyl, aryl, and heterocycloalkyl in R A and R B is optionally substituted with one or more substituents selected from the group consisting of hydroxy, —OC 1 -C 6 -alkyl, halo, —NH 2 , —(C 1 -C 6 -alkyl)NH 2 , —C(O)OH, CN, and oxo,

or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein
R 2a is absent; and
each bond (a) is a double bond and each bond (b) is a single bond.

3. The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein the compound has a structure according to Formula (IA):

4. The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein the compound has a structure according to Formula (IB):

5. A compound of Formula (II):

wherein:
L is O, S, NR, or a bond;
R is H or C 1 -C 6 -alkyl;
R 1 is selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 6 -carbocyclyl, —(C 1 -C 6 -alkyl)(C 3 -C 6 -carbocyclyl), and —(C 1 -C 6 -alkyl)(C 3 -C 6 -cycloalkenyl), wherein:
any alkyl in R 1 is straight or branched, and
R 1 is optionally substituted by 1-6 halo;

or when L is NR, then R and R 1 in combination with L is a 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently N, O, or S) optionally substituted by one or more R A ;
R 2 and R 3 are independently selected from the group consisting of C 6 -C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently N, O, or S), and 3- to 14-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently N, O, or S),
wherein R 2 and R 3 are independently and optionally substituted by one or more substituents that are selected from the group consisting of R A , OR A , halo, —N═N—R A , NR A R B , —(C 1 -C 6 -alkyl)NR A R B , —C(O)OR A , —C(O)NR A R B , —OC(O)R A , and —CN;

R 4 and R 6 are independently selected from the group consisting of R A , OR A , halo, NR A R B , —(C 1 -C 6 -alkyl)NR A R B , —C(O)OR A —C(O)NR A R B , and —OC(O)R A ;
R A and R B are independently selected from the group consisting of H, —CN, -hydroxy, oxo, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, NH 2 , —S(O) 0-2 —(C 1 -C 6 -alkyl), —S(O) 0-2 —(C 6 -C 10 -aryl), —C(O)(C 1 -C 6 -alkyl), —C(O)(C 3 -C 14 -carbocyclyl), —C 3 -C 14 -carbocyclyl, —(C 1 -C 6 -alkyl)(C 3 -C 14 -carbocyclyl), C 6 -C 10 -aryl, 3- to 14-membered heterocycloalkyl, —(C 1 -C 6 -alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently N, O, or S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently N, O, or S);
wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl moiety of R A and R B is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR′ 2 (wherein each R′ is independently selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 6 -C 10 -aryl, 3- to 14-membered heterocycloalkyl, —(C 1 -C 6 -alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently N, O, or S), and 5- to 10 membered heteroaryl (wherein 1-4 heteroaryl members are independently N, O, or S)), —NHC(O)(OC 1 -C 6 -alkyl), —NO 2 , —CN, oxo, —C(O)OH, —C(O)O(C 1 -C 6 -alkyl), —C 1 -C 6 -alkyl(C 1 -C 6 -alkoxy), —C(O)NH 2 , C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -alkyl, —OC 1 -C 6 -alkyl, —Si(C 1 -C 6 -alkyl) 3 , —S(O) 0-2 —(C 1 -C 6 -alkyl), C 6 -C 10 -aryl, —(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl), 3- to 14-membered heterocycloalkyl, —(C 1 -C 6 -alkyl)-(3- to 14 membered heterocycle) (wherein 1-4 heterocycle members are independent

Assignees

• Agios Pharmaceuticals Inc
• Servier Pharmaceuticals Llc

Inventors

• Konteatis Zenon D
• Li Mingzong
• Liu Peng
• Medeiros Matthew
• Reznik Samuel K
• Sui Zhihua
• Travins Jeremy M
• Popovici-Muller Janeta
• Zhou Shubao
• Ma Guangning

Classifications

• A61K31/527

  spiro-condensed · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D471/20 Primary

  Spiro-condensed systems · 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

• A61P35/00

  Antineoplastic agents · CPC title