Substituted dihydropyrazino[1 ′,2′:1,5]pyrrolo[2,3-d]pyrimidine-based antiproliferative agents

Patent metadata

Field	Value
Publication number	US-10829490-B2
Application number	US-201816230396-A
Country	US
Kind code	B2
Filing date	Dec 21, 2018
Priority date	Jul 1, 2016
Publication date	Nov 10, 2020
Grant date	Nov 10, 2020

Abstract

This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers. Representative examples of compounds of the present invention include

First claim

We claim:

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof,
wherein:
y is 1 or 2;
Q is —C(O)—;
R is hydrogen, C 1 -C 6 alkyl, —(C 0 -C 2 alkyl)(C 3 -C 8 carbocyclyl), —(C 0 -C 2 alkyl)(C 3 -C 8 heterocyclyl), —C(O)—O—H, —(C 0 -C 2 alkyl)(aryl), —(C 0 -C 2 alkyl)(heteroaryl), —C(O)—O-alkyl, or —C(O)—O-arylalkyl;
each R 1 is independently alkyl, haloalkyl, cycloalkyl, or aryl, wherein each alkyl, haloalkyl, and cycloalkyl optionally includes in place of a chain carbon atom a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur; or
two geminal R 1 groups, together with the carbon atom to which they are attached, form a 3-8-membered ring; or
two vicinal R 1 groups, together with the carbon atoms to which they are attached, form a 3-8-membered ring;
R 7 is:

wherein:
X 1 is CR 8 or N;
X 2 is CR 8 or N;
X 3 is CR 8 or N;
X 4 is CR 8 or N; and
each R 8 is independently R 2 or R 6 ; or

R 7 is alkyl, cycloalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of —NR 14 R 15 , —OR 14 , R 2 , and R 6 ;
each R 14 is independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, —C(O)H, —C(O)-alkyl, —C(S)-alkyl, —S(O) 2 -alkyl, aryl, or heteroaryl;
each R 15 is independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, —C(O)H, —C(O)-alkyl, —C(S)-alkyl, —S(O) 2 -alkyl, aryl, or heteroaryl;
R 16 is cycloalkyl, wherein the cycloalkyl is substituted with one R 2 ;
each R 2 is independently -(alkylene) m -heterocyclyl, wherein each -(alkylene)m-heterocyclyl is independently substituted with one or more independently selected R x substituents;
each R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—S(O) 2 —R 5 , -(alkylene) m -OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -N(R 3 )—C(S)—OR 5 , -(alkylene) m -N(R 3 )—S(O) 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O)—R 5 , -(alkylene) m -S(O) 2 —NR 3 R 4 , cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
two geminal R x groups, together with the atom to which they are attached, form a ring; or
two vicinal R x groups, together with the atoms to which they are attached, form a ring;
each R 3 is independently hydrogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R 4 is independently hydrogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
R 3 and R 4 , together with the nitrogen atom to which they are attached, form a heterocyclyl ring;
each R 5 is independently hydrogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R 6 is independently hydrogen, halogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each m is independently 0, 1, or 2; and
each n is independently 0, 1, or 2;

with the provisos that:
(1) at least one of X 1 , X 2 , X 3 , or X 4 is CR 8 ; and
(2) one R 8 is R 2 .

2. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

4. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each IV is independently heterocyclyl, wherein each heterocyclyl is independently substituted with one or more independently selected R x substituents.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein at least one R x substituent is cycloalkylalkyl, heterocycloalkyl, or heteroarylalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein y is 1.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein y is 2.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
two geminal R 1 groups, together with the carbon atom to which they are attached, form a 3-8-membered ring; or
two vicinal R 1 groups, together with the carbon atoms to which they are attached, form a 3-8-membered ring.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the 3-8-membered ring is a 6-membered ring.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein at least one R 2 is 4-(morpholino)piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is:

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is:

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein:
R 8 is R 2 ; and
R 2 is heterocyclyl, wherein the heterocyclyl is substituted with one or more independently selected R x substituents.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein each R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently heterocyclyl, wherein each heterocyclyl is independently substituted with one or more independently selected R x substituents.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein each R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkyny

Assignees

• G1 Therapeutics Inc
• Gi Therapeutics Inc

Inventors

• Strum Jay Copeland
• Jung David

Classifications

• C07D487/20

  Spiro-condensed systems · CPC title

• C07D498/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D487/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title