Quinazolinone compounds and derivatives thereof

Patent metadata

Field	Value
Publication number	US-9505749-B2
Application number	US-201314423078-A
Country	US
Kind code	B2
Filing date	Aug 27, 2013
Priority date	Aug 29, 2012
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

Compounds of Formula I are useful inhibitors of tankyrase. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

First claim

What is claimed:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein:
R 1 is selected from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-S—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NH—(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)-NH 2 , or R 1 may additionally be selected from —O—(C 1 -C 6 alkyl), —NH—(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;
R 2 is selected from —H, —NH 2 , —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-S—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NH—(C 1 -C 6 alkyl), or —(C 1 -C 6 alkyl)-NH 2 ;
or R 1 and R 2 , together with the atoms to which they are attached, join to form a 6 membered ring comprising 0, 1, or 2 heteroatoms selected from N, O, or S; wherein the 6-membered ring is optionally substituted with one or two substituents selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), or —NH 2 ;
V is C;
W is CH or NH;
X is CH 2 , S, or SO 2 ;
Y is CH 2 or S;
one or two of X and Y are CH 2 ;
m is 0, 1, or 2;
Z is a group of formula II or formula III

wherein
R 3 is selected from —O—R 4a , —O—CH 2 —R 4a or —R 4a ;
R 4a is selected from a C 6 -C 10 aryl group, a heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, or a heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, or a —CH 2 -phenyl group, wherein the C 6 -C 10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 substituents independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), —R 4b , —OCH 2 —R 4b , —CH 2 O—R 4b , or —(C 1 -C 4 alkylene)-R 4b , and the heterocyclyl group may be further substituted with 1 oxo substituent;
R 4b is selected from C 6 -C 10 aryl group, a C 3 -C 8 cycloalkyl group, a heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, or a heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl group, the C 3 -C 8 cycloalkyl group, the heteroaryl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 substituents independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, or —O—(C 1 -C 6 alkyl, and the heterocyclyl group or cycloalkyl group may be further substituted with 1 oxo substituent
n is 0, 1, 2, or 3;
p is 1, 2, or 3;
q is 1 or 2;
r is 1, 2, or 3;
A is CH or N;
wherein when Z is a group of formula Ill, R 1 and R 2 , together with the atoms to which they are attached, join to form a 6-membered ring;
wherein the ring that includes the A variable in the group of formula Ill may include 0 or 1 double bond and A is C if the bond between an adjacent ring member and A is a double bond;
U is a heterocyclic or heteroaromatic group selected from

R 5 and R 6a are independently in each instance selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, or —O—(C 1 -C 6 alkyl);
R 6b and R 7 are selected from —H and —C 1 -C 6 alkyl;
j is 0, 1, or 2;
k is 0, 1, or 2 and is 1 or 2 if X and Y are both carbon and m is 0; and
Q is selected from Q′ or —CH 2 O-Q′; and
Q′ is selected from C 6 -C 10 aryl group or a heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl group and the heteroaryl group are unsubstituted or are substituted with 1, 2, or 3 substituents independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, or —O—(C 1 -C 6 alkyl);
wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein
R 1 is selected from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-0-(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-S—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NH—(C 1 -C 6 alkyl), or —(C 1 -C 6 alkyl)-NH 2 , or R 1 may additionally be selected from —O—(C 1 -C 6 alkyl), —NH—(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; and
R 2 is selected from —H, —CH 3 , or —NH 2 .

3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 is —H.

4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein the compound of formula I, has the formula IA

5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 and R 2 , together with the atoms to which they are attached, join to form a 6 membered ring comprising 0 or 1 heteroatoms selected from N, O, or S; wherein the 6-membered ring is optionally substituted with one or two substituents selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), or —NH 2 .

6. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 and R 2 , together with the atoms to which they are attached, join to form a 6 membered ring comprising 0 heteroatoms, wherein the 6-membered ring is optionally substituted with one or two substituents selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), or —NH 2 .

7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein the compound of formula I, has the formula IB

wherein b is 0, 1, or 2; and
R a is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl),

Assignees

• Amgen Inc

Inventors

• Bregman Howard
• Buchanan John L
• Chakka Nagasree
• Dimauro Erin F
• Gunaydin Hakan
• Guzman-Perez Angel
• Hua Zihao
• Huang Xin

Classifications

• C07D417/12

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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/12

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

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D471/02 Primary

  in which the condensed system contains two hetero rings · CPC title