Tricyclic compounds as inhibitors of mutant IDH enzymes

Patent metadata

Field	Value
Publication number	US-10442819-B2
Application number	US-201515532549-A
Country	US
Kind code	B2
Filing date	Dec 1, 2015
Priority date	Dec 5, 2014
Publication date	Oct 15, 2019
Grant date	Oct 15, 2019

Abstract

The present invention is directed to tricyclic compounds of formula (I) which are inhibitors of one or more mutant IDH enzymes: (I). The present invention is also directed to uses of the tricyclic compounds described herein in the potential treatment or prevention of cancers in which one or more mutant IDH enzymes are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such cancers.

First claim

What is claimed is:

1. A compound of Formula I:

wherein
A is —C(R 1 )═ or N═, and R 1 is hydrogen or hydroxyl;
B is C(R 9 )(R 10 )—, —N(R 10 )—, —O—, —S— or —S(O) 2 —;
D is —C(R 4 )(R 5 )—, —N(R 5 )—, —O— or —S—;
m is 0, 1 or 2; n is 0 or 1; p is 0, 1 or 2; q is 0 or 1; with the proviso that at least one of m, n, p and q is not 0;
R is selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —(C═O) t —R a , wherein t is 0 or 1, and
(4) —S(O) 2 R a ;

each occurrence of R 2 , R 3 , R 4 , R 6 , R 7 and R 9 is independently selected from the group consisting of:
(1) halogen,
(2) —CN, and
(3) —(C═O) t —R a , wherein t is 0 or 1;

each occurrence of R 5 and R 10 is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl, optionally substituted with one to four substituents independently selected from R b ; and
(3) C 3-7 cycloalkyl, optionally substituted with one to four substituents independently selected from R b ;

R 8 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) —O—R a ,
(5) —(C═O)—NR j R k , wherein each of R j and R k is independently selected from the group consisting of hydrogen and C 1-6 alkyl,
(6) C 1-6 alkyl, optionally substituted with one to four substituents independently selected from R b ,
(7) C 2-6 alkenyl, and
(8) phenyl, optionally substituted with one to four substituents independently selected from R b ;

R 11 and R 12 together form an oxo; or alternatively, each occurrence of R 11 and R 12 is independently selected from the group consisting of:
(1) halogen,
(2) —CN, and
(3) —(C═O) t —R a , wherein t is 0 or 1;

each occurrence of R a is independently selected from the group consisting of:
(1) hydrogen,
(2) —(O) t —R d , wherein t is 0 or 1; R d is selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 3-7 cycloalkyl, and (d) phenyl;
wherein each of the C 1-6 alkyl of (b) and C 3-7 cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from R b ,

(3) —NR x R y , wherein each of R x and R y is independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 3-6 cycloalkyl, (d) —O—C 1-6 alkyl, (e) phenyl optionally substituted with one to four halogens, and (f) heterocyclyl;
wherein the C 1-6 alkyl of (b) is optionally substituted with one to four substituents independently selected from halogen, —O—C 1-4 alkyl, C 3-6 cycloalkyl, and heterocyclyl; and
the C 3-6 cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from halogen, —O—C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl, and C 1-4 alkyl, which is optionally substituted with one to four halogens,
the heterocyclyl of (f) is optionally substituted with one to four substituents independently selected from halogen, C 1-4 alkyl, —O—C 1-4 alkyl, C 3-6 cycloalkyl, and heterocyclyl,

(4) C 2-6 alkenyl, optionally substituted with one to four substituents independently selected from R b ,
(5) C 5-6 cycloalkenyl, optionally substituted with one to four substituents independently selected from R b ,
(6) aryl, optionally substituted with one to four substituents independently selected from R b , and
(7) heterocyclyl, optionally substituted with one to four substituents independently selected from R b ;

each occurrence of R b is independently selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) oxo,
(4) —(O) t —R d , wherein t is 0 or 1; R d is selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 3-7 cycloalkyl, and (d) heterocyclyl;
wherein the C 1-6 alkyl of (b) is optionally substituted with one to four substituents independently selected from (i) halogen, (ii) hydroxyl, (iii) —O—C 1-6 alkyl, (iv) C 3-6 cycloalkyl optionally substituted with 1-3 halogens, (v) —NR x R y , wherein each of R x and R y is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl optionally substituted with one to four halogens, and heterocyclyl, and (vi) heterocyclyl;
the C 3-7 cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from (i) halogen, and (ii) C 1-6 alkyl, which is optionally substituted with one to four halogens, and (iii) —CN; and
the heterocyclyl of (d) is optionally substituted with one to four substituents independently selected from (i) halogen, (ii) hydroxyl, (iii) oxo, (iv) C 1-6 alkyl optionally substituted with one to four halogens, (v) —O—C 1-6 alkyl, (vi) heterocyclyl optionally substituted with halogen or hydroxyl, and (vii) —NR j R k , wherein each of R j and R k is independently selected from the group consisting of hydrogen and C 1-6 alkyl,

(5) —(C═O) t —R c , wherein t is 0 or 1; R c is selected from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, —O—C 1-6 6 alkyl, —NR x R y , and heterocyclyl;
wherein each of R x and R y is independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C 3-6 cycloalkyl, (e) phenyl optionally substituted with one to four halogens, and (f) heterocyclyl;
wherein the C 1-6 alkyl of (b) is optionally substituted with one to four substituents independently selected from halogen, —O—C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl, and —(C═O)—NR j R k , wherein each of R j and R k is independently hydrogen or C 1-6 alkyl;
the C 3-6 cyclolkyl of (d) is optionally substituted with one to four substituents independently selected from halogen and C 1-4 alkyl, which is optionally substituted with one to four halogens; and
the heterocyclyl of (f) is optionally substituted with one to four substituents independently selected from halogen, —CN, C 1-6 alkyl, and —O—C 1-6 alkyl,

(6) —(P═O)R j R k , wherein each of R j and R k is independently hydrogen or C 1-6 alkyl,
(7) C 2-6 alkenyl, and
(8) phenyl, optionally substituted with one to four substituents independently selected from halogen, C 1-6 alkyl, and —O—C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of formula (Ia):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein:
A is —CH═ or —N═;
B is —CH(R 9 )—, —O— or —N(R 10 )—;
D is —CH(R 5 )— or —N(R 5 )—;
m is 0, 1 or 2; q is 0 or 1; and
R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, —CN, and phenyl;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein:
R is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) —S(O) 2 —R f , wherein R f is selected from the group consisting of (a) C 1-4 alkyl optionally substituted with —NH 2 , (b) C 3-6 cycloalkyl, and (c) phenyl optionally substituted with one to three halogens,
(5) C 1-6 alkyl, optionally substituted with one to four substituents independently selected from (a) halogen, (b) —CN, (c) —OR d , (d) —(C═O)—R e , (e) —NR x R y , and (f) heterocyclyl; wherein R d is hydrogen or C 1-4 alkyl optionally substituted with heterocyclyl; R e is hydroxyl or heterocyclyl;
each of R x and R y is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl; wherein the C 3-6 cycloalkyl is optionally substituted with one to four substituents independently selected from halogen and C 1-4 alkyl optionally substituted with one to four halogens; and
the heterocyclyl of (f) is optionally substituted

Assignees

• Fischer Christian
• Bogen Stephane L
• Childers Matthew L
• Fradera Llinas Francesc Xavier
• Ellis J Michael
• Esposite Sara
• Hong Qingmei
• Huang Chunhui
• Kim Alexander J
• Lampe John W
• Machacek Michelle R
• Mcmasters Daniel R
• Otte Ryan D
• Parker Jr Dann L
• Reutershan Michael
• Sciammetta Nunzio
• Shao Pengcheng P
• Sloman David L
• Ujjainwalla Feroze
• White Catherine
• Wu Zhicai
• Yu Yang
• Zhao Kake
• Gibeau Craig
• Biftu Tesfaye
• Biju Purakkattle
• Chen Lei
• Close Joshua
• Fuller Peter H
• Huang Xianhai
• Park Min K
• Simov Valdimir
• Witter David J
• Zhang Hongjun
• Merck Sharp & Dohme

Inventors

• Fischer Christian
• Bogen Stephane L
• Childers Matthew L
• Fradera Llinas Francesc Xavier
• Ellis J Michael
• Esposite Sara
• Hong Qingmei
• Huang Chunhui
• Kim Alexander J
• Lampe John W
• Machacek Michelle R
• Mcmasters Daniel R
• Otte Ryan D
• Parker Jr Dann L
• Reutershan Michael
• Sciammetta Nunzio
• Shao Pengcheng P
• Sloman David L
• Ujjainwalla Feroze
• White Catherine
• Wu Zhicai
• Yu Yang
• Zhao Kake
• Gibeau Craig
• Biftu Tesfaye
• Biju Purakkattle
• Chen Lei
• Close Joshua
• Fuller Peter H
• Huang Xianhai
• Park Min K
• Simov Valdimir
• Witter David J
• Zhang Hongjun

Classifications

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A01N43/00

  Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds (containing cyclic anhydrides, cyclic imides A01N37/00; containing compounds of the formula [IMAGE cpc-sch-A01N-0942.gif] containing only one heterocyclic ring, wherein m>=1 and n>=0 and [IMAGE cpc-sch-A01N-0943.gif]is unsubstituted or alkylsubstituted pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or a polymethyleneimine with four or more CH2 groups, A01N33/00 - A01N41/12; containing cyclopropane carboxylic acids or derivatives thereof, e.g. esters having heterocyclic rings, A01N53/00) · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D471/08

  Bridged systems · CPC title