Compounds and methods for the treatment of isocitrate dehydrogenase related diseases

Patent metadata

Field	Value
Publication number	US-9944633-B2
Application number	US-201514818009-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Mar 29, 2011
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The invention relates to compounds of Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:

First claim

What is claimed is:

1. A compound of Formula (TB) or Formula (IC), or a pharmaceutically acceptable salt thereof:

wherein:
n is 0;
q is 1;
X 2 is —O—
Cy1 is:

R 1 is C 1 -C 6 alkyl;
R 2 is:

R 12 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, CONR 20 R 21 , C(O)R 20 , or C(O)OR 21 ;
R 13 , R 14 , and R 15 are each independently hydrogen;
R 16 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
alternatively, when two of the R 13 , R 14 , R 15 , and R 16 groups are attached to a carbon atom, together said two groups and said carbon atom may form a carbonyl or an optionally substituted vinyl group;
u is 1;
w is 0, 1, 2, 3, 4, 5 or 6;
Cy3 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
R 3 is selected from:

each R 13 ′, R 14 ′ and R 15 ′ is independently hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl;
each of R 16 ′ and R 17 ′ is independently hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl;
R 11 is:

R 13 ″ is hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl;
R 40 is selected from the group consisting of:

and
R 41 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl;
q′ is 1;

and
R 20 and R 21 are each independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl.

2. The compound of claim 1 , wherein R 1 is methyl, ethyl or propyl.

3. The compound of claim 2 , wherein R 1 is methyl.

4. The compound of claim 1 , wherein R 12 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.

5. The compound of claim 1 , wherein R 2 is:

6. The compound of claim 1 , wherein R 3 is:

7. The compound of claim 6 , wherein R 3 is

8. The compound of claim 1 , wherein R 11 is a moiety selected from those shown in Table B:

TABLE B

9. The compound of claim 1 , wherein w is 0, 1 or 2.

10. The compound of claim 1 selected from those shown in Table 1, or a pharmaceutically acceptable salt thereof:

TABLE 1

1

(4R,5R)-8-(cyclopent-1-en-1-yl)-2-((S)-1- hydroxypropan-2-yl)-4-methyl-5- ((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5- tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide

4

N-(((4R,5R)-8-(cyclohexylethynyl)-2-((S)-1- hydroxypropan-2-yl)-4-methyl-1,1- dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin- 5-yl)methyl)-N-methyl-2- (pyridin-4-yl)acetamide

6

N-(((4R,5R)-2-((R)-1-hydroxypropan-2- yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1- dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin- 5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide

8

(4R,5R)-8-(cyclopropylethynyl)-2-((R)-1-hydroxypropan- 2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino

Assignees

• Broad Inst Inc
• Harvard College

Inventors

• Hussain Mahmud
• Ito Daisuke
• Law Jason
• Leiendecker Matthias
• Liu Ke
• Munoz Benito
• Schreiber Stuart
• Shamji Alykhan
• Stern Andrew

Classifications

• C07D413/12

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

• C07D417/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/12

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

• C07D498/04

  Ortho-condensed systems · CPC title