Compounds for the modulation of Myc activity

Patent metadata

Field	Value
Publication number	US-11753418-B2
Application number	US-202117411965-A
Country	US
Kind code	B2
Filing date	Aug 25, 2021
Priority date	Jun 5, 2015
Publication date	Sep 12, 2023
Grant date	Sep 12, 2023

Abstract

The present invention provides novel compounds of Formulas (I) and (II) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angio genesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.

First claim

What is claimed is:

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
each of X 1 , X 2 , X 3 and X 4 is independently selected from the group consisting of C(R), N and N(O), wherein one or two of X 1 , X 2 , X 3 and X 4 is N or one of X 1 , X 2 , X 3 and X 4 is N(O);
each R is independently selected from the group consisting of hydrogen, halogen, —CN, C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 6 alkyl), C(O)O(C 1 -C 6 alkyl), (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, and (C 0 -C 6 alkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R is optionally and independently substituted;
Y is selected from the group consisting of O, S and N(R 3a );
Z is selected from the group consisting of C(R 4a )(N(R 5 )(R 6 )) and N(R 1 );
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl, (C 1 -C 6 heteroalkylene)-heteroaryl, CH 2 C(O)OR 7 , CH 2 C(O)N(R 10 )(R 11 ), and CH 2 CH 2 N(R 10 )(R 11 ) wherein:
R 10 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
R 11 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, (C 0 -C 4 alkylene)-carbocyclyl, (C 0 -C 4 alkylene)-heterocyclyl, (C 0 -C 4 alkylene)-aryl, (C 0 -C 4 alkylene)-heteroaryl, (C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), (C 1 -C 4 alkyl)-N—(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-NH—(C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl), and C(O)—O—(C 1 -C 4 alkyl), or
R 10 and R 11 are taken together with the nitrogen atom to which they are commonly bound to form a 4-11 membered heterocyclyl or heteroaryl; and any alkyl, alkylene, heteroalkyl, heteroalkylene, heterocyclyl, heteroaryl, aryl or carbocyclyl portion of R 1 is optionally substituted;

R 2 is selected from the group consisting of C(R 2a )(R 2b )(R 2c ), carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein any carbocyclyl, aryl, heterocyclyl and heteroaryl is optionally substituted;
R 2a is selected from the group consisting of hydrogen, halogen, —CN, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl and C 1 -C 4 haloalkyl, wherein any alkyl, heteroalkyl or haloalkyl is optionally substituted;
each of R 2b and R 2c is independently selected from the group consisting of hydrogen, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C(O)(C 1 -C 6 alkyl), C(O)(C 1 -C 6 heteroalkyl), C(O)O(C 1 -C 6 alkyl), C(O)O(C 1 -C 6 heteroalkyl), C(O)N(R 3a )(R 3b ), (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl and (C 1 -C 6 heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 2b and R 2c is optionally and independently substituted;
each of R 3a and R 3b is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl, each of which is optionally substituted;
each R 4 is independently selected from the group consisting of halogen, —CN, C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 6 alkyl), C(O)(C 1 -C 6 heteroalkyl), C(O)O(C 1 -C 6 alkyl), C(O)N(R 3a )(R 3b ), (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl, and (C 1 -C 6 heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 4 is optionally and independently substituted;
R 4a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each of R 5 and R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C(O)(C 1 -C 6 alkyl), C(O)O(C 1 -C 6 alkyl), (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl, and (C 1 -C 6 heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of each of R 5 and R 6 is optionally and independently substituted; or
R 5 and R 6 are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl;
R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 3 alkylene)-carbocyclyl, and (C 0 -C 3 alkylene)-heterocyclyl;
R 12 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 3 alkylene)-carbocyclyl, and (C 0 -C 3 alkylene)-heterocyclyl;
n is 0, 1 or 2;
m is 0, 1 or 2;
n+m=1, 2 or 3; and
p is 0, 1, 2, 3, 4, 5 or 6.

2. The compound of claim 1 , wherein one of X 1 , X 2 , X 3 , and X 4 is N or N(O), and the others of X 1 , X 2 , X 3 , and X 4 are, independently, C(R).

3. The compound of claim 2 , wherein X 3 is N, and each of X 1 , X 2 , and X 4 is C(R).

4. The compound of claim 1 , wherein each R is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 4 optionally substituted alkyl), and C(O)O(optionally substituted C 1 -C 4 alkyl).

5. The compound of claim 1 , wherein each R is independently selected from the group consisting of hydrogen, chloro, —CH 3 and —CHF 2 .

6. The compound of claim 1 , wherein Y is S.

7. The compound of claim 1 , wherein Z is N(R 1 ).

8. The compound of claim 7 , wherein R 1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, (C 0 -C 6 alkylene)-morpholin-4-yl, and CH 2 CH 2 N(R 10 )(R 11 ) wherein each of R 10 and R 11 is independently selected from the group consisting of hydrogen and methyl.

9. The compound of claim 8 , wherein R 1 is selected from the group consisting of hydrogen, isopropyl and ethyl.

10. The compound of claim 1 , wherein R 2 is C(R 2a )(R 2b )(R 2c ).

11. The compound of claim 8 , wherein:
R 2a is hydrogen;
R 2b is hydrogen; and
R 2c is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-aryl, and (C 1 -C 6 heteroalkylene)-heteroaryl, and any alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, or heteroaryl portion of R 2c is optionally substituted.

12. The compound of claim 11 , wherein R 2c is selected from the group consisting of C 1 -C 6 alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-O-alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-C(O)—O-alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-cycloalkyl, —(CH 2 )—N(R 13 )-cycloalkyl,

Assignees

• Syros Pharmaceuticals Inc

Inventors

• Marineau Jason J
• Rahl Peter B
• Sprott Kevin
• Ciblat Stephane
• Sow Boubacar
• Larouche-Gauthier Robin
• Berstler Lauren
• Roberts Christopher
• Zhang Yi
• Beaumier Francis
• Lépissier Luce

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title