Max binders as MYC modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-10106555-B2
Application number	US-201715435003-A
Country	US
Kind code	B2
Filing date	Feb 16, 2017
Priority date	Feb 16, 2016
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

The present disclosure provides compounds of Formula (I′), Formula (I), Formula (II), Formula (II-A), Formula (III), and Formula (IV). The compounds described herein are MAX binders and/or modulators of Myc, Mad, or Mxi1 (e.g., inhibitors of Myc, Mad, or Mxi1), and may be useful in treating a subject with a disease associated with Myc, such as proliferative diseases (e.g., cancer). Also provided in the present disclosure are pharmaceutical compositions and kits including the compounds described herein, as well as methods of using and uses of the compounds, compositions, and kits.

First claim

What is claimed is:

1. A compound of Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or nitrogen protecting group;
R 2 is independently hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or of the formula: —CH 2 (R 2b ), wherein:
R 2b is 5 to 8-membered substituted or unsubstituted cycloalkyl, 5 to 10-membered substituted or unsubstituted heterocyclyl, 6 to 14-membered substituted or unsubstituted aryl, or 5 to 10-membered substituted or unsubstituted heteroaryl; and
R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, unsubstituted phenyl, substituted or unsubstituted heteroaryl, or of the formula:

wherein:
x is 1, 2, 3, 4, or 5; and
each instance of R 3 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R b ) 2 , —SR, —CN, —SCN, or of the formula —O(CH 2 ) e OR c1 , wherein:
e is independently 1, 2, 3, or 4; and
R c1 is independently substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R A1 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R b ) 2 , —SR, —CN, or —SCN;
R A2 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R b ) 2 , —SR, —CN, —SCN, —NO 2 , or optionally two instances of R A2 are taken together with the phenyl in Formula (I′) to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
a is 0, 1, 2, 3, or 4;
b is 0, 1, or 2;
z1 and z2 indicate where two instances of R A2 are optionally taken together to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl fused with the phenyl moiety in Formula (I′); and
R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, oxygen protecting group, or sulfur protecting group; and
each instance of R b is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or optionally two R b are taken together to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
wherein acyl is independently —C(═O)R aa , —CHO, —CO 2 R aa , —C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , or —C(═NR bb )N(R bb ) 2 ;
wherein each acyl, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclic ring, heteroaryl ring, aryl, and heteroaryl referred to above is substituted with one or more substituents at a carbon atom, the one or more substituents at the carbon atom are independently selected from the substituents in Group (i);
when any one of the heterocyclyl, heterocyclic ring, heteroaryl, and heteroaryl ring, referred to above is substituted with one or more substituents at a nitrogen atoms, the one or more substituents at the nitrogen atom are independently selected from the substituents in Group (ii);
Group (i) consists of halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3 + X − , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C(═O)R aa , —CO 2 H, —CHO, —C(OR cc ) 2 , —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —OC(═NR bb )R aa , —OC(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —OC(═NR bb )N(R bb ) 2 , —NR bb C(═NR bb )N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —NR bb SO 2 R aa , —SO 2 N(R bb ) 2 , —SO 2 R aa , —SO 2 OR aa , —OSO 2 R aa , —S(═O)R aa , —OS(═O)R aa , —Si(R aa ) 3 , —OSi(R aa ) 3 —C(═S)N(R bb ) 2 , —C(═O)SR aa , —C(═S)SR aa , —SC(═S)SR aa , —SC(═O)SR aa , —OC(═O)SR aa , —SC(═O)OR aa , —SC(═O)R aa , —P(═O)(R aa ) 2 , —OP(═O)(R aa ) 2 , —OP(═O)(OR cc ) 2 , —P(═O)(NR bb ) 2 , —OP(═O)(NR bb ) 2 , —NR bb P(═O)(OR cc ) 2 , —NR bb P(═O)(NR bb ) 2 , —P(R cc ) 2 , —OP(R cc ) 2 , —B(R aa ) 2 , —B(OR CC ) 2 , —BR aa (OR cc ), C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(R bb ) 2 , ═NNR bb C(═O)R aa , ═NNR bb C(═O)OR aa , ═NNR bb S(═O) 2 R aa , ═NR bb , or ═NOR cc ; and
Group (ii) consists of hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R CC ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR bb )R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O)(R aa ) 2 , —P(═O)(NR cc ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
wherein:
each instance of R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
each instance of R bb is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR

Assignees

• Massachusetts Inst Technology

Inventors

• Koehler Angela N
• Stefan Eric
• Caballero Francisco
• Neel Dylan Vijith
• Struntz Nicholas B
• Evans Helen L
• Chen Andrew

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D233/28

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title