Transcriptional enhanced associate domain (TEAD) transcription factor inhibitors and uses thereof
Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases (e.g., proliferative diseases (e.g., cancers, such as carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)) in a subject. Provided are methods of inhibiting a TEAD transcription factors (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject.
1 . A compound of any one of the formulae:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:
R 1 is —CF 3 , halogen, optionally substituted heterocyclyl, —OR f , —N(R f ) 2 , or —SR f ,
each occurrence of R f s independently hydrogen, optionally substituted alkyl, alkynyl, aryl;
R 2 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, haloalkyl, methyl, optionally substituted heteroalkyl, trifluoromethyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR c , —NO 2 , —N(R c ) 2 , or —SR c , wherein R c is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or optionally, R 2 can be joined together with X 1 to form an optionally substituted heterocyclic ring;
m is 0, 1, 2, 3 or 4;
A is an optionally substituted heterocyclic ring, such that: i) Ring A is an optionally substituted heterocyclic ring wherein each heteroatom is selected from nitrogen and sulfur when X 1 is a bond, and ii) Ring A is not indolinyl when X 1 is —O—, —C(R d ) 2 O— or —OC(R d ) 2 —;
X 1 is a bond, —O—, C 1-6 alkyl, —N(R d )—, —C(R d ) 2 N(R d )—, —C(═O)N(R d )—, —N(R d )C(═O)—, —C(R d ) 2 O—, or —OC(R d ) 2 —,wherein R d is independently hydrogen or C 1-6 alkyl;
X 2 is a bond;
D 1 is:
wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —NR L3a —, wherein R L3a is hydrogen;
R E1 is hydrogen;
R E2 is selected from the group consisting of hydrogen and —CH 2 N(R E2a ) 2 , wherein each occurrence of R E2a is independently alkyl; and
R E3 is hydrogen;
Y is —O—.
2 . The compound of claim 1 , wherein the formula is
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
3 . The compound of claim 2 , wherein the compound is any one of the formulae:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
4 . The compound of claim 1 , wherein R 1 is —CF 3 .
5 . The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein A is of any one of the formulae:
wherein:
R 3 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —C(═O)OR e , —C(═O)N(R e ) 2 , —OR e , —N(R e ) 2 , —SR e , or —N(R e )SO 2 R e wherein R e is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or
optionally, two instances of R 3 can be joined together to form an optionally substituted carbocyclic or heterocyclic fused ring; and
n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.
7 . The compound of claim 1 , wherein the compound is of any one of the formulae:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
8 . The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, of the formula:
11 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
12 . A compound of Formula (I-e):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer or isotopically labeled derivative thereof wherein:
R 1 is hydrogen, trifluoromethyl, or N(R a )(R b ), wherein R a is optionally substituted alky;
R b is optionally substituted alkyl, or R a and R b together with the nitrogen atom to which they are attached form a heterocycle;
R 2 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, haloalkyl, optionally substituted heteroalkyl, trifluoromethyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR c , —NO 2 , —N(R c ) 2 , or —SR c , wherein R c is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or optionally, R 2 can be joined together with X 1 to form an optionally substituted heterocyclic ring;
A is an optionally substituted heterocyclic ring, such that: i) Ring A is an optionally substituted heterocyclic ring wherein each heteroatom is selected from nitrogen and sulfur when X 1 is a bond, and ii) Ring A is not indolinyl when X 1 is —O—;
V 1 is —C(R 2 )—;
X 1 is a bond or O, S, —CH 2 N(R d )—, or —N(R d )—, wherein R d is a bond, hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, or optionally R d can be joined together with one instance of R 2 to form an optionally substituted heterocyclic ring;
X 2 is a bond;
m is 0, 1, 2, 3 or 4;
D 1 is
wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —NR L3a —, wherein R L3a is hydrogen;
R E1 is hydrogen;
R E2 is selected from the group consisting of hydrogen and —CH 2 N(R E2a ) 2 , wherein each occurrence of R E2a is independently selected from the group consisting of alkyl; and
R E3 is hydrogen;
Y is O.
13 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.