CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 17/646,787, filed Jan. 3, 2022, which is a divisional of U.S. application Ser. No. 16/886,926, filed May 29, 2020, issued as a U.S. Pat. No. 11,274,082 on Mar. 15, 2022, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62/855,082, filed May 31, 2019; U.S. Provisional Patent Application No. 62/928,931, filed Oct. 31, 2019; U.S. Provisional Patent Application No. 62/944,567, filed Dec. 6, 2019; and U.S. Provisional Patent Application No. 63/025,219, filed May 15, 2020, the contents of each of which are herein incorporated by reference in their entireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Jun. 9, 2023, is named 200703_SL.XML and is 10,579 bytes in size.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for inhibition of Transcriptional Enhancer Associate Domain (TEAD). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various diseases, disorders, and conditions as described herein.

BACKGROUND OF THE INVENTION

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers.

SUMMARY OF THE INVENTION

The Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance. The Hippo pathway is heavily mutated across many cancer indications through loss of function mutations in genes such as NF2. These pro-tumor mutations lead to the constitutive activation of the downstream transcriptional coactivators YAP and TAZ that drive the expression of many pro-survival and proliferation genes through the essential interaction with a TEAD protein family member. In addition, this unrestrained transcriptional program drives enhanced immune suppression in the tumor microenvironment. As described herein, to target this oncogenic pathway novel small molecule inhibitors were identified that selectively bind to TEAD and disrupt their interaction with YAP and TAZ, thereby downregulating YAP- and TAZ-dependent transcription. As demonstrated herein, these TEAD inhibitors prevent TEAD palmitoylation, which is critical for the interaction between YAP and TEAD. Furthermore, the TEAD inhibitors described herein inhibit in vitro proliferation of YAP-dependent (i.e., Hippo pathway-deficient cancer cell lines), but not Hippo pathway wild type cancer cell lines. Importantly, as shown herein, the TEAD inhibitor compounds of the present invention did not affect survival of a differentiated mouse podocyte cell line or compromise mouse kidney histology. Subsequent experiments in vivo demonstrate the TEAD inhibitors described herein downregulate YAP-dependent genes in human tumor xenografts after oral dosing. In addition, the TEAD inhibitors described herein exhibit single agent tumor growth inhibition of human tumor xenografts in mice at well tolerated oral doses. The data described herein demonstrate the ability of the small molecule TEAD inhibitors provided herein for targeting the Hippo pathway in cancers.

It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as TEAD inhibitors. In one aspect, the present invention provides a compound of Formula I′:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In one aspect, the present invention provides a compound of Formula I:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

Compounds of the present invention, and pharmaceutically acceptable salts and compositions thereof, are useful for treating a variety of diseases, disorders or conditions associated with TEAD. Such diseases, disorders, or conditions include cellular proliferative disorders (e.g., cancer as described herein).

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts a schematic of Hippo pathway signaling.

FIG. 2 depicts pharmacodynamic (PD) properties of compound I-27 using real-time PCR.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General Description of Certain Embodiments of the Invention

Compounds of the present invention, and pharmaceutical salts and compositions thereof, are useful as inhibitors of TEAD. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and pharmaceutical compositions thereof, inhibit the activity of TEAD and thus treat diseases, disorders, or conditions associated with TEAD, such as cancer.

In one aspect, the present invention provides a compound of Formula I′:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—;
- Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R^wis an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
- each R is independently —H or optionally substituted —C_1-6aliphatic.

In one aspect, the present invention provides a compound of Formula I:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—;
- Ring A is a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by -halogen, —CN, —NO₂, or —C_1-6aliphatic substituted 0-6 times by -halogen, —CN, or —NO₂;
- R²is —H, or an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R³is —H;
- R⁴is —H, halogen, —S(O)₂N(R)₂, —S(O)N(R)₂, or —C(O)N(R)₂;
- R⁶is —H or —C_1-6aliphatic substituted 0-6 times by -halogen, —CN, or —NO₂; and
- each R is independently —H or optionally substituted —C_1-6aliphatic.

2. Compounds and Definitions

Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[Image Omitted]

Exemplary bridged bicyclics include:

[Image Omitted]

The term “lower alkyl” refers to a C_1-4straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C_1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

As used herein, the term “bivalent C_1-8(or C_1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH₂)_n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

[Image Omitted]

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; —(CH₂)_0-4R^∘; —(CH₂)_0-4OR^∘; —O(CH₂)_0-4R^∘, —O—(CH₂)_0-4C(O)OR^∘; —(CH₂)_0-4CH(OR^∘)₂; —(CH₂)_0-4SR^∘; —(CH₂)_0-4Ph, which may be substituted with R^∘; —(CH₂)_0-4O(CH₂)_0-1Ph which may be substituted with R^∘; —CH═CHPh, which may be substituted with R^∘; —(CH₂)_0-4O(CH₂)_0-1-pyridyl which may be substituted with R^∘; —NO₂; —CN; —N₃; —(CH₂)_0-4N(R^∘)₂; —(CH₂)_0-4N(R^∘)C(O)R^∘; —N(R^∘)C(S)R^∘; —(CH₂)_0-4N(R^∘)C(O)NR^∘₂; —N(R^∘)C(S)NR^∘₂; —(CH₂)_0-4N(R^∘)C(O)OR^∘; —N(R^∘)N(R^∘)C(O)R^∘; —N(R^∘)N(R^∘)C(O)NR^∘₂; —N(R^∘)N(R^∘)C(O)OR^∘; —(CH₂)_0-4C(O)R^∘; —C(S)R^∘; —(CH₂)_0-4C(O)OR^∘; —(CH₂)_0-4C(O)SR^∘; —(CH₂)_0-4C(O)O SiR^∘₃; —(CH₂)_0-4OC(O)R^∘; —OC(O)(CH₂)_0-4SR—, SC(S)SR^∘; —(CH₂)_0-4SC(O)R^∘; —(CH₂)_0-4C(O)NR^∘₂; —C(S)NR^∘₂; —C(S)SR^∘; —SC(S)SR^∘, —(CH₂)_0-4OC(O)NR^∘₂; —C(O)N(OR^∘)R^∘; —C(O)C(O)R^∘; —C(O)CH₂C(O)R^∘; —C(NOR^∘)R^α; —(CH₂)_0-4SSR^∘; —(CH₂)_0-4S(O)₂R^∘; —(CH₂)_0-4S(O)₂OR^∘; —(CH₂)_0-4OS(O)₂R^∘; —S(O)₂NR^∘₂; —S(O)(NR^∘)R^∘; —S(O)₂N═C(NR^∘₂)₂; —(CH₂)_0-4S(O)R^∘; —N(R^∘)S(O)₂NR^∘₂; —N(R^∘)S(O)₂R^∘; —N(OR^∘)R^∘; —C(NH)NR^∘₂; —P(O)₂R^∘; —P(O)R^∘₂; —OP(O)R^∘₂; —OP(O)(OR^∘)₂; SiR^∘₃; —(C_1-4straight or branched alkylene)O—N(R^∘)₂; or —(C_1-4straight or branched alkylene)C(O)O—N(R^∘)₂.

Each R^∘is independently hydrogen, C_1-6aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R^∘ selected from ═O and ═S; or each R^∘is optionally substituted with a monovalent substituent independently selected from halogen, —(CH₂)_0-2R^•, -(haloR^•), —(CH₂)_0-2OH, —(CH₂)_0-2OR^•, —(CH₂)_0-2CH(OR^•)₂; -(haloR^•), —CN, —N₃, —(CH₂)_0-2C(O)R^•, —(CH₂)_0-2C(O)OH, —(CH₂)_0-2C(O)OR^•, —(CH₂)_0-2SR^•, —(CH₂)_0-2SH, —(CH₂)_0-2NH₂, —(CH₂)_0-2NHR^•, —(CH₂)_0-2NR^•₂, —NO₂, —SiR^•₃, —OSiR^•₃, —C(O)SR^•, —(C_1-4straight or branched alkylene)C(O)OR^•, or —SSR^•.

Each R^• is independently selected from C_1-4aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^• is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from ═O, ═S, ═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))_2-3O—, or —S(C(R*₂))_2-3S—, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is —O(CR*₂)_2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C_1-6aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

When R* is C_1-6aliphatic, R* is optionally substituted with halogen, —R^•, -(haloR^•), —OH, —OR^•, —O(haloR^•), —CN, —C(O)OH, —C(O)OR^•, —NH₂, —NHR^•, —NR^•₂, or —NO₂, wherein each R^• is independently selected from C_1-4aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^• is unsubstituted or where preceded by halo is substituted only with one or more halogens.

An optional substituent on a substitutable nitrogen is independently —R^†, —NR^†₂, —C(O)R^†, —C(O)OR^†, —C(O)C(O)R^†, —C(O)CH₂C(O)R^†, —S(O)₂R^†, —S(O)₂NR^†₂, —C(S)NR^†₂, —C(NH)NR^†₂, or —N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1-6aliphatic, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R^† is C_1-6aliphatic, R^† is optionally substituted with halogen, —R^•, -(haloR^•), —OH, —OR^•, —O(haloR^•), —CN, —C(O)OH, —C(O)OR^•, —NH₂, —NHR^•, —NR^•₂, or —NO₂, wherein each R^• is independently selected from C_1-4aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^• is unsubstituted or where preceded by halo is substituted only with one or more halogens.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C_1-4alkyl)₄salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

As used herein, the terms “inhibitor” or “TEAD inhibitor” or “TEAD antagonist” are defined as a compound that binds to and/or inhibits TEAD with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions. The potency of an inhibitor is usually defined by its IC₅₀value (half maximal inhibitory concentration or concentration required to inhibit 50% of the agonist response). The lower the IC₅₀value the greater the potency of the antagonist and the lower the concentration that is required to inhibit the maximum biological response. In certain embodiments, an inhibitor has an IC₅₀and/or binding constant of less than about 100 μM, less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change or inhibition in TEAD activity between a sample comprising a compound of the present invention, or composition thereof, and TEAD, and an equivalent sample comprising TEAD, in the absence of said compound, or composition thereof.

3. DESCRIPTION OF EXEMPLARY EMBODIMENTS

In one aspect, the present invention provides a compound of Formula I′:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- L¹is a covalent bond, or a C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—;
- Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R^wis an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
- each R is independently —H or optionally substituted —C_1-6aliphatic.

In one aspect, the present invention provides a compound of Formula I:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—;
- Ring A is a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, —CN, —NO₂, or —C_1-6aliphatic substituted 0-6 times by halogen, —CN, or —NO₂;
- R²is —H, or an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R³is —H;
- R⁴is —H, halogen, —S(O)₂N(R)₂, —S(O)N(R)₂, or —C(O)N(R)₂;
- R⁶is —H or —C_1-6aliphatic substituted 0-6 times by halogen, —CN, or —NO₂; and
- each R is independently —H or optionally substituted —C_1-6aliphatic.

As defined generally above, L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹is a covalent bond, or a C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹is a covalent bond.

In some embodiments, L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, or —N(R)C(O)N(R)—.

In some embodiments, L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are optionally replaced with —CH(SR)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —C(O)—, —C(O)O—, —OC(O)—, —SO—, —SO₂—, —C(S)—, —C(S)O—, or —OC(S)—.

In some embodiments, L¹is C_1-6bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —SO₂N(R)—, —(R)NSO₂—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹is —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹is —O—, —CH(OR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, or —N(R)C(O)N(R)—.

In some embodiments, L¹is —CH(SR)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹is —O—, —S—, or —N(R)—. In some embodiments, L¹is —O—. In some embodiments, L¹is —S—. In some embodiments, L¹is —N(R)—. In some embodiments, L¹is —NH—.

In some embodiments, L¹is —CH(OR)—, —CH(SR)—, or —CH(N(R)₂)—. In some embodiments, L¹is —CH(OR)—. In some embodiments, L¹is —CH(SR)—. In some embodiments, L¹is —CH(N(R)₂)—.

In some embodiments, L¹is —C(O)—, —C(O)O—, —OC(O)—, —SO—, —SO₂—, —C(S)—, —C(S)O—, or —OC(S)—. In some embodiments, L¹is —C(O)—. In some embodiments, L¹is —C(O)O—. In some embodiments, L¹is —OC(O)—. In some embodiments, L¹is —SO—. In some embodiments, L¹is —SO₂—. In some embodiments, L¹is —C(S)—. In some embodiments, L¹is —C(S)O—. In some embodiments, L¹is —OC(S)—.

In some embodiments, L¹is —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —SO₂N(R)—, —(R)NSO₂—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—. In some embodiments, L¹is —C(O)N(R)—. In some embodiments, L¹is —(R)NC(O)—. In some embodiments, L¹is —OC(O)N(R)—. In some embodiments, L¹is —(R)NC(O)O—. In some embodiments, L¹is —N(R)C(O)N(R)—. In some embodiments, L¹is —SO₂N(R)—. In some embodiments, L¹is —(R)NSO₂—. In some embodiments, L¹is —C(S)N(R)—. In some embodiments, L¹is —(R)NC(S)—. or In some embodiments, L¹is —(R)NC(S)N(R)—.

In some embodiments, L¹is —CH₂—, —CH(CH₃)—, —NH—CH₂—, —NH—CH(CH₃)—, —C(O)—NH—, or —N(CH₃)—.

In some embodiments, L¹is

[Image Omitted]

In some embodiments, L¹is selected from those depicted in Table 1, below.

As defined generally above, Ring A is a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, —CN, —NO₂, or —C_1-6aliphatic substituted 0-6 times by halogen, —CN, or —NO₂.

In some embodiments, Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A is optionally substituted phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen.

In some embodiments, Ring A is optionally substituted

[Image Omitted]

In some embodiments, Ring A is optionally substituted 1-2 times by -halogen, —CN, —NO₂, —C_1-6aliphatic, or —O—C_1-6aliphatic, wherein each of —C_1-6aliphatic and —O—C_1-6aliphatic is independently substituted 0-6 times by -halogen, —CN, or —NO₂. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, —CN, —NO₂, —C_1-6aliphatic, or —O—C_1-6aliphatic, wherein each of —C_1-6aliphatic and —O—C_1-6aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, —CN, or —NO₂. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, —C_1-6aliphatic, or —O—C_1-6aliphatic, wherein each of —C_1-6aliphatic and —O—C_1-6aliphatic is independently substituted 1, 2, 3, 4, 5, or 6 times by halogen.

In some embodiments, Ring A is a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A is a 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A is optionally substituted 1-2 times by halogen, —CN, —NO₂, or —C_1-6aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, —CN, or —NO₂. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, or —C_1-6aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen.

In some embodiments, Ring A is selected from

[Image Omitted]

wherein each of R¹and R⁷is independently as described herein.

In some embodiments, Ring A is selected from

[Image Omitted]

In some embodiments, R¹is —H, -halogen, —CN, —NO₂, —C_1-6aliphatic, or —O—C_1-6aliphatic, wherein each of —C_1-6aliphatic and —O—C_1-6aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R¹is unsubstituted —O—C_1-6aliphatic. In some embodiments, R¹is —OCH₃. In some embodiments, R¹is —O—C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R¹is —O—C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R¹is —O—C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R¹is —OCF₃. In some embodiments, R¹is

[Image Omitted]

In some embodiments, R¹is —H, -halogen, —CN, —NO₂, or —C_1-6aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R¹is —H. In some embodiments, R¹is -halogen. In some embodiments, R¹is —F. In some embodiments, R¹is —Cl. In some embodiments, R¹is —Br. In some embodiments, R¹is —CN. In some embodiments, R¹is —NO₂. In some embodiments, R¹is unsubstituted —C_1-6aliphatic. In some embodiments, R¹is —CH₃. In some embodiments, R¹is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R¹is —C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R¹is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R¹is —C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R¹is —CF 3. In some embodiments, R¹is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —CN. In some embodiments, R¹is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —NO₂.

In some embodiments, R⁷is —H, -halogen, —CN, —NO₂, —C_1-6aliphatic, or —O—C_1-6aliphatic, wherein each of —C_1-6aliphatic and —O—C_1-6aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁷is unsubstituted —O—C_1-6aliphatic. In some embodiments, R⁷is —OCH₃. In some embodiments, R⁷is —O—C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R⁷is —O—C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R⁷is —O—C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁷is —OCF₃. In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is —H, -halogen, —CN, —NO₂, or —C_1-6aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁷is —H. In some embodiments, R⁷is -halogen. In some embodiments, R⁷is —F. In some embodiments, R⁷is —Cl. In some embodiments, R⁷is —Br. In some embodiments, R⁷is —CN. In some embodiments, R⁷is —NO₂. In some embodiments, R⁷is unsubstituted —C_1-6aliphatic. In some embodiments, R¹is —CH₃. In some embodiments, R⁷is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R⁷is —C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R⁷is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁷is —C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁷is —CF 3. In some embodiments, R⁷is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —CN. In some embodiments, R⁷is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —NO₂.

In some embodiments, Ring A is

[Image Omitted]

In some embodiments, Ring A is

[Image Omitted]

In some embodiments, Ring A is selected from those depicted in Table 1, below.

As defined generally above, Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring B is optionally substituted phenyl. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring B is optionally substituted phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen.

In some embodiments, Ring B is optionally substituted

[Image Omitted]

In some embodiments, Ring B is optionally substituted 1-4 times by halogen, —S(O)₂N(R)₂, —S(O)N(R)₂, —C(O)N(R)₂, —C(O)OR, —C_1-6aliphatic, or —O—C_1-6aliphatic, wherein each of —C_1-6aliphatic and —O—C_1-6aliphatic is independently substituted 0-6 times by halogen, —CN, or —NO₂.

In some embodiments, Ring B is optionally substituted 1-4 times by —F, —Cl, —Br—, —S(O)₂NHCH₃, —S(O)NHCH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —C(O)OH, —C(O)OCH₃, —CH₃, —OCH₃, or —C(CH₃)₃.

In some embodiments, Ring B is

[Image Omitted]

In some embodiments, Ring B is selected from those depicted in Table 1, below.

As defined generally above, R²is —H, or an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R²is —H.

In some embodiments, R²is an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R²is a 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by —C_1-6alkyl.

In some embodiments, R²is

[Image Omitted]

wherein R is as described herein. In some embodiments, R²is

[Image Omitted]

wherein R is as described herein.

In some embodiments, R²is

[Image Omitted]

In some embodiments, R²is

[Image Omitted]

In some embodiments, R²is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen. In some embodiments, R²is selected from

[Image Omitted]

In some embodiments, R²is

[Image Omitted]

In some embodiments, R²is

[Image Omitted]

In some embodiments, R²is selected from those depicted in Table 1, below.

As defined generally above, in some embodiments, R³is —H.

In some embodiments, R³is

[Image Omitted]

In some embodiments, R³is

[Image Omitted]

In some embodiments, R³is selected from those depicted in Table 1, below.

As defined generally above, R⁴is —H, halogen, —S(O)₂N(R)₂, —S(O)N(R)₂, or —C(O)N(R)₂.

In some embodiments, R⁴is —H, halogen, —S(O)₂N(R)₂, —S(O)N(R)₂, —C(O)N(R)₂, or —C(O)OR.

In some embodiments, R⁴is —H.

In some embodiments, R⁴is halogen. In some embodiments, R⁴is —F. In some embodiments, R⁴is —Cl. In some embodiments, R⁴is —Br.

In some embodiments, R⁴is —S(O)₂N(R)₂, —S(O)N(R)₂, or —C(O)N(R)₂. In some embodiments, R⁴is —S(O)₂N(R)₂. In some embodiments, R⁴is —S(O)N(R)₂. In some embodiments, R⁴is —C(O)N(R)₂. In some embodiments, R⁴is —S(O)₂NHCH₃.

In some embodiments, R⁴is —S(O)NHCH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —C(O)OH, or —C(O)OCH₃.

In some embodiments, R⁴is

[Image Omitted]

In some embodiments, R⁴is

[Image Omitted]

In some embodiments, R⁴is selected from those depicted in Table 1, below.

As defined generally above, R⁶is —H or —C_1-6aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂.

In some embodiments, R⁶is —H, -halogen, —CN, —NO₂, —C_1-6aliphatic, —OC_1-6aliphatic, or a 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by —C_1-6aliphatic or —OC_1-6aliphatic, wherein each of —C_1-6aliphatic and —OC_1-6aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂.

In some embodiments, R⁶is —H. In some embodiments, R⁶is —F. In some embodiments, R⁶is —Cl. In some embodiments, R⁶is —Br. In some embodiments, R⁶is —CN. In some embodiments, R⁶is —NO₂.

In some embodiments, R⁶is —C_1-6aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁶is unsubstituted —C_1-6aliphatic. In some embodiments, R⁶is —CH₃. In some embodiments, R⁶is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁶is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁶is —C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁶is —CF₃.

In some embodiments, R⁶is —OC_1-6aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁶is unsubstituted —OC_1-6aliphatic. In some embodiments, R⁶is —OCH₃. In some embodiments, R⁶is —OC_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁶is —OC_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁶is —OC_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁶is —OCF₃.

In some embodiments, R⁶is a 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by —C_1-6aliphatic or —OC_1-6aliphatic, wherein each of —C_1-6aliphatic and —OC_1-6aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁶is a 5-membered ring having 1, 2, 3, or 4 nitrogen optionally substituted 1-3 times by —C_1-6aliphatic. In some embodiments, R⁶is

[Image Omitted]

In some embodiments, R⁶is selected from those depicted in Table 1, below.

As defined generally above, R^wis an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^wis an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R^wis a 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by —C_1-6alkyl.

In some embodiments, R^wis

[Image Omitted]

wherein R is as described herein. In some embodiments, R^wis

[Image Omitted]

wherein R is as described herein.

In some embodiments, R^wis a 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by —C_1-6alkyl. In some embodiments, R^wis an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen. In some embodiments, R^wis

[Image Omitted]

In some embodiments, R^wis

[Image Omitted]

In some embodiments, R^wis

[Image Omitted]

In some embodiments, R^wis selected from those depicted in Table 1, below.

As defined generally above, R is independently —H or optionally substituted —C_1-6aliphatic.

In some embodiments, R is —H.

In some embodiments, R is optionally substituted —C_1-6aliphatic. In some embodiments, R is unsubstituted —C_1-6aliphatic. In some embodiments, R is —CH₃. In some embodiments, R is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R is —C_1-3aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R is —CF₃.

In some embodiments, R is selected from those depicted in Table 1, below.

In some embodiments, a compound provided herein is capable of reversibly inhibiting a target protein, for example, TEAD, by interacting with an amino acid residue (such as cysteine, lysine, and histidine) present in the binding pocket of the protein. In some embodiments, a compound provided herein is capable of interacting with cysteine. In some embodiments, a compound provided herein is capable of interacting with serine. In some embodiments, a compound provided herein is capable of interacting with lysine. In some embodiments, a compound provided herein is capable of interacting with Cys359 of hTEAD1, Cys380 of hTEAD2, Cys368 of hTEAD3, and/or Cys367 of hTEAD4. In some embodiments, a compound provided herein is capable of interacting with Ser356 of hTEAD1, Ser345 and/or Ser377 of hTEAD2, Ser365 of hTEAD3, and/or Ser364 of hTEAD4. In some embodiments, a compound provided herein is capable of interacting with Lys336 of hTEAD1, Lys357 of hTEAD2, Lys345 of hTEAD3, and/or Lys344 of hTEAD4. Representative reference amino acid sequences of human TEAD1, human TEAD2, human TEAD3, and human TEAD4 include UniProt KB ID P28347-1 (SEQ ID NO: 1), UniProtKB ID Q15562 (SEQ ID NO: 2), UniProtKB ID Q99594 (SEQ ID NO: 3), and UniProtKB ID Q15561 (SEQ ID NO: 4), respectively. Below is the sequence alignments of TEAD coactivator binding domains, which is shown in Table 1 of “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem. 2018, 61, 5057-5072, the entire content of which is incorporated herein by reference.

SEQ ID NO: 5
hTEAD1
²⁰⁶WQGRSIGTTKLRLVEFSAFLEQQ

RDPDSYNKHLFVHIGHANHSYSDPL

LESVDIRQIYDKFPEKKGGLKE²⁷⁵

SEQ ID NO: 6
hTEAD2
²¹⁸WQARGLGTARLQLVEFSAFVEPP

DAVDSYQRHLFVHISQHCPSPGAPP

LESVDVRQIYDKFPEKKGGLRE²⁸⁷

SEQ ID NO: 7
hTEAD3
²¹⁵WQDRTIASSRLRLLEYSAFMEVQ

RDPDTYSKHLFVHIGQTNPAFSDPP

LEAVDVRQIYDKFPEKKGGLKE²⁸⁴

SEQ ID NO: 8
hTEAD4
²¹⁴WQGRSVASSKLWMLEFSAFLEQQ

QDPDTYNKHLFVHIGQSSPSYSDPY

LEAVDIRQIYDKFPEKKGGLKD²⁸³

SEQ ID NO: 5
hTEAD1
²⁷⁶LFGKGPQNAFFLVKFWADLNCNI

Q-DDAGA--------FYGVTSQYES

SENMTVTCSTKVCSFGKQVVEK³³⁶

SEQ ID NO: 6
hTEAD2
²⁸⁸LYDRGPPHAFFLVKFWADLNWGP

SGEEAGAGGSISSGGFYGVSSQYES

LEHMTLTCSSKVCSFGKQVVEK³⁵⁷

SEQ ID NO: 7
hTEAD3
²⁸⁵LYEKGPPNAFFLVKFWADLNSTI

Q-EGPGA--------FYGVSSQYSS

ADSMTISVSTKVCSFGKQVVEK³⁴⁵

SEQ ID NO: 8
hTEAD4
²⁸⁴LFERGPSNAFFLVKFWADLNTNI

E-DEGSS--------FYGVSSQYES

PENMIITCSTKVCSFGKQVVEK³⁴⁴

SEQ ID NO: 5
hTEAD1
³³⁷VETEYARFENGRFVYRINRSPMC

EYMINFIHKLKHLPEKYMMNSVLEN

FTILLVVTNRDTQETLLCMACV⁴⁰⁶

SEQ ID NO: 6
hTEAD2
³⁵⁸VETERAQLEDGRFVYRLLRSPMC

EYLVNFLHKLRQLPERYMMNSVLEN

FTILQVVTNRDTQELLLCTAYV⁴²⁷

SEQ ID NO: 7
hTEAD3
³⁴⁶VETEYARLENGRFVYRIHRSPMC

EYMINFIHKLKHLPEKYMMNSVLEN

FTILQVVTSRDSQETLLVIAFV⁴¹⁵

SEQ ID NO: 8
hTEAD4
³⁴⁵VETEYARYENGHYSYRIHRSPLC

EYMINFIHKLKHLPEKYMMNSVLEN

FTILQVVTNRDTQETLLCIAYV⁴¹⁴

SEQ ID NO: 5
hTEAD1
⁴⁰⁷FEVSNSEHGAQHHIYRLVKD⁴²⁶

SEQ ID NO: 6
hTEAD2
⁴²⁸FEVSTSERGAQHHIYRLVRD⁴⁴⁷

SEQ ID NO: 7
hTEAD3
⁴¹⁶FEVSTSEHGAQHHVYKLVKD⁴³⁵

SEQ ID NO: 8
hTEAD4
⁴¹⁵FEVSASEHGAQHHIYRLVKE⁴³⁴

In some embodiments, the present invention provides a compound of Formula (II):

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

In some embodiments, the present invention provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein:

- L¹is —O— or —S—;
- R¹is —C_1-6aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen;
- R²is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen;
- R³is —H;
- R⁴is —S(O)₂N(R)₂; —S(O)N(R)₂, or —C(O)N(R)₂, each R independently is selected —H and optionally substituted —C_1-6aliphatic;
- R⁶is —H or —C_1-6aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen; and
- R⁷is —H.

In some embodiments, the present invention provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein:

- L¹is —NH—;
- R¹is —C_1-6aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen;
- R²is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen;
- R³is —H;
- R⁴is —S(O)₂N(R)₂, —S(O)N(R)₂, or —C(O)N(R)₂, each R independently is selected from —H and optionally substituted —C_1-6aliphatic;
- R⁶is —C_1-6aliphatic; and
- R⁷is —H.

In some embodiments, the present invention provides a compound of Formula III:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

In some embodiments, the present invention provides a compound of Formula (IV):

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein each of X is independently C or N; and each of Ring A, R^w, and L¹is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of Formula (IVa) or (IVb):

[Image Omitted]