WO2023154811A2 - Transcriptional enhanced associate domain (tead) degraders and uses thereof - Google Patents

Transcriptional enhanced associate domain (tead) degraders and uses thereof Download PDF

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WO2023154811A2
WO2023154811A2 PCT/US2023/062307 US2023062307W WO2023154811A2 WO 2023154811 A2 WO2023154811 A2 WO 2023154811A2 US 2023062307 W US2023062307 W US 2023062307W WO 2023154811 A2 WO2023154811 A2 WO 2023154811A2
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compound
cancer
pharmaceutically acceptable
acceptable salt
alkyl
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WO2023154811A3 (en
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Nathanael S. Gray
Tinghu Zhang
Wenzhi JI
Wenchao Lu
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The Board Of Trustees Of The Leland Stanford Junior University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

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Abstract

Disclosed herein are bispecific compounds that target and degrade transcriptional enhanced associate domain (TEAD) transcription factors, pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., to treat diseases and disorders characterized or mediated by TEAD transcription factor activity.

Description

TRANSCRIPTIONAL ENHANCED ASSOCIATE DOMAIN (TEAD) DEGRADERS AND
USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/308,265, filed on February 9, 2022, which is incorporated herein byreference in its entirety.
TECHNICAL FIELD
[0002] Disclosed herein are bispecific compounds that target and degrade transcriptional enhanced associate domain (TEAD) transcription factors, pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., to treat, diseases and disorders characterized or mediated by TEAD transcription factor activity.
BACKGROUND
[0003] The Hippo signaling pathway has key roles in organ size control and tumor suppression. Signal transduction involves a core kinase cascade, leading to YAP/TAZ phosphorylation. Physiological or pathological inactivation leads to dephosphorylation and nuclear accumulation. Nuclear YAP/TAZ binds to transcriptional enhanced associate domain (TEAD) transcription factors to mediate target, gene expression. The TEAD- YAP complex regulates organ development and amplification of oncogenic factors in many cancers.
Additionally, several genes in the Hippo signaling pathway have been identified as tumor suppressors, and mutations in these genes have been associated with different human cancers.
SUMMARY
[0004] In one aspect, disclosed herein is a compound of formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
A 1 is CR3 or N;
A2 is CR2 or N;
A/' is CR3 or N;
A4 is CR4 or N;
A5 is CR5 or N;
R1, R2, R~, R4, and R5 are each independently selected from hydrogen, Ci-Ce alkyl, Ci-Cs haloalkyl, C2-C6 alkenyl, C2-C0 alkynyl, Ci-Ce heteroalkyl, (’ ■-( s. cycloalkyl, aryl, aryl-Ci-Co- alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -OR3, -SRa, -N(Ra)(Rb), -C(O)Ra, -C(O)ORa, - C(O)N(Ra)(Rb), -S(O)Ra, -S(O)2Ra, -NRaS(O)2Rb, -NRaC(O)Rb, and -NR3C(O)ORb; wherein R3 and R4, or R* and R5, are optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; each R3 and Rb is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, and heterocyclyl;
Q is selected from a group of formula
Figure imgf000003_0002
and a bond;
X1 is selected from -O-, -NRy-, -(CH2)m-, -C=C~, and a bond, wherein m is 1, 2, 3, or 4, and Ry is selected from hydrogen and Ci-Ce alkyl;
L is a linker;
X2 is selected from -O-, -NR2-, -(CH2)n~, -C=C-, and a bond, wherein n is 1, 2, 3, or 4, and Rz is selected from hydrogen and Ci-Cs alkyl; and Y is a moiety that binds to an E3 ubiquitin ligase; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heterocyclyl is each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents.
[0005] In some embodiments, no more than one of A1, A2, A3, A4, and A5 is N. In some embodiments, A1 is CR1 or N; A2 is CR2; A3 is CR\ A4 is CR4; and A5 is CR5. In some embodiments, R{, R2, R3, R4, and R5 are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, halo, - OR3, -SRa, -N(Ra)(Rb), -C(O)N(Ra)(Rb), -S(O)Ra, -S(O)2Ra, -NRaS(O)2Rb, -NRaC(O)Rb, and - NRaC(O)ORb, wherein each R3 and Rb is independently selected from hydrogen, C1-C3 alkyl, Ci- C2. haloalkyl, and Cs-Ce cycloalkyl. In some embodiments, R’!, R2, R'\ R4, and R5 are each hydrogen.
[0006] In some embodiments, Q is a group of formula
Figure imgf000004_0001
[0007] In some embodiments, the compound has formula (la):
Figure imgf000004_0002
[0008] In some embodiments, X1 is selected from -NRy- and a bond, wherein Ry is hydrogen.
In some embodiments, X2 is selected from -O-, -NRZ-, -(CH2)n-, -C=C-, and a bond, wherein Rz is hydrogen and n is 1. In some embodiments, X2 is selected from -O- and -NH-.
[0009] In some embodiments, Y has a formula selected from:
Figure imgf000004_0003
[0010] In some embodiments, Y is a moiety of formula (a):
Figure imgf000005_0001
wherein:
X is CO or CH2;
Rc is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Rd), -S(O)Rd, -S(O)2Rd, - NRdS(())2Rd, -NRdC(O)Rd, and -NRdC(O)()Rd; and each Rd and Re is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-Cealkynyl, Ci-Ce heteroalkyl, Ch-Cs cycloalkyl, aryl, aryl-Ci-CY-alkyl, heteroaryl, and heterocyclyl.
[0011] In some embodiments, Rc is hydrogen.
[0012] In some embodiments, Y is a moiety of formula (b):
Figure imgf000005_0002
wherein:
R: is C1-C4 alkyl or Cs-Ce cycloalkyl, each of which is optionally substituted with one or more halo groups (e.g., fluoro);
Rs is hydrogen or methyl; and
Z is selected from O, NH, and CH2.
[0013] In some embodiments, Y has a formula selected from:
Figure imgf000006_0001
[0014] In some embodiments, L is a direct bond or comprises any combination of -CH?.-, -
Figure imgf000006_0002
arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents.
[0015] In some embodiments, L comprises any combination of the following moieties:
Figure imgf000007_0001
wherein p is 1, 2, 3, 4, 5, or 6; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
[0016] In some embodiments, L is a direct bond or has a formula selected from:
Figure imgf000007_0002
wherein p is 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and Het is a heterocyclylene.
[0017] In some embodiments, L has a formula selected from:
Figure imgf000007_0003
[0018] In some embodiments, the compound is selected from:
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
and pharmaceutically acceptable salts thereof.
[0019] In another aspect, disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier. [0020] In another aspect, disclosed herein is a method of treating a disorder in a subject in need thereof, wherein the disorder is characterized or mediated by activity of a transcriptional enhancer associate domain (TEAD) transcription factor, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g,, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, the disorder is a proliferative disease. In some embodiments, the disorder is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy. In some embodiments, the disorder is a cancer selected from mesothelioma, esophageal cancer, liver cancer, breast cancer, lung cancer, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. [0021] In another aspect, disclosed herein is a method of degrading a transcriptional enhancer associate domain (TEAD) transcription factor in a sample, comprising contacting the sample with an effective amount of a compound disclosed herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, the TEAD transcription factor is selected from TEAD1, TEAD2, TEAD3, and TEAD4.
[0022] In another aspect, disclosed herein is a compound disclosed herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof), for use in treating a disorder in a subject in need thereof, wherein the disorder is characterized or mediated by activity of a transcriptional enhancer associate domain (TEAD) transcription factor. In some embodiments, the disorder is a proliferative disease. In some embodiments, the disorder is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy. In some embodiments, the disorder is a cancer selected from mesothelioma, esophageal cancer, liver cancer, breast cancer, lung cancer, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows the 24-hour degradation effect of representative degrader compounds in NCI-H226 cells at 5 uM and 0.5 pM.
[0024] FIG. 2 shows the 24-hour degradation effect of representative degrader compounds in NCI-H226 cells at 1 uM, 0,2 pM and 0.04 pM.
[0025] FIG. 3 shows data from rescue experiments for representative degrader compounds in NCI-H226 cells.
[0026] FIG. 4 shows the 24-hour degradation effect of representative degrader compounds in NCI-H226 cells at 1 pM.
[0027] FIG. 5 shows anti-proliferation effects of representative degrader compounds in MSTO-211H cells.
[0028] FIG. 6 shows the 24-hour degradation effect of representative degrader compounds in NCI-H226 cells at 1 pM. DETAILED DESCRIPTION
[0029] Disclosed herein are bispecific compounds that target transcriptional enhanced associate domain (TEAD) transcription factors. In the disclosed compounds, one moiety binds to a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), and another moiety binds to an E3 ubiquitin ligase. The ligase catalyzes covalent attachment of ubiquitin to the TEAD transcription factor, which induces degradation by native proteasomes. Accordingly, compounds of the disclosure can exploit native cellular degradative processes, but the degradative action is directed specifically to the TEAD transcription factor. Pharmaceutical compositions comprising the disclosed compounds, methods of using the disclosed compounds, and kits comprising the compounds are also provided herein.
Definitions
[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary’ skill in the art. In case of conflict, the present document, including definitions, wall control.
[0031] Definitions of specific functional groups and chemical terms are described in more detail below'. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75ta Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry', as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2nd edition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7th Edition, John Wiley & Sons, Inc., New' York, 2013; Larock, Comprehensive Organic Transformations, 3rd Edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
[0032] ,As used herein, the modifier “about” used in connection with a quantity is inclusive of the sta ted value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to ±10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11 %, and “about 1” may mean from 0.9 - 1.1. Other meanings of “about” may be apparent from the context, such as rounding off; for example, “about 1” may also mean from 0.5 to 1.4.
[0033] As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl), 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (CI-CH alkyl), 1 to 12 carbon atoms (Ci- C]? alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (Ci-Cs alkyl), 1 to 6 carbon atoms (Ci-Ce alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 1 to 2 carbon atoms (C1-C2 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3 -dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl.
[0034] As used herein, the term “alkenyl” refers to a radical of a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and no triple bonds. The double bond(s) may be located at any position(s) with the hydrocarbon chain. The alkenyl chain can include, e.g., from 2 to 24 carbon atoms (C2-C24 alkenyl), 2 to 16 carbon atoms (C2-C16 alkenyl), 2 to 14 carbon atoms (C2-C14 alkenyl), 2 to 12 carbon atoms (C2-C12 alkenyl), 2 to 10 carbon atoms (C2-C10 alkenyl), 2 to 8 carbon atoms (C2-C8 alkenyl), 2 to 6 carbon atoms (C2-C6 alkenyl), 2 to 4 carbon atoms (C2-C4 alkenyl), 2 to 3 carbon atoms (C2-C3 alkenyl), or 2 carbon atoms (C2 alkenyl). Representative examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, 2-methyl-2-propeny1, 3-butenyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like.
[0035] As used herein, the term “alkynyl” means a radical of a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. The alkynyl chain can include, e.g., from 2 to 24 carbon atoms (C2-C24 alkynyl), 2 to 16 carbon atoms (C2-C16 alkynyl), 2 to 14 carbon atoms (C2-C14 alkynyl), 2 to 12 carbon atoms (C2-C12 alkynyl), 2 to 10 carbon atoms (C2-C10 alkynyl), 2 to 8 carbon atoms (C2-C8 alkynyl), 2 to 6 carbon atoms (C2-C6 alkynyl), 2 to 4 carbon atoms (C2-C4 alkynyl), 2 to 3 carbon atoms (C2-C3 alkynyl), or 2 carbon atoms (C2 alkynyl). The triple bond(s) may be located at any position(s) with the hydrocarbon chain. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, and the like. [0036] As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tertbutoxy.
[0037] As used herein, the term “amino” refers to a group -NRxRy, wherein Rx and Ry are selected from hydrogen and alkyl (e.g., C1-C4 alkyl). A group -NH(alkyl) may be referred to herein as “alkylamino” and a group -N(alkyl)2 may be referred to herein as “dialky lamino.” [0038] As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14
Figure imgf000016_0001
electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“'Co aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl,” e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl).
[0039] As used herein, the term “arylene” refers to a divalent aryl radical.
[0040] As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2. l ]octanyl, and bi cy cl o[5.2.0] nonan y I .
[0041] As used herein, the term “cycloalkylene” refers to a divalent cycloalkyl radical.
[0042] As used herein, the term “cyano” refers to a -CN group.
[0043] As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I.
[0044] As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hy drogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, di fluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2- tnfluoroethyl, and 3,3,3-tnfluoropropyl. [0045] As used herein, the term “haloalkoxy” refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy , trifluoromethoxy, and 2,2,2- trifluoroethoxy.
[0046] As used herein, the term “heteroalkyl” refers to an alkyl group, as defined herein, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with a heteroatom group such as -NH-,
Figure imgf000017_0001
-S-, -S(O)-, -S(O)2-, -
OP(O)(O”)O-, or the like. By way of example, 1, 2, 3, 4, 5, 6, or more carbon atoms may be independently replaced with the same or different heteroatom group. A heteroalkyl group can also include one or more carbonyl moieties (i.e., wherein a carbon atom of the alkyl group is oxidized to a -C(O)- group).
[0047] As used herein, the term “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5- indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary' 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary' 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isomdolyl, indazolyl, benzotriazo lyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary’ 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazmyl, and quinazolinyl.
[0048] As used herein, the term “heteroarylene” refers to a divalent heteroaryl radical.
[0049] As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non- hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5- membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolmyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2, 2,6,6- tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1 -methylpyridin- 2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1 -methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5- bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplar)'’ 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplar)'’ 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (l,5)-8- azabicyclo[3.2. l]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocycly l ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1 ]nonanyl). [0050] As used herein, the term “heterocyclylene” refers to a divalent heterocyclyl radical.
[0051] As used herein, the term “hydroxy” or “hydroxyl” refers to an -OH group.
[0052] As used herein, the term “nitro” refers to an -NO?, group.
[0053] When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.
[0054] As used herein, in chemical structures the indication:
Figure imgf000020_0001
represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound).
[0055] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
[0056] When substituent groups are specified by their conventional chemical formulae, written from left to right, such indication also encompass substituent groups resulting from writing the structure from right to left. For example, if a bivalent group is shown as -CH2O-, such indication also encompasses -OCH?-; similarly, -OC(O)NH- also encompasses -NHC(O)()-.
When linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction.
[0057] The terms ‘'‘administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition. [0058] As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.
[0059] An “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor.
[0060] A “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
[0061] A “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).
[0062] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delay ing the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
Compounds
[0063] Disclosed herein are compounds of formula (I):
Figure imgf000022_0001
and pharmaceutically acceptable salts thereof, wherein:
A1 is CR1 or N;
A2 is CR2 or N;
A3 is CR3 or N;
A4 is CR4 or N;
A5 is CR5 or N;
R1, Rz, R’, R4, and R5 are each independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Cb-Ce alkenyl, (b-Ce alkynyl, C1-C6 heteroalkyl, Cs-Cs cycloalkyl, aryl, aryl-Ci-Ce- alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORa, -SRa, -N(Ra)(Rb), -C(O)Ra, -C(O)ORa, - C(O)M(Ra)(Rb), -S(O)Ra, -S(O)2Ra, -NRaS(O)?.Rb, -NRaC(0)Rb, and -NRaC(O)ORb; wherein R3 and R4, or R4 and R’, are optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; each Ra and Rb is independently selected from hydrogen, Ci-Ce alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Cs cycloalkyl, aryl, aryl-Ci-Q-alkyi, heteroaryl, and heterocyclyl; Q is selected from a group of formula
Figure imgf000023_0001
and a bond;
X1 is selected from -O-, -NRy-, -(CH?.)™-, -C=C-, and a bond, wherein m is 1, 2, 3, or 4, and Ry is selected from hydrogen and Ci-Ce alkyl;
L is a linker;
X2 is selected from -O-, -NRZ-, -(CH2)n-, -C=C-, and a bond, wherein ms 1, 2, 3, or 4, and Rz is selected from hydrogen and Ci-Ce alkyl; and
Y is a moiety that binds to an E3 ubiquitin ligase; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heterocyclyl is each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents.
[0064] In some embodiments, no more than one of A1, A2, A3, A4, and A5 is N. For example, in some embodiments. A1 is N, A2 is CR2, A3 is CR3, A4 is CR4, and A5 is CR5. In some embodiments, A1 is CR1, A2 is N, A3 is CR3, A4 is CR4, and A5 is CR5. In some embodiments, A1 is CR1, .A2 is CR2, A3 is N, .A4 is CR4, and A3 is CR5. In some embodiments, A1 is CR!, A2 is CR2, A3 is CR3, .A4 is N, and A5 is CR5. In some embodiments, A! is CR1, A2 is CR2, A3 is CR3, A4 is CR4, and A5 is N.
[0065] In some embodiments, A1 is CR1 or N, .A2 is CR2, A3 is CR3, A4 is CR4, and A5 is CR5. In some embodiments, A1 is CR1, A2 is CR2, A3 is CR3, A4 is CR4, and A5 is CR5.
[0066] In some embodiments, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, halo, -OR3, -SR3, -N(Ra)(Rb), -C(O)N(Ra)(Rb), -S(O)Ra, -S(O)?.R3, -NRaS(O)2Rb, - NRaC(O)Rb, and -NRaC(O)ORb, wherein each R3 and Rb is independently selected from hydrogen, Ci-Cs alkyl, C1-C2 haloalkyl, and C3-C6 cycloalkyl. In some embodiments, one of R1, R2, R3, R4, and R3 is selected from C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2~C3 alkynyl, Ci -C3 heteroalkyl, Cs-Ce cycloalkyl, halo, -OR3, -SRa, -N(Ra)(Rb), ~C(O)N(Ra)(Rb), -S(O)Ra, - S(O)?R3, ~NR3S(O)2RD, -NRaC(O)Rb, and -NRaC(O)ORb, wherein each R3 and Rb is independently selected from hydrogen, C1-C3 alkyl, C1-C2 haloalkyl, and C3-C6 cycloalkyl, and the other four of R1, R2, R3, R4, and R5 are hydrogen. In some embodiments, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, methyl, ethyl, trifluoromethyl, ethynyl, C1-C3 heteroalkyl, cyclopropyl, fluoro, chloro, bromo, iodo, -OR3, -SRa, -N(Ra)(Rb), -C(O)N(Ra)(Rb), - S(O)Ra, -S(O)?Ra, -NRaS(O)?Rb, -NRaC(O)Rb, and -NRaC(O)ORb, wherein each Ra and Rb is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and trifluoromethyl. In some embodiments, one of R’!, R2, Ry R4, and R5 is selected from methyl, ethyl, trifluoromethyl, ethynyl, Ci-Cs heteroalkyl, cyclopropyl, fluoro, chloro, bromo, iodo, - OR3, -SRa, -N(Ra)(Rb), -C(O)N(Ra)(Rb), -S(O)Ra, -S(O ) ?Ra, -NRaS(O)?Rb, -NRaC(O)Rb, and - NRaC(())ORb, wherein each R3 and Rb is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and trifluoromethyl, and the other four of Rf, R2, R3, R4, and R? are hydrogen.
[0067] In some embodiments, A1 is CR!, A2 is CR2, A3 is CR3, A4 is CR4, and A5 is CR3, and Rl, R2, R3, R4, and R5 are each hydrogen. In some embodiments, A1 is N, A2 is CR2, A3 is CR3, A4 is CR4, and A' is CR5, and R1, R2, R3, R4, and R5 are each hydrogen.
[0068]
[0069] In some embodiments, Q is a group of formula
Figure imgf000024_0001
some embodiments, Q is a bond.
[0070] In some embodiments, the compound of formula (I) is a compound of formula (la):
Figure imgf000024_0002
wherein A1, X1, L, X2, and Y are as defined and described herein.
[0071] In some embodiments, the compound of formula (I) is a compound of formula (lb):
Figure imgf000025_0001
wherein X1, L, X2, and Y are as defined and described herein.
[0072] Compounds of formula (I) include a moiety:
Figure imgf000025_0002
which is the portion of the compound that binds to a TEAD transcription factor. This moiety may be referred to herein as a “targeting moiety” or a “targeting ligand.” The term “binds” in this context refers to an intermolecular interaction between the targeting moiety and the TEAD transcription factor that may be preferential or substantially specific, in that interactions between the targeting moiety and other proteinaceous entities in the cell is functionally insignificant. The compounds of formula (I) may preferentially bind and recruit a TEAD transcription factor for targeted degradation.
[0073] Y is a moiety that binds to an E3 ubiquitin ligase. The term “binds” in this context refers to an intermolecular interaction sufficient to achieve recruitment of the ligase, and ultimately the selective degradation of the targeted protein. The Ubiquitm-Proteasome Pathway (UPP) is a critical cellular pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases include over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity. In some embodiments, the E3 ubiquitin ligase that binds to the moiety Y is cereblon (CRBN). In some embodiments, the E3 ubiquitin ligase that binds to the moiety Y is the von Hippel-Lindau (VI-IL) tumor suppressor. [0074] In some embodiments, Y has a formula selected from:
Figure imgf000026_0001
[0075] In some embodiments, Y is a moiety of formula (a):
Figure imgf000026_0002
wherein:
X is CO or CI-I2;
Rc is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haioalkyl, Ca-Cc, alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, aryl, aryl-Ci-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Rd), -S(O)Rd, -S(O)2Rd, - NRdS(O)2Rd, -NRdC(O)Rd, and -NRdC(O)ORd; and each Rd and Re is independently selected from hydrogen, Ci-Cc, alkyl, Ci-Cs haioalkyl, C2-C6 alkenyl, C2-Ce alkynyl, C1-C6 heteroalkyl, Cs-Cs cycloalkyl, aryl, aryl-Cs-Ce-alkyl, heteroaryl, and heterocyclyl.
[0076] In some embodiments, X is CO, In some embodiments, X is CH2.
[0077] In some embodiments, Rc is selected from hydrogen, Ci-Ce alkyl, Ci-Cs haioalkyl, halo, cyano, and -ORa, wherein Rd is Ci-Ce haioalkyl. In some embodiments, Rc is selected from hydrogen, C1-C3 alkyl, C1-C3 haioalkyl, halo, cyano, and -ORd, wherein Ra is C1-C3 haioalkyl. In some embodiments, Rc is selected from hydrogen, C1-C3 alkyl, halo, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy. In some embodiments, Rc is hydrogen.
[0078] In some embodiments, Y is a moiety of formula (b):
Figure imgf000027_0001
wherein:
R! is C1-C4 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with one or more halo groups (e.g., fluoro);
Rs is hydrogen or methyl; and
Z is selected from O, NH, and CH2.
[0079] In some embodiments, Rf is C1-C4 alkyl. In some embodiments, Rf is methyl. In some embodiments, R1 is cyclopropyl, which is optionally substituted with one fluoro. In some embodiments, Z is O.
[0080] In some embodiments, Y is a moiety selected from:
Figure imgf000027_0002
Figure imgf000028_0001
[0081] In some embodiments, X1 is selected from -O-, -NRy-, -(CH?)™-, -OC-, and a bond, wherein m is 1, and Ry is selected from hydrogen and methyl. In some embodiments, X1 is -NRy- or a bond, wherein Ry is selected from hydrogen and Ci-Ck alkyl. In some embodiments, X3 is - NRy- or a bond, wherein Ry is selected from hydrogen and methyl. In some embodiments, X1 is - NRy-, wherein Ry is selected from hydrogen and Ci-Ce alkyl. In some embodiments, X1 is -NR'-, wherein Ry is selected from hydrogen and methyl. In some embodiments, X1 is -NR'-, wherein Ry is hydrogen (i.e., Xf is -NH-). In some embodiments, Xf is -O-. In some embodiments, X! is - (CH?)™-, wherein m is 1, 2, 3, or 4. In some embodiments, X1 is -C=C-. In some embodiments, X1 is a bond.
[0082] In some embodiments, X2 is selected from -O-, -NRZ~, -(CH2)n-, -C=C-, and a bond, wherein Rz selected from hydrogen and methyl, and n is 1. In some embodiments, X2 is selected from -O-, -NRZ-, -(CH?.)P~, -C=C-, and a bond, wherein Rz is hydrogen and n is 1. In some embodiments, X2 is -NRZ- or O, wherein Rz is selected from hydrogen and Ci-Ce alkyl. In some embodiments, X2 is -NRZ~ or O, wherein Rz is selected from hydrogen and methyl. In some embodiments, X2 is -NRZ-, wherein Rz is selected from hydrogen and Ci-Ce alkyl. In some embodiments, X2 is -NRZ~, wherein Rz is selected from hydrogen and methyl. In some embodiments, X2 is -NRZ-, wherein Rz is hydrogen (i.e., X2 is -NH-). In some embodiments, X2 is -O-. In some embodiments, X2 is -(CJEbjm-, wherein m is 1, 2, 3, or 4. In some embodiments, X2 is -C=C-. In some embodiments, X2 is a bond.
[0083] In some embodiments, the compound of formula (I) is a compound of formula (Ic):
Figure imgf000029_0001
wherein A1, X1, L, X2, and X are as defined and described herein.
[0084] L is a linker, which, in conjunction with groups X1 and X2, provides a covalent attachment between targeting moiety and the degron group Y. The structure of linker may not be critical, provided it is substantially non-interfering with the activity of the targeting moiety or the degron group Y. In some embodiments, L is a direct bond. In other embodiments, L comprises any combination of -CHz-, -CH-CH-, -OC-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, - S(O)2-, arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, wherein R* is selected from hydrogen and Ci-Cs alkyl, and wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents.
[0085] In some embodiments, the linker comprises an alkylene chain (e.g., having 2-20 - CHz- units). In other embodiments, the linker comprises an alkylene chain that is interrupted by, and/or terminated by (at either or both termini), at least one group selected from -O-, -S-, -N(R')- , -CH=CH-, -OC-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, - C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, - OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(CH3)O-, - S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C3-C12 cycloalkylene, 3- to 12-membered heterocyclylene, 5- to 10-membered arylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein each R' is independently selected from hydrogen and Ci-Ce alkyl, and wherein the interrupting and terminating groups may be the same or different.
[0086] In some embodiments, L comprises an alkylene chain:
Figure imgf000030_0001
, wherein q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. For example in some embodiments, q is 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5, In some embodiments, q is 6. In some embodiments, q is 7. In some embodiments, q is 8. In some embodiments, q is 9. In some embodiments, q is 10. In some embodiments, q is 11. In some embodiments, q is 12. Specific examples of L, wherein L is an alkylene chain, include:
Figure imgf000030_0002
[0087] In some embodiments, L is an alkylene chain interrupted by a functional group, such as -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR)-, -C(O)N(R')-, - C(O)N(R')C(O)-, - C(O)N(R')C(O)N(R')~, ~N(R')C(O)~, -N(R)C(O)N(R)-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR>, -N(R')C(NR’)-, -C( NR)N(R')-, -N(R’)C(NR)N(R!)-, -OB(CH3)O-, -S(O)2-, -OS(O)-, -S(O)O-, - S(O)-, -OS(O)2-, -S(O)2O-, -N(R)S(O)2-, -S(O)2N(R')-, -N(R)S(O)-, -S(O)N(R')-, - N(R')S(O)2N(R')-, or -N(R')S(O)N(R')-. In some embodiments, L is an alkylene chain interrupted by a functional group, such as an amide (-C(O)NH-), group. Examples of L in such embodiments include:
Figure imgf000030_0003
Figure imgf000031_0001
[0088] In some embodiments, L comprises one or more alkylene glycol repeat units, such as ethylene glycol or propylene glycol repeat units. For example, in some embodiments, L comprises a poly- or oligo-ethylene glycol chain:
Figure imgf000031_0002
, wherein p is 1, 2, 3, 4, 5, or 6. In some embodiments, L has a formula:
Figure imgf000031_0003
, wherein p is 1 , 2, 3, 4, 5, or 6. In some embodiments, p is 1-6, 1-5, 1 -4, 1 -3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-6, or 5-6. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5, In some embodiments, p is 6. Specific examples of L include:
Figure imgf000031_0004
[0089] In some embodiments, L comprises a poly- or oligo-ethylene glycol chain:
Figure imgf000031_0006
such as a functional group of formula: O . In some embodiments, L has a formula:
Figure imgf000031_0005
, wherein p is 1, 2, 3, 4, 5, or 6. In some embodiments, L has a structure selected from:
Figure imgf000032_0001
[0090] In some embodiments, L comprises one or more heterocyclylene groups, examples of which include:
Figure imgf000032_0002
[0091] In some embodiments, L comprises a heterocyclylene group, such as one of the above-illustrated heterocyclylene groups, with one or more additional groups on one or both termini, wherein the additional groups are independently selected from -CH2-, -O-, -S-, -N(R')-, - CH CH-. ■( ('••. ('(())-. -C(O)O-, ■()('(()}■. -OC(O)O-, -CfNOR)-, -C(O)N( R! )-, - C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N( R’)C(O)-, -N( R R'(O)N( R'j-. -N(R')C(O)O-, - OC(O)N(R>, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR)N(R')-, -OB(CH3)O-, - S{O)'-. -OS(O)-, -S(O)O-, -S(O)-, OS(0 ) 2-, -S(O)2.O-, -N(R')S(O)2-, -S(O)2N(R’)-, -N(R’)S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, and -N(R')S(O)N(R’)-, or any combination thereof, wherein each R' is independently selected from hydrogen and Ci-Ce alkyl. In some embodiments, L comprises a heterocyclylene group, such as one of the above-illustrated heterocyclylene groups, with one or more additional groups on one or both termini, wherein the additional groups are independently selected from -CH2-, -C(O)-, and -O-. In some such embodiments, L is selected from:
Figure imgf000033_0001
[0092] In some embodiments, L comprises two or more heterocyclylene groups, such as two or three heterocyclylene groups independently selected from those illustrated above, connected to each other via covalent bonds or one or linking groups, optionally with one or more additional linking group son one or both termini, wherein the linking groups are independently selected
Figure imgf000033_0002
or any combination thereof, wherein each R' is independently selected from hydrogen and Ci-Ce alkyl. In some embodiments, L comprises two or more heterocyclylene groups, such as two or three heterocyclylene groups independently selected from those illustrated above, connected to each other via covalent bonds or one or linking groups, optionally with one or more additional linking group son one or both termini, wherein the linking groups are independently selected from -O- and -CH2-. Examples of such groups include:
Figure imgf000033_0003
Figure imgf000034_0001
[0093] In some embodiments, L comprises one or more heterocyciylene groups that are substituted with 1, 2, or 3 substituents, e.g., substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, halo, hydroxy, and the like. In some embodiments, L comprises one or more heterocyciylene groups that are substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl and halo. In some embodiments, L comprises one or more heterocyciylene groups that are substituted with 1 , 2, or 3 substituents independently selected from methyl and fluoro. For example, in some embodiments, L. is selected from:
Figure imgf000034_0002
[0094] In some embodiments, L comprises any combination of moieties selected from:
Figure imgf000034_0003
wherein p is 1, 2, 3, 4, 5, or 6; and q is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,
[0095] In some embodiments, L is a direct bond or has a formula selected from:
Figure imgf000035_0001
wherein p is 1 , 2, 3, 4, 5, or 6; q is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, and Het is a heterocydylene.
[0096] In some embodiments, L has a formula selected from:
Figure imgf000035_0002
[0097] In some embodiments, the compound is selected from:
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
and pharmaceutically acceptable salts thereof.
[0098] When discussing certain features or properties of compounds of formula (I) herein, or compositions, methods, or kits comprising compounds of formula (I), it is understood that such reference also includes compounds of formula (la), (lb), and (Ic), and to specific exemplary compounds disclosed herein.
[0099] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in TUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem. 1976, 45: 13-30. Various stereoisomers and mixtures thereof are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well- known to those of ordinary skill in the art. These methods of resolution are exemplified by: (I ) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furmss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM202JE, England; (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns; or (3) fractional recrystallization methods.
[00100] It should be understood that the compounds may exist in different tautomeric forms, and all such forms are included within the scope of the disclosure.
[00101] The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to 2H, 3H, ! ’C, !4C, ,5N, 180, 1 ?0, 3lP, i2P, 35S, ,8F, and 36C1, respectively. Substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability’, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron -emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positronemitting isotopes that can be incorporated in compounds of formula (I) are nC, 1JN, 15O, and i5F. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non- isotopically-labeled reagent.
[00102] Compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a. mixture of polymorphs. In another embodiment, the compound is in a crystalline form. a. Pharmaceutically Acceptable Saits
[00103] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an ammo group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digiuconate, glycerophosphate, hemisuifate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. Amino groups of the compounds may also be quatemized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.
[00104] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1 -ephenamine and N,N’ -dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. b. Methods of Synthesis
[00105] In another aspect, disclosed herein are methods for making compounds of formula (I), or a pharmaceutically acceptable salt thereof. Broadly, the compounds of formula (I) and pharmaceutically acceptable salts thereof can be prepared by any process known to be applicable to the preparation of chemically related compounds. Exemplary suitable synthetic schemes are provided in the Examples section. [00106] The compounds and intermediates may be isolated and purified by methods wen- known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for example in “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England.
[00107] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature,
[00108] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality' that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method, are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006).
[00109] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution). [00110] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
[00111] The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated.
Pharmaceutical Compositions
[00112] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease or condition, the prophylactically effective amount will be less than the therapeutically effective amount,
[00113] The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable earner,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [00114] Thus, the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.
[00115] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).
[00116] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.
[00117] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate, sugar alcohols, such as glycerin; mannitol, and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90% by weight of the composition.
[00118] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% by weight of the composition. [00119] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylceliulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylceliulose. The amount of bmder(s) in a sy stemic composition is typically about 5 to about 50% by weight of the composition.
[00120] Suitable dismtegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% by weight of the composition.
[00121] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1% by weight of the composition.
[00122] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. [00123] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s), when used, in a systemic or topical composition is typically about 0.001 to about 1% by weight of the compositi on.
[00124] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E, The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% by weight of the composition.
[00125] Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5% by weight of the composition.
[00126] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% by weight of the composition.
[00127] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100% by weight of the composition. [00128] Suitable suspending agents include AVICEL RC-591 (from EMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition.
[00129] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon’s Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5% by weight of the composition.
[00130] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% by weight of actives and 90% to 99.9% by weight of a carrier including a diluent and a solvent, [00131] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5% by weight, and more particularly from about 25% to about 50% by weight of actives. The oral dosage compositions include about 50% to about 95% by weight of earners, and more particularly, from about 50% to about 75% by weight.
[00132] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, dismtegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific dismtegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof. [00133] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable ty pe.
[00134] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability , which are not critical for the purposes of this disclosure.
[00135] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.
[00136] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.
[00137] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.
[ 00138] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (1)), or a pharmaceutically acceptable salt thereof), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.
[00139] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).
[00140] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.
[00141] The earner of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.
[00142] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane-l,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n- butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is ty pically about 5% to about 95% by weight of the composition.
[00143] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is ty pically about 0% to about 95% by weight of the composition.
[00144] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95% by weight of the composition.
[00145] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95% by weight of the composition.
[00146] The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition,
[00147] Suitable powders include beta-cyclodextrms, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95% by weight of the composition.
[00148] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1% by weight of the composition.
[00149] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. Methods of Use
[00150] The disclosed compounds and pharmaceutical compositions may be used in methods for treatment of disorders, such as a disorder characterized or mediated by a TEAD transcription factor. In some embodiments, the disclosed compounds and pharmaceutical compositions are useful in methods of treating proliferative disorders cancers. In some embodiments, the cancer is characterized or mediated by the activity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). In some embodiments, the cancer is mediated by modulation of the interaction between YAP/TAZ and a TEA!) transcription factor.
[00151] Accordingly, in some embodiments, disclosed herein is a method of treating a disorder in a subject in need thereof, wherein the disorder is characterized or mediated by activity’ of a TEAD transcription factor, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is a proliferative disease, i.e., a disease that occurs due to abnormal growth or extension by the multiplication of cells. In some embodiments, the proliferative disease is cancer. The term “cancer” refers to a class of diseases characterized by development of abnormal cells that proliferate uncontrollably and have the abil ity to infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed,; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
[00152] In some embodiments, the compounds and pharmaceutical compositions disclosed herein are used for treating cancer in a subject in need thereof. In some embodiments, the cancer is a solid tumor, such as a sarcoma or a carcinoma. In some embodiments, the cancer is a hematologic malignancy.
[00153] Exemplary sarcomas include, but are not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblast! c tumor, Kaposi sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular epithelioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with perivascular epithelioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET/extraskeletal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma.
[00154] Exemplar}' carcinomas include, but are not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of unknown primary’ (CUP), esophageal cancer (e.g., esophageal squamous cell carcinoma), eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
[00155] Exemplary hematologic malignancies include, but are not limited to, leukemias, lymphomas, myelomas, non-Hodgkm’s lymphomas, Hodgkin’s lymphomas, T-cell malignancies, and B-cell malignancies. Exemplary T-cell malignancies include anaplastic large cell lymphoma, angioimmunoblastic lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, cutaneous T-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta. T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and treatment- related T-cell lymphomas. Exemplary B-cell malignancies include chronic lymphocytic leukemia (CEL), small lymphocytic lymphoma (SEE), high risk CLL, and a non-CLL/SLL lymphoma. In some embodiments, the cancer is selected from B cell pro lymphocytic leukemia, Burkitt’s lymphoma, diffuse large B-cell lymphoma (DLBCL), extranodal marginal zone B cell lymphoma, follicular lymphoma (FL), immunoblastic large cell lymphoma, intravascular large B cell lymphoma, lymphomatoid granulomatosis, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), mediastinal (thymic) large B cell lymphoma, multiple myeloma, nodal marginal zone B cell lymphoma, non-Burkitt high grade B cell lymphoma, plasma cell myeloma, plasmacytoma, precursor B-lymphoblastic lymphoma, primary effusion lymphoma, primary mediastinal B-cell lymphoma (PMBL), splenic marginal zone lymphoma, or Waldenstrom’s macroglobulinemia.
[00156] In some embodiments, the cancer is selected from mesothelioma, esophageal cancer (e.g., esophageal squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), breast cancer, lung cancer (e.g., lung adenocarcinoma), glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some embodiments, the cancer is mesothelioma.
[00157] In some embodiments, the cancer is a relapsed or refractor}' cancer, such as a cancer described herein. In some embodiments, the cancer is a metastasized cancer, such as a cancer described herein.
[00158] In some embodiments, compounds and compositions disclosed herein are useful for treating a congenital disease, such as a congenital disease mediated by modulation of the interaction between YAP/TAZ and a TEAD transcription factor. In some embodiments, the congenital disease is the result of a genetic abnormality, an intrauterine environment, errors related to morphogenesis, infection, epigenetic modifications on a parental germline, or a chromosomal abnormality. Exemplar}/ congenital diseases include, but are not limited to, Sturge- Weber Syndrome, Port-Wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich’s ataxia, galactosemia, hemoglobinopathies, Krabbe disease, limb-girdle muscular dystrophy, medium chain acyl-CoA dehydrogenase deficiency, myasthenia gravis, neural tube defects, phenylketonuria, Pompe disease, severe combined immunodeficiency (SCID), Stickler syndrome (or hereditary progressive arthro-ophthalmopathy), spinal muscular atrophy, and trisomy 18. [00159] In the methods of treatment disclosed herein, a compound or pharmaceutical composition may be administered to the subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g., by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose); rectal; vaginal; parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspmal, mtracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal injection); or by implant of a depot, for example, subcutaneously or intramuscularly. In some embodiments, the administration comprises oral administration. In some embodiments, the administration comprises parenteral administration. Additional modes of administration may include adding the compound and/or a composition comprising the compound to a food or beverage, including a water supply for an animal, to supply the compound as part of the animal’s diet.
[00160] It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary' from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present disclosure. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
[00161] Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. In general, a suitable dose of the compound is in the range of about 100 pg to about 250 nig per kilogram body weight of the subject per day.
[00162] The compound or composition may be administered once, on a continuous basis (e.g. by an intravenous drip), or on a periodic/intermittent basis, including about once per hour, about once per two hours, about once per four hours, about once per eight hours, about once per twelve hours, about once per day, about once per two days, about once per three days, about twice per week, about once per week, and about once per month. The composition may be administered until a desired reduction of symptoms is achieved.
[00163] A compound described herein may be used in combination with other known therapies. Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery,” In other embodiments, the delivery of one treatment ends before the delivery? of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction m a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
[00164] A compound or composition described herein and the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially . For sequential administration, the compound described herein can be administered first, and the additional agent can be administered subsequently, or the order of administration can be reversed.
[00165] In some embodiments, a compound described herein is administered in combination with other therapeutic treatment modalities, including surgery, radiation, transplantation (e.g., stem cell transplantation, bone marrow transplantation), cryotherapy , and/or thermotherapy. Such combination therapies may allow for lower dosages of the administered agent and/or other chemotherapeutic agent, thus avoiding possible toxicities or complications associated with the various therapies.
[00166] In some embodiments, the compound described herein is administered with at least one additional therapeutic agent, such as a chemotherapeutic agent. In certain embodiments, the compound described herein is administered in combination with one or more additional chemotherapeutic agents. The chemotherapeutic agent may be a chemotherapeutic agent identified on the “A to Z List of Cancer Drugs” published by the National Cancer Institute.
[00167] Also disclosed herein are methods of degrading a TEAD transcription factor in a sample, comprising contacting the sample with an effective amount of a compound disclosed herein (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof. In such embodiments, the sample can be an in vitro sample or an in vivo sample. In some embodiments, the TEAD transcription factor is selected from TEAD1, TEAD2, TEAD3, and TEAD4. In some embodiments, the TEAD transcription factor is selected from TEAD1, TEAD2, and TEAD4. In some embodiments, the TEAD transcription factor is TEAD1. In some embodiments, the TEAD transcription factor is TEAD2, In some embodiments, the TEAD transcription factor is TEAD3. In some embodiments, the TEAD transcription factor is TEAD4.
Kits
[00168] Compounds and/or compositions disclosed herein may be assembled into kits or pharmaceutical systems. Kits or pharmaceutical systems according may include a carrier or package such as a box, carton, tube or the tike, having in close confinement therein one or more containers, such as vials, tubes, ampoules, or bottles, which contain a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. Kits or pharmaceutical systems may also include printed instructions for using the compounds and/or compositions. [00169] The following examples further illustrate aspects of the disclosure, but should not be construed as in any way limiting its scope.
EXAMPLES
[00170] The following abbreviations are used in the Examples: BCA is bicinchoninic acid;
BINAP is 2,2'-bis(diphenylphosphino)-l,r-binaphthyl; dba is dibenzylideneacetone; DCM is dichloromethane; DIEA is TV^ZV-diisopropylethylamine; DMF is ALV-dimethylformamide; DMSO is dimethyl sulfoxide; HATU is 1 -[bis(dimethylamino)methylene]-l//-l ,2,3-triazolo[4,5- &]pyridmium 3-oxide hexafluorophosphate, HPLC is high performance liquid chromatography, LC-MS is liquid chromatography mass spectrometry, NMR is nuclear magnetic resonance; and TFA is trifluoroacetic acid.
Example 1 : Compound Syntheses
N"((lS)-l-(6-((l-((2-(2,6-dioxopiperidin-3-yl)-l 3-dioxoisoindolin-4-yl)oxy)- 2-0X0-6,9,12- trioxa-3- azatetradecan- 14-yI)amino)pyridin-2-yl)ethyJ)-5-(4-(trifluoromethyi)phenyJ)-2- naphthamide (Compound 1)
[00171] Step 1. Synthesis of (S)-N-(l-(6-bromopyridin-2-yl)ethyI)-5-(4-
(triflnoromethy9)phenyi)-2-naphthamide (S3).
Figure imgf000057_0001
[00172] To a solution of mixture of SI (316mg, 1.0 eq) and S2 (200mg, 1.0 eq) and DIEA (523 uL, 3 eq) in DMF (5mL) was added HATU (380nig, 1.0 eq), the mixture was stirred at room temperature over 3 hours. LC-MS indicated formation of desired product. The mixture was concentrated and purified via prep-HPLC to afford compound S3 (360mg, 72%) as off-white solid. LC-MS (ESI) ni/z: 499 [M+l]+. [00173] Step 2. Synthesis of tert-buty! (S)-(2-(2-(2-(2-((6-(l-(5-(4- (trifluoromethyl)pheiiyi)-2-naphthamido)ethyI)pyridin-2- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)carbamate (S5).
Figure imgf000058_0001
[00174] To a mixture of S3 (49mg, 1.0 eq), S4 (60mg, 2.0 eq) and Pd?(dba)3 (9mg, 0.1 eq), NaOtBu (28mg, 3.0 eq), BINAP (13mg, 0.2 eq) under Na protection was added toluene (1 mL). The resultant mixture was stirred at 100 °C overnight. The mixture was filtered and purified via prep-HPLC to afford compound S5 (35mg, 54%) as colorless oil. LC-MS (ESI) ni/z: 711 [M+l]+
[00175] Step 3. Synthesis of ( S)-N-( l-(6-((2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyI)amino)pyridin-2-yJ)ethyI)”5-(4-(trifliioromethyl)pheiiyI)” 2-naphthamide (S6).
Figure imgf000058_0002
[00176] S5 (35mg) was added 25% TEA DCM mixed solvent (2 mL) and stirred for Ih. The solvent was removed and lyophilized to give S6 quantitatively.
(ESI) m/z: 611 [M+lf.
[00177] Step 4. Synthesis of N-((lS)-l-(6-((l-((2-(2,6-dioxopiperidin-3-yI)-l,3” dioxoisoindoIin-4-yI)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)amino)pyridin-2- yi)ethyl)-5-(4-(triflnoromethyI)phenyI)-2-naphthamide (Compound 1).
Figure imgf000059_0001
[00178] To a solution of mixture of S6 (8mg, 1 .0 eq) and S7 (4mg, 1 ,0 eq) and DIEA (5 pL , 3 eq) in DMF (500 pL) was added HATU (380mg, 1.0 eq), the mixture was stirred at room temperature over 3 hour. The mixture was concentrated and purified via prep-HPLC to afford Compound 1 (4.5mg, 48%) as off-white solid. *H NMR (500 MHz, DMSO-rfc) 8 11.12 (s, IH), 9.15 (s, IH), 8.66 (s, IH), 8.15 (d, J = 8.3 Hz, IH), 8.03 - 7.89 (m, 4H), 7.87 - 7.77 (m, 2H), 7.73 (dd, J = 14.7, 7.8 Hz, 3H), 7.62 (d, J = 7.0 Hz, IH), 7.49 (d, J = 7.2 Hz, IH), 7.39 (d, J = 8.5 Hz, IH), 6.80 (s, 3H), 5.20 (s, IH), 5.12 (dd, J = 12.9, 5.5 Hz, IH), 4.78 (s, 2H), 3.49 -3.45 (m, 16H), 2.90 (td, J - 16.9, 15.3, 5.3 Hz, 2H), 2.58 (dd, J - 19.4, 14.8 Hz, 2H), 2.09 - 1.98 (m, 2H), 1.57 (d, J - 7.0 Hz, 21 1) LC-MS (ESI) m/z: 925 [M+l ]+ N-(2-(2-(2-((2-(2,6-dioxopiperidh8-3-yI)-l-oxoisohidoiiai”4-y4)amiaio)ethoxy)ethoxy)ethyI)-5- (4-(triflnoromethyl)phenyI)-2-naphthamide (Compound 2).
[00179] Step 1. Synthesis of tert-butyl (2-(2-(2-(5-(4-(tr,ifluoromethyi)phenyI)-2- naphthamido)ethoxy)ethoxy)ethyl)car baanate ( S3).
Figure imgf000060_0001
[00180] To a solution of mixture of SI (32mg, 1.0 eq) and S2 (25nig, 1.0 eq) and DIEA (52 pL, 3 eq) in DMF (1 mL) was added HATU (38mg, 1.0 eq), the mixture was starred at room temperature over 3 hour. LC-MS indicated formation of desired product. The mixture was concentrated and purified via prep-HPLC to afford compound S3 (44mg, 81%) as colorless oil. LC-MS (ESI) m/z: 547 [M+1]T
[00181] Step 2. Synthesis of N-(2-(2-(2-ammoethoxy)ethoxy)ethyI)-5-(4- (trifluoromethy!)phenyl)-2-naphthamide (S9).
Figure imgf000060_0002
[00182] S8 (44mg) was added 25% TFA DCM mixed solvent (1 mL) and stirred for Ih. The solvent was removed and lyophilized to give S8 quantitatively. (ESI) m/z: 447 [M+l ]+, [00183] Step 3. Synthesis of N-(2-(2-(2-((2~(2,6-dioxopiperidm-3-yl)-l-oxoisoindoUn-4- yI)amino)ethoxy)ethoxy)ethyi)-5-(4-(trifluoromethyI)phmyi)-2-naphthainide (Compound 2).
Figure imgf000061_0001
[00184] To a solution of mixture of S9 (20mg, 1.0 eq) and S10 (18mg, 1.5 eq) in DMF (ImL) was added DIEA (23 pL, 3 eq), the mixture was stirred at 110 °C over 6 hour. The mixture was concentrated and purified via prep-HPLC to afford Compound 2 (1 Img, 36%) as off-white solid. LC-MS (ESI) m/z: 689 [M+l]+ !H N.MR (500 MHz, DMSO-tfc) 8 11.00 (s, 1H), 8.73 (t, J = 5.6 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 10.9, 8.6 Hz, 2H), 7.81 (d, J = 8.9 Hz, 1H), 7.76 - 7.66 (m, 3H), 7.59 (dd, J = 7.2, 1.2 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 4.26 - 4.07 (m, 4H), 3.59 (d, J = 5.6 Hz, 6H), 3.49 (q, J = 5.9 Hz, 2H), 3.29 (d, J = 11.9 Hz, 2H), 2.91 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.60 (dt, J = 17.2, 3.7 Hz, 1H), 2.30 (qd, J = 13.2, 4.5 Hz, 1H), 2.02 (dtd, J = 12.8, 5.3, 2.3 Hz, 1H).
[00185] Compounds 3-19 were prepared according to similar methods as Compounds 1 and 2, using appropriate starting materials. Structures and characterization data are provided below.
N-((lS)-1-(6~((6~(2~((2-(2,6-dioxopiperidin~3-yI)~l,3"dioxoisomdolin~4~ y!)oxy)acetamido)hexyI)aniiiio)pyridin-2-y!)ethyl)-5-(4-(trifliioromethy0pheiiyI)-2- naphthamide (Compound 3)
Figure imgf000062_0001
[00186] !H NMR (500 MHz, DMSO-tfc) 8 11.05 (s, 1H), 9.13 (s, 1H), 8.58 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.91 - 7.82. (m, 4H), 7.79 - 7.70 (m, 3H), 7.66 (dd, J = 12.1, 7.8 Hz, 3H), 7.55 (d, J = 7.1 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.90 - 6.63 (m, 2H), 5.16 (s, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 4.69 (s, 2H), 3.26 (d, J = 7.3 Hz, 2H), 3.07 (q, J = 6.7 Hz, 2H), 2.87 - 2.74 (m, 2H), 2.58 - 2.45 (m, 2H), 1.96 (dd, J = 10.2, 4.6 Hz, 1H), 1.53 - 1.47 (d, J = 7.1 Hz, 3H), 1.42 - 1.18 (m, 8H). LC-MS (ESI) m/z: 849 [M +1 ]
N-((1.S)-l-(6-((l l-(2-((2-(2,6-dioxopiperidin-3-yI)-l,3"djoxoisoindolin-4- yI)oxy)acetamido)undecyI)ammo)pyridin-2-yl)ethyI)~5~(4~(trifliioromethy?)phenyI)~2~ naphthamide (Compound 4)
Figure imgf000062_0002
[00187] !H NMR (500 MHz, DMSO-A) 8 11.12 (s, 1H), 9.21 (s, HI), 8.66 (s, 1 H), 8.15 (d, J === 8.2 Hz, 1H), 7.99 -• 7.77 (m, 6H), 7.73 (dd, J === 11.8, 7.9 Hz, 3H), 7.62 (d, J - 7.0 Hz, HI), 7.50 (d, J - 7.2 Hz, 1 H), 7.40 (d, J - 8.6 Hz, HI), 6.82 (s, 2H), 5.23 (s, 1 H). 5.12 (dd, J - 12.7, 5.3 Hz, 1H), 4.77 (s, 2H), 3.39 -• 3.30 (m, 2H), 3.13 (q, J - 6.9 Hz, 2H), 2.90 (ddd, J - 17.6, 13.9, 5.2 Hz, 1 H), 2.65 - 2.53 (m, 2H), 2.05 (dd, J - 11.7, 5.8 Hz, 1H), 1.58 (d, J 7.1 Hz, 4H), 1.47 - 1.30 (m, 4H), 1.28-1.18 (m, 14H). LC-MS (ESI) m/z: 919 | M • H . N-((lS)”l”(6-((2-(2-(2-((2-(2,6-dioxopiperidiii-3-yJ)-l,3-dioxoisoindoliii-4- yl)oxy)acetamido)ethoxy)ethyJ)amino)pyridm-2-yI)ethyi)-5-(4-(trifhioromethyi)phenyi)-2- naphthamide (Compound 5)
Figure imgf000063_0001
[00188] SH NMR (500 MHz, DMSO-cfc) 5 11.12 (s, 1H), 9.20 (s, 1H), 8.65 (s. 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.94 (dd, J = 17.2, 8.4 Hz, 3H), 7.87 - 7.69 (m, 5H), 7.62 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.98 - 6.71 (m, 3H), 6.00 (s, 1H), 5.21 (t, J = 7.3 Hz, 1H), 5.11 (dd, J = 12.7, 5.5 Hz, 1H), 4.78 (d, J = 10.4 Hz, 2H), 3.39 (dtd, J = 37.6, 13.4, 12.6, 6.6 Hz, 6H), 3.16 (s, 1H), 2.94 - 2.81 (m, 2H), 2.68 - 2.52 (m, 2H), 2.09 - 1.96 (m, 1H), 1.57 (d, J = 6.9 Hz, 3H). LC-MS (ESI) m/z: 837 [M+l] \
N-((lS)-1.-(6~((ll~((2-(2,6-dioxopiperidin~3~yI)-1.,3"dioxoisoindolin~4~ y!)amino)undecyI)amino)pyridin-2-yl)ethyI)-5~(4~(trifluoromethyi)phenyi)-2-naphthamide
(Compound 6)
Figure imgf000063_0002
[00189] LC-MS (ESI) m/z: 861 [M+l]+. N”((lS)-l-(6-((2-(2-((2-(2,6-dioxopiperidin-3-yI)-l,3-dioxoisomdolin-4- yl)amino)ethoxy)ethyl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2- naphthamide (Compound 7)
Figure imgf000064_0001
[00190] LC-MS (ESI) m z: 779 [M+l]+.
N-((lS)”l”(6-(7-(2-(2,6~dioxopiperidm-3-yI)”l,3"dioxoisoindoIm-4-yI)~2,7~ diazaspiro[4.4]nonan-2-yl)pyridm-2-yl)ethyJ)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide
(Compound 8)
Figure imgf000064_0002
[00191] !H NMR (500 MHz, DMSO-tfc) 8 10.99 (s. 1H), 9.02 (s. 1H), 8.58 (s, H I). 8.07 (d, J === 8.2 Hz, 1H), 7.15 -• 7.00 (m, 2H), 6.70 (s, 2H), 5.18 (s, 2H), 4.99 (dd, J === 12.5, 5.6 Hz, 1H), 3.73 - 3.43 (m, 6H), 2.80 (ddd, J - 17.9, 13.9, 5.5 Hz, 1 H), 2.49 (dd, J - 17.0, 12.4 Hz, 2H), 2.14
- 1.84 (m, 4H), 1.48 (d, J - 7.0 Hz, 3H). LC-MS (ESI) m/z: 801 [M+l]+.
N-((lS)"l"(6-((l-(2-(2,6"dioxopiperidiii-3-yI)"l,3"dioxoisoindoIm-4-yI)piperidin"4" y!)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyI)phmyl)-2-naphthamide (Compound 9)
Figure imgf000065_0001
[00192] !H NMR (500 MHz, DMSO-do) 5 11.09 (s, IH), 9.14 (s, IH), 8.68 (s, IH), 8.16 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.9 Hz, IH), 7.92 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.9 Hz, 1H), 7.79 - 7.65 (m, 3H), 7.62 (d, J = 7.1 Hz, IH), 7.36 (d, J - 7.1 Hz, 1H), 7.28 (s, 1H), 6.80 (s, IH), 5.22 (s, 1H), 5.11 (dd, J = 12.7, 5.5 Hz, IH), 3.99 (s, IH), 3.67 (dd, J = 31.5, 11.3 Hz, 2H), 2.89 (ddd, J = 16.9, 13.6, 5.4 Hz, 3H), 2.66 - 2.53 (m, 2H), 2.17 - 1.98 (m, 3H), 1.82 - 1.65 (m, 2H), 1.59 (d, J = 7.0 Hz, 2H). I .('-MS (ESI) m/z: 801 [M+lf.
N-((lS)”l”(6-(((l-(2-(2,6~dioxopiperidin-3-yI)”l,3"dioxoisoindoIin-4-yI)piperidm-4” yI)methyl)amino)pyridin~2~yl)ethyI)-5-(4-(triflHoromethyl)phenyl)-2-naphthamide (Compound 10)
Figure imgf000065_0002
[00193] iH NMR (500 MHz, DMS(We) 6 11.01 (s, IH), 9.10 (s, 2H), 8.59 (d. J 1.8 Hz, HI), 8.07 (d, J - 8.2 Hz, IH), 7.90 (dd, J - 8.8, 1.8 Hz, I H), 7.84 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 8.8 Hz, IH), 7.68 - 7.56 (m, 4H), 7.54 (d, J = 7.1 Hz, IH), 7.26 (d, J = 7.1 Hz, IH), 7.20 (d, J = 8.5 Hz, I H), 5.16 (s, I H), 5.02 (dd, J = 12.8, 5.5 Hz, IH), 3.61 (s, 2H), 3.39 - 3.18 (m, 2H), 2.89 - 2.64 (m, 3H), 2.52 (dt, J = 20.1 , 4.2 Hz, 2H), 2.01 - 1.88 (m, I H), 1.77 (d, J = 13.9 Hz, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.40 (t, J == 12.2 Hz, 2H). LC-MS (ESI) m/z: 789 [M+l]+. N-((lS)”l”(6-((l-(2-((2-(2,6"dioxopiperidin-3-yI)-l,3-dioxoisoindoJin-4- yl)oxy)acetyl)piperidin-4-y!)amino)pyridiii”2”yi)ethyI)-8-(4-
(trifluoromethyi)pheny9)quinolme-3-carboxamide (Compound 11)
Figure imgf000066_0001
[00194] !H N.MR (500 MHz, DMSO-tfc) 8 11.12 (s, 1H), 9.42 - 9.25 (m, 2H), 9.02 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.1 Hz, II I), 7.97 (d, J = 7.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.85 (dd, J = 15.5, 7.8 Hz, 2H), 7.78 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.86 (s, 2H), 5.23 (q, J = 13.5, 8.5 Hz, 3H), 5. 11 (dd, J = 12.8, 5.4 Hz, 2H), 4.23 (s, 2H), 4.03 (s, 2H), 3.85 (d, J = 15.2 Hz, 2H), 3.23 (d, J = 12.1 Hz, 1H), 2.90 (dq, J = 18.0, 5.7 Hz, 2H), 2.69 - 2.53 (m, 2H), 2. 11 - 1.89 (m, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.39 (t, J = 11.5 Hz, 1H). LC-MS (ESI) m/z: 834 B1 R.
N-((lS)-1-(6~((2~(2~(2-((2-(2,6~dioxopiperidin-3-y1)~l,3"dioxoisomdoJin-4- yJ)oxy)acetamido)ethoxy)ethyJ)amino)pyridin-2-yI)ethy?)-8-(4-
(trifluoromethy!)phenyI)quino!ine-3-carboxamide (Compound 12)
Figure imgf000066_0002
[00195] !H NMR (500 MHz, DMSO-do) 5 11.04 (s, HI), 9.29 (s, HI), 9.22 (d, J = 2.4 Hz, 1H), 8.92 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.95 (t, J - 5.7 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.84 - 7.68 (m, 6H), 7.40 (d, J = 7.2 Hz, HI), 7.30 (d, J = 8.5 Hz, 1H), 6.90 - 6.71 (m, 2H), 5.15 (s, 2H), 5.03 (dd, J = 12.7, 5.4 Hz, 2H). 4.70 (s, 2H), 3.57 (t, J - 5.4 Hz, 2H), 3.53 - 3.39 (m, 4H), 3.28 (p, J = 5.9 Hz, 2H), 2.91 - 2.75 (m, 2H), 2.58 - 2.45 (m, 2H), 1.95 (ddd, J - 12.8, 7.0, 4.6 Hz, HI), 1.50 (d, J = 6.9 Hz, 3H). LC-MS (ESI) m/z: 838 [ M l ] ,
N-((lS)-l”(6-(7-(2-((2-(2,6”dioxopiperidin-3-yI)”l,3"|iiioxoisoiBdoIiii-4-yI)oxy)acetyI)-2,7” diazaspiro[4.4]nonan-2-yI)pyridm-2-yi)ethyJ)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide
(Compound 13)
Figure imgf000067_0001
[00196] M NMR (500 \1H/. DMSO-tfc) 8 11 .12 (s, 1H), 9.13 (s, 1H), 8.66 (s, H I). 8.16 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.75 (t, J = 14.6, 6.7 Hz, 4H), 7.62 (d, J = 7.0 Hz, 1H), 7.46 (dd, J = 7.3, 3.0 Hz, 1H), 7.37 (dt, J = 8.6, 4.2 Hz, 1H), 6.81 (s, 1H), 5.30 (s, 2H), 5.19 - 4.99 (m, 3H), 2.90 (tt, J = 17.3, 4.8 Hz, 2H), 2.16 - 1.83 (m, 6H), 1.58 (dd, J = 7.0, 2.4 Hz, 3H). LC-MS (ESI) m/z: 859 ] XI 1 1 '.
N-((1.S)-l-(6-((l-(2-((2-(2,6-dioxopiperidin-3-yI)-l,3"dioxoisoiiidoliis-4- yI)oxy)acetyl)piperidin-4-yI)amino)pyridin-2-y!)ethyl)-5-(4-(trifluoromethy0phenyI)-2- naphthamide (Compound 14)
Figure imgf000067_0002
[00197] !H NMR (500 MHz, DMSO-do) 5 11.04 (s, HI), 9.07 (s, 1H), 8.59 (d, J = 1.8 Hz, 1 H), 8.08 (d, J = 8.2 Hz, H i). 7.90 (dd, J = 8.9, 1.8 Hz, H i). 7.85 (d, J = 8.0 Hz, 2H), 7.77 (d, J == 8.9 Hz, 1H), 7.73 - 7.62 (m, 4H), 7.54 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 5.31 - 4.89 (m, 5H), 4.14 (s, 111). 3.94 (s, HI), 3.74 (t, J = 16.1 Hz, 2H), 3.14 (d, J = 12.6 Hz, H i). 2.82 (ddd, J = 16.7, 13.4, 5.4 Hz, 2H), 2.57 - 2.45 (m, 2H), 2.05 - 1.84 (m, 3H), 1.51 (d, J = 7.1 Hz, 4H), 1.32 (d, J = 13.5 Hz, 2H). LC-MS (ESI) m/z: 833 [ M • I ] .
N-((lS)”l”(6-(((l-(2-((2-(2,6-dioxopiperidin-3-yI)-l,3~dioxoisomdolin-4- yl)oxy)acetyl)piperidm-4-yl)methyl)amino)pyridin~2-yl)ethyl)-5-(4-
(trifl«oromethyl)phenyl)~2~naphthamide (Compound 15)
Figure imgf000068_0001
[00198] 4 i NMR (500 MHz, DMSO-cfc) 5 11.04 (s, 1H), 9.12 (s, 1 H ), 8.59 (d, J = 1.8 Hz,
1H), 8.08 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.8, 1 .8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.72 - 7.60 (m, 4H), 7.55 (d, J = 7.0 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.25 - 4.91 (m, 5H), 4.23 (d, J = 12.7 Hz, 2H), 3.83 - 3.65 (m, 2H), 2.96 (t, J = 12.7 Hz, 1H), 2.82 (ddd, J = 17.0, 13.7, 5.4 Hz, 1H), 2.58 - 2.45 (m, 2H), 1.96 (ddd, J = 10.6, 5.9, 3.5 Hz, 2H), 1.74 (dd, J = 37.6, 23.1 Hz, 4H), 1.51 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 12.8 Hz, 2H), 1.02 (d, J = 10.8 Hz, 2H). LC-MS (ESI) m/z: 847 [M+l f.
N"(2-(2-((2-(2,6-dioxopiperidiii-3-yI)"l-oxoisoindoHn-4-y!)amino)ethoxy)ethyl)-5-(4-
(trifluoromethy0phenyI)-2-naphthamide (Compound 16)
Figure imgf000069_0001
[00199] 1-1 NMR (500 MHz, DMSO-cfc) 5 10.92 (s, IH), 8.66 (t, J - 5.6 Hz, 1 H), 8.47 (d, J ==
1.7 Hz, 1 H), 8.02 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 8.7, 2.1 Hz, 3H), 7.72 (d, J = 8.9 Hz, IH), 7.67 (d, J = 8.0 Hz, 2H), 7.62 (dd, J = 8.2, 7.1 Hz, 1H), 7.52 (dd, J = 7.0, 1.2 Hz, 1H), 7.18 (t, J =
7.7 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.00 (dd, J = 13.3, 5.2 Hz, 1H), 4.19 - 3.99 (m, 3H), 3.57 (dt, J = 12.2, 5.9 Hz, 4H), 3.44 (qd, J = 6.3, 5.9, 2.2 Hz, 2H), 3.27 (d, J = 5.8 Hz, 2H), 2.82 (ddd, J = 17.3, 13.6, 5.4 Hz, IH), 2.55 - 2.46 (m, IH), 2.18 (qd, J = 13.3, 4.5 Hz, 1H), 1.90 (dtd, J = 12.7, 5.3, 2.3 Hz, IH). LC-MS (ESI) m/z: 645 [M + 1] \
N-(4~((2~(2,6-dioxopiperidin-3~yl)-l-oxoisoindo!in-4-yl)amino)butyrI)-5-(4~
(trifluoromethy!)phenyl)-2-naphthamide (Compound 17)
Figure imgf000069_0002
[00200] !H NMR (500 MHz, DMSO-A) 8 10.93 (s, IH), 8.62 (t, J - 5.6 Hz, 1 H), 8.47 (d, J -
1.8 Hz, IH), 8.04 (d, J - 8.2 Hz, IH), 7.88 - 7.81 (m, 3H), 7.73 (d, J - 8.9 Hz, IH), 7.67 (d, J - 8.0 Hz, 2H), 7.64 - 7.60 (m, IH), 7.52 (dd, J - 7.1, 1.2 Hz, IH), 7.20 (t, J - 7.7 Hz, I H), 6.85 (d, J - 7.4 Hz, IH), 6.70 (d, J - 8.1 Hz, 1 H), 5.04 (dd, J - 13.3, 5.2 Hz, 2H), 4.21 - 4.00 (m, 3H), 3.31 (q, J - 6.3 Hz, 3H), 3.12 (t, J - 6.3 Hz, 3H), 2.85 (ddd, J - 17.3, 13.6, 5.2 Hz, 2H), 2.53 (dt, J - 17.2, 3.8 Hz, 211}. 2.21 (qd, J === 13.2, 4.5 Hz, 2H), 1.95 (dtd, J == 12.7, 5.3, 2.3 Hz, 1H), 1.68 - 1.52 (m, 5H). LC-MS (ESI) m/z: 629 i\l l i . N-(( 1 S)~ l-(6-((2-(2-(2-(2-((2-(2,6-dioxopiperidm-3-y9)- 1 ,3-dioxoisoindo9in-4- y9)oxy)acetamido)ethoxy)et9ioxy)et9iy9)amino)pyridin-2-y9)et9iyJ)-5-(4-
(trifluoromethy9)phenyi)-2-naphthamide (Compound 18)
Figure imgf000070_0001
[00201] SH NMR (500 MHz, DMSO-cfc) 5 11.05 (s, 1 H), 9.12 (s, 2H), 8.58 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.94 - 7.82 (m, 4H), 7.78 - 7.70 (m, 3H), 7.69 - 7.62 (m, 3H), 7.55 (d, J = 7.1 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 8.5 Hz, IH), 5.14 (s, 2H), 5.04 (dd, J = 12.8, 5.4 Hz, 2H), 4.70 (s, 3H), 3.61 - 3.42 (m, 9H), 3.37 (t, J = 5.7 Hz, 2H), 3.22 (q, J = 5.8 Hz, 3H), 2.82 (ddd, J = 16.6, 13.8, 5.5 Hz, 2H), 2.57 - 2.45 (m, 3H), 2.03 - 1.91 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H). LC-MS (ESI) m/z: 881 [M+l]+.
N-((lS)-l-(6~((2~(2~(2-((2-(2,6~dioxopiperidin-3-yl)~l,3-dioxoisoindo!in-4- y!)amino)ethoxy)ethoxy)ethyI)ammo)pyridin-2-yl)ethyI)~5~(4~(trifluoromethy?)phenyI)-2~ naphthamide (Compound 19)
Figure imgf000070_0002
[00202] Hl NMR (500 MHz, DMSO-tfc) 5 11.02 (s, IH), 9.06 (s, 2H), 8.58 (d, J - 1.8 Hz,
2H), 8,07 (d, J - 8 2 Hz, 1H), 7.92 - 7.81 (m, 3H), 7.76 (d, J - 8.9 Hz, 1H), 7.65 (dd, J - 14.6,
7.7 Hz, 3H), 7.54 (d, J - 7.0 Hz, IH), 7.51 - 7.44 (m, IH), 7.03 (d. J == 8.6 Hz, IH), 6.95 (d, J == 7.0 Hz, II -I), 6.71 (s, 3H), 6.50 (d, J === 6.1 Hz, 1 H), 5.11 (s, 1H), 4.97 (dd, J - 12.7, 5.4 Hz, 1H), 3.35 (q, J = 5.4 Hz, 3H), 2.80 (ddd, J = 18.2, 13.7, 5.4 Hz, 2H), 2.58 - 2.45 (m, 2H), 1.94 (dd, J === 12.3, 6.1 Hz, 2H), 1.49 (d, J = 7.0 Hz, 3H). LC-MS (ESI) m/z: 823 [ M I ] ,
(4R)-l-((S)-3,3-dimethyi-2-(3-(2-((6-((S)-l-(5-(4-(trifluoromethyi)phenyI)-2- naphthamido)ethyl)pyridin"2-yi)amino)ethoxy)propanamido)biitanoy!)-4-hydroxy-N-((S)” l-(4-(4-methylthiazol-5-yI)phenyl)ethyI)pyrroIidine”2"Carboxamide (Compound 21)
Figure imgf000071_0001
[00203] To a mixture of S3 (25mg, 1.0 eq), VHL1 (28mg, 1.0 eq) and Pd2(dba)j (5mg, 0. 1 eq), NaOtBu (14mg, 3.0 eq), BINAP (7mg, 0.2 eq) under N2 protection was added toluene (1 mL). The resultant mixture was stirred at 100 °C overnight. The mixture was filtered and purified via prep-HPLC to afford Compound 21 (1 Img, 24%) as white solid. !H NMR (500 MHz, DMSO-de) 5 9.18 (d, J - 6.9 Hz, 1H), 8.92 (s, 1H), 8.60 (s, 1H), 8.30 (d, J - 7.8 Hz, 1 H), 8.08 (d, J === 8.3 Hz, 1H), 7.90 (dd, J - 9.0, 1.9 Hz, 1H), 7.81 (dt, J === 31.8, 8.4 Hz, 5H), 7.70 - 7.62 (m, 3H), 7.55 (d, J === 6.9 Hz, 1H), 7.36 (d, J - 8.0 Hz, 2H), 7.30 (d, J - 8.0 Hz, 2H), 6.89 (s, H I). 6.80 (d, J - 7.3 Hz, H I). 5.17 (s, H I). 4.83 (q, J - 7.1 Hz, H I). 4.46 (d, J - 9.2 Hz, HI), 4.35 (t, J - 8.1 Hz, 1 H), 4.21 (s, 1 H), 3.66 - 3.43 (m, 8H), 2.50 (dt, J == 13.1, 6.4 Hz, IH), 2.38 (s, 3H), 2.36 - 2.27 (m, IH), 1.95 (t, J === 10.5 Hz, 1 H), 1.72 (ddd, J === 12.9, 8.5, 4.6 Hz, IH), 1.52 (d, J === 7.0 Hz, 3H), 1.29 (d, J == 7.1 Hz, 3H), 0.83 (s, 9H). L( MS (ESI) m/z: 978 [ M l ;
(4R)-l-((S)-3,3-dimethyi-2-(3-(2-(2”((6-((S)-l-(5-(4-(trifluoromethyi)pheuyi)-2- naphthamido)ethyl)pyridm"2-yi)amino)ethoxy)ethoxy)propanamido)butanoyl)-4-hydroxy-
N”((S)-l-(4-(4-methyKhiazoI-5-yI)pheny0ethyl)pyrroIidiiie-2-carboxamide (Compound 22)
Figure imgf000072_0001
[00204] To a mixture of S3 (25mg, 1.0 eq), VHL2 (30mg, 1.0 eq) and Pd2(dba)s (5mg, 0, 1 eq), NaOtBu (14mg, 3.0 eq), BINAP (7mg, 0.2 eq) under N2 protection was added toluene (1 mL). The resultant mixture was stirred at 100 ’C overnight. The mixture was filtered and purified via prep-HPLC to afford Compound 22 (15rng, 29%) as white solid. }H NMR (500 MHz, DMSO-d6) 5 9. 13 (s, I H), 8.92 (s, I H), 8.59 (d, J - 1.9 Hz, HI), 8.30 (d, J - 7.8 Hz, IH), 8.08 (d, J - 8.2 Hz, IH), 7.90 (dd, J - 8.9, 1.9 Hz, HI), 7.85 (d, J - 8.1 Hz, 2H), 7.78 (t, J - 9.6 Hz, 2H), 7.69 - 7.62 (m, 3H), 7.55 (d, J - 6.9 Hz, HI), 7.36 (d, J - 8.2 Hz, 2H), 7.30 (d, J - 8.2 Hz, 2H), 6.80 (d, J - 36.9 Hz, 4H), 5.15 (s, 2H), 4.84 (p, J - 7.3 Hz, 2H), 4.46 (d, J - 9.3 Hz, HI), 4.35 (t, J - 8.1 Hz, 1 H), 4.21 (dq, J == 6.0, 3.3, 2.8 Hz, 1 H), 3.60 - 3.36 (m, 12H), 2.38 (s, 3H), 2.27 (dt, J == 14.9, 6.2 Hz, 2H), 1.99 - 1.91 (m, 210. 1.72 (ddd, J == 13.0, 8.6, 4.6 Hz, 2H), 1.51 (d, J == 7.0 Hz, 3H), 1.29 (d, J - 7.0 Hz, 3H), 0.85 (s, 9H). LC-MS (ESI) m/z: 1022 [M+lf.
(2S,4R)"l"((S)"2-acetamido-3,3-dimethyIbutaiioyI)-4"hydroxy-N”((S)-l-(4-(4-methyIthiazoJ"
5-yi)-2"((5-((6-((S)-l-(5-(4-(trifluoromethyI)phenyI)-2-iiaphthamido)ethy!)pyridiii-2- yl)amino)pentyi)oxy)pheiiy!)ethyl)pyrroIidme-2-carboxamide (Compound 23)
Figure imgf000073_0001
[00205] To a mixture of S3 (25mg, 1.0 eq), VHL3 (29mg, 1.0 eq) and Pd2(dba)3 (5mg, 0, 1 eq), NaOtBu (14mg, 3.0 eq), BINAP (7mg, 0.2 eq) under N2 protection was added toluene (1 mL). The resultant mixture was stirred at 100 °C overnight. The mixture was filtered and purified via prep-HPLC to afford Compound 23 (9mg, 20%) as white solid. XH NMR (500 MHz. DMSO-d6) 5 9.17 (s, 1H), 8.91 (d, J - 4.2 Hz, 1H), 8.59 (s, 1H), 8.35 (d, J - 7.4 Hz, 1 H), 8.07 (d, J - 8.2 Hz, H I). 7.87 (dd, J - 20.0, 8.8 Hz, 4H), 7.77 (t, J - 7.3 Hz, 2H), 7.65 (dd, J - 10.6, 7.7 Hz, 3H), 7.54 (t, J - 6.6 Hz, 2H), 6.99 - 6.69 (m, 5H), 5.18 (s, 1 H), 4.91 (t, J - 7.0 Hz, H i). 4.43 (dd, J - 8.9, 3.5 Hz, 2H), 4.27 (s, 2H), 3.53 (d, J - 9.3 Hz, 2H), 3.34 (d, J - 8.3 Hz, 2H), 2.38 (d, J - 7.5 Hz, 3H), 1 .94 (t, J - 10.5 Hz, H i). 1.81 (d, J - 5.3 Hz, 3H), 1.75 (p, J - 7.3 Hz, 211). 1.63 (q, J == 7.3 Hz, 211). 1.51 (d, J - 7.1 Hz, 3H), 1.23 (d. J == 6.8 Hz, 2H), 0.85 (s, 2H), 0.77 (s, 9H). m/z: 1006 [M + 1] T
(2R,4S)-l-((R)"2-(l-flnorocydopropane-l-carboxamido)"3,3“d™ethyJbntanoyI)-4-hydroxy-
N"(4-(4-methyIthiazoI-5-yi)-2-(2-(2-(2-((6-((S)-l-(5-(4-(trifhioromethyI)phenyl)-2- naphthamido)ethyI)pyridm-2-yi)amino)ethoxy)ethoxy)ethoxy)benzyl)pyrrolidine-2- carboxamide (Compound 24)
Figure imgf000074_0001
[00206] To a mixture of S3 (25mg, 1.0 eq), VHL4 (33mg, 1.0 eq) and Pd2(dba)j (5mg, 0. 1 eq), NaOtBu (14mg, 3.0 eq), BINAP (7mg, 0.2 eq) under N2 protection was added toluene (1 mL). The resultant mixture was stirred at 100 °C overnight. The mixture was filtered and purified via prep-HPLC to afford Compound 24 (17mg, 33%) as white solid. !H NMR (500 MHz, DMSO-de) 59.12 (s, 1H), 8.90 (s, 1H), 8.58 (d, J - 1 .9 Hz, 1H), 8.43 (t, J - 6.0 Hz, 1H), 8.07 (d, J === 8.2 Hz, 1H), 7.90 -• 7.82 (m, 3H), 7.76 (d, J === 8.8 Hz, 1H), 7.65 (dd, J - 12.3, 7.8 Hz, 3H), 7.56 - 7.52 (m, HI), 7.33 (d, J - 7.8 Hz, 1 H), 7.20 (dd, J - 9.3, 2.8 Hz, 1H), 6.94 (d, J - 1.6 Hz, 1H), 6.89 (dd, J - 7.8, 1.6 Hz, 1 H), 5.14 (s, 2H), 4.52 (d, J - 9.3 Hz, 1 H), 4.45 (t, J - 8.2 Hz, 1 H), 4.28 (d, J == 4.7 Hz, 1H), 4.22 (dd, J == 16.5, 6.2 Hz, 210. 4.14 (dd, J == 16.6, 5.7 Hz, 2H), 4.08 (t, J == 4.7 Hz, 3H), 3.69 (t, J - 4.6 Hz, 3H), 3.60 - 3.51 (m, 8H). 2.37 (s, 3H). 2.05 - 1 .98 (m, 1H), 1.97 - 1.79 (m, 2H), 1.50 (d, J == 7.0 Hz, 3H), 1.29 (ddd, J - 17.3, 9.0, 2.4 Hz, 2H), 1.16 (t, J - 8.5, 4.1 Hz, 3H), 0.87 (s, 9H). m/z: 1082 [M+l]+.
Example 2: Degradation and Ceil Proliferation Studies
[00207] Ceil culture. NCI-H226 (ATCC, no. CRL-5826) and MSTO-211H (ATCC, no. CRL- 2081) mesothelioma cells were obtained from American Type Culture Collection and cultured as recommended. Cells were negative for mycoplasma using MycoAlert mycoplasma detection kit (LONZA, no. LT07-418).
[00208] Ceil proliferation. For cell viability experiments, the cells were seeded in a 384-well plate (Corning, no. 3570) at the density of 200 cells/well. The next day, compounds were added using a HP D300e Digital Dispenser. After 5 days of treatment, cell viability was measured by CellTiter-Glo kit (Promega, no. G7570) as the manufacturer recommended. The luminescent signal was collected on PHERAstar® FSX from BMG LABTECH.
[00209] Immimoblotting Analysis. NCI-H226 cells were seeded at a density’ of 200,000/mL in 6-well plates and treated with degrader compounds disclosed herein at indicated times. Then ceil pellets were collected, washed with PBS thrice, and lysed in RIP A buffer with Halt Protease and phosphatase inhibitor (ThermoFisher, #78442) for 30 min on ice. Then samples were centrifuged, and the supernatant was subjected to BCA analysis. In total, 20 pg protein for each sample was loaded for SDS-PAGE separation. Protein was then transferred to a 0.2 pm nitrocellulose membrane at 10 V for 60 min. After wet transfer, the membrane was blocked at rt for 60 mm using Intercept (TBS) blocking buffer (LICOR, #927-60,001 ) and subjected for follow-up procedures. The following antibodies were used: pan- LEAD (Cell Signaling, #132958, 1 : 1000), TEAD1 (Cell Signaling, #12292S, 1: 1000), TEAD3 (Cell Signaling, #13224S, 1: 1000), TEAD4 (Abeam, #ab58310, 1 :1000), p-actin (Cell Signaling, #3700S, 1:2000), IRDye 800CW Goat anti-rabbit IgG secondary' antibody (LICOR, #926-32,211, 1 :5000), and IRDye 680RD Goat anti-mouse IgG secondary antibody (LICOR, #926- 68,070, 1:5000).
[00210] Results. Data from the above experiments are shown in FIGS. 1-6. FIG. 1 shows the degradation effect of Compounds 1, 3, 4, 5, 6, and 7 in NCI-H226 cells, after cells were treated with the compounds for 24 hours at the indicated concentrations. FIG. 2 shows the degradation effect of Compounds 1 , 3, 5, and 7 in NCI-H226 ceils, after cells were treated with the compounds for 24 hours at the indicated concentrations. FIG. 3 shows the degradation effect of Compound 1 in NCI-H226 cells that were pre-treated with a rescue agent (lenalidomide, MLN4924, or carfilzomib) at the indicated concentration for 2 hours, follow'ed by treatment with Compound 1 for an additional 6 hours. FIG. 4 show's the 24-hour degradation effect of Compounds 1, 2, 13, 14, 15, 16, 17, 19, and 20 in NCI-H226 cells at 1 pM. FIG. 5 show's the antiprolif eration effect of Compounds 1, 2, 3, 4, 5, 6, 7, 13, 14, 15, 16, 17, 18, and 20 in MSTO- 211H mesothelioma cells. FIG. 6 shows the degradation effect of Compounds 21-24 in NCI- 11226 cells, after cells w'ere treated with the compounds for 24 hours at 1 pM.
[00211] In FIGS. 4 and 5, Compound 20 is a negative control compound (N-((lS)-l-(6-((2~(2- (2-(2-((2-(l-methyl-2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)ethoxy)ethoxy)ethyl)amino)pyridin-2-yl)ethyl)-5-(4~(trifluoromethyl)phenyl)- 2-naphthamide), which has an N-methylated glutarimide moiety that substantially weakens cereblon binding. In FIG, 5, VT-103 is N-methyl-3-(l -methyl- lH-imidazol-4-yl)-4-((4- (trifluoromethyl)phenyl)amino)benzenesulfonamide, a commercially available TEAD inhibitor.
[00212] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. [00213] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
[00214] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. V ariations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law'. Moreover, any combination of the above-desenbed elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:
A compound of formula (I):
Figure imgf000078_0001
or a pharmaceutically acceptable salt thereof, wherein:
A 1 is CR3 or N;
A2 is CR.2 or N;
A3 is CR3 or N;
A4 is CR4 or N;
A5 is CR5 or N;
R1, R2, R\ R4, and R4 are each independently selected from hydrogen, Ci-Ce alkyl, Ci-Cs haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl,
Figure imgf000078_0002
cycloalkyl, aryl, aryl-Ci-Co- alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -OR3, -SRa, -N(Ra)(Rb), -C(O)Ra, -C(O)ORa, - C(O)N(Ra)(Rb), -S(O)Ra, -S(O)2Ra, -NRaS(O)2Rb, -NRaC(O)Rb, and -NR3C(O)ORb; wherein R3 and R4, or R ' and R5, are optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; each R3 and Rb is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cb heteroalkyl, Cs-Cs cycloalkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, and heterocyclyl;
Q is selected from a group of formula
Figure imgf000078_0003
an(j a bond;
X1 is selected from -O-, -NRy-, -(CH2)m-, -C=C~, and a bond, wherein m is 1, 2, 3, or 4, and R5' is selected from hydrogen and Ci-Ce alkyl; L is a linker;
X2 is selected from -O-, -NR2-, -(CHiR-, -C=C-, and a bond, wherein n is 1, 2, 3, or 4, and Rz is selected from hydrogen and Ci-Ce alkyl; and
Y is a moiety that binds to an E3 ubiquitin ligase; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heterocyclyl is each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein no more than one of A1, A2, A3, A4, and A5 is N.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein AJ is CR1 or N; A2 is CR2; A3 is CR3; A4 is CR4; and A5 is CR3.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and R5 are each independently selected from hydrogen, C1-C3 alkyl, Ci- C3 haloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, halo, -OR3, - SR3, -N(Ra)(Rb), -C(O)N(Ra)(Rb), -S(O)Ra, -S(O)2Ra, -NRaS(O)2Rb, -NR3C(O)Rb, and - NRaC(O)ORb, wherein each Ra and Rb is independently selected from hydrogen, C1-C3 alkyl, Ci- C2 haloalkyl, and C3-C6 cycloalkyl.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1, R2, Rt R4, and R3 are each hydrogen.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein Q is a group of formula
Figure imgf000079_0001
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (la):
Figure imgf000080_0001
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from -NRy- and a bond, wherein Ry is hydrogen.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein X2 is selected from
Figure imgf000080_0002
-NR2-, -(CH2)n-, -CO, and a bond, wherein R2 is hydrogen and n is 1.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein X2 is selected from -O- and -NH-.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Y has a formula selected from:
Figure imgf000080_0003
12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Y is a moiety of formula (a):
Figure imgf000081_0001
wherein:
X is CO or CH2;
Rc is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, Cz-Ce alkynyl, Ci-Ce heteroalkyl, Ch-Cs cycloalkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, NRdS(
Figure imgf000081_0002
each Rd and Re is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Q heteroalkyl, Ci-Cs cycloalkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, and heterocyclyl
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Rc is hydrogen.
14. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Y is a moiety of formula (b):
Figure imgf000081_0003
wherein:
R! is C1-C4 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with one or more halo groups (e.g., fluoro);
Rg is hydrogen or methyl; and
Z is selected from O, NH, and CH2.
15. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Y has a formula selected from:
Figure imgf000082_0001
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein L is a direct bond or comprises any combination of -CH?-, -CH=CH-, -C=C~, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O):?-, arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein L comprises any combination of the following moieties:
Figure imgf000083_0001
wherein p is 1, 2, 3, 4, 5, or 6; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein L. is a direct bond or has a formula selected from :
Figure imgf000083_0002
wherein p is 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12; and Het is a heterocyclylene.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein L has a formula selected from:
Figure imgf000083_0003
Figure imgf000084_0001
20. The compound of claim 1 , wherein the compound is selected from:
Figure imgf000084_0002
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
and pharmaceutically acceptable salts thereof.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. A method of treating a disorder in a subject in need thereof, wherein the disorder is characterized or mediated by activity of a transcriptional enhancer associate domain (TEAD) transcription factor, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21.
23. The method of claim 22, wherein the disorder is a proliferative disease.
24. The method of claim 22, wherein the disorder is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy.
25. The method of claim 22, wherein the disorder is a cancer selected from mesothelioma, esophageal cancer, liver cancer, breast cancer, lung cancer, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
26. A method of degrading a transcriptional enhancer associate domain (TEAD) transcription factor in a sample, comprising contacting the sample with an effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof.
27. The method of claim 26, wherein the TEAD transcription factor is selected from TEAD1 , TEAD2, TEAD3, and TEAD4.
28. A compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, for use m treating a disorder in a subject in need thereof, wherein the disorder is characterized or mediated by activity of a transcriptional enhancer associate domain (TEAD) transcription factor.
29. The compound of claim 28, wherein the disorder is a proliferative disease.
30. The compound of claim 28, wherein the disorder is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy.
31. The compound of claim 28, wherein the disorder is a cancer selected from mesothelioma, esophageal cancer, liver cancer, breast cancer, lung cancer, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
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