Hells helicase degraders and uses thereof

Abstract

Disclosed herein are compounds that can degrade lymphoid-specific helicase (HELLS) protein. Also disclosed herein are pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in the treatment of proliferative diseases such as cancers.

Description

[0001] HELLS HELICASE DEGRADERS AND USES THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefit of U.S. Provisional Application No.

[0004] 63 / 547,885, filed on November 9, 2023, which is incorporated herein by reference in its entirety.

[0005] SEQUENCE LISTING

[0006] The text of the computer readable sequence listing filed herewith, titled “STDU2-41936- 601_SQL.xml”, created November 8, 2024, having a file size of 2,881 bytes, is hereby incorporated by reference in its entirety.

[0007] TECHNICAL FIELD

[0008] Disclosed herein are compounds that can degrade Helicase, Lymphoid Specific (HELLS) protein. Also disclosed herein are pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in the treatment of proliferative diseases such as cancers.

[0009] BACKGROUND

[0010] HELLS is a member of the SNF2 helicase family of chromatin remodeling proteins. It is associated with numerous cellular pathways, including DNA methylation, chromatin packaging, DNA damage response, and cell proliferation. Previous genome-wide CRISPR / Cas9 screens have identified HELLS as a mediator of sensitivity to FDA-approved PARP inhibitors (PARPi).

[0011] SUMMARY

[0012] In one aspect, disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is -C(0)- or -CH2-;

[0013] X1is selected from -O-, -NRy-, -(CH2)m-, -C=C-, and a bond, wherein m is 1, 2, 3, or 4, and Ryis selected from hydrogen and C1-C6 alkyl;

[0014] L is a bond or a linker;

[0015] X2is selected from -O-, -NRZ-, -(CH2X1-, -C=C-, heterocyclyl, and a bond, wherein n is 1, 2, 3, or 4, and Rzis selected from hydrogen and C1-C6 alkyl;

[0016] Q1, Q2, Q3, and Q4are each independently selected from CH and N wherein at least two of Q2, Q3, and Q4are N;

[0017] R1and R2are each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORa, -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 -NRaC(O)ORb;

[0018] R3is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORC, -SRe, -N(Rc)(Rd), -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -S(O)RC, -S(O)2RC, -NRcS(O)2Rd, - NRcC(O)Rd, and -NRcC(O)ORd; and

[0019] Ra, Rb, Rc, and Rdare each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl.

[0020] In some embodiments, R1and R2are each independently selected from hydrogen, halo, C1-C6 haloalkyl, and -ORa, wherein Rais hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1and R2are each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, and methoxy.

[0021] In some embodiments, Q1is CH. In some embodiments, Q1is N.

[0022] In some embodiments, Q2and Q4are N, and Q3is CH. In some embodiments, Q2is CH, and Q3and Q4are N. In some embodiments, Q2, Q3, and Q4are N.

[0023] In some embodiments, R3is H.

[0024] In some embodiments, Z is -C(O)-. In some embodiments, Z is -CH2-.

[0025] In some embodiments: X1is selected from -O-, -NRy-, -C=C-, and a bond, wherein Ryis selected from hydrogen and methyl; and X2is selected from -O-, -NRZ-, -C=C-, and a bond, wherein Rzis selected from hydrogen and methyl.

[0026] In some embodiments: X1is -NRy-, wherein Ryis selected from hydrogen and methyl; and X2is selected from -O-, -NRZ-, -C=C-, and a bond, wherein Rzis hydrogen.

[0027] In some embodiments, L is a direct bond. In some embodiments, L is a linker. In some embodiments, L comprises a moiety selected from -CH2-, -CH=CH-, -C=C-, -O-, -NR'-, -BR'-, - S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, or any combination thereof, wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, amino, aryl, cyano, C3-C6 cycloalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, heteroaryl, heterocyclyl, hydroxy, oxo, and nitro; and R' is selected from hydrogen and C1-C6 alkyl. In some embodiments, L comprises a moiety selected from - In some embodiments, L comprises a moiety selected from -CH2-, -C(O)-, and heterocyclylene moieties, or any combination thereof, wherein the heterocyclylene is a 4- to 6-membered monocyclic heterocyclylene having 1 or 2 nitrogen atoms.

[0028] In some embodiments, -X^L-X2- is selected from:

[0029] In some embodiments, the compound is selected from:

[0030] and pharmaceutically acceptable salts thereof. In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0031] In another aspect, disclosed herein is a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the proliferative disease is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy. In some embodiments, the cancer is selected from acute myeloid leukemia, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, liver cancer, lung cancer, nasopharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, retinoblastoma, stomach cancer, and uterine cancer.

[0033] In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of a PARP inhibitor. In some embodiments, the PARP inhibitor is selected from olaparib, niraparib, and rucaparib.

[0034] In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0035] In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disease. In some embodiments, the proliferative disease is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy. In some embodiments, the cancer is selected from acute myeloid leukemia, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, liver cancer, lung cancer, nasopharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, retinoblastoma, stomach cancer, and uterine cancer.

[0036] In another aspect, disclosed herein is a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0037] Other aspects and embodiments of the disclosure will become apparent in light of the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIGS. 1A-1C show Western blots demonstrating the 5-hour degradation effect of representative compounds (1 μM) in M0LT4 cells.

[0039] FIG. 2 shows data demonstrating the degradation potency of certain compounds in M0LT4 cells expressing a NanoLuc® luciferase (NLuc)-HELLS fusion protein.

[0040] FIG. 3 shows data from a cell proliferation assay using NCI-H82 cells treated with Compound 22 (1 μM) and olaparib (1 μM), either alone or in combination.

[0041] FIG. 4 shows data from a cell cycle analysis, where cells had been treated with Compound 22 (1 μM) and olaparib (1 μM), either alone or in combination.

[0042] FIG. 5 shows a Western blot demonstrating the degradation effect of a representative compound in wildtype and CRBN- / - M0LT4 cells.

[0043] FIG. 6 shows Western blots demonstrating the 5-hour degradation effect of a representative compound in small cell lung cancer (SCLC) cell lines.

[0044] FIG. 7 shows Western blots demonstrating the 5-hour degradation effect of a representative compound in prostate cancer cell lines.

[0045] FIG. 8 shows cell counts over time of NCI-H82, NCI-H69, and NCI-H526 cells treated with Compound 22 (1 μM) and / or olaparib (1 μM).

[0046] FIG. 9 shows cell counts over time of NCI-H82 cells treated with Compound 22 (1 μM) and / or niraparib (100 nM).

[0047] FIG. 10 shows cell counts over time for PC3 and 22RV1 cells treated with Compound 22 (1 μM) and / or olaparib (1 μM).

[0048] FIG. 11 shows results from a NanoBRET assay demonstrating induction of CRBN:cpd 22:HELLS ternary complex in cells.

[0049] FIG. 12 shows results from an ATPase assay confirming the protein activity of recombinant HELLS, and showing that binding of Compound 22 to HELLS protein does not affect its ATPase activity.

[0050] DETAILED DESCRIPTION

[0051] Disclosed herein are compounds that degrade HELLS protein in a cereblon (CRBN) dependent manner. These compounds are proteolysis targeting chimeras (PROTACs) that recruit HELLS to the CRL4CRBNE3 ligase, leading to HELLS ubiquitination and subsequent proteasomal degradation. HELLS is a previously undrugged helicase that is involved in numerous cellular pathways including DNA damage repair and proliferation. Given the identification of HELLS as a mediator of sensitivity to PARPi, targeting HELLS may be a way to overcome intrinsic or acquired resistance to PARPi.

[0052] Also disclosed herein are pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in the treatment of proliferative diseases such as cancers.

[0053] Definitions

[0054] 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, will control.

[0055] 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, 75thEd., 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, 2lldedition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0056] As used herein, the modifier “about” used in connection with a quantity is inclusive of the stated 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. As used herein, the term “alkyl” refers to a radical of a straight or branched fully saturated hydrocarbon chain. The alkyl chain can include, c.g., from 1 to 24 carbon atoms (Ci- C24 alkyl), 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (C1-C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (Ci-Cs alkyl), 1 to 6 carbon atoms (C1-C6 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.

[0057] 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,

[0058] 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, 2-methyl-2-propenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like.

[0059] 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,

[0060] 2-butynyl, and the like.

[0061] 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 tert-butoxy. As used herein, the term “amino” refers to a group -N(R)?, wherein each R is independently selected from hydrogen and alkyl (c.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 “dialkylamino.”

[0062] 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 147t 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 (“Ce 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).

[0063] As used herein, the term “arylene” refers to a divalent aryl radical.

[0064] 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[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl.

[0065] As used herein, the term “cycloalkylene” refers to a divalent cycloalkyl radical.

[0066] As used herein, the term “cyano” refers to a -CN group.

[0067] As used herein, the term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups arc attached to carbon atoms to form carbonyls, nitrogen atoms to form N-oxides, or sulfur atoms to form an S-oxide or S,S-dioxide, valence permitting.

[0068] As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I.

[0069] 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 hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl. In some embodiments, the haloalkyl is a C1-C6 haloalkyl. 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. In some embodiments, the haloalkoxy is a C1-C6 haloalkoxy.

[0070] 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 it 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. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, 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 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzo[&]thiophenyl (e.g., benzo[&]thiophen-5-yl, benzo[Z?]thiophen-6-yl), benzo [c] thiophenyl (e.g., benzo[c]thiophen-5-yl, benzo[c]thiophen-6- yl), 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, phthalazinyl, and quinazolinyl.

[0071] As used herein, the term “hetero arylene” refers to a divalent heteroaryl radical. As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered saturated or partially unsaturated non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“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 a saturated or partially unsaturated monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and is saturated or partially unsaturated in at least one ring of the bicyclic system. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. A heterocyclyl group can 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, and sulfur, 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, and dihydropyrrolyl. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, and imidazolidinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, 1,3,5-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 5,6-bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5,5-bicyclic heterocyclyl groups include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4- c]pyrrolyl), and the like. Exemplary 4,6-spiro heterocyclyl groups include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6,6-bicyclic heterocyclyl groups include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. In some embodiments, one or more carbon ring atoms of the hctcrocyclyl can be substituted by 1-3 oxo (forming, e.g., a lactam, succinimide or glutarimidc) and one or more N (nitrogen) or S (sulfur) atoms can be substituted by 1-2 oxo (forming, e.g., an N-oxide, an S-oxide, or an S,S- dioxide), valence permitting.

[0072] As used herein, the term “heterocyclylene” refers to a divalent heterocyclyl radical.

[0073] As used herein, the term “hydroxy” refers to an -OH group.

[0074] As used herein, the term “nitro” refers to an -NO2 group.

[0075] 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, amino, aryl, cyano, cycloalkyl, halo, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxy, oxo, nitro, or combinations thereof.

[0076] As used herein, in chemical structures the indication: represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound).

[0077] 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.

[0078] 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 -OCH2-; similarly, -0C(0)NH- also encompasses -NHC(0)0-. When linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction. 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.

[0079] As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably .

[0080] 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 ail, 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.

[0081] 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.

[0082] 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). As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying 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.

[0083] Compounds

[0084] Disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0085] Z is -C(O)- or -CH2-;

[0086] X1is selected from -O-, -NRy-, -(CH2)m-, -C=C-, and a bond, wherein m is 1, 2, 3, or 4, and Ryis selected from hydrogen and C1-C6 alkyl;

[0087] L is a linker;

[0088] X2is selected from -O-, -NRZ-, -(CH2)n-, -C=C-, heterocyclyl, and a bond, wherein n is 1, 2, 3, or 4, and Rzis selected from hydrogen and C1-C6 alkyl;

[0089] Q1, Q2, Q3, and Q4are each independently selected from CH and N, wherein at least two of Q2, Q3, and Q4are N;

[0090] R1and R2are each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6alkenyl, C2-C6 alkynyl, Ca-Cs cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORa, -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 -NRaC(O)ORb; R3is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, aryl, aryl-C1-C6-alkyl, hctcroaryl, hctcrocyclyl, halo, nitro, cyano, -ORC, -SRC, -N(Rc)(Rd), -C(O)RC, -C(O)ORe, -C(O)N(Rc)(Rd), -S(O)RC, -S(O)2RC, -NRcS(O)2Rd, - NRcC(O)Rd, and -NRcC(O)ORd; and

[0091] Ra, Rb, Rc, and Rdare each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl.

[0092] In some embodiments, R1and R2are each independently selected from hydrogen, halo, C1-C6 haloalkyl, and -ORa, wherein Rais hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1and R2are each independently selected from hydrogen, halo, C1-C3 haloalkyl, and -ORa, wherein Rais hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R1and R2are each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, and methoxy.

[0093] In some embodiments, Q1is CH. In some embodiments, Q1is N.

[0094] In some embodiments, at least one of Q2, Q3, and Q4is N. In some embodiments, at least two of Q", Q , and Q are N. In some embodiments, at least Q" and Q are N, and Q is CH. In some embodiments, at least Q2is CH, and Q3and Q4are N. In some embodiments, at least Q2, Q3, and Q4are N.

[0095] In some embodiments, R3is H.

[0096] In some embodiments, Z is -C(O)-. In some embodiments, Z is -CH2-. In some embodiments, X1is selected from -O-, -NRy-, -C=C-, and a bond, wherein Ryis selected from hydrogen and methyl. In some embodiments, X1is -NRy-, wherein Ryis selected from hydrogen and methyl.

[0097] In some embodiments, X2is selected from -O-, -NRZ-, -C=C-, and a bond, wherein Rzis selected from hydrogen and methyl. In some embodiments, X2is selected from -O-, -NRZ-, - C=C-, and a bond, wherein Rzis hydrogen.

[0098] In some embodiments, X1is selected from -O-, -NRy-, -C=C-, and a bond, wherein Ryis selected from hydrogen and methyl; and X2is selected from -O-, -NRZ-, -C=C-, and a bond, wherein Rzis selected from hydrogen and methyl. In some embodiments, X1is -NRy-, wherein Ryis selected from hydrogen and methyl; and X2is selected from -O-, -NRZ-, -C=C-, and a bond, wherein Rzis hydrogen.

[0099] L is a linker which, in conjunction with groups X1and X2, provides a covalent attachment moiety that binds to an E3 ubiquitin ligase (e.g., cereblon). In some embodiments, L is a means for linking X1and X2.

[0100] The structure of L may not be critical, provided it is substantially non-interfering with the activity of the other moieties. In some embodiments, L is a direct bond. In other embodiments, L comprises a moiety selected from -CH2-, -CH=CH-, -C=C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, - C(NR')-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, and any combination thereof, wherein R' is selected from hydrogen and C1-C6 alkyl, and wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, amino, aryl, cyano, C3-C6 cycloalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, hctcroaryl, hctcrocyclyl, hydroxy, oxo, and nitro.

[0101] In some embodiments, the linker or means for linking X1to X2comprises an alkylene chain (e.g., having 2-12 -CH2- 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-, -C=C-, -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 C1-C6 alkyl, and wherein the interrupting and terminating groups may be the same or different.

[0102] In some embodiments, L comprises an alkylene chain: , 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,

[0103] 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: In some embodiments, L is an alkylene chain interrupted by a functional group, such as -

[0104] 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.

[0105] 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: , wherein p is 1, 2, 3, 4, 5, or 6. In some embodiments, L has a formula: , wherein p is 1, 2, 3, or 4. In some embodiments, p is 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. Specific examples of L include:

[0106] In some embodiments, L comprises a poly- or oligo-ethylene glycol chain: , wherein p is 1, 2, 3, 4, 5, or 6, with an additional functional group at the terminus, such as a functional group of formula: O . In some embodiments, L has a formula: , wherein p is 1, 2, 3, or 4. In some embodiments, L has a structure selected from:

[0107] In some embodiments, L comprises one or more heterocyclylene groups, examples of which include:

[0108] In some embodiments, L comprises a heterocyclylene group selected from:

[0109] In some embodiments, L comprises a heterocyclylene group, such as one of the aboveillustrated 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=C-, -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')-, and -N(R’)S(O)N(R')-, or any combination thereof, wherein each R' is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, L comprises a heterocyclylene group, such as one of the above-illustrated hctcrocyclylcnc groups, with one or more additional groups on one or both termini, wherein the additional groups are independently selected from -CH2-, -C(O)-, -NH-, and -O-.

[0110] 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-, -S-, -N(R')-, -CH2-, -CH=CH-, -C=C-, -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')-, and -N(R')S(O)N(R')-, or any combination thereof, wherein each R' is independently selected from hydrogen and C1-C6 alkyl.

[0111] 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-. In some embodiments, L comprises one or more heterocyclylene groups that are substituted with 1, 2, or 3 substituents, e.g., substituents independently selected from Ci- C4 alkyl, Ci-C4haloalkyl, C1-C4 alkoxy, halo, hydroxy, and the like.

[0112] In some embodiments, L comprises any combination of -CH2-, -C(O)-, and heterocyclylene moieties, wherein the heterocyclylene is a 4- to 6-membered monocyclic heterocyclylene having 1 or 2 nitrogen atoms.

[0113] In some embodiments, L comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 non-hydrogen atoms. Non-hydrogen atoms include, e.g., C, N, O, S, B, etc. For example, the group -CH2CH2O- includes 3 non-hydrogen atoms, and the group -NH-(CH2)4-NH- includes 6 non-hydrogen atoms. The group L will, of course, include sufficient hydrogen atoms to complete the valence of each non-hydrogen atom. In some embodiments, L comprises 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2- 9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5- 6, 6-9, 6-8, 6-7, 7-9, 7-8, or 8-9 non-hydrogen atoms. In some embodiments, -X^L-X2- is selected from:

[0114] In some embodiments, the compound is selected from:

[0115] and pharmaceutically acceptable salts thereof. 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 IUPAC 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 stalling 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: (1) 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 Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Eongman Scientific & Technical, Essex CM202JE, England; (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns; or (3) fractional recrystallization methods.

[0116] 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.

[0117] 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 to2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, 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 positron-emitting isotopes that can be incorporated in compounds of formula (I) arenC,13N,15O, and18F. 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-labclcd reagent in place of non-isotopically-labclcd reagent.

[0118] 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 Salts

[0119] 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 amino 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, digluconate, glycerophosphate, hemisulfate, 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.

[0120] 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

[0121] 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.

[0122] The compounds and intermediates may be isolated and purified by methods well-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 Fumiss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0123] 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. 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 (4thed.), John Wiley & Sons, NY (2006).

[0124] 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).

[0125] 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.

[0126] 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.

[0127] Pharmaceutical Compositions

[0128] 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 “prophylactic ally 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.

[0129] The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable earner,” as used herein, means a non-toxic, inert solid, semisolid 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, com 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.

[0130] 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.

[0131] 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). 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.

[0132] 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.

[0133] 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.

[0134] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as com starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50% by weight of the composition.

[0135] Suitable disintegrants 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.

[0136] 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.

[0137] 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%.

[0138] 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 composition. Suitable antioxidants include butylated hydroxy anisole (“BHA”), butylated hydroxytolucnc (“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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] Suitable suspending agents include AVICEL RC-591 (from FMC 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.

[0143] 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.

[0144] 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.

[0145] 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 carriers, and more particularly, from about 50% to about 75% by weight.

[0146] 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, disintegrants, 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 disintegrants 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.

[0147] 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 type.

[0148] 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.

[0149] Solid compositions may be coated by conventional methods, typically with pH or timedependent 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.

[0150] 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.

[0151] 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.

[0152] 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 (I)), 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.

[0153] 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).

[0154] 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. The carrier 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.

[0155] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1,3-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 typically about 5% to about 95% by weight of the composition.

[0156] 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 typically about 0% to about 95% by weight of the composition.

[0157] 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.

[0158] 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.

[0159] The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

[0160] Suitable powders include beta-cyclodextrins, 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.

[0161] 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.

[0162] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0163] Methods of Use

[0164] The disclosed compounds and pharmaceutical compositions may be used in methods for treatment of disorders, such as a disorder characterized or mediated by HELLS. In some embodiments, the disclosed compounds and pharmaceutical compositions are useful in methods of treating proliferative disorders such as cancers. In some embodiments, the cancer is characterized or mediated by the activity of HELLS. In some embodiments, the cancer is a cancer in which HELLS is highly expressed, or is overexpressed relative to non-cancerous cells. For example, significant increases in HELLS expression has been noted in several different types of cancers, including bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, colon cancer, esophageal cancer, acute myeloid leukemia, liver cancer, lung cancer, pancreatic cancer, rectal cancer, stomach cancer, and uterine cancer (see, e.g., Liang el al. Front. Immunol. 2022, 13:870726).

[0165] 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 HELLS, 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 ability to infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.

[0166] 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 myofibroblastic 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.

[0167] Exemplary 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.

[0168] Exemplary hematologic malignancies include, but are not limited to, leukemias, lymphomas, myelomas, non-Hodgkin’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-ccll lymphoma, cutaneous T-ccll lymphoma, cntcropathy-typc T-ccll 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 (CLL), small lymphocytic lymphoma (SLL), high risk CLL, and a non-CLL / SLL lymphoma. In some embodiments, the cancer is selected from B cell prolymphocytic 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.

[0169] In some embodiments, the cancer is selected from acute myeloid leukemia, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, liver cancer, lung cancer (e.g., non-small cell lung cancer), nasopharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, retinoblastoma, stomach cancer, and uterine cancer.

[0170] In some embodiments, the cancer is a relapsed or refractory cancer, such as a cancer described herein. In some embodiments, the cancer is a metastasized cancer, such as a cancer described herein.

[0171] 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, intraspinal, intracapsular, 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.

[0172] 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.

[0173] 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 mg per kilogram body weight of the subject per day.

[0174] 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.

[0175] 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 in 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.

[0176] 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.

[0177] 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 thermo therapy. 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.

[0178] In some embodiments, a 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.

[0179] In particular’ embodiments, a compound described herein is administered with at least one PARP inhibitor. Previous genome-wide CRISPR / Cas9 screens identified HELLS as a mediator of sensitivity to FDA-approved PARP inhibitors (PARPi), suggesting that targeting HELLS may be a way to overcome intrinsic or acquired resistance to PARPi. As shown herein, pharmacological degradation of HELLS synergizes with the PARPi olaparib in in vitro cancer cell models. Accordingly, in some embodiments, a compound disclosed herein is administered in combination with at least one PARP inhibitor, such as olaparib, niraparib, or rucaparib.

[0180] Also disclosed herein are methods of reducing proliferation of cancer cells in a sample, comprising contacting the sample with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein.

[0181] Kits

[0182] 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 like, 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 pharmaceu tic ally acceptable salt thereof. Kits or pharmaceutical systems may also include printed instructions for using the compounds and / or compositions.

[0183] The following examples further illustrate aspects of the disclosure, but should not be construed as in any way limiting its scope. EXAMPLES

[0184] The following abbreviations are used in the Examples: DCM is dichloromethane; DIPEA is N,N, -diisopropylethylamine; eq is equivalents; EhN is triethylamine; EtOH is ethanol; HPLC is high-performance liquid chromatography; LC-MS is liquid chromatography-mass spectrometry; and n-BuOH is n-butanol.

[0185] Example 1: Compound Syntheses

[0186] 4-((2-((2-chloropyrimidin-4-yl)amino)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione (S3) and 4-((2-(( 4-chloropyrimidin-2-yl )amino)ethyl )amino)-2-( 2,6-dioxopiperidin-3 - yl)isoindoline-l ,3-dione (S4)

[0187] To a mixture of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3- dione (SI) (630 mg, 1.0 eq), and DIPEA (770 mg, 3.0 eq) in EtOH (10 mL) was added 2,4- dichloropyrimidine (296 mg, 1.0 eq). The mixture was stirred at 50 °C for 2 hours. The solution was concentrated and purified via silica gel flash chromatography to afford major product 4-((2- ((2-chloropyrimidin-4-yl)amino)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione S3 (510 mg, 62%) as yellow solid LC-MS (ESI) m / z: 429 |M+H]+. And minor product 4-((2-((4- chloropyrimidin-2-yl)amino)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (S4) (94 mg, 11%) as yellow solid LC-MS (ESI) m / z: 429 [M+H]+. To a mixture of S3 (10 mg, 1 .0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (10 mL) was added l-(3-(trifluoromcthyl)phcnyl)pipcrazinc S5 (5 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 1 (7 mg) as white solid. LC-MS (ESI) m / z: 623 [M+H]+.

[0188] 4-(2-((2-chloropyrimidin-4-yl)amino)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (S7) and 4-( 2-(( 4-chloropyrimidin-2-yl )amino)ethoxy)-2-( 2, 6-dioxopiperidin-3-yl )isoindoline- 1, 3-dione (S8)

[0189] To a mixture of 4-(2-aminoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (S6) (94 mg, 1.0 eq), and DIPEA (116 mg, 3.0 eq) in EtOH (3 mL) was added 2,4-dichloropyrimidine (45 mg, 1.0 eq). The mixture was stirred at 50 °C for 2 hours. The solution was concentrated and purified via silica gel flash chromatography to afford major product 4-(2-((2-chloropyrimidin-4- yl)amino)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (S7) (80 mg) as white solid LC-MS (ESI) m / z: 430 [M+H]+, and minor product 4-(2-((4-chloropyrimidin-2- yl)amino)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (S8) (10 mg) as white solid LC-MS (ESI) m / z: 430 [M+H]+.

[0190] To a mixture of S7 (40 mg, 1.0 eq), and DIPEA (36 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifhroromethyl)phenyl)piperazine S5 (21 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 2 (24 mg) as white solid. LC-MS (ESI) m / z: 624 [M+H]+. compound 3

[0191] To a mixture of S8 (20 mg, 1.0 eq), and DIPEA (18 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifluoromethyl)phenyl)piperazine S5 (11 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 3 (10 mg) as white solid. LC-MS (ESI) m / z: 624 [M+H]+. To a mixture of S3 (10 mg, 1.0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (10 mL) was added l-(3,5-bis(trifluoromethyl)phenyl)piperazine S9 (7 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 4 (8 mg) as white solid. LC-MS (ESI) m / z: 691 [M+H]+.

[0192] To a mixture of S3 (10 mg, 1.0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (10 mL) was added l-(4-chloro-3-(trifluoromethyl)phenyl)piperazine S10 (7 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 5 (10 mg) as white solid. LC-MS (ESI) m / z: 657 [M+H]+.

[0193] 2-(2,6-dioxopiperidin-3-yl)-4-((2-((6-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)pyrimidin-4- yl)amino)ethyl)amino)isoindoline- 1,3 -dione (Compound 6)

[0194] Step 1: To a mixture of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1, 3-dione (SI) (20 mg, 1.0 eq), and DIPEA (33 mg, 3.0 eq) in EtOH (2 mL) was added 4,6- dichloro-l,3-diazine (10 mg, 1.0 eq). The mixture was stirred at room temperature for 2 hours. The solution was concentrated to give S12 which was used in the next step without further purification.LC-MS (ESI) m / z: 429 [M+H]+.

[0195] Step 2: To a mixture of S12 and DIPEA (10 mg, 3.0 eq) in n-BuOH (1 mL) was added 1- (3-(trifluoromethyl)phenyl)piperazine (7 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 6 (6 mg) as white solid. LC-MS (ESI) m / z: 623 [M+H]+.

[0196] To a mixture of S3 (10 mg, 1.0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-methoxyphenyl)piperazine S13 (7 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 7 (10 mg) as white solid. LC-MS (ESI) m / z: 585 [M+H]+.

[0197] 4-((2-((2-chloropyrimidin-4-yl)amino)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione ( Compound 8 )

[0198] To a mixture of S3 (10 mg, 1 .0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(2-(trifluoromcthyl)phcnyl)pipcrazinc S15 (7 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 8 (9 mg) as white solid. LC-MS (ESI) m / z: 622 [M+H]+. To a mixture of S3 (14 mg, 1 .0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-bromophcnyl)pipcrazinc S16 (7 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 9 (12 mg) as white solid. LC-MS (ESI) m / z: 633 [M+H]+.

[0199] To a mixture of S3 (14 mg, 1.0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3,4-dichlorophenyl)piperazine S17 (8 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 10 (7 mg) as white solid. LC-MS (ESI) m / z: 623 [M+HJ+.

[0200] To a mixture of S3 (12 mg, E0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(4-(trifhioromethyl)phenyl)piperazine S18 (8 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 11 (10 mg) as white solid. LC-MS (ESI) m / z: 623 [M+H]+. 2-(2,6-dioxopiperidin-3-yl)-4-(2-((4-(4-(4-(trifluoromethyl)phenyl)piperazin-l -yl)-l ,3,5-triazin-

[0201] 2-yl)amino)ethoxy)isoindoline-l, 3-dione ( Compound 12)

[0202] Step 1: To a mixture of 4-(2-aminoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3- dione (S6) (30 mg, 1.0 eq), and DIPEA (37 mg, 3.0 eq) in dioxane (2 mL) was added 2,4- dichloro-l,3,5-triazine (14 mg, 1.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The solution was concentrated and gave crude S20 which was used in the next step without further purification. LC-MS (ESI) m / z: 431 [M+H]+.

[0203] Step2: To a mixture of S20 and DIPEA (27 mg, 3.0 eq) in n-BuOH (2 mL) was added 1- (4-(trifluoromcthyl)phcnyl)pipcrazinc S19 (8 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 12 (24 mg) as white solid. LC-MS (ESI) m / z: 625 [M+H]+.

[0204] To a mixture of S8 (6 mg, 1.0 eq), and DIPEA (5 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(4-(trifluoromethyl)phenyl)piperazine (4 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 13 (4 mg) as white solid. LC-MS (ESI) m / z: 624 [M+H]+.

[0205] To a mixture of S8 (6 mg, 1.0 eq), and DIPEA (5 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(4-chloro-3-(trifluoromethyl)phenyl)piperazine (4 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 14 (5 mg) as white solid. LC-MS (ESI) m / z: 658 [M+H]+.

[0206] To a mixture of S7 (10 mg, 1.0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-[5-(trifluoromethyl)pyridine-2-yl]piperazine (6 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 15 (9 mg) as white solid. LC-MS (ESI) m / z: 625 [M+H]+. To a mixture of S7 (10 mg, 1 .0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(2-fluoro-4-(trifluoromcthyl)phcnyl)pipcrazinc (6 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via preparative HPLC to afford Compound 16 (8 mg) as white solid. LC-MS (ESI) m / z: 642 [M+H]+.

[0207] 4-((2-((2-chloropyrimidin-4-yl)amino)ethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l ,3-dione (S22) and 4-((2-((4-chloropyrimidin-2-yl)amino)ethyl)(methyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (S23) To a mixture of 4-((2-aminoethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-

[0208] 1, 3-dione (S21) (180 mg, 1.0 eq), and DIPEA (211 mg, 3.0 eq) in EtOH (5 mL) was added 2,4- dichloropyrimidine (82 mg, 1.0 eq) at room temperature. The mixture was stirred at 50 °C for 2 hours. The solution was concentrated and purified by HPLC to give 4-((2-((2-chloropyrimidin-4- yl)amino)ethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (S22) (101 mg) (LC-MS (ESI) m / z: 443 [M+H]+) and 4-((2-((4-chloropyrimidin-2- yl)amino)ethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (S23) (14 mg) (LC-MS (ESI) m / z: 443 [M+H]+) as white solid.

[0209] 2-( 2,6-dioxopiperidin-3-yl)-4-( methyl(2-((4-(4-(4-( trifluoromethyl)phenyl)piperazin-l- yl)pyrimidin-2-yl)amino)ethyl)amino)isoindoline- 1,3 -dione (Compound 17)

[0210] To a mixture of give 4-((2-((4-chloropyrimidin-2-yl)amino)ethyl)(methyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline- 1,3-dione (S23) (10 mg, 1.0 eq) and DIPEA (10 mg, 3.0 eq) in n- BuOH (1 mL) was added l-(4-(trifluoromethyl)phenyl)piperazine S19 (10 mg, 2.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 17 (7 mg) as white solid. LC-MS (ESI) m / z: 637 [M+H]+.

[0211] To a mixture of give 4 (S22) (10 mg, 1.0 eq) and DIPEA (10 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(4-(trifluoromethyl)phenyl)piperazine S19 (10 mg, 2.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 18 (5 mg) as white solid. LC-MS (ESI) m / z: 637 [M+H]+. 4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l ,3-dione ( S25 ) and 4-( 3-(( 4-chloropyrimidin-2-yl)amino )propyl)-2-( 2, 6-dioxopiperidin-3-yl )isoindoline- 1, 3-dione (S26)

[0212] To a mixture of 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (190 mg, 1.0 eq), and DIPEA (234 mg, 3.0 eq) in EtOH (5 mL) was added 2,4-dichloropyrimidine (90 mg, 1.0 eq) at room temperature. The mixture was stirred at 50 °C for 2 hours. The solution was concentrated and purified by HPLC to give 4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline- 1,3-dione (S25) (132 mg) (LC-MS (ESI) m / z: 428 [M+H]+) and 4-(3-((4-chloropyrimidin-2-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (S26) (25 mg) (LC-MS (ESI) m / z: 428 [M+HJ+).

[0213] To a mixture of S25 (17 mg, 1.0 eq) and DIPEA (16 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine (10 mg, 2.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 19 (13 mg) as white solid. LC-MS (ESI) m / z: 640 [M+H]+.

[0214] To a mixture of S26 (16 mg, 1.0 eq) and DIPEA (16 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(4-chloro-3-(trifluoromethyl)phenyl)piperazine (10 mg, 2.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 20 (10 mg) as white solid. LC-MS (ESI) m / z: 656 [M+H]+.

[0215] 3-(4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (S28) and 3-(4-(3-((4-chloropyrimidin-2-yl)amino)propyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (S29)

[0216] To a mixture of 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (180 mg, 1.0 eq), and DIPEA (230 mg, 3.0 eq) in EtOH (5 mL) was added 2,4-dichloropyrimidine (89 mg, 1.0 eq) at room temperature. The mixture was stirred at 50 °C for 2 hours. The solution was concentrated and purified by HPLC to give 3-(4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (S28) (101 mg) (LC-MS (ESI) m / z: 414 [M+H]+) and 3- (4-(3-((4-chloropyrimidin-2-yl)amino)propyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (S29) (15 mg) (LC-MS (ESI) m / z: 414 [M+H]+). 3-(4-(3-((4-(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-l -yl)pyrimidin-2-yl)amino)propyl)- l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( Compound 21 )

[0217] To a mixture of S28 (14 mg, 1.0 eq) and DIPEA (18 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(4-chloro-3-(trifluoromethyl)phenyl)piperazine (11 mg, 2.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 21 (12 mg) as white solid. LC-MS (ESI) m / z: 642 [M+H]+.

[0218] 3-( 4-( (2-( (2-chloropyrimidin-4-yl )amino)ethyl )amino )-l -oxoisoindolin-2-yl )piperidine-2, 6-dione

[0219] (S31 ) and 3-(4-((2-((4-chloropyrimidin-2-yl)amino)ethyl)amino)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (S32 )

[0220] To a mixture of 3-(4-((2-aminoethyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione S30 (200 mg, 1.0 eq), and DIPEA (257 mg, 3.0 eq) in EtOH (10 mL) was added 2,4- dichloropyrimidine (100 mg, 1.0 eq) at room temperature. The mixture was stirred at 50 °C for 4 hours. The solution was concentrated and purified by HPLC to give 3-(4-((2-((2- chloropyrimidin-4-yl)amino)ethyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (S31) (221 mg) (LC-MS (ESI) m / z: 415 [M+H]+) and 3-(4-((2-((4-chloropyrimidin-2- yl)amino)ethyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (S32) (39 mg) (LC-MS (ESI) m / z: 415 [M+H]+).

[0221] To a mixture of S32 (13 mg, 1.0 eq) and DIPEA (12 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(4-chloro-3-(trifluoromethyl)phenyl)piperazine (10 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via preparative HPLC to afford Compound 22 (7 mg) as white solid. LC-MS (ESI) m / z: 643 [M+H]+. 'H NMR (500 MHz, DMSO) 8 12.61 (s, 1H), 11.01 (s, 1H), 8.39 (s, 1H), 7.90 (s, 1H), 7.53 (d, J= 8.9 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.23 (dd, J = 9.0, 3.0 Hz, 1 H), 6.98 (d, J = 7.3 Hz, 1 H), 6.89 (d, J = 8. 1 Hz, 1 H), 6.55 (d, 7 = 7.7 Hz, 1H), 5.11 (dd, 7= 13.3, 5.2 Hz, 1H), 4.27 (d, 7= 17.1 Hz, 1H), 4.13 (d, 7 = 17.2 Hz, 1H), 3.85 (d, 7= 39.7 Hz, 3H), 3.73 - 3.66 (m, 1H), 3.62 (d, 7= 5.9 Hz, 1H), 3.57 (s, 1H), 3.53 - 3.46 (m, 1H), 3.40 (t, 7= 5.9 Hz, 3H), 3.30 (s, 1H), 2.93 (ddd, 7= 17.3, 13.6, 5.4 Hz, 1H), 2.66 - 2.58 (m, 1H), 2.33 - 2.21 (m, 1H), 2.07 - 1.98 (m, 1H).13C NMR (126 MHz, DMSO) 5 173.35, 171.67, 169.22, 161.18, 153.57, 149.43, 143.48, 143.26, 132.71, 132.55, 129.73, 127.42, (q, J=30), 127.48, 123.50 (q,J= 273.4), 120.28, 119.46, 114.00, 112.51, 111.11, 94.84, 72.63, 70.99, 66.82, 60.64, 51.98, 46.36, 45.21, 44.09, 31.70, 23.34.

[0222] To a mixture of l-[4-chloro-3-(trifluoromethyl)phenyl]piperazine (150 mg, 1.0 eq) and

[0223] DIPEA (220 mg, 3.0 eq) in isopropanol (10 mL) was added 2-Chloro-pyrimidin-4-ylamine (74 mg, 1 .0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via flash column to give 2-(4-(4-chloro-3-(trifluoromcthyl)phcnyl)pipcrazin-l- yl)pyrimidin-4- amine (S33) (152 mg) as white solid. LC-MS (ESI) m / z: 358 [M+H]+.

[0224] 2-bromo-N -(2-(4-(4-chloro-3 -( trifluoromethyl )phenyl )piperazin-l-yl )pyrimidin-4-yl )acetamide (S34)

[0225] To a solution of S33 (107 mg, 1.0 eq) and EtaN (91 mg, 3.0 eq) in DCM (3 mL) was added 2-Bromoacetylbromide (121 mg, 2.0 eq) dropwise at 0 °C. The mixture was stirred at room temperature overnight. The mixture was concentrated and purified via HPLC to give 2-(4- (4-chloro-3-(trifluoromethyl)phenyl)piperazin-l-yl)pyrimidin-4-amine (S34) (77 mg) as white solid. LC-MS (ESI) m / z: 478 [M+H]+.

[0226] The mixture of 4-hydroxy-thalidomide (26 mg, 1.0 eq) and K2CO3 (9 mg, 1.0 eq) and DMF (1 mL) was stirred at room temperature for 20 mins and then S34 (16 mg, 1.0 eq) was added. The mixture was then stirred at 80 °C overnight. The solvent was removed and purified via HPLC to give N-(2-(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-l-yl)pyrimidin-4-yl)-2- ((2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-4-yl)oxy)acetamide (Compound 23) (6 mg).

[0227] LC-MS (ESI) m / z: 672 [M+H]+.

[0228] Synthesis of 3-(4-((2-( (2-chloropyrimidin-4-yl )amino )ethyl )amino)-l -oxoisoindolin-2- yl)piperidine-2, 6-dione (T2) and 3-(4-((2-((4-chloropyrimidin-2-yl)amino)ethyl)amino)-l- oxoisoindolin-2-yl)piperidine-2,6-dione (T3 )

[0229] To a mixture of 3-(4-((2-aminoethyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (Tl) (40 mg, 1.0 eq), and DIPEA (51 mg, 3.0 eq) in EtOH (2 mL) was added 2,4- dichloropyrimidine (20 mg, 1.0 eq). The mixture was stirred at 50 °C for 4 hours. The solution was concentrated and purified via silica gel flash chromatography to afford major product 3-(4- ((2-((2-chloropyrimidin-4-yl)amino)ethyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione T2 (32 mg, 58%) as yellow solid LC-MS (ESI) m / z: 415 [M+H]+. And minor product (T3) 3-(4-((2- ((4-chloropyrimidin-2-yl)amino)ethyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (6 mg, 10%) as yellow solid LC-MS (ESI) m / z: 415 [M+H]+.

[0230] To a mixture of T2 (15 mg, 1.0 eq), and DIPEA (14 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifhioromethyl)phenyl)piperazine S5 (9 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via prep HPLC to afford Compound 24 (17 mg) as white solid. LC-MS (ESI) m / z: 609 [M+H]+.

[0231] To a mixture of 3-(4-((4-aminobutyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (T4) (33 mg, 1.0 eq), and DIPEA (39 mg, 3.0 eq) in EtOH (2 mL) was added 2,4- dichloropyrimidine (15 mg, 1.0 eq). The mixture was stirred at 50 °C for 4 hours. The solution was concentrated and purified via silica gel flash chromatography to afford major product 3-(4- ((4-((2-chloropyrimidin-4-yl)amino)butyl)amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (T5) (26 mg) as white solid LC-MS (ESI) m / z: 443 [M+H]+. And minor product 4-((4-((4- chloropyrimidin-2-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (T6) (4 mg) as white solid LC-MS (ESI) m / z: 443 [M+H]+.

[0232] To a mixture of T5 (15 mg, 1.0 eq), and DIPEA (13 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifluoromethyl)phenyl)piperazine S5 (8 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via prep HPLC to afford Compound 25 (13 mg) as white solid. LC-MS (ESI) m / z: 637 [M+H]+. Synthesis of4-(3-( ( 2-chloropyrimidin-4-yl )amino )azetidin- 1 -yl)-2-( 2, 6-dioxopiperidin-3- yl)isoindoline-l ,3-dione (L2)

[0233] To a mixture of 4-(3-aminoazetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione (LI) (33 mg, 1.0 eq), and DIPEA (24 mg, 3.0 eq) in EtOH (2 mL) was added 2,4- dichloropyrimidine (10 mg, 1.0 eq). The mixture was stirred at 50 °C for 4 hours. The solution was concentrated and purified via silica gel flash chromatography to afford 4-(3-((2- chloropyrimidin-4-yl)amino)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (L2)

[0234] (17 mg) as white solid LC-MS (ESI) m / z: 441 [M+H]+.

[0235] To a mixture of L2 (10 mg, 1.0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifhioromethyl)phenyl)piperazine S5 (5 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via prep HPLC to afford Compound 26 (11 mg) as white solid. LC-MS (ESI) m / z: 635 [M+H]+. Synthesis of4-(3-( ( 2-chloropyrimidin-4-yl )amino )azetidin- 1 -yl)-2-( 2, 6-dioxopiperidin-3- yl )isoindoline-l ,3-dione (L4)

[0236] To a mixture of 4-(3-aminopyrrolidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione (L3) (20 mg, 1.0 eq), and DIPEA (23 mg, 3.0 eq) in EtOH (2 mL) was added 2,4- dichloropyrimidine (9 mg, 1.0 eq). The mixture was stirred at 50 °C for 4 hours. The solution was concentrated and purified via silica gel flash chromatography to afford 4-(3-((2- chloropyrimidin-4-yl)amino)pyrrolidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (L4) (27 mg) as white solid LC-MS (ESI) m / z: 455 [M+H]+.

[0237] To a mixture of L4 (10 mg, 1.0 eq), and DIPEA (9 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifluoromethyl)phenyl)piperazine S5 (5 mg, 1.0 eq). The mixture was stirred at 120 °C for 8 hours. The solution was concentrated and purified via prep HPLC to afford Compound 27 (8 mg) as white solid. LC-MS (ESI) m / z: 649 [M+H]+. Synthesis of 4-(((2-chloropyrimidin-4-yl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1, 3-dione (L6) To a mixture of 4-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione hydrochloride (L5) (71 mg, 1.0 eq), and DIPEA (85 mg, 3.0 eq) in EtOH (5 mL) was added 2,4- dichloropyrimidine (33 mg, 1.0 eq). The mixture was stirred at 50 °C for 4 hours. The solution was concentrated and purified via silica gel flash chromatography to give L6 (31 mg) as white solid LC-MS (ESI) m / z: 400 [M+H]+.

[0238] To a mixture of L6 (14 mg, 1.0 eq), and DIPEA (15 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifhioromethyl)phenyl)piperazine S5 (9 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via prep HPLC to afford Compound 28 (10 mg) as white solid. LC-MS (ESI) m / z: 594 [M+H]+. Synthesis of4-( 3-(( 2-chloropyrimidin-4-yl )amino )prop- 1 -yn- 1 -yl)-2 -( 2, 6-dioxopiperidin-3 - yl )isoindoline-l ,3-dione (L8)

[0239] To a mixture of 4-(3-aminoprop-l-yn-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione (L7) (50 mg, 1.0 eq), and DIPEA (62 mg, 3.0 eq) in EtOH (4 mL) was added 2,4- dichloropyrimidine (24 mg, 1.0 eq). The mixture was stirred at 50 °C for 4 hours. The solution was concentrated and purified via silica gel flash chromatography to L8 (35 mg) as white solid LC-MS (ESI) m / z: 424 [M+H]+.

[0240] To a mixture of L8 (10 mg, 1.0 eq), and DIPEA (19 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifhioromethyl)phenyl)piperazine S5 (11 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via prep HPLC to afford

[0241] Compound 29 (10 mg) as white solid. LC-MS (ESI) m / z: 618 [M+H]+.

[0242] To a mixture of 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (L9) (40 mg, 1.0 eq), and DIPEA (50 mg, 3.0 eq) in EtOH (3 mL) was added 2,4-dichloropyrimidine (19 mg, 1.0 eq). The mixture was stirred at 50 °C for 6 hours. The solution was concentrated and purified via silica gel flash chromatography to L10 (29 mg) as white solid LC-MS (ESI) m / z: 428 [M+H]+.

[0243] To a mixture of LIO (20 mg, 1.0 eq), and DIPEA (18 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifluoromethyl)phenyl)piperazine S5 (11 mg, 1.0 eq). The mixture was stirred at 120 °C overnight. The solution was concentrated and purified via prep HPLC to afford Compound 30 (10 mg) as white solid. LC-MS (ESI) m / z: 622 [M+H]+.

[0244] Synthesis of2-( 2, 6-dioxopiperidin-3-yl)-4-( 6-((2-(4-(3-( trifluoromethyl )phenyl)piperazin-l - yl)pyrimidin-4-yl)amino)hex-l-yn-l-yl)isoindoline- 1,3 -dione (Compound 31)

[0245] Step 1: Synthesis of tert-butyl (6-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)hex-5-yn-l-yl)carbamate

[0246] Cui (50 mg, 0.25 mmol) and Pd(Ph3P)2Ch (90 mg, 0.13 mmol) were added to a solution of tert-butyl hex-5-yn-l -ylcarbamate (256 mg, 1.30 mmol) and 4-bromo-2-(2,6-dioxopiperidin- 3-yl)isoindoline- 1,3-dione (400 mg, 1.30 mmol) in EhN (394mg, 3.9 mmol) and DMF 5 mb. The mixture was stirred at 80 °C under an N2 atmosphere overnight. The reaction mixture was poured into a saturated aqueous solution of NH4CI and after separation of the organic layer the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography to afford tert-butyl (6-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)hex-5-yn-l-yl)carbamate (312mg, 53%) as off white solid. LC-MS (ESI) m / z: 454 [M+H]+.

[0247] Step 2: Synthesis of 4-(6-aminohex-l-yn-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1, 3-dione

[0248] Tert-butyl (6-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hex-5-yn-l- yl)carbamate (312 mg) was dissolved in DCM (10 mL) and then added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed under pressure and the crude was used in the next step without further purification. LC-MS (ESI) m / z: 354 [M+H]+.

[0249] Step 3: Synthesis of 4-(6-((2-chloropyrimidin-4-yl)amino)hex-l-yn-l-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline- 1 ,3-dione (Lil)

[0250] To a mixture of 4-(6-aminohex-l-yn-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3- dione (35mg, 1 .0 eq), and DIPEA (45mg, 3.0 eq) in EtOH (2 mL) was added 2,4- dichloropyrimidinc (15 mg, 1.0 eq) . The mixture was stirred at 50° C for 4 hours. The solution was concentrated and purified via silica gel flash chromatography to afford product Li l (28 mg, 60%) as yellow solid LC-MS (ESI) m / z: 466 [M+H]+.

[0251] Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(6-((2-(4-(3-

[0252] (trifluoromethyl)phenyl)piperazin- 1 -yl)pyrimidin-4-yl)amino)hex- 1 -yn- 1 -yl)isoindoline- 1,3- dione (Compound 31)

[0253] To a mixture of Lil (20 mg, 1.0 eq), and DIPEA (14 mg, 3.0 eq) in n-BuOH (1 mL) was added l-(3-(trifhioromethyl)phenyl)piperazine S5 (10 mg, 1.0 eq) . The mixture was stirred at 120 C for 8 hours. The solution was concentrated and purified via prep HPLC to afford Compound 31 (15 mg) as white solid. LC-MS (ESI) m / z: 660 [M+H]+. Example 2: Biological Data

[0254] Western blots and antibodies. M0LT4 cells were treated with 1 p M compound for 5 hours, collected and washed in PBS, then lysed in M-PER buffer (Thermo Scientific) containing protease / phosphatase inhibitor cocktail (Roche). BCA assays (Pierce) were used to quantify protein concentrations, and equivalent amounts of protein were loaded on 4-12% Bis-Tris gels (Invitrogen), transferred to nitrocellulose membranes (BioRad), and immunoblotted with antibodies against HELLS, GSPT1, 1KZF1, and Actin (Cell Signaling). lRDye®800-labeled goat anti-rabbit IgG and IRDye®680-labeled goat anti-mouse IgG (LI-COR) secondary antibodies were used and detected on an Odyssey CLXsystem. Representative Western blots are shown in FIGS. 1 A-1C. Modifications of linker length and both CRBN- and HELLS -recruiting ligands resulted in the development of highly potent and selective HELLS degraders.

[0255] NanoLuc-HELLS. Human HELLS (NM_001289067,2) was cloned into the pNLFl-N vector (Promega) to generate N-terminal NanoLuc® luciferase (NLuc)-HELLS fusion protein and then stably expressed in M0LT4 cells. To assess the degradation potency of compounds, 1000-5000 cells were plated into 384-well plates and the indicated compounds were dispensed using the D300e Digital Dispenser (Tecan). DC 50 and Dmaxvalues were calculated using Graphpad PRISM software (v.10). DC50 and Dmax values were calculated using Graphpad PRISM software (v.10). Data is shown in FIG. 2 and Table 1.

[0256] Table 1. DC50 and Dmax values

[0257] Proliferation. Equivalent numbers of NCI-H82 cells were plated and treated with Compound 22 (1 μM) and olaparib (1 μM), either alone or in combination. Cell counts were quantified twice weekly using the Countess Automated Cell Counter (ThermoFisher Scientific), with dead cells excluded using Trypan Blue staining. Data are shown in FIG. 3. HELLS degradation on its own had minimal effect on proliferation, consistent with DepMap results. While olaparib treatment alone partially inhibited proliferation, co-treatment with Compound 22 and olaparib strongly blocked proliferation, indicating that HELLS degradation further sensitized NCI-H82 cells to PARP inhibition.

[0258] Cell cycle analysis. NCI-H82 cells were treated with Compound 22 (1 μM) and olaparib (1 μM), either alone or in combination, and fixed for at least 24h in 70% EtOH / PBS. Subsequently, fixed cells were stained with 25 pg / ml propidium iodide (Life Technologies) with 200 pg / ml RNaseA (Life Technologies) in 0.1% TritonX-100 / PBS for 24h. DNA content was quantified by flow cytometry on a LSRFortessa flow cytometer (BD Biosciences) and data was analyzed using FlowJo (v. 10.9). Data are shown in FIG. 4. Combination treatment of Compound 22and olaparib resulted in increased levels of subGO cells, suggesting that co-treatment induced elevated levels of cell death.

[0259] Mechanism of action. To verify the mechanism of action, wildtype or CRBN-Z- MOLT4 cells were treated with Compound 22 for 5h. As shown in FIG. 5, Compound 22 induced HELLS degradation in wildtype but not CRBN- / - MOLT4 cells, indicating that CRBN was necessary for this effect.

[0260] Example 3: Additional Biological Data

[0261] Western blots and antibodies. NC1-H82, NC1-H69, NCLH526, 22RV1 or PC3 cells were treated with Compound 22 (1 μM) for 5 hours, collected and washed in PBS, then lysed in M- PER buffer (Thermo Scientific) containing protease / phosphatase inhibitor cocktail (Roche). BCA assays (Pierce) were used to quantify protein concentrations, and equivalent amounts of protein were loaded on 4-12% Bis-Tris gels (Invitrogen), transferred to nitrocellulose membranes (BioRad), and immunoblotted with antibodies against HELLS and Actin (Cell Signaling). IRDye®800-labeled goat anti-rabbit IgG and IRDye®680-labeled goat anti-mouse IgG (LL COR) secondary antibodies were used and detected on an Odyssey CLXsystem. Representative Western blots from small cell lung cancer (SCLC) cell lines are shown in FIG. 6, and representative Western blots from prostate cancer cell lines are shown in FIG. 7. Compound 22 induced HELLS degradation in SCLC cell lines NCI-H82, NCI-H69 and NCI-H526 as well as prostate cancer lines 22RV1 and PC3.

[0262] Proliferation. Equivalent numbers of SCLC cell lines NCLH82, NCLH69, and NCL H526 or prostate cancer lines 22RV1, and PC3 cells were plated and treated with Compound 22 (1 μM) and olaparib (1 μM), either alone or in combination. Cell counts were quantified twice weekly using the Countess Automated Cell Counter (ThermoFisher Scientific), with dead cells excluded using Trypan Blue staining. Cell counts over time for NCI-H82, NCI-H69, and NCI- H526 cells treated with Compound 22 (1 μM) and / or olaparib (1 μM) arc shown in FIG. 8. Cell counts over time of NCI-H82 cells treated with Compound 22 (1 μM) and / or niraparib (lOOnM) are shown in FIG. 9. Cell counts over time for PC3 and 22RV1 cells treated with Compound 22 (1 μM) and / or olaparib (1 μM) are shown in FIG. 10. [In all proliferation data, Compound 22 alone had minimal effects while Olaparib alone had modest anti-proliferative effects. However, Compound 22 co-treatment strongly enhanced the anti-proliferative effects of Olaparib or niraparib.

[0263] NanoBRET assay. Full-length CRBN was cloned into pHTN HaloTag® CMV-neo Vector (Promega) and full-length HELLS was cloned into pNLFl NanoLuc® Protein Fusion Vectors (Promega). 0.08ug of NanoLuc -tagged HELLS (N-terminus) and 8ug of HaloTag-tagged CRBN (N-terminus) were transfected into HEK293 CRBN- / - cells in 6-well plates using Lipofectamine™ 3000 Transfection Reagent (Invitrogen). The cells were incubated in a 37 °C incubator with 5% CO2 for 2 days. The following day, 5000 transfected cells were re-plated into white 384- well tissue culture plates in the presence or absence of HaloTag NanoBRET 618 Ligand (Promega) and lOOnM cafilzomib and incubated at 37C for Ihr. The cells were then dosed with the indicated concentration of Compound 22 or DMSO as control and then incubated for 5hrs. Dual-filtered luminescence was collected with a 460 / 80 nm bandpass filter and a 610 nm long pass filter using an integration time of 0.5 s. Background-subtracted NanoBRET ratios expressed in milliBRET units were calculated by multiplying NanoBRET ratios by 1000, and fold increase in BRET was calculated by normalizing mBRET ratios to the average mBRET ratios for DMSO controls. A graph showing BRET ratios is shown in FIG. 11. Compound 22 induces formation of a CRBN:degrader:HELLS complex in the NanoBRET™ ternary complex assay.

[0264] AT Pas e Assay. Fork DNA structure was generated by annealing oligo 1 (5’- CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3’, SEQ ID NO: 1) with oligo 2 (5’ GACATTTCATACCGAGCAACAATTCACTGG-3’, SEQ ID NO: 2) and incubated at 95 °C for 2 min, followed by incubation for 10 min each at 65 °C, 37 °C, 25 °C, and 4 °C (protocol adapted from Ghosal et al. EMBO Rep. 2011, 12(6): 574-580). Reaction mixtures (20 pL) contained 20 mM Tris-HCl (pH 8.0), 50 mM NaCl, 5 mM MgCl2, 0.2 mg / mL BSA, 0.1 mM DTT, 0.1 mM EDTA, and the indicated concentration of DNA, ATP and HELLS protein. The ATPase activity of HELLS protein was then measured using the ADP-Glo Kinase Assay (Promcga). Data arc shown in FIG. 12, which confirm, the protein activity of recombinant HELLS, and show that binding of Compound 22 to HELLS protein does not affect its ATPase activity

[0265] Isothermal Titration Calorimetry (ITC)'. ITC experiments were carried out through the Protein Analysis Core at SBP on an Affinity ITC Instrument (Waters TA Instruments), using NanoAnalyze software (TA instruments) in buffer containing 50 mM HEPES, 600 mM NaCl, 1 mM TCEP, 5% (v / v) DMSO at 298 K stirring the sample at 200 rpm. The ITC titration consisted of a 5 pL initial injection (discarded during data analysis) followed by 19 x6 pL injections with 150 s spacing between injections. Compound 22 (150 pM) was directly titrated into HELLS protein (43.2 pM). For a control titration, 150 pM Compound 22 was titrated into buffer. The data was fitted using an independent sites binding model to obtain dissociation constant (Kd), binding enthalpy (AH), and entropy (-TDS). N (stoichiometry) value was fixed to 1. Data are shown in Table 2.

[0266] Table 2. ITC Data with HELLS

[0267] 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.

Claims

CLAIMS:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein:Z is -C(O)- or -CH2-;X1is selected from -O-, -NRy-, -(CH2)m-, -C=C-, and a bond, wherein m is 1, 2, 3, or 4, and Ryis selected from hydrogen and C1-C6 alkyl;L is a direct bond or a linker;X2is selected from -O-, -NRZ-, -(CH2)U-, -C=C-, heterocyclyl, and a bond, wherein n is 1, 2, 3, or 4, and Rzis selected from hydrogen and C1-C6 alkyl;Q1, Q2, Q3, and Q4are each independently selected from CH and N wherein at least two of Q2, Q3, and Q4are N;R1and R2are each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ca-Cs cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORa, -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 -NRaC(O)ORb;R3is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORC, -SRC, -N(Rc)(Rd), -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -S(O)RC, -S(O)2RC, -NRcS(O)2Rd, - NRcC(O)Rd, and -NRcC(O)ORd; andRa, Rb, Rc, and Rdare each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ca-Cs cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl.

1. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1and R2arc each independently selected from hydrogen, halo, C1-C6 haloalkyl, and -ORa, wherein Rais hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, and methoxy.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Q1is CH.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Q1is N.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof,7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Q2and Q4are N, and Q3is CH.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Q2is CH, and Q3and Q4are N.

9. The compound of any one of claims 1 -6, or a pharmaceutically acceptable salt thereof, wherein Q2, Q3, and Q4arc N.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R3is H.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)-.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Z is -CH2-.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein:X1is selected from -O-, -NRy-, -C=C-, and a bond, wherein Ryis selected from hydrogen and methyl; andX2is selected from -O-, -NRZ-, -C=C-, and a bond, wherein Rzis selected from hydrogen and methyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein:X1is -NRy-, wherein Ryis selected from hydrogen and methyl; andX2is selected from -O-, -NRZ-, -C=C-, and a bond, wherein Rzis hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L is a direct bond.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein L is a linker.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein L comprises a moiety selected from -CH2-, -CH=CH-, -C=C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, or any combination thereof, wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, amino, aryl, cyano, C3-C6 cycloalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, heteroaryl, heterocyclyl, hydroxy, oxo, and nitro; and R' is selected from hydrogen and C1-C6 alkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein L comprises a moiety selected from -CH2-, -C(O)-, arylene, and heterocyclylene moieties, or any combination thereof.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein L comprises a moiety selected from -CH2-, -C(O)-, and heterocyclylene moieties, or any combination thereof, wherein the heterocyclylene is a 4- to 6-membered monocyclic heterocyclylene having 1 or 2 nitrogen atoms.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein -X’-L-X2- is selected from:

21. The compound of claim 1, wherein the compound is selected from:and pharmaceutically acceptable salts thereof.Tl. A pharmaceutical composition comprising a compound of any one of claims 1 -21 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the proliferative disease is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy.

25. The method of claim 24, wherein the cancer is selected from acute myeloid leukemia, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, liver cancer, lung cancer, nasopharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, retinoblastoma, stomach cancer, and uterine cancer.

26. The method of any one of claims 23-25, further comprising administering to the subject a therapeutically effective amount of a PARP inhibitor.

27. The method of claim 27, wherein the PARP inhibitor is selected from olaparib, niraparib, and rucaparib.

28. A compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, for use as a medicament.

29. A compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disease.

30. The compound of claim 29, wherein the proliferative disease is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy.31 . The compound of claim 30, wherein the cancer is selected from acute myeloid leukemia, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, liver cancer, lung cancer, nasopharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, retinoblastoma, stomach cancer, and uterine cancer.

32. A kit comprising a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof.

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