CRBN molecular GLUE degraders and uses thereof

Abstract

Disclosed herein are compounds that can degrade proteins having an active role in cancer progression, including CK1α (a negative regulator of the canonical Wnt pathway) and WEE1 (a G2 / M checkpoint kinase). 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] CRBN MOLECULAR GLUE 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. 63 / 609,958, filed on December 14, 2023, which is incorporated herein by reference in its entirety.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0005] This invention was made with Government support under contract CA214608 awarded by the National Institutes of Health. The Government has certain rights in the invention.

[0006] TECHNICAL FIELD

[0007] Disclosed herein are compounds that can degrade proteins having an active role in cancer progression, including CKlα (a negative regulator of the canonical Wnt pathway) and WEE1 (a G2 / M checkpoint kinase). 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.

[0008] BACKGROUND

[0009] Casein kinase 1 α (CKl α) is multifunctional protein in the CK1 family of proteins with broad scrinc / thrconinc protein kinase activity. It is a main component of the Wnt / β-catcnin signaling pathway, and regulates various signaling pathways involved in autoimmune diseases, neurodegenerative diseases, and cancer.

[0010] WEE1 kinase is an important component of the G2 / M cell cycle checkpoint, which prevents entry into mitosis in response to cellular DNA damage. Before mitosis, CDK1 is maintained in an inactive state by WEE1 through phosphorylation of CDK1 at Tyr-15, and then CDK1 is phosphorylated at Thr-14 by myelin transcription factor (MYT1). WEE1 acts as a negative regulator of entry into mitosis at the G2 / M transition by protecting the nucleus from cyclin B complexed with CDK1 activated in the cytoplasm. A WEE1 inhibitor, AZD1775, has advanced to clinical trials in several cancer types.

[0011] SUMMARY

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

[0013] A is a five- or six-membered heteroaromatic ring;

[0014] R1is selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)m- X, and hydrogen, wherein m is 0, 1, 2, or 3, and X is selected from -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, - NRaC(O)ORb, and -Si(C1-C6alkyl)3; n is 0, 1, 2, or 3; each R2is independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two R2are optionally taken together with the atoms to which they are attached to form a five- or six-membered ring that is optionally substituted with 1-3 Rc;

[0015] R3is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl- C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, - ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Re), -S(O)Rd, -S(O)2Rd, -NRdS(O)2Re, - NRdC(O)Re, and -NRdC(O)ORe;

[0016] X is -C(O)- or -CH2-;

[0017] Raand Rbare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Raand Rb, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; each Rcis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two Rcare optionally taken together with the atoms to which they are attached to form a 5- to 6-membered ring that is optionally substituted with 1-3 Rf;

[0018] Rdand Reare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Rdand Re, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-mcmbcrcd ring; and each Rfis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein each cycloalkyl, aryl, heteroaryl, heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, halo, cyano, nitro, and aryl.

[0019] In some embodiments:

[0020] A is a five- or six-membered heteroaromatic ring;

[0021] R1is selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)m- X, and hydrogen, wherein m is 1, 2, or 3, and X is selected from -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, - NRaC(O)ORb, and -Si(C1-C6alkyl)3; n is 0, 1, 2, or 3; each R2is independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two R2are optionally taken together with the atoms to which they are attached to form a five- or six-membered ring that is optionally substituted with 1-3 Rc;

[0022] R3is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Re), -S(O)Rd, -S(O)2Rd, -NRdS(O)2Re, - NRdC(O)Re, and -NRdC(O)ORe;

[0023] X is -C(O)- or -CH2-;

[0024] Raand Rbare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Raand Rb, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; each Rcis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two Rcare optionally taken together with the atoms to which they are attached to form a 5- to 6-membered ring that is optionally substituted with 1-3 Rf; Rdand Reare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, hctcroaryl, and heterocyclyl; wherein Rdand Re, together with the atom(s) to which they are attached, arc taken together to form a 5- or 6-membered ring; and each Rfis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein each cycloalkyl, aryl, heteroaryl, heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl.

[0025] In some embodiments, A is a 5- or 6-membered heteroaromatic ring having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from N, S, and O.

[0026] In some embodiments, n is 0. In some embodiments, n is 1, 2, or 3, and each R2is independently selected from C1-C4alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, cyano, nitro, and phenyl. In some embodiments, each R2is independently selected from methyl, isopropyl, trifluoromethyl, methoxy, fluoro, bromo, cyano, nitro, and phenyl. In some embodiments, n is 2, and the two R2are taken together with the atoms to which they are attached to form an unsubstituted five- or six-membered aromatic, heteroaromatic, or heterocyclic ring. In some embodiments, n is 2, and the two R2are taken together with the atoms to which they are attached to form a six-membered aromatic ring that is unsubstituted or substituted with one substituent selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and halo.

[0027] In some embodiments, the group

[0028]

[0029] In some embodiments, the group

[0030] In some embodiments, the group

[0031]

[0032] In some embodiments, R1is selected from C3-C8alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl-Ci-Ca-alkyl, heteroaryl-C1-C2-alkyl, heterocyclyl-C1-C2-alkyl, and -(CH2)m-X, wherein m is 0 or 1, and X is selected from -ORa, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)(Rb), and -Si(Ci-C4 alkyl)a. In some embodiments, R1is selected from C3-C8alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl-Ci-C?-alkyl, heteroaryl -C1-C2-alkyl, heterocyclyl-C1-C2-alkyl, and -(CH2)m-X, wherein m is 1, and X is selected from -ORa, - C(O)ORa, -C(O)N(Ra)(Rb), and -Si(Ci-C4 alkyl)3. In some embodiments, R1is selected from C3- Ck alkyl, C3-C10 cycloalkyl, phenyl, naphthyl, quinoxalinyl, 1,3-benzodioxolyl, 1,3- benzodioxinyl, phenyl-C1-C2-alkyl, diphenyl-C1-C2-alkyl, pyridinyl-C1-C2- alkyl, morpholino-Ci- Ca-alkyl, and -(CH2)m-X; wherein: m is 0 or 1, X is selected from -ORa, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)(Rb), and -Si(C1-C4alkyl)3; Rais selected from hydrogen, C1-C4alkyl, C4-C7 cycloalkyl, aryl, and aryl-Ci-Ca-alkyl; and Rbis selected from hydrogen and C1-C4alkyl; or Raand Rb, together with the nitrogen atom to which they arc attached, arc taken together to form a five- or six-membered ring. In some embodiments, R1is selected from C3-C8alkyl, C3-C10cycloalkyl, phenyl, naphthyl, quinoxalinyl, 1,3-benzodioxolyl, 1,3-benzodioxinyl, phenyl-C1-C2- alkyl, diphenyl-C1-C2-alkyl, pyridinyl-C1-C2-alkyl, morpholino-C1-C2-alkyl, and -(CH2)m-X; wherein: m is 1, X is selected from -ORa, -C(O)ORa, -C(O)N(Ra)(Rb), and -Si(C1-C4alkyl)3; and Raand Rbare each independently selected from hydrogen and C1-C4alkyl, or Raand Rb, together with the nitrogen atom to which they are attached, are taken together to form a five- or sixmembered ring. In some embodiments, R1is selected from:

[0033] In some embodiments, X is -C(O)-. In some embodiments, X is -CH2-.

[0034] In some embodiments, R3is hydrogen.

[0035] In some embodiments, the compound is selected from compounds listed in Table 1, and pharmaceutically acceptable salts thereof.

[0036] Also disclosed herein are compounds of formula: and pharmaceutically acceptable salts thereof.

[0037] 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.

[0038] In another aspect, disclosed herein is a method of degrading a target protein in a sample, comprising contacting the sample with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the target protein is selected from CKlα and WEE1.

[0039] In another aspect, disclosed herein is a method of reducing proliferation of cancer cells in a sample, comprising contacting the sample with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer cells are selected from acute and chronic leukemia, non-Hodgkin lymphoma, multiple myeloma, hepatocellular carcinoma, breast cancer, cervical cancer, lung cancer, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, and ovarian cancer cells.

[0040] In another aspect, disclosed herein is a method of treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by aberrant activity of CKlα and / or WEE 1, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is selected from acute and chronic leukemias, non-Hodgkin lymphomas, multiple myeloma, hepatocellular carcinoma, breast cancers, cervical cancers, lung cancers, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, and ovarian cancers.

[0041] BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIG. 1 is a cartoon representation of CRBN-dependent protein degrader mechanism of action.

[0043] FIG. 2 is an immunoblot showing selective CKlα degradation (over WEE1, GSPT1, IKZF1 and IKZF2) for compound 40 at indicated concentrations in MOLT-4 cells after 5 hour compound treatment. TMX-4116 (PMID: 34965125) was used as a positive control. Compound 40 also induces stabilization of p53.

[0044] FIG. 3 is an immunoblot showing WEE1 degradation and inhibition of CDK1 phosphorylation (Tyrosine 15) at indicated concentrations of compound in MOLT-4 cells after 5- hour treatment.

[0045] FIGS. 4A-4E show Western blots showing consistent and preferential degradation of WEE1 by selective degraders 131 and 90. CC90009 and compound 29 were used as negative and positive controls, respectively

[0046] FIGS. 5A-5B show heat maps demonstrating effects of compounds disclosed herein on cancer cell viability using EC50 (compound concentration leading to half-maximal cell death) and the maximum relative cell death achieved at 10 pM treatment. FIGS. 6A-6B show evaluation of the cellular viability effect of gemcitabine in the presence of (6A) selective WEE1 molecular glue, and (6B) PROTAC degraders; the cell lines tested are indicated above the graphs.

[0047] FIG. 7 shows long-term compound 90 degradation activity investigation with and without Tariquidar. Jurkat cells were treated with 1 pM compound 90 or DMSO and incubated for 72 hours. Another dose of 1 pM compound 90 was introduced after 72 hours elapsed and the cells were incubated for another 5 hours. DETAILED DESCRIPTION

[0048] Disclosed herein are compounds that degrade proteins having an active role in cancer progression, including CKlα and WEE1. The disclosed compounds are believed to induce degradation of their target proteins by forming a “molecular glue” with cereblon (CRBN).

[0049] Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation (Stanton et al. Science 359(6380):eaao5902 (2018)). Unlike proteolysis-targeting chimeric molecules (PROTACs), molecular glue compounds are small molecules (also known as small molecule degraders) that induce an interaction between a substrate receptor of an E3 ubiquitin ligase and a target protein, leading to proteolysis of the target. In so doing, the compounds are believed to alter the substrate binding site of CRBN, such that the target protein becomes a neosubstrate (Burslem et al. Chem. Rev. 777:11269-11301 (2017)). Dissociation of the molecular glue after the ubiquitination step enables subsequent function on a different molecule of the target protein (Che et al. Bioorg. Med. Chem. Lett. 28: 2585-2592 (2018)). Thus, unlike traditional enzyme inhibitors, these molecular glue degraders can act substoichiometrically to catalyze rapid depletion of target proteins (Chopra et al. Drug Discov. Today Technol. 31:5-13 (2019)).

[0050] Definitions

[0051] 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.

[0052] 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, 2ndedition, 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. 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.

[0053] As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24alkyl), 1 to 16 carbon atoms (C1-C16alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (Ci- C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8alkyl), 1 to 6 carbon atoms (C1-C6alkyl), 1 to 4 carbon atoms (C1-C4alkyl), 1 to 3 carbon atoms (C1-C3alkyl), or 1 to 2 carbon atoms (C1-C2alkyl). 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.

[0054] 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-C24alkenyl), 2 to 16 carbon atoms (C2-C16 alkenyl), 2 to 14 carbon atoms (C2-C14alkenyl), 2 to 12 carbon atoms (C2-C12alkenyl), 2 to 10 carbon atoms (C2-C10alkenyl), 2 to 8 carbon atoms (C2-C8alkenyl), 2 to 6 carbon atoms (C2-C6alkenyl), 2 to 4 carbon atoms (C2-C4alkenyl), 2 to 3 carbon atoms (C2-C3alkenyl), or 2 carbon atoms (C2alkenyl). Representative examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, 2-methyl-2-propenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like.

[0055] 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-C24alkynyl), 2 to 16 carbon atoms (C2-C16alkynyl), 2 to 14 carbon atoms (C2-C14 alkynyl), 2 to 12 carbon atoms (C2-C12 alkynyl), 2 to 10 carbon atoms (C2-C10alkynyl), 2 to 8 carbon atoms (C2-C8alkynyl), 2 to 6 carbon atoms (C2-C6alkynyl), 2 to 4 carbon atoms (C2-C4alkynyl), 2 to 3 carbon atoms (C2-C3 alkynyl), or 2 carbon atoms (C2alkynyl). The triple bond(s) may be located at any position(s) with the hydrocarbon chain. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like.

[0056] 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.

[0057] As used herein, the term “amino” refers to a group -NRxRy, wherein Rxand Ryare selected from hydrogen and alkyl (e.g., C1-C4alkyl). A group -NH(alkyl) may be referred to herein as “alkylamino” and a group -N(alkyl)2may be referred to herein as “dialkylamino.”

[0058] As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 Π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C6-C14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl,” e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl,” e.g., anthracenyl and phenanthrenyl).

[0059] As used herein, the term “arylene” refers to a divalent aryl radical.

[0060] 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.

[0061] As used herein, the term “cycloalkylene” refers to a divalent cycloalkyl radical.

[0062] As used herein, the term “cyano” refers to a -CN group.

[0063] As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I.

[0064] 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 (“pcrhaloalkyl”). Representative examples of haloalky 1 include, but arc not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

[0065] 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.

[0066] As used herein, the term “heteroaryl” or “heteroaromatic” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 Π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” or “heteroaromatic” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5- membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one hctcroatom include, without limitation, azcpinyl, oxcpinyl, and thicpinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0067] As used herein, the term “hetero arylene” refers to a divalent heteroaryl radical.

[0068] As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency pennits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-onc. Exemplary 5- membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2, 2,6,6- tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin- 2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., l-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5- bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1 ,5)-8- azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0069] As used herein, the term “heterocyclylene” refers to a divalent heterocyclyl radical. As used herein, the term “hydroxy” or “hydroxyl” refers to an -OH group. As used herein, the term “nitro” refers to an -NO2 group. When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.

[0070] 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).

[0071] 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.

[0072] 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, -OC(O)NH- also encompasses -NHC(O)O-. When linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction.

[0073] 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.

[0074] As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.

[0075] An “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor.

[0076] 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).

[0077] 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.

[0078] Compounds

[0079] Disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0080] A is a five- or six-membered heteroaromatic ring; R1is selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C10 cycloalkyl, aryl, hctcroaryl, hctcrocyclyl, cycloalkylalkyl, arylalkyl, hctcroarylalkyl, hctcrocyclylalkyl, -(CH2)m- X, and hydrogen, wherein m is 0, 1, 2, or 3, and X is selected from -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, - NRaC(O)ORb, and -Si(C1-C6alkyl)3; n is 0, 1, 2, or 3; each R2is independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two R2are optionally taken together with the atoms to which they are attached to form a five- or six-membered ring that is optionally substituted with 1-3 Rc;

[0081] R3is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Re), -S(O)Rd, -S(O)2Rd, -NRdS(O)2Re, - NRdC(O)Re, and -NRdC(O)ORe;

[0082] X is -C(O)- or -CH2-;

[0083] Raand Rbare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Raand Rb, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; each Rcis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two Rcare optionally taken together with the atoms to which they are attached to form a 5- to 6-membered ring that is optionally substituted with 1-3 Rf;

[0084] Rdand Reare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Rdand Re, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; and each Rfis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein each cycloalkyl, aryl, heteroaryl, heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, halo, cyano, nitro, and aryl.

[0085] In some embodiments: A is a five- or six-membered heteroaromatic ring;

[0086] R1is selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)m- X, and hydrogen, wherein m is 1, 2, or 3, and X is selected from -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, - NRaC(O)ORb, and -Si(C1-C6alkyl)3; n is 0, 1, 2, or 3; each R2is independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two R2are optionally taken together with the atoms to which they are attached to form a five- or six-membered ring that is optionally substituted with 1-3 Rc;

[0087] R3is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ca-Cs cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Re), -S(O)Rd, -S(O)2Rd, -NRdS(O)2Re, - NRdC(O)Re, and -NRdC(O)ORe;

[0088] X is -C(O)- or -CH2-;

[0089] Raand Rbare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl- C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Raand Rb, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; each Rcis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two Rcare optionally taken together with the atoms to which they are attached to form a 5- to 6-membered ring that is optionally substituted with 1-3 Rf;

[0090] Rdand Reare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Rdand Re, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; and each Rfis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein each cycloalkyl, aryl, heteroaryl, heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl. In some embodiments, A is a 5- or 6-membered heteroaromatic ring having one nitrogen atom and 0, 1, or 2 additional hctcroatoms independently selected from N, S, and O. In some embodiments, A is a 6-membered heteroaromatic ring having one or two nitrogen atoms. In some embodiments, A is a 6-membered heteroaromatic ring having one nitrogen atom. In some embodiments, A is a 6-membered heteroaromatic ring having two nitrogen atoms. In some embodiments, A is a 5-membered heteroaromatic ring having one nitrogen atom and one or two additional heteroatoms independently selected from N, S, and O.

[0091] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 1, 2, or 3. In some embodiments, each R2is independently selected from C1-C4alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, cyano, nitro, and phenyl. In some embodiments, each R2is independently selected from methyl, isopropyl, trifluoromethyl, methoxy, fluoro, bromo, cyano, nitro, and phenyl.

[0092] In some embodiments, n is 2, and the two R2are taken together with the atoms to which they are attached to form an unsubstituted five- or six-membered aromatic, heteroaromatic, or heterocyclic ring (e.g., a phenyl ring). In some embodiments, n is 2, and the two R2are taken together with the atoms to which they are attached to form a six-membered aromatic ring (i.e., a phenyl ring) that is unsubstituted or substituted with one substituent selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and halo. In some embodiments, n is 2, and the two R2are taken together with the atoms to which they are attached to form a six-membered aromatic ring (i.e., a phenyl ring) that is unsubstituted or substituted with one substituent selected from methyl, tert-butyl, methoxy, trifluoromethoxy, chloro, and bromo.

[0093]

[0094] In some embodiments, the group

[0095] In some embodiments, the group

[0096]

[0097] In some embodiments, R1is selected from C3-C8alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl-Ci-Ca-alkyl, heteroaryl-Ci-Cr-alkyl, heterocyclyl-C1-C2-alkyl, and -(CH2)m-X, wherein m is 0 or 1, and X is selected from -ORa, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)(Rb), and -Si(Ci-C4 alkyl)a. In some embodiments, R1is selected from C3-C8alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl-Ci-C?-alkyl, heteroaryl -C1-C2-alkyl, heterocyclyl-C1-C2-alkyl, and -(CH2)m-X, wherein m is 1, and X is selected from -ORa, - C(O)ORa, -C(O)N(Ra)(Rb), and -Si(Ci-C4 alkyl)3. In some embodiments, R1is selected from C3- Ck alkyl, C3-C10 cycloalkyl, phenyl, naphthyl, quinoxalinyl, 1,3-benzodioxolyl, 1,3- benzodioxinyl, phenyl-C1-C2-alkyl, diphenyl-C1-C2-alkyl, pyridinyl-C1-C2- alkyl, morpholino-Ci- Ca-alkyl, and -(CH2)m-X; wherein: m is 0 or 1, X is selected from -ORa, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)(Rb), and -Si(C1-C4alkyl)3; Rais selected from hydrogen, C1-C4alkyl, C4-C7 cycloalkyl, aryl, and aryl-Ci-Ca-alkyl; and Rbis selected from hydrogen and C1-C4alkyl; or Raand Rb, together with the nitrogen atom to which they arc attached, arc taken together to form a five- or six-membered ring. In some embodiments, R1is selected from C3-C8alkyl, C3-C10 cycloalkyl, phenyl, naphthyl, quinoxalinyl, 1,3-benzodioxolyl, 1,3-benzodioxinyl, phenyl-C1-C2- alkyl, diphenyl-C1-C2-alkyl, pyridinyl-C1-C2-alkyl, morpholino-C1-C2-alkyl, and -(CH2)m-X; wherein: m is 1, X is selected from -ORa, -C(O)ORa, -C(O)N(Ra)(Rb), and -Si(C1-C4alkyl)3; and Raand Rbare each independently selected from hydrogen and C1-C4alkyl, or Raand Rb, together with the nitrogen atom to which they are attached, are taken together to form a five- or six- membered ring. In some embodiments, R1is selected from:

[0098] In some embodiments, X is -C(O)-. In some embodiments, X is -CH2-. In some embodiments, R3is hydrogen.

[0099] In some embodiments, the compound of formula (I) is selected from compounds listed in Table 1, and pharmaceutically acceptable salts thereof.

[0100] Table 1. Compounds of Formula (I) and pharmaceutically acceptable salts thereof.

[0101] Also disclosed herein are compounds of formula: and pharmaceutically acceptable salts thereof.

[0102] 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 starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well- known to those of ordinary skill in the art. These methods of resolution are exemplified by: (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), Longman Scientific & Technical, Essex CM202JE, England; (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns; or (3) fractional recrystallization methods.

[0103] 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.

[0104] 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 arc 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-labeled reagent in place of non-isotopically-labeled reagent.

[0105] 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

[0106] 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, stcaryl and the like.

[0107] 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.

[0108] 1. Methods of Synthesis

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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).

[0113] 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).

[0114] 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.

[0115] 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.

[0116] Pharmaceutical Compositions

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 (c.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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%. 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.

[0128] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% by weight of the composition.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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. 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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. 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.

[0139] 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.

[0140] 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.

[0141] 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).

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

[0149] 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.

[0150] 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.

[0151] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0152] Methods of Use

[0153] The disclosed compounds and pharmaceutical compositions may be used in methods for treatment of disorders, such as a disorder characterized or mediated by CKlα or WEE1. 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 CKlα or WEE1. In some embodiments, the cancer is a cancer in which CKlα or WEE1 is highly expressed, or is overexpressed relative to non- cancerous cells. For example, CKlα is overexpressed and overactive in acute and chronic leukemias, non-Hodgkin lymphomas (NHL), and in multiple myeloma (MM) (see, e.g., Piazza et al. Curr. Signal Transduct. Ther. 2011, 6, 88-98; Martins et al. Blood 2010, 116, 2724-2731; Piazza et al. Leukemia 2012, 26, 1174-1179; Martins et al. Oncotarget 2014, 5, 258-263; Manni et al. Leukemia 2014, 28, 2094-2097; Hu et al. Leukemia 2015, 29, 474-482; Manni et al. J. Hematol. Oncol. 2017, 10, 157; Ge et al. Leukemia 2021). Additionally, WEE1 is highly expressed in several cancer types, including hepatocellular carcinoma (see, e.g., Masaki et al. (2003) Hepatology 37, 534-543), breast cancers (see, e.g., lorns, E. et al. (2009) PLoS ONE 4, e5120), cervical cancers (id.), lung cancers (id.), squamous cell carcinoma (see, e.g., Magnussen, G.I. et al. (2013) BMC Cancer 13, 288), diffuse intrinsic pontine glioma (DIPG) (see, e.g., Mueller, S. et al. (2014) Neuro. Oncol. 16, 352-360), glioblastoma (see, e.g., Mir, S.E. et al. (2010) Cancer Cell 18, 244-257; Music, D. et al. (2016) J. Neurooncol. 127 , 381-389), medulloblastoma (see, e.g., Harris, P.S. et al. (2014) Mol. Cancer 13, 72), leukemia (see, e.g., Tibes, R. et al. (2012) Blood 119, 2863-2872; Porter, C.C. et al. (2012) Leukemia 26, 1266- 1276), melanoma (see, e.g., Magnussen, G.I. et al. (2012) PLoS ONE 7, e38254), and ovarian cancers (see, e.g., Slipicevic, A. et al. (2014) Gynecol. Oncol. 135, 118-124).

[0154] 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 CK Io. or WEE1, 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.

[0155] 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 lipo sarcoma, pleomorphic rhabdomyosarcoma, PNET / cxtraskclctal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma.

[0156] 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.

[0157] 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-cell lymphoma, cutaneous T-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphomas, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and treatment- related T-cell lymphomas. Exemplary B-cell malignancies include chronic lymphocytic leukemia (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 macroglobulincmia.

[0158] 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.

[0159] 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.

[0160] 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. 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] In some embodiments, the compound described herein is administered with at least one additional therapeutic agent, such as a chemotherapeutic agent. In certain embodiments, the compound described herein is administered in combination with one or more additional chemotherapeutic agents. The chemotherapeutic agent may be a chemotherapeutic agent identified on the “A to Z List of Cancer Drugs” published by the National Cancer Institute.

[0166] Also disclosed herein are methods of degrading a target protein in a sample, comprising contacting the sample with an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein. In some embodiments, the target protein is selected from CKlα and WEE 1.

[0167] 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.

[0168] Kits

[0169] 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 pharmaceutically acceptable salt thereof. Kits or pharmaceutical systems may also include printed instructions for using the compounds and / or compositions.

[0170] The following examples further illustrate aspects of the disclosure, but should not be construed as in any way limiting its scope.

[0171] EXAMPLES

[0172] The following abbreviations are used in the Examples: DIPEA - N,N- diisopropylethylamine. MeCN - acetonitrile. EtiO - diethyl ether. EtOAc - ethyl acetate. MeOH - methanol. NMP - N-Methyl-2-pyrrolidone.

[0173] General synthetic methods. Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification. Reactions were monitored using a Waters Acquity UPLC / MS system (Waters PDA e Detector, QDa Detector, Sample manager - FL, Binary Solvent Manager) using Acquity UPLC® BEH C18 column (2.1 x 50 mm, 1.7 pm particle size): solvent gradient = 85% A at 0 min, 1% A at 1.7 min; solvent A = 0.1% formic acid in water; solvent B = 0.1% formic acid in Acetonitrile; flow rate: 0.6 mL / min. Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 TLC glass plates and analytes were visualized by fluorescence quenching (using 254 nm light). Purification of reaction products was carried out by flash column chromatography using CombiFlash®Rf with Teledyne Isco RediSep® normal-phase silica flash columns (4 g, 12 g, 24 g, 40 g or 80 g) or preparative RP-HPLC using Waters SunFireTM Prep C18 column (19 x 100 mm, 5 pm particle size) using a gradient of 5-95% methanol in water containing 0.05% trifluoroacetic acid (TFA) over 40 min (45 min run time) at a flow of 40 mL / min. Assayed compounds were isolated and tested as TFA salts and purities of assayed compounds were in all cases greater than 95%, as determined by reverse-phase UPLC analysis. NMR spectra were acquired on a 500 MHz Bruker Avance III spectrometer, operating at the denoted spectrometer frequency given in MHz for the specified nucleus. All experiments were acquired at 298.0 K with a calibrated Bruker Variable Temperature Controller unless otherwise noted. The chemical shifts arc reported in pails per million (ppm) and coupling constants (I) are given in Hertz (Hz).1H NMR spectra are reported with the solvent resonance as the reference unless noted otherwise (DMSO-d6 at 2.50 ppm). Peaks are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br = broad signal, coupling constant(s) in Hz, integration).

[0174] Example 1: Compound Syntheses

[0175] Scheme 1. Synthesis of Compounds 1-4

[0176] Compound 1-2. Prepared following a reference procedure (Hayhow et al. Chemistry 2020, 26(70):16818-16823). To the solution of methyl 4-bromo-2-(bromomethyl)benzoate (1000 mg, 1 Eq, 3.247 mmol) and 3-aminopiperidine-2, 6-dione hydrochloride (801.7 mg, 1.5 Eq, 4.871 mmol) in Acetonitrile (12 mL) was added DIPEA (1.259 g, 1.70 mL, 3.0 Eq, 9.741 mmol) under nitrogen flow. The resulting suspension was stirred at 80 °C for 48 hours. The reaction mixture was cooled to 4 °C, vast precipitation observed. The solid was filtered, washed with cold MeCN (30 mL), MeCN:Et2O (25 mL [2:3]) and EtiO (2 x 25 mL) to afford compound 1-2 as a dark blue solid that was used directly in the next step (794 mg, 76%). LC-MS: calculated exact mass = 322.0; found [M+H]+- 323.1.

[0177] Compound 1-3. Prepared following a reference procedure (WO 2022 / 032026). To a solution of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (Compound 1-2, 794 mg, 1 Eq, 2.46 mmol) in 1,4-Dioxane (30 mL) was added tributyl(vinyl)stannane (1.17 g, 1.08 mL, 1.5 Eq, 3.69 mmol) and Bis-(triphenylphosphino)-palladous chloride (86.2 mg, 0.05 Eq, 123 pmol) and the mixture was stirred at 1 10 °C for 18 hour. Confirmed product formation by LC-MS and diluted with water and extracted with EtOAc 3 times. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure onto a silica pad. The compound 1-3 was isolated via silica gel chromatography in hexane:EtOAc gradient elution and used directly in the next step (530 mg, 80%). LC-MS: calculated exact mass = 270.1 ; found [M+H]+= 271.2.

[0178] Compound 1-4. Prepared following a reference procedure (WO 2022 / 032026). To a solution of 3-(l-oxo-5-vinylisoindolin-2-yl)piperidine-2, 6-dione (530 mg, 1 Eq, 1.96 mmol) in Water (5.0 mL) and 1,4-Dioxane (20 mL) was added sodium periodate (1.68 g, 4 Eq, 7.84 mmol), 2,6-dimethylpyridine (420 mg, 454 pL, 2 Eq, 3.92 mmol), and the mixture was cooled to 0 °C. osmium(VIII) oxide (249 mg, 240 pL, 4% Wt, 0.02 Eq, 39.2 pmol) was added dropwise and the mixture was allowed to warm up to 25 °C after 10 min. The color changed to white from deep blue and intense precipitate was observed. The mixture was stirred for 2 hour and then diluted with 20 mL of water, extracted 3x15 mL of EA. Organic layer was washed with brine, dried and evaporated. The compound 1-4 was isolated as a white solid via silica gel chromatography in hexane:EtOAc gradient elution (794 mg, 76%). LC-MS: calculated exact mass = 272.1; found [M+H]+= 273.2. NMR (500 MHz, DMSO) 8 11.02 (s, 1H), 10.15 (s, 1H), 8.15 (s, 1H), 8.06 (dd, J = 7.8, 1.4 Hz, 1H), 7.94 (d, 7= 7.8 Hz, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 17.7 Hz, 1H), 4.45 (d, J = 17.7 Hz, 1H), 2.92 (m, 1H), 2.68 - 2.56 (m, 1H), 2.42 (m, 1H), 2.13 - 1.99 (m, 1H).

[0179] Compound

[0180] Compound 2 was synthesized following the synthetic route in Scheme 1. Yield: 235 mg, 31%. LC-MS: calculated exact mass = 272.1; found [M+H]+= 273.2.

[0181] Compound

[0182] Compound 3 was synthesized following the synthetic route in Scheme 1. Yield: 540 mg, 49%. LC-MS: calculated exact mass = 272.1; found [M+H]+= 273.2.

[0183] Compound Compound 4 was synthesized following the synthetic route in scheme 1 . Yield: 850 mg, 50%. LC-MS: calculated exact mass = 286.1; found [M-H]‘ = 285.0.

[0184] General procedures for Groebke-Blackburn-Bienayme (GBB) cyclization

[0185] Procedure A. Aldehyde (1.1 eq) and amidine (1.0 eq), and acid catalyst were dissolved in anhydrous MeOH (200-300 mM final aldehyde molarity) and stirred for 30-60 minutes. Isocyanide (1.1 eq) was then added, and the reaction was stirred for 24-72 h. The product formation was detected by LC-MS and / or TLC. The mixture was then diluted in DMSO and purified via preparative HPLC using MeOH:H2O (0.035% formic acid additive) elution gradient.

[0186] Procedure B. Stock solutions of aldehyde (1.0 eq per reaction) in NMP (solution A) and amidine (1.1 eq per reaction), and acid catalyst in MeOH (solution B) were prepared. Mixed specified volumes of A and B to reach 150-300 mM final amidine concentration and desired aldehyde: amidine stoichiometry. After stirring for 30-60 minutes, isocyanide (1.2 eq) was added, and the reaction was stirred for 24-72 h. The product formation was detected. By LC-MS and / or TLC. The mixture was then diluted in DMSO and purified via preparative HPLC using MeOH:H2O (0.035% formic acid additive) elution gradient.

[0187] Compound 5

[0188] Compound 5 was synthesized following procedure A. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 13.9 mg, 43%. LC-MS calculated exact mass = 431.2; found [M+H]+= 432.4. ‘H NMR (500 MHz, DMSO) 8 11.03 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J = 7.9, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.87 (s, 2H), 7.46 (s, 1H), 5.24 (s, 1H), 5.16 (dd, J= 13.3, 5.1 Hz, 1H), 4.59 (d, J= 17.4 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 2.94 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.67 - 2.58 (m, 1H), 2.44 (m, 1H), 2.07 (m, 1H), 1.01 (s, 9H). Compound 6

[0189] Compound 6 was synthesized following procedure A. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 16.2 mg, 42%. LC-MS: calculated exact mass = 509.2; found |M+H]+= 510.2.

[0190] Compound 7

[0191] Compound 7 was synthesized following procedure A. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 12.4 mg, 36%. LC-MS: calculated exact mass = 504.2; found [M+H]+= 505.4.

[0192] Compound 8

[0193] Compound 8 was synthesized following procedure A. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 1.7 mg, 5%. LC- MS: calculated exact mass = 480.2; found [M+H]+= 481.4. Compound 9

[0194] Compound 9 was synthesized following procedure A. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 6.5 mg, 20%. LC- MS: calculated exact mass = 485.1; found [M+H]+= 486.3.

[0195] Compound 10

[0196] Compound 10 was synthesized following procedure A. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 2.0 mg, 6%. LC- MS: calculated exact mass = 435.2; found [M+H]+= 436.3.

[0197] Compound 11

[0198] Compound 11 was synthesized following procedure A. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 10.1, 33%. LC- MS: calculated exact mass = 444.2; found [M+H]+= 445.4.

[0199] Compound 12 Compound 12 was synthesized following procedure A. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 5.6 mg, 17%. LC- MS: calculated exact mass = 481.2; found [M+H]+= 482.4.

[0200] Compound 13

[0201] Compound 13 was synthesized following procedure A. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 5.6 mg, 15%. LC- MS: calculated exact mass = 551.2; found [M+H]+= 552.3.

[0202] Compound 14

[0203] Compound 14 was synthesized following procedure A. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 2.4 mg, 7%. LC- MS: calculated exact mass = 530.2; found [M+HJ+= 531.3.

[0204] Compound 15 Compound 15 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 cq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. Yield: 2.5 mg, 7%. LC-MS: calculated exact mass = 501.2; found [M+H]+= 502.4.

[0205] Compound 16

[0206] Compound 16 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. Yield: 16.1 mg, 51%. LC-MS: calculated exact mass = 465.2; found [M+H]+= 466.4.

[0207] Compound 17

[0208] Compound 17 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. Yield: 27.0 mg, 81%. LC-MS: calculated exact mass = 487.3; found [M+H]+= 488.4.

[0209] Compound 17 scale up. Compound 1-4 (280 mg, 1 Eq, 1.03 mmol) was dissolved in NMP (2.40 mL). Pyridin-2- amine (106 mg, 1.1 Eq, 1.13 mmol), Sc(OTf)3 (75.9 mg, 0.15 Eq, 154 pmol), and MeOH (1.20 mL) were added to the mixture and stirred for 30 minutes. 2- isocyano-2,4,4-trimethylpentane (158 mg, 198 pL, 1.1 Eq, 1.13 mmol) was added dropwise and the reaction was stirred for 48 hours at room temperature. The product formation was detected. By LC-MS and / or TLC. The mixture was then diluted in DMSO and purified via preparative HPLC using MeOHiHiO (0.035% formic acid additive) elution gradient. Yield: quantitative. LC- MS: calculated exact mass = 487.3; found [M+H]+= 488.4. The product was directly used in the next step without further purification.

[0210] Compound 18

[0211] Compound 18 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. Yield: 5.6 mg, 20%. LC-MS: calculated exact mass = 415.2; found [M+H]+=

[0212] 416.4.

[0213] Compound 19

[0214] Compound 19 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. Yield: 21.8 mg, 72%. LC-MS: calculated exact mass = 443.2; found [M+H]+=

[0215] 444.4.

[0216] Compound 20

[0217] Compound 20 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. Yield: 5.5 mg, 18%. LC-MS: calculated exact mass = 447.2; found [M+H]+=

[0218] 448.4. Compound 21

[0219] Compound 21 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. 8.5 mg, 26%. LC-MS: calculated exact mass = 489.2; found [M+H]+= 490.4.

[0220] Compound 22

[0221] Compound 22 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)a as the acid catalyst. 250 pL of solution A and B were used. Yield: 4.3 mg, 13%. LC-MS: calculated exact mass = 486.2; found [M+H]+= 487.4.

[0222] Compound 23

[0223] Compound 23 was synthesized following procedure B . Compound 5 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 250 pL of solution A and B were used. Yield: 5.0 mg, 15%. LC-MS: calculated exact mass = 488.2; found [M+H]+= 489.4. Compound 24

[0224] Compound 24 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 11.8 mg, 39%. LC-MS: calculated exact mass = 445.2; found [M+H]+= 446.4.

[0225] Compound 25

[0226] Compound 25 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 2.1 mg, 6%. LC-MS: calculated exact mass = 523.2; found [M+H]+= 524.3.

[0227] Compound 26 Compound 26 was synthesized following procedure B. Compound 2 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 6.2 mg, 21%. LC-MS: calculated exact mass = 431.2; found [M+H]+= 432.4. Compound 27

[0228] Compound 27 was synthesized following procedure B. Compound 2 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)s as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 0.81 mg, 2%. LC-MS: calculated exact mass = 509.2; found [M+H]+= 510.4.

[0229] Compound 28

[0230] Compound 28 was synthesized following procedure B. Compound 2 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 3.5 mg, 12%. LC-MS: calculated exact mass = 431.2; found [M+H]+= 431.4.

[0231] Compound 29 Compound 29 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 27.3 mg, 72%. LC-MS: calculated exact mass = 509.2; found [M+H]+= 510.4.

[0232] Compound 30

[0233] Compound 30 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 27.6 mg, 78%. LC-MS: calculated exact mass = 471.2; found [M+H]+= 472.2.

[0234] Compound 31

[0235] Compound 31 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 29.7 mg, 87%. LC-MS: calculated exact mass = 457.2; found [M+H]+= 458.4.

[0236] Compound 32

[0237] Compound 32 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 18.2 mg, 56%. LC-MS: calculated exact mass = 431.2; found [M+H]+= 432.4. Compound 33

[0238] Compound 33 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 10.3 mg, 32%. LC-MS: calculated exact mass = 433.2; found [M+H]+= 434.4.

[0239] Compound 34

[0240] Compound 34 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. 17.7 mg, 51%. LC-MS: calculated exact mass = 466.2; found [M+H]+= 467.4.

[0241] Compound 35 Compound 35 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 12.5 mg, 38%. LC-MS: calculated exact mass = 432.2; found [M+H]+= 433.2. Compound 36

[0242] Compound 36 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 2.8 mg, 9%. LC-MS: calculated exact mass = 432.2; found [M+H]+= 433.4.

[0243] Compound 37

[0244] Compound 37 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 150 pL of solution A and 50 pL of solution B were used. Yield: 10.0 mg, 32%. LC-MS: calculated exact mass = 523.2; found [M+H]+= 524.4.

[0245] Compound 38

[0246] Compound 38 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 5.7 mg, 22%. LC-MS: calculated exact mass = 523.2; found [M+H]+= 524.3. Compound 39

[0247] Compound 39 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 7.6 mg, 29%. LC-MS: calculated exact mass = 523.2; found [M+H]+= 524.3.

[0248] Compound 40

[0249] Compound 40 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0250] 200 pL of solution A and 50 pL of solution B were used. Yield: 3.0 mg, 12%. LC-MS: calculated exact mass = 523.2; found [M+H]+= 524.3.

[0251] Compound 41 Compound 41 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 11.5 mg, 52%. LC-MS: calculated exact mass = 445.2; found [M+H]+= 446.4. Compound 42

[0252] Compound 42 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf>3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 15.8 mg, 71%. LC-MS: calculated exact mass = 445.2; found [M+H]+= 446.4.

[0253] Compound 43

[0254] Compound 43 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0255] 200 pL of solution A and 50 pL of solution B were used. Yield: 10.3 mg, 46% LC-MS: calculated exact mass = 445.2; found [M+H]+= 446.4.

[0256] Compound 44 Compound 44 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 4.6 mg, 21%. LC-MS: calculated exact mass = 445.2; found [M+H]+= 446.4. Compound 45

[0257] Compound 45 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf>3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 3.2 mg, 12%. LC-MS: calculated exact mass = 459.2; found [M+H]+= 460.3.

[0258] Compound 46

[0259] Compound 46 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0260] 200 pL of solution A and 50 pL of solution B were used. Yield: 3.3 mg, 11%. LC-MS: calculated exact mass = 507.2; found [M+H]+= 508.3.

[0261] Compound 47 Compound 47 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 3.1 mg, 11%. LC-MS: calculated exact mass = 459.2; found [M+H]+= 460.4. Compound 48

[0262] Compound 48 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.3 mg, 7%. LC-MS: calculated exact mass = 569.2; found [M+H]+= 570.3.

[0263] Compound 49

[0264] Compound 49 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0265] 200 pL of solution A and 50 pL of solution B were used. Yield: 9.3 mg, 32%. LC-MS: calculated exact mass = 485.2; found [M+H]+= 486.3.

[0266] Compound 50 Compound 50 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 6.4 mg, 22%. LC-MS: calculated exact mass = 473.2; found [M+H]+= 474.4. Compound 51

[0267] Compound 51 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 4.0 mg, 13%. LC-MS: calculated exact mass = 521.2; found [M+H]+= 522.3.

[0268] Compound 52

[0269] Compound 52 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0270] 200 pL of solution A and 50 pL of solution B were used. Yield: 7.4 mg, 26%. LC-MS: calculated exact mass = 473.2; found [M+H]+= 474.3.

[0271] Compound 53 Compound 53 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1 :1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 3.1 mg, 9%. LC-MS: calculated exact mass = 583.2; found [M+H]+= 584.3. Compound 54

[0272] Compound 54 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 5.1 mg, 17% LC-MS: calculated exact mass = 499.2 found [M+H]+= 500.3.

[0273] Compound 55

[0274] Compound 55 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0275] 190 pL of solution A and 50 pL of solution B were used. Yield: 5.1 mg, 16% LC-MS: calculated exact mass = 533.2 found [M+H]+= 534.3.

[0276] Compound 56 Compound 56 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 8.9 mg, 31% LC-MS: calculated exact mass = 473.2 found [M+H]+= 474.3. Compound 57

[0277] Compound 57 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 5.4 mg, 17% LC-MS: calculated exact mass = 543.3 found [M+H]+= 544.4.

[0278] Compound 58

[0279] Compound 58 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0280] 190 pL of solution A and 50 pL of solution B were used. Yield: 2.7 mg, 9% LC-MS: calculated exact mass = 526.2 found |M+H|+= 527.3.

[0281] Compound 59 Compound 59 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 3.3 mg, 10% LC-MS: calculated exact mass = 557.3 found [M+H]+= 558.3. Compound 60

[0282] Compound 60 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf>3 as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 3.4 mg, 12% LC-MS: calculated exact mass = 487.2 found [M+H]+= 488.3.

[0283] Compound 61

[0284] Compound 61 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0285] 190 pL of solution A and 50 pL of solution B were used. Yield: 4.3 mg, 14% LC-MS: calculated exact mass = 521.2 found [M+H]+= 522.3.

[0286] Compound 62 Compound 62 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 11.6 mg, 35% LC- MS: calculated exact mass = 546.2 found [M+H]+= 547.3. Compound 63

[0287] Compound 63 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 15.6 mg, 46% LC- MS: calculated exact mass = 569.2 found [M+H]+= 570.3.

[0288] Compound 64

[0289] Compound 64 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 2.1 mg, 7% LC- MS: calculated exact mass = 515.2 found [M+H]+= 516.3.

[0290] Compound 65 Compound 65 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1 :1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 1.4 mg, 7% LC- MS: calculated exact mass = 593.2 found [M+H]+= 594.2. Compound 66

[0291] Compound 66 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 5.0 mg, 16% LC- MS: calculated exact mass = 530.3 found [M+H]+= 531.4.

[0292] Compound 67

[0293] Compound 67 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 2.0 mg, 6% LC- MS: calculated exact mass = 544.3 found [M+H]+= 545.3.

[0294] Compound 68 Compound 68 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 5.5 mg, 18% LC- MS: calculated exact mass = 501.3 found [M+H]+= 502.4. Compound 69

[0295] Compound 69 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 6.2 mg, 20% LC- MS: calculated exact mass = 515.3 found [M+H]+= 516.4.

[0296] Compound 70

[0297] Compound 70 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 4.6 mg, 14% LC- MS: calculated exact mass = 533.2 found [M+H]+= 534.3.

[0298] Compound 71 Compound 71 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 12.5 mg, 38% LC-MS: calculated exact mass = 417.2 found [M+H]+= 418.3. Compound 72

[0299] Compound 72 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 22.3 mg, 64% LC-MS: calculated exact mass = 461.2 found [M+H]+= 462.4.

[0300] Compound 73

[0301] Compound 73 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0302] 200 pL of solution A and 150 pL of solution B were used. Yield: 7.2 mg, 18% LC-MS: calculated exact mass = 527.2 found [M+H]+= 528.4.

[0303] Compound 74 Compound 74 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1 :1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 4.8 mg, 13% LC-MS: calculated exact mass = 495.2 found [M+H]+= 496.3. Compound 75

[0304] Compound 75 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 13.1 mg, 38% LC-MS: calculated exact mass = 459.2 found [M+H]+= 460.4.

[0305] Compound 76

[0306] Compound 76 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 150 pL of solution B were used. Yield: 22.6 mg, 70% LC-MS: calculated exact mass = 432.2 found [M+H]+= 433.4.

[0307] Compound 77 Compound 77 was synthesized following procedure A. Compound 1-4 was used as the aldehyde precursor along with 0.15 eq of Sc(OTf)3 as the acid catalyst. Yield: 1.7 mg, 4%. LC- MS calculated exact mass = 551.2; found [M+H]+= 552.2. Compound 78

[0308] Compound 78 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.0 mg, 7% LC-MS: calculated exact mass = 595.2 found [M+H]+= 596.4.

[0309] Compound 79

[0310] Compound 79 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1 :1.1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0311] 200 pL of solution A and 50 pL of solution B were used. Yield: 13.7 mg, 46% LC-MS: calculated exact mass = 595.2 found [M+H]+= 596.4.

[0312] Compound 80 Compound 80 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 11.9 mg, 46% LC-MS: calculated exact mass = 517.2 found [M+H]+= 518.3. Compound 81

[0313] Compound 81 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 8.7 mg, 30% LC-MS: calculated exact mass = 573.2 found [M+H]+= 574.4.

[0314] Compound 82

[0315] Compound 82 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 8.5 mg, 36% LC-MS: calculated exact mass = 471.1 found [M+H]+= 472.3.

[0316] Compound 83

[0317] Compound 83 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1 :1.1 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.0 mg, 7% LC-MS: calculated exact mass = 565.1 found [M+H]+= 565.3. Compound 84

[0318] Compound 84 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.0 mg, 6% LC-MS: calculated exact mass = 587.2 found [M+H]+= 588.4.

[0319] Compound 85

[0320] Compound 85 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0321] 150 pL of solution A and 50 pL of solution B were used. Yield: 2.6 mg, 9% LC-MS: calculated exact mass = 466.2 found [M+H]+= 467.4.

[0322] Compound 86 Compound 86 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 150 pL of solution A and 50 pL of solution B were used. Yield: 1.4 mg, 5% LC-MS: calculated exact mass = 502.2 found [M+H]+= 503.3. Compound 87

[0323] Compound 87 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 150 pL of solution A and 50 pL of solution B were used. Yield: 0.6 mg, 2% LC-MS: calculated exact mass = 515.2 found [M+H]+= 516.3.

[0324] Compound 88

[0325] Compound 88 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0326] 150 pL of solution A and 50 pL of solution B were used. Yield: 6.1 mg, 21% LC-MS: calculated exact mass = 493.2 found [M+H]+= 494.3.

[0327] Compound 89 Compound 89 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 150 pL of solution A and 50 pL of solution B were used. Yield: 18.3 mg, 59% LC-MS: calculated exact mass = 501.2 found [M+H]+= 502.3. Compound 90

[0328] Compound 90 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 150 pL of solution A and 50 pL of solution B were used. Yield: 8.0 mg, 25% LC-MS: calculated exact mass = 515.2 found [M+H]+= 516.3.

[0329] Compound 91

[0330] Compound 91 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)a as the acid catalyst.

[0331] 150 pL of solution A and 50 pL of solution B were used. Yield: 5.4 mg, 18% LC-MS: calculated exact mass = 507.2 found [M+H]+= 508.3.

[0332] Compound 92 Compound 92 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 3.7 mg, 12% LC-MS: calculated exact mass = 515.2 found [M+H]+= 516.3. Compound 93

[0333] Compound 93 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 4.1 mg, 14% LC-MS: calculated exact mass = 493.2 found [M+H]+= 494.2.

[0334] Compound 94

[0335] Compound 94 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst.

[0336] 200 pL of solution A and 50 pL of solution B were used. Yield: 2.7 mg, 9% LC-MS: calculated exact mass = 519.2 found [M+H]+= 520.3.

[0337] Compound 95 Compound 95 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 14.7 mg, 47% LC-MS: calculated exact mass = 519.2 found [M+H]+= 520.3.

[0338] Compound 96 Compound 96 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 9.8 mg, 30% LC-MS: calculated exact mass = 541.3 found [M+H]+= 542.4.

[0339] Compound 97

[0340] Compound 97 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf) as the acid catalyst.

[0341] 200 pL of solution A and 50 pL of solution B were used. Yield: 2.0 mg, 6% LC-MS: calculated exact mass = 529.3 found [M+H]+= 530.4. Compound 98

[0342] Compound 98 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.4 mg, 8% LC-MS: calculated exact mass = 531.2 found [M+H]+= 533.3.

[0343] Compound 99 Compound 99 was synthesized following procedure B . Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 1.4 mg, 4% LC-MS: calculated exact mass = 551.2 found [M+H]+= 552.3.

[0344] Compound 100

[0345] Compound 100 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 6.3 mg, 19% LC-MS: calculated exact mass = 543.2 found [M+H]+= 544.3. Compound 101

[0346] Compound 101 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 33.3 mg, 96% LC-MS: calculated exact mass = 577.3 found [M+H]+= 578.3.

[0347] Compound 102 Compound 102 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 11.9 mg, 43% LC- MS: calculated exact mass = 459.2 found [M+H]+= 460.4.

[0348] Compound 103

[0349] Compound 103 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 13.1 mg, 44% LC- MS: calculated exact mass = 493.2 found [M+H]+= 494.4. Compound 104

[0350] Compound 104 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1 :1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 12.3 mg, 46% LC- MS: calculated exact mass = 445.2 found [M+H]+= 446.4.

[0351] Compound 105 Compound 105 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 10.8 mg, 36% LC- MS: calculated exact mass = 493.2 found [M+H]+= 494.4.

[0352] Compound 106

[0353] Compound 106 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 18.9 mg, 65% LC- MS: calculated exact mass = 485.2 found [M+H]+= 486.5. Compound 107

[0354] Compound 107 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.2 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 190 pL of solution A and 50 pL of solution B were used. Yield: 5.9 mg, 19% LC- MS: calculated exact mass = 507.2 found [M+H]+= 508.4.

[0355] Compound 108

[0356] Compound 108 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1 :1.2 ratio to amidine) along with 0.15 eq of Sc(OTf)3 as the acid catalyst. 150 pL of solution A and 50 pL of solution B were used. Yield: 2.8 mg, 10% LC-MS: calculated exact mass = 479.2 found [M+H]+= 480.3.

[0357] Compound 109

[0358] Compound 109 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.20 eq of tosylic acid monohydratc as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.1 mg, 6% LC-MS: calculated exact mass = 507.19 found [M+H]+= 508.37.

[0359] Compound 110

[0360] Compound 110 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.2 mg, 6% LC-MS: calculated exact mass = 493.18 found [M+H]+= 494.32. Compound 111

[0361] Compound 11 1 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 5.3 mg, 14% LC- MS: calculated exact mass = 493.18 found [M+H]+= 494.32.

[0362] Compound 112

[0363] Compound 112 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 4.0 mg, 12% LC- MS: calculated exact mass = 459.19 found [M+H]+= 460.36.

[0364] Compound 113 Compound 113 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 3.6 mg, 10% LC- MS: calculated exact mass = 473.21 found [M+H]+= 474.36. Compound 114

[0365] Compound 114 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 7.3 mg, 14% LC- MS: calculated exact mass = 509.17 found [M+H]+= 510.22.

[0366] Compound 115

[0367] Compound 115 was synthesized following procedure B. Compound 4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.20 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 8.2 mg, 17% LC- MS: calculated exact mass = 493.18 found [M+H]+= 494.27.

[0368] Compound 116 Compound 116 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 4.6 mg, 11% LC- MS: calculated exact mass = 521.13 found [M+H]+= 522.13. Compound 117

[0369] Compound 117 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 4.8 mg, 10% LC- MS: calculated exact mass = 565.08 found [M+H]+= 566.18.

[0370] Compound 118

[0371] Compound 118 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 1.3 mg, 3% LC-MS: calculated exact mass = 543.23 found [M+H]+= 544.30.

[0372] Compound 119

[0373] Compound 119 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 4.4 mg, 9% LC-MS: calculated exact mass = 571.15 found [M+H]+= 572.25.

[0374] Compound 120 Compound 120 was synthesized following procedure B. Compound 1 -4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 cq of tosylic acid monohydratc as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.6 mg, 6% LC-MS: calculated exact mass = 517.18 found [M+H]+= 518.17.

[0375] Compound 121

[0376] Compound 121 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.6 mg, 6% LC-MS: calculated exact mass = 501.18 found [M+H]+= 502.17.

[0377] Compound 122

[0378] Compound 122 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.7 mg, 7% LC-MS: calculated exact mass = 501.18 found [M+H]+= 502.17.

[0379] Compound 123

[0380] Compound 123 was synthesized following procedure B. Compound 1-4 was used as the aldehyde precursor (1:1.1 ratio to amidine) along with 0.25 eq of tosylic acid monohydrate as the acid catalyst. 200 pL of solution A and 50 pL of solution B were used. Yield: 2.7 mg, 7% LC-MS: calculated exact mass = 487.17 found [M+H]+= 488.16. Compound 124

[0381] Compound 17 (490 mg, 1 Eq, 1 mmol) was dissolved in dioxane (5 mL). 4 M HC1 in dioxane (5 mL) was added and the mixture was stirred for 20 hours, until complete conversion was detected by LC-MS. The mixture was then diluted in DMSO and purified via preparative HPLC in portions using McOHilLO (0.035% formic acid additive) elution gradient. Yield: 282 mg, 75%. LC-MS: calculated exact mass = 375.1 found [M+H]+= 376.3.!H NMR (500 MHz, DMSO) 8 11.02 (s, 1H), 8.67 (d, J = 6.9 Hz, 1H), 8.10 (s, 1H), 8.01 (dd, J = 8.1, 1.6 Hz, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.79 (d, J= 9.0 Hz, 1H), 7.74 (t, J= 8.0 Hz, 1H), 7.42 (t, J= 6.9 Hz, 1H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 2.94 (ddd, J = 17.2, 13.7, 5.4 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.48 - 2.39 (m, 1H), 2.05 (m, 1H).

[0382] Compound 125

[0383] Compound 124 (10.0 mg, 1 Eq, 27 pmol) was dissolved in dry THF (250 pL). DIPEA (37.1 pL, 8 Eq, 213 pmol) was added and the solution was cooled in an ice bath. 2-phenylacetyl chloride (0.5 molar solution in dry THF, 213 pL, 3 Eq, 107 pmol) was added dropwise and the mixture was stirred and monitored by LCMS every 10-15 minutes. After 30 min, the mixture was diluted with DMSO and purified via preparative HPLC using MeOH:H2O (0.035% formic acid additive) elution gradient. Yield: 6.7 mg, 51%. LC-MS: calculated exact mass = 493.18 found [M+H]+= 494.27. *H NMR (500 MHz, DMSO) 5 10.96 (s, 1H), 10.47 (s, 1H), 8.17 (d, J= 6.8 Hz, 1H), 7.93 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 14.3, 8.5 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.40 - 7.30 (m, 4H), 7.30 - 7.23 (m, 1H), 7.08 (t, J= 6.8 Hz, 1H), 5.08 (dd, J= 13.3, 5.1 Hz, 1H), 4.34 (d, J = 17.3 Hz, 1H), 4.23 (d, J = 17.3 Hz, 1H), 3.80 (s, 2H), 2.87 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.60 - 2.53 (m, 1H), 2.43 - 2.30 (m, 1H), 1.97 (m, 1H). Compound 126

[0384] Compound 126 was synthesized following the same protocol as for compound 125. Benzoyl chloride was used instead. Yield: 9.1 mg, 71%. LC-MS: calculated exact mass = 479.16 found [M+H]+= 480.26.

[0385] Compound 127

[0386] Compound 127 was synthesized following the same protocol as for compound 125. Cyclohexanecarbonyl chloride was used instead. Yield: 10.1 mg, 78%. LC-MS: calculated exact mass = 485.21 found [M+H]+= 486.27.

[0387] Compound 127 (9.00 mg, 1 Eq, 24.0 pmol) was mixed with cesium carbonate (23.4 mg, 3 Eq, 71.9 pmol) and aryl bromide (bromobenzene, 4.14 mg, 1.1 Eq, 26.4 pmol) in a glass vial. After three cycles of vacuum / nitrogen, the tBu-XPhos Pd G3 (1.90 mg, 0.1 Eq, 2.40 pmol) was added, and the reaction vessel was purged with vacuum / nitrogen again. Anhydrous dioxane (200 pL, purged with nitrogen for at least 10 minutes) was added and nitrogen was bubbled through the reaction mixture. The mixture was sealed and stirred at 100 °C for 16 hours. Product formation was detected via LC-MS. The mixture was diluted in DMSO, filtered and purified via preparative HPLC using McOILthO (0.035% formic acid additive) elution gradient. Yield: 5.1 mg, 47%. LC- MS: calculated exact mass = 451.2 found [M+H]+= 452.3. ’H NMR (500 MHz, DMSO) 5 11.00 (s, 1H), 8.50 (s, 1H), 8.22 (s, 1H), 8.16 (d, J= 7.8 Hz, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.63 (m, 1H), .22 - 7.13 (m, 3H), 6.78 (t, J = 7.3 Hz, 1H), 6.62 (d, 7= 7.9 Hz, 2H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (d, J= 17.3 Hz, 1H), 4.37 (d, J = 17.3 Hz, 1H), 2.92 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.61 (m, 1H), 2.41 (m, 1H), 2.05 - 1.98 (m, 1H).

[0388] Compound 129

[0389] Compound 129 was synthesized following the compound 110 procedure on a 9.3 pmol scale using 6-bromoquinoxaline (1 Eq.) as aryl bromide. Yield: 2.0 mg, 44%. LC-MS: calculated exact mass = 503.2 found [M+H]+= 504.4.

[0390] Compound 130

[0391] Compound 130 was synthesized following the compound 110 procedure on a 9.3 pmol scale using 5-bromo-2, 3 -dihydrobenzo [b][ 1,4] dioxine (1 Eq.) as aryl bromide. Yield: 1.8 mg, 38%. LC-MS: calculated exact mass = 509.2 found [M+H]+= 510.4.

[0392] Compound 131

[0393] 131

[0394] To a solution of 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindoline-5-carboxylic acid (20 mg, 0.070 mmol) and DIPEA (36 |iL, 0.21 mmol, 3.0 equiv) in DMF (0.3 mL) was added HATU (40 mg, 0.10 mmol, 1.5 equiv) and imidazo[l,2-a]pyridin-2-amine (l lmg, 0.080 mmol, 1.1 equiv) at room temperature. The mixture was stirred at room temperature for 1 h, and then quenched by sodium bicarbonate sat. solution, extracted by Chloroform / isopropanol (4 / 1), concentrated in vacuo. The residue was dissolved in DMSO and purified via preparative HPLC using Me0H:H20 gradient. Yield: 5.7 mg, 21%. LC-MS: calculated exact mass = 403.13 found [M+H]+ = 404.23.

[0395] H NMR (500 MHz, DMSO-d6) 5 = 11.02 (s, 1H), 9.18 (s, 1H), 7.88 (d, J = in Hz, 1H), 7.83 (s, 1H), 7.71 (dd, J = 7.8, 1.4 Hz, 1H), 7.59 (ddd, J = 8.6, 7.0, 1.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.05 (td, 7 = 6.9, 1.3 Hz, 1H), 5.96 (s, 2H), 5.17 (dd, 7 = 13.3, 5.1 Hz, 1H), 4.54 (d, 7 = 17.6 Hz, 1H), 4.43 (d, J = 17.5 Hz, 1H), 2.93 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.65 - 2.57 (m, 1H), 2.49 - 2.36 (m, 1H), 2.10 - 1.99 (m, 1H).

[0396] Compound 132

[0397] 5:3 dioxane: water solvent mixture was degassed under continuous nitrogen flow for at least 10 minutes. A vial was charged with 2-bromo-3-chloroimidazo[l,2-a]pyridine (14 mg, 62 pmol, 1.1 equiv), tert-butyl 5-amino-5-oxo-4-(l-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)pentanoate (25 mg, 56 pmol, 1.0 equiv), Pd(dppf)Ch • DCM (2.3 mg, 2.8 pmol, 0.05 equiv) and K3PO4 (60 mg, 0.28 mmol, 5.0 equiv). After three vacuum / nitrogen cycles, degassed solvent mixture was added and heated overnight at 70 °C. LCMS showed the coupling product formation with partial tert-butyl ester hydrolysis. The mixture was diluted with EtOAc, passed through wet celite pad, and dried under vacuum. The solid residue was dissolved in ACN (500 pL) and TsOH*H2O (24 mg, 120 pmol, 2.2 equiv) were added. The mixture was diluted with DMSO and purified via preparative HPLC using MeOH:H2O gradient. Yield (over two steps): 4.6 mg, 21%. LC-MS: calculated exact mass = 394.08 found [M+H]+ = 395.13. ' H NMR (500 MHz, DMSO) 8 11.01 (s, 1H), 8.45 (d, J = 6.9 Hz, 1H), 8.33 (s, 1H), 8.26 (dd, 7 = 7.9, 1.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.45 (ddd, J = 9.1, 6.8, 1.3 Hz, 1H), 7.17 (td, 7- 6.8, 1.1 Hz, 1H), 5.15 (dd, 7= 13.3, 5.2 Hz, 1H), 4.57 (d, J = 17.3 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 2.93 (ddd, 7= 17.4, 13.6, 5.4 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.49 -

[0398] 2.37 (m, 1H), 2.09 - 2.00 (m, 1H).

[0399] Example 2: Biological Data 30,000 Jurkat WEEl-HiBiT or 20,000 Jurkat CKlα-HiBiT cells per well were plated in

[0400] 384 well plates (50 pL total). Cells were treated with compound for 5 hours. After 5 hours, 25 pL of Nano-Gio® HiBiT Lytic Detection System (Promega) was added and incubated at room temperature for 10 minutes. Luminescence was read. DC50 and Dmax values were calculated using the nonlinear regression with variable slopes on Graph Pad PRISM. Data are shown below in Table 1. Additional data are shown in FIGS. 2 and 3.

[0401] Table 1.

[0402] +++: < 100 nM; ++: 100-1000 nM; +: 1000-10000 nM; -: > 10000 nM N / A stands for not available.

[0403] Example 3: Target Degradation in Tumor Cell Lines Cellular and Molecular Biology Methods

[0404] Cell line growth and maintenance. Jurkat, MOLT-4, SU-DHL-5, Molm-14, NB-4 were maintained in RPM1-1640 (Gibco) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Gibco) and 100 U / mL penicillin-streptomycin (Gibco). LoVo were cultured in F-12K (ATCC) supplemented with 10% heat-inactivated FBS (Gibco) and 100 U / mL penicillin- streptomycin (Gibco). All cell lines were cultured at 37 °C in a humidified incubator in the presence of 5% CO2. Mycoplasma testing was performed monthly using the My co Alert mycoplasma detection kit (Lonza, Basel, Switzerland), and all lines were negative. Immunoblotting. Whole cells lysates for immunoblotting were prepared by pelleting cells from each cell line at 4 °C (500 g) for 5 minutes. The resulting cell pellets were washed once with ice-cold lx PBS and then resuspended in RIPA Lysis and Extraction Buffer (Thermo Fisher Scientific) supplemented with protease and phosphatase cocktails (Roche). Lysates were clarified at 20,000 g for 15 minutes at 4 °C. Protein concentrations were determined by BCA protein assay (Pierce). Whole cell lysates were loaded into 4-20% precast polyacrylamide gels (Bio-Rad) and separated by electrophoresis. The gels were transferred to a nitrocellulose membrane (Bio-Rad) and blocked for 1 hour at room temperature in Intercept (TBS) Blocking Buffer (LLCOR). Membranes were probed using antibodies raised against Weel (Cell Signaling Technology, #13084S), CKlα (Abeam, #abl08296), GSPT1 (Abeam, #ab49878), Ikaros (Cell Signaling Technology, #14859S), Helios (Cell Signaling Technology, #42427S), CRBN (Novus Biologicals, #NBPl-91810), a-Tubulin (Cell Signaling Technology, #3873S), or P-Actin (Cell Signaling Technology, #3700) at 4 °C overnight. Membranes were incubated with the IRDye800-labeled goat anti-rabbit IgG or IRDye680-labeled goat anti-mouse IgG (LI-COR) secondary antibodies at room temperature for 1 hour and imaged using an Odyssey CLx system.

[0405] Cell viability assays (CellTiter-Glo assay). 2.0 x 103 suspension cells were plated in 50 pL per well growth medium in opaque white 384-well plates (Corning) followed by drag treatment immediately at indicated concentrations. 1.0 x 103adherent cells were plated in 50 pL per well growth medium in opaque white 384-well plates (Corning) followed by drag treatment the next day at indicated concentrations. After 72 hours incubation, cellular ATP content was measured using CellTiter-Glo reagent (Promega). Cell viability and IC50 values were determined using a non-linear regression curve fit in GraphPad PRISM 10.2.2 by considering each set of singlicate measurements in a given experiment as an independent replicate for curve fitting. The IC50 is reported as the mean of the DC50 values from the singlicate fits. The error was determined by calculating the standard error of the mean of the associated singlicate DC50 values from the singlicate fits.

[0406] Results and Discussion

[0407] Compounds 5, 6, 17, 24, 26, 29, 77, 89, 90, 124, 128, 131, and 132 were tested for their abilities to induce WEEl / CKlα degradation in multiple tumor cell lines. Selective WEE1 degraders 131 and 90 demonstrated significant and selective degradation of WEE1 over CKlα in Jurkat, MOLM-14, NB-4 (acute promyelocytic leukemia), and LoVo (colorectal adenocarcinoma) cell lines (FIGS. 4A-4E). Compound 90 partially degraded CK l a in SU-DHL- 5 cells (diffuse large B cell lymphoma), while compound 131 maintained WEE1 selectivity in these cells. Compound 29 was used as a reference for potent degradation of both kinases.

[0408] The antiproliferative effects of these compounds were measured in SU-DHL-5, MOLM- 14, NB-4, and LoVo cells. EC50 concentrations and the maximum cell death at 10 pM compound relative to the DMSO control were determined (FIGS. 5A-5B). Compounds X (having the same structure as compound 5, but with a N-methylated glutarimide) and 26 were inactive in all tested cell lines, demonstrating that glutarimide-CRBN engagement and a fitting exit vector from the isoindolinone scaffold are required for activity. Compounds 26 and 29 were the most potent antiproliferative hits, outperforming the GSPT1 degrader CC90009 and ZNL-02- 096. The selective compounds induced mild cytotoxic effects in several tested cell lines but did not decrease relative proliferation below 50%. As WEE1 is known to prevent mitotic catastrophe in malignancies with high genomic instability (Leijen et al. Curr. Clin. Pharmacol. 2010, 5 (3), 186-191), potential synergistic antiproliferative effects were explored by cotreating MOLT-4 or MOLM-14 cells with selective WEE1 degraders and a clinical DNA-damaging chemotherapy agent, gemcitabine (FIG. 6A). Co-treatment with compound 131 results in a modest increase in cytotoxicity. In contrast, the previously reported WEE1 PROTAC ZNL-02-096 showed pronounced synergy with gemcitabine (FIG. 6B). Lack of synergy inspired further exploration of compound 90 degradation activity. Western blot analysis showed that WEE1 rebounds to steady state levels 72 h after compound treatment (FIG. 7). Secondary treatment of cells with compound 90 after an initial 72 h treatment causes significant WEE1 redegradation, confirming the capacity for WEE1 degradation is maintained. Co-treatment with tariquidar, a multidrug resistance protein 1 inhibitor, does not enhance WEE1 downregulation at the 72 h time point, indicating that the efflux of the compound is not a factor at longer treatment time points.

[0409] 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:A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:A is a five- or six-membered heteroaromatic ring;R1is selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)m- X, and hydrogen, wherein m is 0, 1, 2, or 3, and X is selected from -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, - NRaC(O)ORb, and -Si(C1-C6alkyl)3; n is 0, 1, 2, or 3; each R2is independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two R2are optionally taken together with the atoms to which they are attached to form a five- or six-membered ring that is optionally substituted with 1-3 Rc;R3is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Re), -S(O)Rd, -S(O)2Rd, -NRdS(O)2Re, - NRdC(O)Re, and -NRdC(O)ORe;X is -C(O)- or -CH2-;Raand Rbare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Raand Rb, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; each Rcis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two Rcare optionally taken together with the atoms to which they are attached to form a 5- to 6-membered ring that is optionally substituted with 1-3 Rf;Rdand Reare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, hctcroaryl, and heterocyclyl; wherein Rdand Re, together with the atom(s) to which they are attached, arc taken together to form a 5- or 6-membered ring; and each Rfis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein each cycloalkyl, aryl, heteroaryl, heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, halo, cyano, nitro, and aryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is a five- or six-membered heteroaromatic ring;R1is selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)m- X, and hydrogen, wherein m is 1, 2, or 3, and X is selected from -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, - NRaC(O)ORb, and -Si(C1-C6alkylh; n is 0, 1, 2, or 3; each R2is independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two R2are optionally taken together with the atoms to which they are attached to form a five- or six-membered ring that is optionally substituted with 1-3 Rc;R3is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heterocyclyl, halo, nitro, cyano, -ORd, -SRd, -N(Rd)(Re), -C(O)Rd, -C(O)ORd, -C(O)N(Rd)(Re), -S(O)Rd, -S(O)2Rd, -NRdS(O)2Re, - NRdC(O)Re, and -NRdC(O)ORe;X is -C(O)- or -CH2-;Raand Rbare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Raand Rb, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring;each Rcis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein two Rcarc optionally taken together with the atoms to which they are attached to form a 5- to 6-membered ring that is optionally substituted with 1-3 Rf;Rdand Reare each independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, and heterocyclyl; wherein Rdand Re, together with the atom(s) to which they are attached, are taken together to form a 5- or 6-membered ring; and each Rfis independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl; wherein each cycloalkyl, aryl, heteroaryl, heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, cyano, nitro, and aryl.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein A is a 5- or 6-membered heteroaromatic ring having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from N, S, and O.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein n is 0.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and each R2is independently selected from C1-C4alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, cyano, nitro, and phenyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from methyl, isopropyl, trifluoromethyl, methoxy, fluoro, bromo, cyano, nitro, and phenyl.

7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein n is 2, and the two R2are taken together with the atoms to which they are attached to form an unsubstituted five- or six-membered aromatic, hetero aromatic, or heterocyclic ring.

8. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein n is 2, and the two R2are taken together with the atoms to which they are attached to form a six-membered aromatic ring that is unsubstituted or substituted with one substituent selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, Ci-C& haloalkoxy, and halo.

9. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof,10. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the grouphas a structure selected from:

11. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the grouphas a structure selected from:

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1is selected from Ca-Cx alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl- C1-C2-alkyl, heteroaryl-C1-C2-alkyl, heterocyclyl-C1-C2-alkyl, and -(CH2)m-X, wherein m is 0 or 1 , and X is selected from -ORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)(Rb), and -Si(Ci-C4alkyl)3.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1is selected from Cx-Cx alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl- C1-C2-alkyl, heteroaryl-C1-C2-alkyl, heterocyclyl-C1-C2-alkyl, and -(CH2)m-X, wherein m is 1, and X is selected from -ORa, -C(O)ORa, -C(O)N(Ra)(Rb), and -Si(Ci-C4alkyl)3.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1is selected from C3-C8alkyl, C3-C10 cycloalkyl, phenyl, naphthyl, quinoxalinyl, 1,3- benzodioxolyl, 1,3-benzodioxinyl, phenyl-Ci-Ci-alkyl, diphenyl-C1-C2-alkyl, pyridinyl-Ci-Ci- alkyl, morpholino-C1-C2-alkyl, and -(CH2)m-X; wherein: m is 0 or 1, X is selected from -ORa, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)(Rb), and -Si(Ci-C4alkyl)3; Rais selected from hydrogen, Ci-C4alkyl, C4-C? cycloalkyl, aryl, and aryl-Ci-C3-alkyl; and Rbis selected from hydrogen and Ci-C4alkyl; or Raand Rb, together with the nitrogen atom to which they arc attached, are taken together to form a five- or six-membered ring.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1is selected from C3-C8alkyl, C3-C10 cycloalkyl, phenyl, naphthyl, quinoxalinyl, 1,3- benzodioxolyl, 1,3-benzodioxinyl, phenyl-C1-C2-alkyl, diphenyl-C1-C2-alkyl, pyridinyl-C1-C2- alkyl, morpholino-C1-C2-alkyl, and -(CH2)m-X; wherein: m is 1, X is selected from -ORa, - C(O)ORa, -C(O)N(Ra)(Rb), and -Si(Ci-C4alkyl)3; and Raand Rbare each independently selected from hydrogen and Ci-C4alkyl, or Raand Rb, together with the nitrogen atom to which they are attached, are taken together to form a five- or six-membered ring.

16. The compound of any one of claims 1 -15, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)-.

19. The compound of any one of claims 1 -17, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, R3is hydrogen.

21. The compound of claim 1, wherein the compound is selected from:22.A compound selected from:and pharmaceutically acceptable salts thereof.

23. A pharmaceutical composition comprising a compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. A method of degrading a target protein in a sample, comprising contacting the sample with an effective amount of the compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 23.

25. The method of claim 24, wherein the target protein is selected from CK I a and WEE1.

26. A method of reducing proliferation of cancer cells in a sample, comprising contacting the sample with an effective amount of the compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24.

27. The method of claim 26, wherein the cancer cells are selected from acute and chronic leukemia, non-Hodgkin lymphoma, multiple myeloma, hepatocellular carcinoma, breast cancer, cervical cancer, lung cancer, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, and ovarian cancer cells.

28. A method of treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by aberrant activity of CKlα and / or WEE1, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 23.

29. The method of claim 28, wherein the disease or disorder is cancer.

30. The method of claim 29, wherein the cancer is selected from acute and chronic leukemias, non-Hodgkin lymphomas, multiple myeloma, hepatocellular carcinoma, breast cancers, cervical cancers, lung cancers, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, and ovarian cancers.

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