Therapeutic compounds and methods

Abstract

The invention provides a compound of formula (I): (I) or a salt thereof, wherein R'-R2 and A and ¥ have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are useful to bind to or to degrade Aurora kinase A and N-Myc. Methods for treating cancer using the compounds are also provided.

Description

[0001] U of M 2025-025 VHPM 09531.599WO1 THERAPEUTIC COMPOUNDS AND METHODS CROSS REFERENCE TO RELATED APPLICATION This application claims priority to United States Provisional Application Number 5 63 / 681,680 that was filed on August 9, 2024. The entire content of the application referenced above is hereby incorporated by reference herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under W81XWH-21-1-0674 10 awarded by the Medical Research and Development Command. The government has certain rights in the invention. BACKGROUND N-Myc is a member of the Myc family of transcription factors encoded by the MYCN proto-oncogene. Enhanced and deregulated expression of N-Myc drives the development of a 15 number of human cancers, including neuroblastoma, medulloblastoma, neuroendocrine prostate cancer, and small-cell lung cancer, etc. For instance, in neuroblastoma MYCN amplification is the strongest indicator of poor prognosis.5-year survival rates for low- or moderate-risk patients are 80-95%; for high-risk patients that typically have increased N-Myc levels, 5-year survival is only 50% although with more aggressive treatments. Despite recognition of its critical roles in 20 neuroblastoma, N-Myc, like its homolog C-Myc, remains a challenging target for drug discovery scientists. In neuroblastoma, N-Myc is frequently stabilized by binding to Aurora kinase A. One way to inhibit N-Myc signaling has been to disrupt the N-Myc-Aurora kinase A protein-protein interaction. Small molecules have been developed that bind to Aurora kinase A and induce a 25 conformation that is incompatible with N-Myc binding, leading to increased proteasomal degradation of N-Myc and reduced protein levels. The general design of the molecules disclosed herein consists of an Aurora kinase A-binding moiety that is uncompetitive with N-Myc binding to Aurora kinase A. The Aurora kinase A-binding moiety is, connected to an E3 ligase ligand through a chemical linker. 30 International Patent Application Publication Number WO 2020 / 247537 reports certain compounds that degrade Aurora kinase A. In spite of this disclosure, there remains a need for 1 U of M 2025-025 VHPM 09531.599WO1 compounds that degrade Aurora kinase A. In particular, there is a need for compounds having advantages over earlier compounds, such as, for example, enhanced potency, physiochemical properties (e.g., solubility), or differing target specify. 5 SUMMARY Compounds that degrade Aurora kinase A are provided. The compounds are useful for treating N-Myc-driving cancers, including childhood neuroblastoma and neuroendocrine prostate cancer. Certain compounds may demonstrate advantages over earlier compounds, such as, for example, enhanced potency or differing target specify. In some non-limiting 10 embodiments, the molecules disclosed herein disrupt the N-Myc-Aurora kinase A interaction by inducing the proteasomal degradation of Aurora kinase A. Accordingly, a compound of formula (I): or a salt thereof, wherein: 15 R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) 20 substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -NRxRyor -C(=O)R3; R3is (C1-C6)alkoxy, -NRdRe, or -L-X; L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any 25 (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or 30 piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is 2 U of M 2025-025 VHPM 09531.599WO1 optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, provided that Rband Rcare not each methyl; each Rdand Reis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rdand Retogether with the nitrogen to 5 which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; each Rxand Ryis independently selected from the group consisting of H, (C1-C6)alkyl, 10 (C3-C6)cycloalkyl, (C1-C6)alkanoyl and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rxand Rytogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, and 15 X is the residue of an E3 ligase ligand; or wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, CL, and Br; 20 A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; 25 L is a linker that comprises one or more heterocyclic rings; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, 30 (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or U of M 2025-025 VHPM 09531.599WO1 piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and X is the residue of an E3 ligase ligand; 5 or wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl 10 ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; L is absent or is a linker; 15 Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to 20 which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and X is an E3 ligase ligand selected from the group consisting of:

[0002] U of M 2025-025 VHPM 09531.599WO1 is provided. A pharmaceutical composition comprising a compound of formula (I) or a 5 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is also provided. A method for treating cancer (e.g., neuroblastoma, medulloblastoma, neuroendocrine prostate cancer, or small-cell lung cancer) in an animal (e.g., a mammal such as a human) comprising administering a compound of formula (I) or a pharmaceutically acceptable salt 10 thereof to the animal is also provided. A method to degrade Aurora kinase A, comprising contacting Aurora kinase A with a compound of formula (I) or a salt thereof is provided. A method to degrade N-Myc resulting from the degradation of Aurora kinase A, comprising contacting Aurora kinase A with a compound of formula (I) or a salt thereof is 15 provided. A method comprising degrading N-Myc with a molecule that degrades Aurora kinase A. A method comprising concurrently degrading N-Myc and Aurora kinase A with a single molecule. A compound or salt that has both N-Myc degrading properties and Aurora kinase A 20 degrading properties. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in U of M 2025-025 VHPM 09531.599WO1 medical therapy is also provided. A compound of formula (I) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of cancer is also provided. A compound of formula (I) or a salt thereof to degrade Aurora kinase A is provided. 5 The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating cancer in an animal (e.g. a mammal such as a human) is also provided. The use of a of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament to degrade Aurora kinase A in an animal is provided. 10 Processes and intermediates disclosed herein that are useful for preparing a compound of formula (I) or a salt thereof are also provided. In addition to degrading Aurora kinase A, certain compounds can elicit the concomitant degradation of N-Myc by removing the scaffolding function of Aurora kinase A in diseases in which N-Myc is over expressed. 15 BRIEF DESCRIPTION OF DRAWINGS Figures 1A-1E show data from Example 70 for compounds HLB-0534987 and HLB- 0535024. Figure 1A shows the structures of compounds HLB-0534987 and HLB-0535024. Figure 1B shows Aurora kinase A and N-Myc protein levels after treating neuroblastoma cells 20 with HLB-0534987 for 4 hours. Figure 1C shows Aurora kinase A and N-Myc protein levels after treating neuroblastoma cells with HLB-0535024 for 4 hours. Figure 1D shows quantification of Figure 1B immunoblots. Figure 1E shows quantification of Figure 1C immunoblots. Figures 2A-2C show degradation studies of compounds HLB-0535360 and HLB- 25 0535376. Figure 2A shows the structures of HLB-0535360 and HLB-0535376. Figure 2B shows that degradation of Aurora-A and N-Myc are dependent on binding to Cereblon. Figure 2C shows that warheads to Aurora-A and Cereblon do not illicit degradation, and that degradation by active molecules occurs through the ubiquitin-proteasome system. 30 U of M 2025-025 VHPM 09531.599WO1 DETAILEDDESCRIPTIONThe following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a 5 branched chain isomer such as isopropyl being specifically referred to. The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8means one to eight carbons). Examples include (C1-C8)alkyl, (C2-C8)alkyl, C1-C6)alkyl, (C2-C6)alkyl and (C3-C6)alkyl. Examples of alkyl groups include methyl, ethyl, n- 10 propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers. The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”). The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all 15 carbon ring having 3 to 8 carbon atoms (i.e., (C3-C8)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and 20 polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a 25 fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane. The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple 30 condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon U of M 2025-025 VHPM 09531.599WO1 atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl). The rings of the multiple condensed ring system can 5 be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like. 10 The term “heterocycle” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or 15 partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring 20 systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring 25 system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered 30 heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one U of M 2025-025 VHPM 09531.599WO1 embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or 5 bicyclic heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 10 tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'- isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, 15 phthalimide, and 1,4-dioxane. The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further 20 described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems 25 (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls 30 include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, U of M 2025-025 VHPM 09531.599WO1 oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl. The term “alkoxycarbonyl” as used herein refers to a group (alkyl)-O-C(=O)-, wherein the term alkyl has the meaning defined herein. 5 The term “alkanoyloxy” as used herein refers to a group (alkyl)-C(=O)-O-, wherein the term alkyl has the meaning defined herein. As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). As used herein, the term "protecting group" refers to a substituent that is commonly 10 employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a 15 substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- 20 (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4thedition, Wiley-Interscience, New York, 2006. As used herein a wavy line “ ” that intersects a bond in a chemical structure indicatesthe point of attachment of the bond that the wavy bond intersects in the chemical structure to the 25 remainder of a molecule. Linker The linker can be variable provided the compound of formula (I) functions as desired. The linker can vary in length and atom composition and for example can be branched or non- 30 branched or cyclic or a combination thereof. The linker may also modulate the properties of the compound of formula (I), such as solubility, stability and / or aggregation. U of M 2025-025 VHPM 09531.599WO1 In one embodiment, the linker comprises about 3-200 atoms. In one embodiment, the linker comprises about 5-50 atoms selected from H, C, N, S and O. In one embodiment, the linker comprises a branched or unbranched, saturated or 5 unsaturated, hydrocarbon chain, having from about 1 to 50 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, 3-10 membered heterocycle, 5-6-membered heteroaryl or carbocycle and wherein each chain, 3-10 membered heterocycle, 5-6-membered heteroaryl or carbocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1- 10 C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, azido, cyano, nitro, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1-C6)alkyl. In one embodiment, the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more 15 of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, or a 3-10 membered heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais 20 independently H or (C1-C6)alkyl. In one embodiment, the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -N(Ra)-, or a 3-10 membered heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and 25 independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1-C6)alkyl. In one embodiment, the linker comprises a branched or unbranched, saturated or 30 unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, -N(Ra)-, or a 3-10 membered U of M 2025-025 VHPM 09531.599WO1 heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais 5 independently H or (C1-C6)alkyl. In one embodiment, the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -N(Ra)-, or a 3-10 membered heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and independently 10 substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1- C6)alkyl. In one embodiment, the linker comprises a polyethylene glycol having 2, 3, 4, or 5 repeat 15 (e.g., -CH2CH2O-) units (Greenwald, R.B., et al., Poly (ethylene glycol) Prodrugs: Altered Pharmacokinetics and Pharmacodynamics, Chapter, 2.3.1., 283-338; Filpula, D., et al., Releasable PEGylation of proteins with customized linkers, Advanced Drug Delivery, 60, 2008, 29-49; Zhao, H., et al., Drug Conjugates with Poly(Ethylene Glycol), Drug Delivery in Oncology, 2012, 627-656). 20 E3 Ligase Ligand E3 ligase ligands bind to an E3 ligase protein. When an E3 ligase ligand is covalently bonded to a ligand that binds a protein of interest, such as Aurora kinase A in this application, through a chemical linker, a heterobifunctional degrading compound is formed. Such 25 compounds can result in the formation of a ternary protein complex where the E3 protein and associated proteins in the cell, such as E2, are brought in close proximity to the protein of interest such that ubiquitin is transferred to the protein of interest. The poly-ubiquitination of the protein of interest then marks the protein for degradation by the human proteasome. Common E3 ligase ligands are based on thalidomide that binds to Cereblon and synthetic 30 peptides that bind to Von Hippel-Lindau protein (Bricelj, A., et al. Front. Chem.2021, 9). Additional ligands have been developed to bind to E3 ligases found in the nuclear compartment, U of M 2025-025 VHPM 09531.599WO1 such as DCAF16 and L3MTBL3 (Zhang, X., et al. Nat Chem Biol 2019, 15 (7), 737–746 and Nalawansha, D. A., et al. J. Am. Chem. Soc.2022, 144 (12), 5594-5605). Phenyl glutarimide ligands bind to Cereblon, but are believed to have enhanced cellular stability (Min, J., et al. Angewandte Chemie International Edition 2021, 60 (51), 26663–26670). 5 Examples of E3 Ligase Ligands include: . Another example of an E3 Ligase Ligand is: 10 . The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and / or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and / or prophylactic treatment U of M 2025-025 VHPM 09531.599WO1 or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of 5 disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder 10 or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention, The phrase "therapeutically effective amount" or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the 15 particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The term “animal” includes mammals, fish, amphibians, reptiles, birds and invertebrates. The term “mammal” includes humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the animal is a mammal. In one 20 embodiment, the animal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient. The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are 25 contemplated. It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a -CH3group may be substituted with -CD3. 30 The pharmaceutical compositions can comprise one or more excipients. When used in combination with the pharmaceutical compositions the term “excipients” refers generally to an U of M 2025-025 VHPM 09531.599WO1 additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring 5 agents, coatings, preservatives, and dyes. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds can contain asymmetric or chiral centers, and 10 therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R 15 and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific 20 stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. 25 It will be appreciated by those skilled in the art that compounds having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound, which possess the useful properties described herein, it being well known in the art 30 how to prepare optically active forms (for example, by resolution of the racemic form by U of M 2025-025 VHPM 09531.599WO1 recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. 5 When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute 10 stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted. 15 The term “residue” as it applies to the residue of a compound refers to a compound that has been modified in any manner which results in the creation of an open valence wherein the site of the open valence. The open valence can be created by the removal of 1 or more atoms from the compound (e.g., removal of a single atom such as hydrogen or removal of more than one atom such as a group of atoms including but not limited to an amine, hydroxyl, methyl, 20 amide (e.g., -C(=O)NH2) or acetyl group). The open valence can also be created by the chemical conversion of a first function group of the compound to a second functional group of the compound (e.g., reduction of a carbonyl group, replacement of a carbonyl group with an amine, ) followed by the removal of 1 or more atoms from the second functional group to create the open valence. 25 Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded. Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- 30 butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(C1-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, U of M 2025-025 VHPM 09531.599WO1 cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2- 5 pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2-C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C1-C6)alkanoyl can be acetyl, propanoyl or butanoyl; (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, 10 pentoxycarbonyl, or hexyloxycarbonyl; (C1-C6)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl,15 pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N- oxide) or quinolyl (or its N-oxide). A specific compound or salt is a compound of formula (I) or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups 20 independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -NRxRyor -C(=O)R3; 25 R3is (C1-C6)alkoxy, -NRdRe, or -L-X; L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 30 each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to U of M 2025-025 VHPM 09531.599WO1 which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, provided that Rband Rcare not each methyl; 5 X is the residue of an E3 ligase ligand. A specific compound or salt is a compound of formula (I) or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 10 A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; 15 L is a linking group that comprises one or more heterocyclic rings; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, 20 (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; 25 L is a linking group; and X is the residue of an E3 ligase ligand. A specific compound or salt is a compound of formula (I) or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups 30 independently selected from the group consisting of F, Cl, and Br; U of M 2025-025 VHPM 09531.599WO1 A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; 5 R3is -L-X; L is absent or is a linking group; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 10 each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting 15 of (C1-C6)alkyl; L is a linking group; and X is an E3 ligase ligand selected from the group consisting of: . 20 A specific value for R1is H, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, azetadinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, 19 U of M 2025-025 VHPM 09531.599WO1 morpholinocarbonyl, diethylaminocarbonyl, 4-methylpiperidinocarbonyl, acetyl, propanoyl, or cyclopropylcarbonyl. A specific value for R1is dimethylaminocarbonyl. A specific value for R2is cyclopentyl. 5 In one embodiment R1is dimethylaminocarbonyl and R2is cyclopentyl. A specific value for A is a phenyl that is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo. A specific value for A is a phenyl. 10 A specific value for A is a phenyl that is substituted with (C1-C6)alkoxy or halo. A specific value for A is a pyridyl that is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo. A specific value for Y is -NRxRy. 15 A specific value for Y is -C(=O)R3and R3is -NRdRe. A specific value for Y is -C(=O)R3and R3is -L-X. A specific value for L is absent. A specific value for L is a linker. A specific value for X is selected from the group consisting of: 20 U of M 2025-025 VHPM 09531.599WO1 . A specific value for X is selected from the group consisting of: . 5 A specific compound or salt is selected from the group consisting of: U of M 2025-025 VHPM 09531.599WO1 5 and salts thereof. A specific compound or salt is selected from the group consisting of U of M 2025-025 VHPM 09531.599WO1 5 and salts thereof. A specific compound or salt is selected from the group consisting of: U of M 2025-025 VHPM 09531.599WO1 5 and salts thereof. A specific compound or salt is selected from the group consisting of U of M 2025-025 VHPM 09531.599WO1 5 and salts thereof. A specific compound or salt is selected from the group consisting of: U of M 2025-025 VHPM 09531.599WO1 5 U of M 2025-025 VHPM 09531.599WO1 5 U of M 2025-025 VHPM 09531.599WO1 and salts thereof. A specific compound or salt is selected from the group consisting of: 5

[0003] U of M 2025-025 VHPM 09531.599WO1 and salts thereof. A specific compound or salt is selected from the group consisting of: 5 U of M 2025-025 VHPM 09531.599WO1 and salts thereof. A specific compound or salt is selected from the group consisting of: 5 and salts thereof. A specific compound or salt is a compound of formula (I) or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; 10 R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; U of M 2025-025 VHPM 09531.599WO1 A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -NRxRyor -C(=O)R3; 5 R3is (C1-C6)alkoxy, -NRdRe, or -L-X; L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 10 each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting 15 of (C1-C6)alkyl, provided that Rband Rcare not each methyl; each Rxand Ryis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rxand Rytogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and 20 piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, and X is the residue of an E3 ligase ligand; or wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; 25 R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; 30 Y is -C(=O)R3; R3is -L-X; U of M 2025-025 VHPM 09531.599WO1 L is a linker that comprises one or more heterocyclic rings; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 5 each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting 10 of (C1-C6)alkyl; L is a linking group; and X is the residue of an E3 ligase ligand; or wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; 15 R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; 20 Y is -C(=O)R3; R3is -L-X; L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted 25 with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is 30 optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; U of M 2025-025 VHPM 09531.599WO1 L is a linking group; and X is an E3 ligase ligand selected from the group consisting of: 5 is provided. A specific compound or salt is a compound of formula (I) or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 10 A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -NRxRyor -C(=O)R3; R3is (C1-C6)alkoxy, -NRdRe, or -L-X; 15 L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, 20 (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or U of M 2025-025 VHPM 09531.599WO1 piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, provided that Rband Rcare not each methyl; each Rdand Reis independently selected from the group consisting of H, (C1-C6)alkyl, 5 (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rdand Retogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, 10 X is the residue of an E3 ligase ligand. A specific compound or salt is a compound of formula (I) or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 15 A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; 20 L is a linking group that comprises one or more heterocyclic rings; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, 25 (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and 30 X is the residue of an E3 ligase ligand. U of M 2025-025 VHPM 09531.599WO1 A specific compound or salt is a compound of formula (I) or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; 5 A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; 10 L is absent or is a linking group; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, 15 (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and 20 X is an E3 ligase ligand selected from the group consisting of: U of M 2025-025 VHPM 09531.599WO1 . A specific linker is selected from the group consisting of: 5 . A specific linker is selected from the group consisting of: 10 . A specific linker is selected from the group consisting of: U of M 2025-025 VHPM 09531.599WO1 5 . A specific value for X is selected from the group consisting of: 10 U of M 2025-025 VHPM 09531.599WO1 A specific compound or salt is selected from the group consisting of: 5 U of M 2025-025 VHPM 09531.599WO1 5 and salts thereof. A specific compound or salt is selected from the group consisting of: U of M 2025-025 VHPM 09531.599WO1 . 5 One embodiment provides a compound of formula: or a salt thereof. In one embodiment each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether 10 with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the U of M 2025-025 VHPM 09531.599WO1 group consisting of (C1-C6)alkyl, provided that Rband Rcare not each methyl when A is unsubstituted phenyl (except for the -NH- group and the Y group to which the phenyl is attached) or pyridine-2-yl. In one embodiment each Rband Rcis independently selected from the group consisting 5 of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, provided that Rband Rcare not each methyl. 10 In one embodiment for the compound of formula (I) each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3- C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one 15 or more groups independently selected from the group consisting of (C1-C6)alkyl, provided that the compound of formula (I) is not the compound: . Processes for preparing compounds of formula (I) are provided as further embodiments and are illustrated by the following procedures in which the meanings of the generic radicals are 20 as given above unless otherwise qualified. In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula (I) can be useful as an intermediate for isolating or purifying a compound of formula (I). Additionally, administration of a compound of formula (I) as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid 25 addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α- ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. U of M 2025-025 VHPM 09531.599WO1 Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. 5 The compounds of formula (I) can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. Thus, the present compounds may be systemically administered, e.g., orally, in 10 combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, 15 suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. 20 The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. 25 When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a 30 sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should U of M 2025-025 VHPM 09531.599WO1 be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may also be administered intravenously or intraperitoneally by 5 infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. 10 The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or 15 vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action 20 of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. 25 Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any 30 additional desired ingredient present in the previously sterile-filtered solutions. U of M 2025-025 VHPM 09531.599WO1 For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. 5 Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The 10 resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to 15 the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds of formula (I) to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No.4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No.4,559,157) and Wortzman (U.S. Pat. No.4,820,508). 20 Useful dosages of the compounds of formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949. The amount of the compound, or an active salt or derivative thereof, required for use in 25 treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. 30 The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced U of M 2025-025 VHPM 09531.599WO1 administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The invention will now be illustrated by the following non-limiting Examples. EXAMPLES5 Example 1. To a solution of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (4.a, 100 mg, 0.380 mmol) was added HATU (172 mg, 0.450 mmol) and DIPEA (98.2 mg, 0.760 10 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 30 minutes. Methylamine (2M in THF, 0.45 mmol) was added to the reaction mixture, and the reaction was stirred for 18 h at room temperature. After completion, ice cold water was added (10 mL) and the solution was extracted with EtOAc (20 mL). The organic phase was washed with brine (10 mL x 3). The organic layer was concentrated in vacuo and was purified using column 15 chromatography with a gradient of 0-100% EtOAc in hexanes to yield 4.b as a brown solid (110 mg, quantitative). 1H NMR (500 MHz, CDCl3) δ 8.76 – 8.65 (m, 1H), 6.72 – 6.64 (m, 1H), 6.63 – 6.49 (m, 1H), 5.41 – 5.29 (m, 1H), 2.95 (t, J = 4.2 Hz, 3H), 2.38 – 2.25 (m, 2H), 2.07 – 1.97 (m, 4H), 1.73 – 20 1.51 (m, 2H). 13C NMR (151 MHz, DMSO) δ 161.9, 153.9, 153.3, 152.3, 136.4, 117.1, 102.6, 56.9, 30.9 (2C), 26.5, 25.0 (2C). HRMS: C13H16ClN4O Calculated for [M+H]+: 279.1013; Found: 279.1005. U of M 2025-025 VHPM 09531.599WO1 Under argon, 4.b (54.9 mg, 0.197 mmol), 4-amino-N-methylbenzamide (4.c, 35.5 mg, 0.236 mmol), Pd(OAc)2(8.80 mg, 0.039 mmol), rac-BINAP (30.6 mg, 0.049 mmol) and Cs2CO3(160 mg, 0.492 mmol) were suspended in anhydrous dioxane (10 mL). The suspension was flushed 5 with argon and was heated to 100 ºC under argon for 18 h. The reaction mixture was cooled and concentrated in vacuo. The resulting residue was dissolved in EtOAc (40 mL) and washed with water (30 mL x 3) and brine (30 mL). The organic phase was concentrated under vacuo and was purified using column chromatography with a gradient of 0 to 20% of MeOH in CH2Cl2. The compound was further purified via reverse phase HPLC 10-90% MeCN (0.1% TFA) in H2O 10 (0.1% TFA) as a white solid (25.2 mg, 32% after HPLC, 1 X TFA salt). HPLC purity: 99.7% @ 254 nm; 99.8% @ 215 nm. 1H NMR (500 MHz, DMSO) δ 9.88 (s, 1H), 8.87 (d, J = 1.9 Hz, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.26 (d, J = 4.6 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 1.8 Hz, 15 1H), 5.56 (t, J = 9.1 Hz, 1H), 2.78 (d, J = 4.4 Hz, 6H), 2.54 (s, 2H), 2.04 (s, 2H), 1.96 (s, 2H), 1.72 – 1.67 (m, 3H). 13C NMR (151 MHz, DMSO) δ 166.7, 162.5, 155.5, 153.1, 152.3, 143.8, 132.7, 128.1 (2C), 127.0, 117.6 (2C), 111.9, 103.4, 56.6, 29.8 (2C), 26.6, 26.4, 24.6 (2C). HRMS: C21H25N6O2Calculated for [M+H]+: 393.2039; Found: 393.2031. 20 Example 2. 4.d was synthesized in a similar manner as 4.b with starting material isopropylamine, tan solid (90%). U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 6.68 (s, 1H), 6.15 – 6.09 (m, 1H), 5.36 (p, J = 8.6 Hz, 1H), 4.25 – 4.12 (m, 1H), 2.39 – 2.25 (m, 2H), 2.08 – 1.93 (m, 5H), 1.68 – 1.56 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H). 5 HRMS: C15H20ClN4O Calculated for [M+H]+: 307.1326; Found: 307.1311. Example 3. HLB-0534983 was synthesized in a similar manner as HLB-0534984, white solid (70% 10 after HPLC, 1 X TFA salt). HPLC purity: 99.9% @ 254 nm; 99.9% @ 215 nm. 1H NMR (500 MHz, DMSO) δ 9.87 (s, 1H), 8.85 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.26 (q, J = 4.5 Hz, 1H), 7.91 (d, J = 8.6 Hz, 4H), 7.80 (d, J = 8.5 Hz, 2H), 7.57 – 7.50 (m, 2H), 6.94 (s, 1H), 6.55 – 6.49 (m, 2H), 5.58 – 5.47 (m, 3H), 4.06 (dp, J = 14.0, 6.9 Hz, 1H), 2.78 (d, J = 4.5 Hz, 15 4H), 2.71 (d, J = 4.5 Hz, 3H), 2.54 (dt, J = 11.3, 6.3 Hz, 3H), 2.06 – 1.91 (m, 4H), 1.70 (q, J = 5.9 Hz, 3H). 13C NMR (151 MHz, DMSO) δ 166.7, 161.2, 155.4, 152.8, 152.3, 143.7, 133.0, 128.2 (2C), 127.1, 117.6 (2C), 111.8, 103.6, 56.6, 41.3, 29.9 (2C), 26.6, 24.7 (2C), 22.7 (2C). HRMS: C23H27N6O2Calculated for [M+H]+: 421.2352; Found: 421.2338. 20 Example 4. 4.e was synthesized in a similar manner as 4.b with starting material azetidine hydrochloride, tan solid (78%). U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, CDCl3): δ 8.81 (s, 1H), 6.63 (s, 1H), 5.33 (p, J = 8.6 Hz, 1H), 4.28 (dt, J = 37.0, 7.8 Hz, 4H), 2.47 – 2.33 (m, 4H), 2.16 – 2.00 (m, 4H), 1.74 – 1.61 (m, 3H). 513C NMR (126 MHz, CDCl3): δ 162.3, 154.0, 152.5, 152.3, 132.8, 116.7, 102.2, 57.6, 52.9, 48.6, 31.0 (2C), 24.9 (2C), 15.8. HRMS: C15H18ClN4O Calculated for [M+H]+: 305.1169; Found: 305.1160. 10 Example 5. HLB-0535023 was synthesized in a similar manner as HLB-0534984, white solid (30% after HPLC, 1 X TFA salt). HPLC purity: 99.9% @ 254 nm; 95.6% @ 215 nm. 15 1H NMR (500 MHz, DMSO): δ 9.88 (d, J = 3.5 Hz, 1H), 8.82 (s, 1H), 8.26 (d, J = 4.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 6.83 (s, 1H), 5.34 (p, J = 9.0 Hz, 1H), 4.36 (s, 2H), 4.07 (s, 2H), 2.78 (d, J = 4.4 Hz, 3H), 2.28 (p, J = 7.6 Hz, 2H), 2.01 (d, J = 23.7 Hz, 4H), 1.69 (d, J = 6.1 Hz, 2H). 20 13C NMR (151 MHz, DMSO): δ 166.2, 162.2, 155.1, 152.6, 151.6, 143.3, 129.1, 127.7, 126.6, 117.2 (2C), 111.6, 103.8, 56.5, 52.6, 48.2, 40.1, 29.4 (2C), 26.2, 24.2 (2C), 15.3. HRMS: C23H27N6O2Calculated for [M+H]+: 419.2196; Found: 419.2178. 25 Example 6. U of M 2025-025 VHPM 09531.599WO1 4.f was synthesized in a similar manner as 4.b with starting material pyrrolidine, red solid (92%). 5

[0004] U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 6.53 (s, 1H), 4.96 (p, J = 8.7 Hz, 1H), 3.61 (t, J = 7.0 Hz, 2H), 3.44 (t, J = 6.7 Hz, 2H), 2.30 (dtd, J = 16.8, 8.5, 3.3 Hz, 2H),2.05 – 1.94 (m, 6H), 1.91 – 1.85 (m, 2H), 1.66 – 1.54 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 161.4, 153.7, 152.1, 151.9, 136.3, 117.0, 100.1, 57.7, 49.4, 5 46.1, 31.0 (2C), 26.1, 24.8 (2C), 24.3. HLB-0534985 was synthesized in a similar manner as HLB-0534984, white solid (74% after HPLC, 1 X TFA salt). HPLC purity: 97.6% @ 254 nm; 98.4% @ 215 nm. 101H NMR (500 MHz, DMSO) δ 9.86 (s, 1H), 8.81 (s, 1H), 8.26 (q, J = 4.4 Hz, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H), 6.78 (s, 1H), 4.96 (p, J = 8.9 Hz, 1H), 3.54 (dt, J = 28.1, 6.7 Hz, 5H), 2.78 (d, J = 4.4 Hz, 3H), 2.01 (q, J = 6.8 Hz, 5H), 1.89 (dq, J = 17.4, 6.6 Hz, 3H), 1.73 – 1.65 (m, 2H). 13C NMR (151 MHz, DMSO) δ 166.7, 161.2, 154.7, 151.7, 151.6, 143.5, 134.0, 133.9, 128.2, 15 127.3, 117.8, 112.3, 102.1, 57.5, 49.3, 46.2, 30.0 (2C), 26.6, 26.2, 24.7 (2C), 24.3. HRMS: C24H29N6O2 Calculated for [M+H]+: 433.2352; Found: 433.2334. Example 7. 20 4.g was synthesized in a similar manner as 4.b with starting material piperidine, red solid (85%). U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, CDCl3): δ 8.76 (s, 1H), 6.46 (s, 1H), 4.83 (p, J = 8.7 Hz, 1H), 3.73 (d, J = 6.5 Hz, 2H), 3.42 (t, J = 5.5 Hz, 2H), 2.41-2.31 (m, 2H), 2.10 – 1.94 (m, 4H), 1.74 – 1.58 (m, 6H), 1.56 – 1.51 (m, 2H). 513C NMR (126 MHz, CDCl3): δ 161.8, 153.4, 152.1, 151.6, 135.8, 117.2, 98.9, 57.9, 48.7, 43.1, 31.1 (2C), 26.7, 25.6, 24.8 (2C), 24.5. HRMS: C17H22ClN4O Calculated for [M+H]+: 333.1482; Found: 333.1465. 10 Example 8. HLB-0534993 was synthesized in a similar manner as HLB-0534984, white solid (30% after HPLC, 1 X TFA salt). HPLC purity: 99.9% @ 254 nm; 99.9% @ 215 nm. 151H NMR (500 MHz, DMSO): δ 9.84 (d, J = 2.3 Hz, 1H), 8.80 (s, 1H), 8.25 (d, J = 4.7 Hz, 1H), 7.92 – 7.85 (m, 2H), 7.79 (d, J = 8.9 Hz, 2H), 6.56 (s, 1H), 4.71 (p, J = 8.8 Hz, 1H), 3.56 (d, J = 52.2 Hz, 4H), 2.78 (d, J = 4.3 Hz, 3H), 2.48 (d, J = 14.8 Hz, 3H), 2.01 (s, 4H), 1.73 – 1.61 (m, 5H), 1.54 (s, 5H). 2013C NMR (151 MHz, DMSO): δ 166.2, 161.4, 154.5, 154.5, 151.4, 143.3, 132.6, 127.7 (2C), 126.6, 117.1 (2C), 112.0, 99.7, 57.0, 48.1, 42.2, 40.1, 29.8 (2C), 26.2, 25.4, 24.2 (2C), 24.0. HRMS: C25H31N6O2 Calculated for [M+H]+: 447.2509; Found: 447.2501. 25 U of M 2025-025 VHPM 09531.599WO1 Example 9. 4.h was synthesized in a similar manner as 4.b with starting material morpholine, red solid (91%). 5 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 6.51 (s, 1H), 4.90 (p, J = 8.7 Hz, 1H), 3.95 – 3.42 (m, 8H), 2.44 – 2.30 (m, 2H), 2.13 – 1.98 (m, 4H), 1.75 – 1.62 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 162.2, 153.8, 152.4, 152.0, 134.7, 117.0, 100.1, 66.9 (2C), 10 58.0, 48.2, 42.7, 31.3 (2C), 24.9 (2C). HRMS: C16H20ClN4O2 Calculated for [M+H]+: 335.1275; Found: 335.1263. Example 10. 15 HLB-0534994 was synthesized in a similar manner as HLB-0534984, white solid (38% after HPLC, 1 X TFA salt). HPLC purity: 97.0% @ 254 nm; 96.7% @ 215 nm. 1H NMR (600 MHz, DMSO): δ 9.91 – 9.86 (m, 1H), 8.82 (d, J = 1.0 Hz, 1H), 8.27 (q, J = 4.5 20 Hz, 1H), 7.93 – 7.87 (m, 2H), 7.81 (dt, J = 8.8, 1.7 Hz, 2H), 6.65 (d, J = 0.9 Hz, 1H), 4.82 – 4.73 (m, 1H), 3.64 (s, 8H), 2.79 (d, J = 4.3 Hz, 3H), 2.57 – 2.51 (m, 1H), 2.51 – 2.44 (m, 1H), 2.06- 1.98 (m, 4H), 1.74-1.66 (m, 2H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (151 MHz, DMSO): δ 166.2, 161.7, 154.7, 151.7, 151.2, 143.3, 131.6, 127.7 (2C), 126.6, 117.1 (2C), 111.9, 100.9, 66.2, 57.1, 40.1, 39.5, 29.8 (2C), 26.2 (2C), 24.2 (2C). HRMS: C24H29N6O3 Calculated for [M+H]+: 449.2301; Found: 449.2294. 5 Example 11. 4.i was synthesized in a similar manner as 4.b with starting material diethylamine, yellow solid (58%). 101H NMR (500 MHz, CDCl3): δ 8.79 (s, 1H), 6.50 (s, 1H), 4.86 (p, J = 8.6 Hz, 1H), 3.60 (q, J = 7.3 Hz, 2H), 3.35 (q, J = 7.2 Hz, 2H), 2.35 (ddt, J = 16.8, 11.1, 5.6 Hz, 2H), 2.17 – 1.97 (m, 4H), 1.67 (ddt, J = 10.8, 6.9, 4.2 Hz, 2H), 1.28 (t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 163.1, 152.2, 136.2, 117.2, 98.4, 57.9, 43.5, 39.6, 31.1 (2C), 15 24.8 (2C), 14.5, 12.7. HRMS: C16H22ClN4O Calculated for [M+H]+: 321.1482; Found: 321.1473. Example 12. 20 HLB-0535005 was synthesized in a similar manner as HLB-0534984, white solid (33% after HPLC, 1 X TFA salt). HPLC purity: 99.9% @ 254 nm; 99.3% @ 215 nm. 1H NMR (600 MHz, DMSO): δ 9.86 (s, 1H), 8.79 (s, 1H), 8.26 (q, J = 4.6 Hz, 1H), 7.89 (d, J = 25 8.6 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 4.68 (p, J = 8.9 Hz, 1H), 3.52 – 3.46 (m, 2H), 53 U of M 2025-025 VHPM 09531.599WO1 3.38 (s, 2H), 2.77 (d, J = 4.3 Hz, 3H), 2.44 (ddd, J = 16.7, 11.4, 6.6 Hz, 2H), 1.99 (tt, J = 9.7, 5.0 Hz, 4H), 1.69 (dq, J = 11.9, 5.5 Hz, 2H), 1.19 – 1.11 (m, 6H). 13C NMR (151 MHz, DMSO) δ 166.7, 163.1, 155.1, 151.9, 151.5, 143.8, 133.4, 128.2 (2C), 127.0, 117.5 (2C), 112.4, 99.3, 57.4, 43.4, 39.5, 30.2 (2C), 26.6, 24.7 (2C), 14.8, 13.0. 5 HRMS: C24H31N6O2Calculated for [M+H]+: 435.2509; Found: 435.2493. Example 13. 4.j was synthesized in a similar manner as 4.b with starting material 4-methylpiperidine, 10 yellow solid (quantitative). 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 6.42 (s, 1H), 4.78 (p, J = 8.7 Hz, 1H), 4.63 (d, J = 13.2 Hz, 1H), 3.75 (d, J = 13.3 Hz, 1H), 3.01 (t, J = 12.9 Hz, 1H), 2.86 – 2.74 (m, 1H), 2.30 (d, J = 10.7 Hz, 2H), 2.07 – 1.92 (m, 4H), 1.75 (d, J = 7.8 Hz, 1H), 1.69 – 1.54 (m, 4H), 1.21 – 1.02 15 (m, 2H) 0.93 (d, J = 6.4 Hz, 3H). HLB-0535019 was synthesized in a similar manner as HLB-0535984, white solid (42% after HPLC, 1 X TFA salt). HPLC purity: 99.7% @ 254 nm; 99.7% @ 215 nm. 20 1H NMR (500 MHz, DMSO) δ 9.84 (s, 1H), 8.80 (s, 1H), 8.26 (d, J = 4.7 Hz, 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.84 – 7.77 (m, 2H), 6.57 (s, 1H), 4.72 (p, J = 8.8 Hz, 1H), 4.47 (s, 1H), 3.85 (s, U of M 2025-025 VHPM 09531.599WO1 1H), 3.12 (s, 1H), 2.86 (s, 1H), 2.78 (d, J = 4.4 Hz, 3H), 2.50 – 2.31 (m, 3H), 2.01 (s, 4H), 1.74 – 1.67 (m, 5H), 1.10 (d, J = 12.6 Hz, 2H), 0.95 (d, J = 6.2 Hz, 3H). 13C NMR (151 MHz, DMSO) δ 166.7, 161.9155.2, 152.1, 151.5, 143.9, 132.9, 128.1 (2C), 126.9, 117.5 (2C), 112.4, 100.2, 57.5, 47.8, 34.0, 31.2, 30.9, 30.2 (2C), 26.6 (2C), 24.7 (2C), 5 22.0. HRMS: C26H33N6O2 Calculated for [M+H]+: 461.2665; Found: 461.2642. Example 14. 10 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.k, 500 mg, 0.326 mmol) was dissolved in anhydrous DMF (5 mL) in a flame-dried flask and the reaction was cooled in an ice bath. NaH (60%, 156 mg, 0.391 mmol) was then added and the reaction was stirred for 30 mins at room temperature. Bromocyclopentane (728 mg, 0.326 mmol) was added, and the reaction was heated to 60 °C for 2 h. After completion, ice cold water was added (30 mL) and the solution was 15 extracted with EtOAc (20 mL X 2). The organic phase was washed with brine (30 mL x 3). The organic layer was concentrated in vacuo and was purified using column chromatography with a gradient of 0-100% EtOAc in hexanes to yield 4.l as a white solid (632 mg, 87%). 1H NMR (500 MHz, CDCl3) δ 8.71 (d, J = 1.1 Hz, 1H), 7.23 (dd, J = 3.7, 1.2 Hz, 1H), 6.51 (dd, 20 J = 3.7, 1.3 Hz, 1H), 5.16 (p, J = 7.5 Hz, 1H), 2.24 – 2.14 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 152.9, 151.9, 150.4, 127.1, 117.8, 100.3, 55.1, 32.9 (2C), 24.2 (2C). HRMS: C11H13ClN3 Calculated for [M+H]+: 222.0798; Found: 222.0784. 25 U of M 2025-025 VHPM 09531.599WO1 Example 15. HLB-0535044 was synthesized in a similar manner as HLB-0534984, white solid (42% after HPLC, 1 X TFA salt). HPLC purity: 99.4% @ 254 nm; 97.9% @ 215 nm. 5 1H NMR (500 MHz, DMSO) δ 10.07 (s, 1H), 8.96 (s, 1H), 8.29 (q, J = 4.5 Hz, 1H), 7.95 – 7.89 (m, 2H), 7.85 – 7.79 (m, 2H), 7.56 (s, 1H), 5.80 (p, J = 9.2 Hz, 1H), 3.02 (q, J = 7.3 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.55 – 2.52 (m, 1H), 2.50 – 2.46 (m, 2H), 2.11 – 2.02 (m, 2H), 1.96 (ddd, J = 12.9, 10.2, 7.2 Hz, 2H), 1.72 (q, J = 5.9 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H). 1013C NMR (151 MHz, DMSO) δ 166.7, 154.0, 151.7, 149.0, 143.7, 128.3 (2C), 127.2, 126.8, 117.7 (2C), 113.4, 100.7, 55.7, 32.2 (2C), 26.6, 24.2 (2C). HRMS: C19H22N5O Calculated for [M+H]+: 336.1824; Found: 336.1811. Example 16. 15 4.m was synthesized in a similar manner as 4.b with starting material 4.a and N,O- dimethylhydroxylamine, white solid (88%). 1H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H), 6.80 (s, 1H), 4.99 (p, J = 8.7 Hz, 1H), 3.62 (s, 3H), 20 3.40 (s, 3H), 2.52 – 2.31 (m, 2H), 2.18 – 1.98 (m, 4H), 1.76 – 1.60 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 162.4, 153.7, 152.1, 152.0, 134.1, 116.9, 101.8, 61.7, 58.12, 33.5, 31.0 (2C), 24.8 (2C). U of M 2025-025 VHPM 09531.599WO1 HRMS: C14H18ClN4O2 Calculated for [M+H]+: 309.1118; Found: 309.1100. Example 17. 5 4.m (200 mg, 0.648 mmol) was dissolved in anhydrous THF (5 mL) in a flame-dried flask and the reaction was cooled in an ice bath. MeMgBr (477 µL, 1.43 mmol) was then added dropwise and the reaction was stirred for 1 h at room temperature. After completion, ice cold water was added (1 mL) slowly to quench the reaction for 10 mins and the solution was extracted with EtOAc (10 mL x 2). The organic phase was washed with brine (10 mL x 1). The 10 organic layer was concentrated in vacuo and was purified using column chromatography with a gradient of 0-100% EtOAc in hexanes to yield 4.n as a yellow solid (154 mg, 90%). 1H NMR (500 MHz, CDCl3) δ 8.86 (s, 1H), 7.23 (s, 1H), 5.73 (p, J = 8.8 Hz, 1H), 2.59 (s, 3H), 2.25 (ddt, J = 12.0, 8.7, 5.0 Hz, 2H), 2.12 – 2.01 (m, 3H), 2.01 – 1.93 (m, 2H), 1.69 – 1.58 (m, 15 2H). 13C NMR (126 MHz, CDCl3) δ 191.0, 155.6, 154.0, 153.5, 137.1, 116.1, 109.8, 57.1, 30.9 (2C), 28.5, 25.1 (2C). HRMS: C13H15ClN3O Calculated for [M+H]+: 264.0904; Found: 264.0887. 20 Example 18. U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, DMSO) δ 10.08 (s, 1H), 8.97 (s, 1H), 8.29 (q, J = 4.5 Hz, 1H), 7.95 – 7.89 (m, 2H), 7.84 – 7.79 (m, 2H), 7.57 (s, 1H), 5.82 (p, J = 9.2 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H), 2.57 (s, 3H), 2.52 (d, J = 3.4 Hz, 1H), 2.50 – 2.44 (m, 1H), 2.11 – 2.01 (m, 3H), 1.99 – 1.93 (m, 2H), 1.71 (q, J = 5.9 Hz, 2H). 513C NMR (151 MHz, DMSO) δ 191.2, 166.6, 156.7, 155.3, 153.4, 143.4, 134.0, 128.1 (2C), 127.5, 118.0 (2C), 113.0, 111.6, 56.4, 29.7 (2C), 28.5, 26.6, 24.7 (2C). HRMS: C21H24N5O2 Calculated for [M+H]+: 378.1930; Found: 378.1919. Example 19. 10 4.o was synthesized in a similar manner as 4.n with starting material ethylmagnesium bromide, yellow solid (25%). 1H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H), 7.21 (s, 1H), 5.71 (p, J = 8.8 Hz, 1H), 2.96 (q, J = 15 7.3 Hz, 2H), 2.33 – 2.20 (m, 2H), 1.18 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 194.5, 155.5, 154.0, 153.4, 137.0, 116.2, 108.6, 57.1, 33.6, 30.9 (2C), 25.1 (2C), 8.4. HRMS: C14H17ClN3O Calculated for [M+H]+: 278.1060; Found: 278.1045. 20 Example 20. U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, DMSO) δ 10.07 (s, 1H), 8.96 (s, 1H), 8.29 (q, J = 4.5 Hz, 1H), 7.95 – 7.89 (m, 2H), 7.85 – 7.79 (m, 2H), 7.56 (s, 1H), 5.80 (p, J = 9.2 Hz, 1H), 3.02 (q, J = 7.3 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.55 – 2.52 (m, 1H), 2.50 – 2.46 (m, 2H), 2.11 – 2.02 (m, 2H), 1.96 (ddd, J = 12.9, 10.2, 7.2 Hz, 2H), 1.72 (q, J = 5.9 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H). 513C NMR (151 MHz, DMSO) δ 194.4, 166.6, 156.6, 155.2, 153.3, 143.4, 133.9, 128.1 (2C), 127.5, 118.0 (2C), 111.7, 111.6, 56.5, 32.8, 29.7 (2C), 26.6, 24.7 (2C), 9.2. HRMS: C22H26N5O2 Calculated for [M+H]+: 392.2087; Found: 392.2074. Example 21. 10 4.p was synthesized in a similar manner as 4.n with starting material cyclopropyllmagnesium bromide, yellow solid (63%). 1H NMR (500 MHz, CDCl3) δ 8.86 (s, 1H), 7.33 (s, 1H), 5.62 (p, J = 8.7 Hz, 1H), 2.57 (tt, J = 15 7.8, 4.5 Hz, 1H), 2.35 – 2.21 (m, 2H), 1.69 – 1.55 (m, 2H), 1.26 – 1.16 (m, 2H), 1.03 (dq, J = 7.4, 3.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 193.5, 155.3, 153.8, 153.4, 138.3, 116.3, 108.6, 57.3, 30.9 (2C), 25.1 (2C), 19.5, 12.0 (2C). HRMS: C15H17ClN3O Calculated for [M+H]+: 290.1060; Found: 290.1053. 20 Example 22. U of M 2025-025 VHPM 09531.599WO1 HLB-0535043 was synthesized in a similar manner as HLB-0534984, with 4.p and 4.c as starting materials. White solid (79% after HPLC, 1 X TFA salt). HPLC purity: 99.3% @ 254 nm; 97.0% @ 215 nm. 51H NMR (500 MHz, DMSO) δ 10.09 (s, 1H), 8.99 (s, 1H), 8.29 (q, J = 4.5 Hz, 1H), 7.96 – 7.89 (m, 2H), 7.85 – 7.77 (m, 2H), 7.75 (s, 1H), 5.79 (p, J = 9.2 Hz, 1H), 2.91 – 2.83 (m, 1H), 2.79 (d, J = 4.4 Hz, 3H), 2.56 – 2.52 (m, 1H), 2.49 (d, J = 4.9 Hz, 2H), 2.10 – 2.00 (m, 2H), 1.95 (ddd, J = 12.9, 10.3, 7.3 Hz, 2H), 1.70 (p, J = 5.1 Hz, 2H), 1.08 – 0.97 (m, 4H). 13C NMR (151 MHz, DMSO) δ 192.7, 166.6, 156.7, 155.3, 153.4, 143.4, 134.7, 128.2 (2C), 10 127.5, 118.0 (2C), 112.3, 111.8, 56.6, 29.7 (2C), 26.6, 24.7 (2C), 18.8, 11.3 (2C). HRMS: C23H26N5O2 Calculated for [M+H]+: 404.2087; Found: 404.2074. Example 23. 15 HLB-0534999 was synthesized in a similar manner as HLB-0534984 with starting material 4.q, white solid (14% after HPLC, 1 X TFA salt). HPLC purity: 98.7% @ 254 nm; 99.0% @ 215 nm. 1H NMR (500 MHz, DMSO): δ1H NMR (500 MHz, DMSO) δ 9.13 (s, 1H), 8.79 (s, 1H), 8.42 20 (d, J = 5.0 Hz, 1H), 8.18 (t, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 6.63 (s, 1H), 4.73 – 4.66 (m, 1H), 3.05 (s, 7H), 2.79 (d, J = 4.4 Hz, 3H), 2.35 (s, 2H), 1.96 (s, 2H), 1.85 (s, 2H), 1.58 (d, J = 5.7 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 165.5, 163.1, 154.9, 154.3, 152.6, 151.7, 151.6, 133.3, 131.2, 129.4, 123.5, 122.1, 114.5, 112.8, 101.0, 57.4, 39.2, 35.1, 30.4 (2C), 26.7, 24.8 (2C). 2519F NMR (471 MHz, DMSO): δ -124.1. U of M 2025-025 VHPM 09531.599WO1 HRMS: C22H26FN6O2 Calculated for [M+H]+: 425.2101; Found: 425.2094. Example 24. 5 HLB-0535002 was synthesized in a similar manner as HLB-0534984 with starting material 4.r, white solid (37% after HPLC, 1 X TFA salt). HPLC purity: 96.4% @ 254 nm; 96.8% @ 215 nm. 101H NMR (600 MHz, DMSO): δ 8.84 (s, 1H), 8.66 (s, 1H), 8.49 (q, J = 4.5 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.7, 2.0 Hz, 1H), 6.66 (s, 1H), 4.71 (p, J = 8.8 Hz, 1H), 3.07 – 3.02 (m, 6H), 2.79 (d, J = 4.4 Hz, 3H), 2.37 – 2.28 (m, 2H), 2.00 – 1.93 (m, 2H), 1.88 – 1.80 (m, 2H), 1.62 – 1.54 (m, 2H). 1513C NMR (151 MHz, DMSO): δ 164.8, 162.5, 153.8, 151.1, 150.9, 138.8, 133.3, 129.4, 128.2, 126.3, 123.9, 121.4, 112.6, 100.7, 57.0, 38.8, 34.6, 30.0 (2C), 26.3, 24.4 (2C). HRMS: C22H26ClN6O2 Calculated for [M+H]+: 441.1806; Found: 441.1788. 20 Example 25. 25 U of M 2025-025 VHPM 09531.599WO1 1H NMR (600 MHz, DMSO): δ 8.86 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.41 – 8.35 (m, 2H), 7.56 – 7.51 (m, 2H), 6.70 (s, 1H), 4.73 (p, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.06 (d, J = 12.1 Hz, 6H), 2.80 (d, J = 4.4 Hz, 3H), 2.46 – 2.38 (m, 2H), 2.03 – 1.93 (m, 4H), 1.70 – 1.64 (m, 2H). 13C NMR (151 MHz, DMSO) δ 166.50, 162.90, 153.49, 151.81, 150.54, 148.17, 134.01, 5 131.48, 128.46, 120.10, 117.68, 112.63, 109.88, 101.47, 101.45, 57.70, 56.51, 39.24, 35.07, 30.18, 26.69, 24.75. HRMS: C23H29N6O3 Calculated for [M+H]+: 437.2301; Found: 437.2295. Example 26. 10 HLB-0535003 was synthesized in a similar manner as HLB-0534984 with starting material 4.t, white solid (13% after HPLC, 2 X TFA salt). HPLC purity: 99.9% @ 254 nm; 99.9% @ 215 nm. 151H NMR (600 MHz, DMSO): δ 10.01 (s, 1H), 8.89 – 8.86 (m, 1H), 8.78 (s, 1H), 8.49 (q, J = 4.9 Hz, 1H), 8.43 (dd, J = 8.7, 2.5 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 6.59 (s, 1H), 4.71 (p, J = 8.9 Hz, 1H), 2.99 (d, J = 11.6 Hz, 6H), 2.75 (d, J = 4.7 Hz, 3H), 2.38 – 2.31 (m, 2H), 1.99 – 1.86 (m, 4H), 1.63 – 1.57 (m, 2H). 2013C NMR (151 MHz, DMSO): δ 164.3, 162.8, 154.7, 151.9, 151.1, 142.1, 139.9, 138.4, 132.6, 124.4, 121.8, 112.5, 100.6, 56.9, 38.8, 34.6, 29.8 (2C), 25.9, 24.2 (2C). HRMS: C21H26N7O2Calculated for [M+H]+: 408.2148; Found: 408.2140. 25 U of M 2025-025 VHPM 09531.599WO1 Example 27. 4.v was synthesized in a similar manner as 4.1 with starting material 2.a and 4.u, white solid (83%). 51H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.05 (dd, J = 14.2, 2.1 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.11 (dd, J = 8.6, 2.1 Hz, 1H), 6.48 (s, 1H), 4.79 (p, J = 8.9 Hz, 1H), 3.18 (s, 7H), 2.70 – 2.59 (m, 2H), 2.13 (s, 3H), 2.19 – 2.05 (m, 1H), 1.75 (d, J = 6.3 Hz, 2H), 1.62 (s, 9H). 10 HRMS: C25H31FN5O3Calculated for [M+H]+: 468.2411; Found: 468.2390. Example 28. To a solution of 4.v (30.0 mg, 0.0640 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) 15 and the reaction was stirred for 1 h at room temperature. The reactions were concentrated to remove volatiles. To the deprotected 4.v was added DMF (0.25 mL) and was basified with DIPEA until pH = 7 – 8. HATU (29.0 mg, 0.0770 mmol) was added, and the reaction stirred for 0.25 h. To the reaction was added methyl amine (2M in THF, 64 µL, 0.128 mmol). The reaction was stirred at room temperature for 18 h. The mixture was purified by column chromatography 20 with a gradient of 0-20% MeOH in CH2Cl2 and then preparative HPLC to yield HLB-0534990 as a white solid (18.1 mg, 52% after HPLC, 1 X TFA salt). HPLC purity: 95.9% @ 254 nm; 95.3% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 10.06 (s, 1H), 8.83 (s, 1H), 8.03 (dd, J = 14.7, 2.0 Hz, 1H), 25 7.95 – 7.90 (m, 1H), 7.62 (t, J = 8.7 Hz, 1H), 7.49 (dd, J = 8.6, 2.0 Hz, 1H), 6.64 (s, 1H), 4.74 U of M 2025-025 VHPM 09531.599WO1 (p, J = 8.9 Hz, 1H), 3.09 – 3.03 (m, 6H), 2.77 (d, J = 4.5 Hz, 3H), 2.50 – 2.42 (m, 1H), 2.01 (h, J = 6.8 Hz, 4H), 1.69 (d, J = 5.5 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 164.1, 163.2, 161.3, 159.7, 154.9, 152.4, 151.3, 145.2, 133.1, 131.0, 115.1, 114.1, 112.8, 104.5, 101.1, 57.7, 39.3, 35.1, 30.0 (2C), 26.8, 24.4 (2C). 5 19F NMR (471 MHz, DMSO) δ -112.0. HRMS: C22H26FN6O2 Calculated for [M+H]+: 425.2101; Found: 425.2094. Example 29. 10 HLB-0535000 was synthesized in a similar manner as HLB-0534984 with starting material 4.w, white solid (17% after HPLC, 2 X TFA salt). HPLC purity: 99.9% @ 254 nm; 99.9% @ 215 nm. 151H NMR (600 MHz, DMSO): δ 9.91 (s, 1H), 8.81 (t, J = 1.3 Hz, 1H), 8.17 (s, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 1.2 Hz, 1H), 4.74 – 4.67 (m, 1H), 3.06 (s, 5H), 2.74 (d, J = 4.6 Hz, 3H), 2.01 (s, 5H), 1.67 (s, 2H). 13C NMR (151 MHz, DMSO): δ 166.7, 162.8, 154.6, 151.9, 151.0, 142.8, 132.5, 130.4, 129.3, 20 128.6, 117.7, 116.1, 112.2, 100.6, 57.3, 38.8, 34.6, 29.5 (2C), 26.1, 23.8 (2C). HRMS: C22H26ClN6O2 Calculated for [M+H]+: 441.1806; Found: 441.1792. Example 30. U of M 2025-025 VHPM 09531.599WO1 4.y was synthesized in a similar manner as 4.v with starting material 2.a and 4.x, white solid (76%). 51H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 7.83 (dd, J = 8.6, 6.0 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.31 (d, J = 5.1 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 6.47 (s, 1H), 4.92 (p, J = 9.0 Hz, 1H), 2.50 (t, J = 10.5 Hz, 2H), 2.11 – 2.02 (m, 4H), 1.71 (p, J = 6.9 Hz, 2H), 1.62 (s, 9H). HRMS: C26H34N5O4 Calculated for [M+H]+: 480.2611; Found: 480.2593. 10 HLB-0534989 was synthesized in a similar manner as HLB-0534990, white solid (39% after HPLC, 1 X TFA salt). HPLC purity: 97.0% @ 254 nm; 97.6% @ 215 nm. 15 1H NMR (500 MHz, DMSO): δ 9.78 (s, 1H), 8.80 (s, 1H), 8.00 (d, J = 4.9 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.65 – 7.57 (m, 2H), 6.63 (s, 1H), 4.86 (p, J = 9.1 Hz, 1H), 3.91 (s, 3H), 3.06 (s, 7H), 2.80 (d, J = 4.6 Hz, 3H), 2.37 (s, 3H), 2.01 (s, 2H), 1.92 (s, 3H), 1.67 – 1.60 (m, 3H). 2013C NMR (151 MHz, DMSO): δ 165.0, 162.9, 157.8, 154.7, 151.4, 151.3, 144.7, 132.3, 131.3, 114.7, 111.9, 110.0, 101.4, 100.9, 56.6, 55.5, 38.8, 34.6, 29.9 (2C), 26.3, 24.0 (2C). HRMS: C23H28N6O3Calculated for [M+H]+: 437.2301; Found: 437.2286. 25 Example 32. U of M 2025-025 VHPM 09531.599WO1 To a solution of 3.g (49.3 mg, 0.110 mmol) in DMF (1 mL) was added acetic anhydride (16.0 µL, 0.165 mmol), K2CO3 (150 mg, 1.10 mmol), and the reaction was stirred for overnight at room temperature. The mixture was purified by column chromatography with a gradient of 0- 5 20% MeOH in CH2Cl2and then preparative HPLC to yield HLB-0534982 as a white solid (29.5 mg, 66% after HPLC, 1 X TFA salt). HPLC purity: 99.9% @ 254 nm; 99.5% @ 215 nm. 1H NMR (500 MHz, DMSO) δ 9.83 (s, 1H), 9.53 (s, 1H), 8.75 (s, 1H), 7.73 – 7.68 (m, 2H), 7.54 – 7.48 (m, 2H), 6.61 (s, 1H), 4.72 (p, J = 8.9 Hz, 1H), 3.06 (s, 7H), 2.44 (d, J = 10.8 Hz, 10 2H), 2.03 (s, 3H), 2.01 – 1.88 (m, 3H), 1.65 (d, J = 6.1 Hz, 3H). 13C NMR (151 MHz, DMSO) δ 168.3, 163.1, 154.6, 152.1, 150.6, 135.9, 134.1, 133.1, 119.8 (2C), 119.7 (2C), 111.8, 101.4, 57.5, 39.3, 35.1, 30.1 (2C), 24.7 (2C), 24.3. HRMS: C22H27N6O2 Calculated for [M+H]+: 407.2196; Found: 407.2189. 15 Example 33 HLB-0535004 was synthesized in a similar manner as HLB-0534990 with starting material 2.c and 1-methylpiperazine, white solid (48% after HPLC, 2 X TFA salt). HPLC purity: 99.9% @ 254 nm; 99.5% @ 215 nm. 20 1H NMR (600 MHz, DMSO): δ 10.05 (s, 1H), 9.88 (s, 1H), 8.80 (s, 1H), 7.95 – 7.90 (m, 2H), 7.45 – 7.40 (m, 2H), 6.63 (s, 1H), 4.75 (p, J = 8.9 Hz, 1H), 3.45 (d, J = 11.6 Hz, 2H), 3.29 (s, 2H), 3.07 (s, 7H), 3.04 (s, 3H), 2.83 (s, 3H), 2.48 – 2.41 (m, 2H), 2.04 – 1.94 (m, 4H), 1.71 – 1.63 (m, 2H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (151 MHz, DMSO) δ 169.9, 163.3, 155.3, 152.2, 151.6, 143.3, 132.8, 128.8 (2C), 126.6, 117.9 (2C), 112.5, 101.1, 57.5, 52.7 (2C), 42.7 (2C), 40.5, 39.3, 35.1, 30.2 (2C), 24.7 (2C). 5 HRMS: C26H34N7O2 Calculated for [M+H]+: 476.2774; Found: 476.2757. Example 34. 10 HLB-0535017 was synthesized in a similar manner as HLB-0534984 with starting material 4.g and 4.w, white solid (36% after HPLC, 1 X TFA salt). HPLC purity: 98.5% @ 254 nm; 99.8% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 9.91 (s, 1H), 8.81 (s, 1H), 8.22 – 8.15 (m, 2H), 7.62 (dd, J = 15 8.5, 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 4.68 (p, J = 8.9 Hz, 1H), 3.56 (d, J = 62.0 Hz, 5H), 2.75 (d, J = 4.6 Hz, 3H), 2.02 (d, J = 6.9 Hz, 2H), 1.66 (d, J = 12.2 Hz, 5H), 1.55 (s, 6H). 13C NMR (151 MHz, DMSO) δ 167.1, 161.8, 154.9, 152.2, 151.4, 143.2, 133.2, 130.8, 129.7, 20 129.1, 118.2, 116.6, 112.7, 100.1, 57.7, 48.5, 42.8, 30.1 (2C), 26.7, 26.5, 25.7, 24.5, 24.3 (2C). HRMS: C25H30ClN6O2 Calculated for [M+H]+: 481.2119; Found: 481.2112. U of M 2025-025 VHPM 09531.599WO1 Example 35. 4.z was synthesized in a similar manner as HLB-0534984 with starting material 4.g and 2.b, white solid (72%). 5 1H NMR (500 MHz, CDCl3): δ 8.65 (s, 1H), 8.05 – 7.91 (m, 2H), 7.80 (s, 1H), 7.78 – 7.74 (m, 2H), 6.41 (s, 1H), 4.75 (p, J = 8.9 Hz, 1H), 3.64 (b, 4H), 2.65 – 2.55 (m, 2H), 2.08 (dh, J = 12.9, 7.4 Hz, 4H), 1.73 (q, J = 6.2 Hz, 4H), 1.60 (s, 9H), 1.32 – 1.22 (m, 2H). 1013C NMR (126 MHz, CDCl3): δ 165.8, 162.5, 154.4, 152.0, 150.7, 144.0, 133.4, 130.7 (2C), 124.9, 117.3 (2C), 113.0, 100.0, 80.6, 58.2, 48.9, 43.3, 30.4 (2C), 28.4 (3C), 26.9, 25.8, 24.8 (2C), 24.6. HRMS: C28H36N5O3 Calculated for [M+H]+: 490.2818; Found: 490.2793. 15 Example 36. HLB-0535018 was synthesized in a similar manner as HLB-0534990 with starting material 4.z and 1-methylpiperazine, white solid (42% after HPLC, 2 X TFA salt). HPLC purity: 99.5% 20 @ 254 nm; 99.2% @ 215 nm. 1H NMR (600 MHz, DMSO) δ 10.03 (b, 1H, from TFA), 9.88 (s, 1H), 8.81 (s, 1H), 7.96 – 7.91 (m, 2H), 7.46 – 7.41 (m, 2H), 6.57 (s, 1H), 4.73 (p, J = 8.8 Hz, 1H), 4.24 (s, 2H), 3.63 (s, 2H), 3.48 – 3.43 (m, 3H), 3.11 (d, J = 15.6 Hz, 2H), 2.84 (s, 3H), 2.50 – 2.42 (m, 2H), 2.03 – 1.96 (m, U of M 2025-025 VHPM 09531.599WO1 4H), 1.70 – 1.64 (m, 4H), 1.55 (b, 4H). 13C NMR (151 MHz, DMSO) δ 169.88, 161.89, 155.27, 152.18, 151.58, 143.33, 132.87, 128.79, 126.61, 117.86, 112.52, 100.11, 57.42, 52.72, 48.54, 42.96, 42.74, 40.91, 30.30, 26.69, 5 25.81, 24.70, 24.47. HRMS: C29H38N7O2 Calculated for [M+H]+: 516.3087; Found: 516.3064. Example 37. 10 To a solution of 4.y (35.0 mg, 0.0827 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) and the reaction was stirred for 1 h at room temperature. Simultaneously, to a solution of 2.h (33.0 mg, 0.0910 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) and the reaction was stirred for 1 h at room temperature. The reactions were concentrated to remove volatiles. To the 15 deprotected 4.y was added DMF (0.25 mL) and was basified with DIPEA until pH = 7 – 8. HATU (62.0 mg, 0.165 mmol) was added, and the reaction stirred for 0.25 h. To the reaction was added deprotected 2.h dissolved in DMF (0.25 mL) and basified with DIPEA until pH = 7 – 8. The reaction was stirred at room temperature for 18 h. The mixture was purified by column chromatography with a gradient of 0-20% MeOH in CH2Cl2and then preparative HPLC to yield 20 HLB-0534987 as a white solid (32.5 mg, 40% after HPLC, 1 X TFA salt). HPLC purity: 95.8% @ 254 nm; 99.1% @ 215 nm. 1H NMR (500 MHz, DMSO) δ 8.81 (s, 1H), 7.84 – 7.76 (m, 2H), 7.62 (dd, J = 8.7, 2.0 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 6.65 (s, 1H), 5.07 69 U of M 2025-025 VHPM 09531.599WO1 (dd, J = 12.9, 5.5 Hz, 1H), 4.83 (p, J = 9.1 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.94 – 3.82 (m, 6H), 3.30 (t, J = 7.0 Hz, 2H), 3.08 – 3.03 (m, 6H), 2.94 – 2.79 (m, 1H), 2.69 – 2.55 (m, 1H), 2.51 – 2.44 (m, 0H), 2.37 (d, J = 13.4 Hz, 2H), 2.02 (d, J = 8.5 Hz, 3H), 1.92 (d, J = 7.3 Hz, 2H), 1.79 (p, J = 6.6 Hz, 2H), 1.64 (t, J = 6.2 Hz, 2H), 1.54 (dp, J = 22.5, 7.4 Hz, 4H), 1.41 (q, J 5 = 7.7 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 173.2, 170.4, 167.3, 165.8, 164.8, 163.4, 158.2, 156.5, 155.4, 152.1, 151.8, 145.2, 137.5, 133.7, 132.6, 131.8, 120.3, 116.7, 115.6, 115.2, 112.3, 110.4, 101.8, 101.3, 69.2, 57.1, 56.1, 49.2, 39.4, 35.1, 31.4, 30.3 (2C), 29.7, 28.9, 26.6, 25.5, 24.5 (2C), 22.5. 10 HRMS: C41H47N8O8 Calculated for [M+H]+: 779.3517; Found: 779.3505. Example 38. 15 HLB-0535024 was synthesized in a similar manner as HLB-0534987 with starting material 4.z and 2.h, white solid (32% after HPLC, 2 X TFA salt). HPLC purity: 96.5% @ 254 nm; 97.5% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H), 9.83 (s, 1H), 8.80 (d, J = 1.4 Hz, 1H), 8.28 (t, J 20 = 5.5 Hz, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.81 (dt, J = 8.6, 3.5 Hz, 3H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 6.57 (d, J = 1.7 Hz, 1H), 5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.71 (q, J = 8.8 Hz, 1H), 4.22 (t, J = 6.4 Hz, 2H), 3.56 (d, J = 51.0 Hz, 4H), 3.27 (q, J = 6.7 Hz, 2H), 2.94 – 2.83 (m, 1H), 2.65 – 2.54 (m, 1H), 2.50 (s, 6H), 2.06 – 1.99 (m, 5H), 1.79 (p, J = 6.7 Hz, 2H), U of M 2025-025 VHPM 09531.599WO1 1.72 – 1.63 (m, 4H), 1.59-1.48 (m, 8H), 1.41 (q, J = 7.8 Hz, 2H). 13C NMR (151 MHz, DMSO): δ 172.8, 170.0, 166.9, 165.7, 165.3, 161.4, 156.0, 154.5, 151.4, 151.1, 143.3, 137.0, 133.3, 132.5, 127.8 (2C), 126.7, 119.8, 117.1 (2C), 116.2, 115.1, 112.0, 5 99.7, 68.8, 57.0, 48.7, 40.1 (2C), 31.0, 29.8 (2C), 29.3, 28.4, 26.2, 25.1, 24.3 (2C), 24.0, 22.0. HRMS: C43H49N8O7 Calculated for [M+H]+: 789.3724; Found: 789.3709. Example 39. 10 A mixture of 5.b (200 mg, 0.539 mmol, prepared as reported Gray, N. S., et al. WO202002348 A1 2020), DMAP (6.58 mg, 0.0539 mmol), and Et3N (136 mg, 1.35 mmol) in CH2Cl2(7 mL) was cooled to 0ºC. Tosyl chloride (133 mg, 0.700 mmol) was added, and the mixture was warmed to 15 room temperature and stirred for 18 h. The product was diluted with CH2Cl2 (20 mL) and washed with water (20 mL), 5% HCl (20 mL), and saturated NaHCO3(20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in MeCN, and 1-Boc-piperazine (201 mg, 0.1.08 mmol), DIPEA (209 mg, 1.62 mmol), and KI (8.94 mg, 0.0539 mmol) were added. The resulting mixture was stirred at 82 ºC for 18 h. The reaction 20 mixture was concentrated in vacuo and was purified using column chromatography with a gradient of 0-100% EtOAc in hexanes to yield 5.c as a yellow solid (189 mg, 65%). 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H), 7.63 (dq, J = 7.9, 2.6 Hz, 1H), 6.91 (d, J = 3.1 Hz, 1H), 6.64 (dd, J = 8.0, 3.2 Hz, 1H), 4.92 (ddd, J = 12.4, 5.4, 1.9 Hz, 1H), 3.61 – 3.53 (m, 1H), 25 3.48 (d, J = 7.8 Hz, 5H), 3.43 – 3.32 (m, 1H), 3.06 – 2.92 (m, 1H), 2.90 – 2.65 (m, 3H), 2.46 (s, 6H), 2.37 (d, J = 7.2 Hz, 1H), 2.28 – 2.19 (m, 1H), 2.17 – 2.07 (m, 1H), 1.79 – 1.67 (m, 3H), 1.51 – 1.43 (m, 9H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (126 MHz, CDCl3): δ 171.3, 168.6, 168.3, 167.7, 154.8, 152.1, 134.6, 125.5, 116.6, 115.1, 106.1, 79.9, 57.1, 53.8, 53.1 (2C), 49.2, 48.0, 43.5 (2C), 37.1, 31.7, 31.6, 30.3, 28.5 (3C), 22.9. 5 HRMS: C28H38N5O6Calculated for [M+H]+: 540.2822; Found: 540.2799. Example 40. HLB-0535028 To a solution of 5.c (40.0 mg, 0.0840 mmol, prepared as reported Gray, N. S., et al. 10 WO202002348 A12020), in CH2Cl2(0.5 mL) was added TFA (0.5 mL) and the reaction was stirred for 1 h at room temperature. Simultaneously, to a solution of 2.c (30.0 mg, 0.0760 mmol) in CH2Cl2 (0.5 mL) was added TFA (0.5 mL) and the reaction was stirred for 1 h at room temperature. The reactions were concentrated to remove volatiles. To the deprotected 2.c was added DMF (0.25 mL) and it was basified with DIPEA to pH = 7 – 8. HATU (43.0 mg, 0.114 15 mmol) was added, and the reaction stirred for 0.25 h. To the reaction was added deprotected 5.c dissolved in DMF (0.25 mL) and it was basified with DIPEA to pH = 7 – 8. The reaction was stirred at room temperature for 18 h. The mixture was purified by column chromatography with a gradient of 0-20% MeOH in CH2Cl2 and then preparative HPLC to yield HLB-0535028 as a bright yellow solid (25% after HPLC, 2 X TFA). HPLC purity: 97.1% @ 254 nm; 95.0% @ 215 20 nm. 1H NMR (500 MHz, DMSO): δ 11.06 (s, 1H), 9.85 (s, 1H), 9.70 (s, 1H), 8.80 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 2.2 Hz, 1H), 6.82 U of M 2025-025 VHPM 09531.599WO1 (dd, J = 8.7, 2.2 Hz, 1H), 6.63 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.76 (p, J = 8.8 Hz, 1H), 4.24 (s, 2H), 3.64 (dd, J = 10.3, 7.3 Hz, 1H), 3.54 (d, J = 7.9 Hz, 3H), 3.45 – 3.18 (m, 6H), 3.15 – 3.03 (m, 7H), 2.88 (ddd, J = 18.5, 15.0, 5.2 Hz, 1H), 2.64 – 2.51 (m, 2H), 2.48 – 2.39 (m, 1H), 2.40 – 2.30 (m, 1H), 2.20 (d, J = 11.2 Hz, 1H), 2.01 (d, J = 13.7 Hz, 5H), 1.83 (dd, J = 16.2, 7.9 5 Hz, 1H), 1.77 – 1.61 (m, 2H). 13C NMR (151 MHz, DMSO): δ 172.9, 170.2, 169.42, 167.7, 167.2, 162.8, 154.9, 151.9, 151.8, 151.1, 142.9, 134.1, 132.3, 128.4 (2C), 126.1, 125.0, 117.4 (2C), 115.7, 115.2, 112.0, 105.5, 100.7, 57.0, 54.3 (2C), 52.9 (2C), 50.8 (2C), 48.7, 47.4, 38.9, 35.5, 34.6, 31.0, 30.6, 29.7 (2C), 10 26.8, 24.2 (2C), 22.3 HRMS: C44H51N10O6Calculated for [M+H]+: 815.3993; Found: 815.3980. Example 41. 15 To a solution of 5-fluoro-thalidomide (5.d, 150 mg, 0.543 mmol) was added 1-Boc- piperazine (202 mg, 1.09 mmol), DIPEA (211 mg, 1.63 mmol) in NMP (1.5 mL). The reaction mixture was heated to 90 ºC and stirred overnight. After completion, the reaction was cooled to room temperature, and water was added (15 mL). The resulting mixture was extracted with 20 EtOAc (3 x 30 mL). The organic phase was concentrated in vacuo and was purified using column chromatography with a gradient of 0 to 100% EtOAc in hexanes to yield 5.e as a yellow solid (190 mg, 79%). 1H NMR (500 MHz, CDCl3): δ 8.52 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.04 (dd, J = 8.5, 2.4 Hz, 25 1H), 4.94 (dd, J = 12.2, 5.2 Hz, 1H), 3.59 (dd, J = 6.7, 4.0 Hz, 4H), 3.40 (dd, J = 6.6, 4.0 Hz, 4H), 2.89 – 2.66 (m, 4H), 2.15 – 2.06 (m, 1H), 1.47 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 171.4, 168.6, 167.9, 167.3, 155.3, 154.7, 134.4, 125.5, 120.2, 118.4, 109.1, 80.5, 49.3, 47.6 (2C), 42.9 (2C), 31.5, 28.5 (3C), 22.8. U of M 2025-025 VHPM 09531.599WO1 HRMS: C22H30N5O6Calculated for [M+NH4]+: 460.2196; Found: 460.2175. Example 42. 5 To a solution of 5.e (245 mg, 0.554 mmol) in CH2Cl2 (1 mL) was added TFA (0.50 mL) and the resulting solution was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The resulting residue was disolved in MeCN followed by the addition of DIPEA (358 mg, 2.77 mmol), KI (9.19 mg, 0.055 mmol), and 1-Boc-4-(tosyloxymethyl)piperidine (5.f, 450 10 mg, 1.22 mmol). The mixture was heated to 82 °C and stirred overnight. After completion, the reaction mixture was concentrated in vacuo and was purified using column chromatography with a gradient of 0-100% EtOAc in hexanes to yield 5.g as a bright yellow solid (109 mg, 36%). 151H NMR (500 MHz, CDCl3): δ 8.18 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 8.6, 2.3 Hz, 1H), 4.94 (dd, J = 12.2, 5.3 Hz, 1H), 4.11 (b, 2H), 3.41 (t, J = 5.0 Hz, 4H), 2.92 – 2.66 (m, 6H), 2.55 (t, J = 4.9 Hz, 4H), 2.23 (d, J = 7.1 Hz, 2H), 2.16 – 2.08 (m, 1H), 1.75 (d, J = 13.3 Hz, 2H), 1.65 (s, 1H), 1.45 (s, 9H), 1.25 (p, J = 3.9 Hz, 1H), 1.09 (h, J = 9.9 Hz, 2H). 20 13C NMR (126 MHz, CDCl3): δ 171.2, 168.4, 168.1, 167.4, 155.6, 155.0, 134.4, 125.5, 119.5, 117.9, 108.7, 79.5, 64.5, 53.2 (2C), 49.3, 47.6 (2C), 43.7 (2C), 33.7, 31.6, 30.8 (2C), 28.6 (3C), 22.9. 25 HRMS: C28H38N5O6Calculated for [M+H]+: 540.2822; Found: 540.2804. U of M 2025-025 VHPM 09531.599WO1 Example 43. HLB-0535029 was synthesized in a similar manner as HLB-0535028 with starting material 5.g, bright yellow solid (18% after HPLC, 2 X TFA). HPLC purity: 97.0% @ 254 nm; 95.9% @ 5 215 nm. 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H), 9.79 (s, 1H), 9.39 (s, 1H), 8.80 (s, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 12.8, 8.3 Hz, 3H), 6.63 (s, 1H), 5.10 (dd, J = 12.7, 5.5 Hz, 1H), 4.75 (q, J = 8.9 Hz, 1H), 4.22 (d, J = 13.7 Hz, 2H), 10 3.64 (d, J = 11.9 Hz, 2H), 3.33 (t, J = 12.7 Hz, 2H), 3.16 (d, J = 23.1 Hz, 3H), 3.07 (s, 5H), 2.95 – 2.84 (m, 1H), 2.66 – 2.53 (m, 2H), 2.47 (dq, J = 3.7, 1.8 Hz, 1H), 2.38 – 2.35 (m, 0H), 2.17 (s, 1H), 2.01 (d, J = 15.3 Hz, 5H), 1.81 (s, 2H), 1.67 (d, J = 5.9 Hz, 2H), 1.23 (d, J = 14.9 Hz, 3H). 13C NMR (151 MHz, DMSO): δ 172.8, 170.0, 169.2, 167.4, 166.9, 162.8, 155.0, 154.1, 151.9, 15 151.1, 142.2, 133.8, 132.1, 127.9, 127.8 (2C), 125.0, 119.9, 118.8, 117.5 (2C), 111.9, 109.0, 100.7, 60.6, 57.0 (2C), 50.9 (2C), 48.9 (2C), 44.1 (2C), 40.1 (2C), 39.8, 34.6, 31.0, 30.4, 29.7 (2C), 24.2 (2C), 22.2. HRMS: C44H51N10O6 Calculated for [M+H]+: 815.3993; Found: 815.3980. 20 U of M 2025-025 VHPM 09531.599WO1 Example 44. To a solution of 5,6-difluoro-1,3-dihydro-2-benzofuran-1,3-dione (5.h, 651 mg, 3.54 mmol) was added 3-aminopiperidine-2,6-dione hydrochloride (5.i, 654 mg, 3.92 mmol), sodium acetate 5 (643 mg, 7.84 mmol) in acetic acid (10 mL). The reaction was heated to 120 ºC and stirred overnight. After completion, the reaction was concentrated in vacuo, and the residue was dissolved in water (20 mL). The resulting mixture was vacuum filtered, and the solid was collected to yield 5.j as a brown solid (881 mg, 76%). 101H NMR (500 MHz, DMSO): δ 11.15 (s, 1H), 8.15 (t, J = 7.6 Hz, 2H), 5.17 (dd, J = 13.0, 5.4 Hz, 1H), 2.89 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.65 – 2.58 (m, 1H), 2.55 (dd, J = 13.0, 4.5 Hz, 1H), 2.10 – 2.04 (m, 1H). 13C NMR (126 MHz, DMSO) δ 173.2, 170.1, 165.8 (2C), 155.2, 153.3, 129.0 (2C), 114.55, 15 114.3 (2C), 49.84, 31.37, 22.37. 19F NMR (471 MHz, DMSO) δ -127.0. HRMS: C13H9F2N2O4 Calculated for [M+H]+: 295.0530; Found: 295.0511. 20 5.k was synthesized in a similar manner as 5.e with starting material 5.j, yellow solid (91%). 1H NMR (500 MHz, CDCl3): δ 7.49 (dt, J = 10.9, 2.7 Hz, 1H), 7.38 (dt, J = 7.4, 1.5 Hz, 1H), 25 4.93 (dd, J = 12.3, 5.4 Hz, 1H), 3.61 (s, 4H), 3.20 (s, 4H), 3.01 – 2.62 (m, 4H), 2.16-2.09 (m, 1H), 1.48 (s, 9H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (126 MHz, CDCl3) δ 171.0, 168.1, 166.8, 166.3, 158.3, 154.6, 145.7, 129.0, 124.6, 113.9, 112.2, 80.3, 50.0, 49.9, 49.5, 43.4, 31.4, 28.4 (3C), 28.2, 22.7. 519F NMR (471 MHz, CDCl3): δ -110.9. HRMS: C22H29FN5O6 Calculated for [M+NH4]+: 478.2102; Found: 478.2080. 10 HLB-0535036 5.l was synthesized in a similar manner as 5.g with starting material 5.k, yellow solid (12%). Then 5.4 was synthesized in a similar manner as 5.1 with starting material 5.l, bright yellow solid (51% after HPLC, 2 X TFA). HPLC purity: 98.2% @ 254 nm; 96.3% @ 215 nm. 15 1H NMR (500 MHz, DMSO): δ 11.12 (s, 1H), 9.80 (d, J = 2.1 Hz, 1H), 9.48 (s, 1H), 8.80 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 11.1 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 6.62 (s, 1H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 4.75 (p, J = 8.9 Hz, 1H), 3.79 (d, J = 13.0 Hz, 2H), 3.64 (d, J = 11.6 Hz, 2H), 3.34 (t, J = 12.4 Hz, 2H), 3.25 (d, J = 10.5 Hz, 1H), 20 3.14 (s, 1H), 3.07 (s, 6H), 2.90 (ddd, J = 16.8, 13.8, 5.5 Hz, 1H), 2.67 – 2.52 (m, 2H), 2.47 (d, J = 24.2 Hz, 1H), 2.16 (s, 1H), 2.13 – 1.88 (m, 5H), 1.80 (s, 2H), 1.67 (t, J = 6.4 Hz, 2H), 1.23 (d, J = 11.8 Hz, 2H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (151 MHz, DMSO) δ 173.2, 170.3, 169.7, 167.0, 166.6, 166.5, 163.3, 157.8, 155.3, 152.2, 151.6, 144.1, 142.6, 132.7, 129.1, 128.3 (2C), 125.1, 118.0 (2C), 115.0, 112.7, 112.4, 101.2, 61.1, 57.4, 51.7 (2C), 51.6, 49.6, 46.8 (2C), 40.6 (2C), 39.3, 35.1, 31.4, 30.9, 30.2 (2C), 30.0, 24.7 (2C), 22.5. 5 19F NMR (471 MHz, DMSO) δ -111.9. HRMS: C44H50FN10O6Calculated for [M+H]+: 833.3899; Found: 833.3886. 10 Example 45. To a solution of 5.e (207 mg, 0.468 mmol) was added TFA (1 mL) in CH2Cl2 (1 mL). The reaction was stirred for 1 h at room temperature. The mixture was concentrated in vacuo, and the residue was then dissolved in CH2Cl2(2 mL) and MeOH (1 mL) followed by the addition of 15 sodium acetate (192 mg, 2.34 mmol) and 1-Boc-4-piperidone (93.2 mg, 0.468 mmol). The resulting mixture was stirred at room temperature for 4 h. Sodium cyanoborohydride (58.8, 0.936 mmol) was added, and the reaction was stirred for 18 h at room temperature. After completion, the reaction was concentrated in vacuo and directly purified using column chromatography with a gradient of 0-20% of MeOH in CH2Cl2 to yield 5.m as a yellow solid 20 (80.1 mg, 33%). 1H NMR (500 MHz, CDCl3): δ 8.39 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 8.6, 2.3 Hz, 1H), 4.93 (dd, J = 12.2, 5.4 Hz, 1H), 4.18 (s, 3H), 3.50 (s, 4H), 2.92 – 2.66 (m, 9H), 2.16 – 2.08 (m, 1H), 1.89 (d, J = 12.3 Hz, 2H), 1.53 – 1.46 (m, 2H), 1.45 (s, 9H). 25 13C NMR (126 MHz, CDCl3) δ 170.1, 169.9, 167.4, 166.8, 166.1, 154.0, 153.5, 133.2, 124.4, 117.3, 108.0, 78.9, 61.5 (2C), 48.2, 47.3, 46.1 (2C), 41.8 (2C), 30.4, 27.4 (3C), 26.6 (2C), 21.7. U of M 2025-025 VHPM 09531.599WO1 HRMS: C27H36N5O6 Calculated for [M+H]+: 526.2666; Found: 526.2641. Example 46. 5 HLB-0535046 was synthesized in a similar manner as HLB-0535028 with starting material 5.m, bright yellow solid (18% after HPLC, 2 X TFA). HPLC purity: 98.4% @ 254 nm; 96.6% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H), 9.82 (s, 1H), 8.80 (s, 1H), 7.94 – 7.89 (m, 2H), 10 7.78 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.39 (dd, J = 8.8, 2.4 Hz, 3H), 6.63 (s, 1H), 5.11 (dd, J = 12.8, 5.5 Hz, 1H), 4.76 (p, J = 8.8 Hz, 1H), 4.28 (d, J = 9.5 Hz, 2H), 3.62 (s, 3H), 3.24 (d, J = 9.4 Hz, 4H), 3.07 (d, J = 12.2 Hz, 6H), 2.90 (ddd, J = 16.6, 13.6, 5.3 Hz, 3H), 2.71 – 2.51 (m, 2H), 2.49 – 2.34 (m, 1H), 2.24 – 1.87 (m, 7H), 1.76 – 1.59 (m, 4H). 1513C NMR (151 MHz, DMSO) δ 173.3, 170.5, 169.8, 167.9, 167.4, 163.3, 155.5, 154.6, 152.4, 151.6, 143.0, 134.2, 132.6, 128.4 (2C), 127.7, 125.4, 120.5, 119.3, 117.9 (2C), 112.4, 109.5, 101.1, 62.8, 57.4, 49.3, 48.1 (2C), 45.0 (2C), 39.3, 35.1, 31.4, 30.2 (2C), 30.1 (2C), 26.6 (2C), 24.7 (2C), 22.6. 20 HRMS: C43H49N10O6 Calculated for [M+H]+: 801.3837; Found: 801.3825. U of M 2025-025 VHPM 09531.599WO1 Example 47. To a solution of 3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (5.n,100 mg, 0.309 mmol) was added tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate 5 (170 mg, 0.758 mmol), palladium bis(triphenylphosphane) dichloride (21.7 mg, 0.0309 mmol), triethylamine (564 mg, 5.57 mmol), CuI (5.89 mg, 0.0309 mmol) in DMF (1 mL). The mixture was flushed with argon in a sealed vial and heated in a microwave synthesis reactor (Discover) to 100 ºC for 30 minutes. The reaction mixture was cooled, diluted in EtOAc (20 mL), and washed with water (20 mL) and brine (2x20 mL). The organic layer was concentrated in vacuo 10 and was purified using column chromatography with a gradient of 0 to 100% EtOAc in hexanes to yield 5.o as a brown solid (92.0 mg, 64%). 1H NMR (500 MHz, CDCl3): δ 8.59 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.53 (dd, J = 7.9, 1.2 Hz, 1H), 7.51 (s, 1H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.30 (d, J = 16.1 Hz, 1H), 3.55 (s, 2H), 3.50 (t, J = 5.1 Hz, 4H), 2.96 – 2.76 (m, 2H), 2.59 (t, J = 4.9 Hz, 4H), 15 2.33 (qd, J = 13.1, 5.0 Hz, 1H), 2.23-2.17 (m, 1H), 1.45 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 171.2, 169.6, 168.8, 154.9, 141.5, 132.0, 131.1, 127.0, 126.3, 124.3, 87.0, 85.2, 80.0, 52.0, 47.9, 46.9, 43.4 (2C), 31.7, 28.5 (3C), 23.5. HRMS: C25H31N4O5 Calculated for [M+H]+: 467.2295; Found: 467.2269. 20

[0005] U of M 2025-025 VHPM 09531.599WO1 Example 48. HLB-0535047 was synthesized in a similar manner as HLB-0535028 with starting material 5.o, bright yellow solid (55% after HPLC, 2 X TFA). HPLC purity: 98.6% @ 254 nm; 95.8% @ 5 215 nm. 1H NMR (500 MHz, DMSO): δ 11.01 (s, 1H), 9.87 (d, J = 9.1 Hz, 1H), 8.81 (d, J = 1.4 Hz, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.83 – 7.75 (m, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 8.8, 2.2 Hz, 2H), 6.63 (d, J = 1.1 Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.76 (p, J = 8.9 Hz, 1H), 4.53 – 4.30 (m, 4H), 3.38 (s, 5H), 3.08 (s, 6H), 2.92 (ddd, J = 17.3, 13.7, 5.4 Hz, 1H), 2.62 (dd, 10 J = 12.2, 8.9 Hz, 2H), 2.50 – 2.37 (m, 3H), 2.07 – 1.93 (m, 5H), 1.67 (d, J = 6.2 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 173.3, 171.4, 169.9, 167.6, 163.3, 155.3, 152.3, 151.6, 143.3, 142.9, 132.8, 132.7, 132.1, 128.8 (2C), 127.4, 126.6, 124.4, 123.9, 117.9 (2C), 112.5, 101.1, 88.7, 81.6, 57.5, 52.2 (2C), 51.1, 47.6 (2C), 45.9, 39.3, 35.1 (2C), 31.7, 30.2 (2C), 24.6 (2C), 15 22.9. HRMS: C41H44N9O5Calculated for [M+H]+: 742.3465; Found: 742.3453. Example 49. 20 To a solution of 5-hydroxythalidomide (5.p, 205 mg, 0.748 mmol) was added tert-butyl 4- (2-bromoethyl)piperazine-1-carboxylate (263 mg, 0.897 mmol), sodium bicarbonate (126 mg, U of M 2025-025 VHPM 09531.599WO1 0.748 mmol), KI (124 mg, 0.748 mmol) in DMF (4 mL). The mixture was heated to 100 ºC overnight. After completion, water was added (20 mL), and the mixture was extracted with EtOAc (30 mL). The organic layer was concentrated in vacuo and was purified using column chromatography with a gradient of 0 to 100% EtOAc in hexanes to yield 5.q as a white solid 5 (135 mg, 37%). 1H NMR (500 MHz, CDCl3): δ 8.66 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.3, 2.3 Hz, 1H), 4.94 (dd, J = 12.3, 5.2 Hz, 1H), 4.27 (s, 2H), 3.49 (s, 4H), 2.94 – 2.68 (m, 5H), 2.59 (s, 4H), 2.17 – 2.09 (m, 1H), 1.45 (s, 9H). 10 13C NMR (126 MHz, CDCl3): δ 171.2, 168.4, 167.2, 167.1, 164.0, 154.7, 134.5, 125.7, 123.9, 121.0, 109.2, 80.1, 66.8 (2C), 56.9, 53.5, 49.5, 43.2 (2C), 31.6, 28.5 (3C), 22.8. HRMS: C24H31N4O7 Calculated for [M+H]+: 487.2193; Found: 487.2170. 15 HLB-0535050 was synthesized in a similar manner as HLB-0525028 with starting material 5.q, white solid (58% after HPLC, 2 X TFA). HPLC purity: 98.0% @ 254 nm; 93.7% @ 215 nm. 20 1H NMR (500 MHz, DMSO): δ 11.12 (s, 1H), 9.86 (s, 1H), 8.80 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.5, 2.3 Hz, 3H), 6.63 (s, 1H), 5.13 (dd, J = 12.8, 5.5 Hz, 1H), 4.75 (p, J = 8.8 Hz, 1H), 4.59 (t, J = 4.8 Hz, 2H), 4.24 (s, 2H), 3.65 (s, 4H), 3.38 (s, 2H), 3.26 (s, 3H), 3.06 (d, J = 11.3 Hz, 6H), 2.89 (ddd, J = 16.9, 13.8, U of M 2025-025 VHPM 09531.599WO1 5.4 Hz, 1H), 2.67 – 2.52 (m, 2H), 2.49 (s, 2H), 2.09 – 1.96 (m, 4H), 1.67 (d, J = 6.6 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 173.2, 170.4, 169.8, 167.3, 167.2, 163.3, 163.2, 155.4, 152.3, 151.5, 143.4, 134.3, 132.7, 128.8 (2C), 126.6, 125.9, 124.2, 121.4, 117.9 (2C), 112.5, 110.0, 5 101.1, 63.8, 57.5 (2C), 55.0, 52.0 (2C), 49.5 (2C), 40.5, 39.3, 35.1, 31.4, 30.2 (2C), 24.7, 22.5 (2C). HRMS: C40H44N9O7Calculated for [M+H]+: 762.3364; Found: 762.3327. 10 Example 50. To a solution of 5.e (236 mg, 0.533 mmol) was added TFA (1 mL) in CH2Cl2 (1 mL). The mixture was stirred for 1 h at room temperature and then concentrated in vacuo. The residue was dissolved in CH2Cl2(1.5 mL) and EtOH (1.5 mL) followed by the addition of sodium acetate 15 (19.3 mg, 0.235 mmol), acetic acid (14.1 mg, 0.235 mmol), and tert-butyl 3-formylazetidine-1- carboxylate (120 mg, 0.648 mmol). The mixture was stirred at 40 ºC for 1 h followed by the addition of sodium cyanoborohydride (36.9 mg, 0.587 mmol). The resulting solution was stirred overnight at 40 ºC. After completion, the reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 10 mL). The organic layer was concentrated in vacuo and was 20 purified using column chromatography with a gradient of 0 to 20% of MeOH in CH2Cl2 to yield 5.r as a bright yellow solid (125 mg, 46%). 1H NMR (500 MHz, CDCl3): δ 8.31 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.6, 2.3 Hz, 1H), 4.93 (dd, J = 12.2, 5.4 Hz, 1H), 4.03 (t, J = 8.4 Hz, 2H), 3.61 (dd, 25 J = 8.7, 5.3 Hz, 2H), 3.41 (s, 4H), 2.94 – 2.48 (m, 9H), 2.16 – 2.07 (m, 1H), 1.43 (d, J = 2.9 Hz, 9H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (126 MHz, CDCl3): δ 171.2, 168.5, 168.0, 167.3, 156.4, 155.5, 134.4, 125.5, 119.9, 118.2, 108.9, 79.6, 62.3, 53.0 (2C), 52.7 (2C), 49.3, 47.4 (2C), 31.6, 28.5 (3C), 26.5, 22.9. HRMS: C26H34N5O6 Calculated for [M+H]+: 512.2509; Found: 512.2492. 5 Example 51. HLB-05350501 was synthesized in a similar manner as HLB-0535028 with starting material 5.r, bright yellow solid (45% after HPLC, 2 X TFA). HPLC purity: 98.3% @ 254 nm; 94.8% @ 10 215 nm. 1H NMR (500 MHz, DMSO): δ 11.09 (s, 1H), 9.87 (s, 1H), 8.80 (s, 1H), 7.95 – 7.89 (m, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.61 – 7.56 (m, 2H), 7.49 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.6, 2.3 Hz, 1H), 6.63 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 4.76 (p, J = 8.9 Hz, 1H), 4.54 (s, 1H), 4.23 (d, 15 J = 14.8 Hz, 3H), 3.88 (s, 1H), 3.52 (s, 4H), 3.32 – 3.11 (m, 3H), 3.05 (s, 4H), 2.89 (ddd, J = 16.6, 13.7, 5.4 Hz, 1H), 2.63 – 2.52 (m, 1H), 2.49 – 2.34 (m, 0H), 2.01 (dd, J = 17.3, 6.4 Hz, 6H), 1.68 (d, J = 6.8 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 173.3, 170.5, 169.4, 167.9, 167.4, 163.3, 155.3, 154.5, 152.4, 20 151.5, 144.1, 134.3, 132.7, 129.0 (2C), 125.5, 125.0, 120.4, 119.3, 117.7 (2C), 112.6, 109.5, 101.1, 58.8, 57.5, 57.1 (2C), 52.6 (2C), 50.8, 49.3, 44.8, 39.3, 35.1 (2C), 31.4, 30.2 (2C), 24.6 (2C), 22.6. HRMS: C42H47N10O6Calculated for [M+H]+: 787.3680; Found: 787.3645. 25 U of M 2025-025 VHPM 09531.599WO1 Example 52. 5.d 35% 5.s5.s was synthesized in a similar manner as 5.e with starting material 5.d, yellow solid (35%). 1H NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 5 6.55 (dd, J = 8.3, 2.2 Hz, 1H), 4.93 (dd, J = 12.3, 5.4 Hz, 1H), 4.12 (t, J = 8.1 Hz, 2H), 3.92 – 3.83 (m, 4H), 3.08 – 2.96 (m, 1H), 2.93 – 2.67 (m, 3H), 2.19 – 2.08 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 171.2, 168.5, 168.1, 167.7, 155.3, 134.4, 125.4, 117.9, 114.1, 105.0, 64.2, 53.7 (2C), 49.2, 31.7, 31.6, 22.9. 10 HRMS: C17H18N3O5Calculated for [M+H]+: 344.1247; Found: 344.1229. 15 A mixture of 5.s (118 mg, 0.318 mmol), DMAP (3.9 mg, 0.0318 mmol), and Et3N (80.5 mg, 0.795 mmol) in CH2Cl2 (4mL) was cooled to 0 ºC. Tosyl chloride (78.8 mg, 0.413 mmol) was added, and the mixture was warmed to room temperature and stirred for 18 h. The product was diluted with CH2Cl2(20 mL) and washed with water (20 mL), 5% HCl (20 mL), and saturated NaHCO3 (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in 20 vacuo. The resulting residue was dissolved in MeCN, and 1-Boc-piperazine (128.2 mg, 0.688 mmol), DIPEA (133.4 mg, 1.03 mmol), and KI (5.71 mg, 0.034 mmol) were added. The resulting mixture was stirred at 82 ºC for 18 h. The reaction mixture was concentrated in vacuo and was purified using column chromatography with a gradient of 0-100% EtOAc in hexanes to yield 5.t as a yellow solid (52.3 mg, 30%). 25 U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, CDCl3): δ 8.88 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 6.49 (d, J = 8.3 Hz, 1H), 4.92 (dd, J = 12.1, 5.5 Hz, 1H), 4.14 (t, J = 7.9 Hz, 2H), 3.71 (q, J = 7.1 Hz, 2H), 3.46 (s, 4H), 3.06 (s, 1H), 2.89 – 2.66 (m, 4H), 2.46 (s, 4H), 2.11 (dt, J = 13.7, 3.6 Hz, 1H), 1.45 (s, 9H), 1.25 (s, 2H). 5 13C NMR (126 MHz, CDCl3): δ 171.6, 168.9, 168.1, 167.6, 155.2, 154.8, 134.4, 125.4, 114.0, 105.2, 56.1, 55.8, 53.1, 49.1, 43.5, 31.6, 28.5 (3C), 27.5, 22.9 . HRMS: C26H34N5O6Calculated for [M+H]+: 512.2509; Found: 512.2497. 10 HLB-0535052 was synthesized in a similar manner as HLB-0535028 with starting material 5.t, bright yellow solid (56% after HPLC, 2 X TFA). HPLC purity: 98.9% @ 254 nm; 94.7% @ 15 215 nm. 1H NMR (600 MHz, DMSO): δ 11.13 (s, 1H), 9.92 (s, 1H), 8.87 (s, 1H), 8.03 – 7.97 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.53 – 7.48 (m, 2H), 6.87 (d, J = 2.1 Hz, 1H), 6.73 (dd, J = 8.4, 2.1 Hz, 1H), 6.69 (s, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.82 (p, J = 8.9 Hz, 1H), 4.30 (t, J = 8.3 Hz, 20 2H), 3.92 – 3.90 (m, 2H), 3.59 (d, J = 7.1 Hz, 2H), 3.38 – 3.31 (m, 1H), 3.21 – 3.11 (m, 7H), 2.94 (ddd, J = 17.0, 13.9, 5.5 Hz, 1H), 2.68 – 2.56 (m, 3H), 2.56 –2.47 (m, 1H), 2.09 – 2.02 (m, 4H), 1.82 – 1.70 (m, 2H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (151 MHz, DMSO) δ 173.3, 170.5, 169.8, 167.9, 167.6, 163.3, 155.4, 152.5, 151.5, 143.4, 134.2, 132.6, 128.8 (2C), 126.5, 125.4, 117.9 (2C), 117.8, 117.7, 115.7, 114.8, 112.5, 105.0, 101.1, 58.9 (2C), 57.5, 55.7, 51.3 (2C), 49.2, 39.5, 39.3, 35.1 (2C), 31.4, 30.2 (2C), 25.2, 24.7 (2C), 22.7. 5 HRMS: C42H47N10O6 Calculated for [M+H]+: 787.3680; Found: 787.3643. Example 53. 5.v 10 To a solution of benzyl 3-oxoazetidine-1-carboxylate (5.u, 653 mg, 3.18 mmol) was added 1-Boc-piperazine (711 mg, 3.82 mmol), sodium acetate (1.04 g, 3.18 mmol) in methanol (5 mL) and CH2Cl2 (5 mL). The mixture was flushed with argon and stirred at 40 ºC. After 4 h, sodium cyanoborohydride (220 mg, 3.50 mmol) was added and the reaction mixture was stirred overnight at room temperature under argon. After completion, the organic layer was 15 concentrated in vacuo and was purified using column chromatography with a gradient of 0- 100% EtOAc in hexanes to yield 5.v as a yellow solid (295 mg, 25%). 1H NMR (500 MHz, CDCl3): δ 7.29 – 7.17 (m, 5H), 4.99 (s, 2H), 3.91 (dd, J = 8.9, 7.1 Hz, 2H), 3.79 (dd, J = 8.9, 5.3 Hz, 2H), 3.35 (t, J = 5.2 Hz, 4H), 3.01 (tt, J = 7.1, 5.3 Hz, 1H), 2.18 20 (t, J = 5.0 Hz, 4H), 1.37 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 156.5, 154.7, 136.7, 128.6 (2C), 128.2, 128.1 (2C), 80.0, 66.8, 54.3, 53.4, 52.9, 49.5 (2C), 43.6, 42.8, 28.5 (3C). 25 HRMS: C20H30N3O4 Calculated for [M+H]+: 376.2236; Found: 376.2224. U of M 2025-025 VHPM 09531.599WO1 To a solution of 5.v (303 mg, 0.807 mmol) was added TFA (1.1 mL) in CH2Cl2 (1.1 mL). The solution was stirred for 1 h at room temperature and then concentrated in vacuo. The resulting residue was dissolved in NMP (3 mL) followed by the addition of DIPEA (288 mg, 5 2.23 mmol) and 5.d (205 mg, 0.742 mmol). The resulting mixture was stirred at 90 ºC for 18 h. After completion, the reaction was cooled to room temperature and water was added (30 mL). The mixture was extracted with EtOAc (30 mL x 2). The organic phase was concentrated in vacuo and was purified using column chromatography with a gradient of 0-100% EtOAc in hexanes to yield 5.w as a yellow solid (124 mg, 31%). 10 1H NMR (500 MHz, CDCl3): δ 8.18 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.39 – 7.30 (m, 5H), 7.29 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.5, 2.4 Hz, 1H), 5.10 (s, 2H), 4.94 (dd, J = 12.2, 5.4 Hz, 1H), 4.06 (t, J = 7.9 Hz, 2H), 3.95 (s, 2H), 3.45 (s, 4H), 3.20 (s, 1H), 2.92 – 2.67 (m, 3H), 2.53 (s, 4H), 2.18 – 2.08 (m, 1H), 1.29 – 1.22 (m, 1H). 15 13C NMR (126 MHz, CDCl3): δ 171.1, 168.4, 167.9, 167.3, 156.5, 155.4, 136.7, 134.4, 128.6 (2C), 128.3, 128.2 (2C), 125.5, 118.4, 109.0, 67.0, 54.2, 52.8 (2C), 49.2, 49.1, 47.2 (2C), 31.4, 29.7, 22.7. 20 HRMS: C28H30N5O6Calculated for [M+H]+: 532.2196; Found: 532.2170.

[0006] U of M 2025-025 VHPM 09531.599WO1 ), To a solution of 5.w (40 mg, 0.075 mmol) was added 10% palladium on activated carbon (4 mg, 0.11 mmol) in MeOH (4 mL). The reaction mixture was degassed and purged with hydrogen three times. The mixture was stirred under a hydrogen atmosphere (40 psi) at room 5 temperature for 18 h. After completion, the mixture was filtered through celite and washed with CH2Cl2(5 mL) and MeOH (5 mL). The organic phase was concentrated in vacuo. Meanwhile, to a solution of 2.c (37.2 mg, 0.083 mmol) was added TFA (1 mL) in CH2Cl2 (1 mL). The solution was stirred for 1 h at room temperature and then concentrated in vacuo. The residues were dissolved in DMF (1 mL) followed by the addition of DIPEA (48.6 mg, 0.376 mmol), HATU 10 (42.9 mg, 0.113 mmol). The resulting solution was stirred overnight at room temperature. After completion, the reaction mixture was directly loaded onto silica and purified using column chromatography with a gradient of 0-20% MeOH in CH2Cl2to yield HLB-0535059. The compound was further purified reverse phase HPLC as a green solid (11.2 mg, 15% after HPLC, 2 XTFA salt). HPLC purity: 98.1% @ 254 nm; 96.5% @ 215 nm. 15 1H NMR (500 MHz, DMSO): δ 11.09 (s, 1H), 9.91 (s, 1H), 8.81 (s, 1H), 7.98 – 7.91 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.65 – 7.53 (m, 2H), 7.50 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 8.6, 2.3 Hz, 1H), 6.63 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 4.76 (p, J = 8.8 Hz, 1H), 4.60 (d, J = 40.9 Hz, 3H), 4.27 (s, 4H), 4.10 (s, 2H), 3.14 – 3.01 (m, 8H), 2.89 (ddd, J = 16.6, 13.6, 5.4 Hz, 1H), 2.64 20 – 2.51 (m, 4H), 2.49 – 2.40 (m, 2H), 2.01 (p, J = 7.5 Hz, 5H), 1.75 – 1.62 (m, 2H). 13C NMR (151 MHz, DMSO): δ 172.8, 170.01, 169.4, 167.4, 166.9, 162.8, 154.8, 154.2, 151.9, 151.1, 143.9, 133.8, 132.3, 128.7 (2C), 125.0, 124.0, 119.9, 118.9, 117.3 (2C), 112.1, 109.1, 100.6, 57.0, 54.9 (2C), 53.6, 50.7 (2C), 48.9, 48.2, 44.6, 38.8, 34.6 (2C), 31.0, 29.7 (2C), 24.2 U of M 2025-025 VHPM 09531.599WO1 (2C), 22.1. HRMS: C41H45N10O6 Calculated for [M+H]+: 773.3524; Found: 773.3512. 5 Example 54. 5.x was synthesized in a similar manner as 5.s with starting material 5.v, bright yellow solid (35%). 1H NMR (500 MHz, DMSO): δ 11.08 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.2 Hz, 10 1H), 6.65 (dd, J = 8.4, 2.2 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.10 (t, J = 7.8 Hz, 2H), 3.86 (dd, J = 8.8, 4.9 Hz, 2H), 3.37 – 3.31 (m, 6H), 2.89 (ddd, J = 16.6, 13.6, 5.3 Hz, 1H), 2.63 – 2.52 (m, 2H), 2.32 (t, J = 5.0 Hz, 4H), 2.04-1.99 (m, 1H), 1.41 (s, 9H). 13C NMR (126 MHz, DMSO): δ 172.8, 170.1, 167.5, 167.1, 154.9, 153.8, 133.8, 124.8, 116.9, 15 114.2, 104.5, 78.8, 55.0, 54.0, 48.8, 48.7, 43.5 (2C), 42.6 (2C), 31.0, 28.1 (3C), 22.2. HRMS: C25H32N5O6Calculated for [M+H]+: 498.2353; Found: 498.2341. 20 U of M 2025-025 VHPM 09531.599WO1 HLB-0535060 was synthesized in a similar manner as HLB-0535028 with starting material 5.x, bright yellow solid (35% after HPLC, 2 X TFA). HPLC purity: 99.5% @ 254 nm; 97.6% @ 215 nm. 51H NMR (500 MHz, DMSO): δ 11.09 (s, 1H), 9.85 (s, 1H), 8.81 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 6.92 (s, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.63 (s, 1H), 5.08 (dd, J = 12.7, 5.5 Hz, 1H), 4.76 (p, J = 8.9 Hz, 1H), 4.33 (s, 2H), 4.23 (s, 3H), 2.94 – 2.84 (m, 1H), 2.68 – 2.52 (m, 2H), 2.50 (s, 2H), 2.02 (d, J = 18.1 Hz, 5H), 1.68 (d, J = 6.7 Hz, 2H). 10 13C NMR (151 MHz, DMSO): δ 172.8, 170.1, 169.4, 167.4, 167.1, 162.8, 154.8, 154.5, 151.8, 151.1, 142.8, 133.7, 132.3, 128.3 (2C), 126.3, 124.9, 118.3, 117.4 (2C), 115.0, 112.0, 105.2, 100.7, 57.0, 54.0, 53.5 (2C), 48.8, 48.7 (2C), 40.4, 38.8, 34.6 (2C), 31.0, 29.7 (2C), 24.2 (2C), 22.2. 15 HRMS: C41H45N10O6 Calculated for [M+H]+: 773.3524; Found: 773.3508. Example 55. 20 HLB-0535074 was synthesized in a similar manner as HLB-0535028 with starting material 5.y (prepared as reported Crew, A. P., et al. WO2018102725 A12018), bright yellow solid (38% after HPLC, 2 X TFA). HPLC purity: 95.4% @ 254 nm; 96.1% @ 215 nm. U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, DMSO): δ 11.11 (s, 1H), 9.78 (s, 1H), 8.79 (s, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.40 – 7.31 (m, 3H), 6.62 (s, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.73 (p, J = 8.8 Hz, 1H), 4.10 (d, J = 6.4 Hz, 2H), 3.06 (s, 6H), 2.89 (ddd, J = 16.8, 13.7, 5.4 Hz, 1H), 2.63 – 2.52 (m, 4H), 2.45 – 2.36 (m, 3H), 2.09 – 1.95 (m, 5H), 5 1.82 (s, 2H), 1.65 (d, J = 6.7 Hz, 2H), 1.37 – 1.25 (m, 2H). 13C NMR (151 MHz, DMSO) δ 173.2, 170.4, 169.6, 167.4, 167.3, 164.6, 163.2, 155.2, 151.9, 151.7, 142.4, 134.4, 132.8, 128.8, 128.2 (2C), 125.8, 123.5, 121.3, 118.2 (2C), 112.4, 109.4, 101.2, 73.2, 57.5, 49.4, 39.3 (2C), 35.8, 35.1, 31.4, 30.2 (2C), 28.8 (2C), 24.7 (2C), 22.6. 10 HRMS: C39H42N9O7 Calculated for [M+H]+: 748.3207; Found: 748.3272. Example 56. 15 HLB-0535058 was synthesized in a similar manner as HLB-0535028 with starting material 5.e, bright yellow solid (52% after HPLC, 2 X TFA). HPLC purity: 99.7% @ 254 nm; 98.9% @ 215 nm. 1H NMR (500 MHz, DMSO):) δ 11.09 (s, 1H), 9.88 – 9.81 (m, 1H), 8.84 – 8.79 (m, 1H), 7.92 20 (dd, J = 8.7, 2.9 Hz, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.7, 2.0 Hz, 2H), 7.38 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 8.6, 2.3 Hz, 1H), 6.67 – 6.62 (m, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 4.75 (p, J = 8.8 Hz, 1H), 3.69 (s, 4H), 3.57 (s, 4H), 3.06 (s, 6H), 2.89 (ddd, J = 16.8, 13.7, 5.4 Hz, 1H), 2.63 – 2.53 (m, 2H), 2.47 – 2.37 (m, 2H), 2.07 – 1.96 (m, 5H), 1.67 (s, 2H). U of M 2025-025 VHPM 09531.599WO1 13C NMR (151 MHz, DMSO): δ 172.8, 170.1, 169.3, 167.5, 167.0, 162.7, 154.9, 154.6, 151.3, 151.2, 142.3, 133.9, 132.5, 128.2 (2C), 127.5, 125.0, 118.6, 117.9, 117.7 (2C), 112.0, 108.1, 100.7, 57.0, 48.8, 46.8 (2C), 40.1, 38.8, 34.6 (2C), 31.0, 29.7 (2C), 24.2 (2C), 22.2. 5 HRMS: C38H40N9O6Calculated for [M+H]+: 718.3102; Found: 718.3089. Example 57. 5.ab was synthesized by a similar procedure as HLB-0535028 with the commercially 10 available starting material 5.aa, and then HLB-0535062 was synthesized by a similar procedure as HLB-0535028, bright yellow solid (37.4 mg, 2 X TFA salt, 44% after HPLC). HPLC purity: 97.9% @ 254 nm; 96.7% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 11.11 (s, 1H), 10.46 (s, 1H), 9.80 (d, J = 4.6 Hz, 1H), 8.80 (d, J 15 = 1.1 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H), 7.86 (d, J = 8.3 Hz, 3H), 7.33 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 1.2 Hz, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.74 (p, J = 8.9 Hz, 1H), 3.48 – 3.39 (br, 4H), 3.27 (p, J = 8.6 Hz, 1H), 3.05 (d, J = 9.7 Hz, 6H), 2.88 (ddd, J = 16.9, 13.8, 5.4 Hz, 1H), 2.63 – 2.51 (m, 2H), 2.44 (d, J = 11.9 Hz, 3H), 2.13 – 1.96 (m, 10H), 1.65 (d, J = 6.7 Hz, 4H). 20 13C NMR (151 MHz, DMSO) δ 174.7, 173.2, 170.4, 169.6, 167.5, 167.2, 163.2, 154.9, 151.7, 151.5, 145.7, 142.2, 133.3, 133.1, 129.0, 128.2 (2C), 125.2, 125.1, 124.0, 118.3 (2C), 113.4, 112.4, 101.2, 57.5, 49.4, 39.3 (2C), 38.5 (2C), 36.6 (2C), 35.1, 34.6 (2C), 34.0, 31.4, 30.2 (2C), 24.7 (2C), 22.5. U of M 2025-025 VHPM 09531.599WO1 HRMS: C43H46N9O7Calculated for [M+H]+: 800.3520; Found: 800.3506. Example 58. 5 5.ad was synthesized by a similar procedure as HLB-0535028 with the commercially available starting material 5.ac, and then HLB-0535063 was synthesized by a similar procedure as HLB-0535028, yellow solid (9.9 mg, 2 X TFA salt, 17% after HPLC). HPLC purity: 97.6% @ 254 nm; 96.1% @ 215 nm. 10 1H NMR (500 MHz, DMSO): δ 11.11 (s, 1H), 10.52 (s, 1H), 9.85 (s, 1H), 8.80 (s, 1H), 8.23 (d, J = 1.8 Hz, 1H), 7.92 – 7.83 (m, 4H), 7.57 (d, J = 8.4 Hz, 2H), 6.62 (s, 1H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 4.75 (p, J = 8.9 Hz, 1H), 4.39 (s, 1H), 4.28 (s, 1H), 4.07 (s, 1H), 3.97 (s, 1H), 3.06 (s, 6H), 2.88 (ddd, J = 16.9, 13.8, 5.5 Hz, 1H), 2.65 – 2.51 (m, 4H), 2.46 – 2.37 (m, 3H), 2.08 – 15 1.93 (m, 8H), 1.67 (d, J = 5.6 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 173.2, 171.6, 170.4, 169.1, 167.5, 167.2, 163.3, 155.3, 152.2, 151.6, 145.5, 143.8, 133.3, 132.8, 129.0 (2C), 125.5, 125.3, 125.2, 124.0, 117.7 (2C), 113.3, 112.5, 101.1, 57.5, 49.4, 43.5 (2C), 39.3 (2C), 38.7 (2C), 35.2 (2C), 31.4, 30.2 (2C), 26.5, 24.7 20 (2C), 22.5. HRMS: C42H44N9O7Calculated for [M+H]+: 786.3364; Found: 786.3350. U of M 2025-025 VHPM 09531.599WO1 Example 59. To a solution of 2.c (100 mg, 0.222 mmol) in DCM (1 mL) was added TFA (1 mL) and the 5 reaction was stirred for 1 h at room temperature. The volatiles were removed. To the deprotected 2.c was added DMF (0.5 mL) and was basified with DIPEA until pH = 7 – 8. HATU (101 mg, 0.267 mmol) was added, and the reaction stirred for 0.5 h. To the reaction was added 6.a (57.7 mg, 0.267 mmol). The reaction was stirred at room temperature for 18 h. The mixture was purified by column chromatography with a gradient of 0-20% MeOH in CH2Cl2to yield 6.b as a 10 yellow solid. (76%) 1H NMR (500 MHz, MeOD) δ 8.71 (s, 1H), 7.92 – 7.85 (m, 2H), 7.85 – 7.78 (m, 2H), 6.60 (s, 1H), 4.75 (ddd, J = 17.6, 9.5, 8.3 Hz, 1H), 3.38 (t, J = 7.2 Hz, 2H), 3.15 (d, J = 3.8 Hz, 6H), 3.07 15 – 3.01 (m, 3H), 2.66 – 2.55 (m, 2H), 2.17 – 2.03 (m, 4H), 1.75 (pq, J = 9.2, 4.3 Hz, 2H), 1.63 (q, J = 7.1 Hz, 2H), 1.49 (p, J = 7.2 Hz, 2H), 1.43 (d, J = 2.1 Hz, 18H).

[0007] U of M 2025-025 VHPM 09531.599WO1 To a solution of 6.b (30.4 mg, 0.0514 mmol), in CH2Cl2 (0.5 mL) was added TFA (0.5 mL) and the reaction was stirred for 1 h at room temperature. Simultaneously, to a solution of 6.d (27 mg, 5 0.0429 mmol, prepared as reported in Nalawansha, D. A., et al. J. Am. Chem. Soc.2022144 (12), 5594-5605) in CH2Cl2 (0.5 mL) was added TFA (0.5 mL) and the reaction was stirred for 1 h at room temperature. The reactions were concentrated to remove volatiles. To the deprotected 6.d was added DMF (0.25 mL) and it was basified with DIPEA to pH = 7 – 8. PyAOP (26.8 mg, 0.0514 mmol) was added, and the reaction stirred for 1 h. To the reaction was added deprotected 10 6.b dissolved in DMF (0.25 mL) and it was basified with DIPEA to pH = 7 – 8. The reaction was stirred at room temperature for 18 h. The mixture was purified by column chromatography with a gradient of 0-20% (1 / 99 NH4OH / MeOH (v / v)) in CH2Cl2and then preparative HPLC to yield HLB-0535254 as a white solid (28% after HPLC, 4 X TFA). HPLC purity: 97.8% @ 254 nm; 96.3% @ 215 nm. 15 1H NMR (500 MHz, MeOD) δ 8.76 (s, 1H), 7.85 (s, 4H), 7.78 – 7.71 (d, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.14 (dd, J = 7.8, 1.5 Hz, 1H), 7.11 – 7.05 (d, 2H), 6.70 (s, 1H), 4.74 (q, J = 8.8 Hz, 3H), 4.02 – 3.72 (m, 3H), 3.70 – 3.47 (m, 4H), 3.39 (q, J = 7.2 Hz, 6H), 3.17 (d, J = 3.0 Hz, 12H), 2.88 (s, 3H), 2.54 (dd, J = 12.3, 8.4 Hz, 2H), 2.32 – 1.91 (m, 16H), 20 1.85 – 1.24 (m, 16H). U of M 2025-025 VHPM 09531.599WO1 Example 60. 6.f was synthesized by a similar procedure as 6.b with the commercially available starting material 6.e Yellow solid. (90%) 5 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 7.79 (s, 4H), 7.57 (s, 1H), 6.45 (s, 1H), 5.03 (s, 2H), 4.79 (p, J = 9.0 Hz, 1H), 3.66 – 3.60 (m, 3H), 3.56 (td, J = 5.2, 2.1 Hz, 3H), 3.33 (d, J = 8.0 Hz, 3H), 3.16 (s, 6H), 2.60 (ddt, J = 14.6, 11.9, 7.6 Hz, 2H), 2.13 – 2.06 (m, 4H), 1.99 (s, 2H), 1.72 (d, J = 5.2 Hz, 2H), 1.43 (s, 9H). 10 HLB-0535276 was synthesized by a similar procedure as HLB-0535254. White solid (28% after HPLC, 4 X TFA). HPLC purity: 99.7% @ 254 nm; 97.5% @ 215 nm. U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, MeOD) δ 8.74 (s, 1H), 7.87 – 7.80 (m, 4H), 7.73 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.13 (dd, J = 7.8, 1.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 12.5 Hz, 1H), 4.75 (dd, J = 17.1, 7.9 Hz, 3H), 3.98 – 3.75 (m, 3H) 3.70 – 3.64 (m, 8H), 3.55 (t, J = 5.4 5 Hz, 6H), 3.46 – 3.35 (m, 2H), 3.18 – 3.11 (m, 9H), 3.06 (s, 2H), 2.92 – 2.68 (m, 3H), 2.55 (s, 2H), 2.36 – 1.25 (m, 26H). 13C NMR (126 MHz, MeOD) δ 169.84, 168.43, 168.22, 152.11, 149.31 (2C), 143.24, 139.91, 137.50, 128.98, 128.67 (2C), 127.86 (2C), 118.07 (2C), 116.09 (3C), 112.62, 101.24, 69.96 (4C), 69.28 (3C), 61.57 (2C), 61.45 (2C), 58.17, 51.50 (3C), 51.33 (4C), 48.22 (2C), 48.05, 10 39.46 (2C), 39.42 (2C), 29.78 (3C), 24.30 (3C), 22.46 (6C), 22.38. Example 61. 6.h was synthesized by a similar procedure as 6.b with the commercially available starting 15 material 6.g Yellow solid. (90%)’ 1H NMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 6.44 (s, 1H), 4.79 (p, J = 8.9 Hz, 1H), 3.57 (dd, J = 6.9, 4.3 Hz, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.16 (s, 6H), 2.60 (q, J = 9.3 Hz, 2H), 2.13 – 2.03 (m, 4H), 1.72 (d, J = 5.4 Hz, 2H), 1.44 (s, 20 9H). U of M 2025-025 VHPM 09531.599WO1 HLB-0535278 was synthesized by a similar procedure as HLB-0535254. White solid (18% after HPLC, 4 X TFA). HPLC purity: 98.7% @ 254 nm; 95.9% @ 215 nm. 5 1H NMR (500 MHz, MeOD) δ 8.74 (d, J = 5.2 Hz, 1H), 7.92 – 7.81 (m, 4H), 7.78 – 7.73 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.38 – 7.34 (m, 1H), 7.15 (dd, J = 7.8, 1.5 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 11.9 Hz, 1H), 4.78 – 4.71 (m, 2H), 4.01 – 3.71 (m, 3H), 3.62 (s, 7H), 3.51 (s, 1H), 3.45 – 3.37 (m, 2H), 3.16 (d, J = 4.7 Hz, 9H), 3.05 (s, 2H), 2.87 (s, 3H), 2.57 (s, 10 2H), 2.36 – 1.26 (m, 26H). Example 62. Synthesis of HLB-0535279: 15 Prepared using a procedure similar to that described in United States Patent Application Publication Number US2019 / 0055249. To a solution of 7.a (2.01 g, 12.1 mmol) in 30 mL of CH2Cl2 anhydrous was added N- U of M 2025-025 VHPM 09531.599WO1 ethylbis(isopropyl)amine (13.7 mL, 78.6 mmol). The reaction mixture was cooled to 0 °C for 10 minutes. Then, chloromethoxymethane (1.01 mL, 13.3 mmol) was added, and the reaction was warmed and stirred at room temperature for 18 hours. After completion, the reaction was quenched with 20 mL of H2O for 5 minutes. Then, the crude was diluted in 30 mL of H2O, 5 extracted with CH2Cl2(30 mL x 3), and washed with brine (50 mL x 2). The organic layer was dried over Na2SO4, concentrated in vacuo, and purified using column chromatography with a gradient of 0-10 % EtOAc in hexanes to yield 7.b as a colorless liquid (1.01 g, 39 %). 1H NMR (601 MHz, CDCl3): δ 7.20 (d, 2H), 7.00 (d, 2H), 5.16 (s, 2H), 3.68 (s, 3H), 3.57 (s, 10 2H), 3.47 (s, 3H). Prepared using a procedure similar to that described in CN 114957101 A. To a flame-dried flask, 7.b (657 mg, 3.12 mmol) was dissolved in 20 mL of THF 15 anhydrous, and acrylamide (171 mg, 2.4 mmol) was added under argon. Then, potassium 2- methyl-2-propanolate (404 mg, 3.6 mmol) in 30 mL of THF anhydrous was added dropwise at room temperature. The reaction was stirred under Argon for 18 hours. After completion, the reaction mixture was diluted in 50 mL of H2O, extracted with EtOAc (50 mL x 3), and washed with brine (100 mL x 2). The organic layer was dried over Na2SO4, concentrated in vacuo, and 20 purified using column chromatography with a gradient of 0-80 % EtOAc in hexanes to yield 7.c as a white solid (88.7 mg, 15 %). 1H NMR (500 MHz, DMSO): δ 10.79 (s, 1H), 7.15 (d, 2H), 6.99 (d, 2H), 5.18 (s, 2H), 3.79 (dd, J = 11.6, 4.9 Hz, 1H), 3.37 (s, 3H), 3.31 – 3.28 (m, 1H), 2.71 – 2.59 (m, 1H), 2.24 – 2.10 (m, 25 1H), 2.09 – 1.96 (m, 1H). 13C NMR (126 MHz, DMSO): δ 174.44, 173.44, 155.65, 129.60 (2C), 116.02 (2C), 93.82, 73.70, 55.48, 46.58, 31.42, 26.00. U of M 2025-025 VHPM 09531.599WO1 To 7.c (85.8 mg, 344 µmol) was added 20 mL of HCl in dioxane (1M). The reaction mixture 5 was stirred at room temperature for 24 hours. After completion, the reaction mixture was neutralized with 0.1 % NaHCO3and the remaining mixture was extracted with EtOAc (100 mL x 4). The organic layer was dried over Na2SO4, concentrated in vacuo, and purified using column chromatography with a gradient of 0-50 % EtOAc in hexanes to yield 7.d as a white solid (45.2 mg, 64 %). 10 1H NMR (500 MHz, DMSO): δ 10.76 (s, 1H), 9.30 (s, 1H), 7.00 (d, 2H), 6.70 (d, 2H), 3.68 – 3.65 (m, 1H), 2.67 – 2.58 (m, 1H), 2.46 (dt, J = 17.3, 4.5 Hz, 1H), 2.16 – 2.06 (m, 1H), 2.04 – 1.96 (m, 1H). 15 13C NMR (126 MHz, DMSO): δ 174.60, 173.47, 156.20, 129.41(2C), 129.22, 115.05 (2C), 60.18, 31.25, 26.05. 20 To a solution of 7.d (101 mg, 492 µmol), 6-hydroxyhexyl 2-methyl-2-propanecarbamate (106 mg, 487 µmol), and triphenylphosphine (141 mg, 536 µmol) in 3 mL of THF was added DIAD (106 µL, 536 µmol) dissolved in 0.5 mL of THF dropwise. Then, the mixture was stirred at room temperature for 24 hours under Argon. After completion, the crude was concentrated in 25 vacuo and purified with column chromatography with a gradient of 0-60 % EtOAc in hexanes to yield 7.e as a white solid (112 mg, 57 %). U of M 2025-025 VHPM 09531.599WO1 1H NMR (500 MHz, DMSO): δ 10.77 (s, 1H), 7.11 (d, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.76 (s, 1H), 3.94 (t, J = 6.3 Hz, 2H), 3.77 (dd, J = 11.4, 4.9 Hz, 1H), 2.90 (q, J = 6.6 Hz, 2H), 2.69 – 2.57 (m, 2H), 2.21 – 2.05 (m, 2H), 2.05 – 1.96 (m, 2H), 1.73 – 1.64 (m, 4H), 1.36 (s, 9H), 1.33 – 5 1.22 (m, 2H). 10 To 7.f (59.5 mg, 195 μmol) in 10 mL of CH2Cl2 was added 1 mL of TFA. The reaction was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated in vacuo, neutralized with 1M aq. NaOH, and extracted with EtOAc (15 mL x 3). The organic layer was dried in Na2SO4and purified with column chromatography with a gradient of 0-20 % CH3OH in CH2Cl2 to yield a white solid (43.9 mg, 98 %). Then, to a solution of HLB-0535049 (38.4 mg, 15 97.6 µmol) in 5 mL of DMF was added DIPEA (6 mL, 34.5 mmol) and HATU (55.7 mg, 146 µmol). The resulting mixture was stirred for 15 minutes at room temperature. After completion, 7.f (43.9 mg, 144 µmol) was basified with DIPEA (8 mL, 45.9 mmol) and added to the reaction mixture. The reaction was stirred at room temperature for 8 hours. Then, the crude was U of M 2025-025 VHPM 09531.599WO1 concentrated in vacuo, diluted in 50 mL of H2O, and extracted with CH2Cl2 (50 mL x 3). The organic layer was dried in Na2SO4and concentrated under reduced pressure. The resulting crude was precipitated in 10 mL of cold CH3OH and filtered. The filtrate was collected and concentrated in vacuo. Then, it was purified with reverse-phased column chromatography with a 5 gradient of 30-70% CH3CN in H2O to yield HLB-0535279 as a white solid (28 mg, 42 %). HPLC purity: 94.9 % @ 254 nm; 95.6 % @ 215 nm. 1H NMR (500 MHz, DMSO): δ 10.78 (s, 1H), 9.81 (s, 1H), 8.79 (s, 1H), 8.27 (t, J = 5.7 Hz, 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.80 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 10 Hz, 2H), 6.62 (s, 1H), 4.75 (p, J = 8.7 Hz, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.76 (dd, J = 11.4, 4.9 Hz, 1H), 3.26 (q, J = 6.8 Hz, 2H), 3.06 (d, J = 8.1 Hz, 6H), 2.63 (ddd, J = 17.1, 11.7, 5.4 Hz, 1H), 2.47 (t, J = 4.3 Hz, 1H), 2.44 (t, J = 4.3 Hz, 1H), 2.18 – 2.07 (m, 1H), 2.05 – 1.95 (m, 5H), 1.75 – 1.63 (m, 4H), 1.55 (p, J = 7.3 Hz, 2H), 1.45 (p, J = 7.3 Hz, 2H), 1.41 – 1.33 (m, 2H). 1513C NMR (126 MHz, DMSO): δ 174.47, 173.42, 165.66, 162.85, 157.58, 155.05, 152.10, 151.01, 143.53, 132.05, 130.85, 129.51(2C), 127.77(2C), 126.49, 116.88(2C), 114.22(2C), 111.93, 100.60, 67.35, 57.03, 46.48, 31.34, 29.62, 29.24, 28.64, 26.28, 25.97, 25.34, 24.18. ESI MS: Calculated: C38H45N7O5[M+H]+: 680.35; Found: 680.50 20 Example 63. Synthesis of HLB-0535281 Prepared using a procedure similar to that described in CN 114957101 A. 25 In a flame-dried flask, 7.g (205 mg, 894 µmol) was dissolved in 30 mL of THF anhydrous followed by acrylamide (52.2 mg, 734 µmol). Then, potassium tert-butoxide (118 mg, 1.03 mmol) was dissolved in 20 mL of THF anhydrous and added dropwise to the reaction mixture under Argon. The reaction was stirred at room temperature for 20 hours. After completion, the 103 U of M 2025-025 VHPM 09531.599WO1 reaction was concentrated in vacuo, the crude was diluted in 30 mL of H2O, extracted with EtOAc (15 mL x 3), and washed with brine (30 mL x 3). The organic layer was dried in Na2SO4and concentrated in vacuo. The crude was purified with column chromatography with a gradient of 0-5 % CH3OH in CH2Cl2 to yield 7.h as a white solid (94.6 mg, 48 %). 5 1H NMR (500 MHz, DMSO): δ 10.85 (s, 1H), 7.57 – 7.46 (m, 2H), 7.26 – 7.14 (m, 2H), 3.88 (dd, J = 12.0, 4.9 Hz, 1H), 3.30 – 3.25 (m, 1H), 2.74 – 2.60 (m, 1H), 2.30 – 2.14 (m, 1H), 2.06 – 1.93 (m, 1H). 10 Prepared using a procedure similar to that described by Zheng, S., et al., Org. Biomol. Chem. 2019, 17 (17), 4291–4300. To a solution of 7.i (3.01 g, 16.2 mmol) in 21 mL of MeCN anhydrous was added 3- 15 bromopropyne (1.53 mL, 17.7 mmol) and dipotassium carbonate (3.34 g, 24.2 mmol). The reaction mixture was stirred at 60 °C for 2.5 hours. After completion, the reaction was cooled to room temperature, filtered in vacuo, and concentrated under reduced pressure. The crude was diluted in H2O (30 mL) and extracted with CH2Cl2 (30 mL x 3). The organic layer was dried in Na2SO4, concentrated in vacuo, and purified with column chromatography with a gradient of 0 - 20 100 % EtOAc in hexanes to yield 7.j as a brown oil (3.18 g, 88 %). 1H NMR (600 MHz, CDCl3): δ 3.44 (t, J = 5.3 Hz, 4H), 3.29 (d, J = 2.5 Hz, 2H), 2.62 – 2.41 (m, 4H), 2.24 (t, J = 2.4 Hz, 1H), 1.43 (s, 9H). 2513C NMR (126 MHz, CDCl3): δ 154.68, 79.70, 78.42, 73.44, 51.63, 46.99 (2C), 43.43 (d, J = 112.9 Hz, 2C), 28.42, (3C) U of M 2025-025 VHPM 09531.599WO1 In a round bottom flask, 7.h (296 mg, 1.11 mmol), bis(triphenylphosphonium)—dichloro- 5 palladamethane (77.8 mg, 111 µmol), and copper iodide (21.3 mg, 112 µmol) were added and degassed. Then, 40 mL of DMF anhydrous was added followed by triethylamine (2.82 mL, 20.2 mmol). The resulting mixture was degassed. Then, 7.j (612 mg, 2.73 mmol) was dissolved in 12 mL of DMF anhydrous, the resulting solution was degassed and added to the reaction mixture. The solution was degassed and stirred at 100 °C for 18 hours under N2. After completion, the 10 crude was filtered through a short bed of celite, diluted in 50 mL of H2O, extracted with EtOAc (50 mL x 3), and washed with brine (100 mL x 3). The organic layer was dried in Na2SO4, concentrated in vacuo, and purified with column chromatography in a gradient of 0-80 % EtOAc in hexanes to yield 7.k as a dark brown solid (221 mg, 49 %). 151H NMR (600 MHz, CDCl3): δ 9.21 (s, 1H), 7.38 – 7.34 (d, 2H), 7.09 (d, 2H), 3.69 (dd, J = 10.0, 5.2 Hz, 1H), 3.44 (s, 4H), 3.35 (s, 2H), 2.67 – 2.54 (m, 2H), 2.55 – 2.52 (m, 4H), 2.23 – 2.10 (m, 2H), 1.41 (s, 9H).

[0008] U of M 2025-025 VHPM 09531.599WO1 To 2.c (77.6 mg, 173 µmol) in 10 mL of CH2Cl2was added 1 mL of TFA. The reaction was stirred at room temperature for 1 hour. Then, the mixture was concentrated in vacuo, dissolved in 5 mL of DMF, and basified with DIPEA (10 mL, 57.4 mmol). To the resulting solution was 5 added 1,1,3,3-tetramethyl-2-(3H-1,2,3,4-tetraazainden-3-yl)-3-isoureaium hexafluoridophosphate (78.7 mg, 207 µmol). The reaction was stirred for 15 minutes at room temperature. After completion, 7.k (78.6 mg, 191 µmol) was dissolved in 10 mL of CH2Cl2 and stirred with 1 mL of TFA for 1 hour. The resulting crude was concentrated in vacuo, dissolved in 5 mL of DMF, and basified with DIPEA (11 mL, 63.2 mmol). The solution was added to the 10 reaction mixture and was stirred at room temperature for 18 hours. Then, the crude was concentrated in vacuo, diluted in 50 mL of H2O, extracted with EtOAc (30 mL x 3), and washed with brine (100 mL x 2). The organic layer was dried in Na2SO4and concentrated under reduced pressure. Then, it was purified with column chromatography with a gradient of 0-10 % CH3OH in CH2Cl2, followed by reversed-phase chromatography with a gradient of 30-60 % CH3CN in 15 H2O to yield HLB-0535281 as a white solid (24.4 mg, 21 %). HPLC purity: 98.9% @ 254 nm; 97.9 % @ 215 nm. 1H NMR (500 MHz, DMSO): δ 10.85 (s, 1H), 9.77 (s, 1H), 8.78 (s, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.41 (d, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.61 (s, 1H), 4.72 (q, J = 20 8.8 Hz, 1H), 3.90 (dd, J = 11.8, 4.9 Hz, 1H), 3.58 (s, 2H), 3.42 – 3.33 (m, 1H), 3.32 – 3.22 (m, U of M 2025-025 VHPM 09531.599WO1 3H), 3.06 (s, 6H), 2.72 – 2.62 (m, 1H), 2.55 (d, J = 9.0 Hz, 4H), 2.37 – 2.34 (m, 1H), 2.20 (qd, J = 12.3, 4.4 Hz, 1H), 1.98 – 1.95 (m, 5H), 1.67 – 1.62 (m, 3H), 1.24 (s, 1H). 13C NMR (151 MHz, DMSO): δ 173.98, 173.37, 169.26, 162.89, 155.18, 152.11, 151.08, 5 142.42, 142.39, 139.64, 132.01, 131.38, 129.00(2C), 127.98(2C), 127.45, 120.93(2C), 117.46 (2C), 111.93, 100.60, 84.95, 56.99, 53.46, 51.36, 47.18, 46.66, 46.40, 41.71, 40.06, 34.62, 31.42, 29.70, 29.03, 28.70, 25.68, 24.17, 18.04, 16.72, 12.34. ESI MS: Calculated: C39H42N8O4[M+H]+: 687.33; Found: 687.42 10 Example 64. Synthesis of HLB-0535282 Methyl 7.g (3.02 g, 13.2 mmol), tert-butyl 1-piperazinecarboxylate (2.68 g, 14.4 mmol), palladium diacetate (291 mg, 1.28 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (816 mg, 15 1.31 mmol) and dicesium carbonate (6.41 g, 19.7 mmol) were degassed and dissolved in 30 mL of 1,4-dioxane. The resulting mixture was degassed and stirred at 90 °C for 18 hours. After completion, the crude was filtered through a short bed of celite, and the filtrate was concentrated in vacuo. The crude was diluted in 100 mL of H2O, and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was 20 purified with column chromatography in a gradient of 0-20 % EtOAc in hexanes to yield 7.l as a yellow oil (1.78 g, 41 %). 1H NMR (500 MHz, CDCl3): δ 7.17 (d, 2H), 6.87 (d, 2H), 3.68 (s, 3H), 3.57 (t, 4H), 3.11 (t, J = 5.2 Hz, 4H), 1.48 (s, 9H), 1.26 (t, J = 7.2 Hz, 2H). U of M 2025-025 VHPM 09531.599WO1 In a flame-dried flask, 7.l (1.52 g, 4.55 mmol) was dissolved in 4 mL of THF anhydrous. Then, acrylamide (290 mg, 4.08 mmol) was dissolved in 3 mL of THF anhydrous and added to the reaction mixture under argon. The mixture was cooled to 0 °C and a solution of potassium 2- 5 methyl-2-propanolate (686 mg, 6.12 mmol) in 15 mL of THF anhydrous was added dropwise. Then, the reaction was warmed to 50 °C and stirred for 12 hours. After completion, the crude was concentrated under reduced pressure, diluted in 100 mL of H2O, extracted with EtOAc (50 mL x 3), and washed with brine (50 mL x 3). The organic layer was dried over Na2SO4, concentrated in vacuo, and purified with column chromatography in a gradient of 0-100% 10 EtOAc to yield 7.m as a light yellow solid (330 mg, 22 %). 1H NMR (500 MHz, DMSO): δ 10.77 (s, 1H), 7.07 (d, 2H), 6.91 (d, 2H), 3.74 (dd, 1H), 3.45 (t, J = 5.1 Hz, 4H), 3.07 (t, 4H), 2.68 – 2.59 (m, 1H), 2.49 – 2.45 (m, 1H), 2.19 – 2.08 (m, 1H), 2.03 – 1.97 (m, 1H), 1.42 (s, 8H). 15 To a solution of 7.m (249 mg, 911 µmol) in 5 mL of CH2Cl2was added 1 mL of TFA. The reaction mixture was stirred at room temperature for 2 hours. After completion, it was concentrated in vacuo, followed by dilution in 3 mL of 1:1 CH2Cl2:MeOH. The pH of the20 mixture was adjusted to 4-5 by adding drops of triethylamine. Then, tert-butyl 3-formyl-1- azetidinecarboxylate (202 mg, 1.09 mmol) was dissolved in 3 mL of 1:1 CH2Cl2:MeOH, added to the reaction mixture, and stirred at 40 °C for 2.5 hours. After completion, sodium triacetoxyborohydride (212 mg, 1 mmol) was added, and the reaction was stirred at 40 °C for 18 U of M 2025-025 VHPM 09531.599WO1 hours. Then, the reaction was quenched by adding 20 mL of H2O. The resulting mixture was extracted with EtOAc (10 mL x 3). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified with column chromatography in a gradient of 0-20 % CH3OH in CH2Cl2 to yield 7.n as a white solid (106 mg, 26 %). 5 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H), 7.08 (d, 2H), 6.88 (d, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.69 (dd, J = 9.5, 5.1 Hz, 1H), 3.61 (dd, J = 8.7, 5.4 Hz, 2H), 3.20 (s, 4H), 2.81 (s, 2H), 2.74 – 2.56 (m, 7H), 2.26 – 2.13 (m, 2H), 1.42 (s, 10H). 10 To 7.n (106 mg, 240 μmol) in 10 mL of CH2Cl2 was added 1 mL of TFA. The reaction was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated in vacuo, 15 neutralized with 1M aq. NaOH, and extracted with EtOAc (15 mL x 3). The organic layer was dried in Na2SO4 and purified with column chromatography with a gradient of 0-20 % CH3OH in U of M 2025-025 VHPM 09531.599WO1 CH2Cl2 to yield 7.o as a white solid (92.5 mg, 86 %). Then, to a solution of HLB-0535049 (70.9 mg, 180 µmol) in 5 mL of DMF was added DIPEA (11 mL, 63.2 mmol) and HATU (103 mg, 270 µmol). The resulting mixture was stirred for 15 minutes at room temperature. After completion, 7.o (92.5 mg, 270 µmol) was basified with DIPEA (8 mL, 45.9 mmol) and added to 5 the reaction mixture. The reaction was stirred at room temperature for 18 hours. Then, the crude was concentrated in vacuo, diluted in 50 mL of H2O, and extracted with CH2Cl2 (50 mL x 3). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified with column chromatography in a gradient of 0-20 % MeOH in CH2Cl2, as well as reversed- phase with 10-62 % CH3CN in H2O to yield HLB-0535282 as a white solid (32 mg, 25 %). 10 HPLC purity: 98.4 % @ 254 nm; 96.7 % @ 215 nm. 1H NMR (500 MHz, DMSO): δ 10.76 (s, 1H), 9.83 (s, 1H), 8.79 (s, 1H), 7.90 (d, 2H), 7.59 (d, 2H), 7.04 (d, 2H), 6.88 (d, 2H), 6.61 (s, 1H), 4.74 (p, J = 8.9 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.16 – 4.07 (m, 1H), 4.06 – 3.96 (m, 1H), 3.72 (dd, J = 11.1, 4.9 Hz, 2H), 3.09 (t, J = 5.0 Hz, 10H), 15 3.06 (s, 5H), 2.89 (p, J = 7.0 Hz, 1H), 2.68 – 2.57 (m, 3H), 2.49 – 2.42 (m, 4H), 2.17 – 2.07 (m, 1H), 2.06 – 1.92 (m, 5H), 1.73 – 1.61 (m, 2H). 13C NMR (126 MHz, DMSO): δ 174.58, 173.46, 168.76, 162.84, 155.03, 152.06, 151.03, 149.91, 143.44, 132.12, 129.23 (2C), 128.95, 128.55, 124.89, 117.22, 115.30 (2C), 112.04, 20 100.54, 61.66, 57.55, 56.96, 54.75, 52.68 (2C), 48.28 (2C), 46.42, 31.24, 29.70, 26.60, 25.96, 24.19. ESI MS: Calculated: C40H47N9O4[M+H]+: 718.38; Found: 718.50 25 Example 65. Synthesis of HLB-0535361 To a solution of 7.a (3.12 g, 18.8 mmol), N-Boc-4-piperidinemethanol (4.45 g, 20.6 mmol), and U of M 2025-025 VHPM 09531.599WO1 triphenylphosphine (5.42 g, 20.6 mmol) in 4 mL of THF was added DIAD (4.07 mL, 20.6 mmol) dropwise. Then, the mixture was stirred at room temperature for 24 hours in Argon. After completion, the crude was concentrated in vacuo and purified by column chromatography using a gradient of 0-20% EtOAc in hexanes, yielding 7.p as a colorless oil (6.71 g, 98%). 5 1H NMR (500 MHz, CDCl3): δ 7.16 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.14 (s, 1H), 3.77 (d, J = 6.4 Hz, 2H), 3.66 (s, 3H), 3.54 (s, 2H), 2.73 (t, J = 13.0 Hz, 2H), 1.99 – 1.88 (m, 1H), 1.80 (d, J = 12.3 Hz, 2H), 1.49 (ddd, J = 8.4, 6.0, 3.0 Hz, 1H), 1.45 (s, 9H), 1.24 (dd, J = 37.3, 4.3 Hz, 2H).10 In a flame-dried flask, 7.p (6.51 g, 17.9 mmol) and acrylamide (975 mg, 13.7 mmol) were 15 dissolved in anhydrous THF (5 mL). The mixture was cooled to 0 °C and a solution of potassium tert-butoxide (2.32 g, 20.6 mmol) in 10 mL of THF anhydrous was added dropwise under Argon. Then, the reaction was warmed and stirred at room temperature overnight. After completion, the crude was concentrated under reduced pressure and purified with column chromatography using a gradient of 0-50% EtOAc to yield 7.q as a light brown solid (1.01 g, 18 20 %). 1H NMR (500 MHz, DMSO): δ 10.79 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 3.98 (d, J = 11.7 Hz, 2H), 3.83 (d, J = 6.5 Hz, 2H), 3.79 (dd, J = 11.5, 5.0 Hz, 1H), 2.75 (s, 2H), 2.65 (ddd, J = 17.0, 11.7, 5.1 Hz, 1H), 2.49 – 2.44 (m, 1H), 2.21 – 2.10 (m, 1H), 2.05 – 25 1.97 (m, 1H), 1.97 – 1.86 (m, 1H), 1.76 (d, J = 10.8 Hz, 2H), 1.41 (s, 9H), 1.15 (qd, J = 12.6, 4.3 Hz, 2H). U of M 2025-025 VHPM 09531.599WO1 HLB-0535361 was synthesized by a similar procedure as HLB-0535281 using 2.c (433 mg, 1.10 mmol) and 7.q (665 mg, 1.65 mmol). The product was purified using column 5 chromatography in a gradient of 0-5 % CH3OH in CH2Cl2and reversed-phase chromatography (10-60% CH3CN in H2O). White solid (207 mg, 24% after HPLC). HPLC purity: 98.7% @ 254 nm; 98.9% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 10.78 (s, 1H), 9.75 (s, 1H), 8.78 (s, 1H), 7.88 (d, J = 8.8 Hz, 10 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.61 (s, 1H), 4.78 – 4.69 (m, 2H), 3.86 (d, J = 6.4 Hz, 2H), 3.78 (dd, J = 11.4, 5.0 Hz, 1H), 3.05 (s, 6H), 2.68 – 2.59 (m, 2H), 2.47 – 2.40 (m, 2H), 2.37 – 2.35 (m, 2H), 2.21 – 2.09 (m, 2H), 2.09 – 1.92 (m, 6H), 1.81 (s, 2H), 1.65 (td, J = 10.7, 3.9 Hz, 2H), 1.33 – 1.21 (m, 2H). 1513C NMR (126 MHz, DMSO): δ 174.47, 173.43, 169.17, 162.86, 157.54, 155.19, 152.09, 151.07, 142.17, 131.95, 131.05, 129.55 (2C), 128.09, 127.69 (2C), 117.46 (2C), 114.30 (2C), 111.88, 100.57, 71.62, 56.94, 46.49 (2C), 35.54, 31.36, 29.69 (2C), 26.00, 24.18 (2C). Example 66. Synthesis of HLB-0535365 U of M 2025-025 VHPM 09531.599WO1 7.r was synthesized by a similar procedure as 7.p using 7.a (2.01 g, 12.1 mmol) and N-Boc-(2- hydroxyethyl)piperazine (3.06 g, 13.3 mmol). The product was purified using column 5 chromatography in a gradient of 0-50 % EtOAc in hexanes to yield 7.r as a light-yellow oil (2.79 g, 61%). 1H NMR (500 MHz, CDCl3): δ 7.18 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.15 – 4.10 (t, 2H), 3.67 (s, 3H), 3.55 (s, 2H), 3.44 (t, J = 5.1 Hz, 4H), 2.80 (t, J = 5.7 Hz, 2H), 2.51 (t, J = 10 5.1 Hz, 4H), 1.45 (s, 9H). 7.s was synthesized by a similar procedure as 7.q using 7.r (2.70 g, 7.13 mmol) and acrylamide (423mg, 5.95 mmol). The product was purified using column chromatography in a gradient of 0- 15 100 % EtOAc in hexanes to yield 7.s as a light-yellow solid (535 mg, 22 %). 1H NMR (500 MHz, DMSO): δ 10.78 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.11 – 4.05 (m, 2H), 3.78 (dd, J = 11.4, 4.9 Hz, 1H), 3.31 (t, 4H), 3.17 (d, J = 5.2 Hz, 1H), 2.70 (t, J = 5.9 Hz, 2H), 2.66 – 2.59 (m, 1H), 2.43 (t, J = 5.1 Hz, 4H), 2.19 – 2.09 (m, 1H), 2.0220 (q, J = 4.3 Hz, 1H), 1.39 (s, 9H). U of M 2025-025 VHPM 09531.599WO1 HLB-0535365 was synthesized by a similar procedure as HLB-0535281 using 2.c (425 mg, 0.960 mmol) and 7.s (535 mg, 1.28 mmol). The product was purified using column 5 chromatography in a gradient of 0-15 % CH3OH in CH2Cl2 and reversed-phase chromatography (10-50% CH3CN in H2O). White solid (57.4 mg, 11% after HPLC). HPLC purity: 97.3% @ 254 nm; 94.6% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 10.78 (s, 1H), 9.76 (s, 1H), 8.78 (s, 1H), 7.88 (d, J = 8.7 Hz, 10 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.61 (s, 1H), 4.79 – 4.69 (m, 2H), 4.13 – 4.04 (m, 2H), 3.78 (dd, J = 11.3, 5.0 Hz, 1H), 3.52 (s, 4H), 3.06 (s, 6H), 2.78 – 2.70 (m, 2H), 2.69 – 2.58 (m, 2H), 2.58 – 2.53 (m, 2H), 2.44 (d, J = 1.8 Hz, 1H), 2.20 – 2.09 (m, 2H), 1.99 (ddt, J = 13.7, 9.2, 4.7 Hz, 4H), 1.71 – 1.61 (m, 2H), 1.25 (q, J = 7.2 Hz, 2H). 15 Example 67. Synthesis of HLB-0535377 Prepared using a procedure similar to that described in US 20240408085 A1. 7.g (3.21 g, 17.5 mmol) was dissolved in 10 mL of 4M HCl in 1,4-dioxane and stirred at room U of M 2025-025 VHPM 09531.599WO1 temperature for 3 hours. Then, the solvent was removed under reduced pressure. The resulting crude was dissolved in 20 mL of DMSO and basified with potassium carbonate (3.62 g, 26.2 mmol). Then 7.t (2.03 g, 8.86 mmol), L-Proline (402 mg, 3.49 mmol), and CuI (333 mg, 1.75 mmol were added to the reaction mixture. The resulting solution was degassed and stirred at 100 5 °C for 20 hours. After completion, the crude was filtered through a short bed of celite, and the filtrate was concentrated in vacuo. The crude was diluted in 100 mL of H2O, and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine (100 mL × 4) and dried over Na2SO4, then concentrated under reduced pressure. The crude was purified using column chromatography in a gradient of 0-100 % EtOAc in hexanes to yield 7.u as a brown oil (538 mg, 10 26 %). 1H NMR (500 MHz, CDCl3): δ 7.12 (d, J = 8.7 Hz, 2H), 6.42 (d, J = 8.6 Hz, 2H), 3.93 (t, J = 7.5 Hz, 2H), 3.88 – 3.84 (t, 2H), 3.67 (s, 3H), 3.65 (dd, J = 7.2, 5.0 Hz, 2H), 3.52 (s, 2H), 2.88 (ddtd, J = 14.3, 7.7, 6.5, 5.0 Hz, 1H). 15 7.u (538 mg, 2.29 mmol), DMAP (27.9 mg, 0.229) and triethylamine (797 ^L, 5.72 mmol) were dissolved in15 mL of CH2Cl2. The reaction was cooled to 0 °C and stirred for 10 minutes. Then, p-toluenesulfonyl chloride (567 mg, 2.97 mmol) was dissolved in 2 mL of CH2Cl2and added 20 dropwise to the reaction mixture. The reaction was warmed and stirred at room temperature overnight. After completion, the crude was diluted with CH2Cl2 (20 mL) and washed with water (40 mL), 5% HCl (40 mL), and saturated NaHCO3 (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The solvent was removed under reduced pressure and the crude was dissolved in 10 mL of CH3CN. The reaction mixture was basified using 25 DIPEA until the pH reached 8-9. Then, Boc-piperazine (852 mg, 4.57 mmol) and KI (38.0 mg, 0.229 mmol) were added to the reaction mixture and refluxed overnight. After completion, the reaction mixture was concentrated in vacuo and purified using column chromatography (0-100 U of M 2025-025 VHPM 09531.599WO1 % EtOAc in hexanes) to yield 7.v as a brown oil (130 mg, 15%). 1H NMR (500 MHz, DMSO): δ 7.03 (d, J = 8.6 Hz, 2H), 6.35 (d, J = 8.6 Hz, 2H), 3.88 (t, J = 7.4 Hz, 2H), 3.58 (s, 3H), 3.50 (s, 2H), 3.44 – 3.37 (t, 2H), 3.29 (t, J = 4.9 Hz, 4H), 2.89 (hept, J 5 = 7.5 Hz, 1H), 2.56 (d, J = 7.3 Hz, 2H), 2.31 (t, J = 5.1 Hz, 4H), 1.39 (s, 9H) 7.w was synthesized by a similar procedure as 7.q using 7.v (130 mg, 0.322 mmol) and 10 acrylamide (19.1 mg, 0.268 mmol). The product was purified using column chromatography in a gradient of 0-10 % CH3OH in CH2Cl2to yield 7.w as a brown solid (23.1 mg, 21 %). 1H NMR (500 MHz, DMSO): δ 10.74 (s, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.37 (d, J = 8.6 Hz, 2H), 3.89 (t, J = 7.5 Hz, 2H), 3.68 (dd, J = 11.0, 5.0 Hz, 1H), 3.52 (dt, J = 25.4, 6.0 Hz, 1H), 15 3.41 (t, J = 6.4 Hz, 2H), 3.30 (t, 4H), 2.89 (dq, J = 14.3, 7.0 Hz, 1H), 2.66 – 2.53 (m, 2H), 2.31 (t, J = 5.1 Hz, 4H), 2.26 (t, J = 6.7 Hz, 1H), 2.15 – 2.03 (m, 1H), 2.01 – 1.95 (m, 1H), 1.39 (s, 9H).

[0009] U of M 2025-025 VHPM 09531.599WO1 HLB-0535377 was synthesized by a similar procedure as HLB-0535281 using 2.c (25.9 mg, 0.0576 mmol) and 7.w (23.1 mg, 0.0522 mmol). The product was purified using column 5 chromatography in a gradient of 0-10 % CH3OH in CH2Cl2 and reversed-phase chromatography (10-50% CH3CN in H2O). White solid (4.5 mg, 11% after HPLC). HPLC purity: 97.3% @ 254 nm; 98.3% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 11.02 (s, 1H), 9.79 (s, 1H), 8.75 (s, 1H), 8.21 (d, J = 5.7 Hz, 10 2H), 7.83 (d, J = 8.9 Hz, 2H), 7.76 – 7.70 (d, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 7.3 Hz, 1H), 6.76 (s, 1H), 5.27 (dt, J = 18.7, 9.0 Hz, 2H), 5.01 (dd, J = 12.8, 5.5 Hz, 1H), 4.14 (t, J = 6.5 Hz, 2H), 3.19 (q, J = 6.3 Hz, 2H), 2.81 (ddd, J = 17.0, 14.3, 5.4 Hz, 2H), 2.59 – 2.55 (m, 1H), 2.54 – 2.51 (m, 1H), 2.51 – 2.46 (m, 2H), 2.29 (dd, J = 4.5, 2.5 Hz, 1H), 2.21 (p, J = 7.5 Hz, 2H), 2.01 – 1.86 (m, 6H), 1.75 – 1.67 (m, 2H), 1.67 – 1.55 (m, 4H), 1.46 (ddd, J = 32.8, 14.1, 15 7.7 Hz, 4H), 1.37 – 1.27 (m, 2H). Example 68. Synthesis of HLB-0535385 U of M 2025-025 VHPM 09531.599WO1 HLB-0535385 was synthesized by a similar procedure as HLB-0535281 using 2.h (267 mg, 0.0564 mmol) and HLB-0535023 (176 mg, 0.0434 mmol). The product was purified using 5 column chromatography in a gradient of 0-10 % CH3OH in CH2Cl2 and reversed-phase chromatography (10-60% CH3CN in H2O). White solid (87.8 mg, 26 % after HPLC). HPLC purity: 100 % @ 254 nm; 100 % @ 215 nm. 1H NMR (500 MHz, DMSO): δ 11.09 (s, 1H), 9.86 (s, 1H), 8.82 (s, 1H), 8.28 (t, J = 5.6 Hz, 10 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.80 (dt, J = 8.5, 3.6 Hz, 3H), 7.51 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 6.82 (s, 1H), 5.34 (p, J = 9.0 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.35 (s, 2H), 4.21 (t, J = 6.4 Hz, 2H), 4.07 (s, 2H), 3.27 (dt, J = 12.5, 7.8 Hz, 3H), 2.92 – 2.81 (m, 1H), 2.54 (s, 4H), 2.28 (p, J = 7.6 Hz, 2H), 2.01 (d, J = 18.3 Hz, 6H), 1.78 (h, J = 5.9 Hz, 2H), 1.69 (s, 2H), 1.53 (dp, J = 23.1, 7.4 Hz, 4H), 1.40 (q, J = 7.8 Hz, 2H).15 Example 69. Synthesis of HLB-0535389 U of M 2025-025 VHPM 09531.599WO1 HLB-0535389 was synthesized by a similar procedure as HLB-0535281 using 2.h (30.0 mg, 0.0634 mmol) and HLB-0535043 (25.7 mg, 0.0576 mmol). The product was purified using 5 column chromatography in a gradient of 0-20 % CH3OH in CH2Cl2 and reversed-phase chromatography (20-90% CH3CN in H2O). White solid (9.17 mg, 22% after HPLC). HPLC purity: 100% @ 254 nm; 96.9% @ 215 nm. 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H), 10.09 (s, 1H), 8.99 (s, 1H), 8.32 (t, J = 5.6 Hz, 10 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.86 – 7.78 (m, 3H), 7.75 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 5.80 (p, J = 9.4 Hz, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 4.27 – 4.18 (m, 2H), 3.31 – 3.23 (m, 2H), 2.93 – 2.83 (m, 2H), 2.67 – 2.56 (m, 2H), 2.11 – 1.90 (m, 5H), 1.84 – 1.64 (m, 4H), 1.61 – 1.46 (m, 4H), 1.46 – 1.36 (m, 2H), 1.09 – 0.98 (m, 4H).15 Example 70. Biological Data In vitro kinase assays Binding affinity measurements were performed by contract by the KINOMEscan Profiling Service of Eurofins Discovery - DiscoverX, which provided the following description of how 20 assays were performed. For most assays, kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 U of M 2025-025 VHPM 09531.599WO1 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity 5 resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X 10 stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 mL. The assay 15 plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. 20 Preparation of cell lysates and immunoblotting To each well in a 24-well plate, 5 x 105SK-N-BE(2) cells were seeded. Cells were incubated overnight before the indicated treatment. Cells were lysed in RIPA buffer (Pierce) containing complete protease inhibitor cocktail (Roche) and PhosSTOP phosphatase inhibitor cocktail 25 (Roche). The lysates were cleared by centrifugation, and protein concentration was determined using BCA Protein Assay Kit (Pierce) following the manufacturer’s protocol. Protein samples were normalized to the same concentration, and an equivalent amount of protein lysate (15–20 µg) was electrophoresed on a 4-12% NuPAGE gradient gel (Invitrogen) and transferred onto low florescent polyvinylidene difluoride membranes (Bio-Rad). Immunoblotting was performed30 with primary antibodies followed by secondary antibodies. When using horseradish peroxidase- conjugated antibodies, West Femto Maximum Sensitivity Substrate (Thermo Scientific) was U of M 2025-025 VHPM 09531.599WO1 added to the membranes before imaging on an Odyssey Fc Imaging system (Li-Cor). Band intensity was quantified with ImageJ 1.52a, and DC50curves were generated by fitting data to the sigmoidal function of varied slope in GraphPad Prism (v.9.1.1) software. 5 Cell viability assay Cell viability was conducted using an Alamar Blue assay (Invitrogen) following the manufacturer’s protocol. Briefly, to each well in a 96-well plate, 10,000 cells were seeded for 10 IMR-32, SK-N-BE(2), SH-SY5Y, VERO and SK-N-AS overnight before indicated treatments for three days.10 µL Alamar Blue cell viability reagent (Invitrogen) was added for 4 hours and fluorescence data were obtained on a Synergy H1 plate reader (BioTek) with excitation wavelength of 560 nM and emission wavelength of 590 nM. Individual IC50 curves were generated by fitting data to the sigmoidal function of varied slope in GraphPad Prism (v.9.1.1) 15 software. Data for representative compounds is provided below. U of M 2025-025 VHPM 09531.599WO1 Binding affinities of compounds to Aurora Kinase A, CDK4 / Cyclin D1 complex, and CDK9 O R1N NNH NNH Kd(nM) Cmpd R1Aurora-A CDK4 / Cyclin D1 CDK9 HLB- N 0532264 0.85 3.0 5.4 O HLB- NH 0534984 38 64 44 O HLB- NH 0534983 340 950 860 O HLB- N 0535023 2.2 45 190 O HLB- N 0534985 3.4 37 300 O HLB- N 0534993 1.8 180 > 1,000 O O HLB- N 0534994 28 67 170 O HLB- N 0535005 3.1 41 100 O HLB- 0535019 N 18 > 1,000 > 1,000 O 5 122 U of M 2025-025 VHPM 09531.599WO1 Kd(nM) Cmpd R1Aurora-A CDK4 / Cyclin D1 CDK9 N HLB- 0.85 3.0 5.4 0532264 O HLB- –H 160 120 460 0535044 HLB- 35 18 510 0535041O U of M 2025-025 VHPM 09531.599WO1 HLB- 0534999 46 36 60 HLB- 281 10535002 0 n.d. n.d. HLB- 170 n1 10535001 .d. n.d. HLB- 0535013 5.0 3.23.3 HLB- 0534990 2.2 1.8 HLB- 0535000 0.87 3.8 1.6 HLB- 0534989 2.6 19 8.9 HLB- 0534982 1.3 1.6 HLB- 0535004 0.91 9.7

[0010] U of M 2025-025 VHPM 09531.599WO1 Binding affinities of compounds to Aurora Kinase A and the CDK4 / Cyclin D1 complex 5 10 U of M 2025-025 VHPM 09531.599WO1 U of M 2025-025 VHPM 09531.599WO1 Degradation of Aurora Kinase A and N-Myc in SK-N-BE(2) after 4 hours following treatment with compounds 5 Caco Permeability, Kinetic Solubility and LogD Data U of M 2025-025 VHPM 09531.599WO1 Metabolic Stability, Plasma Protein Binding, and Plasma Stability Data U of M 2025-025 VHPM 09531.599WO1 Caco Permeability, Kinetic Solubility and LogD Data U of M 2025-025 VHPM 09531.599WO1 Metabolic Stability, Plasma Protein Binding, and Plasma Stability Data U of M 2025-025 VHPM 09531.599WO1 U of M 2025-025 VHPM 09531.599WO1 Cytotoxicity (IC50, nM) in SK-N-BE(2) and IMR-32 Cell Lines U of M 2025-025 VHPM 09531.599WO1 Example 63. The following illustrate representative pharmaceutical dosage forms, containing a compound of formula (I) ('Compound X'), for therapeutic or prophylactic use in humans. 5 (i) Tablet 1 mg / tablet Compound X= 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 10 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 U of M 2025-025 VHPM 09531.599WO1 (ii) Tablet 2 mg / tablet Compound X= 20.0 Microcrystalline cellulose 410.0 Starch 50.0 5 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg / capsule 10 Compound X= 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 15 600.0 (iv) Injection 1 (1 mg / ml) mg / ml Compound X= (free acid form) 1.0 Dibasic sodium phosphate 12.0 20 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL 25 (v) Injection 2 (10 mg / ml) mg / ml Compound X= (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 30 Polyethylene glycol 400 200.0 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL 35 (vi) Aerosol mg / can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 40 Dichlorotetrafluoroethane 5,000.0 The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. U of M 2025-025 VHPM 09531.599WO1 All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the 5 spirit and scope of the invention.

Claims

1. U of M 2025-025 VHPM 09531.599WO1 CLAIMSWhat is claimed is:

1. A compound of formula (I):or a salt thereof, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -NRxRyor -C(=O)R3; R3is (C1-C6)alkoxy, -NRdRe, or -L-X; L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, provided that Rband Rcare not each methyl when A is unsubstituted phenyl or pyridine-2-yl; each Rdand Reis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rdand Retogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino isU of M 2025-025 VHPM 09531.599WO1 optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; each Rxand Ryis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rxand Rytogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, and X is the residue of an E3 ligase ligand; or wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, CL, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; L is a linker that comprises one or more heterocyclic rings; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and X is the residue of an E3 ligase ligand; or wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc;U of M 2025-025 VHPM 09531.599WO1 R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and X is an E3 ligase ligand selected from the group consisting of: .U of M 2025-025 VHPM 09531.599WO1 2. The compound or salt of claim 1, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -NRxRyor -C(=O)R3; R3is (C1-C6)alkoxy, -NRdRe, or -L-X; L is absent or is a linker; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, provided that Rband Rcare not each methyl when A is unsubstituted phenyl or pyridine-2-yl; each Rdand Reis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rdand Retogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, X is the residue of an E3 ligase ligand.

3. The compound or salt of claim 1, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groupsU of M 2025-025 VHPM 09531.599WO1 independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; L is a linking group that comprises one or more heterocyclic rings; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and X is the residue of an E3 ligase ligand.

4. The compound or salt of claim 1, wherein: R1is H, (C1-C6)alkoxycarbonyl, RaC(=O)-, or -C(=O)NRbRc; R2is (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br; A is a phenyl or a 6-membered heteroaryl ring, which phenyl and 6-membered heteroaryl ring is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo; Y is -C(=O)R3; R3is -L-X; L is absent or is a linking group; Rais (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein any (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, and Br;U of M 2025-025 VHPM 09531.599WO1 each Rband Rcis independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Rband Rctogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino, and piperidino is optionally substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl; and X is an E3 ligase ligand selected from the group consisting of:.

5. The compound or salt of any one of claims 1-4, wherein R1is H, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, azetadinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, diethylaminocarbonyl, 4-methylpiperidinocarbonyl, acetyl, propanoyl, or cyclopropylcarbonyl.

6. The compound or salt of any one of claims 1-5, wherein R2is cyclopentyl.

7. The compound or salt of any one of claims 1-6, wherein A is a phenyl that is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo.U of M 2025-025 VHPM 09531.599WO1 8. The compound or salt of any one of claims 1-6, wherein A is a phenyl.

9. The compound or salt of any one of claims 1-6, wherein A is a phenyl that is substituted with (C1-C6)alkoxy or halo.

10. The compound or salt of any one of claims 1-6, wherein A is a pyridyl that is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, and halo.

11. The compound or salt of any one of claims 1-10, wherein Y is -NRxRy.

12. The compound or salt of any one of claims 1-10, wherein Y is -C(=O)R3and R3is -NRdRe.

13. The compound or salt of any one of claims 1-10, wherein Y is -C(=O)R3and R3is -L-X.

14. The compound of claim 13, wherein L is absent.

15. The compound of claim 13, wherein L is a linker.

16. The compound or salt of claim 15, wherein the linker comprises about 3-200 atoms.

17. The compound or salt of claim 15, wherein the linker comprises about 5-50 atoms selected from H, C, N, S and O.

18. The compound or salt of claim 15, wherein the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 50 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, 3-10 membered heterocycle, 5-6-membered heteroaryl or carbocycle and wherein each chain, 3-10 membered heterocycle, 5-6-membered heteroaryl or carbocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more)U of M 2025-025 VHPM 09531.599WO1 substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1- C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, azido, cyano, nitro, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1-C6)alkyl.

19. The compound or salt of claim 15, wherein the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, or a 3-10 membered heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1-C6)alkyl.

20. The compound or salt of claim 15, wherein the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -N(Ra)-, or a 3-10 membered heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1-C6)alkyl.

21. The compound or salt of claim 15, wherein the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, -N(Ra)-, or a 3-10 membered heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1- C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1-C6)alkyl.U of M 2025-025 VHPM 09531.599WO1 22. The compound or salt of claim 15, wherein the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -N(Ra)-, or a 3-10 membered heterocycle, and wherein each chain and 3-10 membered heterocycle is optionally and independently substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1- C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, -N(Ra)2, hydroxy, oxo (=O), and carboxy, wherein each Rais independently H or (C1-C6)alkyl.

23. The compound or salt of claim 15, wherein the linker comprises a polyethylene glycol having 2, 3, 4, or 5 repeat (e.g., -CH2CH2O-) units (Greenwald, R.B., et al., Poly (ethylene glycol) Prodrugs: Altered Pharmacokinetics and Pharmacodynamics, Chapter, 2.3.1., 283-338; Filpula, D., et al., Releasable PEGylation of proteins with customized linkers, Advanced Drug Delivery, 60, 2008, 29-49; Zhao, H., et al., Drug Conjugates with Poly(Ethylene Glycol), Drug Delivery in Oncology, 2012, 627-656).

24. The compound or salt of claim 15, wherein the linker is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1 25. The compound or salt of claim 15, wherein the linker is selected from the group consisting of:.

26. The compound or salt of any one of claims 13-25, wherein X is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1.

27. The compound or salt of any one of claims 13-25, wherein X is selected from the group consisting of:.

28. The compound or salt of claim 1 that is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1and salts thereof.U of M 2025-025 VHPM 09531.599WO1 29. The compound or salt of claim 1 that is selected from the group consisting of:and salts thereof.U of M 2025-025 VHPM 09531.599WO1 30. The compound or salt of claim 3 that is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1U of M 2025-025 VHPM 09531.599WO1and salts thereof.

31. The compound or salt of claim 1 that is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1and salts thereof.

32. The compound or salt of claim 1 that is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1U of M 2025-025 VHPM 09531.599WO1 33. The compound or salt of claim 1 that is selected from the group consisting of:and salts thereof.U of M 2025-025 VHPM 09531.599WO1 34. The compound or salt of claim 1 that is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1U of M 2025-025 VHPM 09531.599WO1and salts thereof.

35. The compound or salt of claim 1 that is selected from the group consisting of:U of M 2025-025 VHPM 09531.599WO1U of M 2025-025 VHPM 09531.599WO1, and salts thereof.

36. A pharmaceutical composition comprising a compound as described in any one of claims 1-35 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

37. A method for treating cancer in an animal comprising administering a compound as described in any one of claims 1-35 or a pharmaceutically acceptable salt thereof to the animal.

38. A compound as described in any one of claims 1-35 or a pharmaceutically acceptable salt thereof for use in medical therapy.

39. A compound as described in any one of claims 1-35 or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of cancer.

40. Use of a compound as described in any one of claims 1-35 or a pharmaceutically acceptable salt thereof to prepare a medicament for treating cancer in an animal.

41. The method of claim 37, the compound or pharmaceutically acceptable salt of claim 39 or the use of claim 40, wherein the cancer is a N-Myc-driving cancer.

42. The method of claim 37, the compound or pharmaceutically acceptable salt of claim 39 or the use of claim 40, wherein the cancer is a childhood neuroblastoma, neuroendocrine prostate cancer, medulloblastoma, glioma, or acute myeloid leukemia.

43. A method to degrade Aurora kinase A, comprising contacting Aurora kinase A with a compound as described in any one of claims 1-35 or a salt thereof.U of M 2025-025 VHPM 09531.599WO1 44. A compound as described in any one of claims 1-35 or a salt thereof to degrade Aurora kinase A.

45. The use of a compound compound as described in any one of claims 1-35 or a pharmaceutically acceptable salt thereof to prepare a medicament to degrade Aurora kinase A in an animal.

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