Chemical matters for targeting chromatin remodeling complexes and uses thereof

Abstract

The present disclosure relates to compounds, compositions, and methods for treating diseases or conditions mediated by aberrant Bromodomain PHD Finger Transcription Factor (BPTF) activity.

Description

CHEMICAL MATTERS FOR TARGETING CHROMATIN REMODELING COMPLEXES AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No: 63 / 541,946, filed October 2, 2023, which is incorporated herein by reference in its entirety.SUPPORT

[0002] The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and KUNGLIGA TEKNISKA HOEGSKOLAN, DIAMOND LIGHT SOURCE LIMITED, Ontario Institute for Cancer Research, ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING MCGILL UNIVERSITY.BACKGROUND OF THE DISCLOSURE

[0003] Bromodomain PHD Finger Transcription Factor (BPTF), a member of the Imitation Switch (ISWI) family of chromatin remodelers, is either mutated or overexpressed in multiple cancer types. Chromatin modifications play a major role in tumorigenesis, chemotherapeutic resistance, and susceptibility to immune response.

[0004] To date, there have been no reported chemical probes that selectively degrade BPTF. Reported BPTF small molecule inhibitors have been shown to have off-target cytotoxic effects or be ineffective in tumor cell anti-proliferation. Accordingly, there is a need for compounds that provide effective inhibition of tumor cell proliferation while minimizing off-target cytotoxic effects, in treating cancer.SUMMARY OF THE INVENTION

[0005] A first aspect of the present disclosure is directed to a compound having a structure represented by formula I or II:a pharmaceutically acceptable salt or stereoisomer thereof, wherein: the degron binds cereblon (CRBN) or von Hippel Lindau (VHL) tumor suppressor; and the linker represents a moiety that covalently connects the degron and the nitrogen atom.

[0006] Another aspect of the present disclosure is directed to a pharmaceutical composition containing the compound of formula I or II, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0007] In another aspect of the present disclosure, methods of making the compounds of formulas (I) or (II) are provided.

[0008] A further aspect of the present disclosure is directed to a method of treating a cancer that involves aberrant BPTF activity, that includes administering the compound of formula I or II, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 A is a heatmap and FIG. IB is a scatter plot of that show dBPTF-2 is selective for BPTF chemoproteomics using cell line K562.

[0010] FIG. 2A-FIG. 2G are immunoblots showing degradation of BPTF by compounds at indicated concentrations. FIG. 2A shows NVS-BPTF-1, dBPTF-1, dBPTF-2, and dBPTF-3 using cell line VAL after 24 hours FIG. 2B shows dBPTF-2 using cell line VAL after 8 hours. FIG. 2Cshows dBPTF-2, dBPTF-4, dBPTF-5, and dBPTF-6 using cell line VAL after 24 hours FIG. 2D shows dBPTF-2, dBPTF-6, dBPTF-7, and dBPTF-8 using cell line VAL after 24 hours FIG. 2E shows dBPTF-2 and dBPTF-7 using cell line VAL after 6 hours FIG. 2F shows dBPTF-2, dBPTF- 9, dBPTF-10, and dBPTF-11 using cell line VAL after 24 hours. FIG. 2G shows NVS-BPTF-1, dBPTF-2, dBPTF-12, and dBPTF-13 using cell line VAL after 24 hours.

[0011] FIG. 3A and FIG. 3B are immunoblots showing that CRBN knockout rescues degradation. FIG. 3A shows BPTF degradation of dBPTF-2, dBPTF-9, and dBPTF-11 using cell line 293 T after 24 hours FIG. 3B shows that dBPTF-2, dBPTF-9, and dBPTF-1 1 do not degrade BPTF when using cell line 293 T CRBN KO after 24 hours.

[0012] FIG. 4A and FIG. 4B are immunoblots showing degradation of BPTF in different cancer types. FIG. 4A shows BPTF degradation of dBPTF-2, dBPTF-9, and dBPTF-11 using cell line MCF7 (breast) after 24 hours FIG. 4B shows BPTF degradation of dBPTF-2, dBPTF-9, and dBPTF-11 using cell line NCIH2030 (lung) after 24 hours.

[0013] FIG. 5A (6 hours) and FIG. 5B (20 hours) are graphs showing ternary complex formation with various compounds using 293T cells transfected with NanoLuc® Tagged BPTF and HaloTag® Tagged CRBN.

[0014] FIG. 6A-FIG. 6C show that NVS-BPTF-1B degraded BPTF in HiBiT cells using cell line 293T. FIG. 6A is a graph showing Nano-Gio® HiBit lytic detection after 6 hours. FIG. 6B is a graph showing Nano-Gio® HiBit lytic detection after 20 hours. FIG. 6C is a graph showing cell viability after 20 hours.

[0015] FIG. 7A and FIG. 7B show that NVS-BPTF-1B performed consistently across assays. FIG. 7A is an immunoblot showing degradation of BPTF with NVS-BPTF-1B, TP-238-2, and TP- 238-3 using cell line VAL after 8 hours. FIG. 7B is a graph showing Nano-Gio® HiBit lytic detection after 6 hours.

[0016] FIG. 8A and FIG. 8B show that NVS-BPTF-1B degraded BPTF at early time points. FIG. 8A is an immunoblot showing degradation of BPTF at 2h, 4h, 6h, and 8h using cell line VAL. FIG. 8B is a bargraph showing %BPTF band density at indicated times and concentrations.

[0017] FIG. 9A and FIG. 9B show rescue of BPTF degradation via NVS-BPTF-1B using cell line 293T. FIG. 9A is an immunoblot showing BPTF degradation after 8 hours in a series of rescue experiments. FIG. 9B is a bargraph showing %BPTF band density.

[0018] FIG. 10 is an immunoblot showing that NVS-BPTF-1B lifts BPTF off the histone using cell line VAL at indicated times.

[0019]

[0020] FIG. 11 A and FIG. 1 IB show that BPTF remains present in the nucleus for over 24 hours. FIG. 11 A is an immunoblot showing the presence of BPTF using cell line VAL after 8 hours. FIG.1 IB is an immunoblot showing the presence of BPTF using cell line VAL after 24 hours.

[0021] FIG. 12 is an immunoblot showing that upon compound washout, BPTF protein levels begin to recover.

[0022] FIG. 13 is a series of graphs that identify cell types that are sensitive to BPTF loss.

[0023] FIG. 14A and FIG. 14B show that PAX3-FOXO1 dependent cell line RH4 is more sensitive to BPTF loss.

[0024] FIG. 15A and FIG. 15B show that NURF and PAX3-FOXO1 physically interact.

[0025] FIG. 16A and FIG. 16B show BPTF degradation in PAX3-FOXO1 fusion dependent cells. FIG. 16A is an immunoblot showing NVS-BPTF-1 and NVS-BPTF-l-B using cell line RH4 after 48 hours. FIG. 16B is an immunoblot showing NVS-BPTF-1 and NVS-BPTF-l-B using cell line RH4 after 48 hours, histone extract

[0026] FIG. 17 is a series of graphs showing that PAX3 / 7-FOXO1 dependent cells are sensitive to BPTF protein loss.

[0027] FIG. 18A and FIG. 18B show NVS-BPTF-1B can lift fusion protein off histone at later time points. FIG. 18A is an immunoblot showing NVS-BPTF-1 and NVS-BPTF-l-B using cell line RH30 after 48 hours. FIG. 18B is an immunoblot showing NVS-BPTF-1 and NVS-BPTF-1- B using cell line RH30 after 72 hours.

[0028] FIG. 19A and FIG. 19B show that functional loss of BPTF via shRNA knockdown accompanied protein loss of PAX3-FOXO1.

[0029] FIG. 20 is an immunoblot showing BPTF degradation with dBPTF-2, dBPTF-9, and dBPFT-11 using cell line RH4 after 24 hours.

[0030] FIG. 21 is an immunoblot showing BPTF degradation and decrease of PAX3-FOXO1 protein levels with dBPTF-2, dBPTF-9, and dBPFT-11 using cell line RH30 after 24 hours.

[0031] FIG. 22A and FIG. 22B are immunoblots showing that CRBN knockout rescues degradation. FIG. 22A shows BPTF degradation with dBPTF-2 using cell line RH4 after 72 hoursFIG. 22B shows that dBPTF-2 does not degrade BPTF when using cell line RH4 CRBN KO after 72 hours.

[0032] FIG. 23 is a scatterplot of a proteomic study showing selective degration of dBPTF-9.

[0033] FIG. 24 is a graph showing that dBPTF-2, dBPTF-9, and dBPTF-11 are more potent inhibitors than NVS-BPTF-1 using cell line RH4 after 6 days.

[0034] FIG. 25 depicts a colony formation assay using RMS cell lines (fusion negative, fusion positive, fusion positive but lacking CRBN) treated with escalating doses with NVS-BPTF-1 and NVS-BPTF-1 -B for 14 days.

[0035] FIG. 26A and FIG. 26B show cell viability of RH4 and RH28 fusion-positive RMS cell lines after treatment of BPTF targeting compounds.

[0036] FIG. 27A and FIG. 27B are immunoblots showing the effect of dBPTF-9 on fusion protein levels on histone. FIG. 27A shows BPTF degradation with dBPTF-9 using cell line RH4 after 8 hours. FIG. 27B shows BPTF degradation with dBPTF-9 using cell line RH4 after 24 hours.

[0037] FIG. 28A-FIG. 28C depict a xenograft study for tumor bearing mice treated with vehicle control or dBPTF-9. FIG. 28A is a graph showing that treatment with dBPTF-9 slowed tumor progression. FIG. 28B is a graph showing that treatment with dBPTF-9 extended animal surivival. FIG. 28C is a graph showing that treatment with dBPTF-9 was well tolerated in mice, and that mice did not experience changes in weight when compared to mice in the control group.

[0038] FIG. 29A-FIG. 29G depict the selective degradation of dBPTF-13. FIG. 29A is a graph showing Nano-Gio® HiBit lytic detection for indicated compounds. FIG. 29B is a graph showing Nano-Gio® HiBit lytic detection for indicated compounds. FIG. 29C is a graph showing Nano- Glo® HiBit lytic detection for dBPTF-13 at indicated times. FIG. 29D is a graph showing Nano- Glo® HiBit lytic detection for indicated compounds. FIG. 29E is a scatterplot of a proteomic study showing selective degradation of dBPTF-13. FIG. 29F is a model showing binding interaction between dBPTF-13 and BPTF. FIG. 29G is a model showing binding interaction between dBPTF- 13 and BPTF.

[0039] FIG. 30A-FIG. 30G depict the selective degradation of dBPTF-2. FIG. 30A is a graph showing Nano-Gio® HiBit lytic detection for indicated compounds. FIG. 30B is a graph showing Nano-Gio® HiBit lytic detection for indicated compounds. FIG. 30C is a graph showing Nano- Glo® HiBit lytic detection for dBPTF-2 at indicated times. FIG. 30D is a graph showing Nano- Glo® HiBit lytic detection for indicated compounds. FIG. 30E is a scatterplot of a proteomic studyshowing selective degradation of dBPTF-13 at 8 h and 24 h. FIG. 30F is series of bar graphs showing that dBPTF-2 degrades BPTF, STRAP, and CSDE1. FIG. 30G is series of Western blots showing that dBPTF-2 degrades STRAP and CSDE1.

[0040] FIG. 31 is a graph showing Nano-Gio® HiBit lytic detection for indicated compounds and the corresponding tabulated data.

[0041] FIG. 32 is a graph showing Nano-Gio® HiBit lytic detection for indicated compounds and the corresponding tabulated data.DETAILED DESCRIPTION

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present disclosure.

[0043] As used in the description and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Therefore, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an inhibitor” includes mixtures of two or more such inhibitors, and the like.

[0044] Unless stated otherwise, the term “about” means within 10% (e.g, within 5%, 2%, or 1%) of the particular value modified by the term “about.”

[0045] The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. When used in the context of the number of heteroatoms in a heterocyclic structure, it means that the heterocyclic group that that minimum number of heteroatoms. By contrast, the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the disclosure.

[0046] With respect to compounds of the present disclosure, and to the extent the following terms are used herein to further describe them, the following definitions apply.

[0047] As used herein, the term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In some embodiments, the alkyl radical is a Ci-C6group. In some embodiments, and to the extent not disclosed otherwise for any one or more groups of the compounds of formula I or II, the alkyl radical is a Co-C6, C0-C5, C0-C3, Ci-C6, C1-C5, C1-C4 or C1-C3group (wherein Co alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1 -propyl, 2-propyl, i-propyl, 1 -butyl, 2-methyl-l -propyl, 2-butyl, 2-methyl-2-propyl, 1 -pentyl, n- pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l -butyl, 2-methyl-l- butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3- methyl-3 -pentyl, 2-methyl-3 -pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. In some embodiments, an alkyl group is a C1-C3alkyl group. In some embodiments, an alkyl group is a Ci- C2 alkyl group. In some embodiments, an alkyl group is a methyl group.

[0048] As used herein, the term “alkylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to 15 carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the alkylene group contains one to 15 carbon atoms (C1-C15 alkylene). In some embodiments, the alkylene group contains one to 12 carbon atoms (C1-C12alkylene). In some embodiments, the alkylene group contains one to 10 carbon atoms (C1-C10 alkylene). In some embodiments, the alkylene group contains one to 8 carbon atoms (Ci-Cs alkylene). In other embodiments, an alkylene group contains one to 5 carbon atoms (C1-C5 alkylene). In other embodiments, an alkylene group contains one to 4 carbon atoms (C1-C4 alkylene). In other embodiments, an alkylene contains one to three carbon atoms (C1-C3alkylene). In other embodiments, an alkylene group contains one to two carbon atoms (C1-C2 alkylene). In other embodiments, an alkylene group contains one carbon atom (Ci alkylene).

[0049] As used herein, the term “carbocyclic” (also "carbocyclyl") refers to a group that used alone or as part of a larger moiety, contains a saturated, partially unsaturated, or aromatic ring system having 3 to 12 carbon atoms, that is alone or part of a larger moiety (e.g., an alkcarbocyclic group). The term carbocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In one embodiment, carbocyclyl includes 3 to 10 carbon atoms (C3-C10). In one embodiment, carbocyclyl includes 3 to 6 carbon atoms (Cs-C6). In one embodiment,carbocyclyl includes 5 to 6 carbon atoms (Cs-C6). In some embodiments, carbocyclyl, as a bicycle, includes C6-Cio. In another embodiment, carbocyclyl, as a spiro system, includes C5-C11. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent- 1-enyl, l-cyclopent-2-enyl, 1 -cyclopent-3 -enyl, cyclohexyl, 1 -cyclohex - 1-enyl, l-cyclohex-2-enyl, 1 -cyclohex-3 -enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and naphthalene.

[0050] As used herein, the term "heterocyclyl" refers to a "carbocyclyl" that used alone or as part of a larger moiety, contains a saturated, partially unsaturated or aromatic ring system, wherein one or more (e.g., 1, 2, 3, 4, or 5) carbon atoms have been replaced with a heteroatom or heteroatomcontaining group (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes mono-, bi- , tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In some embodiments, a heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a heteroaryl ring system, such as a 5- to 12-membered heteroaryl ring system. The term heterocyclyl also includes C2-C8 heterocycloalkyl, which is a saturated or partially unsaturated mono-, bi-, or spiro-ring system containing 2-8 carbons and one or more (e.g., 1, 2, or 3) heteroatoms.

[0051] In some embodiments, a heterocyclyl group includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to 5 ring atoms is a heteroatom such as nitrogen, sulfur or oxygen. In some embodiments, heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from O, N, and S. In some embodiments, heterocyclyl includes 4- to 6-membered monocycles having one or more heteroatoms selected from O, N, and S. Representative examples of heterocyclyls include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dihydro- IH-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1 -di oxo- thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinonyl, imidazolidinonyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl,dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, piperazinonyl, and piperazindionyl. Examples of 5-membered heterocyclyls containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl (e.g., thiazol-2- yl), thiadiazolyl (e.g, l,3,4-thiadiazol-5-yl and l,2,4-thiadiazol-5-yl), oxazolyl (e.g., oxazol-2-yl), and oxadiazolyl (e.g., l,3,4-oxadiazol-5-yl and l,2,4-oxadiazol-5-yl). Example of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl (e.g, imidazol-2-yl), triazolyl (e.g., l,3,4-triazol-5-yl, l,2,3-triazol-5-yl, and l,2,4-triazol-5-yl), and tetrazolyl (e.g., IH-tetrazol-5-yl). Example of 6-membered heterocyclyls containing one to three nitrogen atoms and optionally a sulfur or oxygen atom are pyridyl (e.g, pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), pyrimidyl (e.g., pyrimid-2-yl and pyrimid-4-yl), triazinyl (e.g., l,3,4-triazin-2-yl and l,3,5-triazin-4-yl), pyridazinyl (e.g, pyridazin-3-yl), and pyrazinyl. In some embodiments, a heterocyclic group includes a heterocyclic ring fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heterocyclic ring, and in some embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring.

[0052] As used herein, the term "heteroaryl" used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also “heteroaralkyl”), or "heteroarylalkoxy" (also “heteroaralkoxy”)) refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5- to6- membered monocyclic aromatic groups where one or more ring atoms is O, N, or S. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolof l,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, l,3-thiazol-2-yl, l,3,4-triazol-5-yl, l,3-oxazol-2-yl, l,3,4-oxadiazol-5-yl, l,2,4-oxadiazol-5-yl, l,3,4-thiadiazol-5- yl, lH-tetrazol-5-yl, and l,2,3-triazol-5-yl. In some embodiments, a heteroaryl group includes a heteroaryl ring fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heteroaryl ring, and insome embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring.

[0053] Unless stated otherwise, and to the extent not further defined for any particular group(s) in the compounds of formula I or II, any of the groups described herein may be substituted or unsubstituted. To the extent not disclosed otherwise for any particular group(s), representative examples of substituents may include alkyl (e.g., Ci-C6, C1-C5, C1-C4, C1-C3, C1-C2, Ci), substituted alkyl (e.g., substituted Ci-C6, C1-C5, C1-C4, C1-C3, C1-C2, Ci), alkoxy (e.g., Ci-C6, Ci- C5, C1-C4, C1-C3, C1-C2, Ci), substituted alkoxy e.g., substituted Ci-C6, C1-C5, C1-C4, C1-C3, Ci- C2, Ci), haloalkyl (e.g., CF3), alkenyl e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C12, Cs-C6), substituted cyclic (e.g., substituted C3-C12, Cs-C6), carbocyclic (e.g., C3-C12, Cs-C6), substituted carbocyclic (e.g., substituted C3-C12, Cs-C6), heterocyclic (e.g., 3- to 12-membered, 5-to 6- membered), substituted heterocyclic (e.g., substituted 3- to 12-membered, 5-to 6-membered), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or substituted phenyl), heteroaryl e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or substituted pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C12, C6), substituted aryloxy (e.g., substituted C6-C12, C6), alkylthio (e.g., Ci-C6), substituted alkylthio (e.g., substituted Ci-C6), arylthio (e.g., C6-C12, C6), substituted arylthio (e.g., substituted C6-C12, C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfmamide, substituted sulfmamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide groups. In some embodiments, the substituent is halo (e.g., F and Cl), alkylhalo (e.g., CF3, CHF2, CH2F, CCI3, CHCI2, CH2CI), cyano, hydroxy, (Ci-C6) alkyl, (Ci-C6) alkoxy, hydroxy(Ci-C6) alkyl, amino, amino(Ci-C6) alkyl, amino-di(Ci-C6) alkyl, or (C3-C7) cycloalkyl.

[0054] In one aspect, compounds of the disclosure are represented by formula I or II:pharmaceutically acceptable salt or stereoisomer thereof, wherein: the degron binds cereblon (CRBN) or von Hippel Lindau (VHL) tumor suppressor; and the linker represents a moiety that covalently connects the degron and the nitrogen atom.

[0055] In some embodiments, the degron that binds cereblon is represented by any one of the following structures:Ri is absent, CH2, C=C, NH, 0, or 5- to 11-membered mono- or bi-cyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S;X’ is absent or C(O);Y is N or CH; andR2 is an optional substituent.

[0056] In some embodiments, the degron is of formula

[0057] In some embodiments, X is C(O). In some embodiments, X is CH2.

[0058] In some embodiments, Ri is absent, CH2, C=C, NH, or O.

[0059] The disclosed compounds also embrace all combinations of the specific X and Ri groups disclosed above.

[0060] In some embodiments, the degron is of formula

[0061] In some embodiments, X’ is absent.

[0062] In some embodiments, R2 is halo (e.g., F and Cl), alkylhalo (e.g., CF3, CHF2, CH2F, CCI3,CHCh, CH2CI), cyano, hydroxy, (Ci-C6) alkyl, (Ci-C6) alkoxy, hydroxy(Ci-C6) alkyl, amino, amino(Ci-C6) alkyl, amino-di(Ci-C6) alkyl, and (C3-C7) cycloalkyl. In some embodiments, R2 is fluoro.

[0063] In some embodiments, Ri is absent, CH2, C=C, NH, or O.

[0064] In some embodiments, Ri is a 6-membered mono-cyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, Ri is piperazinyl. In some embodiments, Ri is piperidinyl.

[0065] In some embodiments, Ri is a 9-membered bi-cyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, Ri is 2,7- diazaspiro[3.5]nonane

[0066] The disclosed compounds also embrace all combinations of the specific X’, Ri, and R2 groups disclosed above.

[0067] In some embodiments, the degron is of formula

[0068] In some embodiments, Ri is CH2, C=C, NH, or O.

[0069] In some embodiments, the degron is of formula

[0070] In some embodiments, Y is CH.

[0071] In some embodiments, R2 is halo (e.g., F or Cl), alkylhalo (e.g., CF3, CHF2, CH2F, CCI3,CHCh, CH2CI), cyano, hydroxy, (Ci-C6) alkyl, (Ci-C6) alkoxy, hydroxy(Ci-C6) alkyl, amino, amino(Ci-C6) alkyl, amino-di(Ci-C6) alkyl, and (C3-C7) cycloalkyl. In some embodiments, R2 is methoxy.

[0072] In some embodiments, Ri is absent, CH2, C=C, NH, or O.

[0073] The disclosed compounds also embrace all combinations of the specific Y, Ri, and R2 groups disclosed above.O O

[0074] In some embodiments, the degron is of formula D5,

[0075] In some embodiments, X is C(O).

[0076] In some embodiments, the degron is represented by any one of the following structures:

[0077] In some embodiments, the degron that binds VHL is represented by D6:(D6) or a stereoisomer thereof,wherein: R3is hydrogen or optionally substituted C1-C3alkyl, or R3and R4, together with the carbon atom to which they are attached, form cyclopropyl; R4is hydrogen, methyl, orR5is C(O)CR6R7R8,R6and R7are hydrogen, or R6and R7, together with the carbon atom to which they are attached, form cyclopropyl; R8is hydrogen, fluoro, cyano, or NM2; andY is hydrogen,or.whereinis a bond between the Degron and the Linker, provided that there is only one bond between the Degron and the Linker.

[0078] In some embodiments, R3and R4are hydrogen.

[0079] In some embodiments, R3is hydrogen and R4is methyl.

[0080] In some embodiments, R3is optionally substituted C1-C3alkyl and R4is hydrogen.

[0081] In some embodiments, R3is optionally substituted C1-C3alkyl and R4is methyl.

[0082] In some embodiments, R3and R4, together with the carbon atom to which they are attached, form cyclopropyl.

[0083] In some embodiments, Y is hydrogen.

[0084] In some embodiments, Y is,or

[0085] In some embodiments R5is.

[0086] In some embodiments, R5is C(O)CR6R7R8.

[0087] In some embodiments, R6, R7, and R8are hydrogen.

[0088] In some embodiments, R6and R7, together with the carbon atom to which they are attached, form cyclopropyl and R8is hydrogen, fluoro, cyano, or NMe2.

[0089] In some embodiments, R3is hydrogen, R4is, and Y is hydrogen.

[0090] In some embodiments, R3is hydrogen, R4is, Y is hydrogen, and R5is C(O)CR6R7R8, wherein R6and R7, together with the carbon atom to which they are attached, form cyclopropyl and R8is fluoro, cyano, or NMe2.

[0091] In some embodiments, Y is , , or and and arehydrogen.

[0092] In some embodiments, Y is,,, or, and hydrogen, and R5is C(O)CR6R7R8, wherein R6and R7, together with the carbon atom to which they are attached, form cyclopropyl and R8is fluoro, cyano, or NMe2.

[0093] In some embodiments R8is, Y is hydrogen, and R3and R4are hydrogen.

[0094] In some embodiments R8is, Y is hydrogen, R3is hydrogen, and R4is methyl.

[0095] In some embodiments R8is, Y is hydrogen, R3is optionally substituted C1-C3alkyl, and R4is hydrogen.

[0096] In some embodiments R8is, Y is hydrogen, R3is optionally substituted C1-C3alkyl, and R4is methyl.

[0097] In some embodiments, the degron that binds VHL is represented by any one of the following structures:wherein Y is O, NH, or CH2, or a stereoisomer thereof.

[0098] The linker (“L”) of formula I or II represents a moiety that covalently connects the degron and the nitrogen atom.

[0099] In some embodiments, the linker comprises at least one alkylene group, and in some embodiments, an alkylene chain (e.g., having 1-20 alkylene units) or a bivalent alkylene chain, either of which may be interrupted by, and / or terminates at either or both termini with at least one of -O-, -S-, -N(R’)-, -C=C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR’)-, - C(O)N(R’)-, -C(O)N(R’)C(O)-, -C(O)N(R’)C(O)N(R’)-, -N(R’)C(O)-, -N(R’)C(O)N(R’)-, - N(R’)C(O)O- -OC(O)N(R’)-, -C(NR’)-, -N(R’)C(NR’)-, -C(NR’)N(R’)-N(R’)C(NR’)N(R’)-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O- -S(O)-, -OS(O)2-, -S(O)2O- -N(R’)S(O)2-, -S(O)2N(R’)-, -N(R’)S(O)-, -S(O)N(R’)-, -N(R’)S(O)2N(R’)-, -N(R’)S(O)N(R’)-, optionally substituted C2-Ci2carbocyclene, optionally substituted 3- to 12- membered heterocyclene, optionally substituted 5- to 12-membered heteroarylene or anycombination thereof, wherein R’ is H or Ci-C6alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.

[0100] “Carbocyclene” refers to a bivalent carbocycle radical, which is optionally substituted.

[0101] “Heterocyclene” refers to a bivalent heterocyclyl radical which may be optionally substituted.

[0102] “Heteroarylene” refers to a bivalent heteroaryl radical which may be optionally substituted.

[0103] In some embodiments, the linker includes an alkylene chain having 3-11 alkylene units and that terminates in C(O). In some embodiments, the linker includes an alkylene chain having 4-11 alkylene units. In some embodiments, the linker includes an alkylene chain having 3-8 alkylene units.

[0104] In some embodiments, the linker is a polyethylene glycol (PEG) chain which may be interrupted by, and / or terminates at either or both termini with at least one of-O-, -S-, -N(R’)- -C=C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR’)-, -C(O)N(R’)-, -C(O)N(R’)C(O)- , -C(O)N(R’)C(O)N(R’)-, -N(R’)C(O)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -OC(O)N(R’)-, - C(NR’)-, -N(R’)C(NR’)-, -C(NR’)N(R’)-, -N(R’)C(NR’)N(R’)-, -0B(Me)0- -S(O)2-, - OS(O) , S(O)O , S(O) , OS(O)2 , S(O)2O , -N(R’)S(O)2 , S(O)2N(R’) , -N(R’)S(O) , S(O)N(R’)-, -N(R’)S(O)2N(R’)-, -N(R’)S(O)N(R’)-, optionally substituted C3-C12carbocyclene, optionally substituted 3- to 12-membered heterocyclene, optionally substituted 5- to 12-membered heteroarylene or any combination thereof, wherein R’ is H or Ci-C6alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.

[0105] In some embodiments, the linker includes a polyethylene glycol chain having 1-5 PEG units and terminates in C(O). In some embodiments, the linker includes a polyethylene glycol chain having 1-5 PEG units.

[0106] Representative examples of linkers that include a polyethylene glycol chain include:(LI), wherein n is an integer of 2-10, examples of which include:

[0107] In some embodiments, the linker is of formula L0:stereoisomer thereof, wherein pl is an integer selected from 0 to 6; p2 is an integer selected from 0 to 12; p3 is an integer selected from 1 to 12; each W is independently absent, CH2, O, S, NR10, or C(0)NRio; each Rio is independently hydrogen or Ci-C6alkyl;Wi and W2 are independently absent, (CH2)I-3, O, or NH; andZi and Z2 are independently absent, -O-, -S-, -N(Rio)-, -C=C~, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -C(NORio)-, -C(0)N(Rio)-, -C(0)N(Rio)C(0)-C(0)N(Rio)C(0)N(Rio)-, -N(Rio)C(0)-, -N(Rio)C(0)N(Rio)-, -N(Rio)C(0)0- -OC(0)N(Rio)-, -C(NRio)-, -N(Rio)C(NRio)-, -C(NRio)N(Rio)-, -N(Rio)C(NRio)N(Rio)-, - OB(Me)O-, -S(O)2- -OS(O)-, -S(O)O- -S(O)-, -OS(O)2- -S(O)2O- -N(Rio)S(0)2- - S(0)2N(RIO)-, -N(RIO)S(0)-, -S(0)N(RIO)-, -N(RIO)S(0)2N(RIO)-, -N(RIO)S(0)N(RIO)-, optionally substituted C3-C12carbocyclene, optionally substituted 3- to 12-membered heterocyclene, or optionally substituted 5- to 12-membered heteroarylene; wherein the Linker is covalently bonded to the degron via thenext to W2, and covalently bonded to the nitrogen atom via thenext to Wi, or the Linker is covalently bonded to the degron via thenext to Wi, and covalently bonded to the nitrogen atom via thenext to

[0108] In some embodiments, pl is an integer selected from 0 to 3.

[0109] In some embodiments, p2 is an integer selected from 0 to 10. In some embodiments, p2 is an integer selected from 0 to 6. In some embodiments, p2 is an integer selected from 0 to 3.

[0110] In some embodiments, p3 is an integer selected from 1 to 10. In some embodiments, p3 is an integer selected from 1 to 6.

[0111] In some embodiments, each W is independently absent, O, or C(0)NRio.

[0112] In some embodiments, Wi and W2 are absent.

[0113] In some embodiments, Zi and Z2 are independently absent, -O-, -N(Rio)-, -C(O)-, - C(O)O-, — OC(O)— , -C(0)N(Rio)-, -N(Rio)C(0)-, optionally substituted C6-carbocyclene, optionally substituted 5- to 6-membered heterocyclene, or optionally substituted 5- to 6-membered heteroarylene.sents the degron.

[0115] In some embodiments, the linker is:Linker (L)

[0116] In some embodiments, the structure of

[0117] In some embodiments, compounds of formula I are represented by any one of the- ,pharmaceutically acceptable salt or stereoisomer thereof.

[0118] In some embodiments, compounds of formula II are represented by any of the following structures:a pharmaceutically acceptable salt or stereoisomer thereof.

[0119] In some embodiments, compounds of the disclosure include:dBPTF-13-NC).

[0120] The figures reference the following compounds:

[0121] Compounds of the present disclosure may be in the form of a free acid or free base, or a pharmaceutically acceptable salt. A pharmaceutically acceptable salt of the compounds of this disclosure can be formed, for example, by reaction of an appropriate free base of a compound of the invention and an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, for example, Gould, P. L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, R. J., et al., “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” OrganicProcess Research and Development, 4:427-435 (2000); and Berge, S. M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19 (1977).

[0122] Compounds of the present disclosure may have at least one chiral center and thus may be in the form of a stereoisomer, which as used herein, embraces all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers which include the (R-) or (S-) configurations of the compounds), mixtures of mirror image isomers (physical mixtures of the enantiomers, and racemates or racemic mixtures) of compounds, geometric (cis / trans or E / Z, R / S) isomers of compounds and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The chiral centers of the compounds may undergo epimerization in vivo, thus, for these compounds, administration of the compound in its (R-) form is consideredequivalent to administration of the compound in its (S-) form. Accordingly, the compounds of the present disclosure may be made and used in the form of individual isomers and substantially free of other isomers, or in the form of a mixture of various isomers, e.g., racemic mixtures of stereoisomers.[00123J In some embodiments, the compound of formula I or II is an isotopic derivative in that it has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound includes deuterium or multiple deuterium atoms. As used herein, the term “hydrogen”, i.e., H, refers to all isotopes of hydrogen, including protium (1H) and deuterium (2H). As used herein, the term “compound” embraces isotopic derivatives.

[0124] Compounds of the present disclosure may also be in the form of N-oxides, crystalline forms (also known as polymorphs), co-crystals, active metabolites of the compounds having the same type of activity, prodrugs, tautomers, and unsolvated as well as solvated (e.g., hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds. As used herein, the term “compound” embraces all these forms.Methods of Synthesis

[0125] In some embodiments, the present disclosure is directed to a method for making a compound of formula I or II, or a pharmaceutically acceptable salt or stereoisomer thereof. Broadly, the compounds or pharmaceutically acceptable salts or stereoisomers thereof, may be prepared by any process known to be applicable to the preparation of chemically related compounds. The compounds of the present disclosure will be better understood in connection with the synthetic schemes that described in various working examples that illustrate non-limiting methods by which the compounds of the disclosure may be prepared.Pharmaceutical Compositions

[0126] Another aspect of the present disclosure is directed to a pharmaceutical composition that includes the compound of formula I or II, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier,” as known in the art, refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present disclosure to mammals. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous alike, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), andgases, that function to carry or transport the compound from one organ, or portion of the body, to another organ, or portion of the body. A carrier is “acceptable” in the sense of being physiologically inert to and compatible with the other ingredients of the formulation and not injurious to the subject or patient. Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0127] Broadly, compounds of formula I or II, and their pharmaceutically acceptable salts and stereoisomers may be formulated into a given type of composition in accordance with conventional pharmaceutical practice such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, e.g., Remington: The Science and Practice of Pharmacy (20thed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York), each of which is incorporated herein by reference in its entirety. The type of formulation depends on the mode of administration which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (s.cf, intravenous (z.v.), intramuscular (i.mf, and intrasternal injection, or infusion techniques, intraocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g., transdermal).

[0128] In general, the most appropriate route of administration will depend upon a variety of factors including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the compound may be administered relatively quickly such as in the case of a single-dose treatment and / or an acute condition.

[0129] In some embodiments, the compounds are formulated for intravenous administration (e.g., systemic intravenous injection).

[0130] Injectable preparations for parenteral administration may include sterile aqueous solutions or oleaginous suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among theacceptable vehicles and solvents (which along with diluents are embraced by the term “carrier”) that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. The effect of the compound may be prolonged by slowing its absorption, which may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. Prolonged absorption of the compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oily vehicle.

[0131] In certain embodiments, compounds of formula I or II may be administered in a local rather than systemic manner, for example, via injection of the conjugate directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compound in a biodegradable polymer, e.g., polylactide-polyglycolides, poly(orthoesters) and poly(anhydrides). The rate of release of the compound may be controlled by varying the ratio of compound to polymer and the nature of the particular polymer employed. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.

[0132] The compositions may include an excipient, representative examples of which include preservatives, antioxidants, buffering agents, solubilizing agents, and surfactants. Representative examples of preservatives that may be suitable include alcohols, quaternary amines, organic acids, parabens, and phenols. Representative examples of antioxidants that may be suitable include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Representative examples of buffering agents that may be suitable include citric, hydrochloric, and lactic acid buffers. Representativeexamples of solubilizing agents that may be suitable include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.

[0133] In other embodiments, the compositions may be formulated for oral, buccal, sublingual administration (examples of which include tablets, lozenges and gels), inhalation, topical, ophthalmic and rectal administration.Dosage Amounts

[0134] The amount of the compound of formula I or II administered to a cancer patient may be effective in producing the desired therapeutic response in the patient. Therefore, the amount of the compound of formula I or II, or a pharmaceutically acceptable salt or a stereoisomer thereof, may induce a positive modification in the disease or disorder to be treated, prevent development or progression of the disease or disorder, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated In a subject, or kills or inhibits the growth of cancer cells, or reduces the amount of BPTF in cancer cells.

[0135] The total daily dosage of the compounds and usage thereof may be decided in accordance with standard medical practice, e.g., by the attending physician using sound medical judgment. The specific dose for any particular subject may depend upon a variety of factors including the disease or disorder being treated and the severity thereof (e.g., its present status); the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the compound; and like factors well known in the medical arts (see, for example, Goodman and Gilma ’ 's The Pharmacological Basis of Therapeutics, loth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001), which is incorporated herein by reference in its entirety.

[0136] Compounds of formula I and II, and their pharmaceutically acceptable salts and stereoisomers may be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for adult humans) may range from about 0.001 to about 1600 mg, from 0.01 to about 1600 mg, from 0.01 to about 500 mg, from about 0.01 to about 100 mg, from about 0.5 to about 100 mg, from 1 to about 100-400 mg per day, from about 1 to about 50 mg per day, and from about 5 to about 40 mg per day, and in yet other embodiments from about 10 to about 30 mg per day. Individual dosages may be formulated to contain the desired dosage amount depending upon the number of times the compound is administered per day. By way of example, capsules may beformulated with from about 1 to about 200 mg of a compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, individual dosages may be formulated to contain the desired dosage amount depending upon the number of times the compound is administered per day.Methods of Use

[0137] In some aspects, the present disclosure is directed to methods of treating cancer by reducing the level or activity of BPTF. The methods entail administration of a compound formula I or II, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof.

[0138] The cancers involve (e.g., are characterized or mediated by) aberrant BPTF activity (e.g., elevated levels of BPTF or otherwise functionally abnormal BPTF, e.g., mutant BPTF activity) relative to a non-pathological state.

[0139] The term “subject” (or “patient”) as used herein includes all members of the animal kingdom prone to or suffering from the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., a human or a non-human mammal. A subject “in need of’ treatment according to the present disclosure may be “suffering from or suspected of suffering from” a specific disease or disorder may have been positively diagnosed or otherwise presents with a sufficient number of risk factors or a sufficient number or combination of signs or symptoms such that a medical professional could diagnose or suspect that the subject was suffering from the disease or disorder. Thus, subjects suffering from, and suspected of suffering from, a specific disease or disorder are not necessarily two distinct groups.

[0140] Cancers that may be amenable to treatment with the disclosed compounds include carcinomas, sarcomas and blood-borne (hematological) cancers alike. In some embodiments, the cancer is melanoma, endometrial carcinoma, bladder urothelial carcinoma, invasive breast carcinoma, undifferentiated stomach adenocarcinoma, esophagogastric adenocarcinoma, cervical squamous cell carcinoma, non-small cell lung cancer, pleural mesothelioma, heptatocellular carcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma, ovarian epithelial tumor, sarcoma, ocular melanoma, non-seminomatous germ cell tumor, adrenocortical carcinoma, head and neck squamous cell carcinoma, mature B-cell neoplasm, pheochromocytoma, diffuse glioma, renal non-clear cell carcinoma, thymic epithelial tumor, well-differentiated thyroid cancer, esophageal squamous cell carcinoma, glioblastoma, prostate adenocarcinoma, leukemia, renal clear cell carcinoma, miscellaneous neuroepitheliam tumor, cervical adenocarcinoma, seminoma,cholangiocarcinoma, acute myeloid leukemia, brain lower grade glioma, diffuse large B-cell lymphoma, glioblastoma multiforme, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, skin cutaneous melanoma, stomach adenocarcinoma, testicular gern cell tumor, thymoma, thyroid carcinoma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, or uveal melanoma.

[0141] Representative examples of sarcomas that may be amenable to treatment in accordance with the present disclosure include fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, leiomyosarcoma, hemangiosarcoma, Kaposi’s sarcoma, lymphangiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, embryonal, alveolar soft part sarcoma, infantile hemangio-pericytoma, extraskeletal myxoid chondrosarcoma, and extraskeletal mesenchymal.

[0142] In some embodiments, the patient has a rhabdoid sarcoma. In some embodiments, the rhabdoid sarcoma affects the kidneys and other soft tissues. Also known as a rhabdoid tumor or a malignant rhabdoid tumor (MRT), it is a rare tumor that afflicts children. In some embodiments, the rhabdoid sarcomas grows in the central nervous system or brain, and is also known as atypical teratoid rhabdoid tumor (AT / RT).

[0143] In some embodiments, the sarcoma is rhabdomyosarcoma.

[0144] These and other aspects of the present disclosure will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the disclosure but are not intended to limit its scope, as defined by the claims.EXAMPLES

[0145] Example 1 : Synthesis of 4-((4-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piDerazin-l-yl)-4- oxobutyl )ainino)-2-C2,6-dioxopiperidin-3-yl jisoindoline- 1 ,3-dione (dBPTF-L NVS-BPTF-1A)

[0146] 7-Bromo-3-methyl-2H-pyrido[ 1, 2-a]pyrimidine-2,4(3H)-dione

[0147] To a solution of 5-bromopyridin-2-amine (20 g, 114.93 mmol) in diethyl 2- methylmalonate (28 mL) was added cone. HC1 (20 drops) and the reaction mixture was stirred at 145°C for 110 hours under nitrogen. The reaction mixture was diluted with EtOAc (100 mL), filtered, the solids were washed with EtOAc (20 mL), and the filtrate was concentrated to give the title compound as a black solid (3.8 g, 10%).rH NMR (400 MHz, DMSO) 6 8.94 (d, J = 1.8 Hz,1H), 8.08 (dd, J = 9.3, 2.2 Hz, 1H), 7.35 (dd, J= 9.3, 0.5 Hz, 1H), 1.92 (s, 3H). LCMS: [M+H]~ =254.9.

[0148] 7-Bromo-2-chloro-3-methyl-4H-pyrido[ 1 ,2-a]pyrimidni-4-one

[0149] A solution of 7-bromo-3-methyl-2H-pyrido[l,2-a]pyrimidine-2,4(3H)-dione (1 g, 5.78 mmol) in POCh (2 mL) was heated to 120°C and stirred for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (30 mL), extracted with EtOAc (50 mL x 6). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography eluted with PE: EtOAc=5: 1 to give the title compound as a yellow solid (0.85 g, 90%). LCMS: [M+H]+=275.0.

[0150] 2-C hloro-7-( 1 -cyclopropyl- 1 H-pyrazol-4-yl)-3-methyl-4H-pyrido[ 1 ,2-a]pyrimidin-4- one

[0151] To a solution of 7-bromo-2-chloro-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (200 mg, 0.73 mmol), KOAc (150 mg, 1.47 mmol), and l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (172 mg, 0.73 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added Pd(dppf)C12(54 mg, 0.073 mmol) and the reaction mixture was stirred for 2 hours at 100°C under nitrogen. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography eluted with PE: EtOAc=3:2 to give the title compound as a yellow oil (0.11 g, 82%). 'H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.55 (s, 1H), 8.33 - 8.21 (m, 1H), 8.08 (s, 1H), 7.69 (d, J= 9.2 Hz, 1H), 3.84-3.74 (m, 1H), 2.23 (s, 3H), 1.16 - 1.06 (m, 2H), 1.05 - 0.96 (m, 2H). LCMS: [M+H]+=300.9.

[0152] tert-Butyl 4-((4-((7-( l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1,2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazine-l-carboxylate

[0153] To a solution of 2-chloro-7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4H-pyrido[l,2- a]pyrimidin-4-one (20 mg, 0.063 mmol), CS2CO3 (44 mg, 0.126 mmol), and terz-butyl 4-((4- amino-3-fluorophenyl)sulfonyl)piperazine-l -carboxylate (30 mg, 0.082 mmol) in toluene (0.5 mL) were added Pd2(dba)3 (6 mg, 0.0063 mmol) and BINAP (8 mg, 0.0126 mmol) and the reaction mixture was degassed with nitrogen three times and stirred for 2 hours at 110°C. The reaction mixture was concentrated, diluted with water (10 mL), and extracted with EtOAc (10 mL x 3). Thecombined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography eluted with PE: EtOAc=l : 1.2 to give the title compound as a white solid (0.04 g, 92%). 'HNMR (400 MHz, DMSO) 8 9.02 (d, J= 1.7 Hz, 1H), 8.47 (d, J = 3.0 Hz, 2H), 8.12-7.98 (m, 3H), 7.61 (d, J = 10.3 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 3.84-3.74 (m, 1H), 3.45-3.40 (m, 4H), 2.98-2.91 (m, 4H), 2.18 (s, 3H), 1.35 (s, 9H), 1.13 -1.07 (m, 2H), 1.03- 0.96 (m, 2H). LCMS: [M+H]+=624.3.

[0154] 7-( 1 -Cyclopropyl- 1 H-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin- 1 - ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one

[0155] A solution of / e / 7-butyl 4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazine-l -carboxylate (40 mg, 0.064 mmol) in HCl / l,4-di oxane (4M, 0.5 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (40 mg, crude) and it was used without further purification.

[0156] 4-((2-(2, 6-Dioxopiperidin-3-yl)-l, 3-dioxoisoindolin-4-yl)amino)butanoic acid

[0157] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l, 3-dione (500 mg, 1.81 mmol) in DMSO (5 mL) were added 4-aminobutanoic acid (560 mg, 5.43 mmol) and DIEA (935 mg, 7.24 mmol) and the reaction mixture was stirred for 16 hours at 120°C. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (800 mg, crude) and it was used without further purification. LCMS: [M+H]+=360.0.

[0158] Perfluorophenyl 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)butanoate

[0159] A solution of 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)butanoic acid (800 mg, crude, 2.23 mmol), 2,3,4,5,6-pentafluorophenol (492 mg, 2.68 mmol), and DCC (688 mg, 3.45 mmol) in DMF (10 mL) was stirred for 16 hours at room temperature. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash chromatography on a silicagel column (0%-30% EA in PE) to give the title compound as a yellow solid (70 mg, two steps 7%). LCMS: [M+H]1=526.3.

[0160] 4-((4-( 4-( ( 4-( ( 7-( l-Cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[l, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)-4-oxobutyl)amino)-2-(2,6- dioxopiperidm-3-yl)isoindoline- 1,3-dione

[0161] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (40 mg, 0.0765 mmol) and perfluorophenyl 4-((2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-4-yl)amino)butanoate (70 mg, 0.13 mmol) in DMSO (4 mL) was added DIEA (99 mg, 0.775 mmol and the reaction mixture was stirred for 2 hours at 25°C. The reaction mixture was diluted with water (40 mL), filtered, and the solids were purified by prep-HPLC to give the title compound as a yellow solid (29 mg, 44%).1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.01 (d, J= 1.7 Hz, 1H), 8.46 (s, 2H), 8.13-7.97 (m, 3H), 7.64-7.59 (m, 1H), 7.58-7.48 (m, 2H), 7.40 (d, J= 9.1 Hz, 1H), 7. 10 (d, J= 8.6 Hz, 1H), 6.97 (d, J= 7.0 Hz, 1H), 6.62 (t, J= 6.1 Hz, 1H), 5.06-4.98 (m, 1H), 3.80-3.71 (m, 1H), 3.62-3.50 (m, 4H), 3.28-3.24 (m, 2H), 3.00-2.91 (m, 4H), 2.90-2.82 (m, 1H), 2.62-2.51 (m, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.18 (s, 3H), 2.05-1.96 (m, 1H), 1.80-1.69 (m, 2H), 1.12-1.07 (m, 2H), 1.03-0.97 (m, 2H). LCMS: [M+H]+=865.4.

[0162] Example 2: Synthesis of 4-((4-(4-((4-((7-(l-cvclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[L2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)-4- oxobutyl)amino)-2-(2.6-dioxopiperidin-3-yl)isoindoline-L3-dione (dBPTF-2, NVS-BPTF-1B)

[0163] tert-butyl 4-(4-hydroxybutyl)piperazine-l -carboxylate

[0164] To a solution of / c / 'Z-butyl piperazine- 1 -carboxylate (5g, 26.84 mmol) and 4- bromobutan-l-ol (6.2 g) in ACN (60 mL) was added DIEA (10 mL) portion-wise with stirring under nitrogen at 100°C for 4 hours. The reaction mixture was concentrated, water (100 mL) was added, and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography eluted with DCM:MeOH=8% to give the title compound as a colorless oil (2.1 g, 95%).

[0165] tert-Butyl 4-( 4-oxobutyl)piperazine-l -carboxylate

[0166] A solution of oxalyl chloride (10.66 ml, 7.74 mmol) in DCM (5 mL) was added dropwise to DMSO (1.1 mL) with stirring under nitrogen at -78°C for 0.5 h. A solution of tert-butyl 4-(4-hydroxybutyl)piperazine-l -carboxylate (0.5 g, 1.94 mmol) in DCM (5 mL) was then added drop-wise at -78°C for 0.5 h. TEA (2.7 mL, 19.35 mmol) was slowly added to the reaction mixture and the reaction mixture was stirred at 25°C for 0.5 h. The reaction mixture was poured into a saturated sodium carbonate aqueous solution and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4, fdtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography eluted with DCM:MeOH=25: l to give the title compound as a yellow oil (0.12 g, 90%). LCMS: [M+H]+=257.2.

[0167] tert-Butyl 4-(4-(4-(( 4-( (7-( I -cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-alpyrimidm-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazm-l-yl)butyl)piperazi e-l- carboxylate

[0168] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (100 mg, 0.19 mmol) and / c / 7-butyl 4-(4-oxobutyl)piperazine-l -carboxylate (100 mg, 0.38 mmol) in DCM (4 mL) was added HO Ac (230 mg, 0.38 mmol) portion-wise with stirring under nitrogen at 0°C. The reaction mixture was stirred at 0°C for 0.5 h and NaBH(OAc)3 (90 mg, 0.38 mmol) was then added and the reaction mixture was stirred at 25°C for 2 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography eluted with DCMMeOH=20: l to give the title compound as a white solid (0.15 g, 100%). LCMS: [M+H]+=764.4.

[0169] 7-( l-Cyclopropyl-lH-pyrazol-4-yl)-2-( ( 2-fluoro-4-( (4-( 4-(piperazin-l- yl)butyl)piperazin-l-yl)sulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one

[0170] A solution of ter / -butyl 4-(4-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[ 1 ,2-a]pyrimidin-2-yl)amino)-3 -fluorophenyl)sulfonyl)piperazin- 1 - yl)butyl)piperazine-l -carboxylate (0.13 g) in HCl / dioxane (2 mL) was stirred at 25°C for 2 h. The reaction mixture concentrated under reduced pressure to give the title compound as a yellow solid (0.13 g, 85%).

[0171] 4-(( 4-(4-( ( 4-( ( 7-( l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)-4-oxobutyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0172] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-((4-(4-(piperazin-l- yl)butyl)piperazin-l-yl)sulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (130 mg, 0.2 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (67 mg, 0.24 mmol) in DMSO (2 mL) was added DIEA (129 mg, 1 mmol) and the reaction mixture stirred under nitrogen at 25°C and then in a microwave at 120°C for 1 hour. The reaction was purified by prep- HPLC to give the title compound as a yellow solid (37 mg).rH NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.00 (d, J= 1.7 Hz, 1H), 8.47 (d, J= 7.6 Hz, 2H), 8.08 (dd, J= 9.2, 2.0 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.63 (t, J = 10.0 Hz, 2H), 7.56 (d, J= 8.6 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.28 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 5.06 (dd, J= 12.8, 5.5 Hz, 1H), 3.77 (s, 1H), 3.38 (d, J= 5.1 Hz, 4H), 2.96 (s, 4H), 2.91 - 2.83 (m, 1H), 2.55 (d, J= 9.2 Hz, 2H), 2.44 (s, 8H), 2.28 (d, J= 5.8 Hz, 4H), 2.18 (s, 3H), 2.05 - 1.97 (m, 1H), 1.41 (s, 4H), 1.09 (d, J = 3.6 Hz, 2H), 1.03 - 0.95 (m, 2H). LCMS: [M+H]+=920.4.

[0173] Example 3: Synthesis of 5-(4-(4-(4-((4-((7-(l-cvclopropyl-lH-pyrazol-4-yl)-3-methyl- 4-oxo-4H-pyrido[l,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)butyl)piperazin-l-yl)-2-(l-methyl-2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Me-dBPTF-

[0174] To a solution of 4-(4-(2-(l-methyl-2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)butanal (89 mg, 0.21 mmol) in DCE (1 mL) was added 7-(l-cyclopropyl-lH- pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2- a]pyrimidin-4-one (109.8 mg, 0.21 mmol) and DIEA (41.3 mg) and the reaction mixture wasstirred at room temperature for 30 min. STAB (133.5 mg, 0.63 mmol) was then added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4and concentrated to give a residue which was purified by prep-HPLC to give the title compound as a yellow solid (28 mg, yield 14%).JH NMR (400 MHz, DMSO) 5 9.00 (s, 1H), 8.47 (d, J= 6.3 Hz, 2H), 8.14 - 7.94 (m, 3H), 7.71 - 7.51 (m, 3H), 7.40 (d, J = 9.1 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 5.13 (dd, J = 13.1, 5.4 Hz, 1H), 3.79 - 3.72 (m, 1H), 3.42 - 3.35 (m, 4H), 3.00 (s, 3H), 2.99 - 2.92 (m, 4H), 2.81 - 2.64 (m, 2H), 2.57 - 2.53 (m, 1H), 2.47 - 2.37 (m, 8H), 2.34 - 2.23 (m, 4H), 2.18 (s, 3H), 2.06 - 1.99 (m, 1H), 1.47 - 1.35 (m, 4H), 1.13 - 1.05 (m, 2H), 1.04 - 0.96 (m, 2H). LCMS: [M+H]+=934.3.

[0175] Example 4: Synthesis of 5-(4-(6-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)hexyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-L3-dione (dBPTF-9, IB-2)

[0176] 6-( 4-( 2-(2, 6-Dioxopiperidin-3-yl)-l, 3-dioxoisoindolin-5-yl)piperazin-l-yl)hexanal

[0177] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-hydroxyhexyl)piperazin-l- yl)isoindoline-l, 3-dione (100 mg, 0.226 mmol) in ACN (30 mL) was added IBX (127 mg, 0.454 mmol) and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was dilutedwith water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by silica gel column eluted with MeOH: DCM (1 :20) to give the title compound as ayellow solid (67 mg, 67%). LCMS: [M+H]+=441.2.[00178J 5-(4-( 6-(4-((4-((7-( 1 -Cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)hexyl)piperazin-l-yl)-2-(2,6- dioxopiperidin-3-yl)isomdoline- 1,3-dione

[0179] To a solution of 6-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin- l-yl)hexanal (60 mg, 0.136 mmol) and 7-(l -cyclopropyl- lH-pyrazol-4-yl)-2-((2-fluoro-4- (piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (85 mg, 0.136 mmol) in DCE (5 mL) was added HOAc (19.1 mg, 0.318 mmol) and the reaction mixture was stirred for 30 min. STAB (101 mg, 0.476mmol) was then added and stirred for 4 hours. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH3.H2O in water, 5% to 95%) to give the title compound as a yellow solid (8 mg, 14%). 'H NMR (400 MHz, DMSO) 11.07 (s, 1δH), 9.01 (s, 1H), 8.46 (s, 2H), 8.14-7.96 (m, 3H), 7.71-7.50 (m, 3H), 7.41 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 7.21 (d, J= 8.5 Hz, 1H), 5.12-5.00 (m, 1H), 3.84-3.72 (m, 2H), 3.05-2.79 (m, 7H), 2.69-2.56 (m, 5H), 2.47-2.40 (m, 6H), 2.26 (t, J= 6.8 Hz, 4H), 2.18 (s, 3H), 2.05-1.97 (m, 1H), 1.46-1.31 (m, 4H), 1.30-1.20 (m, 4H), 1.13-1.06 (m, 2H), 1.03 - 0.94 (m, 2H). LCMS: [M+H]+=948.5.

[0180] Example 5: Synthesis of 5-(4-(2-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)ethyl)piperazin-l-yl)-2-(2.6-dioxopiperidin-3-yl)isoindoline-L3-dione (dBPTF-10. IB-3)

[0181] A solution of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)acetaldehyde (18 mg, 0.048 mmol), 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4- (piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (50 mg, 0.096 mmol), and STAB (20.5 mg, 0.096 mmol) in THF (20 mL) was stirred at room temperature for 20 min. Additional 7-(l -cyclopropyl- lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (18 mg, 0.048 mmol) and STAB (20.5 mg, 0.096 mmol) were added. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH3H2O in water, 5% to 95%) to give the title compound as a yellow solid (20 mg, 18%).!H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.01 (s, 1H), 8.46 (s, 2H), 8.14 - 7.93 (m, 3H), 7.69 - 7.48 (m, 3H), 7.41 (d, J= 9.0 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J= 9.2 Hz, 1H), 5.05 (dd, J= 12.7, 5.4 Hz, 1H), 3.77 (s, 1H), 3.52 - 3.35 (m, 7H), 3.09 - 2.79 (m, 6H), 2.61 - 2.55 (m, 5H), 2.48 - 2.41 (m, 5H), 2.19 (s, 3H), 2.06 - 1.92 (m, 1H), 1.16 - 1.05 (m, 2H), 1.00 (d, J= 5.7 Hz, 2H). LCMS: [M+H]+=892.3.

[0182] Example 6: Synthesis of 4-(4-(8-(4-((4-((7-(l-cvclopropyl-1H-pyrazol-4-yl)-3-methyl- 4-oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)octyl)piperazin- 1 -yl)-2-(2, 6-dioxopiperidin-3 -yl)i soindoline- 1 , 3 -di one ( dBPTF -13, NVS-BPTF-A-2)

[0183] lert-Bulyl 4-(2-(2,6-dioxopipeiidin-3-yl)-l,3-dioxoisoindolin-4-yl)piperazine-l- carboxylate

[0184] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l, 3-dione (10 g, 36.2 mmol) in DMSO (50 mL) were added ze / 7-butyl piperazine- 1 -carboxylate (10.11 g, 54 mmol) and DIEA (14 g, 108.6 mmol). The mixture was heated to 130°C and stirred for 16 hours. The solution was diluted with water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with DCM: MeOH (0-10%) to give the title compound as a green solid (13 g, 81%). 'H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 7.73 (dd, J = 8.3, 7.2 Hz, 1H), 7.38 (dd, J = 15.2, 7.7 Hz, 2H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 3.52 (s, 4H), 3.26 (d, J= 4.3 Hz, 4H), 2.95 - 2.81 (m, 1H), 2.66 - 2.52 (m, 2H), 2.08 - 1.99 (m, 1H), 1.43 (s, 9H). LCMS: [M+H]+=443.0.

[0185] 2-(2, 6-Dioxopiperidm-3-yl)-4-(piperazin-l-yl)isomdoline-l, 3-dione

[0186] To a solution of / c / V-butyl 4-(2-(2, 6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4- yl)piperazine-l -carboxylate (5 g, 11.31 mmol) in dioxane (20 mL) was added dioxane / HCl (4 mL). The mixture was stirred for 16 hours at room temperature, and then concentrated under reducedpressure to give the title compound as a yellow solid (5.1 g, crude), used in the next step without a further purification. LCMS: [M+H] = 343.1.

[0187] 2-(2, 6-Dioxopiperidin-3-yl)-4-( 4-( 8-hydroxyoctyl)piperazin-l-yl) isoindoline- 1, 3-dione

[0188] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-l-yl)isoindoline-l, 3-dione (4.5 g, 13.15 mmol) in ACN (40 mL) were added 8-bromooctan-l-ol (3.026 g, 14.47 mmol), K2CO3 (5.4 g, 39 mmol) and KI (1.941 g, 13.15 mmol). The mixture was heated to 75°C and stirred for 16 hours, diluted with water (40 mL) and extracted with DCM:MeOH = 10: 1 (50 mL x 3), combined organic layers, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with DCM:MeOH (0-5%) to give the title compound as a green solid (2.7 g, 43%).rH NMR (400 MHz, DMSO) 8 11.09 (s, 1H), 7.70 (dd, J= 8.3, 7.3 Hz, 1H), 7.35 (t, J= 8.0 Hz, 2H), 5.09 (dd, J= 12.7, 5.4 Hz, 1H), 4.37 (t, J = 5.2 Hz, 1H), 3.36 (d, J= 6.5 Hz, 3H), 3.30 (s, 4H), 2.86 (dd, J = 8.5, 5.4 Hz, 1H), 2.64 - 2.53 (m, 5H), 2.34 (s, 2H), 2.03 (dd, J= 9.0, 3.6 Hz, 1H), 1.50 - 1.38 (m, 4H), 1.26 (d, J = 10.6 Hz, 9H). LCMS: [M+H]+= 471.1.

[0189] 8-( 4-( 2-(2, 6-Dioxopiperidin-3-yl)-l, 3-dioxoisoindolin-4-yl)piperazin-l-yl)octanal

[0190] A solution of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(8-hydroxyoctyl)piperazin-l- yl)isoindoline-l, 3-dione (2.5 g, 5.32mmol) and PCC (2.3 g, 10.6 mmol) in DCM (20 mL) was stirred for 4 hours at room temperature. The mixture was diluted with water (50 mL) and extracted with DCM:MeOH = 10:1 (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with DCM:MeOH (0-5%) to give the title compound as a yellow solid (1.03 g, 41%). LCMS: [M+H]+= 469.2.

[0191] 4-(4-(8-(4-((4-( (7-( 1 -Cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)octyl)piperazin-l-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione (dBPTF-13, NVS-BPTF-A-2)

[0192] To a solution of 8-(4-(2-(2,6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4-yl)piperazin- l-yl)octanal (930 mg, 1.98 mmol) and 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fhioro-4- (piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (1.039 mg, 1.98 mmol) in DCE (20 mL) was added dodium triacetoxyborohydride (1.7 g, 7.94 mmol). The mixture was stirred for 16 hours at room temperature, and then diluted with water (30 mL) and extracted with DCM (40 mL x 3), dried over Na2SO4, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (acetonitrile with 0.1% of NH3H2O in water 5% to 95%) to give the title compound as a yellow solid (324.3 mg, 17%). 'H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.01 (d, J= 1.9 Hz, 1H), 8.49 - 8.45 (m, 2H), 8.08 (dd, J = 9.2, 2.1 Hz, 1H), 8.04- 7.97 (m, 2H), 7.71 - 7.65 (m, 1H), 7.64 - 7.52 (m, 2H), 7.41 (d, J= 9.1 Hz, 1H), 7.32 (dd, J = 13.9, 7.7 Hz, 2H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 3.81 - 3.73 (m, 1H), 3.32 - 3.21 (m, 7H), 2.99- 2.82 (m, 5H), 2.63 - 2.52 (m, 3H), 2.46 - 2.38 (m, 4H), 2.31 - 2.22 (m, 4H), 2.18 (s, 3H), 2.06 - 1.95 (m, 1H), 1.47 - 1.31 (m, 4H), 1.27 - 1.18 (m, 8H), 1.12 - 1.07 (m, 2H), 1.03 - 0.96 (m, 2H). LCMS: [M+H]+= 976.1.

[0193] Example 7: Synthesis of 4-(4-(8-(4-((4-((7-(l-cvclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[L2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)octyl)piperazin- 1 -yl)-2-( 1 -methyl-2,6-dioxopiperi din-3 -yl)isoindoline- E3 -di one (Me-dBPTF -

[0194] To a solution of 8-(4-(2-(l-methyl-2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)piperazin-l-yl)octanal (20 mg, 0.043 mmol) and 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2- fluoro-4-(piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (23 mg, 0.043 mmol) in DCE (10 mL) was added STAB (36 mg, 0.17 mmol) and the reaction mixture was stirred for 4 h at room temperature. Water (20 mL) was added, extracted with DCM (10 mL x 3), dried over NazSCL, and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH3H2O in water 5% to 95%) to give the title compound as a yellow solid (8 mg, 19% yield). ’H NMR (400 MHz, DMSO) 5 9.01 (s, 1H), 8.46 (s, 2H), 8.08 (dd, J =9.3, 1.9 Hz, 1H), 8.04-7.97 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.57 (dd, J = 22.4, 9.9 Hz, 2H), 7.41 (d, J= 9.1 Hz, 1H), 7.32 (dd, J= 12.0, 7.8 Hz, 2H), 5.15 (dd, J= 13.1, 5.3 Hz, 1H), 3.76 (m, J = 11.1, 3.9 Hz, 1H), 3.29-3.23 (m, 4H), 3.01 (s, 3H), 2.98-2.92 (m, 4H), 2.79-2.71 (m, J= 17.0 Hz, 1H), 2.59-2.52 (m, 4H), 2.46-2.42 (m, 6H), 2.30-2.22 (m, J= 15.1, 8.4 Hz, 4H), 2.18 (s, 3H), 2.06- 2.00 (m, 1H), 1.43-1.33 (m, 4H), 1.26-1.19 (m, 8H), 1.12-1.06 (m, 2H), 1.02-0.96 (m, J = 7.2 Hz, 2H). LCMS: [M+H]+=990.8.

[0195] Example 8: Synthesis of 4-(4-(4-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[L2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)butyl)piperazin- 1 -yl )-2-(2,6-di oxopiperi di n-3 -yl)isoindoline- 1 -dione (dBPTF - 14)

[0196] To a solution of 4-(4-(2-(2,6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4-yl)piperazin- l-yl)butanal (100 mg, 0.24 mmol) and 7-(l -cyclopropyl- IH-pyrazol -4-yl)-2-((2-fluoro-4- (piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (139 mg, 0.26 mmol) in DCE (10 mL) was added STAB (36 mg, 0.17 mmol) and the reaction mixture was stirred for 4 h at room temperature. Water (20 mL) was added, extracted with DCM (10 mL x 3), dried over Na2SO4, and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH.3 H2O in water 5% to 95%) to give the title compound as a yellow solid (22 mg, 10% yield). ’H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.44 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.99 - 7.89 (m, 2H), 7.72 - 7.64 (m, 1H), 7.57 - 7.44 (m, 2H), 7.39 - 7.28 (m, 3H), 7.28 - 7.20 (m, 4H), 5.05 (dd, J = 13.1, 5.9 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.49 (d, J = 10.6 Hz, 4H), 3.28 -3.25 (m, 4H), 3.02 - 2.88 (m, 4H), 2.85 - 2.74 (m, 1H), 2.62 - 2.55 (m, 2H), 2.47 - 2.38 (m, 7H), 2.16 (s, 3H), 2.02 - 1.96 (m, 2H), 1.12 - 1.07 (m, 2H), 1.03 - 0.96 (m, 2H). LCMS: [M+H]1=920.4.[00197J Example 9: Synthesis of 4-(4-(4-((4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyridori,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)methyl)benzyl)piperazin- 1 -yl)-2-(2.6-dioxopiperi din-3 -yl)isoindoline- 1 ,3 -di one (dBPTF- 15

[0198] To a solution of 4-((4-(2-(2,6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4-yl)piperazin- l-yl)methyl)benzaldehyde (26 mg, 0.057 mmol) and 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2- fluoro-4-(piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (30 mg, 0.057 mmol) in MeOH (9 mL) was added Pic-BH3(6 mg, 0.057 mmol) and the reaction mixture was stirred for 2 h at room temperature. Water (20 mL) was added, extracted with DCM (10 mL x 3), dried over Na2SO4, and concentrated to give a residue which was purified by prep- HPLC (acetonitrile with 0.1% of NH3H2O in water 5% to 95%) to give the title compound as a yellow solid (6 mg, 10% yield). ’H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.01 (d, J= 1.7 Hz, 1H), 8.51 - 8.42 (m, J = 5.4 Hz, 2H), 8.12 - 8.11 (m, J= 11.2 Hz, 1H), 8.04 - 7.95 (m, 2H), 7.70 - 7.52 (m, 3H), 7.41 (d, J= 9.0 Hz, 1H), 7.41 (d, J= 9.0 Hz, 1H), 7.33 (d, J= 7.4 Hz, 1H), 5.07 (dd, J = 12.7, 5.3 Hz, 1H), 3.83 - 3.72 (m, 1H), 3.32 - 3.29 (m, 4H), 3.26 - 3.21 (m, 4H), 3.00 - 2.90 (m, J= 7.1, 4.7 Hz, 4H), 2.88 - 2.80 (m, 1H), 2.62 - 2.53 (m, 3H), 2.46 - 2.38 (m, J= 8.0, 6.7 Hz, 4H), 2.32 - 2.26 (m, .7 = 5.0, 3.9 Hz, 3H), 2.18 (s, 3H), 2.04 - 1.96 (m, 1H), 1.50 - 1.35 (m, 4H), 1.13 - 1.05 (m, 2H), 1.05 - 0.96 (m, 2H). LCMS: [M+H]+=968.2.

[0199] Example 10: Synthesis of 3-(6-(7-(4-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3- methyl-4-oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)butyl)-2,7-diazaspiro[ 3 , 51nonan-2-yl)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione (dBPTF - 16)

[0200] tert-Butyl 2-(2-(2, 6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-2, 7- diazaspiro[ 3.5 ]nonane- 7 -carboxylate

[0201] To a solution of 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (2.5 g, 7.7 mmol) in dioxane (50 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.7 g, 7.7 mmol), PEPPSI-Pd (749 mg, 0.77 mmol) and CS2CO3 (7.6 g, 23.2 mmol) and the reaction mixture was stirred at 100°C overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SC>4, and concentrated to give a residue which was purified by silica gelcolumn eluted with 5% MeOH in DCM to give the title compound as a white solid (1 g, 28%). LCMS: [M+H]1=469.2.

[0202] 3-( l-Oxo-6-(2, 7-diazaspiro / 3.5Jnonan-2-yl)isoindolin-2-yl)piperidine-2, 6-dione

[0203] To a solution of te / 7-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.43 mmol) in DCM (10 mL) was added TFA (5 mL) and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (200 mg, crude) and used without a further purification. LCMS: [M+H]+=369.1 .

[0204] 3-( 6-( 7-(3-( 1, 3-Dioxolan-2-yl)propyl)-2, 7 -diazaspiro [ 3.5 ]nonan-2-yl)-l- oxoisoindolin-2-yl)piperidine-2, 6-dione

[0205] To a solution of 3-(l-oxo-6-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine- 2, 6-dione (200 mg, 0.54 mmol) in ACN (30 mL) was added 2-(3-bromopropyl)-l,3-dioxolane (117 mg, 0.60 mmol), K2CO3 (298 mg, 2.16 mmol) and KI (99 mg, 0.60 mmol) and the reaction mixture was stirred at 80°C overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated to give a residue which was purified by silica gel column eluted with 5%- 10% MeOH in DCM to give the title compound as a white solid (130 mg, 50%). LCMS: [M+H]+=483.2.

[0206] 4-(2-( 2-( 2, 6-Dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-2, 7-diazaspiro[3.5 ]nonan- 7- yl) butanal

[0207] To a solution of 3-(6-(7-(3-(l,3-dioxolan-2-yl)propyl)-2,7-diazaspiro[3.5]nonan-2-yl)- l-oxoisoindolin-2-yl)piperidine-2, 6-dione (190 mg, 0.39 mmol) in DCM (10 mL) was added TFA (5 mL) and the reaction mixture stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (190 mg, crude) and used without further purification. LCMS: [M+H]+=439.2.

[0208] 3-( 6-(7-( 4-( 4-( ( 4-((7-( 1 -cyclopropyl -lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[l, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-I-yl)butyl)-2, 7- diazaspiro[ 3.5 ]nonan-2-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0209] To a solution of 4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)butanal (84 mg, 0.16 mmol) and 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2- ((2-fluoro-4-(piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one(70 mg, 0.16 mmol) in DCE (10 mL) was added STAB (144 mg, 0.6317 mmol) and the reaction mixture was stirred for 4 h at room temperature. Water (20 mL) was added, extracted with DCM (10 mL x 3), dried over Na2SO4, and concentrated to give a residue which was purified by prep- HPLC (acetonitrile with 0.1% of NH3H2O in water 5% to 95%) to give the title compound as a yellow solid (17 mg, 11% yield). 'H NMR (400 MHz, DMSO) 6 10.97 (s, 1H), 9.01 (s, 1H), 8.47 (s, 2H), 8.09 (d, J= 9.2 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.60 (dd, J= 23.4, 10.1 Hz, 2H), 7.41 (d, J = 9.2 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 6.64 (s, 2H), 5.07 (dd, J= 13.2, 5.2 Hz, 1H), 4.34 - 4.13 (m, 2H), 3.82 -3.72 (m, 1H), 3.02 - 2.93 (m, 4H), 3.02 - 2.93 (m, 4H), 2.91 - 2.85 (m, 1H), 2.64 - 2.56 (m, 2H), 2.48 - 2.42 (m, 4H),2.39 - 2.33 (m, 2H), 2.32 - 2.23 (m, 4H), 2.22 - 2.15 (m, 4H), 2.07 - 1.93 (m, 2H), 1.81 - 1.62 (m, 4H), 1.46 - 1.31 (m, 4H), 1.13 - 1.08 (m, 2H), 1.04 - 0.98 (m, 2H). LCMS: [M+H]+=946.3.

[0210] Example 11 : Synthesis of 3-((4-(4-(6-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3- methyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)hexyl)piperazin-l-yl)-3-fluorophenyl)amino)piperidine-2.6-dione (dBPTF-17)

[0211] tert-Butyl 4-(2-fluoro-4-mtropheriyl)piperazine-l -carboxylate

[0212] To a solution of l,2-difluoro-4-nitrobenzene (40 g, 251 mmol) in DMF (50 mL) were added Zc' / V-butyl piperazine- 1 -carboxylate (46.7 g, 251 mmol) and K2C0.3 (103.9 g, 753 mmol) and the reaction mixture was stirred at 130°C for 2 h. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (90 mL), dried over Na2SO4, and concentrated to give a residue which was purified by silica gel column eluted with 20% ethyl acetate in petroleum ether to give the title compound as a yellow solid (80 g, 98%). LCMS: [M+H]+=270.1.

[0213] tert-Butyl 4-(4-ammo-2-fluorophenyl)piperazine-l -carboxylate

[0214] To a solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-l -carboxylate (10 g, 30.77 mmol) in MeOH (20 mL) was added Pd / C (1 g) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through C6lite® and washed with ethyl acetate. The filtrate was concentrated to give the title compound as a yellow solid (8.5 g, crude). LCMS: [M+H]+=296.2.

[0215] tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-l- carboxylate

[0216] To a solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-l -carboxylate (8.5 g, 28.81 mmol) in DMSO (20 mL) were added DIEA (19.1 mL) and 3-bromopiperidine-2, 6-dione (6.74 g, 34.57 mmol) and the reaction mixture was stirred at 130°C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, and concentrated to give a residue which was purified by silica gel column eluted with 5% MeOH in DCM to give the title compound as a green solid (3.5 g, 30%). LCMS: [M+H]+=407.2.

[0217] 3-((3-Fluoro-4-(piperazin-l-yl)phenyl)amino)piperidine-2, 6-dione

[0218] To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazine-l -carboxylate (700 mg, 1.72 mmol) in dioxane (5 mL) was added HCl / dioxane (5 mL) at 0°C and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a green solid (525 mg, crude) and was used without further purification. LCMS: [M+H]+=307.2.

[0219] 6-(4-( 4-((2, 6-Dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-l-yl)hexanoic acid

[0220] To a solution of 3-((3-fluoro-4-(piperazin-l-yl)phenyl)amino)piperidine-2, 6-dione (525 mg, 1.72 mmol) in ACN (10 mL) were added DIEA (885 mg, 6.86 mmol), 6-bromohexanoic acid (1.00 g, 5.16 mmol), and KI (314 mg, 1.89 mmol) and the reaction mixture was stirred at 80°C overnight. The reaction mixture was concentrated to give a residue which was purified by silica gel column eluted with 20% MeOH in DCM to give the title compound as a green solid (402 mg, 56%). LCMS: [M+H]- =421.1.

[0221] S-octyl 6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-l- yl)hexanethioate

[0222] To a solution of 6-(4-(4-((2, 6-dioxopiperi din-3 -yl)amino)-2-fluorophenyl)piperazin- 1- yl)hexanoic acid (402 mg, 0.96 mmol) in DCM (3 mL) were added octane- 1 -thiol (116.8 mg, 0.8 mmol), EDCI (183.4 mg, 0.96 mmol), and DMAP (19.5 mg, 0.16 mmol) at 0°C and stirred overnight. The reaction mixture was concentrated to give a residue which was purified by silica gel column eluted with 20% MeOH in DCM to give the title compound as a green solid (162 mg, 34%). LCMS: [M+H]- =549.4.

[0223] 6-(4-(4-((2,6-Dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-l-yl)hexanal

[0224] To a solution of 5-octyl 6-(4-(4-((2,6-dioxopiperi din-3 -yl)amino)-2- fluorophenyl)piperazin-l-yl)hexanethioate (90 mg, 0.16 mmol) in DCM (5 mL) were added Pd(OAc)2 (3.6 mg) and EtsSiH (37.21 mg, 0.32 mmol) and stirred overnight at room temperature. The reaction mixture was filtered through a pad of C6lite® and washed with DCM. The filtrate was purified by pre-TLC to give the title compound as a green solid (32 mg, 50%). LCMS: [M+H]+=405.2.

[0225] 3-( ( 4-(4-( 6-(4-((4-((7-( 1 -Cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-2-yl)ammo)-3-fluorophenyl)sulfonyl)piperazin-l-yl)hexyl)piperazin-l- yl)-3-fluorophenyl)amino)piperidine-2, 6-dione

[0226] To a solution of 6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-l- yl)hexanal (32 mg, 0.079 mmol) in DCE (5 mL) were added 7-(l-cyclopropyl-lH-pyrazol-4-yl)- 2-((2-fluoro-4-(piperazin-l-ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4- one (41.4 mg, 0.079 mmol) and DIEA (15 mg) and the reaction mixture was stirred at room temperature for 30 min. STAB (200 mg, 0.94 mmol) was then added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, and concentrated to give a residue which was purified by prep-HPLC to give the title compound as a white solid (15 mg, 21%).NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.01 (s, 1H), 8.51 - 8.42 (m, 2H), 8.08 (d, J = 9.0 Hz, 1H), 8.05 - 7.96 (m, 2H), 7.61 (d, J= 10.1 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.41 (d, J= 9.2 Hz, 1H), 6.79 (t, J= 9.2 Hz, 1H), 6.49 (d, J = 15.1 Hz, 1H), 6.40 (d, J = 9.2 Hz, 1H), 5.78 (d, J = 7.9 Hz, 1H), 4.29 - 4.18 (m, 1H), 3.80 - 3.72 (m, 1H), 3.02 - 2.89 (m, 4H), 2.86 - 2.76 (m, 4H), 2.76 - 2.56 (m, 3H), 2.46 - 2.37 (m, 7H), 2.29 - 2.20 (m, 4H), 2.19 (s, 3H), 2.12 - 2.02 (m, 1H), 1.88 - 1.80 (m, 1H), 1.45 - 1.33 (m, 4H), 1.28 - 1.18 (m, 4H), 1.13 - 1.05 (m, 2H), 1.05 - 0.96 (m, 2H). LCMS: [M+H]+=912.7.

[0227] Example 12: Synthesis of 3-((4-(4-(l-(4-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3- methyl-4-oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)butyl)-3,3-difluoropiperidin-4-yl)piperazin-l-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (dBPTF-18, A-3)

[0228] To a solution of 4-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin- l-yl)-3,3-difluoropiperidin-l-yl)butanal (42 mg, 0.08 mmol) and 7-(l-cyclopropyl-lH-pyrazol-4- yl)-2-((2-fluoro-4-(piperazin- 1 -ylsulfonyl)phenyl)amino)-3 -methyl-4H-pyrido[ 1 ,2-a]pyrimidin- 4-one (39.7 mg, 0.08 mmol) in DCE (10 mL) was added STAB (57 mg, 0.27 mmol) and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was added, extracted with DCM (30 mL x 3), dried over NasSCh, and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH3H2O in water 5% to 95%) to give the title compound as a white solid (11 mg, 13% yield). 'H NMR (400 MHz, MeOH) δ 9.06 (s, 1H), 8.47 (t, J = 8.1 Hz, 1H), 8.23 (s, 1H), 8.03 (d, J= 9.1 Hz, 1H), 7.93 (s, 1H), 7.70-7.62 (m, 2H), 7.46 (d, J = 9.2 Hz, 1H), 6.83 (t, J = 8.9 Hz, 1H), 6.50-6.37 (m, 2H), 4.23-4.15 (m, 1H), 3.76-3.68 (m, 1H), 3.39- 3.34 (m, 6H), 3.26-3.20 (m, 2H), 3.17- 3.10 (m, 3H), 3.09-2.96 (m, 8H), 2.85-2.63 (m, 5H), 2.62- 2.36 (m, 2H), 2.31-2.19 (m, 4H), 2.12-2.00 (m, 1H), 1.96-1.86 (m, 2H), 1.84-1.74 (m, 2H), 1.73- 1.63 (m, 2H), 1.38-1.24 (m, 1H), 1.19-1.05 (m, 4H). LCMS: [M+H]+=1003.5.[00229J Example 13: Synthesis of 3-((4-(4-(4-(4-((4-((7-(l-cvclopropyl-lH-pyrazol-4-yl)-3- methyl-4-oxo-4H-pyridorE2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)butyl)piperazin- 1 -yl)-3 -fluorophenyl)amino)piperidine-2,6-dione (dBPTF- 19, A-4)

[0230] A solution of 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-l- yl)butanal (50 mg, 0.13 mmol), 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (35 mg, 0.07 mmol), and DIEA (0.3 mL) in DCE (10 mL) was stirred at room temperature for 30 min. STAB (57 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was added, extracted with DCM (30 mL x 3), dried over Na2SO4, and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH3H2O in water 5% to 95%) to give the title compound as a white solid (11 mg, 9% yield).JH NMR (400 MHz, MeOH) δ 9.08 (d, J= 1.8 Hz, 1H), 8.25-8.18 (m, 2H), 8.05-8.00 (m, 1H), 7.93 (s, 1H), 7.65-7.55 (m, 2H), 7.48-7.41 (m, 1H), 6.79 (t, J= 8.9 Hz, 1H), 6.45-6.35 (m, 2H), 4.25-4.15 (m, 1H), 3.77-3.69 (m, 1H), 3.38-3.31 (m, 4H), 3.24-3.00 (m, 10H), 2.84-2.65 (m, 6H), 2.54 (t, J= 6.6 Hz, 2H), 2.34-2.17 (m, 4H), 1.97-1.74 (m, 3H), 1.71-1.58 (m, 2H), 1.19-1.06 (m, 4H). LCMS: [M+H]1=884.4.

[0231] Example 14: Synthesis of N-(4-(4-((4-((7-(' l -cvclopropyl- l H-pyrazol-4-yl)-3-methyl- 4-oxo-4H-pyridol 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)butyl)-3- (2,4-dioxotetrahvdropyrimidin-l(2H)-yl)-4-methoxybenzamide (dBPTF-20)

[0232] tert-Butyl (4-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)butyl)carbamate

[0233] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (100 mg, 0.19 mmol) in NMP (3 mL) were added tert-butyl (4-bromobutyl)carbamate (289 mg, 1.15 mmol), KI (63 mg, 0.38 mmol) and K2CO3 (262 mg, 1.9 mmol) and the reaction mixture was stirred at 150°C for 2 h in a microwave. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, and concentrated to give a residue which was purified by silica gel column eluted with 20% MeOH in DCM ether to give the title compound as a white solid (60 mg, 45%). LCMS: [M+H]+-695.4.

[0234] 2-((4-((4-( 4-Aminobutyl)piperazin-l-yl)sulfonyl)-2-fluorophenyl)amino)- 7-(l- cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4H-pyrido[l,2-a]pyrimidm-4-one

[0235] To a solution of tert-butyl (4-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[ 1 ,2-a]pyrimidin-2-yl)amino)-3 -fluorophenyl)sulfonyl)piperazin- 1 - yl)butyl)carbamate (50 mg, 0.072 mmol) in dichloromethane (2 mL) was added HCl / dioxane (2mL, 4M) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a brown solid (50 mg, crude) and used without further purification. LCMS: [M+H]+=595.2.

[0236] N-( 4-( 4-( ( 4-( (7-( 1 -cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1 , 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)butyl)-3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzamide

[0237] To a solution of 2-((4-((4-(4-Aminobutyl)piperazin-l-yl)sulfonyl)-2- fluorophenyl)amino)-7-(l -cy cl opropyl-lH-pyrazol-4-yl)-3-methyl-4H-pyrido[l,2-a]pyrimi din-4- one (35 mg, 0.059 mmol), 3 -(2, 4-dioxotetrahydropyrimidin-l(2H)-yl)-4-m ethoxybenzoic acid (25 mg, 0.059 mmol), and DIPEA (38 mg, 0.295 mmol) in DCM (5 mL) was added HATU (30 mg, 0.078 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give a residue which was purified by prep-HPLC to give the title compound as a white solid (10 mg, 14%).1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 9.02 (d, J= 2.0 Hz, 1H), 8.47 (d, J= 3.2 Hz, 2H), 8.30 (d, J = 5.4 Hz, 1H), 8.08 (dd, J= 9.2, 2.1 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.82 (dd, J = 8.6, 2.2 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.64 - 7.50 (m, 2H), 7.41 (d, J = 9.3 Hz, 1H), 7.14 (d, J= 8.8 Hz, 1H), 3.83 (s, 3H), 3.80 - 3.73 (m, 1H), 3.60 - 3.54 (m, 2H), 3.23 - 3.18 (m, 2H), 2.95 (s, 4H), 2.69 - 2.65 (m, 2H), 2.43 (s, 4H), 2.33 - 2.27 (m, 2H), 2.18 (s, 3H), 1.51 - 1.38 (m, 4H), 1.14 - 1.06 (m, 2H), 1.00 (m, 2H). LCMS: [M+H]+=841.4.

[0238] Example 15: Synthesis of N-(6-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl- 4-oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)hexyl)-3- (2,4-dioxotetrahvdropyrimidin-l(2H)-yl)-4-methoxybenzamide (dBPTF-21)

[0239] tert-Butyl (6-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-a pyrimidm-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazm-l-yl)hexyl)carbamate

[0240] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (200 mg, 0.38 mmol) in DCE (5 mL) was added DIEA (74 mg, 0.57 mmol) and the reaction mixture was stirred at room temperature for 30 min. A solution of tert-butyl (6-oxohexyl)carbamate (83 mg, 0.38 mmol) and STAB (242 mg, 1.14 mmol) in DCE (5 mL) was added and the reaction mixture stirred overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4and concentrated to give a residue which was purified by silica gel column eluted with 10% MeOH in DCM to give the title compound as a yellow solid (120 mg, 44%). LCMS: [M+H]- =723.4.

[0241] 2-( ( 4-( ( 4-( 6-Aminohexyl)piperazin-l-yl)sulfonyl)-2-fluorophenyl)amino)-7-( 1 - cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one

[0242] To a solution of tert-Z>utyl (6-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l- yl)hexyl)carbamate (120 mg, 0.17 mmol) in DCM (5 mL) was added HCl / dioxane (5 mL, 4M) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture wasconcentrated under reduced pressure to give the title compound as a yellow solid (100 mg, crude) and used without further purification. LCMS: [M+H]1=623.8.

[0243] N-( 6-( 4-( (4-((7-(l -cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[l, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfotiyl)piperazin-l-yl)hexyl)-3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzaniide

[0244] To a solution of 2-((4-((4-(6-aminohexyl)piperazin-l-yl)sulfonyl)-2- fluorophenyl)amino)-7-( 1 -cy clopropyl- lH-pyrazol-4-yl)-3 -methyl-4H-pyrido[ 1 ,2-a]pyrimidin-4- one (100 mg, 0.16 mmol) in DCM (5 mL) were added DIEA (207 mg, 1.61 mmol) and perfluorophenyl 3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzoate (138 mg, 0.32 mmol) and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give a residue which was purified by prep-HPLC to give the title compound as a white solid (28 mg, 18%).1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 9.01 (d, J= 1.9 Hz, 1H), 8.54 - 8.40 (m, 2H), 8.31 (t, J = 5.6 Hz, 1H), 8.14 - 8.05 (m, 1H), 8.04 - 7.98 (m, 2H), 7.82 (dd, J= 8.7, 2.2 Hz, 1H), 7.75 (d, .7= 2.2 Hz, 1H), 7.61 (d, J = 10.4 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.15 (d, J= 8.8 Hz, 1H), 3.84 (s, 3H), 3.80 - 3.73 (m, 1H), 3.58 (t, J= 6.5 Hz, 2H), 3.24 - 3.16 (m, 2H), 3.07 - 2.81 (m, 4H), 2.72 - 2.64 (m, 2H), 2.49 - 2.35 (m, 4H), 2.35 - 2.21 (m, 2H), 2.18 (s, 3H), 1.53 - 1.43 (m, 2H), 1.42 - 1.32 (m, 2H), 1.31 - 1.21 (m, 4H), 1.14 - 1.05 (m, 2H), 1.05 - 0.95 (m, 2H). LCMS: [M+H]+=869.6.

[0245] Example 16: Synthesis of 6-(4-(4-((4-((7-(l-cvclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)butyl)-2- (2,6-dioxopiperidin-3-yl)-6.7-dihvdropyrrolo[3,4-f]isoindole-L3(2H,5H)-dione (dBPTF-22)

[0246] 6-(3-( 1, 3-Dioxolan-2-yl)propyl)-2-(2, 6-dioxopiperidin-3-yl)-6, 7-dihydropyrrolo[ 3, 4- fJisoindole-l,3(2H, 5H)-dione

[0247] To a solution of 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole- l,3(2H,5H)-dione (66 mg, 0.22 mmol) in ACN (8 mL) were added DIEA (114 mg, 0.88 mmol), 2-(3-bromopropyl)-l,3-dioxolane (129 mg, 0.66 mmol), and KI (40 mg, 0.24 mmol) and the reaction mixture was stirred at 80°C for 1 h in a microwave. The reaction mixture was concentrated to give a residue which was purified by flash silica gel chromatography 10% MeOH in DCM to give the title compound as a yellow solid (90 mg, 99%). LCMS: [M+H]+=414.1.

[0248] 4-( 6-( 2, 6-Dioxopiperidin-3-yl)-5, 7-dioxo-3, 5, 6, 7 -tetrahydropyrrole^ 3, 4-f]isoindol-2( lH)-yl)butanal

[0249] To a solution of 6-(3-(l,3-dioxolan-2-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)-6,7- dihydropyrrolo[3,4-f]isoindole-l,3(2H,5H)-dione (90 mg, 0.22 mmol) in DCM (4 mL) was added TFA (3 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixturewas concentrated under reduced pressure to give the title compound as a yellow solid (70 mg, crude) and used without further purification. LCMS: [M+H]1=370.1.

[0250] 6-(4-( 4-((4-(( 7-( 1 -Cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1 , 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfotiyl)piperazin-l-yl)butyl)-2-(2,6-dioxopiperidin-3- yl)-6, 7-dihydropyrrolo[ 3, 4-f]isoindole-l, 3(2H, 5H)-dione

[0251] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (76 mg, 0.15 mmol) in DCE (5 mL) was added DIEA (285 mg, 0.22 mmol) and the reaction mixture was stirred at room temperature for 30 min. 4-(6-(2,6-Dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindol-2(lH)-yl)butanal (70 mg, 0.19 mmol) and STAB (93 mg, 0.44 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give a residue was purified by prep-HPLC to give the title compound as a white solid (11 mg, 8%).JH NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.53 - 8.42 (m, 2H), 8.10 - 8.00 (m, 2H), 7.99 (s, 1H), 7.73 (s, 2H), 7.61 (dd, J= 10.2, 1.9 Hz, 1H), 7.56 (dd, J = 8.5, 1.8 Hz, 1H), 7.39 (d, .7= 9.2 Hz, 1H), 5.12 (dd, J= 12.9, 5.4 Hz, 1H), 3.90 (s, 4H), 3.80 - 3.73 (m, 1H), 3.03 - 2.92 (m, 4H), 2.92 - 2.83 (m, 1H), 2.68 - 2.60 (m, 3H), 2.58 - 2.53 (m, 2H), 2.46 - 2.42 (m, 3H), 2.34 - 2.29 (m, 2H), 2.18 (s, 3H), 2.10 - 1.99 (m, 1H), 1.51 - 1.42 (m, 4H), 1.12 - 1.04 (m, 2H), 1.04 - 0.96 (m, 2H). LCMS: [M+H]+=877.6.

[0252] Example 17: Synthesis of N-(2-(4-((4-((7-(l-cvclopropyl-lH-pyrazol-4-yl)-3-methyl- 4-oxo-4H-pyrido[L2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)ethyl)-3- (2,4-dioxotetrahvdropyrimidin-l(2H)-yl)-4-methoxybenzamide (dBPTF-23)

[0253] 3-(2,4-Dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzoic acid

[0254] 3 -Amino-4-methoxybenzoic acid (5 g, 29.9 mmol) was suspended in acrylic acid (8.62 g, 119.6 mmol) and the resulting suspension was stirred at 100°C for 3 h and then allowed to cool to room temperature. Acetic acid (33 mL) was added and the reaction mixture was stirred at 100°C for 10 min. Urea (11 g, 185.4 mmol) was added and the reaction mixture was stirred at 120°C overnight. The reaction mixture was added into a solution of ice water (1 0 mL) and concentrated aqueous HC1 (37%, 10 mL) and was stirred overnight. The reaction mixture was fdtered and the solids were washed with water and dried. The solids were triturated with HC1 (0.05 M, 300 mL), fdtered, and the solids were washed with / c / V-butyl methyl ether to give the title compound as a brown solid (6.4 g, 84%). LCMS: [M+H]+=265.1.

[0255] Perfluorophenyl 3-(2, 4-dioxotetrahydropyrimidm-l(2H)-yl)-4-methoxybenzoate

[0256] A solution of 3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzoic acid (304 mg, 1.15 mmol), 2,3,4,5,6-pentafluorophenol (212 mg, 1.15 mmol), DMAP (329 mg, 1.73 mmol), and EDCI (14 mg, 0.12 mmol) in DCM (5 mL) was stirred at room temperature for 3 h. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and concentrated to give a residue which was purified by silica gel column eluted with 60% ethyl acetate in PE to give the title compound as a white solid (299 mg, 60%). LCMS: [M+H]+=431.0.

[0257] tert-Butyl (2-(4-((4-( (7-( l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyridof 1 ,2-a]pyrimidin-2-yl)amino)-3-fhiorophenyl)sulfonyl)piperazin-l-yl)ethyl)carbamate

[0258] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (100 mg, 0.19 mmol) in DCE (5 mL) was added DIEA (37 mg, 0.29 mmol) and the reation mixture was stirred at room temperature for 30 min. A solution of ter / -butyl (2-oxoethyl)carbamate (91 mg, 0.57 mmol) and STAB (122 mg, 0.57 mmol) in DCE (5 mL) was added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4and concentrated to give a residue which was purified by silica gel column eluted with 10% MeOH in DCM to give the title compound as a yellow solid (60 mg, 47%). LCMS: [M+H]+=667.3.

[0259] 2-( ( 4-( ( 4-( 2-Aminoethyl)piperazin-l-yl)sulfonyl)-2-fbiorophenyl)amino)- 7-( 1 - cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one

[0260] To a solution of to7-butyl (2-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[ 1 ,2-a]pyrimidin-2-yl)amino)-3 -fluorophenyl)sulfonyl)piperazin- 1 - yl)ethyl)carbamate (50 mg, 0.07 mmol) in DCM (2 mL) was added HCl / dioxane (2 mL, 4 M) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (35 mg, crude) and used without further purification. LCMS: [M+H]+=567.2.

[0261] N-( 2-( 4-( (4-((7-( l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)ethyl)-3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzamide

[0262] To a solution of 2-((4-((4-(2-aminoethyl)piperazin-l-yl)sulfonyl)-2- fluorophenyl)amino)-7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4H-pyrido[l,2-a]pyrimi din-4-one (35 mg, 0.06 mmol) in DCM (5 mL) were added DIEA (39 mg, 0.30 mmol) and perfluorophenyl 3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzoate (15 mg, 0.05 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give a residue which was purified by prep-ELPLC to give the title compound as a white solid (33 mg, 67%). 'H NMR (400 MHz, DMSO) 6 10.34 (s, 1H), 9.01 (d, J = 1.9 Hz, 1H), 8.46 (s, 2H), 8.29 (t, J= 5.6 Hz, 1H), 8.07 (dd, J= 9.2, 2.1 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.80 (dd, J= 8.6, 2.3 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.61 (dd, J= 10.2, 1.9 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.14 (d, = 8.8 Hz, 1H), 3.81 (s, 3H), 3.80 - 3.74 (m, 1H), 3.56 (t, J = 6.6 Hz, 2H), 3.36 - 3.33 (m, 1H), 3.31 - 3.28 (m, 1H), 3.03 - 2.88 (m, 4H), 2.70 - 2.62 (m, 2H), 2.56 - 2.51 (m, 4H), 2.48 - 2.43 (m, 2H), 2.18 (s, 3H), 1.12 - 1.05 (m, 2H), 1.04 - 0.97 (m, 2H). LCMS: [M+H]+=813.5.

[0263] Example 18: Synthesis of (2S,4R)-l-((S)-2-(l l-(4-((4-((7-(l-cvclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[l,2-a1pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)piperazin-l-yl)undecanamido -3,3-dimethylbutanoyl)-4-hydroxy-N-((S)- l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (dBPTF-24)

[0264] Methyl ll-(4-((4-( (7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1,2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)undecanoate

[0265] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (100 mg, 0.19 mmol) in DMF (2 mL) were added methyl 11-bromoundecanoate (53 mg, 0.19 mmol), KI (2 mg, 0.019 mmol), and NaHCCh (24 mg, 0.28 mmol) and the reaction mixture was stirred at 100°C for 1 h in a microwave. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NazSCL, and concentrated to give a residue which was purified by silica gel column eluted with 20% MeOH in DCM ether to give the title compound as a white solid (70 mg, 51%). LCMS: [M+H]+=722.2.

[0266] 11-( 4-( ( 4-( ( 7-( 1 -Cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[l, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)undecanoic acid

[0267] To a solution of methyl 1 l-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[ 1 ,2-a]pyrimidin-2-yl)amino)-3 -fluorophenyl)sulfonyl)piperazin- 1 - yl)undecanoate (70 mg, 0.097 mmol) in MeOH:THF:H2O (4:2: 1) (3 mL) was added LiOH (9 mg, 0.388 mmol) and the reaction mixture stirred for 4 h at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to give the title compound as a white solid (50 mg, crude) and used without further purification. LCMS: [M+H]+=706.2.

[0268] (2S, 4R)-l-( (S)-2-( 11-( 4-((4-( (7-( 1 -cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[ 1 ,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)undecanamido)-3, 3- dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidme-2- carboxamide

[0269] To a solution of 1 l-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)undecanoic acid (50 mg, 0.071 mmol), (2S,4R)-l-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (35 mg, 0.078 mmol), and DIEA (28 mg, 0.213 mmol) in DCM (5 mL) was added HATU (30 mg, 0.078 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SC>4 andconcentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of FA in water 5% to 95%) to give the title compound as a white solid (21 mg, 26%). 'H NMR (400 MHz, DMSO) 8 9.02 (d, J= 1.8 Hz, 1H), 8.98 (s, 1H), 8.47 (s, 2H), 8.36 (d, J= 7.8 Hz, 1H), 8.09 (dd, J = 9.2, 2.1 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.76 (d, J = 9.3 Hz, 1H), 7.61 (dd, J= 10.2, 1.9 Hz, 1H), 7.55 (dd, J= 8.5, 1.9 Hz, 1H), 7.45 - 7.43 (m, 1H), 7.43 - 7.40 (m, 2H), 7.39 - 7.35 (m, 2H), 5.08 (d, J = 3.5 Hz, 1H), 4.94 - 4.87 (m, 1H), 4.50 (d, J= 9.3 Hz, 1H), 4.41 (t, .7= 8.0 Hz, 1H), 4.27 (s, 1H), 3.81 - 3.73 (m, 1H), 3.63 - 3.54 (m, 2H), 2.95 (s, 4H), 2.45 (d, J = 2.5 Hz, 3H), 2.42 (s, 4H), 2.27 - 2.21 (m, 3H), 2.18 (s, 3H), 2.11 - 2.05 (m, 1H), 2.04 - 1.92 (m, 2H), 1.82 - 1.75 (m, 1H), 1.50 - 1.38 (m, 3H), 1.36 (d, J = 7.0 Hz, 4H), 1.23 (s, 2H), 1.20 (s, 9H), 1.13 - 1.08 (m, 2H), 1.02 - 0.98 (m, 2H), 0.94 - 0.90 (m, 9H). LCMS: [M+H]+=1134.4.

[0270] Example 19: Synthesis of N-(3-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl- 4-oxo-4H-pyridori,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)propyl)-3- (2,4-dioxotetrahvdropyrimidin-l(2H)-yl)-4-methoxybenzamide (dBPTF-25)

[0271] 3-(2,4-Dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybeHzoic acid

[0272] 3 -Amino-4-methoxybenzoic acid (5 g, 29.9 mmol) was suspended in acrylic acid (8.62 g, 119.6 mmol) and the resulting suspension was stirred at 100°C for 3 h and then allowed to cool to room temperature. Acetic acid (33 mL) was added and the reaction mixture was stirred at 100°C for 10 min. Urea (11 g, 185.4 mmol) was added and the reaction mixture was stirred at 120°C overnight. The reaction mixture was added into a solution of ice water (150 mL) and concentrated aqueous HC1 (37%, 10 mL) and was stirred overnight. The reaction mixture was filtered and the solids were washed with water and dried. The solids were triturated with HC1 (0.05 M, 300 mL), filtered, and the solids were washed with Zc / 7-butyl methyl ether to give the title compound as a brown solid (6.4 g, 84%). LCMS: [M+H]+265. 1.

[0273] Perfluorophenyl 3-(2, 4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzoate

[0274] A solution of 3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzoic acid (304 mg, 1.15 mmol), 2,3,4,5,6-pentafluorophenol (212 mg, 1.15 mmol), DMAP (329 mg, 1.73 mmol), and EDCI (14 mg, 0.12 mmol) in DCM (5 mL) was stirred at room temperature for 3 h. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SCU and concentrated to give a residue which was purified by silica gel column eluted with 60% ethyl acetate in PE to give the title compound as a white solid (299 mg, 60%). LCMS: [M+H]+=431.0.

[0275] N-(2-( 1, 3-dioxolan-2-yl)ethyl)-3-(2, 4-dioxotetrahydropyrimidin-l(2H)-yl)-4- methoxybenzamide

[0276] To a solution of 2-( 1,3 -di oxolan-2-yl)ethan- 1 -amine (38 mg, 0.32 mmol) in DCM (5 mL) was added DIEA (207 mg, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 min. Perfluorophenyl 3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4- methoxybenzoate (135 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4and concentrated to give a reisdue which was purified by silica gel column eluted with 10% MeOH in DCM to give the title compound as a white solid (100 mg, 86%). LCMS: [M+H]+=364.1.

[0277] 3-(2,4-Dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxy-N-(3-oxopropyl)benzamide

[0278] To a solution of N-(2-(l,3-dioxolan-2-yl)ethyl)-3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-4-m ethoxybenzamide (20 mg, 0.06 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture wasconcentrated under reduced pressure to give the title compound as a yellow solid (15 mg, crude) and used without further purification. LCMS: [M+H]1=320.1.

[0279] N-( 3-( 4-( (4-((7-(l -cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[l, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)propyl)-3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzaniide

[0280] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (21 mg, 0.04 mmol) in DCE (5 mL) was added DIEA (8 mg, 0.06 mmol) and the reaction mixture was stirred at room temperature for 30 min. 3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxy-N-(3- oxopropyl)benzamide (15 mg, 0.05 mmol) and STAB (25 mg, 0.12 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give a residue which was purified by prep-HPLC to give the title compound as a white solid (4 mg, 13%).!H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 9.O1 (d, J= 1.8 Hz, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.43 (s, 1H), 8.38 - 8.27 (m, 1H), 8.07 (dd, J = 9.2, 2.0 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.81 (dd, .7= 8.7, 2.1 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.64 - 7.59 (m, 1H), 7.59 - 7.53 (m, 1H), 7.41 (d, J= 9.2 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 3.84 (s, 3H), 3.81 - 3.72 (m, 1H), 3.57 (t, J = 6.4 Hz, 2H), 3.24 - 3.17 (m, 4H), 2.96 (s, 4H), 2.53 - 2.52 (m, 2H), 2.48 - 2.42 (m, 4H), 2.18 (s, 3H), 1.67 - 1.58 (m, 2H), 1.14 - 1.06 (m, 2H), 1.03 - 0.96 (m, 2H). LCMS: [M+H]+=827.6.

[0281] Example 20: Synthesis of (2S,4R)-l-((S)-2-(13-(4-((4-((7-(l-cyclopropyl-lH-pyrazol- 4-yl)-3-methyl-4-oxo-4H-pyrido[L2-a1pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)piperazin-l-yl)tridecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)- l-(4-(4-methylthiazol-5-yl)phenyl)ethyllpyrrolidine-2-carboxamide (dBPTF-26)

[0282] Methyl 13-(4-((4-((7-( 1 -cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1 ,2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)tridecanoate

[0283] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (120 mg, 0.23 mmol) in DMF (3 mL) were added methyl 13 -bromotridecanoate (70 mg, 0.23 mmol), KI (2 mg, 0.023 mmol), and NaHCOs (30 mg, 0.34 mmol) and the reaction mixture was stirred at 100°C for 1 h in a microwave. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, and concentrated to give a residue which was purified by silica gel column eluted with 20% MeOH in DCM ether to give the title compound as a white solid (110 mg, 64%). LCMS: [M+H]+=750.3.

[0284] 13-( 4-( ( 4-( (7-( 1 -Cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)tridecanoic acid

[0285] To a solution of methyl 13-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)tridecanoate(70 mg, 0.093 mmol) in MeOH:THF:H2O (4:2:1) (3 mL) was added LiOH (9 mg, 0.374 mmol) and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to give the title compound as a white solid (50 mg, crude) and used without further purification. LCMS: [M+H]+=736.2.

[0286] (2S, 4R)-l-( (S)-2-( 13-( 4-((4-( (7-( 1 -cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidm-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazm-l-yl)tridecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-melhylthiazol-5-yl)phenyl)ethyl)pyrrolidme-2- carboxamide

[0287] To a solution of 13-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)tridecanoic acid (50 mg, 0.068 mmol), (2S,4R)-l-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (33 mg, 0.074 mmol), and DIEA (26 mg, 0.204 mmol) in DCM (5 mL) was added HATU (28 mg, 0.074 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of FA in water 5% to 95%) to give the title compound as a white solid (15 mg, 18%).JH NMR (400 MHz, DMSO) 5 9.02 (d, J = 1.5 Hz, 1H), 8.98 (s, 1H), 8.47 (s, 2H), 8.40 - 8.33 (m, 1H), 8.12 - 8.06 (m, 1H), 8.05 - 7.98 (m, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.60 (d, J= 10.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.44 - 7.36 (m, 5H), 5.25 - 5.06 (m, 1H), 4.94 - 4.78 (m, 1H), 4.50 (d, J= 9.3 Hz, 1H), 4.41 (t, J= 8.0 Hz, 1H), 4.27 (s, 1H), 3.82 - 3.73 (m, 1H), 3.64 - 3.55 (m, 2H), 3.39 (s, 1H), 2.95 (s, 4H), 2.45 (s, 3H), 2.41 (s, 4H), 2.27 - 2.21 (m, 3H), 2.18 (s, 3H), 2.11 - 1.97 (m, 2H), 1.84 - 1.74 (m, 1H), 1.51 - 1.41 (m, 2H), 1.37 (d, J= 7.0 Hz, 4H), 1.20 (s, 16H), 1.12 - 1.07 (m, 2H), 1.03 - 0.97 (m, 2H), 0.92 (s, 9H). LCMS: [M+H]+=1162.4.

[0288] Example 21 : Synthesis of 6-(3-(4-((4-((7-(l-cvclopropyl-lH-Dyrazol-4-yl)-3-methyl-4- oxo-4H-pyrido[ 1,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)propyl)-2- (2,6-dioxopiperidin-3-yl)-6.7-dihydropyrrolo[3.4-f]isoindole-L3(2H,5H)-dione (dBPTF-27)

[0289] 2-( ( 4-( ( 4-(2-( 1, 3-Dioxolar)-2-yl)e1hyl)piperazin-l-yl)sulfonyl)-2-fluorophenyl)amir)o)- 7-( 1 -cyclopropyl- 1 H-pyrazol-4-yl)-3-methyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one

[0290] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (140 mg, 0.27 mmol) in DMF (3 mL) were added DIEA (139 mg, 1.08 mmol), 2-(2-bromoethyl)-l,3-dioxolane (147 mg, 0.81 mmol), and KI (49 mg) and the reaction mixture was stirred at 80°C for 1 h in a microwave. This reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated to give a residue which was purified by silica gel column eluted with 10% MeOH in DCM to give the title compound as a yellow solid (60 mg, 36%). LCMS: [M+H]+=624.0.

[0291] 3-( 4-( ( 4-((7-( 1 -Cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1, 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)propanal

[0292] A solution of 2-((4-((4-(2-(l,3-dioxolan-2-yl)ethyl)piperazin-l-yl)sulfonyl)-2- fluorophenyl)amino)-7-( 1 -cyclopropyl- lH-pyrazol-4-yl)-3 -methyl-4H-pyrido[ 1 ,2-a]pyrimidin-4- one (60 mg, 0.1 mmol) in formic acid (2 mL) was stirred at 50°C for 10 h. The reaction mixture was concentrated to give a residue which was purified by silica gel column eluted with 5% MeOH in DCM give the title compound as a white solid (15 mg, 26%). LCMS: [M+H]+=580.1.

[0293] 6-( 3-( 4-( 4-((7-( 1 -Cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1 , 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)propyl)-2-(2,6-dioxopiperidin- 3-yl)-6, 7-dihydropyrrolo[3, 4-f]isoindole-l,3(2H, 5H)-dione

[0294] To a solution of 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole- l,3(2H,5H)-dione (8 mg, 0.02 mmol) in DCM (5 mL) was added DIEA (5 mg, 0.04 mmol) and the reaction mixture was stirred at room temperature for 30 min. 3-(4-((4-((7-(l-cyclopropyl-lH- pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)piperazin-l-yl)propanal (15 mg, 0.02 mmol) and STAB (17 mg, 0.08 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give a residue which was purified by prep-HPLC to give the title compound as a white solid (3 mg, 7%). 'H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.01 (d, 1H), 8.53 - 8.48 (m, 1H), 8.48 - 8.46 (m, 1H), 8.13 - 8.13 (m, 1H), 8.10 - 8.06 (m, 1H), 8.05 - 7.97 (m, 2H), 7.74 (s, 2H), 7.66 - 7.60 (m, 1H), 7.58 - 7.54 (m, 1H), 7.42 (d, J= 9.1 Hz, 1H), 5.12 (dd, J= 12.9, 5.2 Hz, 1H), 3.91 (s, 4H), 3.80 - 3.73 (m, 1H), 3.05 - 2.91 (m, 4H), 2.87 (d, 12.4 Hz, 1H), 2.67 -2.62 (m, 2H), 2.58 - 2.54 (m, 1H), 2.47 - 2.43 (m, 3H), 2.40 - 2.32 (m, 2H), 2.19 (s, 3H), 2.08 - 1.97 (m, 2H), 1.71 - 1.54 (m, 2H), 1.52 - 1.40 (m, 1H), 1.15 - 1.05 (m, 2H), 1.05 - 0.94 (m, 2H). LCMS: [M+H]+=863.6.

[0295] Example 22: Synthesis of 6-(6-(4-((4-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-3-methyl-4- oxo-4H-pyridori,2-a1pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)hexyl)-2- (2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolor3,4-f]isoindole-l,3(2H,5H)-dione (dBPTF-28)

[0296] 6-(5-( 1, 3-Dioxolan-2-yl)pentyl)-2-(2, 6-dioxopiperidin-3-yl)-6, 7-dihydropyrrolo[3, 4- f]isoindole-l,3(2H, 5H)-dione

[0297] To a solution of 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole- l,3(2H,5H)-dione (100 mg, 0.33 mmol) in ACN (2 mL) were added DIEA (129 mg, 1.00 mmol), 2-(5-bromopentyl)-l,3-di oxolane (82.1 mg, 0.37 mmol), and KI (61.1 mg, 0.37 mmol) and the reaction mixture was stirred at 80°C for 1 h in a microwave. The reaction mixture was concentrated to give a residue which was purified by flash silica gel chromatography 10% MeOH in DCM to give the title compound as a yellow solid (78 mg, 35%). LCMS: [M+H]+=442.3.

[0298] 6-( 6-( 2, 6-Dioxopiperidin-3-yl)-5 , 7-dioxo-3, 5, 6, 7 -tetrahydropyrrole [ 3, 4-fjisoindol- 2( lH)-yl)hexanal

[0299] To a solution of 6-(5-(l,3-dioxolan-2-yl)pentyl)-2-(2,6-dioxopiperidin-3-yl)-6,7- dihydropyrrolo[3,4-f]isoindole-l,3(2H,5H)-dione (50 mg, 0.11 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (40 mg, crude) and used without further purification. LCMS: [M+H]+=398.1.

[0300] 6-( 6-( 4-( 4-((7-( 1 -Cyclopropyl- lH-pyrazol-4-yl)-3-methyl-4-oxo-4H-pyrido[ 1 , 2- a]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)piperazin-l-yl)hexyl)-2-(2,6-dioxopiperidin-3- yl)-6, 7-dihydropyrrolo[3, 4-f]isoindole-l, 3(2H, 5H)-dione

[0301] To a solution of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-2-((2-fluoro-4-(piperazin-l- ylsulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (53 mg, 0.10 mmol) in DCE (5 mL) was added DIEA (19 mg, 0.15 mmol) and the reaction mixture was stirred at room temperature for 30 min. 6-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindol-2(lH)-yl)hexanal (40 mg, 0.10 mmol) and STAB (64 mg, 0.30 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give a residue which was purified by prep-HPLC to give the title compound as a white solid (14 mg, 9%).TH NMR (400 MHz, DMSO) 1δ1.11 (s, 1H), 8.99 (d, J = 1.6 Hz, 1H), 8.51 - 8.42 (m, 2H), 8.10 - 8.05 (m, 1H), 8.04 - 7.98 (m, 2H), 7.72 (s, 2H), 7.61 (dd, J = 10.2, 1.8 Hz, 1H), 7.55 (d, J= 8.6 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 3.91 (s, 4H), 3.80 - 3.73 (m, 1H), 2.94 (d, J = 13.1 Hz, 4H), 2.91 - 2.83 (m, 1H), 2.68 - 2.58 (m, 3H), 2.58 - 2.53 (m, 1H), 2.44 (s, 4H), 2.28 (t, J = 6.2 Hz, 2H), 2.17 (s, 3H), 2.11 - 2.02 (m, 1H), 1.52 - 1.43 (m, 2H), 1.43 - 1.35 (m, 2H), 1.35 - 1.19 (m, 5H), 1.13 - 1.05 (m, 2H), 1.05 - 0.96 (m, 2H). LCMS: [M+H]+=905.4.

[0302] Example 23: Synthesis of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)-N-(2-(4-(2-((2-fluoro-4-((4-methylpiperazin-l-yl)sulfonyl)phenyl)amino)-3- methyl-4-oxo-4H-pyridori,2-a1pyrimidin-7-yl)-lH-pyrazol-l-yl)ethyl)pentanamide (dBPTF-29)

[0303] The title compound was prepared following a similar procedure described in the examples above. LCMS: [M+H]+=965.5.

[0304] Example 24: Synthesis of 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-l-yl)-N-(2-(4-(2-((2-fluoro-4-((4-methylpiperazin-l-yl)sulfonyl)phenyl)amino)-3- methyl-4-oxo-4H-pyrido[12-a1pyrimidin-7-yl)-lH-pyrazol-l-yl)ethyl)heptanamide (dBPTF-30)

[0305] The title compound was prepared following a similar procedure described in the examples above. LCMS: [M+H]+=993.6.

[0306] Example 25: Synthesis of 2-(4-(4-((2,6-di oxopiperi din-3 -vPamino)-2- fluorophenyPpiperazin- 1 -yl)-N-(2-(4-(2-((2-fluoro-4-((4-methylpiperazin- 1 - yPsulfonyPphenyPamino)-3-methyl-4-oxo-4H-pyrido[E2-a1pyrimidin-7-yP-lH-pyrazol-l- yPethyl)acetamide (dBPTF-31)

[0307] The title compound was prepared following a similar procedure described in the examples above. LCMS: [M+H]+=887.5.

[0308] Example 26: Synthesis of l l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yP-N-(2-(4-(2-((2-fluoro-4-((4-methylpiperazin-l-y1)sulfonyl)phenyPamino)-3-methyl-4-oxo-4H-Pyrido[ 1,2-a1pyrimidin-7-yl)-lH-pyrazol-l-yl)ethyl)undec-10-vnamide (dBPTF-32)

[0311] The title compound was prepared following a similar procedure described in the examples above. LCMS: [M+H] =1123.6.

[0312] Example 28: Synthesis of (2S,4R)-N-(2-((7-((2-(4-(2-((2-fluoro-4-((4-methylpiperazin- l-yl)sulfonyl)phenyl)amino)-3-methyl-4-oxo-4H-pyrido[l,2-a1pyrimidin-7-yl)-lH-pyrazol-l- yl)ethyl)amino)-7-oxoheptyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-l-((S)-2-(1- fluorocyclopropane-l-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide (dBPTF-34)

[0313] The title compound was prepared following a similar procedure described in the examples above. LCMS: [M+H]+=1183.8.

[0314] Example 29: Synthesis of (2S,4R)-N-(2-((7-((2-(4-(2-((2-fluoro-4-((4-methylpiperazin- l-yl)sulfonyl)phenyl)amino)-3-methyl-4-oxo-4H-pyrido[l,2-a1pyrimidin-7-yl)-lH-pyrazol-l- yl)ethyl)amino')-7-oxoheptyl)oxy)-4-(4-methylthiazol-5-yl')benzyl')-l-((S)-2-(l- fluorocvclopropane-l-carboxamido)-3,3-dimethylbutanoyl)-4-hvdroxypyrrolidine-2- carboxamide (dBPTF-38)

[0315] 2-(2,6-Dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l, 3-dione

[0316] To a solution of Zc' / 'Z-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazine-l -carboxylate (200 mg, 0.45 mmol) in DCM (2 mL) was added 4M HC1 in dioxane (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (200 mg, crude) and used without a further purification. LCMS: [M+H]+=343.1.

[0317] 5-( 4-( 3-(l, 3-Dioxolan-2-yl)propyl)piperazin-l-yl)-2-( 2, 6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0318] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l, 3-dione (200 mg, 0.58 mmol) in MeCN (20 mL) were added 2-(3-bromopropyl)-l,3-dioxolane (226 mg, 1.17 mmol), K2CO3 (242 mg, 1.75 mmol), and KI (106 mg, 0.64 mmol) and the reaction mixture was stirred at 75°C for 3 h. The reaction mixture was diluted with water (100 mL) and extractedwith ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated to give a residue which was purified by silica gel column eluted with 5% MeOH in DCM to give the title compound as a yellow solid (200 mg, 75%). LCMS: [M+H]+=457.3.[00319J 4-(4-(2-(2,6-Dioxopiperidm-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)butanal

[0320] To a solution of 5-(4-(3-(l,3-dioxolan-2-yl)propyl)piperazin-l-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione (50 mg, 0.11 mmol) in DCM (1.5 mL) was added TFA (1 .5 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (400 mg, crude) and used without a further purification. LCMS: [M+H]+=413.1.

[0321] 7-( l-(Azetidin-3-yl)-l H-pyrazol-4-yl)-2-((2-fhioro-4-((4-methylpiperazin-l- yl)sulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one

[0322] To a solution of ter / -butyl 3-(4-(2-((2-fluoro-4-((4-methylpiperazin-l- yl)sulfonyl)phenyl)amino)-3-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-7-yl)-lH-pyrazol-l- yl)azetidine-l -carboxylate (45 mg, 0.069 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (45 mg, crude) and use without a further purification. LCMS: [M+H]+=553.1.

[0323] 2-(2, 6-Dioxopiperidin-3-yl)-5-( 4-( 4-( 3-( 4-(2-( ( 2-fluoro-4-( ( 4-methylpiperazin-I- yl)sulfonyl)phenyl)amino)-3-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-7-yl)-lH-pyrazol-l- yl)azetidin- 1 -yl)butyl)piperazin-l-yl)isoindolme- 1,3-dione

[0324] To a solution of 7-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-2-((2-fluoro-4-((4- methylpiperazin- 1 -yl)sulfonyl)phenyl)amino)-3-methyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one (31 mg, 0.048 mmol) and 4-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)butanal (20 mg, 0.048 mmol) in DCE (6 mL) was added STAB (41.16 mg, 0.19 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SC>4, and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1 % of NH3.H2O in water 5% to 95%) to give the title compound as a yellow solid (4 mg, 7%).1H NMR (400 MHz, DMSO) 11.08 (s, 1δH), 9.07 - 9.03 (m, 1H),8.60 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 8.13 - 8.08 (m, 2H), 8.03 - 7.97 (m, 1H), 7.67 (d, J= 8.5 Hz, 1H), 7.62 (dd, J= 10.2, 1.7 Hz, 1H), 7.55 (dd, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.34 (s, 1H), 7.26 (dd, J= 8.6 Hz, 1H), 5.10 - 5.00 (m, 2H), 3.85 - 3.76 (m, 2H), 3.51 - 3.42 (m, 9H), 2.97 (s, 4H), 2.91 - 2.82 (m, 1H), 2.64 - 2.54 (m, 4H), 2.52 (s, 1H), 2.42 - 2.32 (m, 6H), 2.18 (d, J = 10.1 Hz, 6H), 2.06 - 1.95 (m, 1H), 1.56 - 1.45 (m, 2H), 1.43 - 1.34 (m, 2H). LCMS: [M+H]+=949.3.

[0325] Example 30: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(8-(3-(4-(2-((2-fluoro-4-((4- methylpiperazin-l -yl)sulfonyl)phenyl)amino)-3-methyl-4-oxo-4H-pyrido[1,2-a1pyrimidin-7-yl)-1 H-pyrazol- 1 -yEazetidin- 1 -yl)octy Dpiperazin- 1 -yl)i soindoline- 1 , 3 -di one (dBPTF -39)

[0326] l-(( 3-Fluoro-4-nitrophenyl)sulfonyl)-4-methylpiperazine

[0327] To a solution of 1 -methylpiperazine (836 mg, 8.34 mmol) in DCM (20 mL) were added TEA (2.5 g, 25.04 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (2 g, 8.34 mmol) at 0°C and the reaction mixture was stirred at 0°C for 0.3 h. The reaction mixture was concentrated to give a residue which was purified by silica gel column eluted with 40% MeOH in DCM to give the title compound as a yellow solid (2.3 g, 91%). LCMS: [M+H]+=304.0.

[0328] 2-Fluoro-4-( ( 4-methylpiperazin-l-yl)sulfonyl)aniline

[0329] To a solution of l -((3-fluoro-4-nitrophenyl)sulfonyl)-4-methylpiperazine (2.3 g, 7.59 mmol) in EtOH (20 mL) was added Pd / C (230 mg) and hydrogen was passed through and the reaction mixture was stirred at room temperature 3 h. The reaction mixture was filtered through a pad of C6lite® and washed with DCM. The filtrate was concentrated under reduced pressue to give the title compound as a yellow solid (2 g, crude). LCMS: [M+H]+=274.0.

[0330] tert-Butyl 3-(4-(2-chloro-3-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidm-7-yl)-lH- pyrazol-l-yl)azetidine-l -carboxylate

[0331] To a solution of 7-bromo-2-chloro-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (200 mg, 0.732 mmol) in dioxane (20 mL) and H2O (5 mL) were added / c / 7-butyl 3-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)azetidine-l-carboxylate (255 mg, 0.73 mmol), Na2CC>3 (155 mg, 1.46 mmol), and Pd(dppf)Ch (53 mg, 0.073 mmol) and the reaction mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated to give a residue which was purified by silica gel column eluted with 60% EA in PE to give the title compound as a yellow solid (200 mg, 66%). LCMS: [M+H]+=360.0.

[0332] tert-Butyl 3-(4-(2-((2-fluoro-4-((4-methylpiperazin-l-yl)sulfonyl)phenyl)amino)-3- methyl-4-oxo-4H-pyrido[l, 2 -a Jpyrimidin- 7 -yl)-lH-pyrazol-l-yl)azetidme-l -carboxylate

[0333] To a solution of Zc / 7-butyl 3-(4-(2-chloro-3-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin- 7-yl)-lH-pyrazol-l-yl)azetidine-l-carboxylate (200 mg, 0.48 mmol) in toluene (1.5 mL) were added 2-fluoro-4-((4-methylpiperazin-l-yl)sulfonyl)aniline (157 mg, 0.57 mmol), RuPhospdG.3 (40 mg, 0.048 mmol), and CS2CO3 (314 mg, 0.96 mmol) and the reaction mixture was stirred at 110°C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried overNa2SO4, and concentrated to give a residue which was purified by silica gel column eluted with 5% MeOH in DCM to give the title compound as a pink solid (200 mg, 60%). LCMS: [M+H] =653.6.

[0334] 7-( 1 -(Azetidin-3-yl)-lH-pyrazol-4-yl)-2-( (2-fluoro-4-( ( 4-methylpiperazin-l- yl)sulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one

[0335] To a solution of / / 'Z-butyl 3-(4-(2-((2-fluoro-4-((4-methylpiperazin-l- yl)sulfonyl)phenyl)amino)-3 -methyl-4-oxo-4H-pyrido[ 1 ,2-a]pyrimidin-7-yl)- IH-pyrazol- 1 - yl)azetidine-l -carboxylate (45 mg, 0.069 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (45 mg, crude) and used without further purification. LCMS: [M+H]+=553.5.

[0336] 2-(2, 6-Dioxopiperidin-3-yl)-4-( 4-( 8-( 3-( 4-(2-( ( 2-fluoro-4-( 4-methylpiperazin-l- yl)sulfonyl)phenyl)ammo)-3-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-7-yl)-lH-pyrazol-l- yl)azetidin-l-yl)octyl)piperazin-l-yl)isomdoline-l, 3-dione

[0337] To a solution of 7-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-2-((2-fluoro-4-((4- methylpiperazin-l-yl)sulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (40 mg, 0.072 mmol) and 8-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)piperazin-l- yl)octanal (30 mg, 0.072 mmol) in DCE (6 mL) was added STAB (61 mg, 0.28 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH3.H2O in water 5% to 95%) to give the title compound as a yellow solid (5 mg, 7%). ’H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.05 (d, J = 1.8 Hz, 1H), 8.60 (s, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 8.10 (dd, J = 9.2, 2.0 Hz, 1H), 8.02 - 7.95 (m, 1H), 7.73 - 7.67 (m, 1H), 7.62 (dd, J = 10.2, 1.9 Hz, 1H), 7.56 (dd, J = 8.5, 1.8 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.39 - 7.32 (m, 2H), 5.19 - 5.05 (m, 2H), 3.91 (d, J = 106.8 Hz, 4H), 2.97 (s, 4H), 2.93 - 2.68 (m, 6H), 2.59 (d, J= 18.4 Hz, 2H), 2.53 (d, J= 5.1 Hz, 3H), 2.41 (s, 7H), 2.19 (s, 6H), 2.06 - 1.98 (m, 1H), 1.51 (s, 2H), 1.40 (s, 2H), 1.27 (s, 9H). LCMS: [M+H]+=1005.5.

[0338] Example 31: Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(3-(4-(2-((2-fluoro-4-((4- methylpiperazin-l-yl)sulfonyl)phenyl)amino)-3-methyl-4-oxo-4H-pyridori,2-a1pyrimidin-7-yl)- IH-pyrazol- 1 -yl)azetidin- 1 -yl)hexyl)piperazin- 1 -yl)isoindoline- 1,3 -dione (dBPTF-40)

[0339] 5-(4-(5-(l,3-Dioxolan-2-yl)pentyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3- yl) isoindoline-1, 3-dione

[0340] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l, 3-dione (200 mg, 0.58 mmol) in ACN (20 mL) were added 2-(5-bromopentyl)-l,3-dioxolane (260 mg, 1.17 mmol), DIEA (301 mg, 2.34 mmol), and KI (106 mg, 0.64 mmol) and the reaction mixture was stirred at 80°C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated to give a residue which was purified by silica gel column eluted with 3% MeOHin DCM to give the title compound as a yellow solid (160 mg, 87%). LCMS: [M+H]1=485.3.

[0341] 6-(4-(2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolm-5-yl)piperazin-l-yl)hexancil

[0342] To a solution of 5-(4-(5-(l,3-dioxolan-2-yl)pentyl)piperazin-l-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione (50 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (400 mg, crude) and used without further purification. LCMS: [M+H]+=441.1.

[0343] 2-( 2, 6-Dioxopiperidin-3-yl)-5-( 4-( 6-( 3-(4-( 2-( ( 2-fluoro-4-( 74-methylpiperazin-l- yl)sulfonyl)phenyl)amino)-3-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-7-yl)-lH-pyrazol-l- yl)azetidin-l-yl)hexyl)piperazin-l-yl)isoindoline-l, 3-dione

[0344] To a solution of 7-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-2-((2-fluoro-4-((4- methylpiperazin-l-yl)sulfonyl)phenyl)amino)-3-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (40 mg, 0.072 mmol) and 6-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)hexanal (31 mg, 0.072 mmol) in DCE (6 mL) was added STAB (61.44 mg, 0.29 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated to give a residue which was purified by prep-HPLC (acetonitrile with 0.1% of NH3.H2O in water 5% to 95%) to give the title compound as a yellow solid (5 mg, 7%). ’H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.03 (d, J= 1.7 Hz, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 8.15 (s, 1H), 8.12 - 8.07 (m, 2H), 8.03 - 7.97 (m, 1H), 7.68 - 7.64 (m, 1H), 7.61 (dd, J= 10.2, 1.9 Hz, 1H), 7.55 (dd, J = 8.5, 1.8 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.32 (d, J= 1.8 Hz, 1H), 7.24 (dd, J= 8.6, 2.0 Hz, 1H), 5.10 - 4.94 (m, 2H), 3.76 - 3.68 (m, 2H), 3.41 (d, J= 5.3 Hz, 6H), 3.03 - 2.82 (m, 5H), 2.58 (dd, J= 19.0, 4.5 Hz, 2H), 2.53 - 2.51 (m, 2H), 2.49 - 2.46 (m, 4H), 2.41 - 2.36 (m, 4H), 2.34 - 2.28 (m, 2H), 2.17 (d, J = 10.9 Hz, 6H), 2.06 - 1.95 (m, 1H), 1.52 - 1.41 (m, 2H), 1.32 (s, 6H). LCMS: [M+H]+=977.3.

[0345] Example 32: Biological Data

[0346] Cell Viability Assays

[0347] The C6llTiter-Glo® assay was performed as per the manufacturer's instructions (Promega™). Briefly, 1,000 cells per well were plated into 96-well plates and treated with a range of compound concentrations. C6ll viability was measured at the noted time points based onluminescence by the C6llTiter-Glo® assay (Promega™) and read on an EnVision® 2104 (PerkinElmer) according to the manufacturer's protocol.

[0348] Immunoblots

[0349] C6lls growing in culture were lysed for whole-cell lysates. Nuclear lysates were prepared using the NE-PER™ nuclear lysate kit (Thermo Fisher Scientific™) according to the manufacturer's protocol. Chromatin lysates were prepared with the total histone extraction kit (Epigentek). Briefly, equivalent amounts of protein were resolved by Western blotting using 4% to 12% Bis-Tris NuPAGE™ gels (Thermo Fisher Scientific™) prior to transfer and immunoblotting using primary antibodies to BPTF, PARP, cleaved PARP, P-actin, GSPT1, and IKZF1. Secondary antibodies were IRDye® conjugated antibodies (Licor).

[0350] BPTF is member of a chromatic remodeling complex (NURF) and binds to chromatin to add covalent modifications to histone proteins to impact downstream transcription. Compounds of formula I or II (e.g. NVS-BPTF-lB / dBPTF-2) lift BPTF off of the histone, whereas NVS- BPTF-1, does not. BPTF has two points of contact with histones and NVS-BPTF-1 can only target one of them while the compounds of formula I or II can target both simultaneously in a short period of time (FIG. 10).

[0351] While complete BPTF removal from the histone was achieved by the 8h time point, the presence of BPTF in the nucleus at the 24h time point indicated that it was not completely degraded. Lifting the entire protein off of DNA interrupted disease promoting functions, even without complete protein degradation. BPTF is part of the NURF chromatin remodeling complex and is the member through which the entire complex interacts with DNA. Complete removal of BPTF from the histone, destabilizes NURF as a whole (FIG. 11 A-FIG. 1 IB).

[0352] Colony Formation Assays

[0353] Colony assays were performed by replating cells at 500 cells per well in 6-well dishes and grown in regular growth media for 10 days before 100% methanol fixation, 0.05% crystal violet staining, and subsequent quantitation.

[0354] Lentiviral Infection (shRNA)

[0355] shRNAs targeting BPTF were ordered as bacterial stocks and transformed into competent E. Coll cells. Bacterial DNA was collected and isolated to create lentivirus particles produced in 293T cells. Plasmids were transfected using Lipofectamine™ 2000 (Invitrogen™) along with pMD2.G (Addgene_12259) and psPAX2 (Addgene_12260) into 293T cells to generateviral particles by standard methodologies. Stable Cas9 expressing RH4 cells were infected with BPTF lentivirus particles and selected with puromyocin. Knockdown efficiency was established by immunoblotting.

[0356] Animal Study

[0357] For tumor studies, 6-8-week-old female NSG mice (The Jackson Laboratory) were subcutaneously implanted with 2 x 106 RH4 cells in 50% Matrigel / PBS. Mice were assigned to two groups: vehicle (n = 15) or dBPTF-9 (50 mg / kg / day; n = 15) by i.p. injection. Treatment with small -molecule inhibitors was initiated once tumors engrafted and reached 100 mm3. Mice were treated until endpoint and followed for survival. Tumors were measured by calipers and mice were weighed every three days. Animals were euthanized according to institutional guidelines when tumors reached 2,000 mm in length or width or if animals became moribund.

[0358] Example 33: BPTF Assay

[0359] The cell line of Hela was engineered with HiBit system to report the protein level change. The cell line was treated with the compound and the fluorescence signal was measured at the time point described (6 h or 20 h). The singal reduction at dose responsed manner was observed and used for DCso measure.

[0360] All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All these publications (including any specific portions thereof that are referenced) are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated as being incorporated by reference.

[0361] Although the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present disclosure as defined by the appended claims.

Claims

What is claimed is:

1. A compound having a structure represented by formula I or II:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: the degron binds cereblon (CRBN) or von Hippel Lindau (VHL) tumor suppressor; and the linker represents a moiety that covalently connects the degron and the nitrogen atom.

2. The compound of claim 1, wherein the degron is represented by a structure selected from the group comprising of:wherein,X is CH2or C(O);Ri is absent, CH2, C=C, NH, O, or 5- to 11-membered mono- or bi-cyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S;X’ is absent or C(O);Y is N or CH; andR2 is an optional substituent.

3. The compound of claim 2, wherein the degron is represented by formula DI.

4. The compound of claim 3, wherein X is CH2.

5. The compound of claim 3, wherein X is C(O).

6. The compound of claim 2, wherein the degron is of formula D2.

7. The the compound of claim 6, wherein X’ is absent and R2 is fluoro.

8. The compound of claim 2, wherein Ri is absent or NH.

9. The compound of claim 2, wherein Ri is 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S.

10. The compound of claim 9, wherein Ri is piperazinyl.

11. The compound of claim 2, wherein Ri is a 9-membered bi-cyclic heterocyclyl containing1 or 2 heteroatoms independently selected from N, O, and S.

12. The compound of claim 11, wherein Ri is 2,7-diazaspiro[3.5]nonane.

13. The compound of claim 2, wherein the degron is represented by formula D4.

14. The compound of claim 13, wherein R2 is methoxy.

15. The compound of claim 2, wherein the degron is represented by formula D5.

16. The compound of claim 1, wherein the degron is represented by D6:(D6) or stereoisomer thereof,wherein: R3is hydrogen or optionally substituted C1-C3alkyl, or R3and R4, together with the carbon atom to which they are attached, form cyclopropyl;R s hydrogen, methyl, or;R5is C(O)CR6R7RS,or; R6and R7are hydrogen, or R6and R7, together with the carbon atom to which they are attached, form cyclopropyl;R8is hydrogen, fluoro, cyano, orNMe?; andY is hydrogen, .or_whereinis a bond between the Degron and the Linker, provided that there is only one bond between the Degron and the Linker.

17. The compound of claim 16, wherein the degron is represented by any one of the following structures:stereoisomer thereof, wherein Y is O, NH, or CH2.

18. The compound of claim 1, wherein the linker is an alkylene chain which may be interrupted by, and / or terminate at either or both termini in at least one of -O-, -S-, -N(R')-, -C=C~, -C(O)-, -C(0)0- -0C(0)-, -0C(0)0- -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, - C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O- -OC(O)N(R')-, - C(NR')-, -N(R')C(NR')-, -C(NR')N(R')- -N(R')C(NR')N(R')-, -OB(Me)O- -S(0)2- -0S(0)- , -S(0)0- -S(0)-, -0S(0)2- -S(0)20- -N(R')S(0)2- -S(O)2N(R')- -N(R')S(O)-, - S(O)N(R')-, -N(R')S(O)2N(R')- -N(R')S(O)N(R')-, optionally substituted Cs-Ci2carbocyclene, optionally substituted 3- to 12-membered heterocyclene, optionally substituted 5- to 12-membered heteroarylene or any combination thereof, wherein R' is H or Ci-C6alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.

19. The compound of claim 18, wherein the linker is an alkylene chain having 3-11 alkylene units.

21. The compound of claim 1, which isIlla pharmaceutically acceptable salt or stereoisomer thereof.

22. A compound which is23. A pharmaceutical composition, comprising the compound of any one of claims 1-21, or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

24. The method of treating cancer that involves aberrant activity of Bromodomain PHD Finger Transcription Factor (BPTF), comprising administering to a subject in need thereof the compound of any one of claims 1-21, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 23.

25. The method of claim 24, wherein the cancer is a sarcoma.

26. The method of claim 25, wherein the sarcoma is rhabdomyosarcoma.

27. The method of claim 24, wherein the cancer is breast cancer, lung cancer, or lymphoma.

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