Inhibitors and protein degraders of CDK9 and methods thereof

Abstract

This present disclosure is directed to novel compounds of Formulae I, II, and III, the preparation and use thereof.

Description

PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0INHIBITORS AND PROTEIN DEGRADERS OF CDK9 AND METHODS THEREOF byJia ZhouMichael WangYu XueVivian Changying Jiang

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U. S. Application No. 63 / 737,691, filed on December 21, 2024, the contents of which are hereby incorporated by reference in its entirety.

[0003] FIELD OF THE INVENTION

[0004] The field of the invention relates generally to target-selective inhibitors for the treatment of human diseases. More specifically, the invention relates to molecules targeting the inhibition or degradation of CDK9.

[0005] BACKGROUND

[0006] This background information is provided for the purpose of making information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the information disclosed herein constitutes prior art against the present invention.

[0007] Mantle cell lymphoma (MCL) treatment has achieved great successes with BTK inhibitors (BTKi, such as ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib) and antiCD 19 chimeric antigen receptor (CAR)-T cell therapy, but the gains for those who respond to these therapies are generally followed by the development of acquired resistance and a worse prognosis. The development of novel therapies is therefore urgently needed to prevent or overcome BTKi and CAR-T cell therapy resistance. Recent single-cell RNA-seq-based studies revealed that MYC signatures are progressively enriched in MCL patients with BTKi-resistance and BTKi-CAR-T cell therapy dual resistance; and CDK9 (cyclin-dependent kinasePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 9), a gate keeper of transcription elongation, is upregulated in BTKi-CAR-T cell therapy dual resistant MCL cells. AZD4573 and enitociclib are two highly potent and selective CDK9 inhibitors under preclinical and early clinical development. Preclinical studies demonstrated that targeting CDK9 with AZD4573 and enitociclib are promising in overcoming BTKi resistance and BTKi-CAR-T cell therapy dual resistance in preclinical MCL models. To further improve drug potency or bioavailability, a list of CDK9 inhibitors and PROTAC (PROteolysis TArgeting Chimera)-based degraders was generated using analogs of AZD4573 or enitociclib. Furthermore, to complement compounds inhibiting CDK9 kinase activity, a series of novel chemical compounds were designed, generated, and optimized that can inhibit or degrade CDK9. The top inhibitors and degraders demonstrated promising in vitro and in vivo efficacy in cancer cell line-derived and patient-derived model systems.

[0008] BRIEF DESCRIPTION OF THE FIGURES

[0009] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0010] FIGS. 1A-1B. Figure 1 displays in vitro efficacy of new compounds YX04582, YX4822, YX0526, and YX0798 in MCL cell lines. Figure 1A displays sell viability assays showing the in vitro efficacy of selected new CDK9 inhibitors (YX04582, YX4822, YX0526, and YX0798) in 8 MCL cell lines at 72 hours post treatment. Figure IB displays the IC50 values, calculated based on the cell viability assays.

[0011] FIGS.2A-2B. Figure 2 displays data showing that YX0798 is a highly selective CDK9 inhibitor with greater binding affinity than AZD4573. Figures 2A-2B displays the kinome profiling of YX0798 at 100 nM identified 13 hits across a 468-kinase panel. These hits are highlighted with red circles in the kinase dendrogram (Figure 2A) and in the bar graph (FigurePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 2B, left panel). YX0798 had greater binding affinity (Kd) for CDK9 than AZD4573 did (Figure 2B, right panel).

[0012] FIGS. 3A-3B. Figure 3 displays CDK9i YX0798 potently inhibits cell viability and CDK9 activity in MCL. Figure 3 A displays data showing that YX0798 selectively inhibits cell viability of MCL Cells (left panel) but not healthy PBMCs (right panel). Figure 3B displays data showing that YX0798 effectively inhibited CDK9 activity and downstream signaling and induced apoptosis in JeKo-1, Mino and Z138 cells.

[0013] FIGS. 4A-4B. Figure 4 displays data showing that YX0798 shows oral bioavailability in rats. Figure 4A displays data showing that YX0798 is stable in mouse, rat, and human, as determined by an in vitro liver microsome stability assay (top panel). YX0798 was found to have high cell permeability (bottom panel). Heart medications Nadolol, Propranolol, and Digoxin served as controls. Figure 4B displays the intravenous (IV) and oral (PO) bioavailability of YX0798 in rats (right panel). A comparison between YX0798 and AZD4573 is shown (right panel).

[0014] FIGS. 5A-5B. Figure 5 displays data showing that YX0798 is effective in inhibiting the tumor growth ex vivo and in vivo in primary patient samples and patient-derived models. Figure 5A displays data from one primary sample, derived from a MCL patient who relapsed after pirtobrutinib treatment, which was validated to be resistant to BTKi but remained sensitive to AZD4573, enitociclib, and YX0798 (top panel). CDK9 inhibition by AZD4573 or YX0798, but not BTK inhibition by pirtobrutinib or acalabrutinib, greatly inhibited the growth of patient-derived organoid models (bottom panel). Figure 5B displays patient-derived xenograft models, established from a patient with sequential relapse to ibrutinib and CAR-T therapies. YX0798 treatment significantly inhibited the PDX growth (top panel) and prolonged mouse survival with better efficacy than AZD4573 (bottom panel), ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0015] FIGS. 6A-6B. Figure 6 displays the in vitro efficacy of CDK9 degraders YX05492, YX05672, YX0601, YX0597, YX0766, YX0807, YX1011 and YX1457 in MCL cell lines. Figure 6A displays cell viability assays showing the in vitro efficacy of selected new CDK9 degraders (YX05672, YX0601, YX05492, YX0597, YX0766, YX0807, and YX1011) in 8 MCL cell lines at 72 hours post treatment. Figure 6B displays the IC50 values, calculated based on the cell viability assays.

[0016] FIGS. 7A-7B. Figure 7 displays the in vivo efficacy of CDK9 degraders YX0601 in MCL PDX models. Figures 7A-7B display patient-derived xenograft models, established in NSG mice using primary MCL cells from a patient with ibrutinib-venetoclax resistance and treated with vehicle, AZD4573 (15+15 mg / kg, 2h apart, IP, QW), or YX0601 (10+10 mg / kg, 2h apart IP, QW). Tumor growth was monitored (Figure 7A) and tumors were dissected and weighed at the end of the experiment (Figure 7B). *, p<0.05; **, P<0.01; ***, P<0.001; ****, P0.0001.

[0017] FIGS. 8A-8B. Figure 8 displays data showing that CDK9-PROTACs YX0597, YX0807, and YX0965 induce robust apoptosis and CDK9 degradation. Figure 8A displays cell apoptosis assays showing the potency of AZD4573, YX0597, and YX0807 at 10 and 20 nM for inducing apoptosis (top panel) and Weston blots showing CDK9 degradation induced by YX0597 and YX0807 at 24 hours post treatment (bottom panel). Figure 8B displays cell apoptosis assays showing the potency of YX0965 and YX1009 at 25 and 50 nM for inducing apoptosis (top panel) and Weston blots showing CDK9 degradation induced by YX0965 and YX1009 at 25 and 50 nM at 24 hours post treatment (bottom panel), ns, non-significant; *, p<0.05; **, PO. Ol; ***, P0.001; ****, P0.0001.

[0018] FIGS. 9A-9B. Figure 9 displays data showing that CDK9-PROTAC YX0597 demonstrate in vivo efficacy in inhibiting the tumor growth of MCL CDX and PDX models. Figure 9A displays cell line-derived xenograft (CDX) models, established using JeKo-1 cellsPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 in immunodeficient NSG mice and treated with vehicle, AZD4573 (15+15 mg / kg, 2h apart, IP, QW), or YX0597 (1 mg / kg, IP, QD). Tumor growth (top panel) and mouse survival (bottom panel) were monitored. Figure 9B displays patient-derived xenograft (PDX) models, established using primary MCL cells from a patient with failure to ibrutinib and CD 19 CAR-T cell therapy in immunodeficient NSG mice and treated with vehicle, AZD4573 (15+15 mg / kg, 2h apart, IP, QW), or YX0597 (1 mg / kg, IP, QD). Tumor growth (top panel) and mouse survival (bottom panel) were monitored. *, p<0.05; **, P<0.01; ***, P<0.001; ****, PO. OOOl.

[0019] FIGS. 10A-10B. Figure 10 displays the in vitro efficacy of CDK9 inhibitors YX10522 and YX10941 in MCL cell lines. Figure 10A displays cell viability assays showing YX10522 has better potency than enitociclib in JeKo-1 and JeKo BTK KD cells at 72 hours post treatment. IC50 values shown in right. Figure 10B displays cell viability assays showing YX10941 has better potency than enitociclib in JeKo-1, JeKo BTK KD, Mino, Mino-R and Z138 cells at 72 hours post treatment. IC50 values shown in the table.

[0020] FIGS. 11A-11B. Figure 11 displays the in vitro efficacy of CDK9 degraders in MCL cells. Figure 11A displays cell viability assays showing the in vitro potency of CRBN-based CDK9 degraders YX0832, YX0849 and YX0850 in Z 138 cells at 72 hours post treatment with IC50 values shown in right (left panel) as well as PL-based CDK9 degraders YX0965, YX0969, YX0980, YX0999, YX1003 and YX1009 in JeKo-1 cells at 72 hours post treatment with IC50 values shown in right (right panel). Figure 11B displays CRBN-based CDK9 degraders YX0832, YX0932, YX10503, YX1057, YX1110, YX11242 and YX1148 in Z138 cells at 72 hours post treatment with IC50 values summarized in the bar graph.

[0021] FIGS. 12A-12B. Figure 12 displays data showing that CDK9-PROTACs YX0832, YX0849, YX0965 and YX1009 induce robust apoptosis and CDK9 degradation. Figure 12A displays cell apoptosis assays showing the potency of CRBN-based CDK9-PROTACs (YX0832 and YX0849) at 25 and 50 nM for inducing apoptosis (top panel) and Weston blotsPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 showing CDK9 degradation induced by YX0832 and YX0849 at 24 hours post treatment (bottom panel). Figure 12B displays cell apoptosis assays showing the potency of PL-based CDK9-PR0TACs (YX0965 and YX1009) at 25 and 50 nM for inducing apoptosis (top panel) and Weston blots showing CDK9 degradation induced by YX0965 and YX1009 at 24 hours post treatment (bottom panel), ns, non-significant; *, p<0.05; **, P<0.01; ***, P<0.001; ****, PO. OOOl.

[0022] FIGS. 13A-13B. Figure 13 displays data showing that CDK9-PROTACs YX10503 and YX1057 induce robust apoptosis and CDK9 degradation. Figure 13 A displays cell apoptosis assays showing the potency of CRBN-based CDK9-PROTACs (YX10503 and YX1057) at 10 and 20 nM for inducing apoptosis at 24 and 48 hours post treatment. Figure 13B displays Weston blots showing selective degradation of CDK9, but not other CDKS, upon treatment with YX10503 and YX1057 (25 and 50 nM) at 16 hours post treatment, ns, non-significant; *, p<0.05; **, PO. Ol; ***, P0.001; ****, PO. OOOl.

[0023] FIGS. 14A-14B. Figure 14 displays data showing that CDK9-PROTACs YX11242 and YX1148 induce robust apoptosis and CDK9 degradation. Figure 14A displays cell apoptosis assays showing the potency of CRBN-based CDK9-PROTACs (YX11242 and YX1148) at 50 nM for inducing apoptosis at 24 hours post treatment. Figure 14B displays Weston blots showing robust CDK9 upon treatment with YX11242 and YX1148 at 50 and 100 nM (top panel), and dose-dependent CDK9 degradation upon treatment with YX11242 at 0.1-100 nM (bottom panel). ****, PO. OOOl.

[0024] FIGS. 15A-15B. Figure 15 displays data showing that YX11242 and YX1148 are efficacious in inhibiting MCL PDX growth in vivo. Figures 15A-15B display patient-derived xenograft models, established from a patient with sequential relapse to ibrutinib and CAR-T therapies. YX11242 and YX1148 treatment significantly inhibited the PDX growth (FigurePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 15A) and prolonged mouse survival (Figure 15B). **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.

[0025] Particular non-limiting embodiments of the present invention will now be described with reference to accompanying drawings.

[0026] DESCRIPTION

[0027] All publications mentioned herein are incorporated by reference to the extent they support the present invention.

[0028] Mantle cell lymphoma is a very aggressive subtype of non-Hodgkin lymphoma. There have been paradigm-shifting therapeutic advances in the last decade, including Bruton’s Tyrosine Kinase inhibitors (BTKi), such as ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, and anti-CD19 chimeric antigen receptor (CAR)-T cell therapy. However, therapeutic relapse frequently occurs, and there is an urgent need to prevent or overcome resistance in patients, who will eventually relapse. Recent single-cell RNA sequencing data showed that MYC targets were progressively enriched with BTKi resistance. MYC mRNA expression was upregulated in BTKi-resistant (BTKi-R) compared to BTKi -sensitive (BTKi-S) cells, and its high expression correlated with poor patient survival. Moreover, cyclin-dependent kinase 9 (CDK9) was one of the top upregulated genes in BTKi-CAR-T cell dual resistant (Dual-R) samples compared to BTKi-R samples. Therefore, the transcription gatekeeper CDK9 was targeted to see if this approach could overcome therapeutic resistance. CDK9 inhibition by specific inhibitors, such as AZD4573 and enitociclib, induces acute depletion of CDK9 phosphorylation and loss of short-lived mRNA and proteins such as c-MYC andMCL-1.

[0029] One aspect of the invention pertains to compounds of Formulas I, II, or III, or an enantiomer, diastereomer, stereoisomer, or its pharmaceutically acceptable salt thereof, comprising Targeting Ligands, Substituents, Linkers, and / or Degrons as disclosed herein.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0Targeting Ligand J — [Substituent] [ Targeting Ligand ] — [Linker] — Degron(I) (II)Targeting Ligand Degron_ / (III)

[0030] A further aspect of the invention pertains to a composition, comprising any compound disclosed herein.

[0031] Another aspect of the invention pertains to a method of treating a disease or a condition, comprising contacting one or more cells of a subject with a compound of Formulae I, II, or III. In some embodiments, the method involves inhibiting CDK9 upregulation or blocking CDK9-related signaling pathways in Mantle Cell lymphoma (MCL) cells. In other embodiments, the method involves degrading CDK9 orblocking CDK9-related signaling pathways in MCL cells.

[0032] The method may involve inhibiting or degrading CDK9 in BTKi-CAR-T dual resistant cells to combat therapeutic relapse or therapeutic resistance from MCL.

[0033] The compound of Formulae I, II, or III may inhibit CDK9, degrade CDK9, or treat diseases or medical conditions mediated alone or in part by CDK9.

[0034] Further aspects of the invention are described in the following: “YX0798, a Novel Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma”, Blood Adv (2025) 9 (19): 4963-4976, which is incorporated by reference.

[0035] Definitions

[0036] For the purposes of promoting an understanding of the principles of the invention, reference will now be made to certain embodiments and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, and alterations and modifications in the illustrated invention, and further applications of the principles of the invention as illustrated therein are herein contemplated as would normally occur to one skilled in the art to which the invention relates.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0038] For the purpose of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with the usage of that word in any other document, including any document incorporated herein by reference, the definition set forth below shall always control for purposes of interpreting this specification and its associated claims unless a contrary meaning is clearly intended (for example in the document where the term is originally used).

[0039] The use of “or” means “and / or” unless stated otherwise.

[0040] The use of “a” herein means “one or more” unless stated otherwise or where the use of “one or more” is clearly inappropriate.

[0041] The use of “comprise,” “comprises,” “comprising,” “include,” “includes,” and “including” are interchangeable and not intended to be limiting. Furthermore, where the description of one or more embodiments uses the term “comprising,” those skilled in the art would understand that, in some specific instances, the embodiment or embodiments can be alternatively described using the language “consisting essentially of’ and / or “consisting of.”

[0042] As used herein, the term “about” refers to a ±10% variation from the nominal value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.

[0043] Any ranges given either in absolute terms or in approximate terms are intended to encompass both, and any definitions used herein are intended to be clarifying and not limiting. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples arePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 reported as precisely as possible. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges (including all fractional and whole values) subsumed therein.

[0044] The term "pharmaceutically acceptable salt" refers to those salts of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, and the like. As used herein, the term "pharmaceutically acceptable salt" may include acetate, hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. (See S. M. Barge et al., " Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977), which is incorporated herein by reference in its entirety, for further examples of pharmaceutically acceptable salt).

[0045] The term “DCM” refers to dichloromethane (also known as methylene chloride).

[0046] The term “TFA” refers to trifluoroacetic acid.

[0047] The term “rt” refers to room temperature.

[0048] The term “alkyl” as used herein by itself or as part of another group refers to both straight and branched chain radicals, and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. The term “alkyl” may include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.

[0049] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a linear or branched chain having at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, S, P, and Si. In certain embodiments,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 the heteroatoms are selected from the group consisting of O, and N. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Up to two heteroatoms may be consecutive.

[0050] The term “alkylene” as used herein refers to straight and branched chain alkyl linking groups, i.e., an alkyl group that links one group to another group in a molecule. In some embodiments, the term “alkylene” may include -(CH2)n— where n is 2-8.

[0051] The term “aryl” as used herein refers to a polyunsaturated hydrocarbon substituent. Aryl groups can be monocyclic or polycyclic (e.g., 2 to 3 rings that are fused together or linked covalently). Non-limiting examples of aryl and heteroaryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.

[0052] The term “heteroaryl” as used herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 77t-electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Especially preferred heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino 1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-l,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, 2-aminopyridine, 4-aminopyridine, 2-aminoimidazoline, and 4-aminoimidazoline.

[0053] An “amino” group refers to an -NH2 group.

[0054] An “amido” group refers to an -CONH2 group. An alkylamido group refers to an -CONHR group wherein R is as defined above. A dialkylamido group refers to an -CONRR' group wherein R and R' are as defined above.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0055] The term “halogen” or “halo” as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine.

[0056] The term “hydroxy” or “hydroxyl” as used herein by itself or as part of another group refers to an — OH group.

[0057] An “alkoxy” group refers to an -O-alkyl group wherein “alkyl” is as defined above. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In a further embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons.

[0058] A “thio” group refers to an -SH group.

[0059] An “alkylthio” group refers to an -SR group wherein R is alkyl as defined above.

[0060] The term “heterocycle” or “heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7-membered monocyclic-, or stable 7- to 11-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Rings may contain one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom that results in the creation of a stable structure.

[0061] The term “alkylamino” as used herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms. The term “dialkylamino” as used herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0062] The term “arylamine” or “arylamino” as used herein by itself or as part of another group refers to an amino group which is substituted with an aryl group, as defined above.

[0063] As used herein, the term “arylalkyl” denotes an alkyl group substituted with an aryl group, for example, Ph-CH₂- etc.

[0064] In certain embodiments, the term “cycloalkyl” includes bicyclic ring systems. The bicyclic ring system may be in the form of a bridged, fused, or spiro form.

[0065] Various groups are described herein as substituted or unsubstituted (i.e., optionally substituted). Optionally substituted groups may include one or more substituents independently selected from: halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, oxo, carbamoyl, alkyl, heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In certain aspects the optional substituents may be further substituted with one or more substituents independently selected from: halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl ( — C(O)NR2), unsubstituted alkyl, unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. Exemplary optional substituents include, but are not limited to: — OH, oxo (=0), — Cl, — F, Br, Ci-4alkyl, phenyl, benzyl, — NH2, — NH(Ci-4alkyl), — N(Cl-4alkyl)2, — NO2, — S(Ci-4alkyl), — SO2(Ci-4alkyl), — CO2(Ci-4alkyl), and — O(Cn 4alkyl).

[0066] As used herein, the term “MCL” refers to mantle cell lymphoma.

[0067] As used herein, the term “BTK” refers to Bruton’s Tyrosine Kinase.

[0068] As used herein, the term “BTKi” refers to Bruton’s Tyrosine Kinase inhibitors.

[0069] As used herein, the term “CAR” refers to the chimeric antigen receptor.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0070] As used herein, the term “CDK9” refers to cyclin-dependent kinase 9 inhibitors.

[0071] As used herein, the term “PROTAC” refers to proteolysis targeting chimera.

[0072] As used herein, the term “AZD4573” refers to a compound having the following structure:

[0073] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g. human). " Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.

[0074] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as gastric cancer, and / or other cancers and / or tumors. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition.

[0075] The term "treatment" as used herein can refer to both therapeutic, treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g, causing regression of the disease, disorder and / or condition.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0076] Certain compounds of Formulae I, II, or III can be prepared as exemplified by the following synthesis scheme (Scheme 1, YX-0798):XPhos-Pd-G2 K3PO4, NHBoc 1.4-dioxane / H2O, N2, 30 °C

[0077] Certain compounds of Formulae I, II, or III can be prepared as exemplified by the following synthesis scheme (Scheme 2, YX10522):

[0078] Certain compounds of Formulae I, II, or III can be prepared as exemplified by the following synthesis scheme (Scheme 3, YX0597):PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0079] Certain compounds of Formulae I, II, or III can be prepared as exemplified by the following synthesis scheme (Scheme 4, YX11242):

[0080] Certain compounds of Formulae I, II, or III can be prepared as exemplified by the following synthesis scheme (Scheme 5, YX1148):

[0081] Certain compounds of Formulae I, II, or III can be prepared as exemplified by the following synthesis scheme (Scheme 6, YX1316):PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0082] Certain compounds of Formulae I, II, or III can be prepared as exemplified by the following synthesis scheme (Scheme 7, YX1457):

[0083] It is to be understood that any Schemes disclosed herein may be modified using known methods (such as a N-protecting group, using different halides on the pyridine ring, replacing the pinacol ester; using different reagents, e.g., a mineral acid instead of HC1 and the like). For instance, certain components may be substituted or replaced by similar components which are understood to perform in a similar manner, through methods or techniques known within the art. Such components may include, but are not limited to, solvent, base, acid, catalyst, protecting group, inert gas, temperature, and / or common reagents.

[0084] It is to be understood that both the foregoing descriptions are exemplary, and thus do not restrict the scope of the invention.

[0085] LIST OF EMBODIMENTSPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0086] The following is a list of non-limiting embodiments:1. A compound according to Formula I, II, or III:[Targeting Ligand ] — Substituent] [Targeting Ligand ] — [Linker] — [ Degron](I) (II)Targeting Ligand ■ Degron_ J(III)or an enantiomer, diastereomer, stereoisomer, or its pharmaceutically acceptable salt thereof.2. The compound of embodiment 1, wherein the Targeting Ligand moiety is chosen from Formulae Pl, P2, P3, P4, P5, P6, or P7:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 wherein X, Y, and Z are each independently CH, CR1or N;R1is independently selected from halogen, -Ci-Ce alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-Ce alkyl-O-Ci-Ce alkyl, cycloalkyl, -C(0)NH2, -C(O)H, -OH, -CN, -NO2, each of said -Ci-Ce alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-Ce alkyl-O-Ci-Ce alkyl, cycloalkyl is optionally substituted with halogen, hydroxy, -Ci-Cs alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andfor P2 and P4-P7, J and Q is taken together with 1-3 atoms chosen from C, N, O, and S form a 5-7 membered cycloalkyl or heterocycloalkyl ring.3. The compound of embodiment 1, wherein said 5-7 membered cycloalkyl or heterocycloalkyl ring is saturated, partially saturated or unsaturated.4. The compound of embodiment 1, wherein said Targeting Ligand moiety is5. The compound of embodiment 1, wherein one or two CH2 groups of the cyclohexyl moiety are replaced by a corresponding number of carbonyl (C=O) groups.6. The compound of embodiment 1, wherein the Substituent moiety is0 R2O2b’, whherei.n,T is CH2;b is 0-8;R2is each independently hydrogen, deuterium, halogen, or hydroxyl group.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 7. The compound of embodiment 1, wherein the Degron moiety is chosen from Formulae DI, D2, D4, D5, or D6:wherein:E1and E2are each independently -CH2-, -NH- or -C(O)-;L1is absent, -CH2-, -NH-, or -O-;L2is absent or -C(O)-;p is 1, 2, or 3;q is 0, 1, or 2;is aryl or heteroaryl; andR3is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide.8. The compound of embodiment 1, wherein the Linker moiety is selected from a bond,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0wherein:L3, L4, L5, and L6are each independently chosen from -CH2-, -NH-, -O-, -C(O)-X is each independently -(CH2)g- orr is 0, 1, 2, 3, or 4;g is 0-10;s is 0, 1, 2, or 3;and are independently saturated or unsaturated 5-8 single heterocycle, fused heterocycle, bridged heterocycle, or spiro heterocycle comprising 0- 3 heteroatoms selected from N, O, and S, or are independently 4-7 membered cycloalkane rings; andPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 R4is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide; andwherein more than one R4can be attached to the same atom.9. The compound of any of the preceding embodiments, wherein the Targeting Ligand moiety is Formula Pl or P2:wherein X, Y, and Z are each independently CH, CR1or N; andwherein J and Q is taken together with 1-3 atoms chosen from C, N, O, and S form a 5- 7 membered cycloalkyl or heterocycloalkyl ring.10. The compound of any of the preceding embodiments, wherein R2on said substituent moiety is independently chosen from hydrogen, fluoride, or CF3.11. The compound of any of the preceding embodiments, wherein the Degron moiety is Formula DI or D2wherein:E1and E2are each independently -CH2-, -NH- or -C(O)-;L1is absent, -CH2-, -NH-, or -O-;PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 L2is absent or -C(O)-;p is 1, 2, or 3;q is 0, 1, or 2; andR3is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide.12. The compound of any of the preceding embodiments, wherein the Linker moiety is selected from:V / X. / L5. A / / ''L3L4X Awherein:L3, L4, L5, and L6are each independently chosen from -CH2-, -NH-, -O-, -C(O)-X is each independently -(CH2)g- orr is 0, 1, 2, 3, or 4;g is 0-10;s is 0, 1, 2, or 3;and are independently saturated or unsaturated 5-8 single heterocycle, fused heterocycle, bridged heterocycle, or spiro heterocycle comprising 0- 3 heteroatoms selected from N, O, and S, or are independently 4-7 membered cycloalkane rings; andPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 R4is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide; andwherein more than one R4can be attached to the same atom.13. The compound of any of the preceding embodiments, wherein the compound is 0any of the following:\ / = / ^zWAExample 1 / Z I _ Structure) CO'='N-NALn \ _ / ZT YX0835 / °=UL ANH T i n?(1) 0kA 0 r~\r £ N— ( )=oAnh0 0IZ H N-NXZ_V / 'YX0803Il 1 HH H^^ QQZ(2)ns O"Nr^NnuL EN\ A / °Y0 0NH0kA ° AYX08042 ' ANHCI J Y LYn0un0U T E ANO °(3) N E N A, Y >■' V N0Hu sy A _ / YX0597 ci^ / L „1 1 HH HNN O Y^O 0(4)L LN\ AN / H=o0 0YX0807(5)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX0914(6) o x ^' ^O);= v O / N-N-V,6 YX0917 oci\xLn|| ] n H H (7) ^zY0z1 / _Ho oZA 0 X A ' AAIZ^ / OX= I r v N— (o oN / H=o X ZI 0N-N^Y-- IZy A _ txzYX0811 ci-^ xLII ]? ( Xo=H / ] 1 HZI(8)NY » Y ° O' ZJ XA< / \ / Z _ / 1zz(T I 'n\ / ° < / \ / z _ o O 0o Cf1X ^ °ZO\ _ A Y 0876 YNH C'ULnn UQ1\ V °^\>° (9) \\ I N N r i n N oHL^J SHYX0766(10)YX0857(11)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0 N-NYi / \ _ / YX0904Y |? HN" H '' O'"NV>HO 0(12) M o X y VNHo.6^^ Oxoz-Zo / =\YX0930 yy1 / IZ _ ZI Ato(13)Qzixz / o= IN-N / / ZX\ _ / YX1011 Y 1 H O Os(14)oHU 0 tQ^- \ \ N- P XYYX05 6 °A cYoz6 NHCl A n n UtNV>°(15) N NHr i nUNo OHr IXN—YX05612C|xX,I kl A 1N. > HN 'i,(16) '< YH / x. / XHY / XX, o° ° A r £X N-( r~x )=o NH0 oYX0589(17)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0 1 1 N—YX0601]| ] n H HNN Y^OO(18) kk ° ° r~\L EN\ / r~ N / H ° o oI T N—YX05671c|\ / L _II I u H HNN -r^r Y^^^ o(18a) kk ° ° r N" / r~\ )=° AA O 0NHI T N—YX05672c|x / -L11N1sII H H0(18b)L L 'N— ( N / H=0O 0\ \ N- / ? YX0568 / NHCIU Ti L n n0u n0W T w V?° (19) ll N N r T n — N -J^ —X°0Hu sI X~N—YX0556|| H(20)NK T i n r ° oU o < VX FNH[j T ZN~( )=°0IN—YX0624< ||NA A > HN^u C i o(21) k / J o kxk / ~\L LN\ r° / kNHO 0PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX05492(22)I A.N—o AYX0627 a^ Jx ^^ OOzxZo Y ]?^COz HN ''' r^x| ''N'Y / Xx / X^^NHo(23) ^CO xzzH° Jx AL LN\ Z=0Z INH° ' o O OL° ' o zx^ °= IZYX06331 zx / o=iA °(24)oYv1 INN— \ / X _^^ \ / OO IZ_ YX0634^^ ooz(25)<n Ao''Nr"”Xx° or [Ln\ / =°HNHo o oYX0635(26)r IA'N—YX0652C|\ / LY l || HN N Y >■ Y 0 NH o(27)Hr £ N— ( r~\ )=o ANHO OYX0648 I A-N —T ^7o YXA3Clx A. N / ~NHJL 1 iA hl A J ° i| H unL'N- N— / / ~~ ' C \—l / ''N / >X TXNH(28) W 'V A" CH OPCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0I I N—YX0745I < I 1 A II, / xH / =\ \ _ &,o o(29)NHH'O' VP N=A A oNIN'XKCV n ANMy-NH t (T °oYX0765 I JL.N-_°A oci P\ / i A A o „ N= MN. — / Z~N IH A nNANrH(30) A xzzH [J J V= / \)° ' qI JL.YX0675N—zzci^ AT i nH / =\ zO(31) LVJ 1 O N=N' ' - s. C / H \XN> Xn I / ^NH \-NHd ° ^-^ r0YX0730 V (32)^ZOx _°^\ Z z— W x YX05 r r o N- / ?72ClJ TLn n0u n o W wA>° (33)1^N^NAf>-'NY--AN^ArNH 0HU 0H0[ N—,0HNA YX0661(34) N N r 1 V — / VH 0YX05572 co- YsA ° H »T v(35)NHHT kYJ Y 0^'AH, r HN^N / pHO0PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0 YAr L==; / N H°,YX0573Q Ni N A r 1 Y N Y 'Ao \(36)HU 0H0 X AYYhrQU YX1316 ci^ A. _I 1 HH H(81)NN TA- Y^OoAA ° ° AA AAr Y N— ( A° Xo oNH""0FYA^NNAOYX0825 A 1y 1Y^1N^ J! A Ax / VS,N> YA^n o o oL I] H o AY YNHfi 1 / N\ ) (37)=oo""0NA OtlHYX0838 Y 1V kYA ILNA JI Y AX / S, Y Y? 0 01 I]Ho 0 YNH p-AsA fi yN_ / \=0(38)oo YX0832 if JYN\ / =0(39) Xo.0°FXY'NNA OMHYX0932 1 A it J! A Y Y 9 o 01 1]Ho o YNH (40)FG A^ZN~\ )=°00 YX0849 f JYN\ / 0\ 0 ^r A YNH(41) YXI ° °PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX09222(42)p 0 / YX0854NHfi JLN\ )=0(43) XG. °F'^^H / IZNDFXY'N NX OMHYX0844AAANnAY / S T X T / ?1 JJHX / °0AY / — \ H £ N— ( )=O (44) YNH0 0 oo r^^r-X Y YX0899 [| T N— fN^H=O \ F-. 0 Y^ V\ ' - IZ(45) iXl0XO M-^I O M HYX0847Y Y i / ? r i| H o o / YA. / — \ (46) [ LN\ / ^~NHo ° O 0 p o YNH YX0921 [| 7 N— f }=o \ O YS>\\ ' - I Xi O (47) S'''0FY^NN Y 0YX0884[ £ N — ( )=° (48) #“NH0 0p 0 / NHYX0850 I JLN\ X0(49) 1Y1 iQPCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX0885(50)A^^=iOOzYX0887 ^^ A OsOzZ(51) ^3° \7\~\7z / IZ YX0889z / IZ z )°=z& / A / \ z'• ^co z / / Ao=o=(52) / \ \& z8^ °=' cn' A sz z=Z 3 zx zx 3 / o= 0z= / YX1119\ 33 f k'N\ VN / H0(53) XY / 3 C>°Q / HOj? jCl T0 0F"^A CH'"'0 Y^NNA 0K,YX0954L H A r c o <>h 0 J( \-NH o (54) [f Y2 / N\ )=°Ao oYX08921(55)YX0936(56)''oF'y#5XN NAOHYX0960Y A l / ? °W r II n o o YNH F^^A fi jrN / \=Q (57)0PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX0987(58)A YX1054(59) 3z / zzz / IZ YX1061 zXOC -A \\&' Ui / \ \(60) 33zi= zZ"'oF'^Z zO'N N^N O iMy— r H YX1109Z^ AXX "r o' Z— xnrQ / HO(61)FVbZ. ^ °°A HN^0 Cf1A.oJL / x Z^ YX1148 NDFXN N'" NO|| | N— ( J / \ oo== )=o / z— I V(62) oO YX11242'" OFN^N OKLII NZ >=O J-X^XA AX JS''NY^N^ XNH(63)X° UN^-O ° °o YX1110 \ F-x^' °F'V<bX / \ o N N N OK, Il 1 NA )=O jbr^ Hxo AN^XJ ° ° (64)H H YX10503\ F^ J^TTNI NANH° 1NII N II NO Q, '' ^N., N |. >A. X s Y Y (65) S SFAZPCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX1079(75)YX04582 LN—cixX(82) Y ] uHHU X oQo“ O X LL a Q CNz^N xz xz xz / o=Y r r N—X04822Y zx xz ZX IZ^ zr xz8 z\\O\=O= O=( 3) \=z^Z IANA^''NYCF3tyozzHU ooz> N NYX0526 uo Z / O=ci (x184) Y ] j| HHu s ow YX0798(76)YX10152(77)YX11875(85)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0YX12041(86)oYX1210 Xo Q mQV z- (87) / xz xzo=YX10522 \zx zx IZZ I\oO==7) 0t \(78 0rtozz zz\^ z=o xzoz / IZ YX10941 LL& ■ V' Ui / \ \(79)YX10942 1 io o(88)YX1095(80)YX1457 CO OCl^As,n\(89) T 2 II H T T / ■-( >=o14. The compound of any of the preceding embodiments, wherein the compound is any of the following:PCT Application Applicant Ref. ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0oPCT Application Applicant Ref: ZHOU- JI-24 A (PCT)Atty Dkt. No.: TMB-020PCT09-9 obodiments, wherein said compoundPCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0bodiments, wherein said compoundPCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0orPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 17. A composition, said composition comprising a compound of any of the preceding embodiments.18. A method for inhibiting CDK9 upregulation or blocking CDK9-related signaling pathways in Mantle Cell lymphoma (MCL) cells, said method comprising contacting one or more cells of a subject with a compound of any of the preceding embodiments.19. A method for degrading CDK9 or blocking CDK9-related signaling pathways in MCL cells, said method comprising contacting one or more cells of a subject with a compound of any of the preceding embodiments20. A method for treating cancer, said method comprising administering an effective amount of a compound of any of the preceding embodiments to a subject, wherein said method involves inhibiting CDK9 upregulation, degrading CDK9, or blocking CDK9-related signaling pathways in cancer cells.21. The method of any of the preceding embodiments, wherein said cancer is mediated alone or in part by CDK9.22. The method of embodiment 22, wherein said cancer is chosen from Activated B-Cell Type Diffuse Large B-Cell Lymphoma (ABC-DLBCL), Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and breast cancer.23. The method of embodiment 22, wherein said cancer is Mantle Cell Lymphoma (MCL).24. The method of embodiment 23, wherein the method involves inhibiting or degrading CDK9 in BTKi-CAR-T dual resistant cells to combat therapeutic relapse or therapeutic resistance from MCL.25. The method of any of the preceding embodiments, wherein said compound is chosen from any of the following:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT026. The method of any of the preceding embodiments, wherein said compound is chosen from any of the following:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT027. A method of preparing compound YX0798 according to Scheme 1:Scheme 1PCT Application Applicant Ref ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT028. A method of preparing compound (YX10522) according to Scheme 2:Scheme 2ci(YX10522).29. A method of preparing compound (YX0597) according to Scheme 3:Scheme 3o o (YX0597)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT030. A method of preparing compound (YX11242) according to Scheme 4:Scheme 431. A method of preparing the following compound according to Scheme 5:Scheme 5oo(YX1148)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0o32. A method of preparing the following compound according to Scheme 6:Scheme 6o o (YX1316) comprising the following synthetic method:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 33. A method of preparing compound YX1457 according to Scheme 7:Scheme 7

[0087] EXAMPLES

[0088] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, described herein. In addition to the examples below, more technical details relevant to the present disclosure can be found at: “YX0798, a Novel Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma”, Blood Adv (2025) 9 (19): 4963-4976.

[0089] Example 1. The in vitro efficacy of new compounds YX04582, YX4822, YX0526, YX05492 and YX0798 in MCL cell lines.

[0090] To develop patentable PROTAC -based CDK9 degraders, new compounds were first designed and generated through multiple rounds of optimization. Among them, YX04582 (batch Al), YX04822 (batch A2), YX0526 (batch A3), YX0798 (batch A10) were the top candidates from each batch. From batch Al (n = 25 compounds), YX04582 was identified as the best candidate, with great efficacy at 1000 nM in all eight MCL cell lines tested (JeKo-1,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 JeKo BTK KD, Mino, and Mino-R, Rec-1, Rec-R, Maver and Z138) (Figure 1). YX04582 was therefore chosen as the lead compound for optimization. Based on YX04582, five YX04582 analogs were designed and synthesized as batch A2. YX04822, but not others, was found to be much more potent than YX04582 in all MCL cell lines tested (Figure 1). Based on YX04822, fourteen analogs were designed and synthesized as batch A3. CDK9 inhibitor YX0526 showed efficacy comparable to YX04822 in all four MCL cell lines tested (JeKo-1, Mino, Maver, and Z138) (IC50 = 132.9-330.2 nM) (Figure 1). To further optimize the CDK9 inhibitors, CDK9 inhibitor YX0798 (batch A10) was designed and developed, which exhibited remarkable anticancer potency (IC50 = 25.2-109.9 nM) compared with AZD4573. Overall, among these new compounds, YX0798 was identified as one of the best CDK9 inhibitor candidates for further evaluations.

[0091] Example 2. YX0798 is a novel CDK9 inhibitor with higher target selectivity than AZD4573.

[0092] To determine the selectivity of YX0798, kinome profiling was performed using a scanMax assay (Eurofins), which includes a panel of 468 kinases and some relevant mutants or variants (Figure 2A, left panel). YX0798 at 100 nM led to 13 hits with > 66% reduction in binding (Figure 2B, left panel). The top hit of YX0798 showed 99.8% reduction in binding to CDK9, which is 16-50 fold more selective than hits 2-4 hits (CDK7, CDK3 and CDK4, 96.8-90% reduction) and 60-170 fold more selective than hits 5-13 (Figure 2B, left panel). In contrast, AZD4573 was reported to have 16 hits with > 90% reduction in binding (Figure 2A, right panel). Together, these data indicated that YX0798 is more selective than AZD4573. Next, to quantitively determine the binding affinity of YX0798 to CDK9, an in vitro kdELECT assay (Eurofins) was performed with side-by-side comparison to AZD4573. YX0798 showed an even lower Kd (0.28 nM) for recombinant CDK9 protein, which was 357-fold lower than that used for kinome profiling than AZD4573 (Kd = 0.51 nM) (Figure 2B, right panel).PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0093] Example 3. YX0798 is potent in killing MCL cells by inhibiting CDK9 activity and in vitro.

[0094] To determine the anti-tumor potency of YX0798, cell viability assays were performed using MCL cells. YX0798 is highly potent in BTKi-sensitive MCL cells (Mino and JeKo-1) and BTKi-resistant cells (JeKo BTK KD and Z138) (Figure 3 A, left panel), YX0798 did not show remarkable toxicity in peripheral mononuclear (PBMC) cells isolated from the blood of healthy donors (Figure 3A, right panel). YX0798 potently inhibited cell viability and induced apoptosis in MCL in a dose-dependent manner (data not shown). YX0798 inhibited cellular CDK9 phosphorylation at concentrations of 5-80 nM in a dose-dependent manner. Correspondingly, the compound also induced a dose-dependent cleavage of poly (ADP-ribose) polymerase (PARP) and Caspase 3, and protein reductions of anti-apoptotic MCL-1, showing a short half-life (T1 / 2) in Z138 cells (data not shown). This was also observed in JeKo-1 and Mino cells (Figure 3B). Furthermore, dose-dependent decreases of phosphorylation of the CDK9 substrate polymerase II were also observed in JeKo-1, Mino and Z 138 cells (Figure 3B). In addition to MCL-1, short-lived c-MYC was reduced in a dose-dependent manner upon YX0798 treatment (Figure 3B).

[0095] Example 4. YX0798 is a stable and safe compound with oral bioavailability.

[0096] To further determine the drug-like properties of YX0798, an in vitro liver microsome stability assay was first performed. YX0798 was stable in all three species tested (human, rat, and mouse) (Figure 4A), with comparable T1 / 2 to AZD4573. YX0798 showed high cell permeability (Papp= 17.0 x 10-6cm / s and 40.2 x 10-6cm / s) as determined by the MDCK-MDR1 permeability assay (Figure 4B), but indicating its potential to be a P-gp substate (efflux ratio = 2.4). A kinetics solubility determination was conducted to explore the soluble nature of YX0798 in different solutions. YX0798 has high solubility (451 pM) in acidic FaSSGF (Fasted State Simulated Gastric fluid) buffer (pH1.2), but much lower solubility (24.2 pM) in FaSSIFPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 (Fasted State Simulated Intestinal fluid) (pH6.8), and no solubility in pH7.4 buffer (data not shown). These data indicate that YX0798 is a basic drug and has gastric fluid solubility. Therefore, the in vivo pharmacokinetic properties (PK) of YX0798 in rats was next tested following intravenous (iv, 10 mg / kg) and oral (po, 20 mg / kg) administration. As shown in Figure 4B, YX0798 has much lower CL (15.1 vs 71 mL / h / kg) and much longer T1 / 2 (3.21 h vs 0.18 h) than those of AZD4573. Meanwhile, good plasma exposure after po was observed, and the AUCo-00 values for YX0798 was 4457 ng h / mL. The oral bioavailability (F%) of YX0798 was also determined, which is 16.5%, indicating that YX0798 has the potential for oral administration. The hERG inhibition assay, used to evaluate the potential cardiotoxicity of a drug candidate, showed that YX0798 has weak hERG inhibition (17.56% ± 0.41%) at 10 pM (data not shown), which is much higher than the highest plasma concentration (2.61 pM) the compound can reach by oral administration in rats. Therefore, it is not expected that YX0798 will cause any cardiotoxicity. Together, these data indicated that YX0798 is a stable and safe compound with acceptable oral bioavailability.

[0097] Example 5. YX0798 is effective in inhibiting the tumor growth ex vivo and in vivo in primary patient samples and patient-derived models.

[0098] To assess YX0798’s anti-MCL potency within a clinical context, primary samples from MCL patients at MD Anderson Cancer Center (MDACC) were collected. A sample from a patient who relapsed post pirtobrutinib in clinic was first tested. Consistent with the clinic response, primary cultured cells from the patient no longer responded to treatment with BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib (IC50 = 7.3, >50, 29.0, and >50 pM, respectively), but was highly sensitive to CDK9 inhibition, using either YX0798, AZD4573, or enitociclib (IC50 = 27.8, 13.1, and >50 nM, respectively) (Figure 5A, top panel). Similar to MCL cell lines, YX0798 induced dose-dependent inhibition of CDK9 phosphorylation, cleavage of PARP and caspase 3, and reduction of short-lived MCL-1 (dataPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 not shown) in the cultured MCL patient cells. To further determine the efficacy of YX0798, patient-derived organoid (PDO) models were established from a patient who relapsed post pirtobrutinib therapy. Consistent with clinical response, it was observed that these PDO models were resistant to BTKi including pirtobrutinib (20 pM) and acalabrutinib (20 pM). Interestingly, CDK9 inhibitors AZD4573 (25 nM) and YX0798 (200 nM) were highly potent in killing these PDOs in 3D culture systems (Figure 5A, bottom panel).

[0099] To assess YX0798’s anti-MCL potency in vivo, a PDX model of relapsed MCL was generated using a sample collected from a patient with sequential relapses to BTKi and CAR-T cell therapy. In the newly established PDX models, YX0798 was orally administrated at 5 mg / kg (5 days on and 2 days off every week, equivalent to 30 mg / kg / week), while AZD4573 was administrated interperitoneally at 15+15 mg / kg (two doses at 2 hours apart, once a week, equivalent to 30 mg / kg / week). YX0798 showed noticeably better efficacy in inhibiting the tumor growth and in prolonging mouse survival than AZD4573 (Figure 5B). No apparent side effects, including weight loss, were seen during any of the dosing regimens (data not shown).

[0100] Example 6. The in vitro efficacy of CDK9 degraders YX05942, YX05672, YX0601, YX0597, YX0766, YX0807, and YX1011 in MCL cell lines.

[0101] The first PROTAC -based degrader YX05492 (batch A3) was designed and synthesized. YX05492 showed good efficacy in these MCL cell lines (IC50 = 62.9-750.0 nM) (Figure 6A). For optimization, eight new PROTAC -based degraders were designed and synthesized as batch A4. YX05672 was identified as the top candidates with the greatest efficacy in all eight MCL cell lines (JeKo-1, JeKo BTK KD, Mino, Mino-R, Rec-1, Rec-R, Maver, and Z138) (Figure 6A). Next, the IC50 values of AZD4573, YX04582, YX05492 and YX05672 were determined (IC50 = 50.9-372.1 nM) in each of the aforementioned eight MCL cell lines (Figure 1 and 6B). The CDK9 degrader YX05672 had slightly lower IC50 values than the CDK9 degrader YX05492 and YX04582 (Figure 6B). YX05672 and YX05671 are two possible chemicalPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 isomers of the same molecule and YX05672 showed higher potency than YX05671 (data not shown).

[0102] YX0601 from batch A5 is a mixture of YX05672 and YX05671 without separation. YX0601 showed good efficacy in these MCL cell lines (IC50 = 109.2-125.1 nM) (Figure 6A-B). To assess the in vivo efficacy of YX0601, dose-escalation was first performed in NSG (NOD. Cg-Prkdc scid I12rg tmlWjl / SzJ) mice to determine the maximum tolerated dose (MTD), which was found to be 10+10 mg / kg with intraperitoneal (IP) injection 2 hours apart once a week (QW) (data not shown). Next, patient-derived xenograft (PDX) models were established using an apheresis sample collected from a patient with dual resistance to ibrutinib and venetoclax. The PDX models were treated with vehicle, AZD4573 (15+15 mg / kg, 2h apart, IP, QW), or YX0601 (10+10 mg / kg, 2h apart IP, QW). AZD4573 significantly inhibited tumor growth in the PDX models (P < 0.001) (Figure 7A). YX0601 also significantly inhibited PDX tumor growth (P < 0.05), but with less potency than AZD4573 (Figure 7A).

[0103] Example 7. Further optimization of CDK9 degraders.

[0104] As an alternative approach, eleven new CDK9 degraders were designed and developed as batch A6. YX0597 was one of best candidates with the greatest potency at 100 and 1000 nM (data not shown). YX0597 had a low IC50 (7.7-62.1 nM) (Figure 6A-B), comparable to that of AZD4573 (IC50 = 12.5-25.7 nM) (Figure 8A). In the next batch (A7, n = 6 compounds), YX0766 was identified as the top candidate with the greatest efficacy (Figure 6A), but with less potency (IC50 = 25.0-64.7 nM) than YX0597 in MCL cell lines tested. In the next batch (A8, n = 6 compounds) (Figure 6A). YX0807 was identified as the top candidate with the greatest efficacy (Figure 6A), but with less potency (IC50 = 25.2 nM) than YX0597 (IC50 = 8.2 nM) in JeKo-1 cells (Figure 6B). Both YX0597 and YX0807 were highly potent in inducing apoptosis and inhibiting cell viability at 10 and 20 nM (Figure 6A). As expected, CDK9PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 degraders YX0597 and YX0807, but not CDK inhibitor AZD4573, depleted the expression of CDK9 protein (Figure 8 A).

[0105] Aiming to optimize new CDK9 degraders, an additional batch (A9) (n = 1 compound) were designed and developed, and YX1011 was identified as another potent new CDK9 degrader (Figure 6A). YX1011 showed an low IC50 of 11.7 nM) in JeKo-1 cells (Figure 6A-B). Both YX0597 and YX1011 at 10 and 20 nM are more potent in inducing apoptosis and inhibiting cell viability in JeKo-1 cells (data not shown). As expected, YX0597 and YX1011, but not AZD4573, depleted protein expression of not only CDK9 but also the short-lived proteins c-MYC and MCL-1 in a dose-dependent manner (data not shown). YX1457 showed even lower IC50 values in MCL cells (IC50 = 5.9-10.3 nM) (Figure 6A-B).

[0106] Example 8. In vivo efficacy and toxicity assessment of YX0597 in mouse models.

[0107] The data demonstrate that CDK9 degraders YX0597 and YX1011 are more potent than AZD4573 and new CDK9 degraders (YX0601, YX05671, and YX05672) in killing MCL tumor cells (Figure 6A). Therefore, YX0597 and YX1011 were chosen for further assessment. To assess the in vivo efficacy of YX0597 and YX1011, performed dose-escalation was first performed to determine MTD in NSG mice. YX1011, IP, QD at 1 mg / kg was too toxic in these mice, while YX0597 at 1 mg / kg, IP, QD, was safe (data not shown). Therefore, YX0597 was chosen for in vivo efficacy assessment.

[0108] JeKo-1 -derived xenograft models were established, and were treated with vehicle, AZD4573 (15+15 mg / kg, 2h apart, IP, QW), or YX0597 (1 mg / kg, IP, QD). AZD4573 significantly inhibited PDX tumor growth (P < 0.001) (Figure 9A, top panel). At a much lower dosage, YX0597 also significantly inhibited PDX tumor growth (P < 0.0001), although to a lesser extent than AZD4573 (Figure 9A, top panel ). Once treatment was stopped, the xenografts grew rapidly in vehicle- or AZD4573-treated mice; however, tumor growth was much slower in YX0597-treated mice, leading to prolonged mouse survival (P < 0.05) (FigurePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 9 A, bottom panel). Neither AZD4573 nor YX0597 treatment affected mouse body weight (data not shown). To further assess the in vivo efficacy of YX0597, PDX models were established using an apheresis sample from a patient with dual resistance to BTKi and CAR-T cell therapy. The PDX mouse model was treated with vehicle, AZD4573 (15+15 mg / kg, 2h apart, IP, QW, 6 weeks), or YX0597 (1 mg / kg, IP, QD, 5 days only). Both YX0597 and AZD4573 significantly inhibited the PDX tumor growth (P < 0.001) (Figure 9B, top panel). Once treatment was stopped, the PDXs grew quickly in the vehicle-treated mice; however, tumor growth was much slower in AZD4573-treated or YX0597-treated mice, leading to prolonged mouse survival (P < 0.01 and P < 0.001, respectively) (Figure 9A, bottom panel). Again, neither AZD4573 nor YX0597 treatment affected mouse body weight (data not shown). Together, these data demonstrate that YX0597 was safe and effective in inhibiting PDX tumor growth, and at a much lower dosage (1 mg / kg) than AZD4573 (15+15 mg / kg).

[0109] Example 9. Development of enitociclib-based CDK9 inhibitor and degraders.

[0110] In addition to AZD4573, enitociclib is also a highly selective CDK9 inhibitor, which has been demonstrated to be slightly less potent and less toxic than AZD4573. To exploit this advantage of lower toxicity, new CDK9 inhibitor YX10522 and enitociclib-based CDK9 degraders were designed and synthesized in five consecutive batches (E1-E5, n = 8, 10, 10, 4, and 7 compounds, respectively).

[0111] YX10522 was identified as a novel CDK9 inhibitor, showing higher potency than enitociclib in MCL cell lines (JeKo-1 and JeKo BTK KD) (Figure 10A). In JeKo-1 and JeKo BTK KD cells, YX10522 also showed a much lower IC50 (4.8 and 10.9 nM, respectively) than enitociclib IC50 (21.4 and 110.2 nM) (Figure 10A, left panel). YX10941 from batch E5 showed much better anti -MCL tumor activity than compound YX1095 from the same batch (Figure 10A, right panel). YX10941 showed low IC50 values (28.6-78.3 nM) in JeKo-1, JeKo BTK KD, Mino and Mini-R cells (data not shown). The compound also induced dose-dependent andPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 time-dependent anti-MCL activity (data not shown). CDK9 degraders YX0832, YX0849, and YX0850 from batch El were identified as the top candidates with the greatest efficacy in all four MCL cell lines tested (JeKo-1, Z138, Mino, and Mino-R (Figure 11 A, left panel). YX0832 (IC50 = 28.5 nM) was more potent in Z138 cells than YX0849 (IC50 = 35.7 nM) and YX0850 (IC50 = 59.4 nM) (Figure 11 A, left panel). New compounds YX0597 and YX0807, YX0832 and YX0849 at 20 nM effectively depleted CDK9 protein expression (Figure 12A, bottom panel), demonstrating their bona fide on-target degradation on CDK9. Both YX0832 and YX0849 at 25 and 50 nM were more potent than enitociclib in inducing apoptosis and inhibiting cell viability in JeKo-1 cells (Figure 11 A, top panel).

[0112] YX0932 from batch E2 was identified as the top candidate with the greatest efficacy in all six MCL cell lines tested (JeKo-1, JeKo BTK KD, Mino, and Mino-R, Maver, and Z138) (Figure 11B). YX0932 (IC50 = 49.7-278.2 nM) demonstrated a similar potency as YX0832 (IC50 = 25.6-51.5 nM) and a greater potency than enitociclib (IC50 = 50.0-101.3 nM) (Figure 11B).

[0113] In addition to CRBN-based PROTACs, piperlongumine (PL)-based CDK9 PROTACs were also generated by exploiting Keapl as the E3 ligase. YX0965 and YX1009 from batch E3 were identified as the top candidates with the greatest efficacy in JeKo-1 cells (Figure 11 A, right panel). YX0965 (IC50 = 28.5 nM) and YX1009 (IC50 = 40.2 nM) demonstrated a similar potency as enitociclib (IC50 = 35.4 nM) (Figure 11 A, right panel). In JeKo-1 cells, YX0965 and YX1009 at 25 and 50 nM were more potent in inducing apoptosis than AZD4573 at 25 and 50 nM (Figure 12B, top panel). YX0965 and YX1009 at 10 and 20 nM effectively depleted protein expression of CDK9 and short-lived proteins c-MYC and MCL-1 (Figure 12B, bottom panel), demonstrating their on-target effect for CDK9.

[0114] YX10503 and YX1057 from batch E4 were identified as the top candidates with the greatest efficacy in all four MCL cell lines tested (JeKo-1, JeKo BTK KD, Maver, and Z138)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 (Figure 11B). YX11503 (IC50 = 23.7-88.8 nM) and YX1057 (IC50 = 13.4-88.2 nM) showed a similar potency in MCL cells (Figure 11B). YX10503 and YX1057 at 10 and 20 nM were potent in inducing apoptosis and inhibiting cell viability in JeKo-1 cells (Figure 13 A). YX10503 and YX1057 at 25 and 50 nM were more potent in depleting CDK9 protein expression than YX0832 and YX0932 at 25 and 50 nM, as well as YX0965 at 10 and 20 nM (Figure 13B). These results demonstrate the potent and specific on-target effect for CDK9, with YX10503 and YX1057 showing lower IC50 values than YX0832 and YX0932 but higher values than YX0965 (Figure 1 IB).

[0115] YX11242 and YX1148 from batch E5 were identified as the top candidates with the greatest efficacy in all four MCL cell lines tested (JeKo-1, JeKo BTK KD, Mino-R, and Z 138) (Figure 11B). YX11242 (IC50 = 23.0-100.2 nM) and YX1148 (IC50 = 23.0-100.0 nM) showed similar potency in MCL cells (JeKo-1, Mino, and Z138 (Figure 1 IB). YX11242 and YX1148 at both 50 and 100 nM were potent in inducing apoptosis and inhibiting cell viability in JeKo-1 cells (Figure 14A). Like YX10503, YX11242 and YX1148 at 50 and 100 nM were potent in depleting CDK9 protein expression (Figure 14B, top panel). YX11242 and YX1148, at a concentration of 50 nM, successfully induced apoptosis in JeKo-1 cells (Figure 14A), as well as in Mino and Z138 cells (data not shown). Like YX10503, YX11242 and YX1148 at 50 nM dramatically depleted CDK9 protein in all three MCL cell lines. (Figure 21F). Together, these data demonstrated the on-target effect for CDK9. YX11242 also showed dose-dependent induction of apoptosis, inhibition of cell viability, and depletion of CDK9 protein expression in JeKo-1 cells, starting at 12.5 nM (Figure 14B, bottom panel). Furthermore, YZ11242 and YX1148 significantly inhibited tumor growth of PDX models established from a patient with ibrutinib and CAR-T dual resistance, and promoted mouse survival (Figure 15A-B).

[0116] Example 10. Methods

[0117] Cell samplesPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0118] MCL specimens were acquired from patients and peripheral blood mononuclear cell (PBMC) samples were acquired from healthy donors after obtaining written informed consent following the University of Texas MD Anderson Cancer Center Institutional Review Board-approved protocols and in accordance with the Declaration of Helsinki.

[0119] Reagents

[0120] AZD4573 and enitociclib were purchased from Selleck Chemicals (Houston, TX). DMSO was purchased from Sigma-Aldrich (St Louis, MO). All other new compounds were synthesized in house at UTMB.

[0121] Cell culture

[0122] The MCL cell lines JeKo-1, JeKo-R, JeKo BTK KD_1, JeKo BTK KD_2, Mino, Mino-R, Rec-1, Rec-R, Maver-1, and Z138 were maintained in RPMI 1640 medium supplemented with 1% penicillin / streptomycin, 25 mM 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES), and 10% fetal bovine serum (FBS; all from Sigma-Aldrich, St Louis, MO), and cultured in a CO2 incubator at 37 °C as described previously. JeKo-1 cells are sensitive to ibrutinib but resistant to venetoclax. JeKo BTK KD_1 and 2 cells derived from JeKo-1 cells have intrinsic BTKi resistance due to BTK depletion, and JeKo-R cells have acquired resistance to ibrutinib. Mino-R and Rec-R cells have acquired resistance to venetoclax. In addition, Maver-1 and Z138 have primary resistance to ibrutinib. Cell lines were authenticated by single-nucleotide polymorphism profile fingerprinting.

[0123] Cell viability and apoptosis assays

[0124] These assays were performed as described previously. Briefly, cells from MCL cell lines were seeded at 10,000 cells per well, and PDX tumor cells or primary patient tumor cells were seeded at 125,000 cells per well in a 96-well white flat-bottomed plate (cat. 3558; Corning, Tewksbury, MA). Cells were treated in triplicate with various doses of compounds. The compounds were prepared in DMSO to make stock solutions, from which two-fold serialPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 dilutions were prepared. Cell viability was determined at 72 h (cell lines) or 24 h (primary tumor cells) after seeding. For viability testing, cells were subjected to lysis with Cell Titer-Glo Luminescent Cell Viability Assay Reagent (Promega). Luminescence was measured via a BioTek synergy HTX Multi-mode micro plate reader (BioTek, Winooski, VT). For cell apoptosis assay, cells treated with or without MI-2 for 24 h were stained with annexin-V and propidium iodide (Abeam, Cambridge, UK), followed by flow cytometry in a NovoCyte Flow Cytometer (ACEA Biosciences, San Diego, CA) to quantify apoptosis. The experiments were repeated at least three times.

[0125] Immunoblotting

[0126] The immunoblotting assay was performed as described previously. Briefly, 5-10 x 106cells were seeded and treated as indicated. The cells were lysed in lysis buffer containing 50 mM HEPES (pH 7.4), 250 mM NaCl, 1 mM EDTA, 1% Nonidet P-40, 1 mM Na3VO4, 1 mM PMSF, 1 mM NaF, and a protease inhibitor mixture (all purchased from Roche Diagnostics, Mannheim, Germany). Protein concentration in cell lysates was measured using a Quick Start Bradford Protein Assay Kit (Bio-Rad) and the lysates were subject to SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. The primary antibodies used to detect total proteins and phosphorylated proteins are presented in Supplementary Table S2 with their sources.

[0127] Kinome profiling of YX0798 and its binding affinity to CDK9

[0128] The kinome profiling of YX0798 at 100 nM was performed using a scanMax assay against a panel of 468 kinases and relevant mutants (Eurofins). The kinase selectivity of YX0798 was visualized by using TREEspot software (Eurofins). The binding affinity of YX0798 and AZD4573 to CDK9 was determined using a kdElect assay (Eurofins).

[0129] Efficacy evaluation in patient-derived organoid (PDO) models.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0130] This assay was performed as described previously. Briefly, the PDO models were established using primary samples collected from patients with MCL. To examine the drug sensitivity of primary MCL cells, The PDO models were treated with the BTK inhibitors (pirtobrutinib or acalabrutinib) or CDK9i (YX0798 or AZD4573) for 72 h. The cell viability was measured using CellTiter-Glo 3D assay kits (Promega, G9681) following the manufacturer’s protocol.

[0131] Animal studies

[0132] The Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center approved the experimental protocols involving animals, which are described further below.

[0133] Cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models

[0134] The in vivo experiments using CDX and PDX models were performed as described previously. Cultured cancer cells or PDX cells were injected subcutaneously (5 x 106cells per mouse) into 6- to 8-week-old NSG female mice (Jackson Laboratory, Bar Harbor, ME). Drug treatment began once the tumor became palpable. Pirtobrutinib was dissolved in 0.6% methylcellulose and 0.5% Tween-80. The mice were treated with vehicle or pirtobrutinib (30 mg / kg, orally, twice daily). Mice were monitored daily for health conditions, tumor growth, and survival. Tumor size was measured weekly using calipers.

[0135] Statistical analyses

[0136] All analyses were performed using statistical software R v3.4.3 with packages betareg v3.1-0, nlme v3.1-131, and survival v2.41-3, or with GraphPad Prism v9. Log rank test was used to generate the statistical significance of mouse survival. Where appropriate, the data are presented as mean ± SD of triplicate samples. The IC50 values were calculated from at least three independent experiments. Comparison of differences between groups were conducted byPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 two-sided, two-sample / -tests. Data represent mean ± SD. Results were considered statistically significant as indicated: P < 0.05 (*); P < 0.01 (**); P < 0.001 (***); p < 0.0001 (****).

[0137] Study approval

[0138] Cell samples were acquired from patients and healthy donors after obtaining written informed consent following the University of Texas MD Anderson Cancer Center Institutional Review Board-approved protocols and in accordance with the Declaration of Helsinki. The Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center approved the experimental protocols involving animals.

[0139] Example 11. Synthesis of ( LS.3 / ?)-\-(5-chloro-4-(5.5-diinethyl-5.6-dihydro-4 / / -pyrrolo [1,2-b] pyr azol-3-yl)pyridin-2-yl)-3-(5-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)oxy)acetamido)pentanamido)cyclohexane-l-carboxamide (YX0803)o o

[0140] Step 1: 5-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)pentanoic acid

[0141] A solution of 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (1.0 g, 3.0 mmol) in SOCl2(4.4 mL, 60.2 mmol) was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The mixture was concentrated in vacuo to remove the solvent. To a solution of the residue in THF (20mL) was added 5-aminopentanoic acid (353 mg, 3.0 mmol).PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 The mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature. The mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (gradient eluent: DCM / MeOH = 30 / 1 (with 0.1% AcOH)) to afford product 5-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)pentanoic acid (520 mg, yield 40%) as white solid.JH NMR (300 MHz, DMSO-t / r,) 6 12.03 (s, 1H), 11.11 (s, 1H), 7.98 (t, J= 5.8 Hz, 1H), 7.81 (dd, J= 8.5, 7.3 Hz, 1H), 7.49 (d, J= 7.3 Hz, 1H), 7.38 (d, J= 8.5 Hz, 1H), 5.12 (dd, J= 12.8, 5.4 Hz, 1H), 4.77 (s, 2H), 3.14 (q, J= 6.3 Hz, 2H), 2.90 (ddd, J= 17.1, 13.9, 5.4 Hz, 1H), 2.67 - 2.51 (m, 2H), 2.21 (t, J= 6.8 Hz, 2H), 2.12 - 1.96 (m, 1H), 1.58 - 1.35 (m, 4H).13C NMR (75 MHz, DMSO) 6 174.77, 173.20, 170.30, 167.17, 167.12, 165.92, 155.53, 137.36, 133.48, 120.86, 117.27, 116.49, 68.12, 49.27, 38.46, 33.68, 31.41, 28.96, 22.44, 22.29.

[0142] Step 2: (15,3A)-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4J / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3-(5-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)pentanamido)cyclohexane- 1 -carboxamide

[0143] To a solution of (15,3A)-3-amino-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4J / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyri din-2 -yl)cy cl ohexane-1 -carboxamide hydrochloride (50 mg, 0.118 mmol) and 5-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)pentanoic acid (51 mg, 0.118 mmol) in DMF (5 mL) was added EtsN (25 mg, 0.247 mmol) and HBTU (49 mg, 0.130 mmol). The mixture was stirred at room temperature for 20 h. The mixture was diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried overPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 20 / 1) to afford product (15,3A)-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4J / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3-(5-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)pentanamido)cyclohexane-l-carboxamide (41 mg, yield 43%) as white solid.JH NMR (300 MHz, CDCh) 8 11.60 - 10.65 (m, 1H), 9.58 - 8.95 (m, 1H), 8.34 - 8.20 (m, 2H), 8.10 (s, 1H), 7.85 - 7.69 (m, 2H), 7.56 (d, J= 7.4 Hz, 1H), 7.21 (t, J= 8.2 Hz, 1H), 5.78 - 5.41 (m, 1H), 5.21 - 4.99 (m, 1H), 4.79 - 4.56 (m, 2H), 3.95 (s, 2H), 3.88 - 3.66 (m, 1H), 3.47 - 3.20 (m, 2H), 3.11 - 2.74 (m, 5H), 2.53 (dt, J= 20.3, 12.0 Hz, 1H), 2.29 - 2.10 (m, 4H), 1.83 - 1.50 (m, 6H), 1.49 - 1.19 (m, 9H), 1.18 -0.98 (m, 1H).13C NMR (75 MHz, CDCh) 6 174.24, 174.06, 172.36, 171.93, 171.70, 169.68, 169.45, 166.93, 166.84, 166.74, 166.68, 166.44, 166.15, 154.89, 154.83, 150.24, 150.10, 147.65, 147.47, 145.09, 143.16, 142.08, 141.89, 137.06, 136.87, 133.56, 123.67, 123.59, 120.28, 119.89, 118.47, 118.43, 117.56, 117.33, 112.88, 112.81, 111.74, 68.79, 68.44, 61.19, 49.39, 47.69, 47.62, 45.15, 44.52, 43.50, 40.19, 38.59, 38.36, 37.05, 36.44, 36.22, 35.98, 32.16, 32.10, 31.60, 31.44, 28.98, 28.66, 28.17, 27.82, 27.03, 24.03, 23.86, 22.95, 22.65.

[0144] Example 12. Synthesis of (LS.3 / ?)- \-(5-chloro-4-(5.5-dimethyl-5.6-dihydro-4 / / -pyrrolo[l,2- / >]pyrazol-3-yl)pyridin-2-yl)-3-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanamido)cyclohexane-l-carboxamide (YX0597)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0145] Step 1: 7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanoic acid

[0146] This intermediate was synthesized by following the similar procedures as those described in Step 1, Example 11. 7-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanoic acid (840 mg, yield 61%) was obtained as white solid.

[0147] Step 2: (15,3A)-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4J / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanamido)cyclohexane- 1 -carboxamide

[0148] This product was synthesized by following the similar procedures as those described in Step 2, Example 11. (15,3A)-A-(5-Chloro-4-(5,5-dimethyl-5,6-dihydro-4J / -pyrrolo[l,2-Z»]pyrazol-3-yl)pyridin-2-yl)-3-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanamido)cyclohexane-l -carboxamide (87 mg, yield 71%) was obtained as white solid. 'HNMR (300 MHz, DMSO) 6 11.10 (s, 1H), 10.55 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.90 (t, J= 5.7 Hz, 1H), 7.81 (dd, J= 8.5, 7.3 Hz, 1H), 7.69 (d, J= 7.9 Hz, 1H), 7.49 (d, J= 7.2 Hz, 1H), 7.39 (d, J= 8.5 Hz, 1H), 5.12 (dd, J= 12.8, 5.4 Hz, 1H), 4.75 (s, 2H), 3.94 (s, 2H), 3.66 - 3.50 (m, 1H), 3.13 (t, J= 6.8 Hz, 2H), 2.98 - 2.84 (m, 3H), 2.69 - 2.51 (m, 3H), 2.10 - 1.96 (m, 3H), 1.88 (d, J= 12.3 Hz, 1H), 1.83 - 1.70 (m, 3H), 1.52 - 1.38 (m, 4H), 1.34 - 1.20 (m, 13H), 1.16 - 1.01 (m, 1H).13C NMR (75 MHz, DMSO) 6 174.99, 174.90, 173.19, 173.10, 171.57, 171.49, 170.30, 170.21, 167.18, 167.05, 166.98,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 165.97, 155.50, 151.54, 151.44, 148.48, 145.16, 142.34, 140.87, 137.37, 133.49, 122.32, 120.90, 117.33, 116.52, 112.59, 112.53, 111.49, 68.16, 60.77, 49.29, 47.28, 47.17, 43.97, 43.92, 43.62, 38.76, 38.64, 35.94, 35.89, 35.63, 32.38, 31.40, 29.32, 28.77, 28.70, 27.95, 26.52, 25.76, 24.49, 22.47.

[0149] Example 13. Synthesis of ( l. S.3 / ?)- \-(5-chloro-4-(5.5-diinethyl-5.6-dihydro-4 / / - pyrrolo [1,2-6] pyr azol-3-yl)pyridin-2-yl)-3-(8-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3- dioxoisoindolin-4-yl)oxy)acetamido)octanamido)cyclohexane-l-carboxamide (YX0807)yl)oxy)acetamido)octanoic acido o

[0151] This intermediate was synthesized by following the similar procedures as those described in Step 1, Example 11. 8-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)octanoic acid (415 mg, yield 62%) was obtained as white solid.

[0152] Step 2: (15,3A)-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4J / -pyrrolo[l,2-6]pyrazol-3- yl)pyridin-2-yl)-3-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)octanamido)cyclohexane- 1 -carboxamidePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0153] This product was synthesized by following the similar procedures as those described in Step 2, Example 11. (LS',3 / )-A-(5-Chloro-4-(5,5-dimethyl-5,6-dihydro-4 / 7-pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)octanamido)cyclohexane-l -carboxamide (45 mg, yield 45%) was obtained as white solid. ‘HNMR (300 MHz, CDC13) 8 10.95 - 10.51 (m, 1H), 9.18 -9.00 (m, 1H), 8.29 - 8.20 (m, 2H), 8.10 (s, 1H), 7.74 (t, J= 7.7 Hz, 1H), 7.60 - 7.46 (m, 2H), 7.19 (d, J= 8.0 Hz, 1H), 5.55 (d, J= 7.9 Hz, 1H), 5.20 - 5.03 (m, 1H), 4.63 (s, 2H), 3.95 (s, 2H), 3.91 - 3.74 (m, 1H), 3.50 - 3.21 (m, 2H), 3.05 (d, J= 13.5 Hz, 1H), 2.96 (s, 2H), 2.95 - 2.76 (m, 2H), 2.62 -2.45 (m, 1H), 2.30 - 2.05 (m, 4H), 1.99 - 1.86 (m, 3H), 1.66 - 1.53 (m, 4H), 1.49 - 1.26 (m, 15H), 1.22 - 1.05 (m, 1H).13C NMR (75 MHz, CDCI3) 6 174.07, 173.12, 172.81, 172.50, 172.33, 169.18, 169.03, 166.76, 166.72, 166.63, 166.06, 166.01, 154.50, 150.15, 147.77, 147.68, 145.03, 143.13, 141.85, 141.74, 136.94, 133.66, 133.62, 123.60, 119.52, 119.46, 118.23, 117.31, 112.82, 112.78, 111.76, 68.04, 61.18, 49.39, 49.32, 47.78, 47.72, 44.73, 44.68, 43.50, 40.19, 38.98, 38.90, 36.75, 36.61, 36.35, 32.22, 32.07, 31.40, 31.36, 29.01, 28.96, 28.83, 28.74, 28.17, 27.73, 26.39, 26.32, 25.49, 25.40, 23.92, 22.79, 22.68.

[0154] Example 14. Synthesis of (LS.3 / ?)-\-(5-chloro-4-(5.5-dimethyl-5.6-dihydro-4 / / -pyrrolo[l,2- / >]pyrazol-3-yl)pyridin-2-yl)-3-(3-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)-lH-l,2,3-triazol-4-yl)propanamido)cyclohexane-l-carboxamide (YX0766)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT01)SOCI2, 90 °C NaN32) DCM, 0 to 80 °C DMF, 80 °C

[0155] Step 1: 4-bromo-A-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)butanamide

[0156] A solution of starting material 4-bromobutanoic acid (700 mg, 4.18 mmol) in thionyl chloride (6 mL) was heated reflux for 1 h. The mixture was cooled to room temperature. The solvent was evaporated in vacuo to afford crude product 4-bromobutanoyl chloride as tan oil. The oil was used in next step without further purification. To a solution of 4-bromobutanoyl chloride in THF (25 mL) was added pomalidomide (570 mg, 2.09 mmol) at 0 °C. The mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography (gradient eluent: DCM) to afford product 4-bromo-A-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)butanamide (410 mg, yield 47%) as light yellow solid.

[0157] Step 2: 4-azido-A-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)butanamideo oPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0158] To a solution of 4-bromo-A-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)butanamide (169 mg, 0.4 mmol) in dry DMF (1 mL) was added NaNs (52 mg, 0.8 mmol). The mixture was stirred at 80 °C for 8 h. The mixture was cooled to room temperature and diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo to afford product 4-azido-A-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)butanamide (150 mg, yield 98%) as yellow solid.

[0159] Step 3: 3-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)- 1 H- 1,2,3 -triazol-4-yl)propanoic acid

[0160] To a solution of 4-azido-A-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)butanamide (300 mg, 0.78 mmol) in DMF / H2O (3 mL / 3 mL) was added pent-4-ynoic acid (92 mg, 0.94 mmol), Na ascorbate (31 mg, 0.16 mmol) and Cu(OAc)2 (29 mg, 0.16 mmol). The mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (gradient eluent: DCM / MeOH = 10 / 1) to afford product 3-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)-17 / -l,2,3-triazol-4-yl)propanoic acid (360 mg, yield 93%) as white solid.

[0161] Step 4: (15,3A)-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4J / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3-(3-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)- 1H- 1,2,3 -triazol-4-yl)propanamido)cyclohexane- 1 -carboxamidePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0162] This product was synthesized by following the similar procedures as those described in Step 2, Example 11. (LS',3^)-A-(5-Chloro-4-(5,5-dimethyl-5,6-dihydro-47 / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3-(3-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)-lZZ- 1,2, 3 -triazol -4-yl)propanamido)cy cl ohexane-1 -carboxamide (61 mg, yield 61%) was obtained as white solid.JH NMR (300 MHz, Methanol-t / 4) 8 8.59 (d, J= 8.4 Hz, 1H), 8.30 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.84 - 7.74 (m, 2H), 7.59 (d, J= 7.3 Hz, 1H), 5.15 (dd, J= A, 5.4 Hz, 1H), 4.51 (t, J= 6.8 Hz, 2H), 3.99 (s, 2H), 3.15 (tt, J= 11.8, 3.9 Hz, 1H), 3.00 (s, 2H), 2.93 - 2.72 (m, 3H), 2.69 - 2.56 (m, 1H), 2.53 (t, J= 7.0 Hz, 2H), 2.42 -2.28 (m, 4H), 2.25 -2.12 (m, 2H), 2.10 -2.02 (m, 3H), 1.94- 1.89 (m, 2H), 1.70 - 1.57 (m, 1H), 1.56 - 1.42 (m, 2H), 1.36 (s, 6H), 1.32 - 1.27 (m, 1H).13C NMR (75 MHz, MeOD) 6 175.60, 174.49, 173.13, 171.56, 169.87, 168.37, 166.87, 150.49, 148.07, 147.13, 145.49, 142.19, 140.70, 136.66, 135.66, 131.66, 125.60, 123.21, 122.21, 118.10, 116.96, 112.71, 111.73, 60.50, 49.32, 49.20, 49.01, 43.61, 43.25, 39.64, 33.43, 33.20, 32.80, 30.75, 30.62, 28.24, 26.63, 25.24, 24.24, 23.26, 22.22.

[0163] Example 15. Synthesis of (LS.3 / ?)-\-(5-chloro-4-(5.5-dimethyl-5.6-dihydro-4 / / -pyrrolo[l,2- / >]pyrazol-3-yl)pyridin-2-yl)-3-(4-(2,6-dimethoxy-4-((£)-3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2ET)-yl)prop-l-en-l-yl)phenoxy)butanamido)cyclohexane-l-carboxamide (YX1011)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0164] Step 1: tert-butyl (E)-4-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyri din- 1(277)-yl)prop- 1 -en- 1 -yl)phenoxy)butanoate

[0165] To a solution of (7f)-l-(3-(4-hydroxy-3,5-dimethoxyphenyl)acryloyl)-5,6-dihydropyridin-2(177)-one (225 mg, 0.824 mmol) in DMF (5 mL) were added tert-butyl 4-bromobutanoate (202 mg, 0.907 mmol) and K2CO3 (125 mg, 0.907 mmol). The reaction mixture was stirred at room temperature for 12 h. The solid was removed by filtration and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (gradient eluent: DCM / MeOH = 30 / 1) to afford product tert-butyl (£)-4-(2,6-dimethoxy-4-(3 -oxo-3 -(6-oxo-3,6-dihy dropyridin- 1 (277)-yl)prop- 1 -en- 1 -yl)phenoxy)butanoate (316 mg, yield 86%) as colorless oil.

[0166] Step 2: (7y)-4-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(277)-yl)prop-l-en-l-yl)phenoxy)butanoic acid0%PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0167] To a solution of tert-butyl (E)-4-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(277)-yl)prop-l-en-l-yl)phenoxy)butanoate (156 mg, 0.35 mmol) in DCM (5 mL) was added CF3COOH (0.40 mL, 5.25 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo to remove the solvent. To the residue was added MeOH and DCM along with some amount of Et20 to precipitate out the solid. The solid was collected by filtration to afford the product (£)-4-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3, 6-dihy dropyri din- l(277)-yl)prop-l-en-l-yl)phenoxy)butanoic acid (106 mg, yield 78%) as white solid.

[0168] Step 3: (15,37?)-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-47 / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3 -(4-(2, 6-dimethoxy-4-((£)-3 -oxo-3 -(6-oxo-3, 6-dihy dropyridin- 1 (277)-yl)prop- 1 -en- 1 -yl)phenoxy)butanamido)cyclohexane- 1 -carboxamideci O HN N A •o yHo.

[0169] To a solution of (15,37?)-3-amino-A-(5-chloro-4-(2-methyl-27 / -indazol-4-yl)pyridin-2-yl)cyclohexane-l -carboxamide hydrochloride (36 mg, 0.085 mmol) and (E)-4-(2,6-dimethoxy-4-(3 -oxo-3 -(6-oxo-3, 6-dihy dropyridin- 1 (277)-yl)prop- 1 -en- 1 -yl)phenoxy)butanoic acid (33 mg, 0.085 mmol) in DMF (2 mL) was added EtsN (18 mg, 0.178 mmol) and HBTU (36 mg, 0.093 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 20 / 1 and EA) to afford product (15,37?)-A-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-47 / -pyrrolo[l,2-Z>]pyrazol-3-yl)pyridin-2-yl)-3-(4-(2,6-dimethoxy-4-((E)-3-oxo-3-(6-oxo-3,6-dihydropyridin- 1 (277)-yl)prop- 1 -en- 1 -yl)phenoxy)butanamido)cyclohexane- 1 -carboxamidePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 (32 mg, yield 50%) as white solid.JH NMR (300 MHz, CDC13) 6 8.42 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.66 (d, J= 15.5 Hz, 1H), 7.41 (d, J= 15.6 Hz, 1H), 6.94 (dt, J = 9.7, 4.2 Hz, 1H), 6.81 (s, 2H), 6.12 (d, J= 8.1 Hz, 1H), 6.03 (dt, J= 9.7, 1.8 Hz, 1H), 4.14 -3.98 (m, 4H), 3.94 (s, 2H), 3.87 (s, 6H), 2.96 (s, 2H), 2.54 - 2.41 (m, 5H), 2.30 - 2.11 (m, 3H), 2.09 - 2.00 (m, 2H), 1.97 - 1.84 (m, 3H), 1.51 - 1.38 (m, 2H), 1.35 - 1.32 (m, 6H), 1.17 - 1.01 (m, 1H).13CNMR(75 MHz, CDCI3) 6173.60, 172.41, 168.82, 165.84, 153.30, 150.00, 148.07, 145.56, 145.03, 143.55, 143.09, 141.43, 138.96, 130.70, 125.78, 123.62, 121.22, 112.64, 111.79, 105.85, 72.16, 61.16, 56.28, 47.64, 45.11, 43.50, 41.64, 40.15, 35.62, 33.38, 32.14, 28.48, 28.18, 26.42, 24.79, 24.19.

[0170] Example 16. Synthesis of ( l. S.3 / ?)-\-(5-chl()ro-4-(2-inethyl-2 / / -ind:izol-4-yl)pyridin-2-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)acetamido)cyclohexane-l-carboxamide (YX0566)DCM, N2, 0 °C to rto o

[0171] Step 1: tert-butyl ((lA,35)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamatePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0172] To a solution of (LS',3 / / )-3-((ter / -butoxycarbonyl)amino)cyclohexane-l -carboxylic acid (1.0 g, 4.11 mmol) in DCM (4 mL) was added l-chloro-A, A,2-trimethylprop-l-en-l-amine (0.82 mL, 6.17 mmol). The reaction mixture was cooled to 0 °C and was purged with N2. The reaction mixture was stirred at 0 °C for 1 h. To the mixture was added 5-chloro-4-iodopyridin-2-amine (1.05 g, 4.11 mmol). The reaction mixture was stirred at room temperature for 20 h. Saturated NH4CI was added to quench the reaction. The reaction mixture was extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient eluent: DCM / MeOH = 50 / 1) to afford product tert-butyl ((lA,35)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1.9 g, yield 96%) as white solid.

[0173] Step 2: tert-butyl ((lA,35)-3-((5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate;NNci o

[0174] To a solution of tert-butyl ((lA,35)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (200 mg, 0.42 mmol) in l,4-dioxane / H2O (20 mL / 4 mL) was added (2-methyl-2J / -indazol-4-yl)boronic acid (74 mg, 0.42 mmol), X-Phos-Pd-G2 (98 mg, 0.13 mmol) and K3PO4 (266 mg, 1.25 mmol). The mixture was purged with N2 and stirred at 30 °C for 24 h. After the bulk of solvent was concentrated in vacuo, the residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 20 / 1) to afford productPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 / crt-butyl ((lA,35)-3-((5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate (120 mg, yield 59%) as yellowish solid.

[0175] Step 3: (15,3A)-3-amino-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)cyclohexane- 1 -carboxamide hydrochloride

[0176] To a solution of tert-butyl ((lA,35)-3-((5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate (90 mg, 0.19 mmol) in DCM (2 mL) was added HC1 (1.12 mL, 1.12 mmol, IM in Et2O) dropwisely. The reaction mixture was stirred at room temperature for 15 h. Removed the solvent to afford product (15,3A)-3-amino-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)cyclohexane-l-carboxamide hydrochloride (77 mg, yield 99%) as yellow solid.

[0177] Step 4: (2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetyl)glycine

[0178] This intermediate was synthesized by following the similar procedures as those described in Step 1, Example 11. (2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetyl)glycine (762 mg, yield 86%) was obtained as white solid.

[0179] Step 5: (15',3A)-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)acetamido)cyclohexane-l-carb oxami dePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0180] To a solution of (15,3A)-3-amino-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)cyclohexane-l -carboxamide hydrochloride (20 mg, 0.048 mmol) and (2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetyl)glycine (19 mg, 0.048 mmol) in DMF (2 mL) was added EtsN (10 mg, 0.10 mmol) and HBTU (20 mg, 0.052 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 10 / 1) to afford product (15,3A)-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)acetamido)cyclohexane-l-carboxamide (18 mg, yield 50%) as white solid.JH NMR (300 MHz, DMSO- e) 6 11.10 (s, 1H), 10.75 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H), 8.21 - 8.11 (m, 2H), 7.85 (d, J= 7.9 Hz, 1H), 7.79 (dd, J= 8.5, 7.3 Hz, 1H), 7.71 (d, J= 8.7 Hz, 1H), 7.46 (d, J= 7.2 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.36 (dd, J= 8.7, 6.8 Hz, 1H), 7.08 (d, J= 6.8 Hz, 1H), 5.11 (dd, J= 12.8, 5.3 Hz, 1H), 4.84 (s, 2H), 4.16 (s, 3H), 3.75 (d, J= 5.7 Hz, 2H), 3.69 - 3.55 (m, 1H), 2.90 (td, J= 17.0, 15.8, 5.3 Hz, 1H), 2.72 - 2.53 (m, 3H), 2.10 - 1.97 (m, 1H), 1.88 (d, J= 12.3 Hz, 1H), 1.84 -1.69 (m, 3H), 1.41 - 1.25 (m, 3H), 1.19- 1.06 (m, 1H).13C NMR (75 MHz, DMSO) 8 174.91, 173.18, 170.28, 167.62, 167.58, 167.17, 165.77, 155.48, 151.51, 148.43, 148.13, 147.82, 137.31, 133.51, 129.49, 125.51, 124.77, 123.96, 122.01, 120.87, 120.70, 118.12, 117.17, 116.41, 115.39, 67.87, 49.27, 47.53, 43.86, 42.25, 35.41, 32.21, 31.40, 29.44, 28.65, 24.41, 22.45.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0181] Example 17. Synthesis of (LS.3 / ?)-\-(5-chl()ro-4-(2-methyl-2 / / -indazol-4-yl)pyridin-2-yl)-3-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanamido)cyclohexane-l-carboxamide (YX0601, YX05671 and YX05672)o o

[0182] Step 1: (LS',3^)-A-(5-chloro-4-(2-methyl-27 / -indazol-4-yl)pyridin-2-yl)-3-(7-(2-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanamido)cyclohexane- 1 -carboxamide

[0183] This product was synthesized by following the similar procedures as those described in Step 5, Example 16. Product (15,3A)-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)-3-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanamido)cyclohexane-l -carboxamide (620 mg, yield 79%) was obtained as white solid. ‘H NMR (300 MHz, DMSO) 8 11.12 (s, 1H), 10.74 (s, 1H), 8.51 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 7.91 (t, J= 5.6 Hz, 1H), 7.80 (dd, J= 8.5, 7.3 Hz, 1H), 7.70 (d,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 J= 8.6 Hz, 2H), 7.48 (d, J= 7.3 Hz, 1H), 7.42 - 7.30 (m, 2H), 7.07 (d, J= 6.8 Hz, 1H), 5.12 (dd, J= 12.9, 5.4 Hz, 1H), 4.75 (s, 2H), 4.16 (s, 3H), 3.66 - 3.50 (m, 1H), 3.18 - 3.07 (m, 2H), 2.98 - 2.82 (m, 1H), 2.70 - 2.51 (m, 3H), 2.10 - 1.96 (m, 3H), 1.87 (d, J= 12.4 Hz, 1H), 1.82 - 1.68 (m, 3H), 1.43 (tt, J= 13.5, 6.9 Hz, 4H), 1.34 - 1.16 (m, 7H), 1.13 - 0.99 (m, 1H).13C NMR (75 MHz, DMSO) 6 174.96, 174.88, 173.20, 171.55, 171.46, 170.30, 167.16, 167.03, 166.95, 165.95, 155.46, 151.51, 151.41, 148.42, 148.12, 147.80, 137.35, 133.46, 129.48, 125.50, 124.77, 123.92, 122.00, 120.83, 120.67, 118.11, 117.27, 116.48, 115.37, 115.32, 68.09, 49.26, 47.19, 47.09, 43.91, 38.74, 38.62, 35.90, 35.84, 35.55, 35.52, 32.35, 31.39, 29.31, 28.74, 26.50, 25.74, 24.47, 22.45.

[0184] Compounds YX05671 and YX05672 were obtained by multiple separations ofYX0601 using prepared thin layer chromatography (gradient eluent: DCM / MeOH = 18 / 1).

[0185] Example 18. Synthesis of (LS.3 / ?)-\-(5-chl()ro-4-(2-methyl-2 / / -ind:izol-4-yl)pyridin-2-yl)-3-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanamido)cyclohexane-l-carboxamide (YX05492)

[0186] Step 1: tert-butyl 5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanoatePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0o o

[0187] To a solution of starting material 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (1.0 g, 3.62 mmol) and tert-butyl 5-aminopentanoate (1254 mg, 7.24 mmol) in DMSO (20 mL) was added DIPEA (1.3 mL, 7.24 mmol). The mixture was stirred at 90 °C for 20 h. The mixture was cooled to room temperature and diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient eluent: EtOAc / Hexane = 1 / 1). tert-Butyl 5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanoate (160 mg, yield 51%) was obtained as yellow solid.

[0188] Step 2: 5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanoic acid oo o

[0189] A solution of tert-butyl 5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanoate (140 mg, 0.33 mmol) in TFA / DCM (2 mL / 2 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. 5-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanoic acid (118 mg, yield 97%) was obtained as yellow solid.

[0190] Step 3: (15,3A)-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)-3-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanamido)cyclohexane-l-carboxamidePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0191] This product was synthesized by following the similar procedures as those described in Step 5, Example 16. Product (LS',3 / )-A-(5-chloro-4-(2-methyl-2 / 7-indazol-4-yl)pyridin-2-yl)-3-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanamido)cyclohexane-l -carboxamide (15 mg, yield 78%) was obtained as yellow solid. ‘HNMR (300 MHz, Chloroforms / ) 8 10.93 - 10.56 (m, 1H), 9.19 (d, J= 6.5 Hz, 1H), 8.43 (d, J= 7.1 Hz, 1H), 8.41 (d, J= 4.0 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J= 8.7 Hz, 1H), 7.48 (dd, J= 8.5, 7.1 Hz, 1H), 7.35 (ddd, J= 8.4, 6.9, 1.2 Hz, 1H), 7.17 (d, J= 7.0 Hz, 1H), 7.09 (d, J= 7.0 Hz, 1H), 6.88 (dd, J= 8.6, 5.1 Hz, 1H), 6.33 (dt, J= 11.5, 5.9 Hz, 1H), 5.62 (dd, J= 16.8, 8.1 Hz, 1H), 5.06 - 4.91 (m, 1H), 4.21 (s, 3H), 3.86 - 3.63 (m, 1H), 3.47 - 3.17 (m, 2H), 3.01 - 2.67 (m, 3H), 2.48 (t, J= 12.0 Hz, 1H), 2.27 - 2.06 (m, 4H), 1.90 - 1.83 (m, 1H), 1.82 - 1.60 (m, 6H), 1.48 - 1.36 (m, 2H), 1.31 (d, J= 15.4 Hz, 1H), 1.00 - 0.77 (m, 1H).13C NMR (75 MHz, CDC13) 6 174.09, 171.90, 171.51, 171.45, 170.08, 169.90, 169.71, 169.68, 167.71, 167.67, 150.21, 148.92, 148.74, 148.71, 147.31, 147.25, 146.80, 146.76, 136.22, 136.12, 132.54, 132.45, 128.67, 128.64, 125.38, 125.08, 123.78, 122.88, 120.83, 118.29, 116.85, 116.71, 115.87, 115.83, 111.53, 111.49, 110.20, 110.12, 49.03, 47.48, 47.44, 45.70, 45.27, 42.30, 40.53, 36.13, 36.10, 35.13, 34.77, 32.07, 31.55, 29.68, 28.13, 27.97, 24.05, 23.43, 23.13, 22.79, 22.68.

[0192] Example 19. Synthesis of (15, 3 / ?)- \-(5-Chloro-4-( l / / -pyrrolo [2,3-6] pyridin-4-yl)pyridin-2-yl)-3-(2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)acetamido)cyclohexane-l-carboxamide(YX1457)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0193] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-l-yl)isoindoline- 1, 3 -di oneo

[0194] To a solution of starting material 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline- 1, 3-dione (2.2 g, 7.48 mmol) and piperidin-4-ylmethanol (861 mg, 7.48 mmol) in DMF (30 mL) was added DIPEA (1.93 g, 14.96 mmol). The mixture was stirred at 80 °C for 18 h. The mixture was cooled to room temperature, diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient eluent: DCM / MeOH = 30 / 1 to 20 / 1) to afford product 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-l-yl)isoindoline-l, 3-dione (2.65 g, yield 91%) was obtained as yellow solid.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0195] Step 2: l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde / NHN— ( )=O

[0196] To a solution of compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-l-yl)isoindoline-l, 3-dione (1.2 g, 3.08 mmol) in DCM (30 mL) was added Dess-Martin reagent (1.57 g, 3.70 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (gradient eluent: EtOAc) to afford product l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (1.0 g, yield 84%) as yellow solid.

[0197] Step 3: tert-butyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-l -carboxylate< N•°Y oN^ O

[0198] To a solution of compound l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (1.0 g, 2.58 mmol) and tert-butyl piperazine-1-carboxylate (481 mg, 2.58 mmol) in DCM (40 mL) was added EtsN (522 mg, 5.16 mmol). The mixture was stirred at room temperature for 10 min. To the reaction mixture was added NaBH(OAc)3 (1.64 g, 7.74 mmol) in three batches. The mixture was stirred at room temperature for 2 h. To the mixture was added some MeOH to quench the NaBH(OAc)3. The mixture was diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient eluent:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 EtOAc / Hexane = 1 / 1 to EtOAc) to afford the product tert-butyl 4-((l-(2-(2,6-dioxopiperidin- 3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-l-carboxylate (1.21 g, yield 84%) as yellow solid.

[0199] Step 4: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(piperazin-l-ylmethyl)piperidin-l-yl)isoindoline- 1,3 -di one hydrochlorideo

[0200] To a solution of tert-butyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-l-carboxylate (1.19 g, 2.13 mmol) in DCM (20 mL) was added HC1 (21.3 mL, 1 M in Et2O) at 0 °C. The mixture was stirred at room temperature for 3 h. After the reaction mixture was removed some solvent, the precipitated solid was filtered to afford product 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(piperazin-l-ylmethyl)piperidin-l-yl)isoindoline-l, 3-dione hydrochloride (1.0 g, yield 95%) was obtained as yellow solid.

[0201] Step 5: tert-butyl 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)acetateo

[0202] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(piperazin-l-ylmethyl)piperidin-l-yl)isoindoline-l, 3-dione hydrochloride (300 mg, 0.607 mmol) and tertbutyl 2-bromoacetate (142 mg, 0.729 mmol) in DMF (8 mL) was added K2CO3 (210 mg, 1.52 mmol). The mixture was stirred at room temperature for 20 h. The mixture was diluted with water, and then extracted with DCM several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 20 / 1) to affordPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 the product tert-butyl 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)acetate (205 mg, yield 59%) as yellow solid.

[0203] Step 6: 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)acetic acid

[0204] To a solution of tert-butyl 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)acetate (205 mg, 0.359 mmol) in DCM (8 mL) was added CF3COOH (613 mg, 5.38 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with water, and then extracted with DCM several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 10 / 1) to afford product 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)acetic acid (176 mg, yield 95%) as yellow solid.

[0205] Step 7: (15,3A)-A-(5-chloro-4-(lJ / -pyrrolo[2,3-Z>]pyridin-4-yl)pyridin-2-yl)-3-(2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)acetamido)cyclohexane- 1 -carboxamideoClH N— (, N )=O' VNH

[0206] To a solution of (15',3A)-3-amino-A-(5-chloro-4-(U / -pyrrolo[2,3-Z>]pyridin-4-yl)pyridin-2-yl)cyclohexane-l -carboxamide hydrochloride and 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)acetic acid in DMF (4 mL) was added EtsN and HBTU. The mixture was stirred at roomPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 temperature for 5 h. The mixture was diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 10 / 1). Product (15,3A)-A-(5-chloro-4-(lJT-pyrrolo[2,3-Z>]pyridin-4-yl)pyridin-2-yl)-3-(2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro- I,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)acetamido)cyclohexane-l-carboxamide (48 mg, yield 45%) was obtained as yellow solid.JH NMR (300 MHz, CDCh) 8 II.20 (s, 1H), 10.77 (s, 1H), 9.26 (s, 1H), 8.50 - 8.42 (m, 2H), 8.42 - 8.36 (m, 1H), 7.46 (d, J = 11.0 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.24 - 7.06 (m, 2H), 6.42 (dd, J= 3.6, 1.6 Hz, 1H), 5.00 (dd, J= 11.9, 5.4 Hz, 1H), 4.01 - 3.82 (m, 1H), 3.63 (d, J= 11.5 Hz, 2H), 3.08 - 2.90 (m, 3H), 2.89 - 2.74 (m, 4H), 2.65 - 2.48 (m, 5H), 2.47 - 2.32 (m, 4H), 2.27 -2.11 (m, 4H), 2.03 - 1.78 (m, 5H), 1.77 - 1.60 (m, 1H), 1.56 - 1.28 (m, 5H), 1.25 - 1.07 (m, 1H).13C NMR (75 MHz, CDCh) 6 174.05, 172.57, 169.51, 167.23, 166.60, 166.57, 159.71, 156.33, 150.23, 148.85, 147.59, 147.18, 146.45, 146.33, 142.10, 137.12, 129.03, 129.00, 126.21, 125.00, 123.42, 123.29, 118.71, 116.03, 115.87, 113.79, 112.24, 111.91, 100.37, 64.19, 61.43, 53.68, 53.46, 50.54, 49.48, 46.92, 44.68, 35.39, 33.06, 32.38, 31.57, 30.67, 28.53, 24.09, 22.81.

[0207] Example 20. Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sidfaneylidene)acetamide (YX0825)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0208] Step 1: 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)acetamide

[0209] To a solution of starting material ((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(imino)(methyl)-X6-sulfanone (50 mg, 0.124 mmol) and 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (41 mg, 0.124 mmol) in DMF (3 mL) was added EtsN (27 mg, 0.260 mmol) and HBTU (52 mg, 0.136 mmol). The mixture was stirred at 40 °C for 18 h. The mixture was diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 15 / 1) to afford product 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)acetamide (53 mg, yield 60%) as white solid.JH NMR (300 MHz, DMSO) 8 11.10 (s, 1H), 9.92 (s, 1H), 8.26 (d, J= 1.6 Hz, 1H), 8.21 (d, J= 5.1 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.43 (d, = 7.2 Hz, 1H), 7.36 (dd, J= 8.4, 6.8 Hz, 1H), 7.24 (d, = 8.6Hz, 1H), 7.10 (dd, J= 11.5, 2.4 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.88 (ddd, J= 5.4, 1.6, 0.7 Hz, 1H), 5.10 (dd, J = 12.6, 5.3 Hz, 1H), 4.90 (s, 2H), 3.87 (s, 1H), 3.80 (s, 3H), 3.34 (s, 3H), 2.98 - 2.82 (m, 1H), 2.64-2.51 (m, 2H), 2.09- 1.98 (m, 1H).13CNMR(75 MHz, DMSO) 6175.35, 173.22, 173.12, 170.37, 170.28, 167.24, 165.75, 165.68, 162.50, 158.46, 158.31, 155.95, 154.99, 154.90, 154.08, 151.14, 150.82, 148.26, 137.93, 137.00, 135.36, 135.15, 134.83, 134.48, 133.65,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 132.13, 131.99, 120.38, 119.21, 119.17, 118.54, 116.66, 115.95, 114.22, 113.74, 107.75, 107.46, 100.80, 100.45, 69.07, 56.70, 49.26, 31.42, 22.46.

[0210] Example 21. Synthesis of 6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)hexanamide (YX0832)

[0211] Step 1: 6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-7V- (((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)hexanamideo

[0212] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product 6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)hexanamide (74 mg, yield 72%) was obtained as white solid. Tf NMR (300 MHz, DMSO) 6 11.10 (s, 1H), 9.89 (s, 1H), 8.26 - 8.16 (m, 2H), 7.91 (t, J= 5.7 Hz, 1H), 7.80 (dd, J= 8.5, 7.3 Hz, 1H), 7.73 (d, J= 5.4 Hz, 1H), 7.69 (s, 1H), 7.49 (d, = 7.2 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.09 (dd, J= 11.4, 2.5 Hz, 1H), 6.96 - 6.85 (m, 2H), 5.12 (dd, J= 12.7, 5.4 Hz, 1H), 4.85 (s, 2H), 4.75 (s, 2H), 3.80 (s, 3H), 3.24 (s, 3H), 3.17 - 3.06 (m, 2H), 2.90 (ddd, J= 17.0, 13.8, 5.3 Hz, 1H), 2.66 - 2.51 (m,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 2H), 2.18 (t, J= 7.4 Hz, 2H), 2.09 - 1.98 (m, 1H), 1.55 - 1.34 (m, 4H), 1.30 - 1.17 (m, 2H).13CNMR(75 MHz, DMSO) 6 181.59, 173.20, 170.31, 167.19, 167.07, 165.97, 165.74, 162.49, 158.44, 158.31, 155.52, 154.98, 154.04, 151.16, 151.13, 150.78, 148.12, 138.60, 137.37, 135.32, 135.12, 134.72, 134.37, 133.49, 132.11, 131.97, 120.88, 119.20, 119.16, 118.53, 117.31, 116.51, 114.21, 113.85, 107.73, 107.45, 100.78, 100.43, 68.15, 57.67, 56.69, 49.30, 39.36, 38.98, 38.68, 31.41, 29.26, 26.40, 25.30, 22.46.

[0213] Example 22. 7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)heptanamide (YX0932)

[0214] Step 1: 7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-A- (((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyri din-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)heptanamide

[0215] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product 7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)heptanamide (72 mg, yield 69%) was obtained as white solid.1H NMR (300 MHz, CDC13+ MeOD) 88.20 (d, J= 5.2 Hz, 1H), 8.07 (s, 1H), 7.80 - 7.70 (m, 2H), 7.56 - 7.46 (m, 2H), 7.28 - 7.19 (m, 2H), 6.86 (dd, J =PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 5.2, 1.5 Hz, 1H), 6.76 - 6.67 (m, 2H), 5.07 - 4.94 (m, 1H), 4.86 - 4.63 (m, 2H), 4.59 (s, 2H), 3.78 (s, 3H), 3.41 - 3.33 (m, 1H), 3.29 - 3.18 (m, 1H), 3.13 (d, J= 4.7 Hz, 3H), 2.91 - 2.67 (m, 3H), 2.30 (t, J= 7.5 Hz, 2H), 2.19 - 2.07 (m, 1H), 1.65 - 1.46 (m, 4H), 1.42 - 1.22 (m, 4H).13C NMR (75 MHz, CDC13+ MeOD) 6 183.61, 183.53, 172.71, 172.65, 169.23, 167.41, 166.88, 166.21, 165.89, 162.60, 158.17, 158.04, 154.62, 154.49, 154.42, 151.19, 149.91, 149.88, 148.04, 137.80, 137.67, 137.62, 137.11, 136.01, 135.81, 134.44, 134.07, 133.45, 131.69, 131.68, 131.56, 131.54, 119.80, 118.62, 118.57, 118.00, 117.77, 117.33, 114.28, 113.38, 113.35, 107.34, 107.06, 99.73, 99.39, 67.80, 58.37, 55.81, 49.26, 39.51, 39.48, 39.03, 38.44, 31.28, 28.84, 28.80, 26.46, 25.43, 22.66.

[0216] Example 23. Synthesis of 8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)octanamide (YX0849)

[0217] Step 1: 8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)octanamideo

[0218] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product 8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 yl)oxy)acetamido)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)octanamide (121 mg, yield 95%) was obtained as white solid.JH NMR (300 MHz, CDC13) 6 12.22 - 11.53 (m, 1H), 8.84 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.77 (t, J= 8.0 Hz, 1H), 7.63 - 7.40 (m, 3H), 7.27 - 7.14 (m, 2H), 6.88 (t, J= 6.4 Hz, 1H), 6.77 - 6.62 (m, 2H), 5.03 (s, 1H), 4.81 - 4.52 (m, 4H), 3.80 (s, 3H), 3.44 - 3.23 (m, 2H), 3.19 (d, J= 8.8 Hz, 3H), 3.02 - 2.76 (m, 3H), 2.39 -2.12 (m, 3H), 1.60 - 1.45 (m, 4H), 1.38 - 1.19 (m, 6H).13C NMR (75 MHz, CDCI3) 6 183.09, 173.01, 172.74, 169.30, 169.14, 166.65, 166.53, 166.16, 165.84, 162.54, 158.21, 158.08, 154.69, 154.49, 151.20, 150.07, 147.80, 137.83, 137.78, 136.99, 136.03, 135.88, 134.42, 134.38, 134.03, 133.57, 131.73, 131.59, 119.94, 118.78, 118.29, 117.80, 117.70, 117.43, 114.11, 113.45, 107.36, 107.08, 99.74, 99.40, 68.33, 58.68, 58.61, 55.90, 49.37, 39.76, 39.18, 39.14, 39.06, 39.00, 31.52, 29.00, 28.96, 28.92, 28.84, 28.80, 26.48, 25.82, 25.78, 22.83.

[0219] Example 24. Synthesis of 5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sidfaneylidene)pentanamide (YX0850)N N HO' NH Et3N HBTUS'NH dry DMF, rtA ft- NHO O•NH)=ONH NH

[0220] Step 1: 5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)pentanamidePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0221] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product 5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyri din-2 -yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)pentanamide (34 mg, yield 86%) was obtained as yellow solid.1HNMR (300 MHz, CDC13) 8 10.61 - 10.11 (m, 1H), 8.36 (d, J= 17.5 Hz, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.62 (s, 2H), 7.52 - 7.39 (m, 1H), 7.27 - 7.21 (m, 1H), 7.12 - 7.01 (m, 1H), 6.87 (d, J= 6.1 Hz, 2H), 6.80 - 6.67 (m, 2H), 6.29 (s, 1H), 5.04 - 4.89 (m, 1H), 4.75 - 4.53 (m, 2H), 3.81 (s, 3H), 3.36 - 3.21 (m, 2H), 3.06 (d, J= 12.0 Hz, 3H), 2.94 - 2.71 (m, 3H), 2.41 (t, J = 6.8 Hz, 2H), 2.20 - 2.10 (m, 1H), 1.74 - 1.54 (m, 4H).13C NMR (75 MHz, CDCI3) 6 182.33, 182.28, 171.81, 171.74, 169.83, 169.70, 169.53, 167.69, 165.91, 162.62, 158.20, 158.07, 154.66, 154.54, 151.24, 149.84, 148.35, 146.96, 146.90, 137.56, 136.07, 135.86, 134.55, 134.49, 134.18, 134.11, 132.52, 132.48, 131.79, 131.66, 118.72, 118.67, 117.56, 116.71, 114.19, 113.17, 113.09, 111.36, 109.95, 109.92, 107.43, 107.15, 99.79, 99.45, 58.86, 55.91, 48.92, 42.21, 42.12, 39.00, 38.55, 38.36, 31.46, 28.73, 28.65, 22.95, 22.88, 22.81.

[0222] Example 25. Synthesis of 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)acetamide (YX1148)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0223] Step 1: 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)acetamideo

[0224] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product 2-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)acetamide (40 mg, yield 36%) was obtained as yellow solid.JH NMR (300 MHz, CDC13) 8 10.13 (s, 1H), 8.38 (s, 1H), 8.27 (d, J= 5.2 Hz, 1H), 8.16 (d, J= 1.7 Hz, 1H), 7.77 (s, 1H), 7.54 (d, J= 5.2 Hz, 1H), 7.44 (d, J= 11.1 Hz, 1H), 7.36 (d, J= 7.3 Hz, 1H), 7.26 (d, J= 7.8 Hz, 1H), 6.89 (dd, J= 5.2, 1.5 Hz, 1H), 6.82 - 6.69 (m, 2H), 4.96 (dd, J= 12.0, 5.4 Hz, 1H), 4.80-4.62 (m, 2H), 3.82 (s, 3H), 3.64 (d, J= 11.9 Hz, 2H), 3.25 (s, 2H), 3.14 (s, 3H), 2.94 - 2.73 (m, 5H), 2.63 (s, 4H), 2.53 (s, 4H), 2.25 (d, J= 6.9 Hz, 2H), 2.15 (dd, J= 9.3, 3.9 Hz, 1H), 1.88 (d, J = 12.3 Hz, 2H), 1.80 - 1.63 (m, 1H), 1.44 - 1.30 (m, 2H).13C NMR (75 MHz, CDCI3) 6 178.93, 171.96, 168.93, 167.18, 166.58, 166.54, 165.92, 162.63, 159.69, 158.21, 158.08, 156.31, 154.71, 154.54, 151.24, 149.87, 149.84, 148.32, 146.50, 146.38, 137.51, 135.96, 135.76, 134.68, 134.31, 131.79, 131.66, 129.00, 128.96, 123.28, 123.16,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 118.71, 118.66, 117.67, 114.13, 113.79, 113.72, 113.19, 112.21, 111.87, 107.45, 107.16, 99.82, 99.48, 64.32, 63.59, 58.85, 55.95, 53.31, 53.09, 50.57, 50.50, 49.42, 32.99, 31.50, 30.71, 22.75.

[0225] Example 26. Synthesis of 4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)butanamide (YX11242)

[0226] Step 1: tert-butyl 4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin- 5-yl)piperidin-4-yl)methyl)piperazin-l-yl)butanoate

[0227] This intermediate was synthesized by following the similar procedures as those described in Step 5, Example 19. tert-Butyl 4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)butanoate (225 mg, yield 62%) was obtained as yellow solid.

[0228] Step 2: 4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)butanoic acidoPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0229] This intermediate was synthesized by following the similar procedures as those described in Step 6, Example 19. 4-(4-((l-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)butanoic acid (150 mg, yield 98%) was obtained as yellow solid.

[0230] Step 3: 4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)butanamideo

[0231] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product 4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-l-yl)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)butanamide (23 mg, yield 25%) was obtained as yellow solid. 'H NMR (300 MHz, CDC13) 8 10.42 (s, 1H), 8.33 (s, 1H), 8.29 (d, J= 5.2 Hz, 1H), 8.16 (d, J= 1.7 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J= 5.1 Hz, 1H), 7.45 (d, J= 11.1 Hz, 1H), 7.38 (d, J= 7.3 Hz, 1H), 7.31 - 7.24 (m, 1H), 6.89 (dd, J= 5.2, 1.5 Hz, 1H), 6.81 - 6.69 (m, 2H), 4.96 (dd, J= 12.1, 5.3 Hz, 1H), 4.76 (d, J= 13.6 Hz, 1H), 4.63 (d, J= 13.6 Hz, 1H), 3.82 (s, 3H), 3.65 (d, J= 12.1 Hz, 2H), 3.11 (s, 3H), 2.95 - 2.74 (m, 5H), 2.59 - 2.32 (m, 12H), 2.23 (d, J= 7.0 Hz, 2H), 2.19 -2.10 (m, 1H), 1.95 - 1.78 (m, 4H), 1.77 - 1.63 (m, 1H), 1.46 - 1.30 (m, 2H).13C NMR (75 MHz, CDCI3) 8 182.58, 172.11, 172.05, 169.00, 168.95, 167.18, 166.57, 166.53, 165.91, 162.62, 159.70, 158.22, 158.08, 156.31, 154.67, 154.54, 151.24, 149.90, 149.88, 148.34, 146.51, 146.40, 137.80, 135.95, 135.75, 134.66, 134.30, 131.79, 131.66, 129.02, 128.98,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 123.29, 123.16, 118.71, 118.67, 117.75, 114.11, 113.79, 113.73, 113.08, 112.21, 111.87, 107.44, 107.15, 99.81, 99.47, 64.39, 58.75, 57.89, 55.95, 53.60, 53.09, 50.60, 50.54, 49.42, 38.49, 37.59, 33.05, 31.52, 30.74, 22.76.

[0232] Example 27. Synthesis of 7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin- 2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)-7-oxoheptanamide (YX10503)

[0233] Step 1: / crt-butyl 4-(4-((2, 6-dioxopiperi din-3 -yl)amino)phenyl)piperi dine- 1-carboxylate

[0234] To a solution of starting material tert-butyl 4-(4-aminophenyl)piperidine-l -carboxylate (1.6 g, 5.79 mmol) and 3 -brom opiperidine-2, 6-dione (6.67 g, 34.73 mmol) in DMF (30 mL) was added NaHCCh (2.92 g, 34.73 mmol). The mixture was stirred at 70 °C for 20 h. The mixture was cooled to room temperature, added saturated NH4CI (aq.) to adjust the pH to 7, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue wasPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 purified by prepared thin layer chromatography (gradient eluent: EtOAc / Hexane = 1 / 2) to afford product tert-butyl 4-(4-((2, 6-dioxopiperi din-3 -yl)amino)phenyl)piperi dine- 1-carboxylate (2.22 g, yield 99%) as pale greenish solid.

[0235] Step 2: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione hydrochloride

[0236] This intermediate was synthesized by following the similar procedures as those described in Step 4, Example 19. 3-((4-(Piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione hydrochloride (1.82 g, yield 99%) was obtained as pale solid.

[0237] Step 3: 7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)-7-oxoheptanamide

[0238] To a solution of 6-((((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)amino)-6-oxoheptanoic acid and 3 -((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione hydrochloride in DMF was added EtsN and HBTU. The mixture was stirred at 40 °C for 20 h. The mixture was diluted with water, and then extracted with EtOAc several times. The combined organic phase was washed with water and brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 15 / 1). Product 7 -(4-(4-((2, 6-dioxopiperi din-3 -yl)amino)phenyl)piperidin- 1 -yl)-7V-(((2-((5 -fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 l6-sulfaneylidene)-7-oxoheptanamide (38 mg, yield 57%) was obtained as white solid. 'H NMR(300MHz, CDC13) 69.93 (s, 1H), 8.45 (s, 1H), 8.29 (d, J= 5.1 Hz, 1H), 8.18 (d, J= 1.7 Hz, 1H), 7.75 (s, 1H), 7.68 - 7.54 (m, 1H), 7.34 - 7.28 (m, 1H), 7.06 (d, J= 8.1 Hz, 2H), 6.89 (dd, J= 5.2, 1.5 Hz, 1H), 6.83 - 6.72 (m, 2H), 6.70 - 6.63 (m, 2H), 4.89 - 4.59 (m, 4H), 4.09 (dd, J= 12.0, 4.2 Hz, 1H), 3.96 (d, J= 13.4 Hz, 1H), 3.83 (s, 3H), 3.21 - 3.03 (m, 4H), 2.94 -2.74 (m, 2H), 2.70 - 2.50 (m, 3H), 2.44 - 2.31 (m, 4H), 2.01 - 1.86 (m, 2H), 1.84 - 1.78 (m, 1H), 1.74- 1.62 (m, 4H), 1.61 - 1.47 (m, 2H), 1.47- 1.35 (m, 2H).13C NMR (75 MHz, CDCI3) 6 182.87, 173.18, 173.12, 172.19, 171.39, 165.93, 162.64, 158.23, 158.10, 154.73, 154.54, 151.25, 149.95, 149.92, 148.31, 144.97, 144.93, 137.78, 136.00, 135.88, 135.80, 134.65, 134.29, 131.81, 131.68, 127.70, 118.76, 118.72, 117.75, 114.12, 113.76, 113.71, 113.18, 107.47, 107.18, 99.83, 99.49, 58.71, 55.96, 54.74, 46.39, 42.42, 41.87, 39.52, 38.51, 34.26, 33.15, 31.17, 29.03, 25.80, 25.35, 25.18.

[0239] Example 28. Synthesis of 8-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)-8-oxooctanamide (YX1057)Et3N HBTUOHN •S' Y+HCIHxo •o dry DMF, rto,sxYNHxoN YHs

[0240] Step 1: 8-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)-8-oxooctanamidePCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0241] This product was synthesized by following the similar procedures as those described in Step 3, Example 27. Product 8-(4-(4-((2, 6-dioxopiperi din-3 -yl)amino)phenyl)piperi din- 1-yl)-N-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyri din-2 -yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)-8-oxooctanamide (19 mg, yield 53%) was obtained as white solid. Tf NMR (300 MHz, CDC13) 8 10.14 - 9.88 (m, 1H), 8.76 - 8.55 (m, 1H), 8.27 (d, J= 5.2 Hz, 1H), 8.17 (s, 1H), 7.85 - 7.75 (m, 1H), 7.67 - 7.55 (m, 1H), 7.33 -7.28 (m, 1H), 7.06 (d, J= 8.5 Hz, 2H), 6.89 (dt, J= 5.3, 1.8 Hz, 1H), 6.83 - 6.72 (m, 2H), 6.67 (dd, = 8.6, 2.4 Hz, 2H), 4.97 - 4.51 (m, 4H), 4.08 (dd, J= 12.4, 4.1 Hz, 1H), 3.96 (d, J= 13.5 Hz, 1H), 3.83 (s, 3H), 3.21 - 3.03 (m, 4H), 2.88 - 2.69 (m, 2H), 2.69 - 2.49 (m, 3H), 2.43 -2.31 (m, 4H), 2.01 - 1.85 (m, 2H), 1.85 - 1.78 (m, 1H), 1.71 - 1.61 (m, 4H), 1.61 - 1.48 (m, 2H), 1.42 - 1.33 (m, 4H).13C NMR (75 MHz, CDCI3) 6 182.98, 173.34, 173.19, 172.18, 171.53, 165.94, 162.65, 158.23, 158.10, 154.72, 154.55, 151.24, 149.98, 149.95, 148.17, 144.99, 144.94, 137.90, 137.85, 136.10, 135.87, 134.54, 134.17, 131.81, 131.68, 127.69, 118.73, 117.74, 114.19, 113.70, 113.30, 113.24, 107.47, 107.18, 99.83, 99.49, 58.72, 55.96, 54.77, 46.44, 42.44, 41.86, 39.66, 38.49, 34.25, 33.34, 33.29, 31.16, 29.24, 29.05, 29.02, 25.82, 25.54, 25.50, 25.34.

[0242] Example 29. Synthesis of (Zi)-2-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2ET)-yl)prop-l-en-l-yl)phenoxy)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)acetamide (YX0965)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0243] Step 1: tert-butyl (E)-2-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyri din- 1(2 / / )-yl)prop- 1 -en- 1 -yl)phenoxy)acetate

[0244] This intermediate was synthesized by following the similar procedures as those described in Step 1, Example 15. tert-Butyl (E)-2-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2J7)-yl)prop-l-en-l-yl)phenoxy)acetate (1.30 g, yield 94%) was obtained as colorless oil.

[0245] Step 2: (E)-2-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2J7)-yl)prop-l-en-l-yl)phenoxy)acetic acido

[0246] This intermediate was synthesized by following the similar procedures as those described in Step 2, Example 15. (E)-2-(2,6-Dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2J7)-yl)prop-l-en-l-yl)phenoxy)acetic acid (1.10 g, yield 98%) was obtained as pale solid.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0247] Step 3: (E)-2-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2J7)-yl)prop-l-en-l-yl)phenoxy)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyri din-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)acetamide. S' Y o yN HXO 0.

[0248] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product (E)-2-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-1 (2J7)-yl)prop- 1 -en- 1 -yl)phenoxy)-A-(((2-((5 -fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)acetamide (81 mg, yield 88%) was obtained as white solid.JH NMR (300 MHz, CDCh) 5 8.21 (d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 8.13 (d, J= 1.6 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J= 15.6 Hz, 1H), 7.51 (d, J= 5.1 Hz, 1H), 7.40 (d, J= 15.6 Hz, 1H), 7.25 (dd, J= 8.4, 6.5 Hz, 1H), 6.93 (dt, J= 9.7, 4.2 Hz, 1H), 6.86 (dd, J= 5.2, 1.5 Hz, 1H), 6.80 - 6.69 (m, 4H), 6.03 (dt, J= 9.7, 1.8 Hz, 1H), 4.81 - 4.62 (m, 4H), 4.02 (t, J= 6.4 Hz, 2H), 3.87 - 3.76 (m, 9H), 3.16 (s, 3H), 2.46 (tdd, J= 6.3, 3.9, 1.8 Hz, 2H).13C NMR (75 MHz, CDCh) 8 177.41, 168.87, 165.85, 162.56, 158.16, 158.03, 154.73, 152.70, 151.17, 149.89, 149.86, 148.51, 145.58, 143.66, 138.56, 137.35, 135.67, 135.47, 134.90, 134.54, 131.80, 131.66, 130.40, 125.76, 121.04, 118.70, 118.66, 117.77, 113.96, 113.11, 107.42, 107.13, 105.79, 99.79, 99.45, 73.02, 58.73, 56.27, 55.94, 41.65, 38.67, 24.78.

[0249] Example 30. Synthesis of (Zi)-4-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2ET)-yl)prop-l-en-l-yl)phenoxy)-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)butanamide (YX1009)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0250] Step 1: (E)-4-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-l(2J7)-yl)prop-l-en-l-yl)phenoxy)-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)butanamide

[0251] This product was synthesized by following the similar procedures as those described in Step 1, Example 20. Product (E)-4-(2,6-dimethoxy-4-(3-oxo-3-(6-oxo-3,6-dihydropyridin-1 (2J7)-yl)prop- 1 -en- 1 -yl)phenoxy)-7V-(((2-((5 -fluoro-4-(4-fluoro-2-methoxyphenyl)pyri din-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)butanamide (56 mg, yield 81%) was obtained as white solid. 'HNMR (300 MHz, CDC13) 88.22 (d, J= 5.2 Hz, 1H), 8.16 (s, 1H), 8.12 (d, J= 1.6 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J= 15.5 Hz, 1H), 7.47 (d, J= 5.1 Hz, 1H), 7.41 (d, J= 15.5 Hz, 1H), 7.28 - 7.21 (m, 1H), 6.93 (dt, J= 9.7, 4.1 Hz, 1H), 6.86 (dd, J = 5.1, 1.3 Hz, 1H), 6.79 - 6.69 (m, 4H), 6.04 (dt, J= 9.7, 1.8 Hz, 1H), 4.78 - 4.59 (m, 2H), 4.03 (td, J= 6.4, 3.9 Hz, 4H), 3.83 (s, 6H), 3.80 (s, 3H), 3.10 (s, 3H), 2.61 (t, J= 7.4 Hz, 2H), 2.46 (tdd, J= 6.3, 4.0, 1.8 Hz, 2H), 2.10 - 1.99 (m, 2H).13C NMR (75 MHz, CDCI3) 6 182.55, 168.89, 165.86, 162.59, 158.17, 158.03, 154.71, 154.48, 153.57, 151.18, 149.90, 149.86, 148.52, 145.56, 143.80, 139.25, 137.68, 135.74, 135.54, 134.85, 134.49, 131.80, 131.66, 130.49, 125.78, 120.99, 118.64, 118.60, 117.84, 114.02, 113.00, 107.43, 107.15, 105.64, 99.81, 99.47, 72.78, 58.62, 56.16, 55.94, 41.65, 38.48, 36.00, 26.05, 24.78.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0252] Example 31. Synthesis of (LS.3 / ?)-3-:icet:iinido-\-(5-chloro-4-(2-inethyl-2 / / -indazol-4-yl)pyridin-2-yl)cyclohexane-l-carboxamide (YX04582)i

[0253] Step 1: (15',3A)-3-amino-7V-(5-chloro-4-iodopyridin-2-yl)cyclohexane-l-carboxamide hydrochloride

[0254] To a solution of tert-butyl ((lR,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (30 mg, 0.062 mmol) in DCM (2 mL) was added HC1 (0.38 mL, 0.376 mmol, IM in Et2O) dropwisely. The reaction mixture was stirred at room temperature for 18 h. Removed the solvent to afford product ( I. S'.3 / ?)-3-amino-A'-(5-chloro-4-iodopyridin-2-yl)cyclohcxanc-1 -carboxamide hydrochloride (24 mg, yield 92%) as white solid.

[0255] Step 2: (15',3A)-3-acetamido-7V-(5-chloro-4-iodopyridin-2-yl)cyclohexane-l-carb oxami dei

[0256] To a solution of ( I. S'.3 / )-3-amino- '-(5-chloro-4-iodopyridin-2- l)cyclohcxanc- 1 -carboxamide hydrochloride (24 mg, 0.058 mmol) in DCM (5 mL) was added AC2O (6 pL, 0.063 mmol) and EtsN (26 pL, 0.186 mmol) dropwisely. The reaction mixture was stirred at room temperature for 24 h. After the reaction mixture was concentrated, the residue was purified by prepared thin layer chromatographyPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 (gradient eluent: DCM / MeOH = 30 / 1) to afford product (lS,3J?)-3-acetamido- / V-(5-chloro-4-iodopyridin-2-yl)cyclohexane- 1 -carboxamide (23 mg, yield 95%) as white solid.

[0257] Step 3: (15',3A)-3-acetamido-7V-(5-chloro-4-(2-methyl-2Z / -indazol-4-yl)pyridin-2-yl)cyclohexane- 1 -carboxamide; NNci o H, No

[0258] To a solution of (I. S'.3 / ?)-3-acctamido- '-(5-chloro-4-iodopyridin-2-yl)cyclohcxanc-l-carboxamide (87 mg, 0.21 mmol) in 1,4-dioxane / H2O (15 mL / 3 mL) was added (2-methyl-27 / -indazol-4-yl)boronic acid (36 mg, 0.21 mmol), X-Phos-Pd-G2 (49 mg, 0.062 mmol) and K3PO4 (132 mg, 0.62 mmol). The mixture was purged with N2 and stirred at 30 °C for 24 h. After the bulk of solvent was concentrated in vacuo, the residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 20 / 1) to afford product (15,3A)-3-acetamido-7V-(5-chloro-4-(2-methyl-2Z / -indazol-4-yl)pyridin-2-yl)cyclohexane-l -carboxamide (62 mg, yield 71%) as white solid. 'H NMR (300 MHz, Chloroform-J) 58.58 (s, 1H), 8.35 (d, J= 9.0 Hz, 2H), 7.83 (s, 1H), 7.77 (d, 7= 8.7 Hz, 1H), 7.36 (dd, J= 8.7, 6.9 Hz, 1H), 7.18 (d, J= 6.9 Hz, 1H), 5.67 (d, 7= 8.2 Hz, 1H), 4.22 (s, 3H), 3.88 (dtt,7= 11.8, 7.9, 3.6 Hz, 1H), 2.61 - 2.44 (m, 1H), 2.26 (d,7= 12.6 Hz, 1H), 2.04 - 1.85 (m, 6H), 1.53 - 1.32 (m, 3H), 1.24 - 1.07 (m, 1H).13C NMR (75 MHz, CDCI3) 6 173.60, 169.45, 149.98, 148.94, 148.26, 147.82, 128.76, 125.41, 125.14, 123.76, 122.84, 120.90, 118.20, 115.62, 47.67, 44.92, 40.54, 35.48, 32.22, 28.53, 24.09, 23.43.

[0259] Example 32. Synthesis of (LS.3 / ?)-\-(5-chl()ro-4-(2-methyl-2 / / -indazol-4-yl)pyridin-2-yl)-3-(2,2,2-trifluoroacetamido)cyclohexane-l-carboxamide (YX04822)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0260] Step 1: (15,3A)-A-(5-chloro-4-iodopyridin-2-yl)-3-(2,2,2-trifluoroacetamido)cyclohexane-l -carboxamidei

[0261] This intermediate was synthesized by following the similar procedures as those described in Step 2, Example 31. (15,3A)-A-(5-Chloro-4-iodopyridin-2-yl)-3-(2,2,2-trifluoroacetamido)cyclohexane-l -carboxamide (1.34 g, yield 49%) was obtained as white solid.

[0262] Step 2: (LS',3 / )-IV-(5-chloro-4-(2-rnethyl-2 / / -indazol-4-yl)pyridin-2-yl)-3-(2,2,2-trifluoroacetamido)cyclohexane-l -carboxamideN—A U, H CF3[ 1 n

[0263] This product was synthesized by following the similar procedures as those described in Step 3, Example 31. Product (15,3A)-A-(5-chloro-4-(2-methyl-2J / -indazol-4-yl)pyridin-2-yl)-3 -(2,2,2-trifluoroacetamido)cyclohexane-l -carboxamide (80 mg, yield 47%) was obtained as white solid. 'H NMR (300 MHz, Chloroform^ / ) 8 8.38 (d, J= 13 Hz, 2H), 8.08 (s, 1H), 7.85 (s, 1H), 7.80 (d, J= 8.7 Hz, 1H), 7.39 (dd, J= 8.7, 6.9 Hz, 1H), 7.22 (d, J= 6.9 Hz, 1H), 6.87 (s, 1H), 4.25 (s, 3H), 4.07 - 3.90 (m, 1H), 2.62 - 2.49 (m, 1H), 2.26 (d, J= 12.9 Hz, 1H), 2.06 - 1.88 (m, 3H), 1.65 - 1.32 (m, 4H).13C NMR (75 MHz, CDC13) 6 173.13, 156.63, 156.14,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 149.56, 149.02, 148.39, 148.01, 128.55, 125.51, 125.38, 123.60, 122.95, 120.92, 118.38, 115.61, 47.66, 44.17, 40.53, 33.60, 31.24, 28.51, 22.70.

[0264] Example 33. Synthesis of (l. S.3 / ?)-3-acetamid()- \-(5-chl()ro-4-(l / / -pyrrolo|2.3- / >]pyridin-4-yl)pyridin-2-yl)cyclohexane-l-carboxamide (YX0526)

[0265] Step 1: (15,3A)-3-acetamido-A-(5-chloro-4-(U / -pyrrolo[2,3-Z>]pyridin-4-yl)pyridin-2-yl)cyclohexane- 1 -carboxamide

[0266] This product was synthesized by following the similar procedures as those described in Step 3, Example 31. Product (l£,3A)-3-acetamido-A-(5-chloro-4-(lJ / -pyrrolo[2,3-Z>]pyridin-4-yl)pyri din-2 -yl)cy cl ohexane-1 -carboxamide (40 mg, yield 63%) was obtained as white solid. ‘HNMR (300 MHz, Chloroform^ / ) 8 10.31 (s, 1H), 8.69 (s, 1H), 8.47 - 8.34 (m, 3H), 7.41 (d, J= 3.6 Hz, 1H), 7.19 (d, J= 5.0 Hz, 1H), 6.44 (d, J= 3.5 Hz, 1H), 5.61 (d, J= 7.2 Hz, 1H), 3.89 (dtt, J= 15.2, 7.8, 3.7 Hz, 1H), 2.60 - 2.48 (m, 1H), 2.28 (d, J= 12.7 Hz, 1H), 2.05 - 1.85 (m, 6H), 1.59 - 1.34 (m, 3H), 1.25 - 1.10 (m, 1H).13C NMR (75 MHz, CDC13) 6 173.50, 169.39, 149.96, 148.66, 147.80, 146.92, 142.26, 137.22, 125.91, 125.06, 118.68, 116.12, 115.61, 100.58, 47.69, 44.91, 35.47, 32.20, 28.41, 23.99, 23.44.

[0267] Example 34. (l. S.3 / ?)- \-(5-chl()ro-4-(l / / -pyrrolo|2.3- / >|pyridin-4-yl)pyridin-2-yl)-3-(2,2,2-trifluoroacetamido)cyclohexane-l-carboxamide (YX0798)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0268] Step 1: (15,3A)-A-(5-chloro-4-(U / -pyrrolo[2,3-Z>]pyridin-4-yl)pyridin-2-yl)-3-(2,2,2-trifluoroacetamido)cyclohexane-l -carboxamide

[0269] To a solution of (15',3A)-3-amino-A-(5-chloro-4-(U / -pyrrolo[2,3-Z>]pyridin-4-yl)pyridin-2-yl)cyclohexane-l -carboxamide hydrochloride (50 mg, 0.123 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic anhydride (29 mg, 0.135 mmol) and EtsN (28 mg, 0.271 mmol). The mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo to remove the solvent. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 20 / 1) to afford product (15,3A)-A-(5-chloro-4-(17 / -pyrrolo[2,3-Z>]pyridin-4-yl)pyridin-2-yl)-3-(2,2,2-trifluoroacetamido)cyclohexane-l-carboxamide (15 mg, yield 26%) as white solid. 'H NMR. (300 MHz, MeOD + CDC13) 68.37 (s, 1H), 8.31 (s, 1H), 8.26 (d, J= 5.1 Hz, 1H), 7.36 (s, 1H), 7.12 (d, J= 4.7 Hz, 1H), 6.36 (s, 1H), 3.89 - 3.79 (m, 1H), 2.52 (t, J= 11.4 Hz, 1H), 2.07 (d, J= 12.8 Hz, 1H), 1.96 - 1.82 (m, 3H), 1.47 (dt, J = 20.0, 10.7 Hz, 3H), 1.35 - 1.23 (m, 1H).13C NMR (75 MHz, MeOD + CDC13) 8 174.56, 150.04, 148.14, 147.88, 146.78, 141.78, 137.32, 126.42, 125.04, 118.99, 115.94, 115.74, 100.01, 48.23, 44.28, 33.80, 30.91, 28.24, 23.66.

[0270] Example 35. Synthesis of 2-chloro-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)acetamide (YX10522)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0271] Step 1: 2-chloro-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)acetamide

[0272] To a solution of starting material ((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(imino)(methyl)-X6-sulfanone (100 mg, 0.24 mmol) in THF (3 mL) was added 2-chloroacetyl chloride (28 mg, 0.247 mmol) and EtsN (63 mg, 0.618 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to remove the solvent. The residue was purified by prepared thin layer chromatography (gradient eluent: DCM / MeOH = 20 / 1) to afford product 2-chloro-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyri din-2 -yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)acetamide (90 mg, yield 76%) as white solid.JH NMR (300 MHz, CDCh) 6 8.45 (s, 1H), 8.25 (d, J= 5.2 Hz, 1H), 8.14 (d, J= 1.7 Hz, 1H), 7.77 (s, 1H), 7.47 (d, J= 5.1 Hz, 1H), 7.26 (ddd, J= 8.7, 6.5, 0.8 Hz, 1H), 6.87 (dd, J= 5.2, 1.5 Hz, 1H), 6.80 - 6.69 (m, 2H), 4.80 - 4.65 (m, 2H), 4.11 (s, 2H), 3.81 (s, 3H), 3.19 (s, 3H).13C NMR (75 MHz, CDCh) 6 174.91, 165.91, 162.62, 158.18, 158.05, 154.86, 154.54, 151.24, 149.92, 149.89, 148.60, 136.99, 135.90, 135.70, 134.83, 134.46, 131.79, 131.66, 118.57, 118.53, 117.79, 114.20, 113.11, 107.47, 107.19, 99.86, 99.52, 58.61, 55.95, 45.78, 38.49.

[0273] Example 36. Synthesis of 3-chloro-7V-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)propanamide (YX10941) and 7V-(((2-((5-fluoro-4-(4-fluoro-2-PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-k6-sulfaneylidene)acrylamide (YX10942)

[0274] Step 1: 3-chloro-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)propenamide and A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)acrylamide

[0275] This product was synthesized by following the similar procedures as those described in Step 1, Example 35. Product 3-chloro-A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)propenamide (28 mg, yield 23%) was obtained as white solid.JH NMR (300 MHz, CDC13) 8 8.28 (d, J= 5.1 Hz, 1H), 8.17 (d, J= 1.7 Hz, 1H), 7.91 - 7.70 (m, 2H), 7.46 (d, J = 5.1 Hz, 1H), 7.34 - 7.24 (m, 1H), 6.91 (dd, J = 5.2, 1.5 Hz, 1H), 6.84 - 6.72 (m, 2H), 4.77 (d, J= 13.6 Hz, 1H), 4.67 (d, J= 13.6 Hz, 1H), 3.84 (s, 3H), 3.83 - 3.78 (m, 2H), 3.16 (s, 3H), 2.84 (t, J= 6.6 Hz, 2H).13C NMR (75 MHz, CDCI3) 6 178.83, 165.95, 162.66, 158.20, 158.07, 154.65, 154.61, 151.31, 149.73, 149.69, 148.70, 137.27, 135.91, 135.70, 134.94, 134.57, 131.81, 131.67, 118.60, 118.55, 117.90, 114.02, 112.91, 107.50, 107.21, 99.86, 99.51, 58.78, 55.96, 42.30, 40.24, 38.54.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0

[0276] This byproduct A-(((2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)methyl)(methyl)(oxo)-l6-sulfaneylidene)acrylamide (23 mg, yield 20%) was obtained as white solid. 'HNMR (300 MHz, CDC13) 88.27 (d, J= 5.2 Hz, 1H), 8.16 (d, J= 1.7 Hz, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.46 (d, J= 5.1 Hz, 1H), 7.33 - 7.24 (m, 1H), 6.90 (dd, J = 5.2, 1.5 Hz, 1H), 6.83 - 6.72 (m, 2H), 6.38 (dd, J= 17.2, 2.0 Hz, 1H), 6.23 (dd, J = 17.2, 10.0 Hz, 1H), 5.74 (dd, J= 10.0, 2.0 Hz, 1H), 4.80 (d, J= 13.6 Hz, 1H), 4.70 (d, J = 13.6 Hz, 1H), 3.84 (s, 3H), 3.18 (s, 3H).13C NMR (75 MHz, CDCI3) 6 173.92, 165.94, 162.65, 158.20, 158.06, 154.68, 154.57, 151.27, 149.79, 149.76, 148.61, 137.55, 135.87, 135.66, 134.93, 134.56, 134.52, 131.81, 131.79, 131.68, 131.65, 128.51, 118.61, 118.57, 117.90, 114.01, 112.96, 107.48, 107.20, 99.85, 99.51, 58.79, 55.95, 38.57.

[0277] REFERENCES

[0278] A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.1. Maddocks K. Update on mantle cell lymphoma. Blood. Oct 18 2018;132(16):1647-1656. doi: 10.1182 / blood-2018-03-7913922. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. Aug 8 2013;369(6):507-516. doi:10.1056 / NEJMoal3062203. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. Feb 17 2018;391(10121):659-667. doi:10.1016 / S0140-6736(17)33108-2PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 4. Song YQ, Zhou KS, Zou DH, et al. Zanubrutinib in relapsed / refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood. May 26 2022;139(21):3148-3158. doi:10.1182 / blood.20210141625. Wang ML, Shah NN, Jurczak W, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed / refractory mantle cell lymphoma: additional patients and extended follow-up from the Phase 1 / 2 BRUIN study. Blood. Nov 152022;140(Suppl 1):9368-9372. doi: 10.1182 / blood-2022-l 594256. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. Apr 2 2020;382(14): 1331-1342. doi:10.1056 / NEJMoal9143477. Blenk S, Engelmann JC, Pinkert S, et al. Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis. BMC Cancer. Apr 162008;8:106. doi:10.1186 / 1471-2407-8-1068. Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. Feb 2003;3(2): 185-97. doi:10.1016 / sl535-6108(03)00028-x9. Yan F, Jiang V, Jordan A, et al. The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma. Exp Hematol Oncol. Feb 7 2024; 13(1): 14. doi: 10.1186 / s40164-024-00484-910. Egloff S. CDK9 keeps RNA polymerase II on track. Cell Mol Life Sci. Jul 2021;78(14):5543-5567. doi:10.1007 / s00018-021-03878-811. Cidado J, Boiko S, Proia T, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res. Feb 152020;26(4):922-934. doi:10.1158 / 1078-0432. Ccr-19-1853PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 12. Zhang S, Jiang VC, Han G, et al. Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma. Nat Commun. May 172021;12(l):2877. doi:10.1038 / s41467-021-22872-z13. Li CJ, Jiang C, Liu Y, et al. Pleiotropic action of novel Bruton's tyrosine kinase inhibitor BGB-3111 in mantle cell lymphoma. Mol Cancer Ther. Feb 2019;18(2):267-277. doi:10.1158 / 1535-7163. MCT-18-047814. Huang S, Liu Y, Chen Z, Wang M, Jiang VC. PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma. Am J Cancer Res. 2022;12(3):l 102-1115.15. Friesner RA, Banks JL, Murphy RB, et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry. Mar 25 2004;47(7): 1739-1749. doi:10.1021 / jm030643016. Halgren TA, Murphy RB, Friesner RA, et al. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of Medicinal Chemistry. Mar 25 2004;47(7): 1750-1759. doi:10.1021 / jm030644s17. Nie L, Liu Y, Che YX, et al. Establishment of Patient-Derived Organoid Culture Platform of Mantle Cell Lymphoma. Blood. Nov 232021;138doi: 10.1182 / blood-2021-l 52994 18. Nie L, Liu Y, Jiang CY, et al. Establishment of a Patient-Derived Organoid Culture Platform for Mantle Cell Lymphoma Drug Sensitivity and CAR T Cell Anti-Tumor Activity Assay. Blood. Nov 15 2022;140:9219-9220. doi:10.1182 / blood-2022- 16962219. Jiang VC, Liu Y, Jordan A, et al. The antibody drug conjugate VLS-101 targeting ROR1 is effective in CAR T-resistant mantle cell lymphoma. J Hematol Oncol. Aug 28 2021; 14(1): 132. doi:10.1186 / sl3045-021-01143-w

Claims

PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 CLAIMSWe claim:

1. A compound according to Formula I, II, or III:Targeting Ligand] — [Substituent] [Targeting Ligand ] — [Linker] — [ Degron](I) (II)Targeting Ligand ■ Degrons, / (III)or an enantiomer, diastereomer, stereoisomer, or its pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the Targeting Ligand moiety is chosenPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 wherein X, Y, and Z are each independently CH, CR1or N;R1is independently selected from halogen, -Ci-Ce alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-Ce alkyl-O-Ci-Ce alkyl, cycloalkyl, -C(0)NH2, -C(O)H, -OH, -CN, -NO2, each of said -Ci-Ce alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-Ce alkyl-O-Ci-Ce alkyl, cycloalkyl is optionally substituted with halogen, hydroxy, -Ci-Cs alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andfor P2 and P4-P7, J and Q is taken together with 1-3 atoms chosen from C, N, O, and S form a 5-7 membered cycloalkyl or heterocycloalkyl ring.

3. The compound of claim 1, wherein said 5-7 membered cycloalkyl or heterocycloalkyl ring is saturated, partially saturated or unsaturated.

4. The compound of claim 1, wherein said Targeting Ligand moiety isN—N N H H5. The compound of claim 1, wherein one or two CH2 groups of the cyclohexyl moiety are replaced by a corresponding number of carbonyl (C=O) groups.1? 6. The compound of claim 1, wherein the Substituent moiety iswherein,T is CH2;b is 0-8;R2is each independently hydrogen, deuterium, halogen, or hydroxyl group.PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 7. The compound of claim 1, wherein the Degron moiety is chosen from Formulae D1, D2, D4, D5, or D6:HE1NH NH N NE2(D1)HQ,HN, or wherein:E1and E2are each independently -CH2-, -NH- or -C(O)-;L1is absent, -CH2-, -NH-, or -O-;L2is absent or -C(O)-;p is 1, 2, or 3;q is 0, 1, or 2;cis aryl or heteroaryl; andR3is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide.

8. The compound of claim 1, wherein the Linker moiety is selected from a bond,PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0wherein:L3, L4, L5, and L6are each independently chosen from -CH2-, -NH-, -O-, -C(O)-X is each independently -(CH2)g- orr is 0, 1, 2, 3, or 4;g is 0-10;s is 0, 1, 2, or 3;are independently saturated or unsaturated 5-8 single heterocycle, fused heterocycle, bridged heterocycle, or spiro heterocycle comprising 0- 3 heteroatoms selected from N, O, and S, or are independently 4-7 membered cycloalkane rings; andPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 R4is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide; andwherein more than one R4can be attached to the same atom.

9. The compound of any of the preceding claims, wherein the Targeting Ligand moiety is Formula Pl or P2:wherein X, Y, and Z are each independently CH, CR1or N; andwherein J and Q is taken together with 1-3 atoms chosen from C, N, O, and S form a 5-7 membered cycloalkyl or heterocycloalkyl ring.

10. The compound of any of the preceding claims, wherein R2on said substituent moiety is independently chosen from hydrogen, fluoride, or CF3.

11. The compound of any of the preceding claims, wherein the Degron moiety is Formula DI or D2wherein:E1and E2are each independently -CH2-, -NH- or -C(O)-;L1is absent, -CH2-, -NH-, or -O-;L2is absent or -C(O)-;p is 1, 2, or 3;PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 q is 0, 1, or 2; andR3is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide.

12. The compound of any of the preceding claims, wherein the Linker moiety is selected from:wherein:L3, L4, L5, and L6are each independently chosen from -CH2-, -NH-, -O-, -C(O)- OX is each independently -(CH2)g- orr is 0, 1, 2, 3, or 4;g is 0-10;s is 0, 1, 2, or 3;are independently saturated or unsaturated 5-8 single heterocycle, fused heterocycle, bridged heterocycle, or spiro heterocycle comprising 0- 3 heteroatoms selected from N, O, and S, or are independently 4-7 membered cycloalkane rings; andR4is independently chosen from hydrogen, halogen, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxide; andPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 wherein more than one R4can be attached to the same atom.

13. The compound of any of the preceding claims, wherein the compound is any of the following:Example StructureoN-N'^yC\ / = / ^z _ / YX0835 Hu yj1 a / _YIZt / XoNH(1) i f n? okA o Ao r y £Y N— ( / ~\ )=oZI YNH / °= o o[ N!-N\Y _ / <YX0803 c-x / L _1 k1 A 1x N A H< / -XH" / X / " XHZIN " k Y / XY O(2) kA ° ° k\k r~\r 0 r^°n—( / =°YoY oNHY c)''-zYX08042 ° ° A\oClx Til A n0ni— i0W T W(3) L kx Y,0 °HU OHYX0597(4)°YX0807 kk ' rAyY °YNHCl-A ii y n ° nu ° U Tt wNV>°(5) L kx / X Y,0 °HU OHPCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0° A YX0914 ANH CI. 1 n n UQ V>° Il A ° u0T V(6) o ^N^NA-p>-Ny^N~NH° / / o I \ W IHU o_ / o / z‘z" _K:=' x O fN-NOC Vz*_ / OZ° ^\J<o=iYX0917ci\ / L _T 1 HH HoN N C l — if — NHo(7)H0 o / ~xL LN\ / °#“NH0 0N-N^yC_ / 1IZ IZ f:YX0811c|\ / LIl 1 || H H< A A..\N. z-x z^( \o / °o / \ °8)N1 / zi / 1zx8 O' OM° rAf INO Z=o^ / / _ z \ #“\ / _NH0 0o o / / “O^ ° °x YX0876C'U T L ynoun ° U i ^V w V>° (9) N N r i n NHO 0HYX0766(10)YX0857(11)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0 N-NACn \ _ / YX0904 CK 1NI T f o K l YH0 o(12)HU ° VNH[j J,N\ )=°0 A^^ OzsOZTy O°zQy iYX0930 ZI(13)I IZ / IZo=« N-N \Y _ / ~- YX1011 Y b | H O Ob i °bb ° / 1(14)ZIA y y b *Y \ / Z _HU o <koo^X^N\ \ N- / ?YX0566 -TVcU Tl L A n ° u n ° T W(15) A, / X.'N^ -A,0 °N N T V n NHU OHb XbN—YX05612|| | n H H(16) - - O'Nr^Nnu MbNH0 0YX0589(17)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0I 1 N—YX0601II ] u H HN N ' <>•" o(18) kJ ° ° JAJr £ N— ( )=O A NH O Oi r N—YX05671c|x / L _T C A 1 A H< / -x. xHN. ^-x. ^-x.. NH^N N -r^- o(18a) kJ ° ° / ~\r N" / jo AAANHo o AA[ T N—YX05672c|x / LII 1 ||HH(18b) " B Q- TYx°L L 'N"\ / =oYNHo o rA^N\ \ N- / ? 9\ YX0568C'^ TXi n n0u n0U T Q w V>° (19) L -X A, x> N^ / \x\X\ / ^ A.00HU 0Ht r N—YX0556^1 1?HkN^NA-A>-"NY-NHo 0(20)HkJ o JY vNHL JJ / N\ J00AX^Nt r N—YX0624CI\zJJ ]? HNH r i i JHo(21) kJ 0 JvJ ^-xL LN\ J0AAJ JNH0 oPCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX05492(22)o y z— W I y^0o YZ° ^ YX0627 J< Ko=oo o(23) FzIZ A< IZz° ' o> f°° ' o zxr ° ' o^ °= Ar N- ZI zz / ? °w YX06331 ZI ZIci-A o (o=o u^NO ° (24) pVHU 2 orfjW?y - \ / I _o [ I N— fVi^^ ooH\ / I _YX0634 cK1Y ] || H ^^ ooz^iPhT '' A Q(25) t oHx A>\ oL LN\ C z^0o )^f0 0NHoYX0635(26)YX0652(27)YX0648(28)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0I JoN—YX0745T i nH / =\ c(29) W Y MVr ° n N=N' -v N-. X GH 1 NH c Zx^N yv o°zL L YX0765n—Ck 1 „wV / -NH0II / f N| n 9 H I*'N' / ' A(30) oH J C wHx. °rB‘ZT° / =xzI JoN—YX0675 / I A. IZO=C ^ ° ' oII 1 V H ZI zzzxx n(31) ccAn ^ °k J C o H=NY~N' > — \ C / H Vi °NY 1 NH H V-NH n I t V o ° ^^0[ o T N—YX0730 O °n0Ck A M / NH11 i i 9 H l1'^ r~^ H / 'N^ X-NH (32) A A X / N CN^ H mU. fl N H \ / A Ohu s °YX0572(33)YX0661(34)No QC- ( r YX05572cA ° H » T 0I Y A, ZX 'NX ZAA(35)NH O r HNJHM oH, N 4pHO0PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0 YY L L N- HO,YX0573X i i XXN N YY Y N Y 'f 'O \(36)HU oHo A Ay^° OZ-AX / 0-ISr ^ZHO AZI A YX1316z / IZ II I II H H)NN A' Y^O(810A ° Y°L ° / ~\ / z L LN\ z N zH=0O 0 / °="'o A a'N N" Y 0k, YX0825YZIJ zZ= VNAXXN'P? O oL l| H o / C Y YNHF"^-^ [I IZ T, N— >=° (37) M*oX 7° c=\Y? °""0FY^NNY 0k, HYX0838 1 k! L J! A VN'Yx^^N-xYxnYY-A^NA^^S\ Y Y 9 o OL 1] H o o YY-A / n jrN_ / N\H=0(38) L °i0 oYX0832(39)v'oFYN N'Y ok, HYX0932 1 k it ii JLY Y 9 o 0 1 || H o 0 Y-Yx YNH (40)F0 \ X00YX0849(41)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX09222(42)XX X YX0854 ^^ OOz-ZZI(43)IZ oIZ'"'0 ' ^ NkX o z z n eFY ' OlHYX0844 T L i Ji JgI JIHG c / Xo&xC) z / 0AGA / — \ X \\ z0H X N— ( )= (44) / \ \ 08^ 0= AAAJ YNH ZI 5 0 z=Z ZI o z=ZV)V / ZIYX0899 z / =Q O / ^° iQ / ^° o IZ= yIZ(45)Q / ^°XA oozxoF'V? XN ok, t!YX0847r j H o o X AA 4 ) [j TNX \ o ( 6 / =°^~NHo 0 0 p o 7— NH YX0921 [i jr N— f }=o (47) XG G js>Nr - '0YX0884(48)YX0850(49)PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0NDFN^N N'Y oklYX0885^NAXxNr^ o o1 l| H o / NHF^Y ft ], N — ( )=O (50)O0 YX0887 if JYN\ Z. R Y N V NH=o? Xl 1 1 0 0(51)IF^'NYNDF'V#^N NN oklYX0889 o o1 1] H o YNY / NHF'" YY JL / N\ ) (52)=000 YX1119 [j JY N— ( )=O \ F. Y l YNHX Xfl 1X “^NV-^Y^Y^YOH0° (53)sF'" NYNDFN^N N"^N OYX0954JL JJH 0YNTA / p-^Y^ [j JT N— fN}H=o (54)00 YX08921 fn\ Y°\ F. ^NH? OX O1 °0(55)F'" NY0YX0936. F. i Yf Y iYXN\ \N / H0(56) X XA A! °F"'NYFN^Nok, tlYX0960 1 A l J! A VNXYYYY^-X^N^XL l|Ho o ANH p-'^Y fi JTN— / \=Q (57)0PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX0987(58)YX1054^W ((59) 3<7 \ \=z= zIZ \7 zz\= zizYX1061 ze e(60) 3xc / )3ZI z,—Z= / '"'OF'y^'N 0klz Z / >—— \ |1w 1YX1109 ' Z —Q / HOb,(61)FVb JZ °°<> o 0 H°\Y Y^^° O-=OOZJLzz z- z YX1148 " YY O \ z _Jl / \ o o= zZ z— x V (62) o O0 YX11242"'OF'V^N 0K, Il j ' 7=0 AXA AA>NY^N'N VNH (63)X° UN^-U ° °0 YX1110 \ 0 / \_0 N N oK, II 1 N— < )=O (64)x°0 0H N YX10503 JTYNinh° N N % 0K, 1(65) Ax Ax Y ATxs sF'^-APCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0PCT Application Applicant Ref: ZHOU-JI-24A (PCT)Atty Dkt. No.: TMB-020PCT0YX1079(75)YX04582 L JU'N-coo(82) Y ]? HHU O n LL40 XnY- )o=Z xz xz / o=YX048220 0( ZX XZ zx IZ\(83)O= O=^0tyQzz^zz3Cz i zx0 < izz0 >0>r0YX0526 QO ZI(8 )c|ZI 4 \z-L 11h0 0 w wHU 0YX0798(76)YX10152(77)YX11875(85)PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0YX12041(86)o ooYX1210x" z I z u(87) / \x zxCO8o5 2 5 ZI 3YX10 2 ZI z=Zz=ZO(78) 4 iz ZI^O=Q X•YX10941 ^ / °ZI(79) Yo XYX10942YXT H w(88) XJ ' Hx0YX1095(80)YX1457 ex?o\(89) T JL ji H T JT / N—( / =°hU S14. The compound of any of the preceding claims, wherein the compound is any of the following:PCT Application Applicant Ref. ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0-9 o15. The compound of any of the preceding claims, wherein said compound is any of the following:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT016. The compound of any of the preceding claims, wherein said compound is chosen from the following:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0orPCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT0 17. A composition, said composition comprising a compound of any of the preceding claims.

18. A method for treating cancer, said method comprising administering an effective amount of a compound of any of the preceding claims to a subject, wherein said method involves inhibiting CDK9 upregulation, degrading CDK9, or blocking CDK9-related signaling pathways in cancer cells.

19. The method of any of the preceding claims, wherein said compound is chosen from any of the following:PCT Application Applicant Ref: ZHOU-JI-24A (PCT) Atty Dkt. No.: TMB-020PCT020. The method of any of the preceding claims, wherein cancer is mediated alone or in part by CDK9.

21. The method of claim 20, wherein said cancer is chosen from Activated B-Cell Type Diffuse Large B-Cell Lymphoma (ABC-DLBCL), Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and breast cancer.

22. The method of any of the preceding claims, wherein said cancer is Mantle Cell Lymphoma (MCL).

23. The method of claim 21, wherein the method involves inhibiting or degrading CDK9 in BTKi-CAR-T dual resistant cells to combat therapeutic relapse or therapeutic resistance from MCL.

24. The method of any of the preceding claims, wherein said compound inhibits CDK9.

25. The method of any of the preceding claims, wherein said compound degrades CDK9.

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