MDM2-based degraders targeting CDK9

Abstract

The present invention relates to compounds useful for selective inhibition of MDM2-amplified cancers and pharmaceutical compositions thereof.

Description

MDM2-BASED DEGRADERS TARGETING CDK9BACKGROUND OF THE INVENTION

[0001] Tumor suppressor, p53, plays a central role in preventing tumor formation. Careful control of the activity of p53 is necessary for mammalian survival. Known as the ‘cellular gatekeeper” or “guardian of the genome,” p53 is widely recognized as the most frequently mutated gene in human cancer; its inactivation occurs in nearly half of all human tumors. Fluctuation in p53 levels can be problematic, such that high p53 levels can be lethal and low p53 levels can permit tumorigenesis.

[0002] Murine double minute 2 (MDM2), is an E3 ubiquitin ligase that is over-expressed in many cancers and regulates target proteins through ubiquitination. An oncogene that is critical for the control of p53 activity, MDM2 has both p53-dependent and p53-independent oncogenic activities. MDM2 is a key negative regulator of the p53 protein and forms an auto-regulatory feedback loop with p53. The p53 / MDM2 feedback loop is one of the best-studied examples of a negative feedback loop comprised of a transcription arm and a protein-interaction arm. P53 transcriptionally activates MDM2 which in turn targets p53 for degradation. Under normal conditions, the p53 / MDM2 feedback loop keeps p53 levels relatively low, until stress, such as DNA damage, is applied to the cell. These stress signals block MDM2 and / or promote degradation. The resulting decrease in the activity of MDM2 in the feedback loop leads to stabilization of p53 levels which in turn leads to increased transcription of MDM2 by p53. Overexpression of MDM2 via copy number amplification can lead to increased cancer risk and / or accelerated tumor formation and progress. The overexpression of MDM2 has been observed in human tumors, such as sarcomas (liposarcoma, leiomyosarcoma, osteosarcoma, rhabdomyosarcoma), leukemia, melanoma, and cancers affecting the gastrointestinal tract, pancreas, breast, bladder, and lungs.

[0003] The inhibition of MDM2 represents a treatment approach for cancers with wild-type or functional p53. MDM2 inhibitors, such as navtemadlin, have shown promising clinical efficacy in patients with liposarcoma, relapsed / refractory solid tumors, and acute myeloid leukemia. See WO 2011 / 153509. However, conventional MDM2 inhibitors simply disrupt the p53 / MDM2 feedback loop causing p53 levels to get stabilized quickly which in turn cause MDM2 levels to increase rapidly. Thus, in order to continue p53 stabilization, the MDM2 inhibitor is forced to outcompete the resulting upregulation of MDM2, which requires increased dosing of the inhibitor. The required dosing may result in on-target toxicity to normal cells that severely limits the clinical efficacy of MDM2 inhibitors. Further, primary and acquired resistance have limited the potential benefits. There are two routes to resistance. The more dominant mechanism is acquisition of a p53 inactivating mutation. The alternate mechanism is excessive MDM2 copy number, which results inresistance and is likely enhanced by the feedback loop. Likewise, as resistance becomes an issue, higher doses of the MDM2 inhibitors are required to outcompete the accumulation of MDM2.

[0004] Further, as targeted protein degradation becomes an emerging modality with the potential to target disease-causing proteins that are challenging to conventional small molecules, proteolysistargeting chimera (PROTAC) technology generally harnesses the ubiquitin-proteasome system by recruiting E3 ligases, such as cereblon (CRBN) or von Hippel-Landau (VHL), as another approach that causes cell death and / or tumor growth inhibition. For example, dBET6 is a commercially available BRD4 degrader with the E3 ligase, CRBN. See US Patent No. 9694084. However, relying on E3 ligase activity from CRBN or VHL will cause degradation equally across tumor and normal cells resulting in unintended on-target toxicity in the normal cells.

[0005] Therefore, there is a need to discover new oncolytic compounds that inhibit tumor cells without disrupting the p53 / MDM2 feedback loop. Additionally, the need also exists to selectively target cancer cells while causing minimal toxicity to normal cells.

[0006] The present invention provides new protein degraders that target MDM2-amplified cancers by using high levels of MDM2 to target essential proteins for degradation. Further, the compounds of the present invention do not aim to disrupt the P53 / MDM2 feedback loop and would only benefit from its disruption. MDM2 -based PROTACs display enhanced therapeutic index compared to MDM2 inhibitors alone. Additionally, by leveraging the oncogenic activity of MDM2, the compounds of the present invention selectively direct degradation to protein targets in MDM2- amplified tumor cells only; there is minimal effect on healthy cells.

[0007] The compounds of the present invention also target cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent kinase (CDK) protein family. CDK9 forms a complex with cyclin- Tl, known as the Positive Transcription Elongation Factor b (pTEFb) complex. As part of the pTEFb complex, CDK9 phosphorylates the carboxyl terminal domain (CTD) of RNA polymerase II, allowing for productive transcriptional elongation. CDK9 has been an attractive target for the development of cancer therapies and is a particularly strong dependency of MDM2-amplified tumors. As such, the compounds presented here potently growth inhibit MDM2-amplified tumor models at nanomolar doses that correspond to CDK9 degradation.BRIEF DESCRIPTION OF DRAWINGS

[0008] FIG. 1 shows that MDM2 -based CDK9 degraders have significant therapeutic index between MDM2 amplified (LPS853 and T449, solid lines) and MDM2 wildtype models (U2OS and A375, dashed lines). Incorporation of the potent MDM2 binder, brigimadlin, affords QL-MDM2-51 and QL-MDM2-52 with greater activity and selectivity for MDM2-amplified models compared to molecules that incorporate the less potent MDM2 binders idasanutlin or MI-1061.

[0009] FIG. 2 shows that neither the MDM2 binders MI- 1061, idasanutlin, and brigimadlin, the CDK9 binder SNS-032, nor the cereblon-based CDK9 degrader thal-sns-032 display a significant therapeutic index between MDM2 amplified (LPS853 and T449, solid lines) and MDM2 wildtype models (U2OS and A375, dashed lines).

[0010] FIG. 3 shows that MDM2-based CDK9 PROTACs (QL-MDM2-25, QL-MDM2-26, QL- MDM2-36, and QL-MDM2-51) have stronger degradation activity toward CDK9 compared to the cereblon-based PROTAC thal-sns-032 in LPS853 cells treated with drug for 24 hours.BRIEF SUMMARY OF THE INVENTION

[0011] The present embodiments relate to a compound of the formula:TargetBinder — Linker — E3Binderor a pharmaceutical acceptable salt thereof, wherein the E3Binder is a MDM2 inhibitor, wherein TargetBinder is a CDK9 binder, L is independently a hydrocarbon or polyethylene glycol linker selected from

[0012] wherein x is 2-10, y is 1-5, z is 1-5; or the L is a C3-piperazine-C6 moiety, or L has the following structure:

[0013] In some embodiments, the TargetBinder is a CDK9 binder is SNS-032.

[0014] In other embodiments, the E3Binder is brigimadlin, idasanutlin, or MI-1061.

[0015] The present embodiments relate to a compound of the formula:T argetBi nder — CH2 — C (O) — Li nker — E3 Binderor a pharmaceutical acceptable salt thereof, wherein the TargetBinder is SNS-032, wherein the E3Binder is independently selected from idasanutlin, MI-1061 or brigimadlin, and wherein L is independently a hydrocarbon or polyethylene glycol linker selected fromwherein x is 2-10, y is 1-5, z is 1-5; or the L is a C3-piperazine-C6 moiety, or L has the following structure:

[0016] In some embodiments, the Linker is a PEG2, PEG3, PEG3*, or PEG4 group. In other embodiments, the Linker is a C2 or C6 group. In further embodiments, the Linker is a C3- piperazine-C6 moiety or has the following structure:O JNJ.

[0017] In further embodiments, the E3Binder is idasanutlin and the Linker is PEG2, C6, PEG3, PEG3*, PEG4, or a C3-piperazine-C6 moiety.

[0018] In further embodiments, E3Binder is brigimadlin and the Linker is PEG2 or PEG4.

[0019] In some embodiments, the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of

[0020] Yet additional embodiments have a pharmaceutical composition being made comprising a the compound any of the above-recited embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0021] Methods of treating cancer are also disclosed herein. In one embodiment, the method for treating cancer comprising administering an effective amount any of the above-recited embodiments, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In some of these embodiments, the cancer is an MDM2-amplified cancer. In yet further embodiments, the cancer is selected from neoplasms, lymphoma, sarcoma, solid tumors, and myeloid tumors.

[0022] Further embodiments include a method of activating the production of p53 by targeting MDM2-amplified cancers comprising administering an effective amount of a compound of any of the above-recited embodiments, or a pharmaceutical acceptable salt thereof.

[0023] The present embodiments may be used in a therapy, for example, a therapy to treat cancer.The present embodiments also involve using the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention provides a compound of the formula:TargetBinder — Linker — E3Binderor a pharmaceutical acceptable salt thereof, wherein the TargetBinder is a CDK9 binder. In some embodiments, the CDK9 binder may be derived from SNS-032 (also known as BMS-387032). Other binders that are derived from other CDK9 binders may also be used.

[0025] The E3Binder of the present invention is derived from an MDM2 inhibitor. Further, the inhibitor may be derived from, brigimadlin, idasanutlin, or Ml- 1061.

[0026] The linker (L) may be hydrocarbon of varying length (L-a) or a polyethylene glycol (PEG) chain of varying length (L-b or L-c). The linker is C2-C10 alkyl wherein x is 2 to 10 or a PEG chain having 1 to 5 PEG units, wherein y or z is 1 to 5:L-a L-b L-c

[0027] Preferably, x is 3 to 7, y is 1 to 4, and z is 3. Most preferably, x is 3 to 6 and z is 3.

[0028] In other embodiments, the linker (L) may be a C3-piperazine-C6 moiety. In other embodiments, the Linker (L) is the following structure:

[0029] In some embodiments the Linker may be bonded to the E3Binder via an amide group (O=C — N) . The N of the amide group may be attached either to the E3Binder of the Linker, depending upon the particular embodiment.

[0030] In some embodiments the Linker may be bonded to the TargetBinder via an amide group (O=C — N) . The N of the amide group may be attached either to the TargetBinder of the Linker, depending upon the particular embodiment.

[0031] In further embodiments, the present invention provides a compound of the formula:T argetBi nder — CH2 — C (O) — Li nker — E3 Binderor a pharmaceutical acceptable salt thereof.

[0032] The TargetBinder of the present invention is a CDK9 binder. Further, the CDK9 binder may be derived from SNS-032 (also known as BMS-387032). This molecule is CAS No. 345627-80-7 and has the following structure:SNS-032 is commercially available.

[0033] The E3Binder may be derived from an MDM2 inhibitor. Further, the E3Binder may be derived frp,m idasanutlin (EB-a) or MI-1061 (EB -b), or Brigimadlin (EB -c), whose structures are shown below.EB-bChemical Formula: C31H25CI2FN4O3Exact Mass: 590.13Molecular Weight: 591.46EB-c

[0034] Idasanutlin (also known as RG-7388 or RO-5503781), (CAS No. 1229705-06-9) is a known potent and selective MDM2 inhibitor. It is commercially available or can be made according to the procedures set forth in W02010031713, which is incorporated herein by reference. MI-1061 (CAS No. 1410737-34-6) is a known potent and selective MDM2 inhibitor. It is commercially available or can be made according to the procedures set forth in WO 2012 / 155066, which is incorporated herein by reference. Preferably, the Inhibitor is derived from MI-106. Brigimadlin is a known compound and has CAS No. 2095116-40-6 and is commercially available.

[0035] The Linker may be hydrocarbon of varying length (L-a) or a polyethylene glycol (PEG) chain of varying length (L-b or L-c). The linker is C2-C10 alkyl wherein x is 2 to 10 or a PEG chain having 1 to 5 PEG units, wherein y or z is 1 to 5:L-a L-b L-c

[0036] Preferably, x is 2 to 7 (and more preferably 2 or 6), y is 1 to 4, and z is 3. In some embodiments, the PEG group is a PEG2, PEG3, PEG3* or PEG4 and the alkyl group is C2 or 6. In some embodiments, when these moieties are used for the Linker, they may be bonded such that there is a N group on each end that can be used to connect the Linker to the other parts of the molecule.

[0037] In further embodiments, the linker (L) may be a C3-piperazine-C6 moiety. In other embodiments, the Linker (L) is the following structure:O J'XI

[0038] The E3Binder may be, in some embodiments, linked to the Linker via an amide linkage.Specifically, idasanutlin, MI- 1061 or brigimadlin all have an acid moiety C(O) — OH. The Linker has a terminal amine moiety that may be (in some embodiments) eacted with the acid moiety, thereby forming an amide linkage between the E3Binder and the Linker.

[0039] The TargetBinder SNS-032 has a N in a 6 membered ring. This N group may be reactedwith which is commercially available, thereby forming an acid moiety C(O) — OH attached to the N of the TargetBinder. In some embodiments, this acid group may be subsequently be bonded to a terminal amine moiety on the Linker thereby forming the structure: TargetBinder — CH2 — C(O) — Linker. Thus, those skilled in the art will appreciate that an amide linkage is used to connect one end of the Linker to the CH2 — C(O) group and another amide linkage is used to connect the Linker to the E3Binder.

[0040] Although some of the present embodiments have the Linker attached to E3Binder and / or the TargetBinder via an amide group, those skilled in the art will appreciate that other types of moieties and bonds may be used. Specifically, those skilled in the art will appreciate that the Linker may attached via other moieties, including one or more carbon atoms or other organic chemistry groups (N, O, S, etc.) as a means of bonding the Linker to the E3Binder and / or the TargetBinder.

[0041] Some of the preferred embodiments are listed that target CDK9 in the following table:

[0042] As used herein PEG3* is a PEG group linker which has an extra CEI2 group at each end adjacent the N on each side, such that the Linker has the following structure: B — N-CH2-CH2- CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-CH2-N—

[0043] Additional examples of preferred compounds are shown in the following Table A: Table A<"> "<<<"<> > < >"& >> " ><> >>" ">< ><&<> << <&> <<> <> < >>"> <" <<>> < < <"& " "<>>> "" " "&< < >"" " <<<>"< >" > "<<

[0044] Pretreatment with an MDM2 inhibitor may enhance the therapeutic index of an MDM2- based degrader of the present invention. MDM2 inhibitors are well known in the art and include siremadlin (also known as HDM201), idasanutlin (also known as RG-7388 and RO-5503781), milademetan (also known as DS-3032 and DS-3032b), brigimadlin (also known as BI 907828), navtemadlin (aslo known as KRT-232 and AMG232), ALRN-6924, STEMVAC (also known as EP- 101), UBX-0101, ASTX-295, CGM-097, KT-253, RG-7775 (also known as RO 6839921), alrizomadlin (also known as APG-115), BI-MDM2 (also known as GBM-108 and GBM-14), APG- 265, BI-0252, BI-0282, JW-1-283, MA242, MD-222, MD-224, ADO-21, MI-1061, MX69-114b, OM-301, SP-141, UNP-6457, WB-214, NU-8165, MK-8242 (also known as SCH-900242), Nutlin- 3a (also known as RO-4435385), NW-8-153, RG-7112, SAR-405838 (also known as MI-773), DS- 5272, ATSP7041, laponicone A, SAH-p53-8, SAR-299155, SAR-305801, serdemetan (also known as JNJ-1 and JNJ-26854165), SJ-2011, or VG-0604a.

[0045] The present invention provides a method of activating the production of p53 by targeting MDM2-amplified cancers comprising administering an effective amount of a compound of the invention or a pharmaceutical acceptable salt thereof. The present invention also provides a method of promoting degradation of MDM2-amplified cancers comprising administering an effective amount of a compound of the invention or a pharmaceutical acceptable salt thereof.

[0046] The present invention provides a method of treating cancer comprising administering an effective amount of a compound of the invention or a pharmaceutical acceptable salt thereof. In a further embodiment, the patient is also administered an effective amount of an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof. In another embodiment, the effective amount of the MDM2 inhibitor may be administered in combination or separately, and if separately, simultaneously or sequentially. Preferably, the MDM2 inhibitor is administered separately and before the administration of the MDM2-degrader of the present invention. In another preferred embodiment, the MDM2 inhibitor is siremadlin (also known as HDM201), idasanutlin (also known as RG-7388 and RO-5503781), milademetan (also known as DS-3032 and DS-3032b), brigimadlin (also known as BI 907828), navtemadlin (aslo known as KRT-232 and AMG232), ALRN-6924,STEMVAC (also known as EP-101), UBX-0101, ASTX-295, CGM-097, KT-253, RG-7775 (also known as RO 6839921), alrizomadlin (also known as APG-115), BI-MDM2 (also known as GBM- 108 and GBM-14), APG-265, BI-0252, BI-0282, JW-1-283, MA242, MD-222, MD-224, ADO-21, MI-1061, MX69-114b, OM-301, SP-141, UNP-6457, WB-214, NU-8165, MK-8242 (also known as SCH-900242), Nutlin-3a (also known as RO-4435385), NW-8-153, RG-7112, SAR-405838 (also known as MI-773), DS-5272, ATSP7041, Japonicone A, SAH-p53-8, SAR-299155, SAR-305801, serdemetan (also known as JNJ-1 and JNJ-26854165), SJ-2011, or VG-0604a.

[0047] The present invention additionally provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In a particular embodiment, the composition further comprises one or more other therapeutic agents. In a further embodiment, the therapeutic agent is an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof. In another embodiment, the MDM2 inhibitor may be administered in combination or separately, and if separately, simultaneously or sequentially. Preferably, the MDM2 inhibitor is administered separately and before the administration of the MDM2-degrader of the present invention. In another preferred embodiment the MDM2-inhibitor is siremadlin (also known as HDM201), idasanutlin (also known as RG-7388 and RO-5503781), milademetan (also known as DS-3032 and DS-3032b), brigimadlin (also known as BI 907828), navtemadlin (aslo known as KRT-232 and AMG232), ALRN-6924, STEMVAC (also known as EP-101), UBX-0101, ASTX-295, CGM-097, KT-253, RG-7775 (also known as RO 6839921), alrizomadlin (also known as APG-115), BI-MDM2 (also known as GBM-108 and GBM-14), APG-265, BI-0252, BI-0282, JW-1-283, MA242, MD-222, MD-224, ADO-21, MI-1061, MX69-114b, OM-301, SP-141, UNP-6457, WB-214, NU-8165, MK- 8242 (also known as SCH-900242), Nutlin-3a (also known as RO-4435385), NW-8-153, RG-7112, SAR-405838 (also known as MI-773), DS-5272, ATSP7041, Japonicone A, SAH-p53-8, SAR- 299155, SAR-305801, serdemetan (also known as JNJ-1 and JNJ-26854165), SJ-2011, or VG- 0604a.

[0048] Further, the present invention also provides compounds of the invention or pharmaceutically acceptable salts thereof for use in therapy, in particular for the treatment of cancer. In a further embodiment, the patient is also administered an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof. In another embodiment, the MDM2 inhibitor may be administered in combination or separately, and if separately, simultaneously or sequentially. Preferably, the MDM2 inhibitor is administered separately and before the administration of the MDM2-degrader of the present invention. In another preferred embodiment the MDM2-inhibitor is siremadlin (also known as HDM201), idasanutlin (also known as RG-7388 and RO-5503781), milademetan (also known as DS-3032 and DS-3032b), brigimadlin (also known as BI 907828), navtemadlin (aslo known asKRT-232 and AMG232), ALRN-6924, STEMVAC (also known as EP-101), UBX-0101, ASTX- 295, CGM-097, KT-253, RG-7775 (also known as RO 6839921), alrizomadlin (also known as APG- 115), BI-MDM2 (also known as GBM-108 and GBM-14), APG-265, BI-0252, BI-0282, JW-1-283, MA242, MD-222, MD-224, ADO-21, MI-1061, MX69-114b, OM-301, SP-141, UNP-6457, WB- 214, NU-8165, MK-8242 (also known as SCH-900242), Nutlin-3a (also known as RO-4435385), NW-8-153, RG-7112, SAR-405838 (also known as MI-773), DS-5272, ATSP7041, Japonicone A, SAH-p53-8, SAR-299155, SAR-305801, serdemetan (also known as JNJ-1 and JNJ-26854165), SJ- 2011, or VG-0604a. In another embodiment, the present invention provides the use of activating the production of p53 by targeting MDM2-amplified cancers comprising administering an effective amount of a compound of the invention or a pharmaceutical acceptable salt thereof.

[0049] Furthermore, the present invention provides compounds of the invention or pharmaceutically acceptable salts thereof for use in the treatment of cancer. In a further embodiment, the patient is also administered an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof. In another embodiment, the MDM2 inhibitor may be administered in combination or separately, and if separately, simultaneously or sequentially. Preferably, the MDM2 inhibitor is administered separately and before the administration of the MDM2-degrader of the present invention. In another preferred embodiment the MDM2 inhibitor is siremadlin (also known as HDM201), idasanutlin (also known as RG-7388 and RO-5503781), milademetan (also known as DS-3032 and DS-3032b), brigimadlin (also known as BI 907828), navtemadlin (aslo known as KRT-232 and AMG232), ALRN-6924, STEMVAC (also known as EP-101), UBX-0101, ASTX-295, CGM-097, KT-253, RG-7775 (also known as RO 6839921), alrizomadlin (also known as APG-115), BI-MDM2 (also known as GBM-108 and GBM-14), APG-265, BI-0252, BI-0282, JW-1-283, MA242, MD-222, MD-224, ADO-21, MI-1061, MX69-114b, OM-301, SP-141, UNP-6457, WB-214, NU-8165, MK- 8242 (also known as SCH-900242), Nutlin-3a (also known as RO-4435385), NW-8-153, RG-7112, SAR-405838 (also known as MI-773), DS-5272, ATSP7041, Japonicone A, SAH-p53-8, SAR- 299155, SAR-305801, serdemetan (also known as JNJ-1 and JNJ-26854165), SJ-2011, or VG- 0604a.

[0050] Even further, the present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. In another embodiment, the present invention provides the use of activating the production of p53 by targeting MDM2-amplified cancers comprising administering an effective amount of a compound of the invention or a pharmaceutical acceptable salt thereof.

[0051] The present invention provides preferred embodiments of the methods and uses as described herein, in which cancer is any highly MDM2-amplified cancer. Preferred cancers are neoplasms, lymphoma, sarcoma, solid tumors, and myeloid tumors. More preferred cancers are neoplasms,including hematologic neoplasms and salivary gland neoplasms, sarcoma, including liposarcoma and advanced liposarcoma, leukemia, including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, mixed phenotype acute leukemia, and t-cell prolymphocytic leukemia, melanoma, such as uveal melanoma, multiple myeloma, polycythemia vera, primary myelofibosis, endometrial carcinoma, merkel cell carcinoma, adenoid cystic carcinoma, transitional cell carcimoma, primary myelofibrosis, brain cancers, such as neurofibrosarcoma, neuroblastoma, and glioblastoma, eye cancer, such as retinobalastoma, gastrointestinal cancer, such as stomach cancer and colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, prostate cancer, and lung cancer, such as extensive stage small cell lung cancer, small cell lung cancer, recurrent small cell lung cancer, non-small cell lung cancer, non- sqamous non-small cell lung cancer . Especially preferred cancers are neoplasms, including hematologic neoplasms and salivary gland neoplasms, sarcoma, including liposarcoma and advanced liposarcoma, leukemia, including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, mixed phenotype acute leukemia, and t- cell prolymphocytic leukemia, melanoma, such as uveal melanoma, multiple myeloma, polycythemia vera, primary myelofibosis, endometrial carcinoma, merkel cell carcinoma, adenoid cystic carcinoma, transitional cell carcimoma, primary myelofibrosis, brain cancers, such as neurofibrosarcoma, neuroblastoma, and glioblastoma, eye cancer, such as retinobalastoma, gastrointestinal cancer, such as stomach cancer and colorectal cancer, breast cancer, prostate cancer, and lung cancer, such as extensive stage small cell lung cancer, small cell lung cancer, recurrent small cell lung cancer, non-small cell lung cancer, non-sqamous non-small cell lung cancer .

[0052] The present invention provides a method of treating radiation injuries comprising administering an effective amount of a compound of the invention or a pharmaceutical acceptable salt thereof. In a further embodiment, the effective amount of a compound of the present invention may be administered in combination with radiation treatment or separately, and if separately, simultaneously or sequentially.

[0053] The present invention also provides compounds of the invention or pharmaceutically acceptable salts thereof for use in the treatment of radiation injuries. In a further embodiment, the effective amount of a compound of the present invention may be administered in combination with radiation treatment or separately, and if separately, simultaneously or sequentially.

[0054] The present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of radiation injuries. In a further embodiment, the effective amount of a compound of the present invention may be administered in combination with radiation treatment or separately, and if separately, simultaneously or sequentially.

[0055] The present invention provides a method of treating degenerative diseases, including osteoarthritis, macular dystrophy, and macular degeneration comprising administering an effective amount of a compound of the invention or a pharmaceutical acceptable salt thereof. The present invention also provides compounds of the invention or pharmaceutically acceptable salts thereof for use in the treatment of degenerative diseases, including osteoarthritis, macular dystrophy, and macular degeneration. The present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of degenerative diseases, including osteoarthritis, macular dystrophy, and macular degeneration.

[0056] Although all of the exemplified compounds of the invention are useful

[0057] Compounds of the present invention may be administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd 30 Revised Edition (Wiley-VCR, 2011); S. M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, Jan. 1977.

[0058] Compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy(I) (A. Gennaro, et al., eds., 21st ed., Mack Publishing Co., 2005).

[0059] The compounds of the present invention are generally effective over a wide dosage range. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0060] As used herein, the term “therapeutic index” refers to the range of doses that induce at least 50% growth inhibition across MDM2 amplified lines but not MDM2 wild type lines.

[0061] As used herein, the term “treating” (or “treat” or “treatment”) refers to restraining, slowing, stopping, or reversing the progression or severity of an existing symptom, condition, or disorder.

[0062] As used herein, the phrase "effective amount" means an amount of a compound of the invention that is sufficient to treat in one or more doses a condition or detrimental effect thereof herein described or an amount of a compound of the invention that is sufficient to inhibit MDM2 or BRD4 to achieve the objectives of the invention.

[0063] As used herein, the phrase “administering” (or “administer” or “administration”) means the act of giving a compound of the invention or the direct application of a compound of the invention by ingestion, inhalation, injection, or any other means, to the body of a patient. Two or morecompounds of the invention may be administered in combination or separately, and if separately, simultaneously or sequentially over a period of time as determined by a qualified care giver.

[0064] As used herein, "patient" refers to a mammal, preferably human.

[0065] The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different preparations or examples, to prepare compounds or salts of the present invention. The products of each step in the Preparations and Examples below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the Preparations and Examples below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art.

[0066] Additionally, certain intermediates described in the following Preparations and Examples may contain one or more nitrogen protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example “Green ’s Protective Groups in Organic Synthesis'", Fourth Edition, by Peter G. M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0067] The skilled artisan will appreciate that compounds of the present invention are comprised of a core that contains at least one chiral center. Certain stereochemical centers may have been left unspecified and certain substituents may have been eliminated in the following Preparations and Examples for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Single enantiomers or diastereomers may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomers or racemates may be isolated from mixtures by standard chiral chromatographic or crystallization techniques at any convenient point in the synthesis of compounds of the invention by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions'" , John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen, “Stereochemistry of Organic Compounds'", Wiley Interscience, 1994).

[0068] Some intermediates or compounds of the present invention may have one or more chiral centers. The present invention contemplates all individual enantiomers or diastereomers, as well as mixtures of the enantiomers and diastereomers of said compounds including racemates. It is preferred that compounds of the present invention containing at least one chiral center exist as a single enantiomer or diastereomer. The single enantiomer or diastereomer may be preparedbeginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomer or diastereomer may be isolated from mixtures by standard chiral chromatographic or crystallization techniques. The skilled artisan will appreciate that in some circumstances the elution order of enantiomers or diastereomers may be different due to different chromatographic columns and mobile phases. The abbreviations used herein are defined according to Aldrichimica Acta, vol. 17, No. 1, 1984. Other abbreviations are defined as follows: “AcOH” refers to acetic acid; “BCA” refers to bicinchoninic acid; “Boc” refers to / c / V-buty 1 oxy carbonyl; “CRISPR” refers to Clustered Regularly Interspaced Short Palindromic Repeats; “DCM” refers to di chloromethane; “DIPEA” refers to diisopropylethylamine; “DMEM” refers to Dulbecco’s Modified Eagle Medium; “DMF” refers to dimethylformamide; “DMSO” refers to dimethylsulfoxide; “EMEM” refers to Eagle’s Minimum Essential Medium; “ESIMS” refers to Electrospray Ionization Mass Spectrometry; “FBS” refers to fetal bovine serum; “HATU” refers to l-[bis(dimethylamino)methylene]-l / 7-l,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate; “HPLC” refers to High Performance Liquid Chromatography; “MeOH” refers to methanol; “NMR” refers to nuclear magnetic resonance spectroscopy; “PBS” refers to phosphate-buffered saline; “Pic- BH3” refers to a-picoline borane; “RIP A” refers to radioimmunoprecipitation assay; “TEA” refers to triethylamine; “Tris” refers to 2-amino-2-(hydroxymethyl)propane- 1,3 -diol.PREPARATIONS AND EXAMPLES

[0069] The following Preparations and Examples further illustrate the invention and represent typical synthesis of the compound of the invention. The reagents and starting materials are readily available or may be readily synthesized by one of ordinary skill in the art. It should be understood that the Preparations and Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.

[0070] The (R) or (5) configuration of the compound of the invention may be determined by standard techniques such as X-ray analysis and correlation with chiral-HPLC retention time. The naming of the following Preparations and Examples is generally performed using the IUPAC naming feature in CHEMDRAW® version 22.2.0.

[0071] Unless otherwise specified, percentages in the below Preparations and Examples refer to percent yield.General Scheme A (Reaction of SNS-032)Synthesis of compound 3Compound 1 shown above is SNS-032. To a solution of compound 1 (500 mg, 1.31 mmol) in MeOH (5 mb) was added compound 2 (370 mg, 2.63 mmol). The mixture was stirred at room temperature for 0.5 h. Then, sodium triacetoxyborohydride (1.12 g, 5.26 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure and purified by Prep-HPLC to give compound 3 (300 mg, 52.08% yield) as a white solid.LCMS [M+H]+=439.2.>H NMR (400 MHz, DMSO-r / 6) 57.38 (s, 1H), 6.71 (s, 1H), 4.04 (s, 2H), 3.19 (s, 2H), 3.15 - 3.07 (m, 2H), 2.59 -2.51 (m, 2H), 2.47 -2.43 (m, 1H), 1.86 - 1.68 (m, 4H), 1.17 (s, 9H).General Scheme B (Attachment of Compound 3 to a Linker)Compound 3 will then be reacted with the Linker Moiety. One end of the Linker Moiety will have an amine group that will allow for the formation of an amide bond between Compound 3 and the Linker. The other end of the Linker will also have an N group — but this group will be protected by a Protecting Group shown below as PG. An example of a PG is a BOC group.Once this molecule has been formed, the protecting group may be removed, thereby leaving a free amine.Here is an example of showing how to effectuate General Scheme BSynthesis of compound 5To a solution of compound 3 (150 mg, 0.342 mmol) in DMF (8 mL) was added DIEA (177 mg, 1.370 mmol), and HATU (143 mg, 0.377 mmol). The mixture was stirred at room temperature for 0.5 h. Then, compound 4 (170 mg, 0.685 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over NasSCL, and concentrated. The residue was purified by column chromatography on silica gel eluted with 5% MeOH in DCM to give compound 5 (174 mg, 76.06% yield) as a white solid.LCMS: [M+H]+=669.3.>H NMR (400 MHz, DMSO ) 5 12.22 (s, 1H), 7.79 - 7.61 (m, 1H), 7.38 (s, 1H), 6.90 - 6.33 (m, 2H), 4.05 (s, 2H), 3.49 (s, 4H), 3.46 - 3.36 (m, 4H), 3.28 - 3.21 (m, 2H), 3.10 - 3.01 (m, 2H), 2.89 (s, 2H), 2.86 -2.79 (m, 2H), 2.47- 2.41 (m, 1H), 2.12 - 1.96 (m, 2H), 1.81 - 1.61 (m, 4H), 1.36 (s, 9H), 1.20 (s, 9H).General Scheme C (Attachment to the E3Binder)Once the molecule has been deprotected, it may be reacted with an E3Binder. As noted above, the E3Binder, whether it be Idasanutlin, Ml- 1061, or Brigimadlin all have acid moi eties, that can be reacted with the unprotected N group to form an amide bond.Here is an example of showing how to effectuate General Scheme CTo a solution of compound 5 (174 mg, 0.260 mmol) in DCM (2 mL) was added 4M HC1 in dioxane (1.5 mb). The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give compound 6 (167 mg, crude) as a white solid, which was used for next step without a further purification;LCMS [M+H]+=569.4.Particular Example Molecules will now be exemplified using this General Schemes.EXAMPLE 1 (QL-MDM2-26)Experimental Procedure:1. Synthesis of compound 3To a solution of compound 1 (500 mg, 1.31 mmol) in MeOH (5 mL) was added compound 2 (370 mg, 2.63 mmol). The mixture was stirred at room temperature for 0.5 h. Then, sodium triacetoxyborohydride (1.12 g, 5.26 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure and purified by Prep-HPLC to give compound 3 (300 mg, 52.08% yield) as a white solid.LCMS: [M+H]+=439.2.*H NMR (400 MHz, DMSO ) 57.38 (s, 1H), 6.71 (s, 1H), 4.04 (s, 2H), 3.19 (s, 2H), 3.15 - 3.07 (m, 2H), 2.59 -2.51 (m, 2H), 2.47 - 2.43 (m, 1H), 1.86 - 1.68 (m, 4H), 1.17 (s, 9H).Synthesis of compound 5To a solution of compound 3 (150 mg, 0.342 mmol) in DMF (8 mL) was added DIEA (177 mg, 1.370 mmol), and HATU (143 mg, 0.377 mmol). The mixture was stirred at room temperature for 0.5 h. Then, compound 4 (170 mg, 0.685 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by column chromatography on silica gel eluted with 5% MeOH in DCM to give compound 5 (174 mg, 76.06% yield) as a white solid.LCMS: [M+H]+=669.3.'ll NMR (400 MHz, DMSO ) 5 12.22 (s, 1H), 7.79 - 7.61 (m, 1H), 7.38 (s, 1H), 6.90 - 6.33 (m, 2H), 4.05 (s, 2H), 3.49 (s, 4H), 3.46 - 3.36 (m, 4H), 3.28 - 3.21 (m, 2H), 3.10 - 3.01 (m, 2H), 2.89 (s, 2H), 2.86 -2.79 (m, 2H), 2.47-2.41 (m, 1H), 2.12 - 1.96 (m, 2H), 1.81 - 1.61 (m, 4H), 1.36 (s, 9H), 1.20 (s, 9H).To a solution of compound 5 (174 mg, 0.260 mmol) in DCM (2 mL) was added 4M HC1 in dioxane (1.5 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give compound 6 (167 mg, crude) as a white solid, which was used for next step without a further purification;LCMS: [M+H]+=569.4.3. Synthesis of QL-MDM2-26To a solution of compound 7 (65 mg, 0.11 mmol) in DMF (5 mL) was added DIEA (68 mg, 0.53 mmol), HATU (44 mg, 0.12 mmol) and HOBT (29 mg, 0.21 mmol). The mixture was stirred at room temperature for 0.5 h. Then, compound 6 (60 mg, 0.11 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by prep-HPLC to give QL-MDM2-26 (5.67 mg, 4.61% yield) as a white solid;LCMS: [M+H]+=1166.4.'H NMR (400 MHz, DMSO-rA) 5 12.23 (s, 1H), 10.40 (s, 1H), 8.52 - 8.46 (m, 1H), 8.34 (s, 1H), 8.33 -8.29 (m, 1H), 7.76 - 7.68 (m, 2H), 7.61 - 7.46 (m, 4H), 7.42 - 7.32 (m, 4H), 6.70 (s, 1H), 4.63 - 4.56 (m, 2H), 4.37 (s, 1H), 4.04 (s, 2H), 3.99 - 3.89 (m, 4H), 3.53 (s, 6H), 3.43 - 3.40 (m, 3H), 3.28 - 3.22 (m, 3H), 2.88 (s, 2H), 2.85 - 2.78 (m, 2H), 2.47 - 2.39 (m, 1H), 2.09 - 2.01 (m, 2H), 1.77 - 1.60 (m, 5H), 1.30 - 1.23 (m, 1H), 1.16 (s, 9H), 0.97 (s, 9H).EXAMPLE 2 (QL-MDM2-36)Exact Mass: 1219.4205Molecular Weight: 1221.2964To a solution of compound 1 (150 mg, 0.34 mmol) in DMF (8 mL) was added compound 2 (170 mg, 0.68 mmol), DIEA (220 mg, 1.71 mmol), and HATU (143 mg, 0.38 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by chromatographic column on silica gel, eluted with 5% MeOH in DCM to give compound 3 (200 mg, 77.52% yield) as a white solid;LCMS: [M+H]+=757.9.1H NMR (400 MHz, DMSO-tfc) 5 12.24 (s, 1H), 7.75 - 7.65 (m, 1H), 7.37 (s, 1H), 6.77 - 6.65 (m, 2H), 4.04 (s, 2H), 3.62 - 3.58 (m, 1H), 3.56 - 3.46 (m, 12H), 3.45 - 3.41 (m, 2H), 3.28 - 3.23 (m, 2H), 3.09 - 3.00 (m, 2H), 2.89 (s, 2H), 2.86 -2.78 (m, 2H), 2.47 -2.39 (m, 1H), 2.13 - 1.99 (m, 2H), 1.81 - 1.68 (m, 5H), 1.36 (s, 9H), 1.17 (s, 9H).To a solution of compound 3 (200 mg, 0.26 mmol) in DCM (2 mL) was added 4M HC1 in dioxane (1.5 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give compound 4 (206 mg, crude) as a white solid, which was used for next step without a further purification;LCMS: [M+H]+=657.5.To a solution of compound 5 (53 mg, 0.091 mmol) in DMF (5 mL) was added DIEA (59 mg, 0.46 mmol), HATU (38 mg, 0.10 mmol) and HOBT (25 mg, 0.18 mmol). The mixture was stirred at room temperature for 0.5 h. Then, compound 4 (60 mg, 0.091 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by chromatographic column on silica gel, eluted with 7% MeOH in DCM to give QL-MDM2-36 (5.54 mg, 4.97% yield) as a white solid;LCMS: [M+H]+=1220.4.'H NMR (400 MHz, DMSO-cA) 5 12.23 (s, 1H), 10.59 (s, 1H), 10.23 (s, 1H), 8.48 - 8.35 (m, 1H), 8.31 (s, 1H), 7.87 - 7.78 (m, 2H), 7.72 - 7.60 (m, 4H), 7.51 - 7.42 (m, 1H), 7.40 - 7.30 (m, 2H), 7.19 - 7.10 (m, 1H), 7.06 - 7.00 (m, 1H), 6.71 (s, 1H), 6.70 - 6.67 (m, 1H), 4.81 - 4.64 (m, 2H), 4.04 (s, 2H), 3.54 - 3.51 (m, 5H), 3.50 - 3.48 (m, 8H), 3.43 - 3.38 (m, 4H), 3.27 - 3.21 (m, 3H), 2.89 (s, 2H), 2.86 - 2.79 (m, 2H), 2.46 -2.40 (m, 1H), 2.10 - 2.00 (m, 3H), 1.91 - 1.32 (m, 12H), 1.17 (s, 9H), 1.05 - 0.92 (m, 1H), 0.89 -0.79 (m, 1H).EXAMPLE 3 (QL-MDM2-51)To a solution of compound 2 (60 mg, 0.106 mmol) in DMF (5 mL) was added DIEA (68 mg, 0.528 mmol), HATU (44 mg, 0.116 mmol) and HOBT (29 mg, 0.211 mmol). The mixture was stirred at room temperature for 0.5 h. Then, compound 6 (60 mg, 0.106 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by pre-HPLC to give QL-MDM2-51 (4.57 mg, 3.81% yield) as a white solid;LCMS [M+H]+=1141.7.*H NMR (400 MHz, DMSO-t / e) 5 12.23 (s, 1H), 10.48 (s, 1H), 8.26 (s, 1H), 8.17 - 8.08 (m, 1H), 7.76-7.63 (m, 2H), 7.54 - 7.45 (m, 2H), 7.41 - 7.36 (m, 1H), 7.36 - 7.25 (m, 2H), 7.04 - 6.98 (m, 1H), 6.98 -6.92 (m, 1H), 6.71 (s, 1H), 6.65 - 6.59 (m, 1H), 6.01 - 5.93 (m, 1H), 5.14 - 5.02 (m, 1H), 4.07 -4.01 (m, 3H), 3.72 - 3.60 (m, 1H), 3.59 - 3.48 (m, 6H), 3.48 - 3.42 (m, 2H), 3.42 - 3.37 (m, 3H), 3.27 - 3.21 (m, 2H), 2.87 (s, 2H), 2.85 - 2.75 (m, 2H), 2.47 -2.39 (m, 1H), 2.38 -2.30 (m, 4H), 2.23 -2.15 (m, 1H), 2.10 -1.98 (m, 2H), 1.77 - 1.63 (m, 4H), 1.16 (s, 9H), 0.87 - 0.73 (m, 1H), 0.58 - 0.47 (m, 1H), 0.40 - 0.30 (m, 1H), 0.23 - 0.13 (m, 1H), -0.01 - -0.09 (m, 1H).EXAMPLE 4 (QL-MDM2-23)Made using similar synthetic methodLCMS: [M+H]+=1210.7.EXAMPLE 5 (QL-MDM2-24)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1260.9.EXAMPLE 6 (QL-MDM2-25)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1176.7.EXAMPLE 7 (QL-MDM2-27)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1134.7.EXAMPLE 8 (QL-MDM2-31)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1122.7.EXAMPLE 9 (QL-MDM2-32)Chemical Formula: C52H59Cl2F2N9O6S2Exact Mass: 1077.3375Molecular Weight: 1079.1178Made using similar synthetic method as noted aboveLCMS: [M+H]+=1078.7.EXAMPLE 10 (QL-MDM2-33)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1238.5.EXAMPLE 11 (QL-MDM2-34)Exact Mass: 1253.4423Molecular Weight: 1255.3298Made using similar synthetic method as noted aboveLCMS: [M+H]+=1254.5.EXAMPLE 12 (QL-MDM2-35)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1204.5.EXAMPLE 13 (QL-MDM2-41)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1264.4.EXAMPLE 14 (QL-MDM2-42)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1226.3.EXAMPLE 15 (QL-MDM2-46)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1237.5.EXAMPLE 16 (QL-MDM2-52)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1229.7.EXAMPLE 17 (QL-MDM2-53)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1091.2.EXAMPLE 18 (QL-MDM2-54)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1101.2.Made using similar synthetic method as noted aboveLCMS: [M+H]+=1184.2.EXAMPLE 20 (QL-MDM2-59)Made using similar synthetic method as noted aboveLCMS: [M+H]+=1216.3.EXAMPLE 17A- Additional synthetic data for QL-MDM2-53 (WHICH IS EXAMPLE 17 ABOVE)CC(C)(C1=CN=C(O1)CSC2=CN=C(S2)NC(C3CCN(CC3)CC(N4CC5(CN(C(C6=C(C7=NN(C(C[C@@]8 9[H])=C7C=C6)[C@]8([C@@H]([C@]%1O(C(NC%11=CC(C1)=CC=C%1O%11)=O)N9CC%12CC%12)C %13=CC=CC(C1)=C%13F)[H])C)=O)C5)C4)=O)=O)CExperimental Procedure:4. Synthesis of compound 3To a mixture of compound 1 (150 mg, 0.38 mmol) and compound 2 (112.5 mg, 0.76 mmol ,50% in water) in MeOH (5 mL) was added DIEA (0.5 mL). The mixture was stirred at room temperature for 1 h. Then, STAB was added (322 mg, 1.52 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and washed with brine, dried over Na2SO4, filtered, concentrated and the residue was purified by column to give compound 3 (151 mg, 87.4% yield) as a white solid.LCMS: [M+H]1=453.1'H NMR (400 MHz, DMSO-6 / 6) 58.33 (s, 1H), 7.45 (s, 1H), 6.71 (s, 1H), 4.05 (s, 2H), 3.65 (s, 3H), 3.22 -3.06 (m, 4H), 3.05 -2.94 (m, 1H), 2.61 -2.51 (m, 2H), 1.90 - 1.64 (m, 4H), 1.17 (s, 9H).13C NMR (101 MHz, DMSO-6 / 6) 8 174.95, 162.52, 161.31, 159.18, 144.59, 120.71, 120.59, 60.04, 51.94, 38.57, 34.55, 34.40, 31.41, 28.77, 27.33.5. Synthesis of compound 5To a mixture of compound 3 (50 mg, 0.111 mmol) and compound 4 (66 mg, 0.333 mmol) in ACN (3 mL) were added NMI (27 mg, 0.333 mmol). The mixture was stirred at room temperature for 0.5 h. Then, TCFH (93 mg, 0.333 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and washed with brine, dried over Na2SC>4, filtered, concentrated. The residue was purified by column to give compound 5 (40 mg, 57.2% yield) as a yellow solid.LCMS: [M+H]+=633.2'H NMR (400 MHz, DMSO-fife) 57.46 (s, 1H), 6.71 (s, 1H), 4.31 (s, 2H), 4.12 (s, 2H), 4.08 - 4.06 (m, 2H), 4.04 (s, 2H), 3.99 (s, 2H), 3.66 (s, 3H), 3.18 (s, 2H), 3.11 - 3.05 (m, 2H), 1.91 - 1.85 (m, 2H), 1.82 - 1.75 (m, 2H), 1.37 (s, 9H), 1.18 (s, 9H).13C NMR (101 MHz, DM SO-6 / 6) 5 174.76, 162.50, 161.34, 159.17, 155.77, 144.60, 120.78, 120.57, 79.13, 60.44, 58.30, 52.44, 49.06, 34.56, 34.41, 32.70, 31.41, 28.76, 28.50, 21.51.6. Synthesis of compound 6To a mixture of compound 5 (40 mg, 0.06 mmol) in DCM (1 mL) were added TFA (1 mL) at room temperature for 1 h. The solution was concentrated under reduced pressure to give compound 6 (35 mg, crude) as a yellow solid, which was used for next step without a further purification.LCMS: [M+H]+=533.27. Synthesis of QL-MDM2-53-2To a solution of compound 6 (35 mg, 0.07 mmol) and DIEA (26 mg, 0.20 mmol) in dry-DMSO (5 mL) was added compound 7 (75 mg, 0.10 mmol). Then, the reaction was stirred at room temperature for 1 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined and washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to get QL-MDM2-53-2 (5.32 mg, 7.3 % yield) as a brown solid.LCMS: [M+H]+=l 107.7>H NMR (400 MHz, DMSO-c / 6) 57.70 (t, J= 7.2 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.45 (s, 1H), 7.37 (d, J= 8.2 Hz, 1H), 7.30 (t, J= 8.0 Hz, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.90 (d, J= 9.1 Hz, 1H), 6.70 (s, 1H), 6.63 (s, 1H), 5.98 (t, J= 8.5 Hz, 1H), 5.09 (m, 1H), 4.40 - 4.31 (m, 2H), 4.19 (s, 2H), 4.10 (d, J= 8.3 Hz, 1H), 4.05 (s, 1H), 4.00 (t, J= 11.6 Hz, 4H), 3.68 (d, J= 8.0 Hz, 1H), 3.64 (s, 3H), 2.95 (s, 2H), 2.91 - 2.88 (m, 1H), 2.85 - 2.80 (m, 2H), 2.36 - 2.33 (m, 1H), 2.31 (s, 3H), 2.22 - 2.16 (m, 1H), 2.14 - 2.08 (m, 2H), 1.79 - 1.72 (m, 2H), 1.69 - 1.53 (m, 3H), 1.36 (s, 1H), 1.23 (s, 3H), 1.17 (s, 9H), 0.89 - 0.76 (m, 2H), 0.57- 0.50 (m, 1H), 0.39- 0.33 (m, 1H), 0.21 - 0.14 (m, 1H), -0.02 - -0.10 (m, 1H).13C NMR (101 MHz, DMSO- d6) 8 177.46, 175.33, 170.73, 169.60, 162.57, 161.31, 159.18, 154.91, 153.80, 144.61, 144.25, 139.17, 134.26, 130.53, 130.14, 129.05, 126.61, 125.69, 125.38, 122.47, 120.58, 119.98, 119.50, 118.42, 116.10, 110.10, 79.80, 68.96, 67.13, 60.90, 59.93, 58.33, 54.76, 52.72, 50.89, 34.52, 34.40, 32.84, 31.40, 28.76, 28.39, 14.36, 11.04, 5.97, 3.90.EXAMPLE 21 (QL-MDM2-63)CC(C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N4CC5(C4)CN(CC6CCC7(CN(CC7)C(C8=C(C)C9=NN([ C@@]%1O([H])[C@H](C%11=CC=CC(C1)=C%11F)[C@@]%12(N%13CC%14CC%14)C(NC%15=CC( Cl)=CC=C%12%15)=O)C(C[C@@]%10%13[H])=C9C=C8)=O)CC6)C5)=O)CC3)=O)S2)Ol)(C)CQL-MDM2-63(MED02142)Synthetic SchemeExperimental Procedure:8. Synthesis of compound 3To a mixture of compound 1 (80 mg, 0.15 mmol) and compound 2 (80 mg, 0.30 mmol) in DCM (2 mL / MeOH (2 mL) was added DIEA (0.2 mL). The mixture was stirred at room temperature for 0.5 h. Then, AcOH (2 drops) and STAB (37 mg, 0.30 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatographic column to give compound 3 (70 mg, 58.9% yield) as a yellow solid.LCMS [M+H]+=770.4'H NMR (400 MHz, DMSO-t / e) d A (s, 1H), 7.38 (s, 1H), 6.71 (s, 1H), 4.28 (s, 2H), 4.04 (s, 2H), 3.93 (s, 2H), 3.59 - 3.52 (m, 2H), 3.26 - 3.22 (m, 2H), 3.17 (s, 2H), 3.04 (s, 1H), 2.95 (s, 2H), 2.82 (d, J= 10.8Hz, 2H), 2.48 - 2.35 (m, 2H), 2.02 (t, J= 10.9 Hz, 2H), 1.91 (s, 1H), 1.77 - 1.71 (m, 2H), 1.65 - 1.47 (m, 8H), 1.39- 1.37 (m, 7H), 1.25 - 1.20 (m, 10H), 1.17 (s, 9H).13C NMR (101 MHz, DMSO-t ) <5 174.24, 161.71, 161.29, 159.21, 145.61, 120.59, 119.03, 78.56, 64.20, 52.77, 49.06, 41.42, 34.47, 33.85, 31.40, 28.77, 28.66, 28.53, 21.55.9. Synthesis of compound 4To a mixture of compound 3 (70 mg, 0.09 mmol) in DCM (1 mL) were added TFA (1 mL). This reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give compound 4 (70 mg, crude) as a yellow solid, which was used for next step without a further purification.LCMS: [M+H]+=670.3To a solution of compound 4 (70 mg, 0.11 mmol) and DIEA (0.2 mL) in dry-DMSO (5 mL) was added compound 5 (83 mg, 0.11 mmol). Then, the reaction was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to get QL-MDM2-63 (24.51 mg, 18.9 % yield) as a white solid.LCMS: [M+H]+=1242.2'H NMR (400 MHz, DMSO-cL) 12.24 (s, 1H), 10.50 (s, 1H), 8.24 (s, 1H), 7.70 (t, J= 7.0 Hz, 1H), 7.59 -7.46 (m, 2H), 7.43 - 7.33 (m, 2H), 7.30 (t, J= 8.0 Hz, 1H), 7.06 - 6.96 (m, 1H), 6.84 - 6.76 (m, 1H), 6.72(s, 1H), 6.64 (s, 1H), 5.98 (t, J = 8.2 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.27 - 4.18 (m, 2H), 4.14 - 4.10 (m, 1H), 4.05 (s, 2H), 3.91 - 3.83 (m, 2H), 3.68 - 3.62 (m, 2H), 3.55 - 3.49 (m, 2H), 3.43 (d, J= 17.2 Hz, 2H), 3.39 - 3.32 (m, 1H), 3.30 - 3.18 (m, 4H), 3.13 - 3.05 (m, 1H), 2.95 - 2.89 (m, 2H), 2.83 - 2.78 (m, 2H), 2.50 -2.39 (m, 2H), 2.39 - 2.26 (m, 2H), 2.26 - 2.13 (m, 5H), 2.09 - 2.00 (m, 2H), 1.76 - 1.71 (m, 2H), 1.67 - 1.44 (m, 7H), 1.29 - 1.09 (m, 12H), 1.01 - 0.95 (m, 1H), 0.85 - 0.74 (m, 1H), 0.57 - 0.49 (m, 1H), 0.42 - 0.32 (m, 1H), 0.23 -0.13 (m, 1H), -0.00 - -0.14 (m, 1H).13C NMR(101 MHz, DMSO-t / 6) d 177.43, 174.24, 169.54, 161.73, 161.28, 159.21, 154.91, 153.62, 145.60, 144.19, 139.12, 134.27, 130.52, 129.02, 126.56, 125.69, 122.99, 122.49, 120.60, 119.03, 118.82, 115.74, 110.09, 79.83, 69.00, 67.06, 64.59, 60.97, 59.74, 57.99, 54.77, 52.76, 50.91, 42.25, 41.49, 41.07, 34.47, 33.99, 32.92, 31.39, 28.77, 28.57, 14.20, 11.05, 5.98, 3.92.EXAMPLE 22 (QL-MDM2-64)CC(C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N4CC5(C4)CN(CC6CC7(C6)CN(C7)C(C8=C(C)C9=NN([ C@@]%1O([H])[C@H](C%11=CC=CC(C1)=C%11F)[C@@]%12(N%13CC%14CC%14)C(NC%15=CC( C1)=CC=C% 12% 15)=O)C(C[C@@]% 10% 13 [H])=C9C=C8)=O)C5)=O)CC3)=O)S2)01 )(C)CQL-MDM2-64(MED02112)Synthetic SchemeExperimental Procedure:11. Synthesis of compound 3To a solution of compound 1 (200 mg, 0.39 mmol) and compound 2 (88 mg, 0.39 mmol) in DCM (2 mL and MeOH (2 mL) was added DIEA (0.2 mL) and AcOH (2 drops). The mixture was stirred at room temperature for 0.5 h. Then, STAB (248 mg, 1.17 mmol) was added to this reaction mixture. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by column to give compound 3 (200 mg, 71.3% yield) as a yellow solid.LCMS [M+H]+=728.3’H NMR (400 MHz, CDCh) d 7.23 (s, 1H), 6.56 (s, 1H), 4.31 (s, 2H), 4.03 (s, 2H), 3.90 (d, J= 8.5 Hz, 3H), 3.75 (s, 2H), 3.70 - 3.61 (m, 2H), 3.54 (d, J= 8.5 Hz, 2H), 3.45 - 3.40 (m, 4H), 3.12 - 3.03 (m, 2H), 3.01 (s, 1H), 2.94 - 2.85 (m, 2H), 2.51 (d, 2H), 2.42 - 2.35 (m, 1H), 2.26 - 2.20 (m, 2H), 2.18 - 2.13 (m, 2H), 1.84- 1.77 (m, 2H), 1.42 - 1.40 (m, 1H), 1.37 (d, J = 6.7 Hz, 9H), 1.30 (d, J= 6.5 Hz, 1H), 1.22 (s, 9H).13C NMR(101 MHz, CDCh) 8 176.03, 173.44, 169.71, 163.03, 161.89, 158.93, 156.32, 143.48, 120.66, 120.13, 79.46, 63.88, 63.68, 61.42, 59.80, 57.79, 53.27, 52.86, 50.62, 42.21, 41.71, 37.64, 34.87, 34.70, 34.22, 31.50, 28.60, 28.46, 28.18, 27.38, 21.99, 18.18, 11.83.To a solution of compound 3 (100 mg, 0.14 mmol) in DCM (1 mL) were added TFA (1 mL). This reaction mixture was stirred at room temperature for 1 h. This reaction was concentrated under reduced pressure to give compound 4 (70 mg, crude) as a yellow solid, which was used for next step without further purification.LCMS: [M+H]+=628.513. Synthesis of QL-MDM2-64To a solution of compound 4 (70 mg, 0.11 mmol) and DIEA (0.2 mL) in dry-DMSO (5 mL) was added compound 5 (83 mg, 0.11 mmol). Then, the reaction was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford QL-MDM2-64 (22.16 mg, 16.6 % yield) as a white solid.LCMS: [M+H]+=1200.9'H NMR (400 MHz, DMSO- fc) 12.23 (s, 1H), 10.49 (s, 1H), 8.19 (s, 1H), 7.69 (t, J= 6.9 Hz, 1H), 7.53 -7.47 (m, 2H), 7.39 - 7.33 (m, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.01 (dd, J= 8.0, 1.7 Hz, 1H), 6.85 (dd, J= 8.5, 2.9 Hz, 1H), 6.71 (s, 1H), 6.63 (d, J= 1.7 Hz, 1H), 5.97 (t, J= 8.3 Hz, 1H), 5.11 - 5.01 (m, 1H), 4.22 (s, 2H), 4.10 (d, J= 7.4 Hz, 1H), 4.05 - 4.01 (m, 3H), 3.92 - 3.86 (m, 3H), 3.81 (s, 1H), 3.70 - 3.49 (m, 6H), 3.46 - 3.38 (m, 2H), 2.93 (s, 2H), 2.80 (d, J= 10.7 Hz, 2H), 2.43 - 2.31 (m, 4H), 2.28 (s, 2H), 2.24 - 2.07 (m, 4H), 2.01 (t, J = 11.1 Hz, 2H), 1.85 - 1.70 (m, 4H), 1.66 - 1.55 (m, 2H), 1.16 (s, 9H), 0.82 - 0.74 (m, 1H), 0.57- 0.48 (m, 1H), 0.38 - 0.30 (m, 1H), 0.20- 0.11 (m, 1H), -0.02- -0.10 (m, 1H).13C NMR (101 MHz, DMSO- d6) <5 177.42, 174.24, 170.75, 169.54, 161.72, 161.28, 159.21, 153.78, 145.60, 144.19, 139.11, 134.27, 130.46, 129.03, 126.57, 125.67, 125.01, 123.91, 122.49, 120.59, 119.99, 119.45, 119.03, 118.44, 116.04, 110.10, 79.80, 68.97, 67.11, 64.09, 60.84, 59.77, 57.89, 54.77, 52.75, 50.92, 41.47, 37.16, 34.98, 34.47, 34.19, 32.92, 31.39, 28.77, 28.55, 14.33, 11.04, 5.97, 3.91.EXAMPLE 23 (QL-MDM2-61)CC(C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N4CC5(C4)CN(CC6CCN(CC6)C(C7=C(C)C8=NN([C@@ ]9([H])[C@H](C% 1 O=CC=CC(C1)=C% 1 OF)[C@@]%11 (N% 12CC% 13CC% 13)C(NC%14=CC(C1)=CC=C %11%14)=O)C(C[C@@]9%12[H])=C8C=C7)=O)C5)=O)CC3)=O)S2)O1)(C)CMay be made using similar synthetic methods as noted above.EXAMPLE 24 (QL-MDM2-62)CC(C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N4CC5(C4)CN(CC6CCC7(CN(C7)C(C8=C(C)C9=NN([C @@]%10([H])[C@H](C%ll=CC=CC(Cl C0 / ollF)[C@@]%12(N%13CC%14CC%14)C(NC%15=CC(Cl )=CC=C%12%15)=O)C(C[C@@]%10%13[H])=C9C=C8)=O)CC6)C5)=O)CC3)=O)S2)Ol)(C)CMay be made using similar synthetic methods as noted above.EXAMPLE 25 (QL-MDM2-67)Chemical Formula: C55H58CI2FNgO4S2Exact Mass: 1061.34Molecular Weight: 1063.15CC(C)(C1=CN=C(CSC2=CN=C(NC(C3CCN(CC4CC5(C4)CN(C(C6=C(C)C7=NN([C@@]8([H])[C@H]( C9=CC=CC(C1)=C9F)[C@@]%1O(N%11CC%12CC%12)C(NC%13=CC(C1)=CC=C%10%13)=0)C(C[C @@]8%11[H])=C7C=C6)=O)C5)CC3)=O)S2)O1)CMay be made using similar synthetic methods as noted above.EXAMPLE 26 (QL-MDM2-68)CC(C1=CN=C(O1)CSC2=CN=C(S2)NC(C3CCN(CC(NCCOCCOCCNC(C4=C(C)C5=NN([C@]6([H])[C @@H](C7=CC=CC(Cl)=C7F)[C@]8(N9CC%10CC%10)C(NC° / ol 1=CC(C1)=CC=C8%11)=O)C(C[C@]69 [H])=C5C=C4)=O)=O)CC3)=O)(C)CMay be made using similar synthetic methods as noted above.EXAMPLE 27 (QL-MDM2-70)CC(C1=CN=C(O1)CSC2=CN=C(S2)N(C)C(C3CCN(CC(NCCOCCOCCNC(C4=C(C)C5=NN([C@@]6([ H])[C@H](C7=CC=CC(C1)=C7F)[C@@]8(N9CC%1OCC%1O)C(NC%11=CC(C1)=CC=C8%11)=O)C(C[ C@@]69[H])=C5C=C4)=O)=O)CC3)=O)(C)CMay be made using similar synthetic methods as noted above.EXAMPLE 28 (QL-MDM2-82)CC(C1=CN=C(CSC2=CN=C(N(C(C3CCN(CC(N4CC5(C4)CN(C5)C(C6=C(C)C7=NN([C@@]8([H])[C @H](C9=CC=CC(C1)=C9F)[C@@]% 10(N% 11 CC% 12CC% 12)C(NC% 13=CC(C1)=CC=C% 10% 13)=O)C (C[C@@]8%11 [H])=C7C=C6)=O)=O)CC3)=O)C)S2)O1)(C)CMay be made using similar synthetic methods as noted above.EXAMPLE 29 (QL-MDM2-84)CC(C)(C1=CN=C(O1)CSC2=CN=C(S2)NC(C3CCN(CC3)CC(N4CC5(CN(C(C6=C(C7=NN(C(C[C@]89[ H])=C7C=C6)[C@] 8( [H])[C@@H](C% 1 O=CC=CC(C1)=C% 10F)[C@@]% 11 (C(NC% 12=CC(C1)=CC=C % 12% 11 )=O)N9CC%13 CC% 13)C)=O)C5)C4)=O)=O)CMay be made using similar synthetic methods as noted above.EXAMPLE 30 (QL-MDM2-101)Molecular Weight: 1285.48May be made using similar synthetic methods as noted above.May be made using similar synthetic methods as noted above.EXAMPLE 32 (QL-MDM2-103)May be made using similar synthetic methods as noted above.EXAMPLE 32 (QL-MDM2-104)Chemical Formula: C60H68CI2FN -|-|O5S2Exact Mass: 1175.42Molecular Weight: 1177.29CC(C)(C)C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N4CCN(CC5CCN(CC5)C(C6=C(C)C7=NN([C@@]8 ([H])[C@H](C9=CC=CC(C1)=C9F)[C@@]%1O(N%11CC%12CC%12)C(NC%13=CC(C1)=CC=C%1O%1 3)=O)C(C[C@@]8%11[H])=C7C=C6)=O)CC4)=O)CC3)=O)S2)O1May be made using similar synthetic methods as noted above.EXAMPLE 33 (QL-MDM2-105)Chemical Formula: C57H61CI2FN10O5S2CC(C)(C)C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N4CC5(CCN(CC5)C(C6=C(C)C7=NN([C@@]8([H]) [C@H](C9=CC=CC(C1)=C9F)[C@@]% 10(N% 11 CC% 12CC% 12)C(NC% 13=CC(C1)=CC=C% 10% 13)=O )C(C [C@@] 8% 11 [H])=C7C=C6)=O)C4)=O)CC3)=O)S2)O 1May be made using similar synthetic methods as noted above.EXAMPLE 34 (QL-MDM2-106)CC(C)(C)C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N4CCC(CN5CCN(CC5)C(C6=C(C)C7=NN([C@@]8 ([H])[C@H](C9=CC=CC(C1)=C9F)[C@@]%1O(N%1 lCC%12CC%12)C(NC%13=CC(Cl)=CC=C%10° / ol 3)=O)C(C[C@@]8%11[H])=C7C=C6)=O)CC4)=O)CC3)=O)S2)O1May be made using similar synthetic methods as noted above.EXAMPLE 35 (QL-MDM2-107)CC(C)(C)C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(N(CC4)CCC54CN(C(C6=C(C)C7=NN([C@@]8([H]) [C@H](C9=CC=CC(C1)=C9F)[C@@]%1O(N%11CC%12CC%12)C(NC%13=CC(C1)=CC=C%10%13)=0 )C(C [C@@] 8% 11 [H])=C7C=C6)=O)C5)=O)CC3)=O)S2)O 1May be made using similar synthetic methods as noted above.EXAMPLE 36 (QL-MDM2-108)Chemical Formula: C56H61CI2FN10O5S2CC(C)(C)C1=CN=C(CSC2=CN=C(NC(C3CCN(CC3)CC(N[C@H](CC4)CC[C@@H]4NC(C5=C(C6=NN (C(C[C@@]78[H])=C6C=C5)[C@]7([C@@H]([C@]9(C(NC%10=CC(C1)=CC=C9%10)=0)N8CC%11C C% 11 )C% 12=CC=CC(C1)=C% 12F)[H])C)=O)=O)=O)S2)O 1May be made using similar synthetic methods as noted above.EXAMPLE 37 (QL-MDM2-113)CC(C)(C)C1=CN=C(CSC2=CN=C(NC(C3CCN(CC(CC4)CCC54CN(C(C6=C(C)C7=NN([C@@]8([H])[C @H](C9=CC=CC(C1)=C9F)[C@@]% 10(N% 11 CC% 12CC% 12)C(NC% 13=CC(C1)=CC=C% 10% 13)=O)C (C[C@@]8%11[H])=C7C=C6)=O)C5)CC3)=O)S2)O1May be made using similar synthetic methods as noted above.EXAMPLE 38 (QL-MDM2-114)CC(C)(C1=CN=C(O1)CSC2=CN=C(S2)NC(C3CCN(CC3)CC(N4CCC5(CN(C5)CC6CCC7(CC6)CN(CC7 )C(C8=C(C)C9=NN([C@@]%1O([H])[C@H](C%11=CC=CC(C1)=C%11F)[C@@]%12(N%13CC%14CC %14)C(NC%15=CC(C1)=CC=C%12%15)=0)C(C[C@@]%10%13[H])=C9C=C8)=0)CC4)=0)=0)CMay be made using similar synthetic methods as noted above.Table B below gives the structures of known molecules (Idasanutlin, MI-1061, Brigimadlin) as well as THAL-SNS-032 which is used as a control in the assays below. THAL-SNS-032 is commercially available. Table B<>ASSAYS

[0072] Cell lines and cell culture

[0073] All liposarcoma cell lines used in this study are commercially available from Cellosaurus:LPS853 (RRID:CVCL_V415), T449 (RRID:CVCL_M807). The Cellosaurus is developed by Amos Bairoch of the CALIPHO group at the SIB - Swiss Institute of Bioinformatics as part of the neXtProt project. All liposarcoma cell lines are maintained in RPMI-1640 medium (Gibco, ThermoFisher Scientific) supplemented with 15% FBS, 1% GLUTAMAXTM (Gibco), and 1,000 Units / mL Penicillin and 1 mg / mL Streptomycin (Gibco). A-375, and U-2 OS cell lines are purchased from ATCC. A-375 (Cat# CRL-1619) cells are maintained in DMEM medium (Gibco, ThermoFisher Scientific) with 10% FBS, 1,000 Units / mL Penicillin and 1 mg / mL Streptomycin (Gibco). U-2 OS (Cat# HTB-96) cells are maintained in McCoy's 5A medium (Gibco, ThermoFisher Scientific) with 10% FBS, 1,000 Units / mL Penicillin and 1 mg / mL Streptomycin (Gibco). All cell lines are regularly screened for mycoplasma.

[0074] Dose response curves

[0075] Cells are seeded in 96 well plates at the following densities: LPS853 = 750 cells / well, T449 = 1000 cells / well, U2OS = 500 cells / well, A375 = 250 cells / well. The following day, regular growth media is replaced with drug-containing media. The optimal dose range for each drug is determined for each cell line and is tested across 9 half-log doses. Each plate includes 0.1% DMSO as a negative control for growth inhibition. Drug media is changed 48 h after initial treatment. Plates are incubated in drug at 37 °C for a total of 96 h or 120 h and lysed by adding 20 pL CELL TITER-GLO® reagent (Promega, Cat. No. G7570) to 100 ml cell media. Luminescence is measured using a GLOMAX® explorer (Promega) plate reader and growth inhibition is calculated relative to DMSO treated wells. All experiments are performed in biological duplicates and, within a given experiment, at least 3 technical replicates are tested per condition. The drm R package is used to fit data to a four- parameter logistic curve using the LL.4() model. From this curve IC50 values were obtained for the following cell lines as illustrated in Table 1 below.Table 1

[0076] Western Blotting

[0077] Cells are plated and, the following day, normal growth media is removed and replaced with DMSO or drug-containing media. Cells are incubated in drug media for 24 h and washed two times with lx PBS and scraped on ice in RIPA buffer (50 mM Tris- HC1 pH 7.5, 150 mMNaCl, 0.5% sodium deoxycholate, 1%NP-4O, 0.1% SDS) supplemented with fresh protease (HALTTM, Thermofisher) and phosphatase inhibitors (Thermofisher). Protein is quantified and normalized using the BCA Protein Assay kit (Thermo #23227) according to the manufacturer's protocol. Equivalent micrograms of protein per sample are loaded and run using SDS-PAGE gel electrophoresis.

Claims

We claim:

1. A compound of the formula:T argetBi nder — Li nker — E3 B inderor a pharmaceutical acceptable salt thereof,wherein TargetBinder is a CDK9 binder;L is independently a hydrocarbon or polyethylene glycol linker selected fromwherein x is 2-10, y is 1-5, z is 1-5; or the L is a C3-piperazine-C6 moiety, or L has the following structure:the E3Binder is a MDM2 inhibitor.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein the TargetBinder is a CDK9 binder is SNS-0323. The compound or pharmaceutically acceptable salt of claim 1, wherein the E3Binder is brigimadlin, idasanutlin, or MI- 1061.

4. A compound of the formula:T argetB inder — CH2 — C (O) — Linker — E3 B inderor a pharmaceutical acceptable salt thereof,wherein:the TargetBinder is SNS-032;the E3Binder is independently selected from idasanutlin, MI-1061 or brigimadlin; and L is independently a hydrocarbon or polyethylene glycol linker selected fromwherein x is 2-10, y is 1-5, z is 1-5; or the L is a C3-piperazine-C6 moiety, or L has the following structure:The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the Linker is aPEG2, PEG3, PEG3*, or PEG4 group.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the Linker is a PEG2, PEG3, PEG3*, or PEG4 group.

6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the Linker is a C2 or C6 group.

7. The compound of any of claims 4 to 5, or a pharmaceutically acceptable salt thereof, wherein E3Binder is idasanutlin.

8. The compound of any of claims 4 to 5, or a pharmaceutically acceptable salt thereof, wherein E3Binder is brigimadlin.

9. The compound of any of claims 4 to 5, or a pharmaceutically acceptable salt thereof, wherein E3Binder is Ml- 1061.

10. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the Linker is a C3-piperazine-C6 moiety.

11. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the Linker has the following structure:

12. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the E3Binder is MI-1061 and the Linker is PEG3, PEG3*, PEG4, a C3-piperazine-C6 moiety or has the following structure:

13. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the E3Binder is idasanutlin and the Linker is PEG2, C6, PEG3, PEG3*, PEG4, or a C3- piperazine-C6 moiety.

14. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the E3Binder is brigimadlin and the Linker is PEG2 or PEG4.

15. The compound of claim 4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of16. A pharmaceutical composition comprising a compound any of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

17. A method for treating cancer comprising administering an effective amount of a compound of any of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

18. The method of claim 16, wherein the cancer is an MDM2-amplified cancer.

19. The method of claim 15 or 16, wherein the cancer is selected from neoplasms, lymphoma, sarcoma, solid tumors, and myeloid tumors.

20. A method of activating the production of p53 by targeting MDM2-amplified cancers comprising administering an effective amount of a compound of any of Claims 1 to 14, or a pharmaceutical acceptable salt thereof.

21. A compound of any of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in therapy.

22. A compound of any of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

23. A compound of any of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.

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