Substituted imidazolyl dihydropyrimidine-2,4-dione and substituted imidazolyl piperidine-2,6-dione derivatives and uses thereof

Abstract

The present disclosure provides a Compound of Formula (I); or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R1, R2a, R2b, R2c, R2d, R4, R4a, R5, and X1 are as defined herein, and methods of making and using same.

Description

[0001] SUBSTITUTED IMIDAZOLYL DIHYDROPYRIMIDINE-2, 4-DIONE AND

[0002] SUBSTITUTED IMIDAZOLYL PIPERIDINE-2, 6-DIONE DERIVATIVES AND USES

[0003] THEREOF

[0004] CLAIM OF PRIORITY

[0005] The present application claims priority to U.S. Application No. 63 / 679,048, filed August 2, 2024.

[0006] The entire content of the foregoing application is incorporated by reference in its entirety.

[0007] FIELD OF THE DISCLOSURE

[0008] The present disclosure relates to substituted imidazolyl dihydropyrimidine-2, 4-dione and substituted imidazolyl piperidine-2, 6-dione compounds and compositions for modulation of Cyclin E1 (CCNE1) and their use for the treatment of CCNE1 -dependent diseases or disorders or where reduction of CCNE1 protein levels can ameliorate a disease or disorder.

[0009] BACKGROUND OF THE DISCLOSURE

[0010] The CCNE1 gene functions as a critical regulator of the G1 / S cell cycle transition and is found on chromosome 19q12 which encodes the G1-S phase-specific protein cyclin E1. Cyclin E1, a critical regulator of the G1 / S cell cycle transition, forms a complex with its cyclin-dependent kinase (CDK) partner CDK2 in response to mitotic signals, resulting in phosphorylation of several targets including the retinoblastoma protein (Rb). As a result of phosphorylation of Rb, E2F transcription factors are released, initiating S phase through the expression of S-phase proteins. Cyclin E1-CDK2 also phosphorylates other proteins including proteins involved in centrosome duplication, DNA synthesis, and DNA repair. Cyclin E1 protein levels are tightly regulated in normal cells with levels peaking at the G1 / S phase boundary and degraded as the cell passes through the S phase. Regulation of this periodicity occurs through the cell cycle- dependent transcription and post-translational control by ubiquitin-dependent proteolysis. In addition to the regulation G1 / S cell cycle transition, Cyclin E1 also has kinase independent functions such as centriole duplication, centrosome separation, and endoreplication. (Au-Yeung, G. et. al., J. Clin. Onco., 2024, 41(9), 1770-1773)

[0011] Cyclin E1 is frequently amplified and / or overexpressed in human cancer. CCNE1 copy-number gam and overexpression have been identified in ovarian, gastric, endometrial, breast and other cancers and been associated with poor outcomes in these tumors (Keyomarsi, K., et. al., N Engl J Med, 2002, 347(20): 1566- 75; Nakayama, N., et. al., Cancer, 2010, 116(11):2621-34; Au-Yeung, G., et. al., Clin Cancer Res, 2017, 23(7): 1862-1874; Rosen, D. G., et al., Cancer, 2006, 106(9): 1925-32). Amplification and / or overexpression of CCNE1 also reportedly contribute to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011, 108(9) : 3761 -6; Herrera-Abreu, M. T„ et al., Cancer Res, 2016, 76(8):2301-13). In high grade serous ovarian cancer, cyclin E1 amplification is detected in approximately 20% of patients and is associated with chemo resistance / refractory (TCGA, Integrated genomic analyses of ovarian carcinoma, Nature. 2011; 474: 609-615; Nakayama et al; Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, Cancer (20 1 0) 116: 2621-34). Poor outcomes and drug resistance were also associated with high Cyclin E1 expression in endometrial, gastric, breast and other cancers (Noske et al.. Detection of CCNE 1 / URI (19q 12) amplification by in situ hybridization is common in high grade and type II endometrial cancer, Oncotarget (2017) 8. 14794-14805; Ooi et al.. Gene amplification of CCNE1, CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization, Hum Pathol. (2017) 61 :58-67; Keyomarsi et al., Cyclin E and survival in patients with breast cancer. N Engl J Med. (2002) 347: 1566-75).

[0012] These data provide a rationale for considering CCNE1 as a potential target for new drug development in cancer associated with deregulated CCNE1 activity as well as other CCNE1-related diseases. Thus, there is a considerable need for novel and potent small molecule modulators of CCNE1.

[0013] SUMMARY OF THE DISCLOSURE

[0014] The compounds of the disclosure have use as therapeutic agents, particularly for cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, allergic and genetic diseases, and other CCNE1-related diseases. In one aspect, the compounds of the disclosure have CCNE1 degrader activity, preferably having such activity at or below the 50 pM level, and more preferably having such activity at or below the 10 μM level. Tire compounds of the disclosure have usefulness in treating cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, allergic and genetic diseases, and other diseases for which such degrader activity would be beneficial.

[0015] A first aspect of the present disclosure relates to compounds of Formula (I): or a pharmaceutically accept-able salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X1is N or CR3; X2is N or CR6; X2’is N or CR6’; X3is N or CR6; X3’is N or CR6’; X4is N or CR6; R1is H, D, -C(O)R15, -C(R21)2OC(O)R15, -C(R21)2OC(O)NHR16, -C(R21)2OC(O)OR16, -P(O)(OR16)2, - C(R21)2OP(O)(OR16)2, -C(R21)2OP(O)(OH)OR16, -C(R21)2OP(O)(R16)2, - C(R21)2OC(O)CH2NHC(O)CH2NH2, -C(R21)2OC(O)CH(R16’)NHR16’, -C(R21)2OC(O)(CH2)qC(O)OR16’, - C(R21)2OC(O)-(5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), or -C(R21)2(C6-C10)aryl), wherein the heteroaryl and aryl are optionally substituted with one or more R17; R2a, R2b, R2c, and R2dare each independently H or D; R3is H or D; R4is H, (C1-C3)alkyl, (C1- C3)haloalkyl, (C2-C3)hydroxyalkyl, or (C3-C10)carbocyclyl, wherein alkyl is optionally substituted with one or more R18; R4ais H, (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3- C10)carbocyclyl, or 3- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N,NH,and S; R5 is R6and R6’are each independently at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1- C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R7and R7’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, halogen, -C(O)O(R16’), or (C3-C10)carbocyclyl, wherein alkyl is optionally substituted with one or more R19; or two R7on the same atom together form (C3-C5)carbocyclyl; R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R9is hydrogen, -(CH2)o’C(O)O(R16’), -(CH2)o’C(O)N(R16’)(R10), (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, or (C1-C6)hydroxyalkyl wherein the alkyl, haloalkyl, and hydroxyalkyl are substituted with one or more R10and optionally substituted with one or more R20; R9’is (C1-C6)alkyl, (C1-C6)haloalkyl, -R10’, or a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O, N, and NH, wherein the alkyl and haloalkyl are substituted with one or more R10’, and the heterocyclyl is substituted with one or more R10a; R10is (C2-C6)alkynyl, (C3-C10)carbocyclyl, 5- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10)aryl, or 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are substituted with R11and optionally substituted with one or more R12; R10’is ; R10ais –(CH2)0-2-(C6-C10)aryl or –(CH2)0-2-(5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, NH, and S), wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one or more R12; R11is -L-(C6-C10)aryl, -L-(5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, NH, and S), -L-(C3- C10)carbocyclyl, -L-(4- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R14; L is absent, -(C(R13)R13’)o-, -O(C(R13)R13’)o-, -(C(R13)R13’)oO(C(R13)R13’)o-, or - N(R16’)(C(R13)R13’)o-; R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN; or two R12on the same atom together form oxo or =N(R16’); R13and R13’are independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or (C3-C10)carbocyclyl; or R13and R13’on the same atom together form oxo or methylene; or two R13together with the atoms they are attached to form a (C3-C5)carbocyclyl; R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; or two R14on the same atom together form oxo; R15is H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6- C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6- C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16’is independently at each occurrence H or (C1-C6)alkyl; R17is independently at each occurrence (C1-C6)alkoxy; R18is independently at each occurrence (C1-C3)alkoxy, (C3-C10)carbocyclyl, or -OH; R19is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -CN; R20is independently at each occurrence -R16’, - O(R16’), or -C(O)O(R16’); R21is independently at each occurrence H, D, halo, methyl, or (C1)haloalkyl; q, n, r, s, and t are each independently 1, 2, or 3; p is 0, 1, 2, or 3; and o is each independently 0, 1 or 2; and o’ is 0, 1, 2, 3, 4, or 5.

[0016] In one aspect of the disclosure, the hydrogens in the Compound of Formula (I) are present in the normal isotopic abundances. In a preferred aspect of the disclosure, the hydrogens are isotopically enriched in deuterium (D), as discussed in more detail concerning isotopes and isotopic enrichment below.

[0017] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful in the treatment of CCNE1 -dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0018] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of an CCNE 1 -dependent disease or disorder by reducing CCNE1 protein levels wherein reduction of CCNE1 protein levels treats the CCNE 1 -dependent disease or disorder. The pharmaceutical composition is useful in the treatment of CCNE 1 -dependent diseases or disorders. The pharmacal composition may further comprise at least one additional pharmacal agent.

[0019] Another aspect of the present disclosure relates to a pharmacal composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmacal composition is useful in the treatment of diseases or disorders affected by the reduction of CCNE1 protein levels. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0020] In another aspect, the present disclosure relates to a method of degrading CCNE1, comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Another aspect of the present disclosure relates to a method of degrading CCNE1, comprising administering to a patient in need thereof an effective amount of a pharmacal composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0021] Another aspect of the present disclosure relates to a method of modulating CCNE1 levels comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect, the present disclosure relates to a method of modulating CCNE1 levels, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0022] In another aspect, the present disclosure relates to a method of reducing CCNE1 protein levels, comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Another aspect of the present disclosure relates to a method of reducing CCNE1 protein levels, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0023] Another aspect of the present disclosure relates to a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect, the present disclosure relates to a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cancer is characterized by an amplification or overexpression of cyclin E1.

[0024] In another aspect, the present disclosure relates to a method for treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1) in a subject in need thereof comprising, administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Another aspect of the present disclosure relates to a method for treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1) in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0025] Another aspect of the present disclosure relates to a method of treating a disease or disorder that is affected by the modulation of CCNE1 protein levels comprising, administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect, the present disclosure relates to a method of treating a disease or disorder that is affected by the modulation of CCNE1 protein levels, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0026] In another aspect, the present disclosure relates to an in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0027] In another aspect, the present disclosure relates to an in vivo method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cell is a mammalian cell.

[0028] Another aspect of the present disclosure relates to a method of degrading CCNE1 in a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect, the present disclosure relates to a method of degrading CCNE1 in a cell, comprising contacting the cell with an effective amount of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the contacting occurs in vivo. In another embodiment, the contacting occurs in vitro. In yet another embodiment, the cell is a mammalian cell. In another embodiment, the mammalian cell is a mammalian cancer cell.

[0029] In another aspect, the present disclosure relates to a method of treating a solid tumor in a subject in need thereof comprising, administering to a subject in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Another aspect of the present disclosure relates to a method of treating a solid tumor in a subject in need thereof the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0030] Another aspect of the present disclosure relates to a method of treating a liquid tumor in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect, the present disclosure relates to a method of treating a liquid tumor in a subject in need thereof the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0031] In another aspect, the present disclosure relates to a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of CCNE1 protein levels. Another aspect of the present disclosure relates to a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of CCNE1 protein levels.

[0032] Another aspect of the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of CCNE1 protein levels. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of CCNE1 protein levels.

[0033] In another aspect, the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1). Another aspect of the present disclosure relates to a pharmaceutical composition comprising a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1).

[0034] Another aspect of the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of CCNE1 protein levels. In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising a Compound of Fonnula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of CCNE1 protein levels

[0035] In another aspect, the present disclosure relates to tire use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of CCNE1 protein levels. Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of CCNE1 protein levels.

[0036] Another aspect of the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of characterized by amplification or overexpression of Cyclin E1 (CCNE1). In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of characterized by amplification or overexpression of Cyclin E1 (CCNE1).

[0037] In some embodiments, the methods of the present invention further comprise at least one additional pharmacal agent or therapy. In one embodiment, the at least one additional pharmaceutical agent is an anticancer agent. In another embodiment, the at least one additional pharmaceutical agent or therapy is selected from surgety, radiotherapy, endocrine therapy, biologic response modifiers, hyperthermia and cryotherapy, agents to attenuate any adverse effects, alkydating drugs, antimetabolites, purine antagonists and pyrimidine antagonists, spindle poisons, podophyllotoxins, antibiotics, nitrosoureas, inorganic ions, enzymes, and honnones.

[0038] In some embodiments, the administration of the Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmacal composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is oral, parenteral, subcutaneous, by injection, or by infusion.

[0039] The present disclosure provides degraders of CCNE1 that are therapeutic agents in the treatment of diseases such as cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, allergic and genetic diseases, in the treatment of diseases affected by the modulation of CCNE1 protein levels, and in the treatment CCNE1 -dependent diseases or disorders.

[0040] In one embodiment, the cancer that can be treated by the compounds of the present disclosure is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney' cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multifonn, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma In one embodiment, the disease or disorder that can be treated by the compounds of the present disclosure is selected from (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0041] Tire present disclosure provides agents with novel mechanisms of action toward CCNE1 proteins in the treatment of various types of diseases including cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, allergic and genetic diseases, in the treatment of diseases affected by the modulation of CCNE1 protein levels, and in the treatment CCNE1 -dependent diseases or disorders. Ultimately the present disclosure provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with CCNE1 proteins.

[0042] DETAILED DESCRIPTION OF THE DISCLOSURE

[0043] Tire present disclosure relates to compounds and compositions that are capable of modulating CCNE1 protein levels. The disclosure features methods of treating, preventing, or ameliorating a disease or disorder in which CCNE1 plays a role by administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present disclosure can be used in the treatment of a variety of CCNE1 -dependent diseases and disorders by modulating CCNE1 protein levels. Modulation of CCNE1 protein levels through degradation provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, and other CCNE1 -dependent diseases or disorders.

[0044] In one aspect, the compounds of the disclosure have use as therapeutic agents, particularly for cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, allergic and genetic diseases, and other CCNE1-related diseases. In one aspect, the compounds of the disclosure have CCNE1 degradation activity, preferably having such activity at or below the 50 pM level, and more preferably having such activity at or below the 10 μM level. The compounds of the disclosure have usefulness in treating cancer and other diseases for which such degradation activity would be beneficial for the patient. In summary, the present disclosure provides novel CCNE1 degraders useful for the treatment of cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, allergic and genetic diseases, and other disease related to the modulation of CCNEl-related diseases.

[0045] In a first aspect of the disclosure, the compounds of Formula (I) are described:

[0046] or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein R1, R2a, R2b, R2c, R2d, R4, R4a, R5, and X1are as defined herein. The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. 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 disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definition of Terms and Conventions Used Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification and appended claims, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. A. Chemical Nomenclature, Terms, and Conventions In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, (C1-C10)alkyl means an alkyl group or radical having 1 to 10 carbon atoms. In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, "alkylaryl" means a monovalent radical of the formula alkyl-aryl-, while "arylalkyl" means a monovalent radical of the formula aryl-alkyl-. Furthermore, the use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. The articles "a" and "an" refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The term "and / or" means either "and" or "or" unless indicated otherwise. The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. "Optionally substituted" as used herein also refers to substituted or unsubstituted whose meaning is described below. The term "substituted" means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms. The term "unsubstituted" means that the specified group bears no substituents. Unless otherwise specifically defined, "aryl" means a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group is optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, -O-(C1-C6)alkyl, (C1-C5)alkyl, -O-(C2-C5)alkenyl, -O-(C2- C6)alkynyl, (C2-C5)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C5)alkyl, -C(O)(C1-C6)alkyl, - OC(O)O(C1-C6) alkyl, NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)- alkyl, and S(O)N((C1-C6)alkyl)2. The substituents are themselves optionally substituted. Furthermore, when containing two fused rings, the aryl groups optionally have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like. Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno [3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b ][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3- a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H- 1Δ2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3- c]pyridinyl, 1H­pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[l,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c] [1,2,5]thiadiazoly1, benzo[c] [l,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H- pyrazolo [1,5-b] [1,2]oxazinyl,4,5,6, 7-tetrahydropyrazolo [1,5-a]pyridinyl, thiazolo[5,4d]thiazolyl, imidazo[2,1-b] [1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro­1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl. "Alkyl" means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6)alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. "Alkoxy" means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal "O" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. "Alkenyl" means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted and may be straight or branched. "Alkynyl" means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted. "Alkylene" or "alkylenyl" means a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a (C1-C5)alkylene. An alkylene may further be a (C1-C4)alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH-, and the like. "Amino" means a substituent containing at least one nitrogen atom (e.g., NH2). "Cyano" means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., . "Cycloalkyl" or "carbocyclyl" means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic carbon ring containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A (C3-C8)cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane). "Deuteroalkyl" means an alkyl group substituted with one or more deuterium (“D”). Examples of deuteroalkyl groups include -CDH2, -CD3, -CHD2, -CD2CH3, -CD2CD3, CH2CD3, -CHDCH3, - CD2CH2CD3, etc. “Halogen” or "halo" mean fluorine, chlorine, bromine, or iodine. "Haloalkyl" means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. "Haloalkoxy" means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. “Halohydroxyalkyl” means an alkyl group substituted with at least one halogen and at least one - OH group. Examples of halohydroxyalkyl groups include, but are not limited to, HO-C(H)F-, HO-CH(F)- CH2-, CF3-CH(OH)-CH2-, and CH3-CH(OH)-, etc. "Heterocyclyl" or "heterocycloalkyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S) and wherein there is not delocalized n electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocycloalkyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl. "Hydroxyalkyl" means an alkyl group substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2CH2-, and CH3-CH(OH)-. "Alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups. Examples of alkoxyalkyl groups include H3CO-CH2-, H3CO-CH2C(OC2H5)H-, and (CH3)2C(H)O-CH2-CH2-. "Spirocarbocyclyl " or "spirocycloalkyl" means carbogenic bicyclic ring systems with both rings connected through a single atom. The rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. A (C3-C12)spirocarbocyclyl is a spirocycle containing between 3 and 12 carbon atoms. "Spiroheterocyclyl" or "spiroheterocycloalkyl" means a spirocycle wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g., one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings). One or both of the rings in a spiroheterocyclyl can be fused to another ring, e.g., carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions "Prodrug" or "prodrug derivative" means a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). In general, such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased aqueous solubility), and / or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991. particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), E1sevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.). Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E.B. Roche (ed.), E1sevier. 1987, each of which is incorporated herein by reference in their entireties.

[0047] "Pharmaceutically acceptable prodrug" as used herein means a prodrug of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.

[0048] "Salt" means an ionic form of the parent compound or the product of the reaction between the parent compound with a suitable acid or base to make the acid salt or base salt of the parent compound. Salts of the compounds of the present disclosure can be synthesized from tire parent compounds which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid parent compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

[0049] "Pharmaceutically acceptable salt" means a salt of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and tire like, commensurate with a reasonable benefit / risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. As the compounds of the present disclosure are useful in both free base and salt form, in practice, the use ofthe salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Set, 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

[0050] "Phannaccutically-acccptablc acid addition salt" means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzene sulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2- naphthalene sulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3 -phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like.

[0051] "Pharmaceutically-acceptable base addition salt" means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically -acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N -dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N- dibenzylphenethylamine, 1 -ephenamine, N,N'-dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0052] "Solvate" means a complex of variable stoichiometry fonned by a solute, for example, a Compound of Formula (I) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0053] "Hydrate" means a solvate wherein the solvent molecule(s) is / are water.

[0054] Tire compounds of the present disclosure as discussed below include the free base or acid thereof, their salts, solvates, and prodrugs and may include oxidized sulfur atoms or quatemized nitrogen atoms in their structure, although not explicitly stated or shown, particularly the pharmacally acceptable forms thereof Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.

[0055] C. Isomer Terms and Conventions

[0056] "Isomers" means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

[0057] "Stereoisomer" or "optical isomer" mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane -polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well known in the art.

[0058] "Enantiomers" means a pair of stereoisomers that arc non -superimposable mirror images of each other.

[0059] "Diastereoisomers" or "diastereomers" mean optical isomers, which are not mirror images of each other.

[0060] "Racemic mixture" or "racemate" mean a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" means a mixture containing unequal parts of individual enantiomers. "Geometrical isomer" means a stable isomer, which results from restricted freedom of rotation about double bonds (e.g., cis-2-butene and trans-2-butene) or in a cyclic structure (e.g., cis-1,3- dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Because carbon-carbon double (olefinic) bonds, C=N double bonds, cyclic structures, and the like may be present in the compounds of the disclosure, the disclosure contemplates each of the various stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and in these cyclic structures. The substituents and the isomers are designated using the cis / trans convention or using the E or Z system, wherein the term "E" means higher order substituents on opposite sides of the double bond, and the term "Z" means higher order substituents on the same side of the double bond. A thorough discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is hereby incorporated by reference in its entirety. Several of the following examples represent single E isomers, single Z isomers, and mixtures of E / Z isomers. Determination of the E and Z isomers can be done by analytical methods such as x-ray crystallography,1H NMR, and13C NMR. Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers. It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art. Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while inactive, R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.

[0061] Tirus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in tire body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way. the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.

[0062] Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation. resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc.. 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC. HPLC. CE, or NMR. and assignment of absolute configuration and conformation, for example, CD ORD, X-ray crystallography, or NMR.

[0063] In general, all tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or compound is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure.

[0064] D. Pharmaceutical Administration and Treatment Terms and Conventions

[0065] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog. cat. horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0066] An "effective amount" or "therapeutically effective amount" when used in connection with a compound means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0067] The terms "pharmaceutically effective amount" or "therapeutically effective amount" means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease -states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound of according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0068] As used herein, the term "pharmaceutical composition" refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0069] "Carrier" encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carry ing or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. A subject is "in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).

[0070] As used herein, the term "inhibit", "inhibition", or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0071] As used herein, the term "treat", "treating", or "treatinent" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof): or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0072] As used herein, the temi "prevent", "preventing", or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0073] "Pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0074] "Disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. "Administer", "administering", or "administration" means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body. "Prodrug" means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. "Compounds of the present disclosure", "compounds of the disclosure", and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formulae (I), (I’), (Ia), (Ia-1), (Ia’), (Ib), (Ib’), (Ic), (Ic’), (Id), (Id’), (Ie), (Ie’), (If), (If-1), (Ig), (Ig-1), (Ih), (Ii), (Ij) (Ik), (Il), (Im), (In), (In-1), (Io), (Ip), (Iq), (Ir), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), and (Ibb) as herein described including the tautomers, the prodrugs, salts particularly the pharmaceutically acceptable salts, and the solvates and hydrates thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates and / or hydrates). For the purposes of this disclosure, solvates and hydrates are generally considered compositions. In general and preferably, the compounds of the disclosure and the formula designating the compounds of the disclosure are understood to only include stable compounds thereof and exclude unstable compounds, even if an unstable compound might be considered to be literally embraced by the compound formula. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative, and it is not intended to exclude other instances when the context so permits. "Stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent. For example, a compound, which would have a "dangling valency" or is a carbanion is not a compound contemplated by the disclosure. In a specific embodiment, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield. "Simultaneously" or "simultaneous" when referring to a method of treating or a therapeutic use means with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by the same route and at the same time.

[0075] "Separately" or "separate" when referring to a method of treating or a therapeutic use means with a combination of a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by different routes and at approximately the same time.

[0076] By therapeutic administration "over a period of time" means, when referring to a method of treating or a therapeutic use with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s), administration of the compound and the one or more second agent(s) by the same or different routes and at different times. In some embodiments, the administration of the compound or the one or more second agent(s) occurs before the administration of the other begins. In this way, it is possible to administer a one of the active ingredients (i.e., a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agent(s)) for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. Another therapeutic administration over a period of time consists of the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain time points in time simultaneous administration of all of the active ingredients takes place whereas at other time points in time only a part of the active ingredients of the combination may be administered (e.g., for example, a compound of fonnula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and the one or more second agents the therapeutic administration over a period of time could be such that a Compound of Fonnula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is administered once a day and the one or more second agent(s) is administered once even' four weeks).

[0077] The compounds can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other dmg therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

[0078] "CCNE1 -dependent disease or disorder" means any disease or disorder which is directly or indirectly affected by the modulation of CCNE1 protein levels.

[0079] "Colitis" is an inflammation of the colon. The colitis may be acute or chronic. As used herein, colitis includes ulcerative colitis, microscopic colitis, lymphocytic colitis, collagenous colitis, diversion colitis, chemical colitis, ischemic colitis, infections colitis, pancolitis, left-sided colitis, extensive colitis, segmental colitis, microscopic colitis, radiation -induced colitis, medication-induced colitis and proctitis. E. Specific Embodiments and Methods for Testing Compounds of Formula (I) The present disclosure relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of modulating CCNE1 protein levels, which are useful for the treatment of diseases and disorders associated with modulation of CCNE1 protein levels. The disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for reducing or decreasing CCNE1 protein levels. In one embodiment, the compound of Formula (I) are compounds of Formula (I’): or a pharmaceutically accept­able salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X1is N or CR3; X2is N or CR6; X2’is N or CR6’; X3is N or CR6; X3’is N or CR6’; X4is N or CR6; R1is H, D, -C(O)R15, -CH2OC(O)R15, -CH2OC(O)NHR16, -CH2OC(O)OR16, -P(O)(OR16)2, -CH2OP(O)(OR16)2, - CH2OP(O)(OH)OR16, -CH2OP(O)(R16)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R16’)NHR16’, - CH2OC(O)(CH2)qC(O)OR16’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S); R2a, R2b, R2c, and R2dare each independently H or D; R3is H or D; R4is H, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C2-C3)hydroxyalkyl; R5is and R6’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R7and R7’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen; R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN; R9is (C1-C6)alkyl or (C1-C6)haloalkyl, wherein the alkyl and haloalkyl are substituted with one or more R10; R9’is (C1-C6)alkyl, (C1-C6)haloalkyl, -R10’, or a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O, N, and NH, wherein the alkyl and haloalkyl are substituted with one or more R10’, and the heterocyclyl is substituted with one or more R10a; R10is (C6-C10)aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one or more R12; R10’is R10ais –(CH2)0-2-(C6-C10)aryl or –(CH2)0-2-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one or more R12; R11is -(C(R13)R13’)o(C6-C10)aryl, -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -(C(R13)R13’)o(C3- C7)carbocyclyl, -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o(C6-C10)aryl, -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -O(C(R13)R13’)o(C3-C7)carbocyclyl, or -O(C(R13)R13’)o4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R14; R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R13and R13’are independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH; R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R15is H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6- C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6- C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16’is independently at each occurrence H or (C1-C6)alkyl; q, n, r, s, and t are each independently 1, 2, or 3; p is 0, 1, 2, or 3; and o are each independently 0, 1 or 2. In one embodiment, the compounds of Formula (I) have the structure of Formula (Ia): harmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ia-1): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ib): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Ic): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Id): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ie): harmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In one embodiment, the compounds of Formula (I) have the structure of Formula (Ia’): harmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ib’): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Ic’): r pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Id’): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ie’): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (If): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (If-1): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ig): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ig-1): harmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Ih): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ii): r pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ij): r pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ik): harmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Il): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Im): r pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (In): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (In-1): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Io): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ip):

[0080] or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Iq): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Iq-1): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ir): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Ir-1): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Iu): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Iv): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Iw): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ix): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Iy): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Iz): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Iaa): harmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ibb): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In some embodiments of the formulae above (e.g., Formula (I’), Formula (Ia’), Formula (Ib’), Formula (Ic’), Formula (Id’), Formula (Ie’), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Il), Formula (Im), Formula (In), Formula (In-1), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (Iu), Formula (Iv), Formula (Iw), Formula (Ix), Formula (Iy), Formula (Iz), Formula (Iaa), and / or Formula (Ibb)), or In some embodiments of the formulae above (e.g., Formula (I), Formula (Ia), Formula (Ia-1), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (If-1), Formula (Ig), Formula (Ig-1), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Il), Formula (Im), Formula (In), Formula (In-1), Formula (Io), Formula (Ip), Formula (Iq), Formula (Iq-1), Formula (Ir), Formula (Ir-1), Formula (Iu), Formula (Iv), Formula (Iw), Formula (Ix), Formula (Iy), Formula (Iz), Formula (Iaa), and / or Formula (Ibb)), X1is N or CR3; X2is N or CR6; X2’is N or CR6’; X3is N or CR6; X3’is N or CR6’; X4is N or CR6; R1is H, D, -C(O)R15, -CH2OC(O)R15, -CH2OC(O)NHR16, -CH2OC(O)OR16, -P(O)(OR16)2, -CH2OP(O)(OR16)2, -CH2OP(O)(OH)OR16, -CH2OP(O)(R16)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R16’)NHR16’, -CH2OC(O)(CH2)qC(O)OR16’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S); R2a, R2b, R2c, and R2dare each independently H or D; R3is H or D; R4is H, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C2-C3)hydroxyalkyl; R5is R6and R6’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R7and R7’are each independently at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen; R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R9is (C1-C6)alkyl or (C1-C6)haloalkyl, wherein the alkyl and haloalkyl are substituted with one to four R10; R9’is (C1-C6)alkyl, (C1-C6)haloalkyl, -R10’, or a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O, N, and NH, wherein the alkyl and haloalkyl are substituted with one to four R10’, and the heterocyclyl is substituted with one to four R10a; R10is (C6-C10)aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one to four R12; R10’is R10a is –(CH2)0-2-(C6-C10)aryl or –(CH2)0-2-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one to four R12R11is -(C(R13)R13’)o(C6-C10)aryl, -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -(C(R13)R13’)o(C3-C7)carbocyclyl, -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o(C6-C10)aryl, -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -O(C(R13)R13’)o(C3-C7)carbocyclyl, or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four R14; R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R13and R13’are independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH; R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R15is H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16’is independently at each occurrence H or (C1-C6)alkyl; q, n, r, s, and t are each independently 1, 2, or 3; p is 0, 1, 2, or 3; and o are each independently 0, 1 or 2. In some embodiments of the formulae above, X1is N. In another embodiment, X1is CR3. In yet another embodiment, X1is CD. In another embodiment, X1is CH. In some embodiments of the formulae above, X1is N or CH. In some embodiments of the formulae above, X2is N or CR6. In another embodiment, X2is N. In another embodiment, X2is CR6. In some embodiments, X2is CH. In some embodiments, X2is CF. In some embodiments, X2is CCH3. In some embodiments, X2is C(OCH3). In some embodiments, X2is N or CH. In some embodiments of the formulae above, X2’is N or CR6’. In another embodiment, X2’is N. In another embodiment, X2’is CR6’. In some embodiments of the formulae above, X3is N or CR6. In another embodiment, X3is N. In another embodiment, X3is CR6. In some embodiments, X3is CH. In some embodiments, X3is CF. In some embodiments, X3is CCH3. In some embodiments of the formulae above, X3is N or CH. In some embodiments of the formulae above, X3’is N or CR6’. In another embodiment, X3’is N. In another embodiment, X3’is CR6’. In some embodiments of the formulae above, X4is N or CR6. In another embodiment, X4is N. In another embodiment, X4is CR6. In some embodiments, X4is CH. In some embodiments, X4is CF. In some embodiments, X4is CCH3. In some embodiments of the formulae above, X4is N or CH. . In some embodiments, X4is N, CH, or CF. In some embodiments of the formulae above, R1is H, D, -C(O)R15, -CH2OC(O)R15, -CH2OC(O)NHR14, -CH2OC(O)OR14, -P(O)(OR14)2, -CH2OP(O)(OR14)2, -CH2OP(O)(OH)OR14, -CH2OP(O)(R14)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R14’)NHR14’, -CH2OC(O)(CH2)qC(O)OR14’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S). In another embodiment, R1is H, D, -C(O)R15, -CH2OC(O)R15, -CH2OC(O)NHR14, -CH2OC(O)OR14, -P(O)(OR14)2, -CH2OP(O)(OR14)2, -CH2OP(O)(OH)OR14, or -CH2OP(O)(R14)2. In yet another embodiment, R1is H, D, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R14’)NHR14’, -CH2OC(O)(CH2)qC(O)OR14’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S). In some embodiments of the formulae above, R1is -C(O)R15, -CH2OC(O)R15, -CH2OC(O)NHR16, -CH2OC(O)OR16, -P(O)(OR16)2, -CH2OP(O)(OR16)2, -CH2OP(O)(OH)OR16, -CH2OP(O)(R16)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R16’)NHR16’, -CH2OC(O)(CH2)qC(O)OR16’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S). In yet another embodiment, R1is -C(O)R15, -CH2OC(O)R15, -CH2OC(O)NHR16, -CH2OC(O)OR16, -P(O)(OR16)2, -CH2OP(O)(OR16)2, -CH2OP(O)(OH)OR16, or -CH2OP(O)(R16)2. In another embodiment, R1is -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R16’)NHR16’, -CH2OC(O)(CH2)qC(O)OR16’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S). In another embodiment, R1is H or D. In yet another embodiment, R1is D. In another embodiment, R1is H. In some embodiments of the formulae above, R1is H, D, -C(O)R15, -C(R21)2OC(O)R15, - C(R21)2OC(O)NHR16, -C(R21)2OC(O)OR16, -P(O)(OR16)2, -C(R21)2OP(O)(OR16)2, - C(R21)2OP(O)(OH)OR16, -C(R21)2OP(O)(R16)2, -C(R21)2OC(O)CH2NHC(O)CH2NH2, - C(R21)2OC(O)CH(R16’)NHR16’, -C(R21)2OC(O)(CH2)qC(O)OR16’, -C(R21)2OC(O)-(5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), or -C(R21)2(C6-C10)aryl), wherein the heteroaryl and aryl are optionally substituted with one or more R17. In some embodiments, R1is - C(R21)2(C6-C10)aryl), wherein the aryl is optionally substituted with one or more R17. In another embodiment, R1is H, D, or -C(R21)2(C6-C10)aryl), wherein the aryl is optionally substituted with one or more R17. In some embodiments, R1is 2,4-dimethoxybenzyl. In some embodiments of the formulae above, R2ais H or D. In another embodiment, R2ais D. In yet another embodiment, R2ais H. In some embodiments of the formulae above, R2bis H or D. In another embodiment, R2bis D. In yet another embodiment, R2bis H. In some embodiments of the formulae above, R2cis H or D. In another embodiment, R2cis D. In yet another embodiment, R2cis H. In some embodiments of the formulae above, R2dis H or D. In another embodiment, R2dis D. In yet another embodiment, R2dis H. In some embodiments of the formulae above, R3is H or D. In another embodiment, R3is D. In yet another embodiment, R3is H. In some embodiments of the formulae above, R4is H, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C2- C3)hydroxyalkyl. In another embodiment, R4is H, (C1-C3)alkyl, or (C1-C3)haloalkyl. In yet another embodiment, R4is H, (C1-C3)alkyl, or (C2-C3)hydroxyalkyl. In another embodiment, R4is H, (C1- C3)haloalkyl, or (C2-C3)hydroxyalkyl. In another embodiment, R4is (C1-C3)alkyl, (C1-C3)haloalkyl, or (C2- C3)hydroxyalkyl. In yet another embodiment, R4is H or (C2-C3)hydroxyalkyl. In another embodiment, R4is H or (C1-C3)haloalkyl. In yet another embodiment, R4is (C1-C3)alkyl or (C2-C3)hydroxyalkyl. In another embodiment, R4is H, (C1-C3)alkyl or (C1-C3)haloalkyl. In yet another embodiment, R4is (C1-C3)haloalkyl or (C2-C3)hydroxyalkyl. In another embodiment, R4is (C1-C3)haloalkyl. In yet another embodiment, R4is (C2-C3)hydroxyalkyl. In another embodiment, R4is H or (C1-C3)alkyl In another embodiment, R4is (C1- C3)alkyl or (C1-C3)haloalkyl. In yet another embodiment, R4is H. In another embodiment, R4is (C1- C3)alkyl. In another embodiment, R4is (C1-C3)haloalkyl. In some embodiments of the formulae above, R4is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2- C3)hydroxyalkyl, (C2-C5)alkoxyalkyl, or (C3-C10)carbocyclyl, wherein alkyl is optionally substituted with one or more R18. In some embodiments, R4is (C1-C3)alkyl that is optionally substituted with one or more R18. In some embodiments, R4is (C2-C5)alkoxyalkyl. In some embodiments, R4is (C3-C10)carbocyclyl. In some embodiments of the formulae above, R4ais H, (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3-C10)carbocyclyl, or 3- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In some embodiments, R4ais H. In some embodiments, R4ais (C1-C4)alkyl. In some embodiments, R4ais H or (C1-C4)alkyl. In some embodiments, R4ais H or methyl. In some embodiments of the formulae above, R5is n another embodiment, R5is another

[0081] In some embodiments of the formulae above, R6is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, or -N((C1-C6)alkyl)2. In yet another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, or -CN. In another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, -OH, -NH2, -N(H)(C1- C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, - N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, - N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6is independently at each occurrence H, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or - CN. In yet another embodiment, R6is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, or -OH. In yet another embodiment, R6is independently at each occurrence H, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R6is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen. In some embodiments of the formulae above, R6’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, or -N((C1-C6)alkyl)2. In yet another embodiment, R6’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, -OH, -NH2, -N(H)(C1- C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, - N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, - N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R6’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1-C6)haloalkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R6’is independently at each occurrence (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1- C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, or -OH. In yet another embodiment, R6’is independently at each occurrence H, halogen, -OH, -NH2, -N(H)(C1- C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R6’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R6’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen. In some embodiments of the formulae above, R7is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen. In another embodiment, R7is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, or (C1-C6)hydroxyalkyl. In yet another embodiment, R7is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen. In another embodiment, R7is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, or halogen. In yet another embodiment, R7is independently at each occurrence H, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen. In another embodiment, R7is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen. In yet another embodiment, R7is independently at each occurrence H, (C1-C6)alkyl, or halogen. In another embodiment, R7is independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl. In yet another embodiment, R7is independently at each occurrence H or (C1-C6)alkyl. In some embodiments of the formulae above, R7is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, halogen, -C(O)O(R16’), or (C3-C10)carbocyclyl, wherein alkyl is optionally substituted with one or more R19; or two R7on the same atom together form (C3- C5)carbocyclyl. In some embodiments, R7is -C(O)O(R16’). In other embodiments, R7is (C3- C10)carbocyclyl, In some embodiments, two R7on the same atom together form (C3-C5)carbocyclyl. In yet other embodiments, R7is (C1-C6)alkyl optionally substituted with one or more R19. In some embodiments of the formulae above, R7’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen. In another embodiment, R7’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, or (C1-C6)hydroxyalkyl. In yet another embodiment, R7’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen. In another embodiment, R7’is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, or halogen. In yet another embodiment, R7’is independently at each occurrence H, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen. In another embodiment, R7’is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen. In yet another embodiment, R7’is independently at each occurrence H, (C1-C6)alkyl, or halogen. In another embodiment, R7’is independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl. In yet another embodiment, R7’is independently at each occurrence H or (C1-C6)alkyl In some embodiments of the formulae above, R8is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, or -N((C1-C6)alkyl)2. In yet another embodiment, R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, or -CN. In another embodiment, R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, -OH, -NH2, -N(H)(C1-C6)alkyl, - N((C1-C6)alkyl)2, or -CN. In another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or - CN. In yet another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or - CN. In another embodiment, R8 is independently at each occurrence H, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or - CN. In yet another embodiment, R8 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In another embodiment, R8 is independently at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen. In yet another embodiment, R8is independently at each occurrence H, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In some embodiments of the formulae above, R9is (C1-C6)alkyl or (C1-C6)haloalkyl, wherein the alkyl and haloalkyl are substituted with one to four R10. In another embodiment, R9is (C1-C6)alkyl substituted with one to four R10. In another embodiment, R9is (C1-C6)haloalkyl substituted with one to four R10. In some embodiments of the formulae above, R9is hydrogen, -(CH2)o’C(O)O(R16’), - (CH2)o’C(O)N(R16’)(R10), (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)hydroxyalkyl wherein the alkyl, haloalkyl, and hydroxyalkyl are substituted with one or more R10and optionally substituted with one or more R20. In some embodiments, R9is H. In some embodiments, R9is - (CH2)o’C(O)N(R16’)(R10). In some embodiments, R9is (C1-C6)alkyl substituted with one R10and optionally substituted with one or more R20. In some embodiments, R9is (C1-C6)haloalkyl substituted with one R10and optionally substituted with one or more R20. In some embodiments, R9is (C1-C6)hydroxyalkyl substituted with one R10and optionally substituted with one or more R20. In some embodiments, R9is selected from herein each R20’is independently R20or H. In some embodiments, R9is . n some embodiments, R9is , wherein each R20’is independently R20or H. In some embodiments, R9is herein each R20’is independently R20or H. In some embodiments, R9is wherein each R20’is independently R20or H. In some embodiments, R9is wherein each R20’is independently R20or H. In some embodiments, R9is wherein each R20’is independently R20or H. In some embodiments, R9is , wherein each R20’is independently R20or H. In some embodiments, R9is , wherein each R20’is independently R20or H. In some embodiments, R9is , herein each R20’is independently R20or H. In some embodiments, R9is , wherein each R20’is independently R20or H. In some embodiments, R9is , wherein each R20’is independently R20or H. In some embodiments of the formulae above, R9is

[0082] In some embodiments of the formulae above, R9’is (C1-C6)alkyl, (C1-C6)haloalkyl, -R10’, or a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O, N, and NH, wherein the alkyl and haloalkyl are substituted with one to four R10’, and the heterocyclyl is substituted with one to four R10a. In another embodiment, R9’is (C1-C6)alkyl or (C1-C6)haloalkyl, wherein the alkyl and haloalkyl are substituted with one to four R10’. In yet another embodiment, R9’is (C1-C6)alkyl substituted with one to four R10’. In another embodiment, R9’is (C1-C6)haloalkyl substituted with one to four R10’. In another embodiment, R9’is -R10’or a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O, N, and NH, wherein the heterocyclyl is substituted with one to four R10a. In yet another embodiment, R9’is -R10’. In another embodiment, R9’is a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O, N, and NH, substituted with one to four R10a. In some embodiments of the formulae above, R10is (C6-C10)aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one to four R12. In another embodiment, R10is (C6-C10)aryl substituted with R11and optionally substituted with one to four R12. In yet another embodiment, R10is 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, substituted with R11and optionally substituted with one to four R12. In another embodiment, R10is 5- membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, substituted with R11and optionally substituted with one to four R12. In yet another embodiment, R10is 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, substituted with R11and optionally substituted with one to four R12. In some embodiments of the formulae above, R10is (C2-C6)alkynyl, (C3-C10)carbocyclyl, 5- to 6- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are substituted with R11and optionally substituted with one or more R12. In some embodiments, R10is (C2-C6)alkynyl substituted with R11and optionally substituted with one or more R12. In some embodiments, R10is (C3-C10)carbocyclyl substituted with R11and optionally substituted with one or more R12. In some embodiments, R10is 5- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heterocyclyl is substituted with R11and optionally substituted with one or more R12. In some embodiments, R10is (C6-C10)aryl substituted with R11and optionally substituted with one or more R12. In some embodiments, R10is 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heteroaryl is substituted with R11and optionally substituted with one or more R12. In some embodiments of the formulae above, R10is , wherein each R12’is independently R12or H. In some embodiments, R10is n some embodiments, R10is , , herein R12’is independently R12or H. In some embodiments, R10is , wherein R12’is independently R12or H. In some embodiments, R10is In some embodiments, R10is herein R12’is independently R12or H. In some embodiments of the formulae above, R10is

[0083] In an embodiment, R10is

[0084]

[0085] In some embodiments of the formulae above, R10’is n some embodiments of the formulae above, R10ais –(CH2)0-2-(C6-C10)aryl or –(CH2)0-2-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one to four R12. In another embodiment, R10ais –(CH2)0-2-(C6-C10)aryl substituted with R11and optionally substituted with one to four R12. In yet another embodiment, R10ais –(CH2)0-2-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, substituted with R11and optionally substituted with one to four R12. In another embodiment, R10ais –(CH2)0-2-5-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, substituted with R11and optionally substituted with one to four R12. In yet another embodiment, R10ais – (CH2)0-2-6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, substituted with R11and optionally substituted with one to four R12. In some embodiments of the formulae above, R11is -(C(R13)R13’)o(C3-C7)carbocyclyl, - (C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -(C(R13)R13’)o(C6-C10)aryl, -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -O(C(R13)R13’)o(C3-C7)carbocyclyl, -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o(C6-C10)aryl, or -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C3-C7)carbocyclyl, -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -(C(R13)R13’)o(C6-C10)aryl, - (C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, - O(C(R13)R13’)o(C3-C7)carbocyclyl, -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o(C6-C10)aryl, or -O(C(R13)R13’)o-5 or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl, -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -O(C(R13)R13’)o(C6-C10)aryl, or - O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C3-C7)carbocyclyl, -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o(C3- C7)carbocyclyl, or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl, -(C(R13)R13’)o(C3-C7)carbocyclyl, -O(C(R13)R13’)o(C6-C10)aryl, or -O(C(R13)R13’)o(C3-C7)carbocyclyl, wherein the aryl and carbocyclyl are optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl or -(C(R13)R13’)o(C3-C7)carbocyclyl, wherein the aryl and carbocyclyl are optionally substituted with one to four R14. In yet another embodiment, R11is -O(C(R13)R13’)o(C6-C10)aryl or -O(C(R13)R13’)o(C3- C7)carbocyclyl, wherein the aryl and carbocyclyl are optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S or -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four R14. In another embodiment, R11is -O(C(R13)R13’)o- 5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl, -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o(C6-C10)aryl, or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the aryl and heterocyclyl are optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl or -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the aryl and heterocyclyl are optionally substituted with one to four R14. In another embodiment, R11is independently at each occurrence- O(C(R13)R13’)o(C6-C10)aryl, or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the aryl and heterocyclyl are optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -(C(R13)R13’)o(C3-C7)carbocyclyl, -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or -O(C(R13)R13’)o(C3-C7)carbocyclyl, wherein the heteroaryl and carbocyclyl are optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S or -(C(R13)R13’)o(C3-C7)carbocyclyl, wherein the heteroaryl and carbocyclyl are optionally substituted with one to four R14. In another embodiment, R11is -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or -O(C(R13)R13’)o(C3-C7)carbocyclyl, wherein the heteroaryl and carbocyclyl are optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl or -O(C(R13)R13’)o(C6-C10)aryl, wherein the aryl is optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S or -O(C(R13)R13’)o-5 or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heteroaryl is optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C3-C7)carbocyclyl or -O(C(R13)R13’)o(C3-C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein heterocyclyl is optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C3-C7)carbocyclyl optionally substituted with one to four R14. In yet another embodiment, R11is -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, optionally substituted with one to four R14. In another embodiment, R11is -O(C(R13)R13’)o(C6-C10)aryl optionally substituted with one to four R14. In yet another embodiment, R11is -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to four R14. In another embodiment, R11is -O(C(R13)R13’)o(C3- C7)carbocyclyl optionally substituted with one to four R14. In yet another embodiment, R11is -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, optionally substituted with one to four R14. In another embodiment, R11is -(C(R13)R13’)o(C6-C10)aryl, - O(C(R13)R13’)o(C3-C7)carbocyclyl, or -O(C(R13)R13’)o(C6-C10)aryl, wherein the carbocyclyl and aryl are optionally substituted with one to four R14. In some embodiments of the formulae above, R11is -L-(C1-C6)alkyl, -L-(C6-C10)aryl, -L-(5- to 10- membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, NH, and S), -L-(C3- C10)carbocyclyl, -L-(4- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), wherein the alkyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R14. In some embodiments of the formulae above, R11is -L-(C1-C6)alkyl, wherein the alkyl is optionally substituted with one or more R14. In some embodiments of the formulae above, R11is - L-(C6-C10)aryl, wherein the aryl is optionally substituted with one or more R14. In some embodiments of the formulae above, R11is -L-(5- to 10-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R14. In some embodiments of the formulae above, R11is -L-(4- to 10- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), wherein the heterocyclyl is optionally substituted with one or more R14. In some embodiments of the formulae above, R11is -L-(C3-C10)carbocyclyl, wherein the carbocyclyl is optionally substituted with one or more R14. In some embodiments of the formulae above, L is absent, -(C(R13)R13’)o-, -O(C(R13)R13’)o-, - (C(R13)R13’)oO(C(R13)R13’)o-, or -N(R16’)(C(R13)R13’)o-; In some embodiments, L is absent. In some embodiments, L is -(C(R13)R13’)o-. In some embodiments, L is -O(C(R13)R13’)o-. In some embodiments, L is -(C(R13)R13’)oO(C(R13)R13’)o-. In some embodiments, L is -N(R16’)(C(R13)R13’)o. In some embodiments of the formulae above, R11is , ,

[0086]

[0087]

[0088]

[0089] In some embodiments of the formulae above, R9is ,

[0090] wherein each R20’is independently R20or H. In some embodiments, R9is H. In some embodiments, R9is . In some embodiments, R9is In some embodiments, R9is , wherein each R20’is independently H or R20. In some embodiments, R9is , wherein each R20’is independently H or R20. In some embodiments, R9is wherein each R20’is independently H or R20. In some embodiments, R9 is wherein each R20’is independently H or R20. In some embodiments, R9is , wherein each R20’is independently H or R20. In some embodiments, R9is wherein each R20’is independently H or R20. In some embodiments, R9is R20. In some embodiments, R9is , wherein each R20’is independently H each R20’is independently H or R20. In some embodiments, R9is , herein each R20’is independently H or R20. In some embodiments, R9is wherein each R20’is independently H or R20. In some embodiments, R9is

[0091]

[0092] In some embodiments of the formulae above, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, - N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, or -N((C1-C6)alkyl)2. In yet another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, or -CN. In another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, halogen, –OH, -NH2, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, halogen, –OH, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, –OH, -NH2, -N(H)(C1-C6)alkyl, - N((C1-C6)alkyl)2, or -CN. In another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or - CN. In yet another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R12is independently at each occurrence (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, or –OH. In another embodiment, R12is independently at each occurrence halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, halogen, or –OH. In another embodiment, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkoxy, halogen, or –OH. In some embodiments of the formulae above, R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, - N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; or two R12on the same atom together form oxo or =N(R16’). In some embodiments, two R12on the same atom together form oxo. In some embodiments, two R12on the same atom together form =N(R16’). In some embodiments of the formulae above, R13is at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In another embodiment, R13is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R13is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, or -OH. In another embodiment, R13is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, or -OH. In yet another embodiment, R13is at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, halogen, or -OH. In another embodiment, R13is at each occurrence H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In yet another embodiment, R13is at each occurrence H, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In another embodiment, R13is at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In yet another embodiment, R13is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, or -OH. In another embodiment, R13is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, or - OH. In yet another embodiment, R13is at each occurrence H, (C1-C6)alkyl, or -OH. In some embodiments of the formulae above, R13is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or (C3-C10)carbocyclyl; or R13and R13’on the same atom together form oxo or methylene; or two R13together with the atoms they are attached to form a (C3-C5)carbocyclyl. In some embodiments, R13is (C3-C10)carbocyclyl. In some embodiments, R13and R13’on the same atom together form oxo or methylene. In some embodiments, two R13together with the atoms they are attached to form a (C3-C5)carbocyclyl. In some embodiments of the formulae above, R13’is at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, or -OH. In another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, halogen, or -OH. In yet another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, or -OH. In another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In yet another embodiment, R13’is at each occurrence H, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In another embodiment, R13’is at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, halogen, or -OH. In yet another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, or -OH. In another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, (C1- C6)haloalkyl, or -OH. In yet another embodiment, R13’is at each occurrence H, (C1-C6)alkyl, or -OH. In some embodiments of the formulae above, R13’is independently at each occurrence H, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or (C3-C10)carbocyclyl; or R13and R13’on the same atom together form oxo or methylene. In some embodiments, R13is (C3- C10)carbocyclyl. In some embodiments, R13and R13’on the same atom together form oxo or methylene. In some embodiments of the formulae above, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, - N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, or -N((C1-C6)alkyl)2. In yet another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, or -CN. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, halogen, –OH, -NH2, -N((C1-C6)alkyl)2, or -CN. In yet another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, halogen, –OH, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, –OH, -NH2, -N(H)(C1-C6)alkyl, - N((C1-C6)alkyl)2, or -CN. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In yet another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, or -CN. In another embodiment, R14is independently at each occurrence (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or - CN. In yet another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, or –OH. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)hydroxyalkyl, or halogen. In yet another embodiment, R14is independently at each occurrence halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen. In yet another embodiment, R14is independently at each occurrence (C1-C6)alkyl or halogen. In another embodiment, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN. In some embodiments of the formulae above, R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, - N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; or two R14on the same atom together form oxo. In some embodiments, two R14on the same atom together form oxo. In some embodiments of the formulae above, R15is independently at each occurrence H, (C1- C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R15is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R15is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R15is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1- C6)alkyl, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6- C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6- C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R15is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N((C1-C6)alkyl)2, (C1- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R15is independently at each occurrence H, (C1-C6)alkoxy, -N(H)(C1- C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R15is independently at each occurrence H, -NH2, -N(H)(C1-C6)alkyl, -N((C1- C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6- C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R15is independently at each occurrence (C1-C6)alkoxy, -NH2, -N(H)(C1- C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R13is independently at each occurrence H, (C1-C6)alkoxy, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In some embodiments of the formulae above, R16is independently at each occurrence H, (C1- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R16is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, or (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R16is independently at each occurrence H, (C1-C6)alkyl substituted with one to four substituents independently selected from (C6- C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6- C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R16is independently at each occurrence H, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R16is independently at each occurrence H. In another embodiment, R16is independently at each occurrence (C1- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R16is independently at each occurrence (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R16is independently at each occurrence (C1-C6)alkyl substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R16is independently at each occurrence (C6-C10)aryl substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In some embodiments of the formulae above, R16’is independently at each occurrence H or (C1- C6)alkyl. In another embodiment, R16’is independently at each occurrence H or (C1-C3)alkyl. In another embodiment, R16’is independently at each occurrence (C1-C6)alkyl. In another embodiment, R16’is independently at each occurrence H. In some embodiments of the formulae above, R17is independently at each occurrence (C1- C6)alkoxy. In some embodiments of the formulae above, R18is independently at each occurrence (C1- C3)alkoxy, (C3-C10)carbocyclyl, or -OH. In some embodiments, R18is independently in at least one occurrence (C1-C3)alkoxy. In some embodiments, R18is independently in at least one occurrence (C3- C10)carbocyclyl. In some embodiments, R18is independently in at least one occurrence -OH. In some embodiments of the formulae above, R19is independently at each occurrence (C1- C6)alkoxy, (C1-C6)haloalkoxy, or -CN. In some embodiments, R19is independently in at least one occurrence (C1-C6)alkoxy. In some embodiments, R19is independently in at least one occurrence (C1- C6)haloalkoxy. In some embodiments, R19is independently in at least one occurrence -CN. In some embodiments of the formulae above, R20is independently at each occurrence -R16’, - O(R16’), or -C(O)O(R16’). In some embodiments, R20is independently in at least one occurrence -R16’. In some embodiments, R20is independently in at least one occurrence -O(R16’). In some embodiments, R20is independently in at least one occurrence -C(O)O(R16’). In some embodiments of the formulae above, R21is independently at each occurrence H, D, halo, methyl, or (C1)haloalkyl. In some embodiments, R21is independently in at least one occurrence H. In some embodiments, R21is independently in at least one occurrence D. In some embodiments, R21is independently in at least one occurrence halo. In some embodiments, R21is independently in at least one occurrence methyl. In some embodiments, R21is independently in at least one occurrence (C1)haloalkyl. In some embodiments of the formulae above, q is 1, 2, or 3. In another embodiment, q is 1 or 3. In yet another embodiment, q is 2 or 3. In another embodiment, q is 1 or 2. In yet another embodiment, q is 1. In another embodiment, q is 2. In yet another embodiment, q is 3. In some embodiments of the formulae above, n is 1, 2, or 3. In another embodiment, n is 1 or 3. In yet another embodiment, n is 2 or 3. In another embodiment, n is 1 or 2. In yet another embodiment, n is 1. In another embodiment, n is 2. In yet another embodiment, n is 3. In some embodiments of the formulae above, r is 1, 2, or 3. In another embodiment, r is 1 or 3. In yet another embodiment, r is 2 or 3. In another embodiment, r is 1 or 2. In yet another embodiment, r is 1. In another embodiment, r is 2. In yet another embodiment, r is 3. In some embodiments of the formulae above, s is 1, 2, or 3. In another embodiment, s is 1 or 3. In yet another embodiment, s is 2 or 3. In another embodiment, s is 1 or 2. In yet another embodiment, s is 1. In another embodiment, s is 2. In yet another embodiment, s is 3. In some embodiments of the formulae above, t is 1, 2, or 3. In another embodiment, t is 1 or 3. In yet another embodiment, t is 2 or 3. In another embodiment, t is 1 or 2. In yet another embodiment, t is 1. In another embodiment, t is 2. In yet another embodiment, t is 3. In some embodiments of the formulae above, p is 0, 1, 2, or 3. In another embodiment, p is 0, 1, or 2. In yet another embodiment, p is 0, 1, or 3. In another embodiment, p is 0, 2, or 3. In yet another embodiment, p is 1, 2, or 3. In another embodiment, p is 0 or 1. In yet another embodiment, p is 0 or 2. In another embodiment, p is 0 or 3. In yet another embodiment, p is 1 or 2. In another embodiment, p is 1 or 3. In yet another embodiment, p is 2 or 3. In another embodiment, p is 0. In yet another embodiment, p is 1. In another embodiment, p is 2. In yet another embodiment, p is 3. In some embodiments of the formulae above, o is 0, 1 or 2. In another embodiment, o is 0 or 2. In yet another embodiment, o is 0 or 1. In another embodiment, o is 1 or 2. In yet another embodiment, o is 0. In another embodiment, o is 1. In yet another embodiment, o is 2. In some embodiments of the formulae above, o’ is 0, 1, 2, 3, 4, or 5. In another embodiment, o’ is 0 or 2. In yet another embodiment, o’ is 0 or 1. In another embodiment, o’ is 1 or 2. In yet another embodiment, o’ is 0. In another embodiment, o’ is 1. In yet another embodiment, o’ is 2. In some embodiments, o’ is 0, 1, or 2. In some embodiments of the formulae above, X1is N or CR3. In another embodiment, X1is N or CR3and R1is H. In another embodiment, X1is N or CR3, R1is H, and R2ais H. In another embodiment, X1is N or CR3, R1is H, R2ais H, and R2bis H. In yet another embodiment, X1is N or CR3, R1is H, R2ais H, R2bis H, and R2cis H. In another embodiment, X1is N or CR3, R1is H, R2ais H, R2bis H, R2cis H, and R2dis H. In yet another embodiment, X1is N or CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, and R3is H. In another embodiment, X1is N or CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, R3is H, and R4is (C1- C3)alkyl or (C1-C3)haloalkyl. In yet another embodiment, X1is N or CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, and R3is D. In another embodiment, X1is N or CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, R3is D, and R4is (C1-C3)alkyl or (C1-C3)haloalkyl. In some embodiments of the formulae above, X1is N. In another embodiment, X1is N and R1is H. In yet another embodiment, X1is N, R1is H, R2ais H, R2bis H, and R2cis H. In another embodiment, X1is N, R1is H, R2ais H, R2bis H, R2cis H, and R2dis H. In another embodiment, X1is N, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, and R4is (C1-C3)alkyl or (C1- C3)haloalkyl. In some embodiments of the formulae above, X1is CR3. In another embodiment, X1is CR3and R1is H. H. In another embodiment, X1is CR3, R1is H, R2ais H, and R2bis H. In yet another embodiment, X1is CR3, R1is H, R2ais H, R2bis H, and R2cis H. In another embodiment, X1is CR3, R1is H, R2ais H, R2bis H, R2cis H, and R2dis H. In yet another embodiment, X1is CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, and R3is H. In another embodiment, X1is CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, R3is H, and R4is (C1-C3)alkyl or (C1-C3)haloalkyl. In yet another embodiment, X1is CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, and R3is D. In another embodiment, X1is CR3, R1is H, R2ais H, R2bis H, R2cis H, R2dis H, R3is D, and R4is (C1-C3)alkyl or (C1-C3)haloalkyl. Non-limiting illustrative compounds of the disclosure include the compounds in Table 1: Table 1. Exemplary Compounds * Absolute and relative stereochemistry was not assigned. Embodiment 1: A compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: X1is N or CR3; X2is N or CR6; X2’is N or CR6’; X3is N or CR6; X3’is N or CR6’; X4is N or CR6; R1is H, D, -C(O)R15, -CH2OC(O)R15, -CH2OC(O)NHR16, -CH2OC(O)OR16, -P(O)(OR16)2, -CH2OP(O)(OR16)2, -CH2OP(O)(OH)OR16, -CH2OP(O)(R16)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R16’)NHR16’, -CH2OC(O)(CH2)qC(O)OR16’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S); R2a, R2b, R2c, and R2dare each independently H or D; R3is H or D; R4is H, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C2-C3)hydroxyalkyl; R5is R6and R6’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R7and R7’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or halogen; R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R9is (C1-C6)alkyl or (C1-C6)haloalkyl, wherein the alkyl and haloalkyl are substituted with one or more R10; R9’is (C1-C6)alkyl, (C1-C6)haloalkyl, -R10’, or a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O, N, and NH, wherein the alkyl and haloalkyl are substituted with one or more R10’, and the heterocyclyl is substituted with one or more R10a; R10is (C6-C10)aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one or more R12; R10’is R10ais –(CH2)0-2-(C6-C10)aryl or –(CH2)0-2-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one or more R12; R11is -(C(R13)R13’)o(C6-C10)aryl, -(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -(C(R13)R13’)o(C3-C7)carbocyclyl, -(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O(C(R13)R13’)o(C6-C10)aryl, -O(C(R13)R13’)o-5 or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, -O(C(R13)R13’)o(C3-C7)carbocyclyl, or -O(C(R13)R13’)o4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R14; R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R13and R13’are independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH; R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R15is H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16’is independently at each occurrence H or (C1-C6)alkyl; q, n, r, s, and t are each independently 1, 2, or 3; p is 0, 1, 2, or 3; and o are each independently 0, 1 or 2. Embodiment 2. The compound according to claim 1, having a Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Il), Formula (Im), Formula (In), Formula (In-1), Formula (Io), or Formula (Ip): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Embodiment 3. The compound according to any one of Embodiment 1 or 2, wherein R2ais H. Embodiment 4. The compound according to any one of Embodiments 1-3, wherein R2bis H. Embodiment 5. The compound according to any one of Embodiments 1-4, wherein R2cis H. Embodiment 6. The compound according to any one of Embodiments 1-5, wherein R2dis H. Embodiment 7. The compound according to any one of Embodiments 1-6, wherein X1is CR3. Embodiment 8. The compound according to any one of Embodiments 1-6, wherein X1is N. Embodiment 9. The compound according to any one of Embodiments 1-8, wherein R1is H. Embodiment 10. The compound according to Embodiment 1, having a Formula (Iq), Formula (Ir), Formula (Iu), Formula (Iv), Formula (Iw), Formula (Ix), Formula (Iy), Formula (Iz), Formula (Iaa), or Formula (Ibb): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Embodiment 11. The compound according to any one of Embodiments 1-10, wherein R3is H. Embodiment 12. The compound according to any one of Embodiments 1-11, wherein n is 1 and t is 1. Embodiment 13. The compound according to any one of Embodiments 1-11, wherein n is 1 and t is 2. Embodiment 14. The compound according to any one of Embodiments 1-11, wherein n is 2 and t is 1. Embodiment 15. The compound according to any one of Embodiments 1-14, wherein X2is CR6and X3is N. Embodiment 16. The compound according to any one of Embodiments 1-14, wherein X2is CR6and X3is CR6. Embodiment 17. The compound according to any one of Embodiments 1-14, wherein X2is N and X3is CR6. Embodiment 18. The compound according to any one of Embodiments 1-17, wherein R9is (C1- C6)alkyl substituted with one to two R10. Embodiment 19. The compound according to any one of Embodiments 1-17, wherein R9’is (C1- C6)alkyl substituted with one to two R10’. Embodiment 20. The compound according to any one of Embodiments 1-18, wherein R10is (C6- C10)aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one to three R12. Embodiment 21. A compound selected from the group consisting of: 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-methyl-1H- imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(4-((6-((2-chloro-6-fluorobenzyl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1-methyl- 1H-imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(4-((7-((2-chloro-6-fluorobenzyl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1-methyl- 1H-imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-methyl- 1H-imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-methyl- 1H-imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)piperidine- 2,6-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-1-methylisoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-6-methoxyisoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(3-((2-chloro-6-fluorobenzyl)oxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-((6-((2-chloro-6-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)-2-hydroxybenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2,6-difluorobenzyl)oxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-6-fluorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(3-(2-chloro-6-fluorobenzyl)benzyl)is;oindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(4-((6-(2-chloro-6-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1-methyl-1H- imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-3-methylisoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(4-((7-(2-chloro-6-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1-methyl-1H- imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(4-((5-(2-chloro-6-fluorobenzyl)isoindolin-2-yl)methyl)phenyl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(3-chlorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-7-methylisoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(4-chlorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chlorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-6-fluorophenoxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-6-methylisoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-7-methoxyisoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-7-fluoroisoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-4-fluorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(5-chloro-2-fluorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(3-chloro-2-fluorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2,6-difluorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)-3-fluorobenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)-2-fluorobenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)-2-methylbenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(1-(5-((2-chloro-6-fluorobenzyl)oxy)isoindolin-2-yl)-2,3-dihydro-1H-inden-4-yl)-1-methyl-1H- imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-6-fluorobenzyl)-3-fluorobenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)-3-methylbenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-6-fluorobenzyl)-2-fluorobenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2-fluoro-6-methylbenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2,4-difluorobenzyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-6-fluorobenzyl)-3-methylbenzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; l-(2-(2-(4-((2-chloro-6-fluorophenyl)(hydroxy)methyl)benzyl)isoindolin-5-yl)-l-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione; l-(2-(2-(4-(2-chloro-3-fluorobenzyl)benzyl)isoindolin-5-yl)-l -methyl-1H-imidazol -5- yl)dihydropyrimidine-2,4(1H,3H) -dione; l-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-4-fluoroisoindolin-5-yl)-l-methyl-1H-imidazol-5- yl)dihydropyrimidine-2.4(1H.3H)-dione; l-(2-(2-(4-(2-chloro-6-fluorobenzyl)-2-hydroxybenzyl)isoindolin-5-yl)-l-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione; l-(2-(2-(4-(2-chloro-4,6-difluorobenzyl)benzyl)isoindolin-5-yl)-l -methyl- 1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione; l-(l-methyl-2-(2-(4-(2,4,6-trifluorobenzyl)benzyl)isoindolin-5-yl)-1H-imidazol-5-yl)dihydropyrimidine-

[0093] 2,4(1H,3H)-dione; l-(2-(2-((5-(2-chloro-6-fluorobenzyl)pyridin-2-yl)methyl)isoindolin-5-yl)-l-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione; l-(2-(2-(4-(2-chloro-6-fluorobenzyl)-2-methylbenzyl)isoindolin-5-yl)-l -methyl- 1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione;

[0094] 1 -(2-(2-( 1 -(4-((2-chloro-6-fluorobenzyl)oxy)phenyl)ethyl)isoindolin-5 -yl)- 1 -methyl- 1H-imidazol-5 - yl)dihydropyrimidine-2.4(1H.3H)-dione; l-(2-(2-(4-(2-chloro-6-fluorobenzyl)-3-hydroxybenzyl)isoindolin-5-yl)-l-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione;

[0095] 1 -(2-(2-(4-(2-chloro-4-fluorophenoxy)benzyl)isoindolin-5-yl)- 1 -methyl- 1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione; l-(l-methyl-2-(2-(4-(2,4,6-trifluorophenoxy)benzyl)isoindolin-5-yl)-1H-imidazol-5- yl)dihydropyrimidine-2.4(1H.3H)-dione; l-(2-(2-(4-(2,6-dichloro-4-fluorophenoxy)benzyl)isoindolin-5-yl)-l -methyl- 1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione;

[0096] 1 -(2-( 1 -(5-(2-chloro-6-fluorobenzyl)isoindolin-2-yl)-2,3-dihydro- 1H-inden-5-yl)- 1 -methyl-1H-imidazol- 5-yl)dihydropyrimidine-2,4(1H,3H) -dione; l-(2-(2-(2-chloro-4-((2-chloro-6-fluorobenzyl)oxy)benzyl)isoindolin-5-yl)-l-methyl-1H-imidazol-5- yl)dihydropyrimidine-2.4(1H.3H) -dione; l-(2-(2-(4-(4-fluoro-2,6-dimethylphenoxy)benzyl)isoindolin-5-yl)-l -methyl- 1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H) -dione;

[0097] 1 -(2-(2-(4-(2-cthyl-6-fluorobenzyl)benzyl)isoindolin-5 -yl)- 1 -methyl- 1H-imidazol-5 - yl)dihydropyrimidine-2,4(1H,3H) -dione; 1-(2-(6-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-1-methyl- 1H-imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1-methyl- 1H-imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-4,6-difluorophenoxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2,6-dichlorophenoxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-(1-(2-chlorophenyl)ethyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(1-(2-chloro-6-fluorophenyl)ethyl)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-6-fluorophenoxy)benzyl)isoindolin-5-yl)-1-(difluoromethyl)-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(cyclohexyloxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-(cyclopentyloxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)-2-(difluoromethoxy)benzyl)isoindolin-5-yl)-1-methyl-1H- imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-(cyclohexylmethoxy)benzyl)isoindolin-5-yl)-1-methyl-1H-imidazol-5-yl)dihydropyrimidine- 2,4(1H,3H)-dione; 1-(2-(2-(4-(2-chloro-6-fluorophenoxy)benzyl)isoindolin-5-yl)-1-(difluoromethyl)-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)isoindolin-5-yl)-1-(difluoromethyl)-1H-imidazol-5- yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(difluoromethyl)- 1H-imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; and 1-(2-(2-(4-((2-chloro-6-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-ethyl-1H- imidazol-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof Embodiment 22. A pharmaceutical composition comprising a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and a pharmaceutically acceptable carrier or excipient.

[0098] Embodiment 23. The pharmaceutical composition of Embodiment 22, further comprising at least one additional pharmaceutical agent.

[0099] Embodiment 24. The pharmaceutical composition of Embodiment 22 or 23. wherein the at least one additional pharmaceutical agent is an anticancer agent.

[0100] Embodiment 25. The pharmaceutical composition of anyone of Embodiments 22-24 for use in the treatment of a disease or disorder that is affected by the reduction of Cyclin E1 (CCNE1) protein levels.

[0101] Embodiment 26. A method of degrading Cyclin E1 (CCNE1) protein, comprising administering to a patient in need thereof an effective amount of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of Embodiment 22.

[0102] Embodiment 27. A method of modulating Cyclin E1 (CCNE1) protein levels comprising administering to a patient in need thereof an effective amount of a compound of any one of Embodiments 1-21, or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmacal composition of Embodiment 22.

[0103] Embodiment 28. A method for reducing Cyclin E1 (CCNE1) protein levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of Embodiment 22.

[0104] Embodiment 29. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-21. or a pharmacally acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof or the pharmacal composition of Embodiment 22.

[0105] Embodiment 30. The method of Embodiment 29, wherein the cancer is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC). liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0106] Embodiment 31. The method of Embodiment 29 or 30, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer, and thyroid cancer.

[0107] Embodiment 32. Hie method of Embodiment 29 or 30, wherein the cancer is selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer. Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0108] Embodiment 33. Tire method of Embodiment 29 or 30, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, neuroblastoma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for w hich the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma.

[0109] Embodiment 34. The method of anyone of Embodiments 28-32, wherein the cancer is characterized by an amplification or overexpression of cyclin E1.

[0110] Embodiment 35. A method for treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1) in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt thereof or tire pharmaceutical composition of Embodiment 22.

[0111] Embodiment 36. A method of treating a disease or disorder that is affected by the modulation of CY CLIN E 1 ( CCNE 1 ) protein levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of Embodiment 22. Embodiment 37. The method of Embodiment 35 or 36, wherein the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC). liver cancer (including HCC). ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, orophary ngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma. renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer

[0112] Embodiment 38. The method of any one of Embodiments 35-37, wherein the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus- associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein -Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0113] Embodiment 39. Tire method of any one of Embodiments 35-37, wherein the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma.

[0114] Embodiment 40. The method of Embodiment 35 or 36, wherein the disease or disorder is one or more selected from rheumatoid arthritis, inflammation, autoimmune disease, lymphoproliferative conditions, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, pancreatic fibrosis, hepatic fibrosis, acute and chronic renal disease, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neural trauma, Alzheimer's disease, Huntington's disease, Parkinson's disease, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptures, or prolapsed intervertebral disk syndrome, osteopetrosis, thrombosis, restenosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, graft-versus-host reaction. Multiple Sclerosis, lupus, fibromyalgia, AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus, and diabetes mellitus.

[0115] Embodiment 41. The method of any one of Embodiments 26-40, further comprising at least one additional pharmaceutical agent or therapy.

[0116] Embodiment 42. The method of Embodiment 41, wherein the at least one additional pharmacal agent is an anticancer agent.

[0117] Embodiment 43. The method of Embodiment 41 , wherein the at least one additional pharmaceutical agent or therapy is selected from surgery, radiotherapy, endocrine therapy, biologic response modifiers, hyperthermia and cryotherapy, agents to attenuate any adverse effects, alkylating drugs, antimetabolites, purine antagonists and pyrimidine antagonists, spindle poisons, podophyllotoxins, antibiotics, nitrosoureas, inorganic ions, enzymes, and hormones.

[0118] Embodiment 44. The method of any one of Embodiments 26-43, wherein the administration is oral, parenteral, subcutaneous, by injection, or by infusion.

[0119] Embodiment 45. An in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0120] Embodiment 46. An in vivo method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound of any one of Embodiments 1 -21 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0121] Embodiment 47. The method of Embodiments 45 or 46, wherein the cell is a mammalian cell.

[0122] Embodiment 48. A method of degrading Cyclin E1 (CCNE1) in a cell, comprising contacting the cell with an effective amount of a compound of any one of Embodiments 1-21, or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmacal composition of Embodiment 22.

[0123] Embodiment 49. The method of Embodiment 48, wherein the contacting occurs in vivo.

[0124] Embodiment 50. The method of Embodiment 48, wherein the contacting occurs in vitro. Embodiment 51. The method of any one of Embodiments 48-50, wherein the cell is a mammalian cell.

[0125] Embodiment 52. The method of Embodiment 51, wherein the mammalian cell is a mammalian cancer cell.

[0126] Embodiment 53. A method of treating a solid tumor in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of Embodiment 22.

[0127] Embodiment 54. A method of treating a liquid tumor in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmacal composition of Embodiment 22.

[0128] Embodiment 55. A compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of Cyclin E1 (CCNE1) protein levels.

[0129] Embodiment 56. A compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of Cyclin E1 (CCNE1) protein levels.

[0130] Embodiment 57. A compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1).

[0131] Embodiment 58. Use of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of Cyclin E 1 (CCNE 1 ) protein levels.

[0132] Embodiment 59. Use of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of Cyclin E1 (CCNE1) protein levels.

[0133] Embodiment 60. Use of a compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of characterized by amplification or overexpression of Cyclin E1 (CCNE1).

[0134] Embodiment 61. The compound for use of any one of Embodiments 55-57 or the use of any one of Embodiments 58-60, wherein the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer. Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasophary ngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0135] Embodiment 62. The compound for use of any one of Embodiments 55-57 or the use of any one of Embodiments 58-60, wherein the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0136] Embodiment 63. The compound for use of any one of Embodiments 55-57 or the use of any one of Embodiments 58-60, wherein the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma. gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma.

[0137] Embodiment 64. Tire compound for use of any one of Embodiments 55-57 or the use of any one of Embodiments 58-60, wherein the disease or disorder is one or more selected from rheumatoid arthritis, inflammation, autoimmune disease, lymphoproliferative conditions, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary' disease, chronic pulmonary inflammation, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, pancreatic fibrosis, hepatic fibrosis, acute and chronic renal disease, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neural trauma, Alzheimer's disease. Huntington's disease, Parkinson's disease, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptures, or prolapsed intervertebral disk syndrome, osteopetrosis, thrombosis, restenosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, graft-versus-host reaction, Multiple Sclerosis, lupus, fibromyalgia, AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus, and diabetes mellitus.

[0138] In another embodiment of the disclosure, the compounds of the present disclosure are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of the present disclosure may be (+) or (-) enantiomers.

[0139] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0140] Compounds of the disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0141] The compounds of the disclosure may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0142] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as. for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Masher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers or via chiral chromatography. Also, some of the compounds of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0143] It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure and chemical structures and names. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.

[0144] All stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds (including those of the salts, solvates, esters, and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as. for example, 4-pyridyl and 3-pyridyl). (For example, if a Compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.) Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or is admixed, for example, as racemates or with all other, or other selected, stereoisomers.

[0145] The chiral centers of the compounds of the disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)- form.

[0146] The use of the terms "salt", "solvate", "ester," "prodrug", and the like, is intended to equally apply to the salt, solvate, ester, and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the inventive compounds.

[0147] The compounds of the disclosure may fonn salts which are also within the scope of this disclosure. Reference to a compound of the Formula herein is generally understood to include reference to salts thereof, unless otherwise indicated.

[0148] The compounds and intermediates may be isolated and used as the compound per se. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms arc replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and, such as2H,3H,11C,13C,14C,15N,18F,31P,32P, respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as3H,13C, and14C, are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F, lie or labeled compound may be particularly desirable for PET or SPECT studies. Further, substitution with heavier isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent) or an improvement in therapeutic index. For example, substitution with deuterium may modulate undesirable side effects of the undeuterated compound, such as competitive CYP450 inhibition, time dependent CYP450 inactivation, etc. It is understood that deuterium in this context is regarded as a substituent in compounds of the present disclosure. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation, at 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by carrying out the procedures disclosed in the schemes or in the examples and preparations described below using an appropriate isotopically-labeled reagent in place of the non-isotopically labeled reagent. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6-DMSO. The present disclosure relates to compounds which are modulators of CCNE1 protein levels. In one embodiment, the compounds of the present disclosure decrease CCNE1 protein levels. In yet one embodiment, the compounds of the present disclosure reduce CCNE1 protein levels. In another embodiment, the compounds of the present disclosure are degraders of CCNE1. As used herein, the term “IC50” refers to half maximal inhibitory concentration. As used herein, the term “DC50” refers to half maximal degradation concentration. As used herein, the term “EC50” refers to half maximal effective concentration. As used herein, the term “AC50” refers to half maximal activation. As used herein, Dmax is the maximum level of degradation achievable. In some embodiments, the degradation of CCNE1 is measured by DC50. Potency of a compound of the present disclosure towards degradation of CCNE1 can be measured by its DC50value. A compound with a lower DC50value, as determined under substantially similar degradation conditions, is a more potent degrader relative to a compound with a higher DC50value. In some embodiments, the substantially similar conditions comprise determining degradation of protein levels in cells expressing the specific protein, or a fragment of any thereof. As used herein, Dmax is the maximum level of degradation achievable. The disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. F. Methods of Synthesizing Compounds of Formula (I) The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below. The compounds of the present disclosure may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of Compounds of Formula (I). Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure. Accordingly, the present disclosure includes all possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereo specific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994). The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds Compounds of the present disclosure can be synthesized by following the steps outlined in General Schemes I, II and III which comprise different sequences of assembling intermediates I-a, I-b, I-c, I-d, I- e, I-f, I-g, I-h, I-i, IIa, IIb, IIc, IId, IIIa, and IIIb. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated in the Examples section herein below. General Scheme I wherein R2a, R2b, R2c, R2d, R4, and R5are as defined in Formula (I), and R1is as defined in Formula (I) or is a protecting group. The general way of preparing Compounds of Formula (I), wherein X1is N, by using intermediates I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, and I-i is outlined in General Scheme I. Coupling of boronic ester I-b with I-a using a suitable metal catalyst (e.g., Pd(dppf)Cl2•DCM, Pd(tBu3P)2, Pd-PEPPSI-IHept-Cl, etc.) and a base (e.g., N,N-diisopropylethylamine (DIPEA), triethylamine (Et3N), KOAc, K2CO3, Cs2CO3, K3PO4, etc.), in a solvent (e.g., N,N-dimethylformamide (DMF), 1,4-dioxane, water, etc. or a combination thereof) and optionally at elevated temperature (e.g., heat, microwave) provides I-c. In an alternative preparation of I-c, reaction of nitrile I-f with a catalytic amount of an alkoxide reagent (e.g., sodium methoxide, sodium ethoxide, etc.) in an alcoholic solvent (e.g., methanol, ethanol, etc.), optionally at elevated or reduced temperature, generates an intermediate imino ether. Subsequent treatment with acetic acid and I-g, at about room temperature to about 50 ºC, followed by treatment with a concentrated mineral acid (e.g., hydrochloric acid, etc.) at a temperature, e.g., of about 50 ºC, to about 80 ºC, provides I-c. In another alternative preparation of I-c, reaction of I-h with glyoxal and ammonium hydroxide in a suitable solvent (e.g., methanol, ethanol, etc.) at, e.g., about 0 ºC to about rt, furnishes I-i. Reaction of I-i with an alkylating agent R4X’’, where X’’ is Br or I, in a suitable solvent (e.g., DMSO, DMF, etc.), with a suitable base (e.g.. sodium hydroxide, sodium hydride, K2CO3, etc.), optionally at reduced or elevated temperature provides I-c. Halogenation of I-c using a suitable halogenating agent (e.g., N-bromosuccinimide (NBS) or molecular bromine (Br2) when X’ is Br, or N-iodosuccinimide (NIS) or molecular iodine (I2) where X’ is I) in a suitable solvent (e.g., DCM, DCE, THF, etc.), optionally at reduced or elevated temperature provides 1-d. Coupling of I-d with I-e can be carried out under Ullmann conditions in the presence of a suitable metal catalyst and ligand combination (e.g., copper (II) acetate (Cu(OAc)2) or copper iodide (CuI) with N,N’-dimethyl-1,2-diaminocyclohexane or a proline derivative) in the presence of a suitable base (e.g., K3PO4, Cs2CO3, etc.), in a suitable solvent (e.g., dioxane, toluene, 2-methyl-THF, DMF, etc.), optionally at elevated temperature (e.g., room temperature to about 100 ºC) provides the Compound of Formula (I) wherein X1is N. The reaction sequence may also be carried out with an R5group that is a precursor for an R5group as defined in Formula (I), for example, bearing a protected amino group or aldehyde precursor, which upon deprotection / conversion and reductive amination, furnishes the Compound of Formula (I). R1may also be a protecting group, which upon deprotection furnishes the Compound of Formula (I) wherein R1is H. General Scheme II wherein R2a, R2c, R4, and R5are as defined in Formula (I). The general way of preparing the Intermediate of Formula II-d, which are a sub-genus of Compounds of Formula (I) wherein X1is CR3, and R2b, R2d,and R3are H, by using intermediates II-a, II- b, and II-c is outlined in General Scheme II. Coupling of boronic ester II-b with II-a using a suitable metal catalyst (e.g., Pd(dppf)Cl2•DCM, Pd(tBu3P)2, Pd-PEPPSI-IHept-Cl, etc.) and a base (e.g., DIPEAEt3N, KOAc, K2CO3, Cs2CO3, K3PO4, etc.), in a solvent (e.g., DMF, 1,4-dioxane, water, etc. or a combination thereof) and optionally at elevated temperature (e.g., heat, microwave) provides II-c. Hydrogenation of II- c in the presence of a suitable catalyst (e.g., dihydroxypalladium (Pd(OH)2), palladium on carbon (Pd / C), platinum dioxide (PtO2), etc.) in a solvent (e.g., DMF, methanol (MeOH), ethanol (EtOH), THF, etc. or a combination thereof) and under an atmosphere of hydrogen gas provides the Intermediate of Formula II-d. The reaction sequence may also be carried out with an R5group that is a precursor for an R5group as defined in Formula (I), for example, bearing a protected amino group or aldehyde precursor, which upon deprotection / conversion and reductive amination, furnishes the Compound of Formula (I). General Scheme III wherein t, n, R2a, R2b, R2c, R2d, R4, R6,R7, R9, X1, X2, and X3are as defined in Formula (I), and R1is a protecting group. The general way of preparing Compounds of Formula (Ia) by using intermediates III-a and III-b is outlined in General Scheme III. III-a is prepared according to the methods of General Scheme I or General Scheme II or by other suitable methods. When P and R1are acid-labile protecting groups (e.g., tert- butyloxycarbonyl (Boc), 2-(trimethylsilyl)ethoxymethyl (SEM), dimethoxybenzyl, etc), intermediate III-a can be deprotected using a strong acid (e.g., trifluoroacetic acid (TFA), hydrochloric acid (HC1), trifluoromethanesulfonic acid, or methanesulfonic acid, or a combination of such acids) in a solvent (e.g., DCE, DCM, diethylether (Et2O), etc.), optionally at elevated temperature to provide III-b. Reductive animation of III-b with an aldehyde or ketone in the presence of a reducing agent (e.g., sodium borohydride (NaBH4), sodium triacetoxyborohydride (STAB), sodium cyanoborohydride (NaBH3CN), MP- cyanoborohydride, decaborane, etc.), optionally a base (e.g., DIPEA, sodium acetate, etc.) or an acid (e.g., acetic acid, etc.), and in a solvent (e.g., DMF, methanol (MeOH), DCM, etc.) optionally at elevated temperature provides the Compound of Formula (Ia). By analogy, Compounds of Formula (Ib), (Ic), and (Id) may be prepared by a similar reaction sequence. In some cases, rather than having a protected amine as in III-a, the corresponding intermediates will bear an aldehyde or ketone precursor, which is converted to an aldehyde or ketone by standard methods (e.g., oxidation of an alkene using osmium tetroxide and sodium metaperiodate, oxidation of an alcohol using Dess-Martin periodinane, etc.). Subsequent reductive amination with a suitable amine furnishes the Compounds of Formula (Ib), (Ic), and (Id). A mixture of enantiomers, diastereomers, and cis / trans isomers resulting from the process described above can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation. Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic compounds of the present disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization. It should be understood that in the description and formula shown above, the various groups R1, R2a, R2b, R2c, R2d, R4, R5, and X1, and other variables are as defined above, except where otherwise indicated. Furthermore, for synthetic purposes, the compounds of General Schemes I, II, and III merely representative with elected radicals to illustrate the general synthetic methodology of the Compounds of Formula (I) as defined herein. G. Methods of Using Compounds of Formula (I) In one aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with or affected by modulation of CCNE1 protein levels. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of CCNE1 protein levels an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Examples of diseases or conditions associated with or affected by modulation of CCNE1 protein levels include, but not limited to, ianian cancer (including high grade serous ovarian cancer and clear cell ovarian cancer), endometrial cancer (including high grade endometrial cancer, uterine serous carcinoma, and uterine carcinosarcoma), esophageal cancer, gastroesophageal junction cancer, gastric cancer, stomach cancer, breast cancer or breast carcinoma (including triple negative breast cancer and breast invasive ductal carcinoma), lung cancer (including non- small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, and small cell lung cancer (SCLC)), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, gastrointestinal stromal tumor, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), prostate cancer, testicular cancer, gall bladder cancer, pancreatic cancer, liposarcoma, glioblastoma, glioblastoma multifonn, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer. Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, liposarcoma, leiomyosarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer. Ewing's sarcoma. Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0149] In another aspect, the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder that is affected by the reduction of or decrease in CCNE1 protein levels. Tire method comprises administering to a patient in need of a treatment for diseases or disorders affected by the reduction of CCNE1 protein levels an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer. Human Papilloma Virus- associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0150] Another aspect of the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is associated with or affected by the modulation of CCNE1 protein levels. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma. glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0151] In another aspect, the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is affected by the reduction of or a decrease in CCNE1 protein levels. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma. glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasophary ngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0152] Another aspect of the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder that is associated with or affected by the modulation of CCNE1 protein levels. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another aspect, the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder that is associated with or affected by the reduction of, or a decrease in CCNE1 protein levels. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multifonn, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus- associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0153] Another aspect of the present disclosure relates to a method of modulating, reducing, or decreasing CCNE1 protein levels. The method involves administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, CCNE1 protein levels are modulated, reduced, or decreased through degradation of the CCNE1 protein. In other embodiments, CCNE1 protein levels are modulated, reduced, or decreased through degradation of the CCNE1 protein mediated by an E3 ligase.

[0154] In another aspect, the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is associated with or affected by the modulation, reduction, decrease of CCNE1 protein levels. In some embodiments, CCNE1 protein levels are modulated, reduced, or decreased through degradation of the CCNE1 protein. In other embodiments, CCNE1 protein levels are modulated, reduced, or decreased through degradation of the CCNE1 protein mediated by an E3 ligase.

[0155] Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a CCNE1 -dependent disease or disorder in a patient in need thereof by modulating CCNE1 protein levels through the degradation of CCNE1. In some embodiments, CCNE1 protein degradation is mediated by an E3 ligase.

[0156] In another aspect, the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrag, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrag, stereoisomer, or tautomer thereof, for treating, preventing, inhibiting, or eliminating a CCNE1 -dependent disease or disorder in a patient in need thereof by modulating CCNE1 protein levels through the degradation of CCNE1. In some embodiments, CCNE1 protein degradation is mediated by an E3 ligase.

[0157] Another aspect of the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrag, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrag, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition or elimination of a CCNE1 -dependent disease or disorder in a patient in need thereof by modulating CCNE1 protein levels through the degradation of CCNE1. In some embodiments, CCNE1 protein degradation is mediated by an E3 ligase.

[0158] In another aspect, the present disclosure relates to a method of reducing the proliferation of a cell, the method comprising contacting tire cell with a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrag, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrag, stereoisomer, or tautomer thereof, that reduces CCNE1 protein levels. In some embodiments, CCNE1 protein levels are reduced through degradation of the CCNE1 protein. In some embodiments, CCNE1 protein levels are reduced through degradation of the CCNE1 protein is mediated by an E3 ligase.

[0159] Another aspect of the present disclosure relates to a method of degrading CCNE1. The method comprises administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrag, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate. solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, CCNE1 protein degradation is mediated by an E3 ligase.

[0160] In another aspect, the present disclosure relates to a method for treating a CCNE1 -dependent disease or disorder. Tire method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0161] Another aspect of the disclosure relates to a Compound of Formula (1), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a CCNE 1 -dependent disease or disorder. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory- related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0162] In another aspect, the present disclosure relates to tire use of a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a CCNE1 -dependent disease or disorder. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory -related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0163] Another aspect of the disclosure relates to a Compound of Fonnula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a CCNE1 -dependent disease or disorder. In one embodiment, the disease or disorder is selected from cancers, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC). ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

[0164] In another aspect, the present disclosure relates to a method of modulating CCNE1 protein levels. The method comprises administering to the patient in need thereof a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0165] Another aspect of the disclosure relates to a method of modulating CCNE1 protein levels, wherein the modulation of CCNE1 protein levels treats or ameliorates the disease or disorder. Tire method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0166] In another aspect, the present disclosure relates to a method of degrading CCNE1 protein. The method comprises administering to the patient in need thereof a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0167] Another aspect of the disclosure relates to a method of degrading CCNE1 protein, wherein the degradation of CCNE1 protein levels treats or ameliorates the disease or disorder. The method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0168] In another aspect, the present disclosure relates to a method of reducing CCNE1 protein levels. The method comprises administering to the patient in need thereof a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0169] Another aspect of the disclosure relates to a method of reducing CCNE1 protein levels, wherein the reduction of CCNE1 protein levels treats or ameliorates the disease or disorder. Tire method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Fonnula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0170] In another aspect, the present disclosure relates to a method of treating cancer. The method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Fonnula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cancer is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e.. gastric) cancer, liposarcoma. glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another embodiment, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer, and thyroid cancer. In yet another embodiment, the cancer is selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In another embodiment, the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, neuroblastoma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In yet another embodiment, the cancer is selected from ovarian cancer, endometrial cancer, gastric cancer, uterine cancer, lung cancer, breast cancer, liver cancer, and colorectal cancer. In another embodiment, the cancer is characterized by an amplification or overexpression of cyclin E1.

[0171] Another aspect of the disclosure relates to a method of treating a cancer that is characterized by an amplification or overexpression of cyclin E1. Tire method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof.

[0172] In another aspect, the present disclosure relates to a method of treating cancer wherein the cancer is characterized by an amplification or overexpression of cyclin E1. The method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0173] In a further embodiment, the present disclosure provides a method of treating a cancer condition, wherein the CCNE1 inhibitor is effective in one or more of inhibiting proliferation of cancer cells, inhibiting metastasis of cancer cells, killing cancer cells and reducing severity or incidence of symptoms associated with the presence of cancer cells. In some other embodiments, said method comprises administering to the cancer cells a therapeutically effective amount of a CCNE1 inhibitor. In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo.

[0174] In a further embodiment, the present disclosure provides a method of treating a cancer condition, wherein the CCNE1 degrader is effective in one or more of inhibiting proliferation of cancer cells, inhibiting metastasis of cancer cells, killing cancer cells and reducing severity or incidence of symptoms associated with the presence of cancer cells. In some other embodiments, said method comprises administering to the cancer cells a therapeutically effective amount of a CCNE1 degrader. In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo.

[0175] In another aspect, the present disclosure relates to a method for treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1). Tire method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0176] Another aspect of the present disclosure relates to a method of treating a disease or disorder that is affected by the modulation of CCNE1 protein levels. The method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is one or more selected from lung cancer (including non -small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC). liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another embodiment, the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In yet another embodiment, the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In another embodiment, the disease or disorder is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0177] In another aspect, the present disclosure relates to an in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0178] Another aspect of the present disclosure relates to an in vivo method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cell is a mammalian cell.

[0179] In another aspect, the present disclosure relates to a method of degrading CCNE1 in a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the contacting occurs in vivo. In another embodiment, the contacting occurs in vitro. In yet another embodiment, the cell is a mammalian cell. In another embodiment, the mammalian cell is a mammalian cancer cell.

[0180] Another aspect of the present disclosure relates to a method of treating a solid tumor in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a Compound of Fonnula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0181] In another aspect, the present disclosure relates to a method of treating a liquid tumor in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodnig, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0182] Another aspect of the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodnig, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodnig, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of CCNE1 protein levels. In one embodiment, the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another embodiment, the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus- associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In yet another embodiment, the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In another embodiment, the disease or disorder is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0183] In another aspect, the present disclosure relates to a Compound of Fonnula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of CCNE1 protein levels. In one embodiment, the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC). liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another embodiment, the disease or disorder is one or more selected from liposarcoma. glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer. Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In yet another embodiment, the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In another embodiment, the disease or disorder is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly: rheumatoid spondylitis; osteoarthritis: gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis: toxic shock syndrome: asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary' inflammation; inflammatory' bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis: cerebral malaria; stroke and ischemic injury: neural trauma; Alzheimer's disease; Huntington's disease: Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure: acute coronary syndrome; cachexia: malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary' sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia: AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0184] Another aspect of the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1). In one embodiment, the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC). liver cancer (including HCC). ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma. renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another embodiment, the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus- associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In yet another embodiment, the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multifonn, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In another embodiment, the disease or disorder is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease: Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0185] In another aspect, the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of CCNE1 protein levels. In one embodiment, the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC). SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma. glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer. Ewing's sarcoma. Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another embodiment, the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In yet another embodiment, the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasophary ngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which tire immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In another embodiment, the disease or disorder is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome: chronic obstructive pulmonary disease; chronic pulmonary inflammation: inflammatory bowel disease; Crohn's disease; psoriasis: eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis: restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary' syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis: herniated, ruptures, or prolapsed intervertebral disk syndrome: osteopetrosis; thrombosis; restenosis: silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0186] Another aspect of the present disclosure relates to the use of a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of CCNE1 protein levels. In one embodiment, the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC). liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma. renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-ccll lymphoma, and parathyroid cancer. In another embodiment, the disease or disorder is one or more selected from liposarcoma. glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In yet another embodiment, the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In another embodiment, the disease or disorder is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly: rheumatoid spondylitis; osteoarthritis: gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis: toxic shock syndrome: asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary' inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis: cerebral malaria; stroke and ischemic injury: neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure: acute coronary syndrome; cachexia: malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia: AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0187] In another aspect, the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of characterized by amplification or overexpression of Cyclin E1 (CCNE1). In one embodiment, the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer. In another embodiment, the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In yet another embodiment, the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma. In another embodiment, the disease or disorder is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mcllitus. Another aspect of the present disclosure relates to a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the abnormal cell growth is cancer.

[0188] In another aspect, the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of abnormal cell growth in a subject. In one embodiment, the abnonnal cell growth is cancer.

[0189] Another aspect of the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for the treatment of abnormal cell growth in a subject. In one embodiment, the abnonnal cell growth is cancer.

[0190] In another aspect, the present disclosure relates a compound of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodnig, stereoisomer, or tautomer thereof, for use as a medicament, in particular a medicament for the treatment of abnonnal cell growth. In one embodiment, the abnormal cell grow th is cancer.

[0191] In yet another aspect, the present disclosure relates to the use of a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject. In one embodiment, the abnormal cell growth is cancer.

[0192] In another aspect, the present disclosure relates to a method of inhibiting cancer cell proliferation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in an amount effective to inhibit cell proliferation.

[0193] Another aspect of the present disclosure relates to a method of inhibiting cancer cell invasivcncss in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in an amount effective to inhibit cell invasiveness.

[0194] In another aspect, the present disclosure relates to a method of inducing apoptosis in cancer cells in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in an amount effective to induce apoptosis.

[0195] Another aspect of the present disclosure relates to a method of inhibiting cancer cell metastasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in an amount effective to inhibit cell metastasis.

[0196] In another aspect, the present disclosure relates to a method of inhibiting angiogenesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in an amount effective to inhibit angiogenesis.

[0197] In some embodiments, the abnormal cell growth is cancer. In some such embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC. SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer or thyroid cancer. In further embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, pros-tate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer or stomach cancer. In some embodiments, the abnormal cell growth is cancer characterized by amplification or overexpression of CCNE 1 and / or CCNE2. In another embodiment, the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer. In some such embodiments, the cancer is breast cancer or ovarian cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) breast cancer or ovarian cancer; (b) characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b).

[0198] Examples of diseases or disorders treatable using compounds of the present disclosure include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; systemic lupus erythematosus (SLE); . primary Sjogren's syndrome (pSS); lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary' disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; uveitis; pemphigus vulgaris; sepsis; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0199] Examples of cancers that are treatable using compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathy-roid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lympho-cytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadeno-carcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, sarcoma, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.

[0200] In one embodiment, the cancer treatable using compounds of the present disclosure include, but are not limited to, a cancer selected from lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadeno-carcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, and sarcoma. In another embodiment, the cancer treatable using compounds of the present disclosure is a cancer selected from lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocar-cinoma, and stomach adenocarcinoma. In yet another embodiment, the cancer treatable using compounds of the present disclosure is a cancer selected from adenocarcinoma, carcinoma, and cystadenocarcmoma. In another embodiment, the cancer is a cancer selected from uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, and breast cancer.

[0201] In another embodiment, the cancer treatable using compounds of the present disclosure include, but are not limited to, a cancer selected from is ovarian cancer, endometrial or uterine cancer, or breast cancer, characterized by amplification or overexpression of CCNE1. In one embodiment, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / 6 inhibition. In another embodiment, the breast cancer is advanced or metastatic breast cancer. In another embodiments, the breast cancer is selected from ER- positive / EIR-positive, HER2 -negative breast cancer; ER-positive / HR-positive, HER2 -positive breast cancer, triple negative breast cancer (TNBC); and inflammatory breast cancer. In yet another embodiments, the breast cancer is selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition. In another embodiment, the breast cancer is advanced or metastatic breast cancer.

[0202] In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarci-noma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high microsatellite instability (MSIhlgh). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using tire compounds of the disclosure.

[0203] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), relapsed or refractory Acute Myeloid Leukemia, Myelodysplastic Syndromes, chronic lymphocytic leukemia (CLL) (e.g., relapsed or refractory Chronic Lymphocytic Leukemia (CLL)), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including follicular lymphoma, including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple my eloma) and combinations of said cancers.

[0204] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma. Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma. Merkel cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer. Fallopian tube cancer, gas-trointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, lary ngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer.

[0205] In some embodiments, the compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0206] In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0207] Exemplary hematological cancers treatable using compounds of the present disclosure include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocy tic leukemia (CLL), chronic my elogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recur-rent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)). myelodys-plasia syndrome (MDS). T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM).

[0208] Exemplary sarcomas treatable using compounds of the present disclosure include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhab-dosarcoma. fibroma, lipoma, hamiatoma. and teratoma. Exemplary lung cancers treatable using compounds of the present disclosure include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell, undifferentiated small cell, undif-ferentiated large cell, adenocarcinoma, alveolar (bronchio-lar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0209] Exemplary gastrointestinal cancers treatable using compounds of the present disclosure include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leio-myosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insuli-noma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0210] Exemplary genitourinary tract cancers treatable using compounds of the present disclosure include cancers of the kidney (adenocarcinoma. Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0211] Exemplary liver cancers treatable using compounds of the present disclosure include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0212] Exemplary bone cancers treatable using compounds of the present disclosure include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondro-blastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors

[0213] Exemplary nervous system cancers treatable using compounds of the present disclosure include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glio-blastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0214] Exemplary gynecological cancers treatable using compounds of the present disclosure include cancers of the uterus (endometrial carcinoma, uterine serous carcinoma, carcinosarcoma, high grade emdometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (high grade serous ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosathecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepi­thelial carcinoma, adenocarcinoma, fibrosarcoma, mela­noma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma). Exemplary skin cancers treatable using compounds of the present disclosure include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma. Exemplary viruses causing infections treatable using compounds of the present disclosure include, but are not limited to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cyto­megalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSY-II, and CMY, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, den­gue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus. Exemplary pathogenic bacteria causing infections treatable using compounds of the present disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria. Exemplary pathogenic fungi causing infections treatable using compounds of the present disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum. Exemplary pathogenic parasites causing infections treatable using compounds of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia Zambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania dono­vani, Toxoplasma gondi, and Nippostrongylus brasiliensis. The disclosed compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects. H. Administration, Pharmaceutical Compositions, and Dosing of Compounds of the Disclosure Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0215] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage fonn, such as, for example, injectables. tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, and all using fomrs well known to those skilled in the pharmaceutical arts.

[0216] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application. The pharmaceutical compositions of the present disclosure can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0217] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby fomr an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize tire disclosed compounds. The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0218] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0219] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0. 1 % to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0220] Tire dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0221] Effective dosage amounts of the disclosed compounds...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: X1is N or CR3; X2is N or CR6; X2’is N or CR6’; X3is N or CR6; X3’is N or CR6’; X4is N or CR6; R1is H, D, -C(O)R15, -C(R21)2OC(O)R15, -C(R21)2OC(O)NHR16, -C(R21)2OC(O)OR16, - P(O)(OR16)2, -C(R21)2OP(O)(OR16)2, -C(R21)2OP(O)(OH)OR16, -C(R21)2OP(O)(R16)2, - C(R21)2OC(O)CH2NHC(O)CH2NH2, -C(R21)2OC(O)CH(R16’)NHR16’, -C(R21)2OC(O)(CH2)qC(O)OR16’, - C(R21)2OC(O)-(5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), or -C(R21)2(C6-C10)aryl), wherein the heteroaryl and aryl are optionally substituted with one or more R17; R2a, R2b, R2c, and R2dare each independently H or D; R3is H or D; R4is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C3)hydroxyalkyl, (C2-C5)alkoxyalkyl, or (C3- C10)carbocyclyl, wherein alkyl is optionally substituted with one or more R18;R4ais H, (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3- C10)carbocyclyl, or 3- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S; R5isR6and R6’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R7and R7’are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, halogen, -C(O)O(R16’), or (C3-C10)carbocyclyl, wherein alkyl is optionally substituted with one or more R19; or two R7on the same atom together form (C3-C5)carbocyclyl; R8is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; R9is hydrogen, -(CH2)o’C(O)N(R16’)(R10), (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)hydroxyalkyl wherein the alkyl, haloalkyl, and hydroxyalkyl are substituted with one or more R10and optionally substituted with one or more R20; R9’is (C1-C6)alkyl, (C1-C6)haloalkyl, -R10’, or a 4- to 7-membered heterocyclyl comprising 1 to 2 heteroatoms selected from O and N, wherein the alkyl and haloalkyl are substituted with one or more R10’, and the heterocyclyl is substituted with one or more R10a; R10is (C2-C6)alkynyl, (C3-C10)carbocyclyl, 5- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N and S, wherein the alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are substituted with R11and optionally substituted with one or more R12;R10’isR10ais –(CH2)0-2-(C6-C10)aryl or –(CH2)0-2-(5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S), wherein the aryl and heteroaryl are substituted with R11and optionally substituted with one or more R12; R11is -L-(C1-C6)alkyl, -L-(C6-C10)aryl, -L-(5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S), -L-(C3-C10)carbocyclyl, -L-(4- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, and S), wherein the alkyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R14; L is absent, -(C(R13)R13’)o-, -O(C(R13)R13’)o-, -(C(R13)R13’)oO(C(R13)R13’)o-, or - N(R16’)(C(R13)R13’)o-; R12is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy,(C1- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; or two R12on the same atom together form oxo or =N(R16’); R13and R13’are independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or (C3-C10)carbocyclyl; or R13and R13’on the same atom together form oxo or methylene; or two R13together with the atoms they are attached to form a (C3-C5)carbocyclyl; R14is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, –OH, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or -CN; or two R14on the same atom together form oxo; R15is H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN;R16is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1- C6)haloalkyl, halogen, -OH, -NH2, and -CN; R16’is independently at each occurrence H or (C1-C6)alkyl; R17is independently at each occurrence (C1-C6)alkoxy; R18is independently at each occurrence (C1-C3)alkoxy, (C3-C10)carbocyclyl, or -OH; R19is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -CN; R20is independently at each occurrence -R16’, -O(R16’), or -C(O)O(R16’); R21is independently at each occurrence H, D, halo, methyl, or (C1)haloalkyl; q, n, r, s, and t are each independently 1, 2, or 3; p is 0, 1, 2, or 3; and o is each independently 0, 1 or 2; and o’ is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1, wherein X1is CR3.

3. The compound according to claim 1, wherein X1is N.

4. The compound according to claim 1, wherein X2is CR6and X3is N.

5. The compound according to claim 1, wherein X2is CR6and X3is CR6.

6. The compound according to claim 1, wherein X2is N and X3is CR6.

7. The compound according to claim 1, wherein R1is H.

8. The compound according to claim 1, wherein R2ais H.

9. The compound according to claim 1, wherein R2bis H.

10. The compound according to claim 1, wherein R2cis H.

11. The compound according to claim 1, wherein R2dis H.

12. The compound according to claim 1, wherein R3is H.

13. The compound according to claim 1, wherein R9is (C1-C6)alkyl substituted with one to two R10.

14. The compound according to claim 1, wherein R9is selected from hydrogen, N-(R16’)-N- (R10)acetamidyl, methyl, ethyl, difluoroethyl, and (-OR16’)-functionalized ethyl, wherein the methyl, ethyl, difluoroethyl, and (-OR16’)-functionalized ethyl are substituted with one or more R10and optionally substituted with one or more R20.

15. The compound according to claim 1, wherein R9is selected from hydrogen,, wherein each R20’is independently R20or H, and R10, R16’, and R20are as defined in claim 1.

16. The compound according to claim 1, wherein R9is selected from hydrogen,wherein R10is defined as in claim 1.

17. The compound according to claim 1, wherein R9’is (C1-C6)alkyl substituted with one to two R10’.

18. The compound according to claim 1, wherein R10is (C3-C10)carbocyclyl, 5- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, and S, wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are substituted with R11and optionally substituted with one to three R12.

19. The compound according to claim 1, wherein R10is selected fromwherein each R12’is independently R12or H, and R11and R12are defined as in claim 1.

20. The compound according to claim 1, wherein R10is selected from, wherein R11is defined as in claim 1.

21. The compound according to claim 1, wherein R11is selected fromwherein R13, R13’, and R14are defined as in claim 1.

22. The compound according to claim 1, wherein R11is selected from23. The compound according to claim 1, wherein R9is selected from H,wherein each R20’is independently R20or H, and R12, R13, R13’, R14, R16’, and R20are as defined in claim 1.

24. The compound according to claim 1, wherein R9is selected from H,25. The compound according to claim 1, wherein n is 1 and t is 1.

26. The compound according to claim 1, wherein n is 1 and t is 2.

27. The compound according to claim 1, wherein n is 2 and t is 1.

28. The compound according to claim 1, having a Formula (la), Formula (la-1), Formula (lb), Formula (Ic). Formula (Id). Formula (le). Formula (If). Formula (lf-1). Formula (1g). Formula (lg-1), Formula (Ih), Formula (li). Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (In), Formula (In-l), Formula (Io), or Formula (Ip):or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

29. The compound according to claim 1, having a Formula (Iq), Formula (Iq- 1 ), Formula (Ir), Formula (Ir-1), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), or Formula (Ibb):or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

30. A compound according to claim 1. wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

31. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and a pharmaceutically acceptable carrier or excipient.

32. The pharmaceutical composition of claim 31, further comprising at least one additional pharmaceutical agent.

33. The pharmaceutical composition of claim 32, wherein the at least one additional pharmaceutical agent is an anticancer agent.

34. Tire pharmaceutical composition of claim 31 for use in tire treatment of a disease or disorder that is affected by the reduction of Cyclin E1 (CCNE1) protein levels.

35. A method of degrading Cyclin E1 (CCNE1) protein, comprising administering to a patient in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

36. A method of modulating Cyclin E1 (CCNE1) protein levels comprising administering to a patient in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

37. A method for reducing Cyclin E1 (CCNE1) protein levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmacally acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

38. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

39. Tire method of claim 38, wherein the cancer is selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.c., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multifonn, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-ccll lymphoma, and parathyroid cancer.

40. The method of claim 38, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer prostate cancer, lung cancer (including NSCLC. SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer, and thyroid cancer.

41. Tire method of claim 38, wherein the cancer is selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer. Hodgkin lymphoma, and diffuse large B-cell lymphoma.

42. The method of claim 38, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, neuroblastoma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma. gastric cancer, soft tissue sarcomas,rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma.

43. The method of claim 38, wherein the cancer is characterized by an amplification or overexpression of cyclin E 1.

44. A method for treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1) in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 31.

45. A method of treating a disease or disorder that is affected by the modulation of CYCLIN E1 (CCNE1) protein levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

46. The method of claim 44, wherein the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC). ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multifonn, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer. Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus -associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

47. The method of claim 44, wherein the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.

48. The method of claim 44, wherein the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma. gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma.

49. The method of claim 44, wherein the disease or disorder is one or more selected from rheumatoid arthritis, inflammation, autoimmune disease, lymphoproliferative conditions, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, other arthritic conditions, sepsis, septic shock, cndotoxic shock, gram negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, inflammatory bowel disease. Crohn's disease, psoriasis, eczema, ulcerative colitis, pancreatic fibrosis, hepatic fibrosis, acute and chronic renal disease, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neural trauma, Alzheimer's disease, Huntington's disease, Parkinson's disease, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute coronary’ syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptures, or prolapsed intervertebral disk syndrome, osteopetrosis, thrombosis, restenosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, graft-versus- host reaction, Multiple Sclerosis, lupus, fibromyalgia, AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza vims and cytomegalovirus, and diabetes mellitus.

50. Tire method of claim 35, further comprising at least one additional pharmaceutical agent or therapy.

51. Hie method of claim 50, wherein the at least one additional pharmaceutical agent is an anticancer agent.

52. The method of claim 50, wherein the at least one additional pharmaceutical agent or therapy is selected from surgery, radiotherapy, endocrine therapy, biologic response modifiers, hyperthermia and cryotherapy, agents to attenuate any adverse effects, alkylating drags, antimetabolites, purine antagonists and pyrimidine antagonists, spindle poisons, podophyllotoxins, antibiotics, nitrosoureas, inorganic ions, enzymes, and hormones.

53. Hie method of claim 35, wherein the administration is oral, parenteral, subcutaneous, by injection, or by infusion.

54. An in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

55. An in vivo method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

56. The method of claim 54, wherein the cell is a mammalian cell.

57. A method of degrading Cyclin El (CCNE1) in a cell, comprising contacting the cell with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

58. The method of claim 57, wherein the contacting occurs in vivo.

59. The method of claim 57, wherein the contacting occurs in vitro.

60. The method of claim 57, wherein the cell is a mammalian cell.

61. The method of claim 60, wherein the mammalian cell is a mammalian cancer cell.

62. A method of treating a solid tumor in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

63. A method of treating a liquid tumor in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 31.

64. A compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of Cyclin El (CCNE1) protein levels.

65. A compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of Cyclin El (CCNE1) protein levels.

66. A compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder characterized by amplification or overexpression of Cyclin E1 (CCNE1).

67. Use of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of Cyclin E1 (CCNE1) protein levels.

68. Use of a compound of claim 1. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of Cyclin E1 (CCNE1) protein levels.

69. Use of a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of characterized by amplification or overexpression of Cyclin E1 (CCNE1).

70. The compound for use of claim 64 or the use of claim 67, wherein the disease or disorder is one or more selected from lung cancer (including non-small cell lung cancer (NSCLC), SCLC, squamous cell carcinoma or adenocarcinoma), skin cancer, bladder cancer, breast cancer, breast carcinoma, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, lymphomas, leukemia, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach (i.e., gastric) cancer, liposarcoma, glioblastoma, glioblastoma multiform, glioma, nasopharyngeal cancer, adrenocortical cancer, myeloma, multiple myeloma, thyroid cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, Epstein-Barr Virus-associated nasopharyngeal carcinoma, neuroblastoma, bladder carcinoma, cutaneous melanoma, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, tongue cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, Ewing's sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, and parathyroid cancer.

71. The compound for use of claim 64 or the use of claim 67, wherein the disease or disorder is one or more selected from liposarcoma, glioblastoma, neuroblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.

72. The compound for use of claim 64 or the use of claim 67, wherein the disease or disorder is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing's sarcoma.

73. The compound for use of claim 64 or the use of claim 67, wherein the disease or disorder is one or more selected from rheumatoid arthritis, inflammation, autoimmune disease, lymphoproliferative conditions, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, pancreatic fibrosis, hepatic fibrosis, acute and chronic renal disease, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neural trauma, Alzheimer's disease, Huntington's disease, Parkinson's disease, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptures, or prolapsed intervertebral disk syndrome, osteopetrosis, thrombosis, restenosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, graft-versus-host reaction. Multiple Sclerosis, lupus, fibromyalgia, AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus, and diabetes mellitus.

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