NZ617580B2

NZ617580B2 - Spiro-oxindole mdm2 antagonists

Info

Publication number: NZ617580B2
Application number: NZ617580A
Authority: NZ
Inventors: Angelo Aguilar; Carlos Garciaecheverria; Wei Sun; Shaomeng Wang
Original assignee: Sanofi; The Regents Of The University Of Michigan
Priority date: 2011-05-11
Filing date: 2012-05-11
Publication date: 2015-11-03

Abstract

Disclosed herein are spiro-oxindole-based compounds of formula (I), compositions, and methods in the field of medicinal chemistry, wherein the variables shown in formula (I) are as defined in the specification. The compounds and compositions provided herein relate to spiro oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of hyperproliferative disease, particularly cancer selected from the group consisting of melanoma, lung cancer, sarcoma, colon cancer, prostate cancer, choriocarcinoma, breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymph multiple myeloma, and leukemia. s antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of hyperproliferative disease, particularly cancer selected from the group consisting of melanoma, lung cancer, sarcoma, colon cancer, prostate cancer, choriocarcinoma, breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymph multiple myeloma, and leukemia.

Description

SPIRO-OXINDOLE MDM2 ANTAGONISTS CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to pending US. Provisional Patent Application No. 61/484,986, ﬁled May 11, 2011, the contents of which are incorporated by reference in its entirety.

STATEMENT REGARDING LLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with ment support under 79 awarded by the National Institutes of Health. The government has certain rights in the invention BACKGROUND The aggressive cancer cell phenotype is the result of a variety of genetic and epigenetic tions leading to deregulation of ellular signaling pathways (Ponder, Nature 411:336 (2001)). Cancer cells typically fail to execute an apoptotic program, and lack of appropriate apoptosis due to defects in the normal apoptosis machinery is considered a hallmark of cancer (Lowe et al., Carcinogenesis 21:485 ). The inability of cancer cells to execute an apoptotic program due to defects in the normal apoptotic machinery is often ated with an increase in resistance to chemotherapy, radiation, or immunotherapy-induced apoptosis. Primary or ed resistance of human cancer of different origins to current treatment protocols due to apoptosis defects is a major problem in current cancer therapy (Lowe et al., Carcinogenesis 21:485 (2000); Nicholson, Nature 407:810 (2000)). Accordingly, current and future s towards designing and developing new lar target—specific anticancer therapies to improve survival and quality of life of cancer patients must include strategies that specifically target cancer cell resistance to apoptosis.

The p53 tumor suppressor plays a l role in controlling cell cycle progression, senescence, and apoptosis (Vogelstein et al., Nature 408:307 (2000); Goberdhan, Cancer Cell 7:505 (2005)). MDM2 and p53 are part of an auto- regulatory feed-back loop (Wu et al., Genes Dev. 7:1126 ). MDM2 is transcriptionally activated by p53 and MDM2, in turn, inhibits p53 activity by at least three mechanisms (Wu et al., Genes Dev. 7:1126 (1993). First, MDM2 protein ly binds to the p53 transactivation domain and y inhibits p53-mediated transactivation. Second, MDM2 protein contains a nuclear export signal ce, and upon binding to p53, s the nuclear export of p53, preventing p53 from binding to the targeted DNAs. Third, MDM2 protein is an E3 ubiquitin ligase and upon binding to p53 is able to promote p53 degradation.

Although high-affinity peptide-based inhibitors of MDM2 have been successfully designed in the past (Garcia-Echeverria et al., Med. Chem. 43:3205 (2000)), these inhibitors are not suitable therapeutic molecules because of their poor cell permeability and in vivo bioavailability. Despite intensive efforts by the pharmaceutical industry, high throughput screening strategies have had very d success in identifying potent, non-peptide small molecule inhibitors. Accordingly, there is a need for non-peptide, drug-like, small molecule inhibitors of the p53-MDM2 interaction. The structural basis of the interaction p53 and MDM2 has been established by x-ray crystallography (Kussie et al., Science 274:948 (1996)). Spirooxindole-based antagonists of the p53-MDM2 interaction are described in U.S. Patent Nos. 7,759,383 B2 and 174 B2, U.S. Patent Appl. Pub. No. 2011/0112052 A2, and U.S. Appl.

No. 13/294,315.

SUMMARY OF THE INVENTION According to a first aspect of the present invention, there is provided a compound selected from the group consisting of: , , , , AH26(10205595_1):CCG , , , , , , , , , , , , , , 0205595_1):CCG , , , , , , , 0205595_1):CCG , , , , , , , , , or a pharmaceutically acceptable salt f.

AH26(10205595_1):CCG [0006a] According to a second aspect of the present ion, there is provided a pharmaceutical composition comprising a compound of the first aspect of the invention, or a pharmaceutically acceptable salt f, and a ceutically acceptable carrier. [0006b] According to a third aspect of the present ion, there is provided use of the compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the ent of melanoma, lung cancer, sarcoma, colon cancer, prostate cancer, choriocarcinoma, breast cancer, blastoma, stomach carcinoma, acute myeloid leukemia, lymphoma, multiple myeloma, or leukemia. [0006c] According to a fourth aspect of the present invention, there is provided a kit comprising a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, thereof, and instructions for administering the nd to a patient having cancer. [0006d] In another aspect, the present disclosure provides spiro-oxindoles having Formula I: wherein: R1a, R1b, R1c, and R1d are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, y, AH26(10205595_1):CCG optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R3a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, R3b is selected from the group consisting of halo, optionally substituted alkyl, ally substituted alkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, or R3a and R3b taken together form a 3- to ered optionally substituted cycloalkyl or a 3— to 9—membered optionally substituted heterocyclo, E is selected from the group consisting of —OR26a and -NR26bR26c; R26a is selected from the group consisting of hydrogen, optionally substituted alkyl, ally substituted lkyl, and optionally substituted aryl; R26b is R4; R26c is ed from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted lkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, —SOZR5b, and R5; or R26b and R26c taken er form a 4- to 9-membered optionally substituted heterocyclo, wherein R4 and R5 has the meanings as described below in connection with Formula II; R5b is selected from the group consisting of optionally tuted alkyl, ally substituted lkyl, optionally substituted heterocyclo, optionally substituted aryl, and ally substituted heteroaryl, X is selected from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; 2012/037570 R is selected from the group consisting of hydrogen, optionally tuted alkyl, aralkyl, and optionally substituted cycloalkyl, R" is selected from the group consisting of hydrogen, optionally substituted alkyl, l, and optionally substituted lkyl, and = represents a single or a double bond, or a pharmaceutically acceptable salt, solvate, or prodrug f.

In another aspect, the present disclosure provides spiro—oxindoles having Formula II: wherein: R”, Rlb, R”, and R1d are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted lkenyl, optionally substituted aryl, optionally substituted heteroaryl, amido, and sulfonamido; R2 is selected from the group consisting of optionally substituted aryl and optionally substituted aryl; R3a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, R3b is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted alkyl)alkyl, optionally substituted lkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, or R3a and R3b taken together form a 3- to 9-membered ally substituted cycloalkyl, R4 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl; R5 is selected from the group consisting of fr R13 R12a R18R 17b \I'I R23 R22a 1 7 5 R W R R12b q R22b W2 ORZ’la s -(CR6aR6b) R120 z Rm and n R22° P , R20 R17d t ‘R24 R8a R8b R12d R14 R19 0R21b R22d R5-3 R5'4 R5-1 R5-2 wherein: each R6a and R6b is independently selected from the group ting of hydrogen and optionally substituted C1-C6 alkyl; R7 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted lkyl, R8a and R8b are each independently selected from the group consisting of hydrogen, optionally tuted C1-C6 alkyl, and optionally substituted cycloalkyl, or R8a and R8b taken together with the carbon that they are attached form a 3- to 8—membered optionally substituted lkyl, W1 is selected from the group consisting of —OR9a and 9c; R9a is en; R9b is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SOZR9d, and —CONR96R9f; R90 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted lkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R9b and R9° taken together with the nitrogen atom to which they are attached form a 4— to 8—membered ally substituted heterocyclo; R9d is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl, R96 and R9f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and ally substituted cycloalkyl, or R96 and R9f taken together with the en atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; W2 is selected from the group consisting of —OR10 and -NR11aR11b; with the proviso that when W1 is -OR9a and W2 is -OR10 then at least one of R7, Rga, and R8b is other than hydrogen; R10 is hydrogen; or one of R9a and R10 is hydrogen and the other is a metabolically cleavable group; R11a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally tuted aryl, optionally substituted aryl, -SOZR11C, and —CONR11dele; R11b is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally tuted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R11a and R11b taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; R11c is selected from the group ting of optionally substituted alkyl and optionally substituted cycloalkyl; R11d and R116 are each independently ed from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted lkyl; or R11d and R116 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered ally substituted heterocyclo; n is l, 2, 3, 4, or 5; each Rlza, Rlzb, R12c and R12d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; R13 is ed from the group consisting of hydrogen and optionally substituted C1—C6 alkyl; R14 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl; Z is selected from the group consisting of —OR15 and -NR16aR16b; or Z and R14 taken together form a carbonyl, i.e., a C=O, group.

R15 is ed from the group consisting of hydrogen and metabolically cleavable group; WO 55066 R16a is selected from the group consisting of —SOzR16c and —CONR16dR16e; R16b is selected from the group consisting of hydrogen and optionally substituted alkyl; R16c is selected from the group consisting of optionally substituted alkyl, ally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R16d and R166 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally tuted aryl, and optionally tuted heteroaryl; or R16d and R166 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered heterocyclo; o is l, 2, or 3; p is 0,1, 2, or 3; each Rm, Rm’, R17c and R17d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; R18 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl; R19 is selected from the group consisting of en, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl; R20 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl; R21a and R21b are each hydrogen; or one of R21a and R21b is en and the other is metabolically ble group; qis 0, l,2,or3; r is l, 2, or 3; each Rm, Rm, Rm, and R22d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; R23 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl; R24 is ed from the group consisting of —SOZR24a and —CONR24bR24c; 2012/037570 R24a is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, ally substituted aryl, and optionally substituted heteroaryl; R24b and R24c are each independently selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R24b and R24c taken together with the en atom to which they are attached form a 4— to 8—membered heterocyclo; s and t are each independently l, 2, or 3; X is selected from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; R is selected from the group consisting of en, optionally substituted alkyl, aralkyl, and optionally tuted cycloalkyl; R" is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and : represents a single or a double bond, or a pharmaceutically able salt, solvate, or prodrug thereof.

In another aspect, the present disclosure provides compounds having Formula I that inhibit the interaction between p53 or p53—related proteins and MDM2 or MDM2-related proteins.

In another aspect, the present disclosure provides methods to induce senescence, cell cycle arrest and/or apoptosis in cells containing functional p53 or p53-related proteins, sing contacting the cell with a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0010] In another , the present disclosure provides methods of treating, ameliorating, or preventing a hyperproliferative disease, e. g., cancer, e. g., adrenal cortical cancer, advanced cancer, anal cancer, aplastic anemia, bile duct cancer, r cancer, bone cancer, bone metastasis, brain/CNS tumors in adults, brain/CNS tumors in children, breast cancer, breast cancer in men, cancer in children, cancer of n primary, Castleman disease, cervical , colon/rectum , endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, adder cancer, gastrointestinal carcinoid tumors, gastrointestinal l tumor (GIST), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia - acute lymphocytic (ALL) in adults, ia - acute myeloid (AML), leukemia - chronic lymphocytic (CLL), leukemia - chronic myeloid (CML), leukemia - chronic myelomonocytic (CMML), leukemia in en, liver cancer, lung cancer - non-small cell, lung cancer - small cell, lung oid tumor, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and sal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, ry gland cancer, sarcoma - adult soft tissue cancer, skin cancer - basal and squamous cell, skin cancer — melanoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, or Wilms Tumor, in a patient comprising administering to the patient a compound of a I, or a pharmaceutically acceptable salt, solvate, or g thereof.

In another , the present sure provides methods of treating, ameliorating, or preventing a hyperproliferative disease, e. g., cancer, in a patient comprising administering to the patient a compound of Formula I, or a pharmaceutically able salt, solvate, or prodrug thereof, in combination with one or more onal eutic agents, e.g., one or more additional anticancer agents.

In another aspect, the present disclosure provides pharmaceutical compositions comprising a nd of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for ng, ameliorating, or preventing a hyperproliferative disease, e.g., cancer, in a patient.

In another , the present disclosure provides kits comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating, ameliorating, or preventing a hyperproliferative disease, e.g., cancer, in a patient.

BRIEF DESCRIPTION OF DRAWINGS Fig. 1 is a line graph showing cell growth inhibition of MDM2 inhibitors in the SJSA—l cell line as determined using the WST—based assay. SJSA—l cells were treated with each compound for 4 days.

[0015] Fig. 2 is a line graph showing cell growth tion of MDM2 tors in the RS4;11 leukemia cell line as determined using the WST—based assay.

RS4;11 cells were treated with each compound for 4 days.

Fig. 3 is a line graph showing the antitumor activity of Compound e Nos. 22 and 24 in the SJSA-l xenograft tumor model. Mice bearing SJSA—l tumors (one tumor per mouse) were d with Compound Example Nos. 22 and 24 daily for 2 weeks via oral gavage at 100 mg/kg qD.

Fig. 4 is a line graph showing the stability of MDM2 inhibitors in a 1:1 methanol/water solution. The Y-axis represents the percent amount of the compound measured by UPLC. The X—axis represents the number of days the sample has been in the methanol/water solution.

Fig. 5 is a line graph showing the stability of MDM2 inhibitors in a 1:1 acetonitrile/water solution. The Y-axis represents the percent amount of the stable isomer measured by UPLC. The X—axis represents the number of days the sample has been in the acetonitrile/water solution.

[0019] Fig. 6 is a line graph showing the stability of Compound e Nos. 10 and 11 in a 1:1 methanol/water solution with 10% TFA added. The Y-axis represents the percent amount of the compound ed by UPLC. The X—axis represents the number of hours the sample has been in solution.

DETAILED DESCRIPTION OF THE INVENTION

[0020] Provided herein are compounds having Formulae I-XXVIII. These compounds inhibit the interaction between p53 or p53-related proteins and MDM2 or MDM2-related proteins. By inhibiting the negative effect of MDM2 or MDM2—related ns on p53 or p53—related proteins, these compounds sensitize cells to inducers of apoptosis and/or cell cycle . In one ment, compounds having Formulae I-XXVIII induce apoptosis and/or cell cycle arrest. Therefore, also provided herein are methods of sensitizing cells to inducers of sis and/or cell cycle arrest and to methods of inducing apoptosis and/or cell cycle arrest in cells. In one embodiment, the methods comprise contacting the cells with one or more compounds having Formulae I-XXVIII alone or in combination with additional agent(s), e.g., an inducer of apoptosis or a cell cycle disrupter.

Also provided herein are methods of treating, ameliorating, or ting disorders in an t, comprising administering to the patient one or more nds having Formulae I-XXVIII alone or in combination with additional agent(s), e.g., an inducer of sis. Such disorders include those characterized by a dysregulation of sis and those characterized by the proliferation of cells expressing onal p53 or p53-related proteins. In another embodiment, methods of protecting normal (e.g., perproliferative) cells in an animal from the toxic side effects of chemotherapeutic agents and treatments are provided. This method comprises administering to the animal one or more compounds having Formulae I-XXVIII.

Also provided herein are compounds having any one of Formulae I-XXVIII for use in the cture of a medicament for treating a hyperproliferative disease such as cancer.

Also provided herein are compounds having any one of Formulae I-XXVIII, or a pharmaceutical composition comprising a compound having any one of Formulae I-XXVIII, for use in treating a hyperproliferative disease such as cancer.

Definitions The term “anticancer agent” as used herein, refers to any therapeutic agent (e.g., chemotherapeutic compound and/or molecular therapeutic nd), antisense therapy, radiation therapy, or surgical intervention, used in the treatment of hyperproliferative diseases such as cancer (e.g., in mammals, e. g.., in The term “prodrug” as used herein, refers to a pharmacologically inactive derivative of a parent “drug” molecule that requires biotransformation (e. g., either spontaneous or enzymatic) within the target physiological system to release, or to t (e.g., enzymatically, physiologically, mechanically, 2012/037570 electromagnetically) the prodrug into the active drug. Prodrugs are designed to overcome problems associated with stability, water solubility, toxicity, lack of specificity, or limited bioavailability. Exemplary prodrugs comprise an active drug molecule itself and a chemical masking group (e. g., a group that reversibly suppresses the activity of the drug). Some prodrugs are variations or tives of compounds that have groups cleavable under metabolic 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 & , 1991, particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 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. 6; 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; and Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987.

Exemplary prodrugs become ceutically active in vivo or in vitro when they undergo ysis under physiological ions or undergo enzymatic degradation or other biochemical transformation (e. g., orylation, hydrogenation, dehydrogenation, ylation). Prodrugs often offer advantages of water solubility, tissue compatibility, or delayed release in the mammalian organism. (See e. g., Bundgard, Design of Prodrugs, pp. 7—9, 21-24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352—401, Academic Press, San Diego, CA (1992)). Common prodrugs include acid derivatives such as esters prepared by reaction of parent acids with a suitable alcohol (e. g., a lower alkanol) or esters prepared by reaction of parent alcohol with a suitable carboxylic acid, (e. g., an amino acid), amides ed by on of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide), or orus—containing derivatives, e. g., phosphate, phosphonate, and phosphoramidate , including cyclic phosphate, phosphonate, and phosphoramidate, see, e.g., US 2007/0249564 A1.

The term "metabolically cleavable group" as used herein, refers to groups which can be cleaved from the parent le by metabolic ses and be substituted With en. Certain compounds containing metabolically cleavable groups may be prodrugs, i.e., they are pharmacologically inactive. n other compounds containing metabolically cleavable groups may be antagonists of the interaction between p53 and MDM2. In such cases, these compounds may have more, less, or equivalent activity of the parent molecule.

Examples of metabolically ble groups include those derived from amino acids (see, e.g., US 2006/0241017 A1; US 2006/0287244 A1; and WO 46575 A2) or phosphorus—containing compounds (see, e.g., US. 2007/0249564 A1) as illustrated in Scheme 1.

Schemel O O NH R—OJKHVH2 lic R-OH + HO)K( 2 —> R-OH R' R' cleavage parent amino acid amino acid ester parent drug drug 9 9 p\ .. 9R.. - _. R—o’k 0'? —»metabolic R-OH + Cl’\ R—OH OR OR cleavage parent phosphite phosphate ester pgrrfgt drug The term “pharmaceutically acceptable salt” as used herein, refers to any salt (e. g., obtained by reaction with an acid or a base) of a compound provided herein that is physiologically tolerated in the target animal (e.g., a mammal).

Salts of the compounds of provided herein may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, sulfonic, naphthalenesulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves ceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds ed herein and their pharmaceutically acceptable acid on salts.

Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e. g., magnesium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1_4 alkyl, and the like.

[0030] Examples of salts include, but are not limited to: acetate, adipate, alginate, ate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, oate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, fate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.

Other examples of salts include anions of the compounds provided herein compounded with a suitable cation such as Na+, NH4+, and NW4+ (wherein W is a C1_4 alkyl group), and the like. For therapeutic use, salts of the compounds provided herein are contemplated as being pharmaceutically acceptable.

However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically able compound.

[0031] The term "solvate" as used , refers to the al association of a compound provided herein with one or more solvent molecules, whether c or inorganic. This al association often includes hydrogen bonding. In certain instances, the solvate is capable of isolation, for example, when one or more solvate les are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution—phase and isolable es. ary solvates include hydrates, ethanolates, and methanolates.

The term "monovalent pharmaceutically acceptable cation" as used herein refers to inorganic s such as, but not limited to, alkaline metal ions, e. g., WO 55066 Na+ and K+, as well as organic cations such as, but not limited to, um and substituted ammonium ions, e.g., NH4+, NHMef, NHzMef, NHMe3+ and NMef.

The term "divalent pharmaceutically acceptable cation" as used herein refers to inorganic cations such as, but not limited to, alkaline earth metal cations, e.g., Ca2+ and Mg”.

Examples of monovalent and divalent pharmaceutically acceptable cations are discussed, e.g., in Berge et a]. J. Pharm. Sci, 9 (1997).

The term “therapeutically effective ,” as used herein, refers to that amount of the therapeutic agent (including the compounds and compositions of matter provided herein) sufficient to result in amelioration of one or more symptoms of a disorder, or prevent advancement of a disorder, or cause regression of the disorder. For example, with respect to the treatment of cancer, in one embodiment, a therapeutically effective amount can refer to the amount of a therapeutic agent that decreases the rate of tumor growth, decreases tumor mass, decreases the number of metastases, increases time to tumor progression, increase tumor cell apoptosis, or increases survival time by at least 5%, at least %, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

The terms “sensitize” and “sensitizing,” as used herein, refer to making, through the administration of a first therapeutic agent (e.g., a compound provided herein), an animal or a cell within an animal more susceptible, or more responsive, to the biological effects (e. g., promotion or retardation of an aspect of ar function including, but not limited to, cell division, cell growth, proliferation, invasion, angiogenesis, is, or apoptosis) of a second therapeutic agent. The sensitizing effect of a first agent on a target cell can be measured as the difference in the intended biological effect (e. g., ion or retardation of an aspect of cellular function including, but not limited to, cell growth, proliferation, invasion, enesis, or apoptosis) observed upon the stration of a second agent with and without administration of the first agent. The response of the ized cell can be increased by at least about 10%, WO 55066 at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least 300%, at least about 350%, at least about 400%, at least about 450%, or at least about 500% over the response in the e of the first agent.

The term "dysregulation of sis," as used herein, refers to any aberration in the ability of (e. g., predisposition) a cell to o cell death via apoptosis. Dysregulation of apoptosis is associated with or induced by a variety of conditions, non—limiting examples of which include, autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, versus—host disease, myasthenia gravis, or Sjogren's syndrome), chronic atory ions (e.g., psoriasis, asthma or Crohn's disease), hyperproliferative disorders (e.g., tumors, B cell lymphomas, or T cell lymphomas), viral infections (e.g., , papilloma, or HIV), and other conditions such as osteoarthritis and atherosclerosis. It should be noted that when the dysregulation is induced by or associated with a viral infection, the viral infection may or may not be detectable at the time dysregulation occurs or is observed. That is, viral—induced dysregulation can occur even after the disappearance of symptoms of viral infection.

[0038] The term "functional p53," as used herein, refers to Wild—type p53 expressed at normal, high, or low levels and mutant or allelic variants of p53 that retain(s) at least about 5% of the activity of Wild—type p53, e.g., at least about %, about 20%, about 30%, about 40%, about 50%, or more of Wild—type activity.

[0039] The term "p53—related protein," as used herein, refers to proteins that have at least 25% sequence homology with p53, have tumor suppressor activity, and are inhibited by interaction with MDM2 or MDM2-related ns. Examples of p53—related proteins include, but are not limited to, p63 and p73.

The term "MDM2-related protein," as used herein, refers to ns that have at least 25% sequence homology with MDM2, and interact with and inhibit p53 or p53-related proteins. Examples of MDM2-related proteins include, but are not limited to, MDMX.

The term "senescence" as used herein, refers to the phenomenon whereby non—cancerous diploid cells lose the ability to divide, and characterized in part by telomeric dysfunction or shortening.

The term “hyperproliferative disease,” as used herein, refers to any condition in which a localized population of erating cells in an animal is not governed by the usual limitations of normal growth. Examples of roliferative disorders include tumors, neoplasms, lymphomas, leukemias and the like. A neoplasm is said to be benign if it does not undergo on or metastasis and malignant if it does either of these. A “metastatic” cell means that the cell can invade neighboring body structures. Hyperplasia is a form of cell proliferation involving an increase in cell number in a tissue or organ without icant alteration in structure or function. Metaplasia is a form of controlled cell growth in which one type of fully differentiated cell tutes for another type of differentiated cell.

[0043] The pathological growth of ted lymphoid cells often results in an autoimmune disorder or a chronic inﬂammatory condition. As used , the term “autoimmune disorder” refers to any condition in which an organism produces antibodies or immune cells which recognize the organism's own molecules, cells or tissues. Non—limiting examples of autoimmune disorders include autoimmune hemolytic anemia, autoimmune hepatitis, ’s e or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn’s disease, dermatomyositis, f1bromyalgia, graft versus host disease, Grave’s disease, Hashimoto’s thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, sis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like.

The term “neoplastic disease,” as used , refers to any abnormal growth of cells being either benign ancerous) or malignant (cancerous).

The term "normal cell," as used herein, refers to a cell that is not undergoing abnormal growth or division. Normal cells are non-cancerous and are not part of any hyperproliferative disease or disorder.

WO 55066 The term “anti—neoplastic agent,” as used herein, refers to any compound that retards the proliferation, growth, or spread of a targeted (e.g., ant) neoplasm.

The terms “prevent,” “preventing,” and “prevention,” as used herein, refer to a decrease in the occurrence of pathological cells (e. g., roliferative or neoplastic cells) in an animal. The prevention may be complete, e.g., the total absence of pathological cells in a subject. The prevention may also be partial, such that the occurrence of pathological cells in a subject is less than that which would have occurred without treatment with one or more compounds provided herein.

The term osis-modulating agents," as used herein, refers to agents which are involved in ting (e. g., inhibiting, decreasing, increasing, promoting) sis. Examples of apoptosis-modulating agents include proteins which comprise a death domain such as, but not limited to, Fas/CD95, TRAMP, TNF RI, DRl, DR2, DR3, DR4, DR5, DR6, FADD, and RIP. Other examples of apoptosis-modulating agents include, but are not limited to, TNFOt, Fas ligand, antibodies to 95 and other TNF family receptors, TRAIL (also known as Ap02 Ligand or ApoZL/TRAIL), antibodies to TRAIL-R1 or TRAIL-R2, Bcl-2, p53, BAX, BAD, Akt, CAD, PI3 kinase, PPl, and caspase proteins. Modulating agents broadly include agonists and antagonists of TNF family ors and TNF family ligands. Apoptosis-modulating agents may be soluble or membrane bound (e.g. ligand or receptor). Apoptosis—modulating agents include those which are inducers of apoptosis, such as TNF or a TNF—related ligand, particularly a TRAMP ligand, a 95 ligand, a TNFR—l ligand, or TRAIL.

[0049] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable e" encompasses any of the standard ceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard ceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

The terms "pulsatile administration, H Hpulsatile dose administration" or "pulsatile dosing" as used herein, refer to ittent (i.e., not continuous) administration of compounds having Formulae I-XXVIII, or pharmaceutically able salts, solvates, or gs thereof, to a t. Pulsatile dose administration regimens useful in the t disclosure encompass any discontinuous stration regimen that provides a therapeutically effective amount of compounds having Formulae I-XXVIII, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, to a patient in need thereof Pulsatile dosing regimens can use equivalent, lower, or higher doses of compounds having Formulae I-XXVIII than would be used in uous dosing regimens. ages of pulsatile dose administration of compounds having Formulae II, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, include, but are not limited to, ed safety, decreased toxicity, increased exposure, increased efficacy, and increased patient compliance. These advantages may be ed when compounds having Formulae I-XXVIII, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, are administered as a single agent or are administered in ation with one or more additional anticancer agents. On the day that compounds having Formulae II, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, are scheduled to be administered to the patient, administration can occur in a single or in divided doses, e.g., once—a—day, twice—a—day, three times a day, four times a day or more.

In one embodiment, compounds having Formulae I-XXVIII, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, are administered once (QD) or twice (BID) on the day it is schedule to be administered The term “alkyl” as used herein by itself or part of another group refers to a straight-chain or branched saturated aliphatic hydrocarbon having from one to eighteen carbons or the number of carbons designated (e.g., C1—C18 means 1 to 18 carbons). In one embodiment, the alkyl is a C1-C10 alkyl. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1-C3 alkyl. In another embodiment, the alkyl is a C2-C10 alkyl. In another embodiment, the alkyl is a C3-C10 alkyl. In another embodiment, the alkyl is a C3-C6 alkyl. Exemplary alkyl groups include methyl, ethyl, n—propyl, isopropyl, n-butyl, sec—butyl, isobutyl, tert—butyl, yl, isopentyl, neopentyl, n-hexyl, yl, n-heptyl, 4,4-dimethylpentyl, n-octyl, 2,2,4-trimethylpentyl, nonyl, decyl and the like.

The term "optionally substituted alkyl" as used herein by itself or part of another group means that the alkyl as deﬁned above is either tituted or substituted with one, two or three substituents independently selected from hydroxy (26., —OH), nitro (226., —NOz), cyano (26., -CN), amino, optionally S substituted cycloalkyl, ally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, —C02Rc, —CORC, —sosz, -N(Re)CORf, —N(Re)SOZRg or —N(Re)C=N(Rh)—amino, wherein R0 is hydrogen, optionally tuted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rd is optionally tuted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Re is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rf is hydrogen, optionally substituted alkyl, optionally substituted aryl, or ally substituted heteroaryl; Rg is optionally substituted alkyl, optionally substituted aryl, or ally substituted heteroaryl; and Rh is hydrogen, -CN, optionally substituted alkyl, optionally tuted aryl, or optionally substituted heteroaryl. In one ment, the optionally tuted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. In r embodiment, the substituents are selected from hydroxyl (226., a hydroxyalkyl, 6.g., a monohydroxyalkyl or dihydroxyalkyl), optionally substituted cycloalkyl (226., a alkyl)alkyl), optionally substituted heterocyclo (226., a ocyclo)alkyl), —COZH, or amino (226., an aminoalkyl). Exemplary optionally substituted alkyl groups include —CH20CH3, —CH2CH2NH2, —CH2CH2NH(CH3), —CH2CH2CN, —CH2C02H, —CH2CONH2, —CHZSOZCH3, —CH2CHZSOZCH3, )2COZH, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

The term "alkylenyl" as used herein by itself or part of another group refers to a divalent alkyl radical containing one, two, three, four, or more joined methylene groups. Exemplary alkylenyl groups e —(CH2)—, —(CH2)2—, - (CH2)3-, -(CH2)4-, and the like.

[0054] The term "optionally substituted alkylenyl" as used herein by itself or part of another group means the alkylenyl as deﬁned above is either unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of ally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted aryl. In one embodiment, the optionally substituted C1-C6 alkyl is methyl. In one embodiment, the optionally tuted aryl is a phenyl optionally substituted with one or two halo groups. Exemplary optionally substituted alkylenyl groups include —CH(CH3)—, —C(CH3)2—, (CH3)—, —CH2CH(CH3)CH2—, -CH2CH(Ph)CH2-, -CH(CH3)CH(CH3)-, and the like.

The term "haloalkyl" as used herein by itself or part of another group refers to an alkyl as defined above having one to six halo substituents. In one embodiment, the haloalkyl has one, two or three halo substituents. Exemplary haloalkyl groups include trifluoromethyl, -CH2CH2F and the like.

The term "monohydroxyalkyl" as used herein by itself or part of another group refers to an alkyl as defined above having exactly one hydroxy tuent.

Exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0057] The term roxyalkyl” as used herein by itself or part of another group refers to alkyl as defined above having exactly two hydroxyl substituents.

Exemplary dihydroxyalkyl groups include —CH2CH2CCH3(OH)CHZOH, —CH2CH2CH(OH)CH(CH3)OH, —CH2(OH)CHZOH, (CHZOH)2, —CH2CH2CH(OH)C(CH3)ZOH, —CH2CH2CCH3(OH)CH(CH3)OH, and the like, including stereoisomers thereof.

The term "hydroxycycloalkyl" as used herein by itself or part of another group refers to an optionally substituted cycloalkyl as defined below having a least one, e.g., one or two hydroxy substituents. Exemplary hydroxycycloalkyl groups include: EAO’OHEAOLOH EK>OH §—<>40H OH OH EJ:>—OH OH 31/6014 *3wa and the like, including stereoisomers thereof.

The term "optionally substituted (cycloalkyl)alkyl" as used herein by itself or part of another group refers to an optionally substituted alkyl as deﬁned above having an ally substituted cycloalkyl (as defined below) substituent. ary optionally substituted (cycloalkyl)alkyl groups include: \B, VQVQ anvaN and the like, including stereoisomers thereof.

The term "(heterocyclo)alkyl" as used herein by itself or part of another group refers to an alkyl as defined above having an optionally substituted heterocyclo (as defined below) tuent.

[0061] The term "aralkyl" as used herein by itself or part of another group refers to an optionally substituted alkyl as defined above having one, two or three ally substituted aryl substituents. In one embodiment, the aralkyl has two optionally substituted aryl substituents. In another embodiment, the aralkyl has one optionally substituted aryl substituent. In another embodiment, the aralkyl is an 1-C4 alkyl). In another embodiment, the aryl(C1-C4 alkyl) has two optionally substituted aryl substituents. In another embodiment, the aryl(C1-C4 alkyl) has one ally substituted aryl substituent. Exemplary aralkyl groups include, for example, benzyl, phenylethyl, (4-fluorophenyl)ethyl, phenylpropyl, diphenylmethyl (i.e., PhZCH-), diphenylethyl (thCHCH2-) and the like.

[0062] The term "cycloalkyl" as used herein by itself or part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic hydrocarbon groups ning one to three rings having from three to twelve carbon atoms (i.e., C3—C12 cycloalkyl) or the number of carbons designated. In one embodiment, the cycloalkyl has one ring. In another embodiment, the cycloalkyl is a C3-C6 cycloalkyl. Exemplary cycloalkyl groups include ropyl, utyl, cyclopentyl, exyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl and the like. 2012/037570 The term “optionally substituted cycloalkyl” as used herein by itself or part of r group means the cycloalkyl as deﬁned above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, ally substituted alkyl, haloalkyl, yalkyl, aminoalkyl, l, ally substituted cycloalkyl, ally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, —COch, —CORC, —sosz, —N(RC)CORf, —N(Re)sozRg or —N(Re)C=N(Rh)—amino, wherein RC, Rd, Re, Rf, Rg, and Rh are as deﬁned above in connection with optionally substituted alkyl. The term "optionally substituted cycloalkyl" also means the cycloalkyl as deﬁned above may be fused to an optionally substituted aryl. In one embodiment, the ally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In another embodiment, the substituents are selected from hydroxy (i.e., a hydroxycycloalkyl, e. g., a monohydroxycycloalkyl or oxycycloalkyl) or —COZH. Exemplary optionally substituted cycloalkyl groups include: b B % w “a. MIL/OWL. it 3’1. , SCH COzH OH OH 52,. , ii/U, g and 1.1% .771 and the like.

The term yl" as used herein by itself or part of another group refers to an alkyl group as deﬁned above containing one, two or three carbon—to—carbon double bonds. In one embodiment, the alkenyl has one carbon—to—carbon double bond. Exemplary alkenyl groups include —CH=CH2, —CH2CH=CH2, — CHZCHZCH=CH2, -CH2CH2CH=CHCH3 and the like.

The term "optionally substituted alkenyl" as used herein by itself or part of another group means the alkenyl as deﬁned above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, ally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally S substituted heteroaryl, optionally tuted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido. Exemplary optionally substituted l groups include —CH=CHPh, -CH2CH=CHPh and the like.

The term "cycloalkenyl" as used herein by itself or part of r group refers to a lkyl group as defined above containing one, two or three carbon— to—carbon double bonds. In one embodiment, the cycloalkenyl has one carbon—to— carbon double bond. Exemplary lkenyl groups e entene, cyclohexene and the like.

The term "optionally substituted cycloalkenyl" as used herein by itself or part of another group means the cycloalkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, ally substituted aryl, optionally substituted heteroaryl, ally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, hio, carboxamido or sulfonamido.

The term "alkynyl" as used herein by itself or part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-to-carbon triple bond.

Exemplary l groups include —CECH, —CECCH3, —CH2CECH, — CHZCHZCECH and —CH2CH2CECCH3.

The term "optionally substituted alkynyl" as used herein by itself or part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally tuted cycloalkyl, ally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or amido. Exemplary ally substituted alkenyl groups include —CECPh, —CH2CECPh and the like.

The term "aryl" as used herein by itself or part of another group refers to monocyclic and bicyclic aromatic ring systems having from six to fourteen carbon atoms (i.e., C6—C14 aryl) such as phenyl (abbreviated as Ph), l—naphthyl and 2-naphthyl and the like.

The term “optionally substituted aryl” as used herein by itself or part of another group means the aryl as defined above is either unsubstituted or substituted with one to five tuents ndently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ally substituted heteroaryl, ally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, —CONHSOzMe, —COch, —CORC, —SOsz, — N(Re)CORf, -N(Re)SOZRg or —N(Re)C=N(Rh)—amino, n RC, Rd, Re, Rf, Rg, and Rh are as defined above in connection with optionally substituted alkyl. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally tuted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In r embodiment, the ally substituted phenyl has one substituent. Exemplary substituted aryl groups include 2-methylphenyl, 2- methoxyphenyl, 2—ﬂuorophenyl, 2—chlorophenyl, 2-bromophenyl, 3- methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4- methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, rophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, oxyphenyl, 2-ethyl, 3- methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-ﬂuorophenyl 3,5-di-methylphenyl and 3,5-dimethoxy, 4-methylphenyl, 2—ﬂuorochlorophenyl, 3-chloro ﬂuorophenyl, 4-COzH-phenyl and the like. The term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include s—CO $466| | | / / 0 é—CEOJ/ and the like.

The term "heteroaryl" as used herein by itself or part of another group refers to monocyclic and bicyclic aromatic ring systems having from ﬁve to fourteen ring atoms (i.e., 5— to bered heteroaryl) and one, two, three, or four heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. In one ment, the heteroaryl has three heteroatoms. In one embodiment, the heteroaryl has two heteroatoms. In one embodiment, the heteroaryl has one heteroatom. In one embodiment, the aryl is a 5-membered heteroaryl. In another embodiment, the heteroaryl is a 6-membered aryl. In r embodiment, the heteroaryl is a 6-membered heteroaryl having one or two nitrogen atoms. Exemplary aryl groups include l-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2—thiazolyl, 4-thiazolyl, 5-thiazolyl, 2—furyl, 3-furyl, 2—thienyl, 3-thienyl, 2—pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, purinyl, 2—benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 5-indolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, l-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl 3-quinolyl, 6-quinolyl and the like. The term heteroaryl is meant to include possible N—oxides. Exemplary N—oxides include pyridyl N—oxide and the like.

The term nally substituted heteroaryl" as used herein by itself or part of another group means the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, typically one or two substituents, independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally tuted alkenyl, ally substituted alkynyl, optionally tuted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, , aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, , —CORC, —sosz, —N(RC)CORf, —N(Re)SOZRg or -N(Re)C=N(Rh)-amino, wherein RC, Rd, Re, Rf, Rg, and Rh are as defined above in connection with optionally substituted alkyl. In one ment, the optionally substituted heteroaryl has one substituent. In another embodiment, the substituent is an optionally substituted aryl, aralkyl, or ally substituted alkyl. In another embodiment, the substituent is an optionally substituted phenyl.

Any available carbon or nitrogen atom may be substituted. Exemplary ally substituted heteroaryl groups include Ph Ph s:\\/\>Ph 0:\\/\>Ph T3 \N:\\/\>Ph i\ Ph N N N N “a. a a “a. “a.

Ph Ph Ph ph Ph O {D Q \ S \ o \ / HN HN N \ ”11% KkN EJQN E’kN «51% Ph Ph ph Ph HNQ HN/QN FIN/Q HN/g") “arkN a»N a.»N ”11%N and the like.

The term "heterocyclo" as used herein by itself or part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic groups ning one to three rings haVing from three to fourteen ring members (i.e., 3— to bered heterocyclo) and at least one oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atom. In one embodiment, the heterocyclo group is chosen from a 5— or ered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is a 6—membered cyclic group containing one ring and one sulfur atom, including sulfoxide and sulfone. The heterocyclo can be optionally linked to the rest of the molecule h a carbon or nitrogen atom. Exemplary heterocyclo groups include: 2012/037570 N N N é—O $1 1 $1 1 $10 , KO , KN O\\ ”O N S 8 §{) é—Q and é—Q and the like.

The term “optionally substituted heterocyclo” as used herein by itself or part of another group means the heterocyclo as deﬁned above is either unsubstituted or substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, amido, sulfonamido, —C02Rc, —CORC, —SOsz, -N(Re)CORf, —N(Re)SOZRg or —N(Re)C=N(Rh)—amino, wherein RC, Rd, Re, Rf, Rg, and Rh are as defined above in connection with optionally substituted alkyl.

Substitution may occur on any ble carbon or en atom. Exemplary substituted heterocyclo groups include é—O—Ph é—“NLP“ V and the like. An optionally substituted heterocyclo may be fused to an aryl group to provide an optionally substituted aryl as described above.

The term y" as used herein by itself or part of another group refers to a haloalkyl, ally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. ary alkoxy groups include methoxy, tert—butoxy, —OCH2CH=CH2, —OCH2CHZOH, —OC(CH3)2COZH, and the like.

The term "aryloxy" as used herein by itself or part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. Exemplary aryloxy groups include y and the like.

The term "aralkyloxy" as used herein by itself or part of another group refers to an aralkyl attached to a terminal oxygen atom. ary aralkyloxy groups include benzyloxy and the like.

The term "alkylthio" as used herein by itself or part of another group refers to a haloalkyl, aralkyl, ally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a al sulfur atom. Exemplary alkyl groups include -SCH3 and the like.

The term "halo" or "halogen" as used herein by itself or part of another group refers to ﬂuoro, chloro, bromo or iodo. In one embodiment, the halo is ﬂuoro or chloro.

The term "amino" as used herein by itself or part of another group refers to a radical of formula -NRaRb wherein Ra and Rb are ndently hydrogen, haloalkyl, l, optionally substituted alkyl, ally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl or optionally substituted heteroaryl; or Ra and Rb taken together with the nitrogen atom to which they are attached form a four to seven membered optionally substituted heterocyclo. Exemplary amino groups include —NH2, —N(H)CH3, —N(CH3)2, —N(H)CH2CH3, —N(CH2CH3), -N(H)CH2Ph and the like.

The term "carboxamido" as used herein by itself or part of another group refers to a radical of formula ino. Exemplary carboxamido groups include —CONH2, —CON(H)CH3, —CON(H)Ph, )CH2CH2Ph, — CON(CH3)2, CON(H)CHPh2 and the like.

The term "sulfonamido" as used herein by itself or part of another group refers to a radical of formula -SOz-amino. Exemplary sulfonamido groups include —S02NH2, —SOzN(H)CH3, H)Ph and the like.

The term ," as used herein, includes the recited number :: 10%.

Thus, "about 10" means 9 to 11.

Certain of the nds of the present disclosure may exist as stereoisomers, i.e., isomers that differ only in the spatial ement of atoms, including optical isomers and conformational isomers (or conformers). The disclosure includes all stereoisomers, both as pure individual isomer preparations and enriched preparations of each, and both the racemic mixtures of such stereoisomers as well as the individual diastereomers and enantiomers that may be separated according to methods that are well known to those of skill in the art.

The term "substantially free of" as used herein means that the compound comprises less than about 25% of other isomers, e.g., diastereomers and/or enantiomers, as established using conventional ical methods routinely used by those of skill in the art. In one embodiment, the amount of other stereoisomers is less than about 24%, less than about 23%, less than about 22%, less than about 21%, less than about 20%, less than about 19%, less than about 18%, less than about 17%, less than about 16%, less than about 15%, less than about 14%, less than about 13%, less than about 12%, less than about 11%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5%.

Stereoisomerically enriched compounds that contain about 95% or more of a desired isomer, for example, about 96% or more, about 97% or more, about 98% or more, or about 99% or more are referred to herein as "substantially pure stereoisomers." Stereoisomerically enriched compounds that contain about 99% or more of a desired stereoisomer are referred to herein as "pure" isomers." The purity of any stereoisomerically ed compound can be determined using conventional analytical methods such as, for example, normal phase HPLC, reverse phase HPLC, chiral HPLC, and 1H and 13C NMR.

Compounds In one embodiment, compounds of Formula I are provided: wherein: R”, Rlb, R”, and R1d are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted l, optionally substituted cycloalkenyl, optionally tuted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is selected from the group consisting of optionally substituted aryl and optionally tuted heteroaryl; R3a is selected from the group consisting of halo, ally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, R3b is selected from the group consisting of halo, optionally substituted alkyl, ally substituted alkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, or R3a and R3b taken together form a 3- to 9-membered optionally substituted cycloalkyl or a 3— to 9—membered optionally substituted cyclo; E is selected from the group consisting of —OR26a and -NR26bR26c; R26a is selected from the group consisting of hydrogen, optionally tuted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; R26b is R4; R26c is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally tuted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, —SOzR5b, and R5; wherein R4 and R5 have the meanings as described below for a II; or R26b and R26c taken together form a 4- to 9-membered optionally substituted heterocyclo; R5b is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl, X is selected from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; R is selected from the group ting of en, optionally substituted alkyl, l, and optionally substituted cycloalkyl; R" is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and T— ents a single or a double bond, or a pharmaceutically acceptable salt, e, or prodrug thereof.

[0090] In another embodiment, compounds of Formula I are provided, wherein: R”, Rlb, R”, and R1d are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted alkyl, haloalkyl, optionally tuted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, amido, and sulfonamido; R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R3a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, R3b is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, ally tuted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, or R3a and R3b taken together form a 3- to 9-membered optionally substituted cycloalkyl or a 3— to ered optionally substituted heterocyclo; E is selected from the group consisting of —OR26a and R26c; R26a is selected from the group consisting of hydrogen, ally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; R26b is selected from the group ting of hydrogen and ally substituted alkyl, R26c is ed from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally tuted aryl, aralkyl, and —SOzR5b; 2012/037570 or R26b and R26c taken together form a 4- to 9-membered optionally substituted heterocyclo; R5b is selected from the group consisting of ally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally S substituted aryl, and optionally substituted heteroaryl, X is selected from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; R is selected from the group consisting of hydrogen, ally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; R" is ed from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted lkyl; and = represents a single or a double bond, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In r embodiment, compounds of Formula I are provided, wherein: R”, Rlb, R”, and R1d are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, , aryloxy, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is selected from the group ting of optionally substituted aryl and ally substituted heteroaryl, R3a and R3b taken together form a 3- to 9-membered optionally substituted cycloalkyl or a 3— to 9—membered optionally tuted heterocyclo; E is ed from the group consisting of —OR26a and -NR26bR26c; R26a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; R26b is selected from the group consisting of hydrogen and optionally substituted alkyl, R26c is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, ally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, and —SOzR5b; wherein R4 and R5 have the meanings as described below for Formula II; or R26b and R26c taken together form a 4- to 9-membered optionally substituted heterocyclo; R5b is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and ally substituted aryl, X is ed from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; R is ed from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl, R" is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl, and = represents a single or a double bond, or a pharmaceutically able salt, solvate, or g thereof.

[0092] In another embodiment, compounds of Formula II are provided: wherein: R”, Rlb, R”, and R1d are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted alkyl, haloalkyl, ally substituted lkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is ed from the group consisting of ally substituted aryl and optionally substituted heteroaryl; R3a is selected from the group consisting of halo, ally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl, R3b is selected from the group ting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted lkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, ally substituted aryl, and ally substituted heteroaryl, or R3a and R3b taken together form a 3- to 9-membered optionally substituted cycloalkyl, R4 is selected from the group consisting of hydrogen and optionally substituted alkyl, R5 is selected from the group ting of: 18 R178 9‘51 R13 R128 R w1 R7 g R17b R12b _(CR6aR6b)>S<W2 q o 21 a R120 Z R170 n a (3? p , R17d R R88 R8b R12d R14 R19 0R21b R5-1 R5-2 R5-3 R5'4 wherein: each R6a and R6b is independently ed from the group consisting of hydrogen and optionally substituted C1-C6 alkyl, R7 is ed from the group consisting of en, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl, R8a and R8b are each independently selected from the group consisting of hydrogen, optionally tuted C1-C6 alkyl, and optionally substituted cycloalkyl, or R8a and R8b taken together with the carbon that they are attached form a 3- to 8—membered optionally substituted cycloalkyl, W1 is selected from the group consisting of —OR9a and -NR9bR9C; R9a is hydrogen; R9b is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SOZR9d, and —CONR96R9f; R90 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R9b and R90 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; R9d is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl, R96 and R9f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted lkyl, or R96 and R9f taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; W2 is selected from the group consisting of —OR10 and -NR11aR11b; with the proviso that when W1 is -OR9a and W2 is -OR10 then at least one of R7, Rga, and R8b is other than hydrogen; R10 is hydrogen; or one of R9a and R10 is hydrogen and the other is a metabolically cleavable group; R11a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, ally tuted aryl, ally tuted heteroaryl, -SOZR11C, and —CONR11dele; R11b is selected from the group consisting of hydrogen, optionally tuted alkyl, ally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R11a and R11b taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; R11c is selected from the group consisting of optionally substituted alkyl and optionally substituted lkyl, R11d and R116 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl, or R11d and R116 together with the nitrogen atom to which they are ed form a 4— to 8—membered optionally tuted cyclo; n is l, 2, 3, 4, or 5; each Rm, Rlzb, R12c and R12d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; R13 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl; R14 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted lkyl; Z is selected from the group consisting of —OR15 and -NR16aR16b; or Z and R14 taken together form a carbonyl, i.e., a C=O, group.

R15 is selected from the group ting of en and metabolically cleavable group; R16a is selected from the group ting of —SOZR16c and —CONR16dR16e; R16b is selected from the group consisting of hydrogen and optionally substituted alkyl; R16c is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R16d and R166 are each independently selected from the group consisting of hydrogen, ally tuted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R16d and R166 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered heterocyclo; o is 1, 2, or 3; p is 0,1, 2, or 3; each Rm, Rm, R17c and R17d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; R18 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl; R19 is selected from the group consisting of hydrogen, ally tuted C1—C6 alkyl, and optionally substituted cycloalkyl; R20 is selected from the group consisting of hydrogen, ally substituted C1—C6 alkyl, and optionally substituted cycloalkyl; R21a and R21b are each hydrogen; or one of R21a and R21b is hydrogen and the other is metabolically cleavable group; qis 0,1, 2, or 3; ris 1,2, or 3; each Rm, Rm, Rm, and R22d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl, R23 is selected from the group ting of hydrogen and optionally substituted C1—C6 alkyl, R24 is selected from the group consisting of -SOZR24a and —CONR24bR24c; R24a is selected from the group ting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R24b and R24c are each independently ed from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally tuted aryl, and optionally substituted heteroaryl; or R24b and R24c taken together with the nitrogen atom to which they are attached form a 4— to 8—membered heterocyclo; s and t are each independently l, 2, or 3; X is selected from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; R is selected from the group consisting of en, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; R" is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and = represents a single or a double bond, or a ceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, the compound of Formula I or II is provided as a mixture of stereoisomers, e.g., a mixture of diastereomers and/or omers, e. g., a c e. In another embodiment, the compound of Formula I or II is provided as a single stereoisomer.

In another embodiment, compounds of Formula 111 are provided: 2012/037570 wherein R”, Rlb, R16, Rld, R2, R3a, R3b, E, X, and Y have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula 111 are provided wherein E is NR4R5, and R13, Rlb, R16, R“, R2, R33, R3b, R4, R5, X, and Y have the meanings as described above for Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In r embodiment, compounds of Formula IV are provided: wherein R”, Rlb, R16, Rld, R2, R3a, R3b, E, X, and Y have the meanings as described above for Formula I, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula IV are provided wherein E is -NR4R5, and R13, Rlb, R16, R”, R2, R33, R3b, R4, R5, X, and Y have the meanings as described above for Formula II, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula V are ed: i.e., R3a and R3b of Formula I are taken er form a 3- to 9-membered optionally substituted cycloalkyl, wherein R”, Rlb, Rlc, Rld, R2, E, X, and Y have the gs as described above for Formula I, u is 0, l, 2, 3, 4, 5, or 6, v is 0, l, 2, 3, or 4, and each R is independently halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aralkyl, optionally tuted lkyl, optionally substituted l, optionally substituted l, optionally substituted aryl, optionally substituted heteroaryl, optionally tuted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula V are provided wherein E is NR4R5, and R”, Rlb, R16, Rld, R2, R4, R5, X, and Y have the meanings as described above for Formula 11, u is 0, l, 2, 3, 4, 5, or 6, V is 0, l, 2, 3, or 4, and each R is independently halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted l, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, loxy, alkylthio, carboxamido or sulfonamido, or a pharmaceutically acceptable salt, solvate, or prodrug f.

In r embodiment, compounds of Formula V are provided wherein u is l, 2, 3, 4, 5, or 6, each R is independently (C1-C4)alkyl and v is 0, l, or 2, or a pharmaceutically acceptable salt, e, or prodrug f.

] In another embodiment compounds of Formula V are provided wherein v is 0 and u is 0, l, 2, 3, 4, 5, or 6, , i.e., R3a and R3b of Formula I are taken together form a 3— to 9—membered unsubstituted cycloalkyl.

In another embodiment compounds of Formula V are provided wherein v is 0 and u is 2, 3, or 4, i.e., R3a and R3b of Formula I are taken er form a 5-, 6—, or 7—membered unsubstituted lkyl.

In another embodiment, compounds of any one of Formulae VI-XXI are provided: VI VII VIII 1x XVIII XIX XX XXI where1n R- 1a 1b 1c 1d 2 3a 3b R R R R R R the meanlngs- as , , , , , , , E, X, and Y have described above for a I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is NR4R5, and R13, Rlb, R”, R“, R2, R33, R3b, R4, R5, X, and Y have the meanings as described above for Formula II, or a pharmaceutically acceptable salt, e, or prodrug thereof.

In another embodiment, compounds of any one of Formulae VI—XXI are provided substantially free of one or more other stereoisomers. In another embodiment, compounds of any one of Formulae VI-XXI are substantially pure stereoisomers. In another embodiment, compounds of any one of Formulae VI-XXI are pure stereoisomers.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug f, are provided wherein: a) R”, Rlb, R16, and R1d are independently selected from the group consisting of hydrogen, ﬂuoro, and chloro; b) R1a and R1d are hydrogen; R1b is selected from the group ting of hydrogen and ﬂuoro; and R10 is selected from the group consisting of ﬂuoro and chloro; c) R2 is optionally substituted ; d) R3a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, and optionally substituted cycloalkyl; e) R3b is selected from the group ting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, and optionally substituted lkyl; f) R3a and R3b taken together form an optionally substituted 3— to 9—membered cycloalkyl; g) E is -NR4R5 and R4 is hydrogen; h) X is NH; i) X is 0; j) X is S; k) Y is O; 1) Y is S; m) Y is NH; or n) X and Y are NH; or any combination thereof.

In another embodiment, compounds of any one of Formulae I-XXI, or a ceutically acceptable salt, e, or prodrug thereof are provided, wherein E is —NR4R5, R5 is R5-1; R6a and R6b are hydrogen; R7 is C1-C4 alkyl; R8a and R8b are hydrogen; W is -OR10, R9 and R10 are hydrogen; and n is 2.

In another embodiment, nds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR4R5; R5 is R5-1; R6a and R6b are hydrogen; R7 is C1-C4 alkyl; R8a and R8b are hydrogen; W is -NR11aR11b, R9 is hydrogen; and n is 2.

[0107] In another embodiment, compounds of any one of Formulae I-XXI, or a ceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR4R5; R5 is R5-1; R6a and R6b are en; R7 is C1-C4 alkyl; R8a and R8b are hydrogen; W is -OR10, one of R9 and R10 is hydrogen and the other is a metabolically cleavable group; and n is 2.

[0108] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is ; R5 is R5-2; R123, Rm, R126, and R12d are each hydrogen; R13 is en; Z is -OR15 and R15 is hydrogen; 0 is l or 2; and p is l or 2.

In r embodiment, of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR4R5; R5 is R5-2; Rm, Rab, Rue, and R12d are each hydrogen; R13 is hydrogen; Z is -NR16aR16b; o is l or 2; and p is l or 2.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR4R5; R5 is R5-2; Rm, Rab, Rue, and R12d are each hydrogen; R13 is hydrogen; Z is -OR15 and R15 a metabolically cleavable group; 0 is l or 2; and p is l or 2.

In another embodiment, compounds of any one of Formulae I-XXI, or a ceutically acceptable salt, e, or prodrug thereof are provided, wherein E is ; R5 is R5-3; Rm, Rm, Rm, and R17d are each hydrogen; R18, R19, and R20 are hydrogen; R21a and R21b are en; and q and r are l.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically able salt, solvate, or prodrug thereof are provided, wherein E is -NR4R5; R5 is R5-3; R173, Rm, R176, and R17d are each hydrogen; R18, R19, and R20 are hydrogen; one of R21a and R21b is hydrogen and the other is a metabolically cleavable group; and q and r are l.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or g thereof are provided, wherein R2 is an optionally substituted aryl having the Formula R2-1: R25d R250 R256 R25b 3‘ R25a RZ—l and sta, RZSb, RZSC, RM, and R256 are each independently selected from the group consisting of hydrogen, n, hydroxy, nitro, amino, cyano, alkoxy, optionally substituted alkyl, kyl, optionally substituted aryl, and ally substituted heteroaryl. In one embodiment, sta is selected from the group consisting of hydrogen and fluoro; R25b is chloro; R25c is selected from the group consisting of hydrogen and fluoro; and R25d and R256 are hydrogen.

In another embodiment, compounds of any one of Formulae I-XXI, or a ceutically able salt, solvate, or prodrug thereof are provided, wherein R2 is an optionally substituted pyridyl.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is —NR4R5, R4 is hydrogen, and R5 is selected from the group consisting of: 2012/037570 OR9a 1"” ORga NRQbRQC EWOWO VCR”R14 3W0“) EWNRllaRW R7 . R7 R7 R5-8 R5"; R5'7 R5-5 NR16aR16b OR15 ﬁNRWawa ' . Um?” ’ R14 R14 R14 R5-9 R540 R541 R5-12 a? éé R20 16 16b OR15 UNRwawa 21 R14 R190R21b R5-14 R5-15 R5-13 R5-16 :3 \‘é 9; \QORR20 21a NR16aRl6b and N‘R24 R190R21b R5-18 R5-19 R5-1 7 ing stereoisomers, e.g., enantiomers, thereof, wherein: R7 is optionally substituted C1-C4 alkyl; R9a and R10 are each hydrogen; or one of R9a and R10 is hydrogen and the other is a metabolically cleavable group; R9b is selected from the group consisting of hydrogen, ally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aryl, -SOzR9d, and —CONR96R9f; R90 is selected from the group ting of en, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R9b and R90 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; R9d is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl; R96 and R9f are each independently selected from the group consisting of hydrogen, ally substituted alkyl, and optionally substituted cycloalkyl; or WO 55066 R96 and R9f taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; R11a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SOZR11C, and -CONR11dele; R11b is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and ally substituted heteroaryl; or R11a and R11b taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; R11c is selected from the group consisting of ally substituted alkyl and optionally substituted cycloalkyl, R11d and R116 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl, or R11d and R116 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; R14 is selected from the group consisting of hydrogen, C1—C4 alkyl, or C3—C6 lkyl, R15 is en or a metabolically cleavable group; R16a is selected from the group consisting of 6c and —CONR16dR16e; R16b is selected from the group consisting of en and optionally substituted alkyl; R16c is selected from the group ting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R16d and R166 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and ally substituted aryl; or R16d and R166 taken together with the nitrogen atom to which they are attached form a 4— to ered heterocyclo; R19 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl, R20 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted lkyl; R21a and R21b are each en; or one of R21a and R21b is hydrogen and the other is lically cleavable group; R24 is ed from the group consisting of —SOZR24a and —CONR24bR24C; R24a is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R24b and R24c are each independently ed from the group consisting of hydrogen, optionally substituted lkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R24b and R24c taken together with the nitrogen atom to which they are attached form a 4— to 8—membered heterocyclo.

[0116] In another ment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, n E is —NR4R5, R4 is hydrogen, and R5 is selected from the group consisting of R5—5, R5—6, R5-10, R5—11, R5-12, R5-13, and R5—14.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is —NR4R5, R4 is hydrogen, and R5 is selected from the group consisting of R5-10 and R5-12 and R14 is hydrogen or methyl and R15 is hydrogen.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically able salt, solvate, or prodrug thereof are provided, wherein E is —NR4R5, R4 is hydrogen, and R5 is selected from the group consisting of: OH OH OH OH EWOH r‘;\/—5k/OH EWOH R7 R7 ’ EvikrOH 1 R7 1 R7 R83 R8a , ”Rab OH fr" OH is OH R 5' , H3C R8b wherein: R7 is selected from the group consisting of methyl, ethyl, propyl, pyl, and cyclopropyl; and R8a and R8b are each independently selected from the group consisting of hydrogen, methyl, ethyl, , isopropyl, and cyclopropyl.

In r embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug f are provided, n E is —NR4R5, R4 is hydrogen, and R5 is selected from the group consisting of: OH OH OH EWNHSOZRﬂc fWk/NHSOZR11C re; NHSOZR11C R7 R7 , R7 95‘ NHso2R11° 9’; NHso2R110 6‘; __- NHSOsz RBaR8b H36 Rab R88 ’ NHSOZRQd NHSOZRQd NHSOZRQd EACH «EV—:k/OH ‘5; ~ V—EWOH7 R7 ’ R7 R NHSOZRQd NHSOZRQd NHSOZRQd EWOH 4; 9; OH OH :.

R7 and 1 R8b H36 Rab R8a R88 wherein: R7 is selected from the group consisting of methyl, ethyl, propyl, pyl, and cyclopropyl; R8a and R8b are each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopropyl; R9d is selected from the group consisting of methyl, triﬂuoromethyl, ethyl, propyl, isopropyl, and cyclopropyl; and R11c is selected from the group consisting of methyl, triﬂuoromethyl, ethyl, propyl, isopropyl, and cyclopropyl.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, e, or prodrug thereof are provided, wherein E is —NR4R5, R4 is hydrogen, and R5 is selected from the group consisting of: OH OH OH g:\//—%\V/NHCONHR“d §:\//—J\V/NHCONHR“d 5 NHCONHR11d R7 ’ , §7 R7 R83 , NHCONHR11d 5 R11d 3 NHCONHR11d R8R8b H3C R8b R83 ! NHCONHR9e NHCONHR9e NHCONHRe ‘ 7 R7 ’ R7 R NHCONHR9e R% NHCONHR9e R7 and . R7 Rat; H36 Rab R821] R83 wherein: R7 is selected from the group ting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; R8a and R8b are each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopropyl; R96 is selected from the group consisting of methyl, triﬂuoromethyl, ethyl, propyl, isopropyl, and cyclopropyl; and R11d is selected from the group consisting of methyl, triﬂuoromethyl, ethyl, propyl, isopropyl, and cyclopropyl.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically able salt, solvate, or g thereof are provided, wherein E is —NR4R5, R4 is hydrogen, and R5 is ed from the group consisting of: "'LG “a f {a5o, O><lI 2% 1 'IIR14 3 OI “Lu "a ,,,E( 1H, “H, Ii:maI OI OI El“ 4; - <50‘: "Mn : im0I 5:C")I 0I a4; 444,. M :44.” ’14:». 6 g0I .IlOH :9OI 444,. m "In,“ "44,. :0“;“gr . :OI :E‘OH-, A —‘ \\ R R R14 3‘ -“OH OH 5"“ 5 .\\OH OH R20 ’R20 R20 1 ’R20 . -, a OH 3 R19 OH OH R19 bH R19 R19 OH \Q"‘OH OH QMOH OH , OH OH OH ‘5; re: 33/1,]. " “OH II/RZO R20 ’Rzo R20 _ _ and ' OH OH OH ~;90H R19 R19 R19 R wherein: R14 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and ropyl; and R19 and R20 are each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is —NR4R5, R4 is en, and R5 is selected from the group ting of: EV ’ fly , EW'RM , NHSOZR160 NHSOZR160 NHSOZR160 E E ER” EL ,4: b 1 : 1 NHSOZR16C NHso2R160 °2NHsoR160 (RD. ﬂR f NHSOZR’IGC ’ 'HNHSQ2R160 U E NH802R160 EU UNHSOZRWC \QR-JNHSOZR160 , "'NHso2R160 é” \O'HNHSOZRmC \O‘NHSOZRmC 51.0I , 1 1 "NHSOZR160 "3m. "'14..

ZI (I)O 7E2 -|NH802R160 \07NHSOZR160R14 III'Q'NHSOZR160 ’ MOFNHSOZR1600 R14 ’R14 NHSO2R160 NHSO2R15C , NHso2R160 wherein: R14 is selected from the group ting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; and R16c1s selected from the group consisting of methyl triﬂuoromethyl, ethyl, propyl, pyl, and cyclopropyl.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, n E is , R4 is hydrogen, and R5 is selected from the group consisting of: K7 ’ EV? ’ KYRM NHCONHRW NHCONHR16d NHCONHR16d WW \CL \3 , 2 ’ 16d h ’ . HINHCQNHRW 16d , U NHCONHR g NHCONHR16d g e” 5D NHCONHR16d \qWNHCONHRm" ’ NHCONHR16d FE4 \O-HNHCONHRmd \O‘NHCONHR16d;, IO "NHCONHR15d , $951, O‘NHCONHRW ...NHCONHR16d , \O‘NHCONHRW R14 R4 ’ ...NHCQNHR16d,,NHCONHR16d R14 R14 NHCONHR16d \O‘NHCONHR16d . 'aer O‘NHCONHR1Gd NHCONHR16d wherein: R14 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; and R16d1s selected from the group consisting of methyl triﬂuoromethyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0124] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or g thereof are provided, wherein E is —NR4R5, R4 is hydrogen, and R5 is selected from the group consisting of: f f 9, \O"'OH of W: 6,,.IIOH’ \O‘OH é:”OHCH3 \QSH‘Z” <5“ W ?:W rri5”“V70H and "mum CH3 CH3 CH3

[0125] In another embodiment, nds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or g thereof are provided wherein E is -NR4R5, R4 is en, and R5 is selected from the group consisting of: WO 55066 g f a“ UOR15 U---0R15 h.OR15 “'OR15 : and43:4 ’ 14 ’ R14 R §14 R14 wherein: R14 is ed from the group consisting of hydrogen and C1—C4 alkyl, and R15 is hydrogen or a metabolically cleavable group.

[0126] In one embodiment, the metabolically cleavable group at R15 is selected from the group consisting of: O R29a I 9 V 30 a . N‘R29b and E/R—OR R28a c’RZBb ORsob wherein: each R28a and R28b is independently selected from the group consisting of en, optionally substituted alkyl, and aralkyl, R29a and R29b are each selected from the group consisting of hydrogen and optionally substituted alkyl, V is l, 2, 3, or 4; and R30a and R30b are each selected from the group consisting of hydrogen, ally substituted alkyl, aralkyl, optionally substituted aryl, and monovalent ceutically acceptable cation; or taken together R30a and R30b represent a divalent pharmaceutically acceptable cation or an optionally substituted alkylenyl.

In another embodiment, the metabolically cleavable group at R15 is the residue of a natural or unnatural amino acid. In another embodiment, the metabolically ble group at R15 is the residue of glycine, isoleucine alanine, leucine, asparagine, lysine, ic acid, nine, cysteine, phenylalanine, glutamic acid, threonine, ine, tryptophan, valine, proline, serine, tyrosine, arginine, and histidine.

[0128] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided wherein X is NH and Y is NH. 2012/037570 In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug f are provided wherein X is O and Y is NH.

In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided wherein X is S and Y is NH.

In another embodiment, compounds of any one of Formulae I-IV or VI—XXI, or a pharmaceutically acceptable salt, solvate, or g thereof, are provided, wherein R3a and R3b are the same or different C1-C10 alkyl.

[0132] In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein R3a and R3b are the same or different C2-C10 alkyl.

In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug f, are ed, wherein R3a and R3b are the same or different C1-C6 alkyl, e.g., methyl, ethyl, n—propyl, isopropyl, n-butyl, sec—butyl, isobutyl, tert—butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.

In another embodiment, compounds of any one of Formulae I-IV or VI—XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are ed, wherein R3a and R3b are the same or different C2-C6 alkyl.

In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein R3a and R3b are the same or different C1-C4 alkyl.

In another ment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, e, or prodrug thereof, are ed, wherein R3a and R3b are the same or different C2-C4 alkyl.

In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a ceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein R3a and R3b are the same or different C1-C3 alkyl.

[0138] In another embodiment, compounds of any one of ae I-IV or VI—XXI, or a pharmaceutically acceptable salt, solvate, or prodrug f are provided, wherein R3a and R3b are the same or different halo.

In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are ed, n R3a and R3b are the same or different, and are selected from the group consisting of methyl, ethyl, propyl, pyl, butyl, and neopentyl.

[0140] In another embodiment, compounds of any one of Formulae I-IV or , or a pharmaceutically acceptable salt, solvate, or g thereof are provided, wherein R3a and R3b are the same or different, and are selected from the group consisting of ethyl, propyl, isopropyl, butyl, and neopentyl.

In another embodiment, compounds of any one of ae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R3a and R3b are ﬂuoro.

In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R3a and R3b are the same, e. g., R3a is methyl and R3b is methyl, R3a is ethyl and R3b is ethyl, R3a is propyl and R3b is propyl, etc. If R3a and R3b are the same, the carbon atom to which R3a and R3b are attached is not an asymmetric center. Under these circumstances, Formula VI and X; Formula VII and XIII; Formula VIII and IX; Formula XI and X11; Formula XIV and XVI; Formula XV and XXI; Formula XVII and XX; and Formula XVIII and XIX represent equivalent s.

In another embodiment, compounds of any one of Formulae I-IV or , or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R3a and R3b are different, e. g., R3a is methyl and R3b is ethyl, R3a is methyl and R3b is neopentyl, R3a is ethyl and R3b is propyl, etc.

[0144] In another embodiment, compounds of any one of ae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R3a and R3b are taken together to form an optionally tuted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring. In one embodiment, the optional substituent is a (C1-C4)alkyl. In another embodiment, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or eptyl ring is unsubstituted.

In r embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R1a and R1d are hydrogen, R1b and R1c are each independently selected from the group consisting of hydrogen, chloro, and ﬂuoro, and R2 is R2—l wherein sta, RZSb, RZSC, RZSd, and R256 are each independently selected from the group ting of hydrogen, chloro, and ﬂuoro.

[0146] In another embodiment, compounds haVing any one of Formulae , or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein: E is NR4R5; Rla, Rlb, R”, and R1d are each independently selected from the group consisting of hydrogen, ﬂuoro, and chloro; R2 is: R25b R25C R25a R25d 655 R258 wherein: sta, Rm, R256, R2“, and R256 are each independently selected from the group consisting of en, ﬂuoro, and ; R3a is 01—06 alkyl; R3b is C1-C4 alkyl; or R3a and R3b are taken together to form an optionally substituted 3— to 7—membered cycloalkyl; R4 is selected from the group consisting of hydrogen and optionally substituted C1—C4 alkyl; R5 is selected from the group consisting of: x r‘ s 5 OH ﬁll-OH UOHand q-I-OH [:14 R14 R14 R14 wherein: R14 is selected from the group consisting of hydrogen and optionally substituted C1—C4 alkyl; X is selected from the group consisting of O, S, and NR'; Y is ed from the group consisting of O, S, and NR"; R is selected from the group consisting of hydrogen and optionally substituted C1—C4 alkyl; and R" is selected from the group consisting of hydrogen and ally substituted C1—C4 alkyl, wherein the compounds are ntially free of one or more other stereoisomers.

In another embodiment, compounds haVing any one of Formulae VI-XXI, or a pharmaceutically acceptable salt, e, or prodrug thereof are provided, E is NR4R5; R1a is hydrogen; Rlb, R16, and R1d are each independently selected from the group consisting of hydrogen, ﬂuoro, and chloro; R2 is: R25b R25C R25a R25d :5 R25e wherein: sta, RZSb, RZSC, RM, and R256 are each independently selected from the group consisting of hydrogen, ﬂuoro, and chloro; R3a and R3b are methyl; or R3a and R3b taken together form a cyclopentyl, cyclohexyl, or cycloheptyl ring; R4 is hydrogen; R5 is selected from the group consisting of: a" E h hop. "'OH ’ Eb” ’ X and Y are NH, n the compounds are substantially free of one or more other stereoisomers.

In another ment, nds having any one of Formulae VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein E is NR4R5, R4 is hydrogen, and R5 is selected from the group consisting mg and : : wherein the compound is substantially free of one or more other stereoisomers.

In another embodiment, compounds having Formula VI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, n the compounds are ntially pure stereoisomers.

In another embodiment, compounds having Formula XVIII, or a pharmaceutically able salt, solvate, or prodrug f, are provided, wherein the compounds are substantially pure stereoisomers.

[0151] In another ment, compounds having Formula XVI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein the compounds are substantially pure stereoisomers.

In another embodiment, compounds having Formula XVI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein: E is NR4R5; R4 is hydrogen; X and Y are NH; R3a and R3b are methyl or ethyl, or R3a and R3b taken er form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring, each optionally substituted by one of more C1—C4 alkyl groups; and R5 is selected from the group consisting of: W; e OH ’ OOH wherein the compounds are substantially pure stereoisomers.

In r embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is —OR263 and R13, Rlb, R”, R”, R2, R33, R3b, R263, X, and Y have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, R26a is hydrogen.

In another embodiment, compounds of any one of ae VI—XXI are provided, wherein E is -OR26a; Rla, Rlb, R16, Rld, R2, R26a, X, and Y have the meanings as described above for Formula I; and R3a and R3b taken er form a 4— to 7—membered optionally substituted cycloalkyl or 4— to 7—membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt, e, or prodrug thereof. In r embodiment, R26a is hydrogen. In another embodiment, R3a and R3b taken together form a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or optionally substituted piperidinyl group.

In another embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is —NR26bR26c; R13, Rlb, R1211“, R2, R33, R3b’ R26b, R266, X, and Y have the meanings as described above for Formula I, or a ceutically acceptable salt, solvate, or prodrug f.

[0156] In another embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is —NR26bR26C; R13, Rlb, R”, R”, R2, Rm, R266, X, and Y have the meanings as described above for a I; and R3a and R3b taken together form a 4- to 7-membered optionally substituted cycloalkyl or 4- to 7—membered optionally substituted heterocyclo, or a ceutically able salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is —NR26bR26c; R13, Rlb, R”, R“, R2, Rm, R262 X, and Y have the meanings as described above for Formula I; and R3a and R3b taken together form a 4- to 7-membered optionally substituted cycloalkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is —NR26bR26c, and R13, Rlb, R”, R“, R2, Rm, R266, X, and Y have the meanings as described above for Formula I, and R3a and R3b taken together form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is R26c, and R13, Rlb, R”, R“, R2, Rm, R266, X, and Y have the meanings as described above for Formula I, and R3a and R3b taken together form a 4— to ered ally substituted heterocyclo, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formula VI—XXI are provided, wherein E is R26C, and R13, Rlb, R”, R“, R2, Rm, R266, X, and Y have the meanings as described above for Formula I, and R3a and R3b taken er form a tetrahydropyranyl or optionally substituted piperidinyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of ae VI—XXI are provided, wherein E is —NR26bR26C, and R13, Rlb, R”, R“, R2, R33, R3b, X, and Y have the meanings as described above for Formula I, R26b is hydrogen, and R26c is optionally substituted cycloalkyl. In another embodiment, R26c is hydroxycycloalkyl. In r embodiment, R26c is cycloalkyl substituted with —COzH.

[0162] In another embodiment, compounds of any one of Formulae VI—XXI are provided, wherein E is —NR26bR26C, and R13, Rlb, R”, R“, R2, R33, R3b, X, and Y have the meanings as described above for Formula I, R26b is hydrogen, and R26c is optionally tuted aryl. In another embodiment R26c is phenyl tuted with —COZH.

[0163] In another ment, compounds of Formula XXII are provided: XXII wherein: R”, Rlb, R”, R”, R2, E, X, and Y have the meanings as described above for Formula I; A is ed from the group consisting of CR27aR27b, O, S, SO, $02, and NR”; R27a is selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, sulfonamido, and -C02R31; R27b is selected from the group consisting of en and optionally substituted alkyl, or R27a and R27b taken together form a 3- to 6-membered optionally substituted cycloalkyl or 3— to 6—membered optionally substituted heterocyclo; R28 is ed from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, ally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally tuted heterocyclo, carboxamido, sulfonamido, amino, 2a, —COR32a, —SOzR32b, C)COR32d, C)SOzR3ze and —N(R3ZC)C=N(R32f)—amino; R32a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and ally substituted heteroaryl, R32b is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R32c is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, R32d is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R326 is selected from the group consisting of optionally substituted alkyl, optionally tuted aryl, and optionally tuted heteroaryl; and R32f is selected from the group consisting of hydrogen, —CN, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; B is _(CR29aR29b )W_; D is 3R30b)X—; each Rzga, Rm, R30a, and R30b is independently selected from the group consisting of hydrogen, halo, nitro, cyano, y, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aralkyl, ally substituted cycloalkyl, optionally tuted alkenyl, ally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido and sulfonamido; R31 is ed from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl; W is 0, l, 2, 3, 4, 5, 6, 7, or 8; and xis 0, 4, 5, 6, 7, or 8; with the proviso that the sum ofW plus X is l, 2, 3, 4, 5, 6, 7 or 8, or a ceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are provided as a single stereoisomer, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are provided wherein w is l, 2, or 3, x is l, 2, or 3, and each R293, Rng, R303, and R30b is independently hydrogen or (C1-C4)alkyl, or a ceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are provided wherein w is l, 2, or 3, x is l, 2, or 3, each Rzga, Rm, R30a, and R30b is independently hydrogen or (C1-C4)alkyl, and A is CR27aR27b, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are ed wherein w is l, 2, or 3, x is l, 2, or 3, each Rzga, Rm, R30a, and R30b is independently hydrogen or (C1—C4)alkyl, A is CR27aRZ7b, and R27a and R27b are independently selected from the group consisting of hydrogen and alkyl, or a pharmaceutically acceptable salt, solvate, or g thereof.

In another embodiment, compounds of Formula XXII are provided wherein w is l, 2, or 3, x is l, 2, or 3, each R293, Rm, R30a, and R30b is ndently hydrogen or )alkyl, A is CR27aRZ7b, and R27a and R27b are hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are provided wherein w is l, 2, or 3, x is l, 2, or 3, each R293, Rm, R303, and R30b is independently hydrogen or (C1-C4)alkyl, and A is O, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are provided wherein w is l, 2, or 3, x is l, 2, or 3, each Rzga, Rm, R30a, and R30b is independently hydrogen or (C1-C4)alkyl, and A is $02, or a ceutically acceptable salt, solvate, or prodrug thereof.

[0171] In another embodiment, compounds of Formula XXII are provided n w is l, 2, or 3, x is l, 2, or 3, each R293, Rm, R303, and R30b is ndently hydrogen or (C1-C4)alkyl, and A is NRZS, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, nds of Formula XXII are provided wherein w is l, 2, or 3, x is l, 2, or 3, Rzga, Rng, R30a, and R30b are hydrogen, and A is NRZS, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are provided wherein w is l, 2, or 3, x is l, 2, or 3, R293, Rm, R303, and R30b are hydrogen, A is NR”, and R28 is selected from the group consisting of hydrogen, optionally substituted alkyl, amido, sulfonamido, amino, —COzR32a, —COR32a, —SOzR32b, -N(R3ZC)COR32d, —N(R3ZC)SOZR326 and —N(R3ZC)C=N(R32f)—amino, or a ceutically acceptable salt, solvate, or g thereof.

In another embodiment, compounds of Formula XXII are provided wherein w and x are 1, each Rzga, Rng, R30a, and R30b is hydrogen, A is NR28, and R28 is selected from the group consisting of hydrogen, optionally substituted alkyl, carboxamido, sulfonamido, —C02R3za, COR”, —SOzR32b, —N(R3ZC)COR32d, —N(R3ZC)SOZR326 and -N(R3ZC)C=N(R32f)-amino, or a pharmaceutically able salt, solvate, or prodrug thereof.

In r embodiment, compounds of Formula XXII are provided wherein w and x are 2, each Rzga, Rng, R30a, and R30b is hydrogen, A is NR28, and R28 is selected from the group consisting of hydrogen, optionally tuted alkyl, carboxamido, sulfonamido, —C02R3za, COR”, —SOzR32b, —N(R3ZC)COR32d, -N(R3ZC)SOZR326 and -N(R3ZC)C=N(R32f)-amino, or a ceutically acceptable salt, e, or prodrug thereof.

In r embodiment, compounds of a XXII are provided wherein w and x are 3, each R293, Rng, R303, and R30b is hydrogen, A is NR”, and R28 is selected from the group consisting of hydrogen, optionally substituted alkyl, amido, sulfonamido, za, COR”, —SOzR32b, —N(R3ZC)COR32d, -N(R3ZC)SOZR326 and -N(R3ZC)C=N(R32f)-amino, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are ed wherein E is -OR26a, or a pharmaceutically able salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXII are provided wherein E is —NR26bR26c, or a pharmaceutically acceptable salt, solvate, or prodrug thereof

[0179] In another embodiment, compounds of Formula XXIII are provided: XXIII wherein R”, Rlb, R16, R”, R2, E, X, and Y have the meanings as described above for Formula I, A has the meaning as described above for Formula XXII, and z is 0, l, or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

WO 55066 In r embodiment, compounds of Formula XXIV are provided: XXIV wherein R”, Rlb, R”, R”, R2, E, X, and Y have the meanings as described above for Formula I, A has the g as bed above for Formula XXII, and z has the meaning as bed above for Formula XXIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of a XXV are provided: wherein R”, Rlb, R”, R”, R2, E, X, and Y have the meanings as described above for Formula I, A has the meaning as described above for Formula XXII, and 2 has the meaning as described above for Formula XXIII, or a pharmaceutically acceptable salt, solvate, or g thereof.

In another embodiment, compounds of any one of Formulae XXIII-XXV are provided, wherein E is —OR26a and R is hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another ment, compounds of any one of Formulae XXIII-XXV are provided, wherein E is -NR26bR26c, R26b is hydrogen, and R26c is ed from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and aralkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, R26c is a hydroxyalkyl, e. g., a monohydroxyalkyl or dihydroxyalkyl. In another embodiment, R26c is an optionally tuted (cycloalkyl)alkyl. In another embodiment, R26c is a (heterocyclo)alkyl. In another embodiment, R26c is optionally substituted cycloalkyl. In another embodiment, R26c is optionally substituted phenyl.

In another ment, nds of any one of Formulae XXIII-XXV are provided wherein A is Z7b, O, or NRZS, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CHR27a, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CHR27a and R27a is selected from the group consisting of hydrogen, y, amino, alkoxy, optionally substituted alkyl, kyl, substituted heteroaryl, carboxamido, sulfonamido, and —COZH, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CH2 or NRZS, or a pharmaceutically acceptable salt, solvate, or prodrug thereof

[0188] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CH2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof In another embodiment, compounds of any one of ae XXIII-XXV are provided wherein A is NRZS, or a pharmaceutically acceptable salt, solvate, or prodrug thereof In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CH2 and z is l, or a pharmaceutically able salt, solvate, or prodrug thereof In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CH2, 2 is l, E is -NR26bR26C, R26b is hydrogen, and R26c is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and aralkyl, or a pharmaceutically acceptable salt, e, or prodrug thereof In another embodiment, R26c is optionally substituted cycloalkyl, e. g., a hydroxycycloalkyl, or a pharmaceutically acceptable salt, solvate, or g f. In r embodiment, R26c is optionally substituted aryl, or a ceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, R26c is optionally tuted heteroaryl, or a pharmaceutically able salt, solvate, or prodrug f.

In another embodiment, compounds of Formula XXVI are provided: XXVI wherein R”, Rlb, R”, R”, R2, and R26c have the meanings as bed above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of Formula XXVII are provided: YN‘R26c XXVII wherein R”, Rlb, R”, R”, R2, and R26c have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of a XXVIII are provided: - ‘R26c XXVIII wherein R”, Rlb, R”, R”, R2, and R26c have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or g thereof.

[0195] In another embodiment, compounds of any one of Formulae XXVI-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein: R”, Rlb, R”, and R1d are ndently selected from the group consisting of hydrogen, ﬂuoro, and chloro; R2 is optionally substituted phenyl; and R26c is selected from the group consisting of optionally substituted (C1—C4) alkyl, optionally substituted (C4-C8) cycloalkyl, optionally substituted , optionally substituted heteroaryl, and aralkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, compounds of any one of Formulae I or III—XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, n R26c is optionally substituted alkyl. In another embodiment, R26c is hydroxyalkyl. In r embodiment, R26c is dihydroxyalkyl. In r embodiment, R26c is (heterocyclo)alkyl.

[0197] In another embodiment, compounds of any one of ae I or III-XXVIII, or a ceutically acceptable salt, e, or prodrug thereof are provided, wherein R26c is optionally substituted cycloalkyl. In another embodiment, R26c is hydroxycycloalkyl. In r embodiment, R26 is cycloalkyl substituted with —COzH.

[0198] In another embodiment, compounds of any one of Formulae I or III—XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R26c is selected from the group consisting of: E ,9 e" r"! E W: ‘ELOH OH , ’ ’OH “549 Me 5 5 5 \oOH ‘0, ma o’OH ’ 5 Me Me K a s s ,, U and Um C02H ’ ’ ’COZH C02H l0021'] In another embodiment, compounds of any one of Formulae I or III—XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are ed, wherein R26c is optionally substituted aryl. In another embodiment, R26c is optionally substituted phenyl. In another embodiment, R26c is phenyl substituted with one or two of the following groups: halo, cyano, hydroxy, alkyl, haloalkyl, alkoxy, carboxamido, sulfonamido, —CONHSOzMe, —COch, —CORC, —sosz, -N(Re)CORf, —N(Re)sozRg or —N(Re)C=N(Rh)—amino, wherein RC, Rd, Re, Rf, Rg, and Rh are as deﬁned above in connection with ally substituted alkyl. In another embodiment, R26c is phenyl substituted with one or two of the following groups: halo, cyano, alkyl, haloalkyl, alkoxy, carboxamido, sulfonamido, -COZRC, or -SOsz, wherein Rc and Rd are as deﬁned above in connection with optionally substituted alkyl. In another embodiment, R26c is phenyl substituted with —COzH.

In another ment, compounds of any one of Formulae I or VIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R26c is selected from the group consisting of: o o o 0 OH ﬁlm-12 ﬁ OH , o ‘ o o VG:O\/\ / NH2 NH2 ’1‘ O ‘ ' , o , CI O o O O\/\OH ‘ o i \ F O\ O\ o\ O\ o\ o o o OH NH2 VG dam0 ' OH 0 \i O\/\s/ \/\OH VEE/O OH g 0” ‘\O Cos/IO Cos/p Cos/,0 Cos/,0 \ CO H ‘NHZ \ ‘NH2 2 . F .

O\ 0\ COZH O/VCOZH H020 ”a; ; and ‘CI CI CI VQ/COzH ' ' F F F F In another embodiment, compounds of any one of Formulae I or VIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R26c is optionally substituted heteroaryl. In another embodiment, the optionally substituted heteroaryl is an ally substituted furyl, thienyl, pyridyl, pyrimidyl, benzimidazolyl, benzthiazolyl, or indolyl, In r embodiment, R26c is heteroaryl substituted with one or two of the following groups: halo, cyano, hydroxy, alkyl, haloalkyl, alkoxy, amido, sulfonamido, —CONHSOzMe, —C02Rc, —CORC, —sosz, —N(RC)CORf, —N(Re)SOZRg or -N(Re)C=N(Rh)-amino, wherein RC, Rd, Re, Rf, Rg, and Rh are as defined above in connection with ally substituted alkyl. In another embodiment, R26c is heteroaryl substituted with one or two of the following groups: halo, cyano, alkyl, haloalkyl, alkoxy, carboxamido, sulfonamido, —COch, or —SOsz, wherein Rc and Rd are as deﬁned above in connection with optionally substituted alkyl. In another embodiment, R26c is heteroaryl substituted with —COzH.

In another embodiment, compounds of any one of ae I or III-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R26c is ed from the group consisting of: N o ‘ $0” O W0 \ NH2 I I \ | / /N S NH2 , "{ NH2 N\ HOZC o N\ N’N 0 CI / an CI 6N N F \ In another embodiment, compounds of any one of Formulae I or III—XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R26c is aralkyl.

In r embodiment, nds of any one of Formulae I or III—XXVIII, or a ceutically acceptable salt, solvate, or prodrug thereof are ed, wherein R26c is selected from the group consisting of: O O O IQ/‘Lcm HZ OH ' ’ fQ/‘LNHZ O\ Q\ , O OVic“ IUOH (U WOH (U O\/[L O\/\ OH xsx/ NH2 0’ ‘0 In another ment, compounds of any one of Formulae I or III—XXVIII areOprovided, wherein R26c is selected from the group consisting of: HEP? H”OH COZH O Q COZH 008\\O :I: 90WH/COZHWC002"]WW: ,COZH c02H N’N\ HO “\s‘ Q‘ I ‘N :S/ OMe N, | H and

[0206] In another embodiment, compounds of Formulae XXVII or XXVIII are provided substantially free of one or more other stereoisomers. In another embodiment, compounds of any one of Formulae XXVII or XXVIII are substantially pure stereoisomers. In another embodiment, nds of any one of Formulae XXVII or XXVIII are pure stereoisomers.

[0207] In another embodiment, compounds of Formula I are provided having the structure: o 0 ’ CI N CI H CI H ’ H H CI H O N"OH O OH NH O “H O 0 o . O O , CI H CI M ’ CI H H CI H Cl FO N N F0 WOH O ’ O N CI a N N M CI CI H H H H C' F 0 NW CI H CI N F o W W OH O OH Na NH O 0 o a O N O N H H CI H CI F O CI F O NO F 0 Nﬂ O OH OH O NH NH O NH 0 O O CI N or stereoisomers thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In r embodiment, compounds of Formula I are provided having the structure: or pharmaceutically acceptable salts, es, or prodrugs thereof.

In another embodiment, compounds of Formula I are provided having the structure: or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In r embodiment, compounds of Formula I are provided having the structure: o N_<:>...OH WO 55066 WO 55066 WO 55066 or ceutically acceptable salts, solvates, or prodrugs thereof.

In another embodiment, the disclosure provides a method of preparing a compound having Formula XVI: wherein R”, Rlb, R”, R”, R2, R3a, R3b, and E have the meanings as described above for Formula I, and X and Y are NH. In r embodiment, E is .

In another embodiment, E is —NR26bR26c. In another ment, R26b is hydrogen, and R26c - is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted aryl. In another embodiment, R3a and R3b are taken together form an unsubstituted 4— to 8—membered cycloalkyl.

In r embodiment, the method of preparing a compound having Formula XVI comprises allowing a compound having Formula VI: to ize to a compound having Formula XVI.

In another ment, the method of preparing a compound having Formula XVI ses dissolving a compound having Formula VI in a solvent or a mixture of solvents.

[0215] In another embodiment, the method of preparing a compound having Formula XVI comprises: a) dissolving a compound having Formula VI in a solvent or a mixture of solvents; and b) allowing the compound having Formula VI to isomerize to a nd having a XVI.

In another embodiment, the method of preparing a compound having Formula XVI comprises: a) allowing the compound having Formula VI to isomerize to a compound having Formula XVI; and b) isolating the nd having Formula XVI substantially free from the compound having Formula VI, and one or more other stereoisomers.

In another embodiment, the method of preparing a compound having Formula XVI comprises: a) dissolving a compound having Formula VI in a solvent or a mixture of solvents; b) allowing the compound having Formula VI to isomerize to a compound having Formula XVI; and c) isolating the compound having a XVI substantially free from the compound having Formula VI, and one or more other stereoisomers.

In r embodiment, the solvent is selected from the group consisting of acetonitrile, methanol, ethyl acetate, and water, or a mixture thereof.

In r ment, the ization is carried out at a pH of less than 7, e. g., at a pH of about 6, about 5, about 4, about 3, about 2, or about 1. In one embodiment, the ization is carried out at a pH of about 7. In one embodiment, the ization is carried out at a pH of greater than 7, e. g., at a pH of about 8, about 9, about 10, about 11, about 12, or about 13.

In another embodiment, the isomerization is carried out in the presence of an acid, e. g., triﬂuoroacetic acid or acetic acid.

[0222] In one embodiment, the isomerization is carried out in the presence of a base, e.g., NaHCO3.

In another embodiment, isomerization is carried out at a temperature of about 20°C to about 100°C, e.g., at a temperature of about 20°C to about 70°C, e.g., at a temperature of about 45°C to about 65°C. In one embodiment the isomerization is carried out at about room temperature, e.g., at about 20°C. In one embodiment the isomerization is carried out above room temperature, e. g., at about 25°C, at about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C.

[0224] In another embodiment, the isomerization is carried about for a period of time between about 0.5 hours and about 2 weeks, e.g., for about 1 hour, about 3 hours, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 1 week. The period of time needed for isomerization to occur may depend on a variety of factors including the chemical structure of Formula VI, the solvent(s), the temperature, and/or the In n aspects, the disclosure provides the following particular embodiments: I. A compound having Formula II: wherein: R”, Rlb, R”, and R1d are ndently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted lkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R3a is ed from the group consisting of halo, ally substituted alkyl, optionally tuted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally tuted aryl, and optionally substituted heteroaryl; R3a is selected from the group consisting of halo, optionally substituted alkyl, ally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally tuted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; or R3a and R3b taken together form a 3— to 9—membered optionally substituted cycloalkyl, R4 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl, R5 is selected from the group consisting of: E R13 R128 W1 R7 R12b _(CR68R6b)n>S<W2 O ’R12C Z RSa R8b 12d R14 wherein: each R6a and R6b is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; R7 is selected from the group consisting of hydrogen, ally S substituted C1—C6 alkyl, and optionally substituted lkyl; R8a and R8b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl; or R8a and R8b taken together with the carbon that they are attached form a 3- to 8—membered optionally substituted cycloalkyl; W1 is selected from the group ting of —OR9a and -NR9bR9c; R9a is hydrogen; R9b is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, ally substituted aryl, optionally substituted heteroaryl, -SOzR9d, and —CONR96R9f; R90 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted lkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R9b and R90 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered ally tuted heterocyclo; R9d is selected from the group consisting of optionally substituted alkyl and ally substituted cycloalkyl; R96 and R9f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or R96 and R9f taken together with the nitrogen atom to which they are attached form a 4— to 8—membered optionally substituted heterocyclo; W2 is selected from the group consisting of —OR10 and -NR11aR11b; with the o that when W1 is -OR9a and W2 is -OR10 then at least one of R7, Rga, and R8b is other than hydrogen; R10 is hydrogen; or one of R9a and R10 is hydrogen and the other is a metabolically cleavable group; R11a is selected from the group consisting of hydrogen, ally substituted alkyl, optionally tuted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SOZR11C, and —CONR11dele; R11b is selected from the group consisting of hydrogen, optionally tuted alkyl, optionally substituted lkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R11a and R11b taken together with the nitrogen atom to which they are attached form a 4— to ered optionally substituted heterocyclo; R11c is ed from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl, R11d and R116 are each independently ed from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl, or R11d and R116 taken together with the nitrogen atom to which they are attached form a 4— to ered ally substituted heterocyclo; nis l,2,3,4,or5; each Rlza, Rlzb, R12c and R12d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; R13 is selected from the group consisting of en and optionally substituted C1—C6 alkyl; R14 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl, Z is selected from the group consisting of —OR15 and -NR16aR16b; or Z and R14 taken together form a carbonyl, i.e., a C=O, group.

R15 is selected from the group consisting of hydrogen and metabolically cleavable group; R16a is selected from the group consisting of —SOZR16c and —CONR16dR16e; R16b is ed from the group consisting of hydrogen and optionally substituted alkyl; R16c is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R16d and R166 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and ally substituted heteroaryl; or R16d and R166 taken together with the nitrogen atom to which they are attached form a 4— to 8—membered heterocyclo; o is l, 2, or 3; p is 0,1, 2, or 3; each Rm, Rm, R17c and R17d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl, R18 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl, R19 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl, R20 is selected from the group consisting of hydrogen, optionally substituted C1—C6 alkyl, and optionally substituted cycloalkyl, R21a and R21b are each hydrogen; or one of R21a and R21b is hydrogen and the other is metabolically cleavable group; qis 0,1, 2, or 3; ris 1,2, or3; each Rm, Rm, Rm, and R22d is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl, R23 is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl, R24 is selected from the group ting of —SOzR24a and —CONR24bR24c; R24a is selected from the group consisting of ally substituted alkyl, optionally tuted cycloalkyl, ally tuted aryl, and optionally substituted heteroaryl; R24b and R24c are each independently selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally tuted aryl, and optionally substituted aryl; or R24b and R24c taken together with the nitrogen atom to which they are attached form a 4— to 8—membered heterocyclo; s and t are each independently l, 2, or 3; X is selected from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; R is ed from the group consisting of hydrogen, optionally S substituted alkyl, aralkyl, and optionally substituted lkyl; R" is selected from the group ting of hydrogen, optionally substituted alkyl, aralkyl, and optionally tuted cycloalkyl; and = represents a single or a double bond, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0227] II. The compound of ular embodiment I haVing the formula: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

III. The compound of particular embodiment 11 having formula: or a pharmaceutically acceptable salt, solvate, or prodrug thereof IV. The compound of any one of particular embodiments 1-111, wherein: R”, Rlb, R”, and R1d are each independently selected from the group consisting of hydrogen, ﬂuoro, and chloro; R2 is ally substituted aryl; R3a is halo or C1-C10 alkyl, R3b is halo or C1-C10 alkyl, or R3a and R3b taken together form a 3- to 9-membered optionally substituted cycloalkyl; R4 is hydrogen; and X and Y are NH, or a pharmaceutically acceptable salt, e, or prodrug thereof.

V. The compound of particular embodiment IV, wherein: R1a and R1d are each hydrogen; R1b is ed from the group consisting of hydrogen and ﬂuoro; and R1c is selected from the group consisting of ﬂuoro and chloro, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

VI. The nd of any one of particular embodiments I-V, n R2 is an optionally substituted aryl haVing Formula R2-1: R25d R250 R256 R25b 3‘ R258 R2_1 wherein sta, RZSb, RZSC, RZSd, and R256 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, alkyl, or haloalkyl, or a pharmaceutically acceptable salt, e, or prodrug thereof.

VII. The compound of particular embodiment VI, wherein: sta is selected from the group ting of hydrogen and ﬂuoro; R25b is chloro; R25c is selected from the group consisting of hydrogen and ﬂuoro; and R25d and R256 are each hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

VIII. The nd of any one of particular embodiment I-VH, wherein R5 is selected from the group consisting of: R93 ORga NRQbRQC N“ OR10 NR11aR11b OR10 L51 1L!- >LOR15 R7 "LLL/\j(:\/ R7 R5-8 R55 “'7 R5-5 rr‘: is PMW>LNR1621R1613yr;r h16 16b OR15 “NR 3R OR15 , ' R R14 R14 R5-9 R5-10 R541 R5-12 QNRW‘RW) ; ’ 15 5UNNR163R16b R14 e;\Ez/OOR21..0R2“) R5-14 R5-15 R543 R5-16 5Q:ORZla R16b R19 ORZ’lb R5-18 R5-17 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

IX. The compound of particular embodiment VIII, wherein R5 is selected from the group consisting of: OR15 R14 R14 wherein: R14 is hydrogen or C1-C4 alkyl, and is hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

X. The com oundp of any one of particular embodiments I-IX, wherein R3a and R3b are each independently C1-C6 alkyl, or a pharmaceutically acceptable salt, e, or prodrug thereof.

XI. The nd of any one of particular embodiments I-IX, wherein R3a and R3b are taken together to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

XII. The compound of any one of particular embodiments I—XI, wherein R5 is selected from the group consisting of: f 5 ; UOH ’ \O'o—I , g'OH , (Ea-0H e“ i‘ f 9“ ‘EL ‘D 0..

OH ’ OH 6H3 CH3 or a pharmaceutically able salt, solvate, or prodrug thereof.

XIII. A compound ed from the group consisting of: or a pharmaceutically acceptable salt, e, or prodrug thereof.

[0239] XIV. A pharmaceutical composition comprising the compound of any one of particular ments I-VIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

XV. A method of treating a patient comprising administering to the t a therapeutically effective amount of the compound of any one of particular embodiments I-VIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the patient has a hyperproliferative disease.

XVI. A method of treating a patient comprising administering to the patient a therapeutically effective amount of the pharmaceutical ition of ular embodiment XIV, wherein the patient has a hyperproliferative disease.

XVII. The method of ular embodiments XV or XVI, wherein the hyperproliferative disease is cancer.

XVIII. The method of particular embodiments XV or XVI, wherein cells of the hyperproliferative disease express functional p53.

XIX. The method of particular embodiment XVII, further comprising administering to the patient one or more anticancer agents.

XX. The method of particular embodiment XIX, wherein the anticancer agent is a chemotherapeutic agent.

XXI. The method of particular embodiment XIX, wherein the anticancer agent is radiation therapy.

XXII. A method of treating a t, wherein the patient has a hyperproliferative er and is being treated with an anticancer agent, comprising administering to the patient a nd of any one of particular embodiments I-XIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

XXIII. The method of ular embodiment XXII, wherein the patient is experiencing side-effects of the anticancer agent treatment selected from the group consisting of mucositis, stomatitis, xerostoma, alopecia, and gastrointestinal disorder.

[0249] XXIV. The method of particular embodiment XXII, wherein cells of the hyperproliferative disorder express functional p53.

XXV. A kit comprising a compound of any one of particular ments I-XIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and instructions for administering the compound to a patient haVing a hyperproliferative disease.

XXVI. The kit of ular embodiment XXV, wherein the hyperproliferative disease is cancer.

XXVII. The kit of particular embodiment XXVI, further comprising one or more anticancer .

[0253] XXVIII. The kit of particular ment XXVII, n the instructions direct co-administration of the compound together with the one or more anticancer agents.

XXIX. A nd haVing Formula I: wherein: R”, Rlb, R”, and R1d are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally tuted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, ally substituted lkenyl, ally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is selected from the group ting of optionally substituted aryl and optionally substituted heteroaryl; R3a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally tuted cycloalkyl, optionally tuted alkenyl, optionally substituted lkenyl, optionally substituted aryl, and optionally substituted heteroaryl, R3a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally tuted aryl, and optionally substituted heteroaryl, or R3a and R3b taken together form a 3— to 9—membered optionally tuted cycloalkyl or a 3— to ered optionally substituted heterocyclo; E is selected from the group consisting of —OR26a and -NR26bR26c; R26a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; R26b is selected from the group consisting of hydrogen and optionally substituted C1—C6 alkyl, R26c is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally tuted aryl, optionally substituted heteroaryl, aralkyl, and -SOzR5b; or R26b and R26c taken together form a 4- to 9-membered optionally substituted heterocyclo; X is selected from the group consisting of O, S, and NR'; Y is selected from the group consisting of O, S, and NR"; R is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; R" is selected from the group consisting of en, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and = represents a single or a double bond, or a pharmaceutically acceptable salt f.

XXX. The compound of particular embodiment XXIX haVing Formula 111: or a pharmaceutically acceptable salt thereof.

[0256] XXXI. The compound of particular embodiment XXX haVing Formula VI: or a pharmaceutically able salt f.

[0257] XXXH. The compound of particular embodiment XXX haVing Formula XVI: or a pharmaceutically acceptable salt thereof.

XXXHI. The compound of any one of particular embodiments XXIX-XXXII, wherein: E is R26c; R2 is optionally substituted aryl; R3a is halo or C1-C10 alkyl; R3b is halo or C1-C10 alkyl; or R3a and R3b taken together form a 3- to 9-membered optionally tuted cycloalkyl or a 3— to 9—membered optionally substituted heterocyclo; R26b is hydrogen; and X and Y are NH, or a pharmaceutically acceptable salt thereof.

XXXIV. The nd of any one of particular embodiments XXIX-XXXIII, wherein R3a and R3b are each independently C1-C10 alkyl.

XXXV. The nd of any one of particular embodiments XXIX-XXXHI, wherein R3a and R3b taken together form a 4- to 8—membered optionally tuted cycloalkyl or a 4- to 8-membered optionally substituted cyclo, or a pharmaceutically acceptable salt thereof.

[0261] XXXVI. The nd of particular embodiment XXXV, wherein R3a and R3b taken together form a 6—membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt thereof.

XXXVII. The compound of particular embodiment XXXVI, wherein R3a and R3b taken together form an optionally substituted piperidine or a tetrahydropyran.

XXXVIII. The nd of particular embodiment XXXV, wherein R3a and R3b taken together form a 4- to 8-membered optionally substituted cycloalkyl, or a pharmaceutically acceptable salt thereof 2012/037570 XXXIX. The compound of particular embodiment XXXVIII, wherein R3a and R3b are taken er to form an unsubstituted utyl, cyclopentyl, cyclohexyl, or cycloheptyl ring, or a pharmaceutically acceptable salt thereof.

[0265] XL. The compound of any one of particular embodiments XXIX—XXXIX, n: R1a and R1d are each hydrogen; R1b is selected from the group consisting of hydrogen and ﬂuoro; and R1c is selected from the group consisting of ﬂuoro and chloro; or a pharmaceutically acceptable salt thereof.

XLI. The compound of any one of particular embodiments L, wherein R2 is optionally substituted aryl haVing Formula R2-l: R25d R25c R25e R25b 3‘ R258 R2_1 wherein R253, RZSb, R256, RZSd, and R256 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, , alkyl, or haloalkyl, or a pharmaceutically acceptable salt thereof.

XLII. The compound of any one of particular embodiments XXIX-XL, wherein R2 is optionally substituted pyridyl, or a pharmaceutically acceptable salt f.

XLIII. The compound of particular embodiment XXIX haVing Formula XXVI XXVI or a pharmaceutically acceptable salt thereof

[0269] XLIV. The compound of particular embodiment XLIII haVing Formula XXVII: XXVII or a pharmaceutically acceptable salt thereof.

XLV. The compound of particular embodiment XLIII having Formula XXVIII: XXVIII, or a pharmaceutically acceptable salt thereof.

XLVI. The compound of any one of particular embodiments XXIX-XLV, wherein R260 is optionally substituted alkyl, or a pharmaceutically acceptable salt thereof.

[0272] XLVII.The compound of ular embodiment XLVI, wherein the optionally substituted alkyl is tuted with an optionally tuted cycloalkyl, or a pharmaceutically acceptable salt thereof XLVIII. The compound of particular embodiment XLVI, wherein the optionally tuted alkyl is tuted with an optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof.

XLIX. The compound of any one of claims XXIX-XLV, wherein R26c is aralkyl, or a pharmaceutically acceptable salt f.

L. The compound of any one of particular embodiments XXIX—XLV, wherein R26c is optionally substituted cycloalkyl, or a pharmaceutically acceptable salt thereof L1. The compound particular embodiment L, n R is hydroxycycloalkyl, or a pharmaceutically acceptable salt thereof.

LII. The compound of particular embodiment L, wherein the ally substituted cycloalkyl is substituted with at least one —COZH, or a pharmaceutically acceptable salt thereof.

L1H. The compound of particular embodiment L, wherein R26c is selected from the group consisting of: UH.I IOH H360 H3C if}; 3 g .6 03 EOH IIIOH OH ’ CH3 CH3 s f s COZH 2 H3C H3C RD 3 9“ h ECOZH W1 I COZH I 'COZH COZH 5H3 or a pharmaceutically able salt thereof.

LIV. The compound of any one of particular embodiment XXIX-XLV, wherein R26c is optionally substituted heterocyclo, or a pharmaceutically acceptable salt f.

LV. The compound of any one of particular embodiment LV, wherein R26c is optionally substituted aryl, or a pharmaceutically acceptable salt thereof.

LVI. The compound of particular embodiment LV wherein R26c1s' ally substituted phenyl, or a pharmaceutically acceptable salt thereof LVII. The compound of particular embodiment LVI, n the optionally substituted phenyl is substituted with at least one -COZH, or a pharmaceutically acceptable salt thereof.

LVIII. The compound of any one of particular embodiments XXIX-XLV, wherein R26c is optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof.

LIX. The compound of particular embodiment LVIII, wherein R26c is optionally substituted pyridyl, or a ceutically acceptable salt f.

LX. A compound selected from the group consisting of: CO HN 0V S\ WO 55066 WO 55066 or a pharmaceutically acceptable salt thereof.

LX1. A nd selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

LX11. The compound of particular embodiment XXIX, wherein E is -OR26a, or a pharmaceutically acceptable salt thereof.

LX111. The compound of particular embodiment LX11, wherein R26a is en, or a pharmaceutically acceptable salt thereof.

LXIV. A pharmaceutical composition comprising the compound of any one of particular embodiments XXIX-LXI, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable r.

LXV. A method of treating a patient sing administering to the patient a therapeutically effective amount of the compound of any one of ular embodiments XXIX-LXI, or a pharmaceutically acceptable salt thereof, wherein the patient has a hyperproliferative e.

LXVI. The method of particular embodiment LXV, wherein the hyperproliferative disease is cancer.

[0292] The method of particular embodiment LXVI, wherein the cancer is selected from the group consisting of melanoma, lung cancer, sarcoma, colon cancer, prostate cancer, carcinoma, breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymphoma, multiple myeloma, and leukemia.

[0293] LXVHI. The method of particular embodiment LXVH, wherein the cancer is selected from the group consisting of liposarcoma and melanoma.

LXIX. A kit comprising a compound of any one of particular embodiments XI, or a pharmaceutically able salt, thereof, and instructions for administering the compound to a t haVing a hyperproliferative disease.

LXX. The kit of particular embodiment LXIX, wherein the hyperproliferative disease is cancer.

LXXI. A method of preparing a compound haVing Formula XVI: comprising: a) allowing a compound of particular embodiment XXXI to isomerize; b) isolating the compound haVing Formula XVI substantially free from the compound of claim 3, WO 55066 wherein X and Y are NH.

The method of particular embodiment LXXI, wherein E is -OR26a.

LXXIII. The method of particular embodiment LXXI, wherein E is _NR26bR26c

[0299] LXXIV. The method of any one of particular ments XXIH, wherein R3a and R3b taken together form a 3— to ered optionally substituted cycloalkyl.

The compounds provided herein will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds ed herein may be prepared. Starting materials can be obtained from commercial sources or prepared by well—established literature methods known to those of ordinary skill in the art. It will be readily apparent to one of ordinary skill in the art that the compounds deﬁned above can be synthesized by substitution of the appropriate reagents and agents in the syntheses shown below.

[0301] Compounds of Formula 111 wherein Y is NH and E is -NR26CR26c can be synthesized as described in Schemes 2 and 3.

Scheme 2 Rlb / + R33 0 AR3b 4-0;:j—>Molecular Sieve 4APhMe reflux 12 h R10 X R‘ld HNRZGbR266 CAN 2.5 equiv —. THF/HZO THF, rt, 12h or Pb(OAc)4 Formula ”I (wherein Y is NH and E is NRZGDRZGC) Scheme 3 Molecular Sieve 4A R“) / + R3a 0%R3b + r ‘R O PhMe. reflux, 12 h COZtBu R1 C x R‘ld HNRzeszec DC HCI |2 —» —’ iPr2NEt NBS, THF/HZO R = hydrogen, p—OMeBn-, Bn-, Me- or other alkyl group or DDQ, THF/HZO (when R not H) Formula lll (wherein Y is NH and E is NRZGbRZGC) Compounds of a 111 can be separated by chiral resolution s well known in the art, e. g., chiral column chromatography, to give compounds of Formulae VI-XXI. Suitable chiral columns for use in chiral resolutions e, for example, Daicel CHIRALCEL® OD—H, Daicel CHIRAKPAK® AD—H and Regis Technologies ULMO chiral columns. Other chiral resolution methods are also possible. Compounds of Formulae VI—XXI can also be prepared by asymmetric synthetic methods. For e, compounds of Formula VI, wherein Y is NH and E is NR26bRZ6c, can be synthesized by using a asymmetric 1,3—dipolar cycloaddition as the key step as previously described (See US. Patent Nos. 7,759,383 B2 and 7,737,174 B2, and Ding et al., J. Am. Chem. Soc. [27:10130—10131 (2005)). Compounds of Formula VI can undergo isomerization in solution to give compounds of Formula XVI.

Scheme 4 MeO OMe R3a><R3b +R1b / R3aJLR3b O R10 X NRZGbRZGC O§_/ 1 OH 2 '- CAN HNRzeszec N/R3\b(Ph R“, CH3CN/H20 R10 X/— Formula VI (wherein Y is NH) O§/NR26bR26c R2 ‘: R13 NH ,.n\\ R3b ngement w' R33 _, 0 R10 X a XVI (wherein Y is NH) Without intending to be bound by theory, the isomerization of Formula VI to Formula XVI may involve formation of the imine intermediate shown in Scheme 5. Compounds of Formula XVI may be less likely to isomerize, i.e., they may be chemically more stable, than compounds of Formula VI. In addition, isolation and puriﬁcation of nds of Formula XVI may be improved When R3a and R3a are the same, e. g., R3a and R3b are methyl, R3a and R3b taken together form a cyclohexyl ring, e the 2' position of the pyrrolidine ring is not an asymmetric center, and the number of possible ization products of Formula V1 is reduced. General methods to prepare compounds provided in the present disclosure are shown in Schemes 4—8.

Scheme 5 isomerization Formula XVI F0m“ a1 VI \ (wherein Y = NH) (wherein Y = NH) 1:1 CH3CN: H20, CAN RT, 30 min Formula Vl O ZGC (E is -OH) AGE in 1:1 DCM, EDCI __ MeOH:H20 HOBt, DIEA —> —> 2 d HNstszsc RT overnight Formula XVI Formula XVI (E is -OH) (E is _NR26bR260) Scheme 7 2 O R13 NH + IO methanol, \ RZJ —>.. * . Rra plperldlne HN R1b R1d overnight R1° Rlb Rld 0 Ph R}:\/ ' Ph 101 R131 R26°NH2, THF Toluene:THF R1 ’ reflux, overnight reflux, 3h R” N N_R26c o H R2 ’ \\(/N_R26c 1 R2 CAN, 1:1 Ria NH AGE, 1:1 Rla NH —> —> R1b 1b H20 R , " MeOH/HZO w- ml“ 10% TFA 0 R’lC ” R“; N R’ld R’Id Formula XXVll Formula XXVlll H2804 conc. CAN, 1:1 —> —> MeOH 50°C CH3CN/HZO ’ 15 min R26°NH2, LiOH.H20 Amide coupling —> —> 1:1THF/H20 R1C conditions Formula XXVIII Methods The present disclosure contemplates that exposure of animals suffering from cancer to therapeutically ive amounts of drug(s) (e.g., small molecules) that se the function(s) of p53 and p53—related proteins (e.g., p63, p73) inhibits the growth of cancer cells or ting cells. The compounds provided herein t the interaction between p53 or p53-related proteins and MDM2 or MDM2-related proteins (e.g., MDMX). Inhibiting the interaction between p53 or lated proteins and MDM2 or MDM2—related ns inhibits the growth of cancer cells or supporting cells and/or s such cells as a population more susceptible to the cell death-inducing activity of cancer eutic drugs or radiation therapies. In one embodiment, the inhibitors provided herein prolong the half-life of p53 by interfering with the p53-MDM2 ction that would normally promote degradation of p53. The compounds provided herein satisfy an unmet need for the ent of multiple cancer types, either when administered as monotherapy to induce senescence, cell growth inhibition, apoptosis and/or cell cycle arrest in cancer cells, or when administered in a temporal relationship with additional agent(s), such as other cell death—inducing or cell cycle disrupting cancer therapeutic drugs or radiation therapies (combination therapies), so as to render a r proportion of the cancer cells or supportive cells susceptible to executing the apoptosis program compared to the corresponding proportion of cells in an animal d only with the cancer therapeutic drug or radiation therapy alone.

In one embodiment, treatment of patients with a eutically effective amount of one or more compounds having Formulae I-XXVIII and one or more anticancer agents produces a greater anti-tumor activity and clinical benefit in such patients compared to those treated with the compound or anticancer drugs/radiation alone. Put another way, e the compounds provided herein can lower the apoptotic threshold of cells that express p53 or p53—related protein, the proportion of cells that successfully execute the apoptosis program in response to the apoptosis inducing activity of anticancer drugs/radiation will be increased when used in combination with one or more of the compounds provided herein. Alternatively, compounds having Formulae I-XXVIII can be used to allow administration of a lower, and therefore less toxic and more tolerable, dose of an anticancer drug and/or radiation to e the same tumor response/clinical benefit as the conventional dose of the anticancer drug/radiation alone. Since the doses for approved anticancer drugs and radiation treatments are known, the compounds, compositions, and methods provided herein can be used with one or more approved anticancer drugs and/or radiation treatment. Also, since compounds having Formulae I-XXVIII may act, at least in part, by stimulating the pro-apoptotic and/or cell cycle-inhibiting ties of p53 and p53—related proteins, the exposure of cancer cells and supporting cells to therapeutically effective amounts of these compounds can be ally linked to coincide with the attempts of cells to execute the sis program in response to the anticancer drug or ion y. Thus, in one embodiment, administering the compounds or pharmaceutical compositions provided herein in combination with other known anticancer drugs provides especially eff1cacious therapeutic practices.

In one embodiment, the tors of the interaction between p53 or p53— related proteins and MDM2 and MDM2-related proteins having Formulae I-XXVIII may protect normal (e.g., non-hyperproliferative) cells from the toxic effects of certain chemotherapeutic agents and radiation, possibly through the ability of the inhibitors to induce cell cycle arrest of normal cells.

For example, the inhibitors provided herein may cause cell cycle arrest in cells comprising wild-type or functional p53 (and/or wild-type or functional p53- related ns) while having no or less effect on cancer cells comprising mutated, deleted, or otherwise non— or less functional p53 (and/or mutated, deleted, or otherwise non—or less functional p53—related proteins). This differential protective effect may allow for more effective treatment of cancer by allowing the use of higher doses or longer treatments of chemotherapeutic agents or treatments t increasing the toxic side effects of such treatment when administered in combination with inhibitors provided herein.

[0307] Also provided herein are methods of using nds having Formulae I-XXVIII for izing cells to additional agent(s), such as inducers of ence, apoptosis and/or cell cycle arrest. Compounds having Formulae I-XXVIII can also be used to provide chemoprotection of normal cells through the induction of cell cycle arrest prior to treatment with chemotherapeutic . In one ment, methods of rendering a normal cell resistant to chemotherapeutic agents or treatments ses contacting the cell with one or more compounds having Formulae I-XXVIII are provided. In another embodiment, methods of protecting normal cells in an animal having a hyperproliferative disease from the toxic side effects of chemotherapeutic agents or treatments, comprises administering to the animal a compound having Formulae I-XXVIII are provided. Also provided herein are methods for the treatment, amelioration, or prevention of disorders, side effects, or conditions caused by the administration of chemotherapeutic agents to normal cells comprising administering to an animal undergoing chemotherapy a compound having Formulae I-XXVIII. Examples of such disorders and conditions caused by chemotherapy include, t limitation, mucositis, stomatitis, xerostomia, gastrointestinal disorders, and ia.

[0308] Compounds having ae I-XXVIII are useful for the treatment, amelioration, or prevention of ers, such as those sive to induction of apoptotic cell death, e.g., disorders characterized by dysregulation of apoptosis, including hyperproliferative diseases such as cancer. In one embodiment, these compounds can be used to treat, ameliorate, or prevent cancer that is characterized by resistance to cancer therapies (e.g., those cancer cells which are esistant, radiation resistant, hormone resistant, and the like). In r embodiment, these compounds can be used to treat hyperproliferative diseases characterized by expression of functional p53 or p53-related proteins. In another embodiment, these compounds can be used to protect normal (e.g., non-hyperproliferative) cells from the toxic side effects of chemotherapeutic agents and treatments by the induction of cell cycle arrest in those cells.

In one embodiment, compounds having Formulae II induce cell cycle arrest and/or apoptosis and also potentiate the ion of cell cycle arrest and/or apoptosis either alone or in response to onal apoptosis induction signals. Therefore, it is contemplated that these compounds ize cells to induction of cell cycle arrest and/or apoptosis, including cells that are resistant to such inducing stimuli. By inhibiting the interaction between p53 or lated proteins and MDM2 or MDM2-realted proteins, these compounds can be used to induce apoptosis in any disorder that can be treated, ameliorated, or prevented by the ion of apoptosis. In one embodiment, compounds having Formulae I-XXVIII can be used to induce apoptosis in cells comprising functional p53 or p53—related proteins.

In another embodiment, the disclosure pertains to modulating apoptosis with compounds having Formulae I-XXVIII in combination with one or more additional apoptosis-modulating agents, e.g., anticancer agents. Examples of apoptosis-modulating agents include, but are not limited to, Fas/CD95, TRAMP, TNF RI, DRl, DR2, DR3, DR4, DR5, DR6, FADD, RIP, TNFq, Fas ligand, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2, Bel-2, p53, BAX, BAD, Akt, CAD, PI3 kinase, PPl, and caspase proteins. Other agents involved in the initiation, decision and degradation phase of apoptosis are also included.

Examples of sis-modulating agents include agents, the activity, presence, or change in concentration of which, can modulate apoptosis in a subject.

Apoptosis—modulating agents include those which are inducers of apoptosis, such as TNF or a TNF-related ligand, particularly a TRAMP ligand, a Fas/CD95 ligand, a TNFR-l ligand, or TRAIL.

In one embodiment, the compounds, compositions, and methods provided herein are used to treat ed cells, s, organs, or pathological conditions and/or disease states in an animal (e.g., a ian patient including, but not limited to, humans and veterinary animals). In this , various diseases and pathologies are amenable to treatment or prophylaxis using the present methods and itions. A non-limiting exemplary list of these diseases and conditions includes, but is not d to, breast cancer, prostate , lymphoma, skin cancer, pancreatic cancer, colon cancer, ma, malignant melanoma, ovarian cancer, brain , primary brain carcinoma, head—neck cancer, glioma, glioblastoma, liver , bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, le myeloma, adrenal carcinoma, renal cell oma, endometrial carcinoma, adrenal cortex carcinoma, malignant atic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, ia, acute lymphocytic ia, c lymphocytic leukemia (CLL) including B-CLL, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute ocytic ia, hairy cell leukemia, neuroblastoma, sarcoma such as liposarcoma malignant ﬁbrous histiocytoma, arcoma, Ewing’s sarcoma, leiomyosarcoma, and rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non—Hodgkin's lymphoma, soft-tissue sarcomas such as lipoma, and malignant noma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma, and the like, T and B cell mediated autoimmune diseases; inﬂammatory diseases; infections; hyperproliferative diseases; AIDS; degenerative conditions, vascular diseases, and the like. In one embodiment, the cancer cells being treated are metastatic. In another embodiment, the cancer cells being treated are resistant to other anticancer .

In one embodiment, the nds, compositions, and methods provided herein are used to treat cancers that express functional or wild type p53 or p53—related ns. In one embodiment, the compounds, compositions, and methods provided herein are used to treat cancers that s elevated levels of MDM2 or MDM2-related proteins.

In one embodiment, the compounds, compositions, and methods provided herein can be used to treat a patient having a sarcoma, including, for example, liposarcoma, malignant fibrous histiocytoma, osteosarcoma, and rhabdomyosarcoma. In another embodiment, the compounds, compositions, and methods provided herein can be used to treat a patient having a soft tissue tumor, including, for example, Ewing’s sarcoma, leiomyosarcoma, lipoma, and malignant Schwannomas. In another embodiment, the compounds, compositions, and methods provided herein can be used to treat a patient having lung, breast, liver, or colon cancer. In another embodiment, the compounds, compositions, and methods provided herein can be used to treat a patient having B-cell chronic lymphocytic leukemia and acute myeloid leukemia.

In one embodiment, the compounds, compositions, and methods ed here can be used to treat a t having melanoma, lung cancer, sarcoma, colon cancer, prostate , carcinoma, breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, ma, multiple a, or leukemia.

In one embodiment, the compounds, compositions, and methods provided here can be used to treat a patient having liposarcoma or melanoma.

In one embodiment, infections suitable for treatment with the compounds, compositions, and methods ed herein include, but are not limited to, infections caused by viruses, bacteria, fungi, mycoplasma, prions, and the like.

A further aspect of the present disclosure is to provide the use of a compound having any one of Formulae I-XXVIII for the manufacture of a medicament for treating a hyperproliferative disease such as cancer. In one embodiment, the medicament is to be administered with one or more additional agents.

A further aspect of the present sure is to provide a compound having any one of Formulae I-XXVIII, or a pharmaceutical composition sing a nd having any one of Formulae I-XXVIII, for use in treating a hyperproliferative disease such as cancer.

In one embodiment, methods are provided for administering an ive amount of a compound having Formulae I-XXVIII in combination with at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosis-modulating agents, antimicrobials, antivirals, antifungals, and anti-inﬂammatory agents) and/or eutic technique (e.g., surgical intervention, and/or radiotherapies). In one ment, the additional therapeutic agent(s) is an anticancer agent.

[0320] A number of suitable therapeutic or anticancer agents are contemplated for use in the methods provided . Indeed, the methods provided herein can include but are not limited to, administration of numerous therapeutic agents such as: agents that induce apoptosis; polynucleotides (e.g., anti—sense, ribozymes, siRNA); ptides (e.g., enzymes and dies); biological mimetics (e.g., gossypol or BH3 mimetics); agents that bind (e.g., erize or complex) with a Bcl-2 family protein such as Bax; alkaloids; alkylating agents; antitumor otics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins), toxins; radionuclides; biological response ers (e.g., interferons (e.g., IFN—(x) and interleukins (e.g., IL-2)); ve immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid); gene therapy reagents (e.g., antisense therapy reagents and nucleotides); tumor vaccines; enesis inhibitors; proteosome inhibitors: NF-KB modulators; anti-CDK compounds; HDAC inhibitors; and the like.

Numerous other examples of eutic agents such as chemotherapeutic compounds and anticancer therapies suitable for co-administration with the disclosed compounds are known to those skilled in the art.

[0321] In one embodiment, anticancer agents comprise agents that induce or stimulate apoptosis. Agents that induce or ate apoptosis include, for e, agents that interact with or modify DNA, such as by intercalating, cross-linking, alkylating, or otherwise ng or chemically modifying DNA.

Agents that induce apoptosis include, but are not limited to, radiation (e. g., X- rays, gamma rays, UV); tumor necrosis factor (TNF)-related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2); kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitor. Additional ncer agents include: ar growth factor receptor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) kinase inhibitor, platelet-derived growth factor receptor (PDGFR) kinase inhibitor, and Bcr-Abl kinase inhibitors (such as GLEEVEC)); antisense molecules; antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN, and AVASTIN); anti-estrogens (e. g., fene and tamoxifen); anti-androgens (e. g., flutamide, bicalutamide, f1nasteride, aminoglutethamide, nazole, and corticosteroids); cyclooxygenase 2 ) tors (e.g., celecoxib, meloxicam, NS-398, and non-steroidal anti-inﬂammatory drugs (NSAIDs)); anti- inflammatory drugs (e.g., butazolidin, DECADRON, DELTASONE, dexamethasone, dexamethasone intensol, DEXONE, HEXADROL, hydroxychloroquine, METICORTEN, ORADEXON, ORASONE, oxyphenbutazone, RED, phenylbutazone, PLAQUENIL, prednisolone, prednisone, PRELONE, and TANDEARIL); and cancer chemotherapeutic drugs (e.g., irinotecan (CAMPTOSAR), CPT-ll, fludarabine RA), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP-l6, cisplatin, carboplatin, latin, 5-FU, doxorubicin, gemcitabine, bortezomib, gef1tinib, bevacizumab, TAXOTERE or TAXOL); cellular signaling molecules; des and cytokines; staurosporine, and the like.

In one embodiment, the compositions and methods provided herein include one or more compounds provided herein and at least one WO 55066 yperproliferative or anticancer agent, e.g., alkylating agents, antimetabolites, and natural ts (e. g., herbs and other plant and/or animal derived compounds).

Alkylating agents suitable for use in the present compositions and methods include, but are not limited to: l) nitrogen ds (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan colysin); and chlorambucil); 2) ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa); 3) alkyl sulfonates (e.g., busulfan); 4) nitrosoureas (e.g., carmustine (BCNU); lomustine (CCNU); semustine (methyl— CCNU); and streptozocin (streptozotocin)); and 5) triazenes (e.g., dacarbazine (DTIC; dimethyltriazenoimid-azolecarboxamide).

In one embodiment, antimetabolites suitable for use in the present compositions and s include, but are not limited to: l) folic acid analogs (e. g., methotrexate opterin)); 2) pyrimidine analogs (e.g., ﬂuorouracil (5- ﬂuorouracil; 5-FU), ﬂoxuridine de-oxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (e.g., mercaptopurine (6— topurine; 6-MP), thioguanine (6-thioguanine; TG), and pentostatin (2’- deoxycoformycin)).

In one embodiment, chemotherapeutic agents suitable for use in the present compositions and methods include, but are not limited to: l) vinca alkaloids (e.g., vinblastine (VLB), vincristine); 2) epipodophyllotoxins (e.g., etoposide and side); 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)); 4) enzymes (e.g., L— asparaginase); 5) biological response modiﬁers (e.g., interferon-alfa); 6) platinum coordinating complexes (e.g., cisplatin (cis-DDP) and carboplatin); 7) anthracenediones (e.g., ntrone); 8) substituted ureas (e.g., hydroxyurea); 9) methylhydrazine derivatives (e.g., procarbazine hylhydrazine; MIH)); 10) adrenocortical suppressants (e. g., mitotane (o,p’—DDD) and aminoglutethimide); ll) adrenocorticosteroids (e.g., sone); 12) progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and rol acetate); 13) estrogens (e.g., diethylstilbestrol and ethinyl estradiol); l4) antiestrogens (e. g., tamoxifen); 15) androgens (e. g., testosterone propionate and WO 55066 ﬂuoxymesterone); 16) antiandrogens (e.g., ﬂutamide): and 17) tropinreleasing hormone analogs (e.g., leuprolide).

Any ncer agent that is routinely used in a cancer therapy context ﬁnds use in the compositions and methods of the present disclosure. For example, the US. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. International counterpart agencies to the U.S.F.D.A. maintain similar formularies. Table 1 provides a list of exemplary antineoplastic agents approved for use in the US. Those skilled in the art will iate that the “product labels” required on all US. approved chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents.

Table l eukin Proleukin des-alan l-l, serine-125 human interleukin-2 Alemtuzumab Campath I_G1K anti CD52 antibod Alitretinoin in 9-cis-retinoic acid Allopurinol Zyloprim (l,5-dihydro-4 H -pyrazolo[3,4-d]pyrimidinone monosodium salt) Altretamine Hexalen (N,N,N',N',N",N",- hexamethyl-l,3,5-triazine-2, 4, 6-triamine) tine Ethyol (ethanethiol, 2-[(3-aminopropyl)amino]—, dihydrogen phosphate (6ster)) Anastrozole Arimidex (1,3 -Benzenediacetonitrile, a, a, a', a'-tetramethyl-5 -( l H- l ,2,4- triazol- l -ylmethyl)) c trioxide Trisenox ginase Elspar L-asara_ine amidoh drolase,t e EC-Z BCG Live TICE BCG (lyophilized preparation of an attenuated strain ofMycobacterium bovis (Bacillus te-Gukz'n [BCG], substrain Montreal) bexarotene capsules Targretin (4-[ l -(5,6,7,8-tetrahydro-3 ,5 ,5 entamethylnapthalenyl) ethenyl] benzoic acid) bexarotene gel Targretin Bleomycin Blenoxane (cytotoxic glycopeptide antibiotics produced by Streptomyces verticz'llus; bleomycin A2 and cin B2) Capecitabine Xeloda (5'-deoxyﬂuoro-N-[(pentyloxy)carbonyl] -cytidine) Carboplatin Paraplatin (platinum, diammine [l,l-cyclobutanedicarboxylato(2-)-0, 0']—,(SP- 4-2)) BCNU, BiCNU 1,3-bis Z-chloroeth l nitrosourea Carmustine with Poliferosan 20 Imlant Gliadel Wafer Celecoxib CelebreX (as 4-[5 -(4-methylphenyl) (triﬂuoromethyl)-1H-pyrazolyl] benzenesulfonamide) Chlorambucil Leukeran s(Zchlorethyl)amino]benzenebutanoic acid) Cisplatin ol éNz) Cladribine Leustatin, Z-CdA (2-chloro-2'-deoxy-b-D-adenosine) Cyclophosphamide Cytoxan, Neosar (2-[bis(2-chloroethyl)amino] tetrahydro-ZH-13 ,2-oxazaphosphorine 2-oxide monohydrate) bine Cytosar-U 1-b-D-Arabinofuranos lc osine, C9H13N3O5 c arabine liosomal De oC t Dacarbazine DTIC-Dome - 3,3 h l-l-triazeno zolecarboxamide DTIC Dactinomycin, actinomycin D Cosmegen omycin produced by Streptomyces parvullus, C62H86N12016) Darbepoetin alfa Aranesp (recombinant peptide) daunorubicin liposomal DanuoXome ((8S-cis)—8-acetyl[(3 -amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,1 1-trihydroxy methoxy-5,12-naphthacenedione hydrochloride) Daunorubicin HCl, daunomycin Cerubidine ((1 S ,3 S )-3 -Acetyl-1,2,3 1-hexahydro-3,5,12-trihydroxy methoxy-6,1 1-dioxonaphthacenyl 3-amino-2,3 ,6-trideoxy-(alpha)- L- Zyxo -hexopyranoside hydrochloride) Denileukin diftitox Ontak recombinant e tide oxane Zinecard o i o erazinedione Docetaxel Taxotere ((2R,3 S)-N-carboxy-3 -phenylisoserine, N—tert-butyl ester, 13 -ester with 5bepoxy-12a,4,7b,10b,13a-hexahydroxytax- 1 1-enone 4- acetate oate, trihydrate) Doxorubicin HCl Adriamycin, Rubex (8S,10S)—10-[(3-amino-2,3 ,6-trideoxy-a—L-lyxo-hexopyranosyl)oxy] glycolyl-7,8,9,10-tetrahydro-6,8, 1 1- trihydroxymethoxy-5 , 12- naphthacenedione hydrochloride) doxorubicin ycin PFS Intravenous injection doxorubicin liposomal Doxil dromostanolone propionate Dromostanolone (17b-Hydroxy-2a-methyl-5a-androstanone propionate) dromostanolone propionate Masterone injection Elliott's B Solution Elliott's B on Epirubicin Ellence ((8S-cis)[(3-amino-2,3,6-trideoxy-a-L-arabino- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,1 1-trihydroxy h drox acet l methox -5,12-nahthacenedione h drochloride Epoetin alfa recombinant e tide Estramustine (estra-l,3,5(10)-triene-3,l7-diol(l7(beta))-, 3-[bis(2- chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate, or estradiol 3-[bis(2-chloroethyl)carbamate] l7- (dihydrogen phosphate), disodium salt, monohydrate) Etoposide phosphate Etopophos (4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-(beta)-D- glucopyranoside], 4'-(dihydrogen phosphate)) etoposide, VP- 1 6 Vepesid (4'-demethylepipodophyllotoxin 9-[4,6(R)—ethylidene-(beta)-D- glucopyranoside]) Exemestane Aromasin 6-meth lenandrosta-l,4-diene-3, l7-dione Filgrastim Neupogen r-metHuG-CSF ﬂoxuridine (intraarterial) FUDR 2'-deox ﬂuorouridine Fludarabine Fludara (ﬂuorinated nucleotide analog of the antiviral agent Vidarabine, 9-b - D-arabinofuranosyladenine (ara-A)) Fluorouracil, 5-FU Adrucil (5-ﬂuoro-2,4(lH,3H)-pyrimidinedione) Fulvestrant Faslodex (7-alpha-[9-(4,4,5,5,5 -penta ﬂuoropentylsulphinyl) nonyl]estra- l ,3 ,5 - (10)- triene-3 , l 7-beta-diol) Gemcitabine Gemzar (2'-deoxy-2', 2'-diﬂuorocytidine monohydrochloride (b-isomer)) Gemtuzumab Ozogamicin Mylotarg CD33 hP67.6) lin acetate Zoladex Implant Hydroxyurea Hydrea Ibritumomab Tiuxetan Zevalin (immunoconjugate resulting from a ea covalent bond between the monoclonal antibody Ibritumomab and the -chelator tiuxetan [N-[Z-bis(carboxymethyl)amino](p- isothiocyanatophenyl)- propyl]-[N-[2-bis(carboxymethyl)amino] (methyl) -ethyl]glycine) Idarubicin Idamycin (5, hthacenedione, yl[(3-amino-2,3,6-trideoxy- (alpha)-L- lyxo -hexopyranosyl)oxy]-7,8,9, l 0-tetrahydro-6,9,l l- trihydroxyhydrochloride, (7S- cis )) Ifosfamide (3 -(2-chloroethyl)[(2-chloroethyl)amino]tetrahydro-2H- 1 ,3 ,2- oxazaphosphorine 2-oxide) Imatinib Mesilate (4-[(4-Methyl- l -piperazinyl)methyl] -N-[4-methyl-3 3 - nyl)pyrimidinyl]amino]—phenyl]benzamide methanesulfonate) Interferon alfa-Za n-A recombinant e tide Interferon b Intron A (Lyophilized recombinant e tide Betaseron Irinotecan HCl sar ((4S)—4,l l-diethylhydroxy[(4- - dinopiperidino)carbonyloxy]-lH-pyrano[3', 4': 6,7] indolizino[l,2-b] quinoline-3,l4(4H, 12H) dione hydrochloride trihydrate) Letrozole Femara (4,4'-( l H- l ,2,4 -Triazol- l -ylmethylene) dibenzonitrile) orin Wellcovorin, WO 55066 (L-Glutamic acid, N[4[[(2aminoformyll,4,5,6,7,8 hexahydro4oxo- Leucovorin 6-pteridinyl)methyl]amino]benzoyl], calcium salt (1:1)) Levamisole HCl Ergamisol ((-)-( S)—2,3,5, 6-tetrahydrophenylimidazo [2,1-b] thiazole monohydrochloride C11H12N2S - HCl) Lomustine CeeNU (1 loro-ethyl)-3 -cyclohexylnitrosourea) rethamine, nitrogen mustard Mustargen (2-chloro-N—(2-chloroethyl)-N-methylethanamine hydrochloride) Vlegestrol acetate Megace - 6- meth lre_na- 4,6- diene- 3,20- dione Vlelphalan, L-PAM Alkeran 4- bis Z-chloroeth 1 amino -L-hen lalanine Vlercaptopurine, 6-MP Purinethol 1,7-dih dro-6 H -urinethione monoh drate Vlesna MesneX sodium Z-mercatoethane sulfonate Vlethotrexate Methotrexate (N-[4-[[(2,4-diaminopteridinyl)methyl]methylamino]benzoyl] -L- glutamic acid) Vlethoxsalen Uvadex (9-methoxy-7H-furo[3,2-g][1]-benzopyranone) Vlitomycin C Mutamycin mitomycin C Mitozytrex ane en (1 , loro(o-chlorophenyl)(p-chlorophenyl) ethane) Vlitoxantrone rone (1 ,4-dihydroxy-5 ,8-bis[[2- [(2-hydroxyethyl)amino]ethyl] amino] - 9,10-anthracenedione dihydrochloride) —\Iandrolone phenpropionate Durabolin-50 —\Iofetumomab Verluma Oprelvekin Neumega IL-1 1 Oxaliplatin Eloxatin (cis-[(1R,2R)—1,2-cycloheXanediamine-N,N’] [oxalato(2-)-0,0 ’] platinum) Paclitaxel (SB, 20-Epoxy-1,2a, 4,78, 108, 13a-hexahydroxytaXenone iacetate 2- benzoate 13-ester with (2R, 3 S)— oyl phenylisoserine) Pamidronate Aredia (phosphonic acid (3 -aminohydroxypropylidene) bis-, disodium salt, pentahydrate, (APD)) Pegademase Adagen (Pegademase ((monomethoxypolyethylene glycol succinimidyl) 11 adenosine Bovine) deaminase) Pegaspargase Oncaspar (monomethoxypolyethylene glycol succinimidyl L-asparaginase) Pegﬁlgrastim Neulasta ent conjugate of recombinant nyl human G-CSF (Filgrastim) and monomethoxypolyethylene glycol) Pentostatin Nipent Pipobroman Vercyte Plicam cin, Mithram cin Mithracin antibiotic oroducedb Slretom ces licatus Porﬁmer sodium Photofrin Procarbazine Matulane (N-isopropyl-u-(Z-methylhydrazino)-p-toluamide drochloride) Quinacrine Atabrine (6-chloro( 1 emethyldiethyl-amine) butylamino-Z- methoxyacridine) Rasburicase Elitek (recombinant peptide) Rituximab n recombinant D20 antibod Sargramostim Prokine recombinant e tide Streptozocin Zanosar (streptozocin 2 ﬂeoxy [[(methylnitrosoamino)carbonyl]amino] - - D - _luco ranose and 220 m ; citric acid anh drous Talc Sclerosol (Mg3Si4010 (OH)2) Tamoxifen Nolvadex ((Z)2-[4-(1,2-diphenyl-1 -butenyl) phenoxy]—N, N- dimethylethanamine Z-hydroxy- 1 ,2,3 - propanetricarboxylate (1 : 1 )) Temozolomide Temodar (3 ydro-3 -methyloxoimidazo [5 , 1 -d] -as-tetrazine carboxamide) teniposide, VM-26 methylepipodophyllotoxin 9- [4,6(R)—2- thenylidene-(beta)- D-glucopyranoside]) Testolactone Teslac (13-hydroxy-3 -oxo-13 ,17-secoandrosta-1,4-dienoic acid [dgr ]- lactone) Thioguanine, 6-TG Thioguanine 2-amino-1,7-dih dro-6 H - urinethione Thiotepa Thioplex (Aziridine, "-phosphinothioylidynetris-, or Tris (1 -aziridinyl) phosphine ) can HCl Hycamtin ((S)[(dimethylamino) methyl] ethyl-4,9-dihydroxy- 1 H- pyrano [3 ', 4': 6,7] indolizino [1 ,Z-b] quinoline-3 ,14-(4H,12H)—dione monohydrochloride) Toremifene Fareston (2-(p-[(Z)chloro- 1 ,Z-diphenylbutenyl] -phenoxy)—N,N- dimethylethylamine citrate (1 :1)) Tositumomab, I 131 Tositumomab Bexxar (recombinant murine immunotherapeutic monoclonal IgG2a lambda Trastuzumab Herceptin recombinant monoclonal 1 _G1 ka a anti-HERZ antibod Tretinoin, ATRA Vesanoid (all-trans retinoic acid) Uracil Mustard Uracil Mustard Caosules icin, N-triﬂuoroacetyladriamycinValerate Valstar ((ZS-cis) [1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7 methoxy- 6,1 o-[[4 2,3,6-trideoxy [(triﬂuoroacetyl)-amino-ot-L-lyx0- hexopyranosyl]oxyl]naphthacenyl]oxoethyl pentanoate) Vinblastine, Leurocristine Velban 6N4010'H2SO4) stine Oncovin (C46H56N4010'H2SO4) Vinorelbine Navelbine (3' ,4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1 :2)(salt)]) Zoledronate, Zoledronic acid ((1 -Hydroxyimidazol-l -yl-phosphonoethyl) onic acid monohydrate) Anticancer agents further include compounds which have been identiﬁed to have anticancer activity. Examples include, but are not limited to, 3-AP, l2-O- tetradecanoylphorbol-l3-acetate, 17AAG, 852A, ABI-007, 7620, ABT- 751, ADI—PEG 20, , AG—013736, AGROlOO, alanosine, AMG 706, antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN—l6l, atrasenten, azacitidine, BB-10901, BCX-l777, bevacizumab, 1, bicalutamide, BMS 247550, bortezomib, bryostatin-l, buserelin, calcitriol, CCI—779, CDB—2914, ceﬁxime, cetuximab, CG0070, cilengitide, clofarabine, combretastatin A4 phosphate, CP—675,206, ,7l4, CpG 7909, curcumin, decitabine, DENSPM, doxercalciferol, E7070, E7389, ecteinascidin 743, efaproxiral, eﬂornithine, EKB-569, enzastaurin, erlotinib, exisulind, fenretinide, ﬂavopiridol, ﬂudarabine, ﬂutamide, fotemustine, FR901228, Gl7DT, mab, geﬁtinib, genistein, glufosfamide, GTI-2040, histrelin, HKI-272, homoharringtonine, HSPPC—96, hul4.l8-interleukin-2 fusion protein, HuMax- CD4, st, imiquimod, inﬂiximab, eukin-l2, IPI-504, irofulven, ilone, lapatinib, lenalidomide, lestaurtinib, leuprolide, LMB-9 immunotoxin, mib, luniliximab, amide, MB07133, MDX-010, MLN2704, monoclonal antibody 3F8, monoclonal antibody J59l, ﬁn, MS-275, MVA-MUCl-IL2, nilutamide, nitrocamptothecin, nolatrexed dihydrochloride, nolvadex, NS—9, O6—benzylguanine, oblimersen sodium, ONYX—015, oregovomab, OSI—774, panitumumab, paraplatin, 5901, pemetrexed, PHY906, pioglitazone, idone, pixantrone, PS-34l, PSC 833, PXD101, pyrazoloacridine, R115777, RAD001, ranpirnase, rebeccamycin analogue, rhuAngiostatin protein, rhuMab 2C4, rosiglitazone, rubitecan, S-l, S- 8184, satraplatin, SB-, 15992, SGN—0010, SGN—40, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, talabostat, WO 55066 talampanel, tariquidar, temsirolimus, TGFa-PE38 immunotoxin, thalidomide, thymalfasin, tipifarnib, tirapazamine, TLK286, trabectedin, trimetrexate onate, TroVax, UCN—l, valproic acid, vinﬂunine, VNP40101M, volociximab, vorinostat, VX-680, ZD1839, , zileuton, and zosuquidar trihydrochloride.

For a more detailed description of anticancer agents and other therapeutic agents, those skilled in the art are referred to any number of instructive s including, but not limited to, the Physician's Desk Reference and to n and Gilman's "Pharmaceutical Basis of Therapeutics" tenth edition, Eds.

Hardman et al., 2002.

In one embodiment, the methods provided herein comprise administering one or more compounds having Formulae I-XXVIII in combination with radiation therapy. The methods provided herein are not limited by the types, amounts, or delivery and administration systems used to deliver the therapeutic dose of radiation to an animal. For e, the animal may e photon radiotherapy, le beam radiation therapy, other types of radiotherapies, and combinations thereof. In one embodiment, the radiation is delivered to the animal using a linear accelerator. In another embodiment, the ion is delivered using a gamma knife.

[0330] The source of radiation can be external or al to the animal. External radiation y is most common and involves directing a beam of nergy radiation to a tumor site through the skin using, for instance, a linear accelerator.

While the beam of radiation is localized to the tumor site, it is nearly impossible to avoid exposure of normal, healthy tissue. However, external radiation is usually well tolerated by animals. Internal radiation therapy involves implanting a radiation—emitting source, such as beads, wires, pellets, capsules, particles, and the like, inside the body at or near the tumor site including the use of delivery systems that specifically target cancer cells (e.g., using particles attached to cancer cell binding ligands). Such implants can be removed ing treatment, or left in the body ve. Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmunotherapy, and the like.

The animal may optionally e radiosensitizers (e.g., idazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (IudR), nitroimidazole, 5-substitutednitroimidazoles, 2H-isoindolediones, [[(2— bromoethyl)-amino]methyl]-nitro-1H-imidazoleethanol, nitroaniline derivatives, DNA-affinic hypoxia selective cytotoxins, halogenated DNA ligand, 1,2,4 riazine oxides, 2-nitroimidazole derivatives, e-containing nitroazole derivatives, benzamide, nicotinamide, ne-intercalator, 5- thiotretrazole derivative, 3-nitro-1,2,4-triazole, 4,5-dinitroimidazole derivative, hydroxylated texaphrins, cisplatin, mitomycin, tiripazamine, nitrosourea, mercaptopurine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide, paclitaxel, heat (hyperthermia), and the like), radioprotectors (e. g., cysteamine, aminoalkyl dihydrogen phosphorothioates, amifostine (WR 2721), IL-1, IL-6, and the like). ensitizers enhance the killing of tumor cells. Radioprotectors protect healthy tissue from the harmful effects of radiation.

Any type of radiation can be administered to an animal, so long as the dose of radiation is ted by the animal without unacceptable negative side- effects. Suitable types of radiotherapy e, for example, ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) or particle beam radiation therapy (e. g., high linear energy radiation). Ionizing radiation is defined as radiation comprising particles or photons that have sufficient energy to produce ionization, i.e., gain or loss of electrons (as described in, for example, U.S. 5,770,581 incorporated herein by reference in its entirety). The s of ion can be at least partially controlled by the clinician. In one embodiment, the dose of radiation is fractionated for maximal target cell exposure and reduced toxicity.

In one embodiment, the total dose of ion stered to an animal is about .01 Gray (Gy) to about 100 Gy. In another embodiment, about 10 Gy to about 65 Gy (e.g., about 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy) are administered over the course of treatment. While in some embodiments a complete dose of ion can be administered over the course of one day, the total dose is ideally fractionated and administered over several days. Desirably, radiotherapy is administered over the course of at least about 3 days, e.g., at least 5, 7, 10, 14, 17, 21, 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1—8 weeks). ingly, a daily dose of radiation will comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy), or 1—2 Gy (e.g., 1.5—2 Gy).

The daily dose of radiation should be sufficient to induce destruction of the targeted cells. If stretched over a period, in one embodiment, radiation is not administered every day, thereby allowing the animal to rest and the effects of the therapy to be realized. For example, radiation bly is administered on 5 consecutive days, and not administered on 2 days, for each week of treatment, y allowing 2 days of rest per week. However, radiation can be administered 1 ek, 2 days/week, 3 days/week, 4 days/week, 5 days/week, 6 days/week, or all 7 days/week, depending on the animal’s responsiveness and any potential side effects. Radiation therapy can be initiated at any time in the therapeutic period. In one embodiment, ion is initiated in week 1 or week 2, and is administered for the remaining duration of the therapeutic period. For example, ion is administered in weeks 1-6 or in weeks 2-6 of a therapeutic period comprising 6 weeks for treating, for instance, a solid tumor. Alternatively, radiation is administered in weeks 1—5 or weeks 2—5 of a therapeutic period comprising 5 weeks. These exemplary radiotherapy administration schedules are not intended, however, to limit the methods provided herein.

Antimicrobial therapeutic agents may also be used as therapeutic agents in combination with the compounds having Formulae I-XXVIII. Any agent that can kill, inhibit, or otherwise attenuate the function of ial organisms may be used, as well as any agent contemplated to have such activities. Antimicrobial agents include, but are not limited to, l and synthetic antibiotics, antibodies, inhibitory proteins (e. g., ins), antisense nucleic acids, membrane tive agents and the like, used alone or in combination. Indeed, any type of otic may be used including, but not limited to, antibacterial agents, antiviral , antifungal agents, and the like.

[0335] In one embodiment of the methods provided herein, one or more compounds having Formulae I-XXVIII are administered to an animal in need thereof. In another embodiment of the methods provided herein, one or more compounds having ae I-XXVIII and one or more additional therapeutic agents or anticancer agents are administered to an animal in need thereof under one or more of the following conditions: at different periodicities, at different durations, at ent concentrations, by different administration routes, etc. In one embodiment, the compound having ae I-XXVIII is administered prior to the therapeutic or anticancer agent, e. g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of the therapeutic or anticancer agent. In another embodiment, the compound having Formulae I-XXVIII is administered after the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5,10,12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the anticancer agent. In another embodiment, the compound having Formulae I-XXVIII and the therapeutic or anticancer agent are administered concurrently but on ent schedules, e.g., the compound is administered daily while the therapeutic or anticancer agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In another embodiment, the compound is administered once a week while the therapeutic or anticancer agent is administered daily, once a week, once every two weeks, once every three weeks, or once every four weeks.

In one embodiment, a method of treating, preventing, or ameliorating cancer in a patient is provided, wherein the method ses pulsatile administration to the patient a therapeutically effective amount of a compound having Formulae I-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof In one ment, the pharmaceutical compositions provided herein comprise one or more nds having Formulae I-XXVIII in an amount which is ive to achieve its intended purpose. While dual needs vary, determination of optimal ranges of ive amounts of each ent is within the skill of the art. Typically, the nds may be administered to s, e. g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis. In one embodiment, about 0.01 to about 25 mg/kg is orally administered to treat, ameliorate, or prevent such disorders. For intramuscular injection, the dose is generally about one-half of the oral dose. For example, a WO 55066 suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, or from about 0.01 to about 5 mg/kg.

The unit oral dose may comprise from about 0.01 to about 1000 mg, for e, about 0.1 to about 100 mg of the compound. The unit dose may be stered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound or its es.

In a topical formulation, the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In a one embodiment, the compound is t at a concentration of about 0.07—l.0 mg/ml, for example, about 0.1—0.5 mg/ml, and in one embodiment, about 0.4 mg/ml.

In addition to administering the compound as a raw chemical, compounds having Formulae I-XXVIII may be administered as part of a pharmaceutical preparation or composition. In one ment, the pharmaceutical composition ses one or more pharmaceutically acceptable carriers, excipients, and/or aries. In another embodiment, the one or more carriers, excipients, and auxiliaries facilitate processing of the compound having Formulae I-XXVIII into a preparation which can be used pharmaceutically. The compositions, particularly those compositions which can be administered orally or topically and which can be used for one type of administration, such as s, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also ations which can be administered rectally, such as itories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the one or more carriers, excipients, and/or auxiliaries.

The pharmaceutical compositions provided herein may be stered to any patient which may experience the beneficial effects of compounds having Formulae I-XXVIII. Foremost among such patients are mammals, e.g., humans, although the methods and compositions provided herein are not intended to be so limited. Other patients include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like).

Compounds having Formulae I-XXVIII and ceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, stration may be by parenteral, subcutaneous, intravenous, uscular, intraperitoneal, ermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be ent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0343] The pharmaceutical compositions and preparations provided herein are ctured by means of conventional , granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for e cium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or nyl pyrrolidone. If desired, disintegrating agents may be added such as the above—mentioned starches and also carboxymethyl—starch, cross—linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

Auxiliaries can be suitable ﬂow-regulating agents and lubricants. Suitable auxiliaries include, for e, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to c juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, nyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent es. In order to e coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0345] Other pharmaceutical preparations which can be used orally include push— fit capsules made of n, as well as soft, sealed capsules made of n and a plasticizer such as glycerol or sorbitol. The it capsules can n the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft es, the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations which can be used rectally e, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also le to use gelatin rectal es which consist of a ation of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0347] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for e, water- soluble salts and alkaline solutions. In addition, suspensions of the active nds as appropriate oily injection suspensions may be administered.

Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol—400. Aqueous injection suspensions may contain nces which increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.

[0348] The topical compositions ed herein are formulated in one embodiment as oils, , lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft parafﬁn), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). The rs may be those in which the active ingredient is soluble. Emulsif1ers, stabilizers, ants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers can be ed in these l formulations. Examples of such enhancers can be found in US. Pat.

Nos. 3,989,816 and 4,444,762.

Ointments may be formulated by mixing a on of the active ingredient in a vegetable oil such as almond oil with warm soft in and allowing the mixture to cool. A typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight.

Lotions may be iently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.

The following examples are illustrative, but not limiting, of the compounds, compositions, and methods provided herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally tered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the methods, compounds, and itions provided herein.

EXAMPLE 1 Synthesis of Compound Example N0. 3 Scheme 7 0 o | methanol, NH + —> piperidine F overnight 1 2 3

[0351] 3—Chloro—2—fluorobenzaldehyde (6.24 g, 39.4 mmol) was added to a solution of piperidine (3.88 mL, 39.4 mmol) and 6—chlorooxindole (6.0 g, 35.8 mmol) dissolved in methanol (100 mL). After stirring overnight, the resulting solid was filtered and washed with methanol and hexanes to give 10.6 g of (E)—6— chloro—3 —(3 —chloro—2—fluorobenzylidene)indolin—2—one (3) as a green solid.

Scheme 8 :1 Toluene:THF Cl reflux, 3h 3 4 5a = CH2 5b = CF2 5c = 0 5d = NBoc 5e = NMe 5f = NAC Compound 3 (19.5 mmol), (5R,6S)—5,6-diphenylmorpholin—2—one (4) (23.4 mmol), and ketone 5 (39 mmol) were dissolved in THF (7.5 mL) and toluene (75 mL) and reﬂuxed for 3 hours. After cooling to room temperature, the reaction was ﬁltered. The solution was concentrated and puriﬁed by column chromatography to give the t (30—50% yield) as a solid.

Scheme 9 isomerize MeOH/HZO , 2d 3 Compound Example No. 3

[0353] Trans—4—aminocyclohexanol (1.8 g, 15.6 mmol) was added to a solution of intermediate 63 (1.0 g, 1.56 mmol), dissolved in THF (30 mL), and d overnight. The solvent was removed and the crude product was puriﬁed by 2012/037570 column chromatography to give 0.568 g of ediate 7 as an off white solid.

Intermediate 7 (0.568 g, 0.75 mmol) was dissolved in acetonitrile (5 mL). CAN (823 mg, 1.50 mmol) and water (5 mL) were added. After 15 minutes, the reaction was quenched with ted sodium bicarbonate, extracted with ethyl acetate, dried over sodium sulfate, and ﬁltered through celite. The solvent was d and the crude product was puriﬁed by column chromatography to give 340 mg of the product 8 as a solid. The solid was dissolved in 1:1 methanol/water with 10% TFA and aged (for isomerization) in this solution for 1- 2 days. The solvent was removed. The resulting oil was re—dissolved in 3:1 methanol/water, puriﬁed by preparative HPLC, and lyophilized to give Compound Example No. 3 (as the TFA salt) as a white powder. 1H NMR (300 MHz, CD3OD) 6 ppm 8.19 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 6.6 Hz, 1H), 7.48 (dd, J = 2.1, 8.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.10 (dd, J = 1.9, 8.2 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 5.09 (d, J = 11.1 Hz, 1H), 4.78 (d, J = 11.1 Hz, 1H), 3.70-3.55 (m, 1H), 3.48—3.35 (m, 1H), 2.84 (d, J = 8.0 Hz, 1H), 2.19 (d, J = 13.4 Hz, 1H), 2.05—1.82 (m, 5H), 1.82—1.65 (m, 3H), 1.64—1.41 (m, 2H), 1.40—1.08 (m, 5H), 1.01—0.83 (m, 1H); ESI—MS m/z 560.9 (M+H)+.

EXAMPLE 2 Synthesis of nd Example No. 22 Scheme 10 o OMeO'ﬁh CI oV 1—' 1:1 CH CN: H2804 COHC. N Ph H20, (SAN —> —> MeOH, 50°C RT, 30 min Concentrated ic acid (2 mL) was added to a solution of intermediate 63 (3.65 g, 5.69 mmol) dissolved in methanol (50 mL), and the resulting solution was heated to 50°C for 5 hours. The ol was removed by evaporation, and the resulting concentrate was cooled to 0°C and slowly neutralized with a solution of ted sodium bicarbonate. The aqueous solution was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, ﬁltered, and concentrated. The crude product was puriﬁed by column chromatography to give 2.20 g (57% yield) of intermediate 11.

Intermediate 11 (2.20 g, 3.25 mmol) was dissolved in acetonitrile (25 mL) and THF (5 mL), CAN (3.56 g, 6.50 mmol), and water (25 mL) were added.

After 15 minutes, the reaction was quenched with saturated sodium bicarbonate, extracted with ethyl acetate, dried over sodium sulfate, and filtered through celite.

The t was removed and the crude product was purified by column chromatography to give 1.43 g (92% yield) of the methyl ester intermediate 12 as a solid.

The methyl ester intermediate 12 (1.43 g, 3.0 mmol) was dissolved in THF (20 mL) and LiOH.HZO (377 mg, 9.0 mmol) was added, followed by water (20 mL). After 2 hours, the reaction was quenched with water and ted ammonium chloride, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate on was dried over sodium sulfate, filtered, and concentrated to produce the carboxylic acid intermediate 13 as an off white solid. The acid was used t further purification. EST-MS m/z 463.17 (M+H)+.

Scheme 11 1. CICHZCHZCI, 0 CDI, 50°C + H2N —> 2. aniline, reflux LiOH.H20 NaOH 1:1 THF/H20 ClD:-IZ Compound Example No. 22 CD1 (525 mg, 3.24 mmol), DIEA (0.941 mL, 5.4 mmol), and DMAP (catalytic) were added to a solution of carboxylic acid intermediate 13 (500 mg, 1.08 mmol) dissolved in l,2-dichloroethane, and the resulting solution was heated to 50°C. After 30 minutes, methyl 4-aminobenzoate 14 (816 mg, 5.4 mmol) was added to the reaction and the on was heated to reﬂux. After heating overnight, the t was removed and the crude product was puriﬁed by column chromatography to give 265 mg (41% yield) of ediate 15 as a white solid.

The resulting methyl ester intermediate 15 (265 mg, 0.44 mmol) was dissolved in THF (10 mL) then LiOH.H20 (56 mg, 1.33 mmol), NaOH (53 mg, 1.33 mmol), and H20 were added. After 2 hours, 3 mL of TFA was added, d brieﬂy, and the solvent was evaporated. The resulting oil was re—dissolved in methanol and water, purified by preparative HPLC, and lyophilized to give 235 mg of Compound Example No. 22 (as the TFA salt) as a white solid. 1H NMR (300 MHz, CD3OD) 6 ppm 7.98 (d, J = 8.5 Hz, 2H), 7.72 (t, J = 7.1 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.69 (s, 1H), 5.32 (d, J = 10.9 Hz, 1H), 4.97 (d, J = 10.9 Hz, 1H), 2.89 (d, J = 9.9 Hz, 1H), 2.19 (d, J = 14.0 Hz, 1H), 2.08-1.85 (m, 3H), 1.78 (d, J = 11.8 Hz, 2H), 1.54 (q, J = 14.2 Hz, 1H), .10 (m, 2H); ESI—MS m/z 582.17 (M+H)+.

EXAMPLE 3 Synthesis of nd Example N0. 23 Scheme 12 DCM, EDCI HC' ,,0 HOBt, DIEA, H2N s —> DMAP (cat) RT overnight 13 16 Compound Example No. 23 EDCI (19 mg, 0.097 mmol), HOBt (13 mg, 0.097 mmol), and DIEA (0.034 mL, 0.195 mmol) were added to a solution of carboxylic acid intermediate 13 (30 mg, 0.065 mmol) dissolved in DCM. After 10 minutes, otetrahydro-2H-thiopyran-1,1-dioxide hydrochloride (24 mg, 0.13 mmol) and a tic amount of DMAP were added. After stirring overnight, the solvent was removed and the crude product was puriﬁed by column chromatography to give 15 mg of Compound Example No. 23 as a white solid.

The solid was further puriﬁed by preparative HPLC, and lyophilized to give 10 mg of Compound Example No. 23 (as the TFA salt) as a white powder. 1H NMR (300 MHz, CD3OD) 6 ppm 7.64 (t, J = 7.1 Hz, 1H), 7.49 (dd, J = 2.1, 8.1 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 9.9 Hz, 1H), 7.11 (dd, J = 1.6, 8.2 Hz, 1H), 6.79 (d, J = 1.6 Hz, 1H), 5.10 (d, J = 11.1 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.10—3.94 (m, 1H), 3.27—2.91 (m, 3H), 2.88—2.74 (m, 2H), 2.35—1.64 (m, 10H), 1.52 (q, J = 13.9 Hz, 1H), 1.31—1.11 (m, 2H); ESI—MS m/z 594.50 (M+H)+.

EXAMPLE 4 Synthesis of Compound Example 24 Scheme 13 DCM, EDCI HZN—<:>IIII/< —>0M9.HCl 0 HOBt, DIEA, DMAP (cat) RT overnight LiOH.H20 CI 1:1 THF/H20 Clb:N Compound Example No. 24 EDCI (19 mg, 0.097 mmol), HOBt (13 mg, 0.097 mmol), and DIEA (0.034 mL, 0.195 mmol) were added to a solution of carboxylic acid intermediate 13 (30 mg, 0.065 mmol) dissolved in DCM. After 10 s, methyl trans—4— aminocyclohexanecarboxylate hydrochloride (25 mg, 0.13 mmol) and a catalytic amount of DMAP were added. After stirring overnight, the t was removed and the crude product was puriﬁed by column chromatography to give the 30 mg of intermediate 18 as a white solid.

[0361] Methyl ester intermediate 18 (30 mg, 0.05 mmol) was dissolved in THF (1 mL) then LiOH.H20 (6.2 mg, 0.15 mmol) and H20 were added. After 2 hours, 0.5 mL of TFA was added, and the t was evaporated. The oil was re— dissolved in 3:1 methanol/water with 10% TFA, purified by ative HPLC, and lyophilized to give 20 mg of Compound Example No. 24 (as the TFA salt) as a white powder. 1H NMR (300 MHz, 013301)) 5 ppm 7.64 (t, J = 7.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.79 (s, 1H), 5.08 (d, J = 11.1 Hz, 1H), 4.79 (d, J = 11.1 Hz, 1H), 3.72-3.54 (m, 1H), 2.84 (d, J = 8.4 Hz, 1H), 2.25—2.07 (m, 2H), 2.04—1.84 (m, 6H), 1.77 (d, J = 12.0 Hz, 2H), 1.63 (d, J = 13.0 Hz, 1H), 1.56—1.34 (m, 3H), 1.32-1.11 (m, 3H), 0.99—0.82 (m, 1H) ESI—MS m/z 588.33 (M+H)+. 2012/037570 EXAMPLE 5 The following compounds were prepare using methodology described in Examples 1-4. Unless otherwise ted, each Compound Example was puriﬁed by reverse phase HPLC and isolated as the TFA salt. Unless otherwise indicated, all 1H NMR chemical shifts reported herein are d by the delta (8) scale. nd Example No. 1: CI F OyNNO 2 "’OH CI ﬂ 1H NMR (300 MHz, MeOH-d4): 8.14 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.51 (dd, J = 1.9, 8.1 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.17 (dd, J =19, 8.2 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 5.07 (d, J = 11.2 Hz, 1H), 4.70—4.90 (m, 1H), 3.51—3.72 (M, 1H), 3.35—3.48 (m, 1H), 1.93 (s, 3H), 1.85—1.95 (m, 1H), 1.85—1.95 (m, 1H), 1.78 (d, J = 12.3 Hz, 1H), 1.59 (d, J = 12.3 Hz, 1H), 1.41 (s, 3H), 1.10—1.35 (m, 4H), 0.85—1.05 (m, 1H); ESI—MS m/z 520.3 (M+H)+, 542.1 (M+Na)+.

Compound Example No. 2: 0' .030 =- "'OH 1H NMR (300 MHz, MeOH—d4): 8.24 (d, J = 7.7 Hz, 1H), 7.45—7.62 (m, 2H), 7.39 (t, J = 6.9 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.10 (dd, J = 1.9, 8.2 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 5.07 (d, J = 11.1 Hz, 1H), 4.69 (d, J = 11.1 Hz, 1H), 3.51—3.70 (m, 1H), 3.35—3.48 (m, 1H), 2.65—2.82 (m, 1H), 2.38—2.54 (m, 1H), 2.11—2.24 (m, 1H), 1.95—2.11 (m, 1H), 1.84—1.95 (m, 2H), 1.78—1.74 (m, 2H), 1.43—1.78 (m, 4H), 1.10—1.40 (m, 3H), 0.83—1.05 (m, 1H); ESI—MS m/z 546.7 (M+H)+.

WO 55066 Compound Example No. 4: CI F O¥N~O ‘- "'OH 1H NMR (300 MHz, MeOH-d4): 8.25 (d, J = 7.5 Hz, 1H), 7.50-7.66 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 5.10 (d, J = 11.2 Hz, 1H), 4.80-4.88 (m, 1H), 3.53-3.67 (m, 1H), 3.35-3.47 (m, 1H), 3.05 (dd, J = 8.3, 15.3 Hz, 1H), 2.41 (dd, J = 8.8, 14.4 Hz, 2H), 1.89 (d, J = 10.2 Hz, 2H), 1.65—1.84 (m, 4H), 1.40—1.65 (m, 5H), 1.14—1.38 (m, 4H), 1.00—1.12 (m, 1H), 0.82—1.00 (m, 1H); ESI—MS m/z 574.6 (M+H)+, 596.1 (M+Na)+.

[0369] nd Example No. 5: CI F OVNO ‘: "’OH 1H NMR (300 MHz, MeOH—d4): 8.25 (d, J = 7.3 Hz, 1H), 7.28—7.42 (m, 2H), 6.91—7.12 (m, 2H), 6.77 (d, J = 1.8 Hz, 1H), 4.80—4.97 (m, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.04 (d, J = 12.4 Hz, 1H), 3.84 (d, J = 12.6 Hz, 1H), 3.51—3.68 (m, 1H), 3.36—3.51 (m, 1H), 1.91 (d, J = 9.3 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.49 (d, J = 12.3 Hz, 1H), 1.14—1.36 (m, 3H), 0.86—1.05 (m, 1H); ESI—MS m/z 492.60 (M+H)+. nd Example No. 6:

[0372] ESI—MS m/z 563.67 (M+H)+.

WO 55066 Compound Example No. 7: The title compound was prepared as described in E 1 using intermediate 6b and 2-morpholinoethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 7.64 (t, J = 7.1 Hz, 1H), 7.49 (dd, J = 2.2, 8.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.16—7.07 (m, 2H), 6.77 (d, J = 1.7 Hz, 1H), 5.02 (d, J = 10.2 Hz, 1H), 4.82 (d, J = 10.3 Hz, 1H), 4.12—3.38 (m, 11H), 2.75—1.73 (m, 7H), 1.50—1.31 (m, 1H); EST—MS m/z 611.25 (M+H)+.

Compound Example No. 8: The title compound was prepared as described in Example 1 using intermediate 6b and holinoethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 7.33 (t, J = 7.3 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.05—6.84 (m, 3H), 6.82 (s, 1H), 4.68 (d, J = 9.2 Hz, 1H), 4.56 (d, J = 9.2 Hz, 1H), 4.16-3.01 (m, 11H), 2.48—1.63 (m, 7H), 1.31 (dt, J = 3.8, 14.0 Hz, 1H); ESI—MS m/z 611.25 (M+H)+.

Compound Example No. 9: The title compound was prepared as described in EXAMPLE 1 using intermediate 6b. 1H NMR (300 MHz, CD3OD) 6 ppm 8.12 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.49 (dd, J = 2.3, 8.2 Hz, 1H), 7.33 (t, J =8.3 Hz, 1H), .05 (m, 2H), 6.78 (d, J = 1.9 Hz, 1H), 4.77 (d, J = 10.3 Hz, 1H), .41 (m, 2H), 2.74—1.64 (m, 11H), 1.48—1.21 (m, 4H), 1.18—1.02 (m, 1H); ESI—MS m/z 596.75 (M+H)+.

Compound Example No. 10: The title compound was prepared as described in Example 1 using intermediate 6c. 1H NMR (300 MHz, CD3OD) 6 ppm 8.02 (d, J = 8.0 Hz, 1H), 7.31—7.15 (m, 3H), 7.01—6.91 (m, 2H), 6.82 (d, J = 1.9 Hz, 1H), 4.70 (d, J = 10.4 Hz, 1H), 4.59 (d, J = 10.4 Hz, 1H), .80 (m, 3H), 3.76—3.48 (m, 3H), 2.25— 0.94 (m, 12H); ESI-MS m/z 562.92 (M+H)+.

Compound Example No. 11: The title compound was prepared as described in EXAMPLE 1 using intermediate 6c. 1H NMR (300 MHz, CD30D) 6 ppm 8.19 (d, J = 7.9 Hz, 1H), 7.63 (ddd, J = 1.5, 6.5, 7.9 Hz, 1H), 7.51 (dd, J = 2.3, 8.2 Hz, 1H), 7.37 (t, J = 8.3 Hz, 1H), 7.19—7.07 (m, 2H), 6.80 (d, J = 1.9 Hz, 1H), 5.02 (d, J = 10.8 Hz, 1H), 4.74 (d, J = 10.8 Hz, 1H), 4.11—3.93 (m, 2H), 3.87 (dd, J = 3.9, 12.4 Hz, 1H), 3.69—3.55 (m, 2H), 3.50—3.38 (m, 1H), 2.62 (d, J = 13.2 Hz, 1H), 2.26—2.12 (m, 1H), 2.04—1.73 (m, 4H), 1.70—1.17 (m, 5H), 1.08 (ddd, J = 3.5, 12.7, 24.0 Hz, 1H); ESI—MS m/z 562.67 (M+H)+.

Compound Example No. 12: The title compound was prepared as described in Example 1 using intermediate 6c, and holinoethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 7.64 (t, J = 7.9 Hz, 1H), 7.49 (dd, J = 2.6, 8.2 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H), 7.15-7.07 (m, 2H), 6.78 (d, J = 1.9 Hz, 1H), 5.00 (d, J = 10.3 Hz, 1H), 4.77 (d, J = 10.3 Hz, 1H), 4.12—3.57 (m, 14H), 3.36—3.19 (m, 2H), 2.37 (d, J = 10.3 Hz, 1H), .04 (m, 1H), 1.96—1.80 (m, 1H), 1.50—1.34 (m, 1H); ESl—MS m/z 577.75 (M+H)+.

[0385] Compound Example No. 13: The title compound was prepared as described in EXAMPLE 1 using intermediate 6d and methyl amine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 8.10 (s, 1H), 7.27—7.15 (m, 3H), 7.00—6.89 (m, 2H), 6.79 (d, J = 1.6 Hz, 1H), 4.66 (d, J = 10.2 Hz, 1H), 4.60 (d, J = 10.1 Hz, 1H), 3.60 (t, J = 11.8 Hz, 1H), 3.39—3.15 (m, 3H), 2.76 (s, 3H), 2.33—2.02 (m, 2H), 1.71 (d, J = 14.2 Hz, 1H), 1.53—1.33 (m, 1H); ESI—MS m/z 477.17 (M+H)+.

Compound e No. 14: \\(/N_CH3 The title compound was prepared as described in EXAMPLE 1 using intermediate 6d and methyl amine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 8.24 (s, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.49 (dd, J = 2.2, 8.1 Hz, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.13—7.03 (m, 2H), 6.68 (s, 1H), 4.79 (d, J = 9.6 Hz, 1H), 4.64 (d, J = 9.6 Hz, 1H), 3.70 (t, J = 13.1 Hz, 1H), 3.44—3.18 (m, 3H), 2.77 (d, J = 4.3 Hz, 3H), 2.39 (d, J = 14.5 Hz, 1H), .88 (m, 2H), 1.50—1.26 (m, 1H); ESI—MS m/z 477.17 (M+H)+.

Compound e No. 15:

[0390] The title compound was prepared as described in EXAMPLE 1 using intermediate 63 and 2-morpholinoethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD30D) 6 ppm 7.65 (t, J = 7.1 Hz, 1H), 7.47 (dd, J = 2.3, 8.1 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.17—7.05 (m, 2H), 6.77 (s, 1H), .02 (d, J = 10.3 Hz, 1H), 4.80 (d, J = 10.5 Hz, 1H), 3.94—3.80 (m, 4H), 3.61 (t, J = 6.2 Hz, 2H), .17 (m, 5H), 2.56 (d, J = 12.5 Hz, 1H), 2.11—1.48 (m, 7H), 1.29—1.02 (m, 2H); ESI—MS m/z 575.25 .

Compound Example No. 16: The title compound was prepared as described in EXAMPLE 1 using intermediate 6e and methyl amine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 8.12 (d, J = 5.4 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.26—7.13 (m, 2H), 6.99 (dd, J = 1.9, 8.1 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 1.9 Hz, 1H), 4.67 (d, J = 9.9 Hz, 1H), 4.61 (d, J = 9.9 Hz, 1H), 3.67 (dt, J = 3.8, 13.0 Hz, 1H), 3.56—3.41 (m, 2H), 3.26—3.13 (m, 1H), 2.87 (s, 3H), 2.77 (d, J = 3.7 Hz, 3H), 2.36—2.10 (m, 2H), 1.77—1.63 (m, 1H), 1.54—1.38 (m, 1H); ESI— MS m/z 491.42 (M+H)+.

Compound Example No. 17:

[0394] The title compound was ed as described in EXAMPLE 1 using intermediate 6e and methyl amine (2 lents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 8.25 (d, J = 5.8 Hz, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.47 (dd, J = 2.1, 8.2 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.12—7.01 (m, 2H), 6.77 (d, J = 1.6 Hz, 1H), 4.76 (d, J = 9.5 Hz, 1H), 4.62 (d, J = 9.5 Hz, 1H), 3.75 (t, J: 12.5 Hz, 1H), 3.52-3.40 (m, 2H), .12 (m, 1H), 2.86 (s, 3H), 2.76 (d, J = 4.0 Hz, 3H), 2.40 (d, J = 14.4 Hz, 1H), 2.12-1.86 (m, 2H), 1.54—1.34 (m, 1H); ESI—MS m/z 491.08 (M+H)+' Compound Example No. 18:

[0396] The title compound was prepared as described in EXAMPLE 1 using intermediate 6f and methyl amine (2 equivalents) at room temperature. ESI-MS m/z 519.17 (M+H)+' Compound Example No. 19: \yN_CH3 The title compound was prepared as described in EXAMPLE 1 using intermediate 6f and methyl amine (2 equivalents) at room temperature. ESI-MS m/z 519.17 (M+H)+.

Compound Example No. 20: The title compound was prepared as described in EXAMPLE 1 using intermediate 63 and 2-(methylsulfonyl)ethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD30D) 6 ppm 7.63 (t, J = 7.9 Hz, 1H), 7.50 (dd, J = 2.7, 8.2 Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H), 7.19—7.07 (m, 2H), 6.77 (d, J = 1.9 Hz, 1H), 5.13 (d, J = 10.7 Hz, 1H), 3.84—3.51 (m, 2H), 3.25 (t, J = 6.3 Hz, 2H), 2.90 (s, 3H), 2.75 (d, J = 10.6 Hz, 1H), 2.13 (d, J = 14.6 Hz, 1H), 2.01—1.67 (m, 5H), 1.64—1.42 (m, 1H), 1.31—1.10 (m, 2H); ESI—MS m/z 568.25 (M+H)+ nd Example No. 21:

[0402] The title compound was ed as described in EXAMPLE 1 using intermediate 63 and methyl amine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD3OD) 6 ppm 8.29 (s, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.51 (dd, J = 2.4, 8.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.21—7.07 (m, 2H), 6.77 (d, J =1.5 Hz, 1H), 5.13 (d, J = 10.9 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 2.83 (d, J = 8.3 Hz, 1H), 2.73 (s, 3H), 2.17 (d, J = 15.3 Hz, 1H), 2.04—1.68 (m, 5H), 1.52 (q, J = 14.6 Hz, 1H), 1.31—1.09 (m, 2H); ESI—MS m/z 476.25 (M+H)+.

WO 55066 Compound Example No. 25: O=S/ The title compound was prepared using l-(2- (methylsulfonyl)ethyl)piperidinamine hydrochloride. 1H NMR (300 MHz, CD3OD) 6 ppm 7.64 (t, J = 7.1 Hz, 1H), 7.47 (dd, J = 1.8, 8.2 Hz, 1H), 7.37 (t, J: 7.8 Hz, 1H), 7.15 (t, 8.1 Hz, 1H), 7.09 (dd, J = 1.5, 8.3 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 5.04 (d, J = 10.1 Hz, 1H), 4.79 (d, J = 10.8 Hz, 1H), 4.05—3.86 (m, 1H), 3.73—3.41 (m, 6H), 3.25—3.10 (m, 2H), 3.08 (s, 3H), 2.79—2.64 (m, 1H), 2.15 (t, J = 15.6 Hz, 2H), 2.01—1.44 (m, 9H), 1.32—1.08 (m, 2H); ESI—MS m/z 651.83 (M+H)+.

Compound Example No. 26: Intermediate 13 (see EXAMPLE 3) was dissolved in 3:1 methanol/water, treated with 10% TFA, and d by ative HPLC to give the title compound as the TFA salt. 1H NMR (300 MHz, CD30D) 6 ppm 7.64 (t, J = 7.1 Hz, 1H), 7.56 (dd, J = 2.1, 8.3 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.18—7.08 (m, 2H), 6.77 (d, J = 1.4 Hz, 1H), 5.17 (d, J = 10.6 Hz, 1H), 2.64—2.49 (m, 1H), 2.14 (d, J = 13.6 Hz, 1H), 2.02—1.84 (m, 3H), 1.84—1.48 (m, 3H), 1.32—1.10 (m, 2H); ESI—MS m/z 463.17 (M+H)+. nd Example No. 27: The title compound was prepared using methyl 4-aminobutanoate hydrochloride. 1H NMR (300 MHz, CD3OD) 6 ppm 7.64 (t, J = 7.1 Hz, 1H), 7.51 (dd, J = 2.2, 8.3 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.11 (dd, J =1.6, 8.2 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 5.12 (d, J = 11.0 Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 3.21—3.04 (m, 1H), 2.81 (d, J = 7.4 Hz, 1H), 2.17 (d, J = 12.0 Hz, 1H), 2.06 (t, J = 7.4 Hz, 2H), 2.01—1.84 (m, 3H), 1.84—1.40 (m, 5H), 1.32—1.12 (m, 2H); ESI—MS m/z 548.42 (M+H)+.

[0409] Compound Example No. 28: The title compound was ed using methyl trans (aminomethyl)cyclohexanecarboxylate hydrochloride. 1H NMR (300 MHz, CD3OD) 6 ppm 8.36—8.26 (m, 1H), 7.67 (t, J = 6.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.20 (t, d = 8.0 Hz, 1H), 7.12 (dd, J = 1.4, 8.2 Hz, 1H), 6.78 (d, J = 1.5 Hz, 1H), 5.14 (d, J = 11.1 Hz, 1H), 4.78 (d, J = 11.3 Hz, 1H), 3.48—3.34 (m, 1H), 2.90—2.64 (m, 2H), 2.19 (d, J = 11.3 Hz, 1H), 2.09—1.70 (m, 8H), 1.61—1.11 (m, 8H), 0.79—0.59 (m, 2H); ESI—MS m/z 602.58 (M+H)+.

Compound Example No. 29: 2012/037570 The title compound was prepared using methyl 4-(aminomethyl)benzoate hydrochloride. 1H NMR (300 MHz, CD3OD) 6 ppm 7.87 (d, J = 8.2 Hz, 2H), 7.66 (t, J = 7.0 Hz, 1H), 7.50 (dd, J = 2.3, 8.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.22—7.08 (m, 2H), 7.04 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 1.6 Hz, 1H), 5.20 (d, J: 11.2 Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 4.66 (d, J = 15.3 Hz, 1H), 4.20 (d, J =15.3 Hz, 1H), 2.83 (d, J = 10.0 Hz, 1H), 2.20 (d, J = 15.8 Hz, 1H), 2.04—1.85 (m, 3H), 1.77 (d, J = 11.9 Hz, 2H), 1.52 (q, J = 13.7 Hz, 1H), 1.33—1.10 (m, 2H); ESI—MS m/z 596.33 (M+H)+.

[0413] Compound Example No. 30: The title compound was prepared using methanesulfonamide. 1H NMR (300 MHz, CD3OD) 6 ppm 7.61 (t, J = 7.5 Hz, 1H), 7.53 (dd, J = 2.1, 8.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.17—7.06 (m, 2H), 6.76 (d, J =1.7 Hz, 1H), 4.98 (d, J = 10.4 Hz, 1H), 3.09 (s, 3H), 2.60 (d, J = 13.7 Hz, 1H), 2.09 (d, J = 16.1 Hz, 1H), 2.01—1.43 (m, 6H), 1.34—1.06 (m, 2H); ESI—MS m/z 540.08 (M+H)+.

WO 55066 Compound Example No. 31: The title compound was prepared using methyl 4-amino methoxybenzoate. 1H NMR (300 MHz, CD30D) 6 ppm 8.26 (d, J = 8.6 Hz, 1H), 7.79 (t, J = 7.1 Hz, 1H), 7.66 (dd, J = 1.4, 8.4 Hz, 1H), 7.60 (s, 1H), 7.51 (dd, J = 2.2, 8.3 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.21 (t, J = 8.6 Hz, 1H), 7.10 (dd, J: 1.8, 8.1 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 5.49—5.23 (m, 1H), 3.80 (s, 3H), 2.68—2.47 (m, 1H), 2.21—1.52 (m, 7H), 1.35—1.07 (m, 2H); ESI—MS m/z 612.17 (M+H)+.

[0417] Compound Example No. 32: The title compound was ed using (lH-tetrazolyl)methanamine hydrochloride. 1H NMR (300 MHz, CD3OD) 6 ppm 7.63 (t, J = 7.2 Hz, 1H), 7.51 (dd, J = 2.3, 8.1 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.19-7.06 (m, 2H), 6.77 (d, J: 1.4 Hz, 1H), 5.19 (d, J = 10.7 Hz, 1H), 4.67 (q, J = 16.1 Hz, 2H), 2.77 (d, J: 11.4 Hz, 1H), 2.15 (d, J = 12.5 Hz, 1H), 2.03-1.81 (m, 3H), 1.76 (d, J = 13.3 Hz, 2H), 1.67—1.09 (m, 3H); ESI—MS m/z 544.25 (M+H)+.

Compound Example No. 33: The title compound was prepared using )—3—(tert— butyldimethylsilyloxy)—3 -methylcyclobutanamine. 1H NMR (300 MHz, CD3OD) 6 ppm 8.62 (d, J = 6.9 Hz, 1H), 7.64 (t, J = 6.8 Hz, 1H), 7.49 (dd, J = 2.4, 8.2 Hz, 1H), 7.39 (t, J = 7.1 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.10 (dd, J = 1.8, 8.2 Hz, 1H), 6.78 (d, J = 1.7 Hz, 1H), 5.10 (d, J = 11.0 Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 3.98—3.76 (m, 1H), 2.84 (d, J = 9.8 Hz, 1H), 2.45-2.23 (m, 2H), 2.17 (d, J = 13.5 Hz, 1H), 2.05-1.82 (m, 4H), 1.82-1.61 (m, 3H), 1.61-1.34 (m, 1H), 1.30 (s, 3H), 1.27—1.07 (m, 2H); ESI—MS m/z 546.67 (M+H)+.

Compound Example No. 34 1H NMR (300 MHz, CD30D) 5 ppm 8.15 (d, J = 5.3 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 2.4, 8.9 Hz, 1H), 7.06 (dd, J = 1.6, 8.3 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 5.25 (d, J = 11.3 Hz, 1H), 4.96 (d, J = 11.4 Hz, 1H), 2.85 (d, J = 8.5 Hz, 1H), 2.69 (s, 3H), 2.19 (d, J = 12.2 Hz, 1H), 2.03—1.83 (m, 3H), 1.77 (d, J = 15.3 Hz, 2H), .40 (m, 7H), 1.40—1.08 (m, 2H); ESI—MS m/z 560.58 (M+H)+.

Compound Example No. 35 1H NMR (300 MHz, CD3OD) 6 ppm 7.93 (dd, J = 2.2, 18.7 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 1.3 Hz, 1H), 4.91 (s, 1H), 2.79—2.62 (m, 4H), 2.13 (d, J = 14.4 Hz, 1H), 2.01-1.83 (m, 3H), 1.83-1.68 (m, 2H), 1.66—1.40 (m, 7H), .08 (m, 2H); ESI—MS m/z 561.33 (M+H)+.

Compound e No. 36 O OH R; \ The title compound was prepared using methyl 5-aminopicolinate. 1H NMR (300 MHZ, CD3OD) 6 ppm 8.80 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.37 (t, J: 7.1 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.80 (s, 1H), .30 (d, J = 11.1 Hz, 1H), 5.00 (d, J = 10.8 Hz, 1H), 2.90—2.75 (m, 1H), 2.16 (d, J: 16.9 Hz, 1H), 2.06—1.84 (m, 3H), 1.78 (d, J = 13.2 Hz, 2H), 1.66—1.42 (m, 1H), 1.32—1.11 (m, 2H); ESI—MS m/z 583.96 (M+H)+.

Compound Example No. 37 The title compound was prepared using methyl 2-(4-aminopiperidin yl)acetate hloride. 1H NMR (300 MHz, CD30D) 6 ppm 7.66 (t, J = 7.1 Hz, 1H), 7.48 (dd, J = 2.1, 8.2 Hz, 1H), 7.39 (t, J = 7.3 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.10 (dd, J = 1.6, 8.1 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 5.12 (d, J = 11.0 Hz, 1H), 4.80 (d, J = 10.9 Hz, 1H), 4.05—3.89 (m, 3H), .39 (m, 2H), 3.29—3.04 (m, 2H), 2.79 (d, J = 9.4 Hz, 1H), 2.17 (d, J = 9.4 Hz, 2H), 2.03—1.42 (m, 8H), 1.42—1.33 (m, 2H), 1.31—1.10 (m, 2H); EST—MS m/z 603.67 (M+H)+.

[0429] nd Example No. 38 OVH.8 The title compound was prepared using tert-butyl 3-aminoazetidine carboxylate. The Boc protecting group was removed by treating the compound with TFA in DCM. The free amine was then treated with AcOH, EDCI, HOBt, DIEA, and DMAP(catalytic) in DCM. After ng overnight, the solvent was removed and the product was puriﬁed by column chromatography then preparative HPLC to give Compound Example No. 38 (as the TFA salt) as a white powder. 1H NMR (300 MHz, CD3OD) 6 ppm 7.64 (t, J = 7.2 Hz, 1H), 7.50 (dd, J = 1.8, 8.2 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.11 (dd, J = 1.7, 8.2 Hz, 1H), 6.79 (s, 1H), 5.10 (d, J = 10.6 Hz, 1H), 4.64—4.36 (m, 2H), 4.29—4.11 (m, 1H), 4.09—3.56 (m, 2H), 2.79 (d, J = 9.8 Hz, 1H), 2.16 (d, J = 14.9 Hz, 1H), 2.01—1.68 (m, 8H), 1.64—1.37 (m, 1H), 1.34—1.11 (m, 2H); ESI— MS m/z 560.08 (M+H)+.

[0431] Compound Example No. 39 0Y0“ OVNH 0' ' The title compound was prepared using methyl trans aminocyclobutanecarboxylate hydrochloride. 1H NMR (300 MHz, CD30D) 6 ppm 7.65 (t, J = 7.0 Hz, 1H), 7.49 (dd, J = 1.7, 8.0 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 5.06 (d, J = 10.8, 1H), 4.79 (d, J = 10.8 Hz, 1H), 4.47 (p, J = 8.1 Hz, 1H), 2.96—2.71 (m, 2H), 2.63—2.38 (m, 2H), .08 (m, 2H), 2.05—1.83 (m, 4H), 1.76 (d, J = 16.2 Hz, 2H), 1.62—1.39 (m, 1H), 1.33—1.11 (m, 2H); ESI—MS m/z 560.50 (M+H)+.

Compound Example No. 40 1H NMR (300 MHz, CD30D) 6 ppm 7.67 (t, J = 6.61 Hz, 1H), 7.49 (dd, J = 2.0, 8.1 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 1.7, 8.3 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 5.20 (d, J = 11.3 Hz, 1H), 4.76 (d, J = 11.2 Hz, 1H), 3.89—3.75 (m, 1H), 2.84 (d, J = 9.1 Hz, 1H), .29 (m, 1H), 2.20 (d, J = 15.3 Hz, 1H), 2.03—1.12 (m, 16H); ESI—MS m/z 588.50 (M+H)+.

Compound Example No. 41 1H NMR (300 MHz, CD3OD) (5 ppm 8.18 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 6.8 Hz, 1H), 7.48 (dd, J = 2.3, 8.2 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.10 (dd, J = 1.8, 8.2 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 4.78 (d, J = 11.1 Hz, 1H), 3.83—3.65 (m, 2H), 2.83 (d, J = 9.9 Hz, 1H), 2.18 (d, J = 13.0 Hz, 1H), 2.03—1.10 (m, 17H); ESI—MS m/z 560.83 (M+H)+.

Compound Example No. 42 1H NMR (300 MHz, CD30D) 6 ppm 8.45 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.89 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.14 (dd, J = 1.8, 8.2 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.47 (d, J = 10.9 Hz, 1H), 3.73—3.57 (m, 1H), .36 (m, 1H), 2.83 (d, J = 12.5 Hz, 1H), 2.17 (d, J = 14.3 Hz, 1H), 2.03—1.70 (m, 8H), 1.70—1.13 (m, 7H), 1.08—0.88 (m, 1H); ESI— MS m/z 543.75 (M+H)+.

Compound e No. 43 1H NMR (300 MHz, CD3OD) 5 ppm 8.14 (s, 1H), 7.84—7.67 (m, 3H), 7.55 (dd, J = 1.9, 8.2 Hz, 1H), 7.48—7.34 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (dd, J = 1.6, 8.2 Hz, 1H), 6.79 (d, J = 1.6 Hz, 1H), 5.29 (d, J = 11.0 Hz, 1H), 4.97 (d, J: 10.7 Hz, 1H), 2.96—2.84 (m, 1H), 2.18 (d, J = 14.0 Hz, 1H), 2.08—1.85 (m, 3H), 1.78 (d, J = 12.2 Hz, 2H), 1.63—1.42 (m, 1H), 1.35—1.13 (m, 3H); ESI—MS m/z 582.58 (M+H)+.

Compound Example 44 ESI—MS m/z 596.42 (M+H)+.

Compound Example No. 45 1H NMR (300 MHz, CD30D) 6 ppm 7.98 (d, J = 8.6 Hz, 2H), 7.72 (t, J = 7.2 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 2.4, 8.1 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (dd, J = 1.6, 8.2 Hz, 1H), 6.80 (d, J= 1.7 Hz, 1H), 5.34 (d, J = 10.7 Hz, 1H), 4.97 (d, J = 10.9 Hz, 1H), 2.91 (d, J: 7.1 Hz, 1H), 2.20 (d, J = 14.8 Hz, 1H), 2.06-1.86 (m, 3H), 1.78 (d, J = 12.3 Hz, 2H), 1.64—1.42 (m, 1H), 1.34—1.14 (m, 2H); ESI—MS m/z 582.50 (M+H)+. nd Example No. 46 1H NMR (300 MHz, CD30D) 6 ppm 7.90 (t, J = 8.4 Hz, 1H), 7.74-7.61 (m, 2H), 7.55 (dd, J = 2.5, 8.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.26 (dd, J = 1.7, 8.6 Hz, 1H), 7.19 (t, J = 8.2 Hz, 1H), 7.12 (dd, J = 1.8, 8.2 Hz, 1H), 6.80 (d, J=1.7 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 4.97 (d, J = 10.8 Hz, 1H), .84 (m, 1H), 2.20 (d, J = 15.7 Hz, 1H), 2.06-1.85 (m, 3H), 1.79 (d, J = 10.9 Hz, 2H), 1.65-1.43 (m, 1H), 1.34—1.11 (m, 2H); ESI—MS m/z 600.42 (M+H)+.

[0447] Compound Example No. 47 1H NMR (300MHz, CD3OD) 5 ppm 8.42-8.31 (m, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.91—7.79 (m, 1H), 7.79-7.67 (m, 2H), 7.52 (dd, J = 2.4, 8.2 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.25-7.06 (m, 2H), 6.79 (d, J = 1.7 Hz, 1H), 5.41 (d, J = 9.4 Hz, 1H), 2.81—2.67 (m, 1H), 2.14 (d, J = 14.7 Hz, 1H), 2.00—1.84 (m, 3H), 1.84—1.70 (m, 2H), 1.68—1.47 (m, 1H), 1.41—1.09 (m, 2H); ESI—MS m/z 600.83 (M+H)+.

EXAMPLE6 Fluorescence-polarization MDM2 binding assay The binding afﬁnity of the MDM2 inhibitors disclosed herein was determined using a ﬂuorescence polarization—based (FP—based) binding assay using a recombinant human gged MDM2 protein (residues l-118) and a ﬁuorescently tagged sed peptide.

[0450] The design of the ﬂuorescence probe was based upon a previously reported high-afﬁnity p53 -based peptidomimetic compound called PMDM6-F (Garcia—Echeverria et al., J. Med. Chem. 43: 3205—3208 (2000)). The Kd value of PMDM6-F with the recombinant MDM2 n was determined from the saturation curve. MDM2 protein was serially double diluted in a Dynex 96-well, black, bottom plate, and the PMDM6-F e was added at lnM concentration. The assay was performed in the buffer: 100 mM potassium phosphate, pH 7.5; 100 ug/mL bovine gamma globulin; 0.02% sodium azide, 0.01% Triton X-100) and the polarization values were measured after 3 h of incubation using an ULTRA READER (Tecan US. Inc., Research Triangle Park, NC). The IC50 value was obtained by ﬁtting the mP values in a sigmoidal dose- response curve (variable slope) with a near regression, and was determined to be 1.40 nM :: 0.25. The Kd value was calculated using the on: Kd value = IC50 — L0/2. L0/2 is the concentration of the free ligand -F). Since PMDM6-F was used at a ﬁnal concentration of lnM, L0/2 was 0.5 nM.

[0451] Dose—dependent, competitive binding experiments were performed with serial dilutions of a tested compound in DMSO. A 5 [1L sample of the tested compound and pre—incubated MDM2 protein (10 nM) and PMDM6—F peptide (1 nM) in the assay buffer (100 mM ium phosphate, pH 7.5; 100 ug/mL bovine gamma globulin; 0.02% sodium azide, 0.01% Triton X—lOO), were added in a Dynex 96-well, black, round-bottom plate to produce a ﬁnal volume of 125 ”L. For each assay, the controls included the MDM2 protein and PMDM6-F (equivalent to 0% inhibition), PMDM6-F peptide alone (equivalent to 100% inhibition). The polarization values were measured after 3 h of incubation. The IC50 values, i.e., the tor concentration at which 50% of bound peptide is displaced, were determined from a plot using nonlinear least-squares analysis.

Curve ﬁtting was performed using GRAPHPAD PRISM software (GraphPad Software, Inc., San Diego, CA). The s of this assay are present in Table 2.

EXAMPLE 7 Cell growth assay Isogenic HCT-116 colon cancer cell lines were a kind gift from Prof. Bert Vogelstein (Johns Hopkins, Baltimore, MD) and were maintained in McCoy's 5A medium containing 10% PBS. The SJSA-1 cell lines were obtained from ATCC, (Manassas, VA) and were maintained in RPMI-1640 medium containing 10% PBS.

Cells were seeded in 96—well flat bottom cell culture plates at a y of 2—3><103 well with compounds and incubated for 4 days. The rate of cell growth inhibition after treatment with increasing concentrations of the tested nds was determined by WST—8 (2—(2—methoxynitrophenyl)—3—(4— nitrophenyl)(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (Dojindo Molecular Technologies Inc., Gaithersburg, nd). WST—8 was added at a final concentration of 10% to each well, and then the plates were incubated at 37°C for 2—3 hrs. The absorbance of the s was measured at 450 nm using a TECAN ULTRA Reader. The concentration of the compounds that inhibited cell growth by 50% (IC50) was calculated by comparing absorbance in the untreated cells and the cells treated with the nds using the GraphPad Prism software (GraphPad Software, La Jolla, CA 92037, USA). The results of this assay are presented in Table 2 and Fig. 1 and Fig. 2.

Table 2 Binding afﬁnities to MDMZ (1-118) Compound Number 1c50 . HCT116 HCT116 K1011“) SJSA'I .53 WT 53 KO OUI-bWNH 26.4 1.8 > 30 2.3 4.6 0.4 > 30 0 5 19.3:5.2 1.5:0.7 0.12 24 0.33 48 1.9 7 <1,000 <5 8 <5 9 <1 <5 11 <5 12 <10 13 >10 14 >10 <3 m lawn m lam- m lam. <5 n lam. a 23 _<100 26 /\ 28 aagaa /\ 31 A; 32 <100 33 <100 <1 34 >10,000 % lam. <1 % lam. <1 w lam. <1 m lam- “ lam- 42 _<1,000 43 <100 EXAMPLE 8 In Vivo efﬁcacy s using SJSA—Xenograft models SJSA—l (osteosarcoma) tumor cells were harvested with Trypsin (0.05%)— EDTA (0.53 mM) (GIBCOTM, lnvitrogen C0rp.), growth medium was added, and the cells were placed on ice. A cell sample was mixed 1:1 with Trypan Blue (GIBCOTM, lnvitrogen Corp.) and counted on a hemocytometer to determine the number of live/dead cells. Cells were washed once with 1X PBS (GIBCOTM, Invitrogen Corp.) and resuspended in PBS. For Matrigel injections, after washing in PBS, cells are resuspended in an ice cold mixture of 1:1 PBS and Matrigel (BD Biosciences, Invitrogen Corp.) for a ﬁnal Matrigel protein concentration of 5 mg/ml. SJSA—l tumors were inoculated into C.B—17 SCID mice at 5 x 106 cells in 0.1ml with Matrigel. Cells were injected so into the ﬂank region of each mouse using a 27 gauge .

The size of tumors growing in the mice was measured in two dimensions using calipers. Tumor volume (mm3) = (AxB2)/2 where A and B are the tumor length and width (in mm), respectively. During treatment, tumor volume and body weight was measured three times a week. After the treatment was stopped, tumor volume and body weight was measured at least once a week. Mice were kept for an additional 60 days for further observation of tumor growth and toxicity. The anti-tumor activity of nd e Nos. 22 and 24 are shown in Fig. 3.

Suitable vehicles for in viva administration of the compounds ed herein include, without limitation, 10% PEG 400:3% Cremophor:87% PBS; 98% PEG 200:2% polysorbate 80; 98% PEG 200:2% TPGS; and 0.5% polysorbate 80:0.6% methyl cellulose:98.9% water.

EXAMPLE 9 Stability of Compounds in on The stability of nd Example Nos. 3, 22, 24, and 39, and MI—77301 (See US. Patent Appl. Pub. No. 2011/0112052 A2) were determined in 1:1 MeOH:HZO (Fig. 4) and 1:1 CH3CN:HZO (Fig. 5) using ultra performance liquid chromatography. In both solvent s, Compound Example Nos. 3, 22, 24, and 39 were more stable than MI—77301.

The stability of Compound Example Nos. 10 and 11 were determined in 1:1 MeOH:HZO with 10% TFA added using ultra performance liquid chromatography (Fig. 6). Compound Example No. 10 is converted into Compound e No. 11 under these conditions.

Having now fully described the compounds, compositions, and methods provided herein, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the compounds, methods, and itions provided herein or any embodiment thereof. All patents, patent ations, and publications cited herein are fully incorporated by reference herein in their entirety.

I

Claims

WE CLAIM:

1. A nd selected from the group consisting of: , , , , , , , , , , , , , AH26(10205595_1):CCG , , , , , , , , , , 0205595_1):CCG , , , , , , , , , 0205595_1):CCG , , or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a ceutically acceptable carrier.

3. Use of the compound of any claim 1, or a ceutically acceptable salt thereof, in the cture of a medicament for the treatment of melanoma, lung cancer, sarcoma, colon cancer, prostate cancer, choriocarcinoma, breast , retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymphoma, multiple myeloma, or leukemia.

4. A kit comprising a compound of claim 1, or a pharmaceutically acceptable salt, thereof, and instructions for administering the compound to a patient having .