Spiro-oxindole MDM2 antagonists

专利摘要:
Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. 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 cancer and other diseases.
公开号:AU2012253339A1
申请号:U2012253339
申请日:2012-05-11
公开日:2014-01-09
发明作者:Angelo AGUILAR；Carlos Garcia-Echeverria；Wei Sun；Shaomeng Wang
申请人:Sanofi SA；University of Michigan；
IPC主号:C07D487-10

专利说明:
WO 2012/155066 PCT/US2012/037570 1 SPIRO-OXINDOLE MDM2 ANTAGONISTS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to pending U.S. Provisional Patent Application No. 61/484,986, filed May 11, 2011, the contents of which are 5 incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with government support under CA121279 awarded by the National Institutes of Health. The government has certain rights 10 in the invention BACKGROUND [0003] The aggressive cancer cell phenotype is the result of a variety of genetic and epigenetic alterations leading to deregulation of intracellular signaling pathways (Ponder, Nature 411:336 (2001)). Cancer cells typically fail to execute 15 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 (2000)). The inability of cancer cells to execute an apoptotic program due to defects in the normal apoptotic machinery is often associated with an increase in resistance to chemotherapy, radiation, or 20 immunotherapy-induced apoptosis. Primary or acquired 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 efforts towards designing and developing new molecular target-specific 25 anticancer therapies to improve survival and quality of life of cancer patients must include strategies that specifically target cancer cell resistance to apoptosis. [0004] The p53 tumor suppressor plays a central 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- WO 2012/155066 PCT/US2012/037570 2 regulatory feed-back loop (Wu et al., Genes Dev. 7:1126 (1993)). 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 directly binds to the p53 transactivation domain and thereby inhibits p53 5 mediated transactivation. Second, MDM2 protein contains a nuclear export signal sequence, and upon binding to p53, induces 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. [0005] Although high-affinity peptide-based inhibitors of MDM2 have been 10 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 limited success in identifying potent, non-peptide small molecule inhibitors. 15 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)). Spiro-oxindole-based antagonists of the p53-MDM2 interaction are described in U.S. Patent Nos. 7,759,383 B2 and 7,737,174 B2, U.S. Patent 20 Appl. Pub. No. 2011/0112052 A2, and U.S. Appl. No. 13/294,315. SUMMARY OF THE INVENTION [0006] In one aspect, the present disclosure provides spiro-oxindoles having Formula I: 0 E R2 Ra y b R 3 b X 0 R1e X OR0 25 Rid wherein: la lb le id R , R , R , and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, WO 2012/155066 PCT/US2012/037570 3 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 5 optionally substituted heteroaryl;
R
3 a 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; 10 R 3 b 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; or
R
3 a and R 3 b taken together form a 3- to 9-membered optionally substituted 15 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, optionally substituted cycloalkyl, and optionally substituted aryl; 20 R26b is R4; R 26 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, 5b 5 -S0 2
R
5 , and R ; or 25 R 26 b and R 26 c taken together form a 4- to 9-membered optionally substituted heterocyclo; wherein R 4 and R 5 has the meanings as described below in connection with Formula II; R5b is selected from the group consisting of optionally substituted alkyl, 30 optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl; X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR; WO 2012/155066 PCT/US2012/037570 4 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 hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and 5 ~-~ represents a single or a double bond, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0007] In another aspect, the present disclosure provides spiro-oxindoles having Formula II: R4 R 2 0 ,R 5 R la ,I R1b R 3 b X 0 Rid 10 wherein: la lbi R , R", RiC, and R" 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 cycloalkenyl, optionally 15 substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R
3 a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, 20 optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; R 3 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 25 substituted aryl, and optionally substituted heteroaryl; or
R
3 a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl; WO 2012/155066 PCT/US2012/037570 5
R
4 is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl;
R
5 is selected from the group consisting of f R 13
R
12 a R 18
R
17 a / R 23
R
2 2 a W1 R7 N/'s R12b /, 22b 6) w R Zr R2a adR NS -(CR aR 6 ) R 12 and R 22 c N lr P174d F20 tR 24 Rs R1 2 d R 1 4
R
19
OR
2 1b R 22 d R5-1 R5-2 R5-3 R5-4 5 wherein: each R 6 a and R 6 b is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl;
R
7 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; 10 R 8 a and R 8 b are each independently selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; or R a and R'b taken together with the carbon that they are attached form a 3 to 8-membered optionally substituted cycloalkyl; 15 W is selected from the group consisting of -OR 9 a and -NR 9R9;
R
9 a is hydrogen; R9 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, 9d 9eR9f. optionally substituted heteroaryl, -SO 2 R9', and -CONR R 20 R 9 ' is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
R
9 b and R 9 ' taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; 25 R 9 d is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl; R9e and R9f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or WO 2012/155066 PCT/US2012/037570 6 R9' 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 -OR4 and -NR'iaR ib with the proviso that when Wl is -OR9a and W2 is -OR 10 then at least one 5 of R 7 , R 8 a, and R b is other than hydrogen; RIO is hydrogen; or one of R9a and RIO is hydrogen and the other is a metabolically cleavable group; RIa is selected from the group consisting of hydrogen, optionally 10 substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SO 2 R Il, and -CONR RIle ; Ri l is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 15 Rla and Ru b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; R" is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl; R and R" are each independently selected from the group consisting of 20 hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or Rld and R" taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; n is 1, 2, 3, 4, or 5; each Ra 1 2 , R1 2 b, R1 2 c and R12d is independently selected from the group 25 consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl;
R
14 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; 30 Z is selected from the group consisting of -OR and -NR 16aR 6 ; or Z and R14 taken together form a carbonyl, i.e., a C=O, group.
R
15 is selected from the group consisting of hydrogen and metabolically cleavable group; WO 2012/155066 PCT/US2012/037570 7 Ri a is selected from the group consisting of -SO 2 R1 6 ' and -CONR 1dR 1e R 6b is selected from the group consisting of hydrogen and optionally substituted alkyl; R 16 is selected from the group consisting of optionally substituted alkyl, 5 optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R1 6 d and R 1e are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 10 R 6 d and R1 6 e 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 Ra 17 , R17b, Rl1 7 c and R1 7 d is independently selected from the group 15 consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R's is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R19 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; 20 R 20 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; pl 2 lb
R
2 a and R are each hydrogen; or one of R 21 and R 21 is hydrogen and the other is metabolically cleavable group; 25 qis0,1,2,or3; r is 1, 2, or 3; each R 22 a, R 22 b, R 22 c, and R 2 2 d is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl;
R
23 is selected from the group consisting of hydrogen and optionally 30 substituted C 1
-C
6 alkyl; R24 is selected from the group consisting of -SO 2
R
2 4 a and -CONR24b R24c WO 2012/155066 PCT/US2012/037570 8 R24a is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R24b and R 24 are each independently selected from the group consisting of 5 hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
R
24 b and R 2 4 c taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclo; s and t are each independently 1, 2, or 3; 10 X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, 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 hydrogen, optionally 15 substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and --- represents a single or a double bond, or a pharmaceutically acceptable salt, solvate, or prodrug thereof [0008] In another aspect, the present disclosure provides compounds having Formula I that inhibit the interaction between p53 or p53-related proteins and 20 MDM2 or MDM2-related proteins. [0009] 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, comprising contacting the cell with a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 25 [0010] In another aspect, 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, bladder cancer, bone cancer, bone metastasis, brain/CNS tumors in adults, brain/CNS tumors in children, breast cancer, breast cancer in men, cancer in 30 children, cancer of unknown primary, Castleman disease, cervical cancer, colon/rectum cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin WO 2012/155066 PCT/US2012/037570 9 disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia - acute lymphocytic (ALL) in adults, leukemia - acute myeloid (AML), leukemia - chronic lymphocytic (CLL), leukemia - chronic myeloid (CML), leukemia - chronic myelomonocytic (CMML), leukemia in children, liver cancer, 5 lung cancer - non-small cell, lung cancer - small cell, lung carcinoid tumor, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, oral cavity and oropharyngeal cancer, osteosarcoma, 10 ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary 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 15 macroglobulinemia, or Wilms Tumor, in a patient comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof [0011] In another aspect, the present disclosure provides methods of treating, ameliorating, or preventing a hyperproliferative disease, e.g., cancer, in a patient 20 comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in combination with one or more additional therapeutic agents, e.g., one or more additional anticancer agents. [0012] In another aspect, the present disclosure provides pharmaceutical 25 compositions 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. [0013] In another aspect, the present disclosure provides kits comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or 30 prodrug thereof, for treating, ameliorating, or preventing a hyperproliferative disease, e.g., cancer, in a patient.
WO 2012/155066 PCT/US2012/037570 10 BRIEF DESCRIPTION OF DRAWINGS [0014] Fig. 1 is a line graph showing cell growth inhibition of MDM2 inhibitors in the SJSA-1 cell line as determined using the WST-based assay. SJSA-1 cells were treated with each compound for 4 days. 5 [0015] Fig. 2 is a line graph showing cell growth inhibition of MDM2 inhibitors 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. [0016] Fig. 3 is a line graph showing the antitumor activity of Compound Example Nos. 22 and 24 in the SJSA-1 xenograft tumor model. Mice bearing 10 SJSA-1 tumors (one tumor per mouse) were treated with Compound Example Nos. 22 and 24 daily for 2 weeks via oral gavage at 100 mg/kg qD. [0017] 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 15 sample has been in the methanol/water solution. [0018] 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. 20 [0019] Fig. 6 is a line graph showing the stability of Compound Example 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 measured by UPLC. The X-axis represents the number of hours the sample has been in solution. DETAILED DESCRIPTION OF THE INVENTION 25 [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 proteins on p53 or p53-related proteins, these compounds sensitize cells to inducers of apoptosis and/or cell cycle arrest. In one 30 embodiment, compounds having Formulae I-XXVIII induce apoptosis and/or cell cycle arrest. Therefore, also provided herein are methods of sensitizing cells WO 2012/155066 PCT/US2012/037570 11 to inducers of apoptosis 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 5 inducer of apoptosis or a cell cycle disrupter. [0021] Also provided herein are methods of treating, ameliorating, or preventing disorders in an patient, comprising administering to the patient one or more compounds having Formulae I-XXVIII alone or in combination with additional agent(s), e.g., an inducer of apoptosis. Such disorders include those characterized 10 by a dysregulation of apoptosis and those characterized by the proliferation of cells expressing functional p53 or p53-related proteins. In another embodiment, methods of protecting normal (e.g., non-hyperproliferative) 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 15 compounds having Formulae I-XXVIII. [0022] Also provided herein are compounds having any one of Formulae I-XXVIII for use in the manufacture of a medicament for treating a hyperproliferative disease such as cancer. [0023] Also provided herein are compounds having any one of 20 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 [0024] The term "anticancer agent" as used herein, refers to any therapeutic agent 25 (e.g., chemotherapeutic compound and/or molecular therapeutic compound), antisense therapy, radiation therapy, or surgical intervention, used in the treatment of hyperproliferative diseases such as cancer (e.g., in mammals, e.g.., in humans). [0025] The term "prodrug" as used herein, refers to a pharmacologically inactive 30 derivative of a parent "drug" molecule that requires biotransformation (e.g., either spontaneous or enzymatic) within the target physiological system to release, or to convert (e.g., enzymatically, physiologically, mechanically, WO 2012/155066 PCT/US2012/037570 12 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 5 suppresses the activity of the drug). Some prodrugs are variations or derivatives 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 & Breach, 1991, 10 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. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John 15 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. [0026] Exemplary prodrugs become pharmaceutically active in vivo or in vitro 20 when they undergo solvolysis under physiological conditions or undergo enzymatic degradation or other biochemical transformation (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation). 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, 25 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 30 amino acid), amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide), or phosphorus-containing derivatives, e.g., phosphate, phosphonate, WO 2012/155066 PCT/US2012/037570 13 and phosphoramidate esters, including cyclic phosphate, phosphonate, and phosphoramidate, see, e.g., US 2007/0249564 Al. [0027] The term "metabolically cleavable group" as used herein, refers to groups which can be cleaved from the parent molecule by metabolic processes and be 5 substituted with hydrogen. Certain compounds containing metabolically cleavable groups may be prodrugs, i.e., they are pharmacologically inactive. Certain 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. 10 Examples of metabolically cleavable groups include those derived from amino acids (see, e.g., US 2006/0241017 Al; US 2006/0287244 Al; and WO 2005/046575 A2) or phosphorus-containing compounds (see, e.g., U.S. 2007/0249564 Al) as illustrated in Scheme 1. Scheme 1 O 0 R-OH + HO NH2 : R-O NH 2 metabolic R-OH R' R' cleavage parent amino acid amino acid ester parent drug drug O 0 .,P-OR" -OR" metabolic R-OH + Cl R-O' - R-OH OR" OR" cleavage parent phosphate phosphate ester parent 15 drug du [0028] 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). 20 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, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, WO 2012/155066 PCT/US2012/037570 14 citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, sulfonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds 5 provided herein and their pharmaceutically acceptable acid addition salts. [0029] 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 NW 4 +, wherein W is C 1 4 alkyl, and the like. 10 [00301 Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, 15 lactate, maleate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, pirate, 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+, NH 4 +, and NW 4 + (wherein W is a 20 C 1 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 acceptable compound. 25 [0031] The term "solvate" as used herein, refers to the physical association of a compound provided herein with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In certain instances, the solvate is capable of isolation, for example, when one or more solvate molecules are incorporated in the crystal lattice of the crystalline 30 solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, and methanolates. [0032] The term "monovalent pharmaceutically acceptable cation" as used herein refers to inorganic cations such as, but not limited to, alkaline metal ions, e.g., WO 2012/155066 PCT/US2012/037570 15 Na and K, as well as organic cations such as, but not limited to, ammonium and substituted ammonium ions, e.g., NH4, NHMe3+, NH 2 Me2+, NHMe3+ and NMe4I. [0033] The term "divalent pharmaceutically acceptable cation" as used herein 5 refers to inorganic cations such as, but not limited to, alkaline earth metal cations, e.g., Ca2+ and Mg2+. [0034] Examples of monovalent and divalent pharmaceutically acceptable cations are discussed, e.g., in Berge et al. J. Pharm. Sci., 66:1-19 (1997). [0035] The term "therapeutically effective amount," as used herein, refers to that 10 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 15 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 10%, 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 20 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 9 5 %, or at least 100%. [0036] 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 25 responsive, to the biological effects (e.g., promotion or retardation of an aspect of cellular function including, but not limited to, cell division, cell growth, proliferation, invasion, angiogenesis, necrosis, 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., promotion or 30 retardation of an aspect of cellular function including, but not limited to, cell growth, proliferation, invasion, angiogenesis, or apoptosis) observed upon the administration of a second agent with and without administration of the first agent. The response of the sensitized cell can be increased by at least about 10%, WO 2012/155066 PCT/US2012/037570 16 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 3 50%, at least about 4 00 %, at least about 4 50%, or at 5 least about 500% over the response in the absence of the first agent. [0037] The term "dysregulation of apoptosis," as used herein, refers to any aberration in the ability of (e.g., predisposition) a cell to undergo 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 10 (e.g., systemic lupus erythematosus, rheumatoid arthritis, graft-versus-host disease, myasthenia gravis, or Sj6gren's syndrome), chronic inflammatory conditions (e.g., psoriasis, asthma or Crohn's disease), hyperproliferative disorders (e.g., tumors, B cell lymphomas, or T cell lymphomas), viral infections (e.g., herpes, papilloma, or HIV), and other conditions such as osteoarthritis and 15 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. 20 [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 10%, about 2 0%, about 3 0%, about 4 0%, about 50%, or more of wild-type activity. 25 [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 proteins. Examples of p53-related proteins include, but are not limited to, p63 and p73. [0040] The term "MDM2-related protein," as used herein, refers to proteins that 30 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.
WO 2012/155066 PCT/US2012/037570 17 [0041] 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. [0042] The term "hyperproliferative disease," as used herein, refers to any 5 condition in which a localized population of proliferating cells in an animal is not governed by the usual limitations of normal growth. Examples of hyperproliferative disorders include tumors, neoplasms, lymphomas, leukemias and the like. A neoplasm is said to be benign if it does not undergo invasion or metastasis and malignant if it does either of these. A "metastatic" cell means that 10 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 significant alteration in structure or function. Metaplasia is a form of controlled cell growth in which one type of fully differentiated cell substitutes for another type of differentiated cell. 15 [0043] The pathological growth of activated lymphoid cells often results in an autoimmune disorder or a chronic inflammatory condition. As used herein, 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 20 include autoimmune hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic 25 arthritis, scleroderma, Sj6gren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like. [0044] The term "neoplastic disease," as used herein, refers to any abnormal growth of cells being either benign (non-cancerous) or malignant (cancerous). [0045] The term "normal cell," as used herein, refers to a cell that is not 30 undergoing abnormal growth or division. Normal cells are non-cancerous and are not part of any hyperproliferative disease or disorder.
WO 2012/155066 PCT/US2012/037570 18 [0046] The term "anti-neoplastic agent," as used herein, refers to any compound that retards the proliferation, growth, or spread of a targeted (e.g., malignant) neoplasm. [0047] The terms "prevent," "preventing," and "prevention," as used herein, refer 5 to a decrease in the occurrence of pathological cells (e.g., hyperproliferative 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 10 herein. [0048] The term "apoptosis-modulating agents," as used herein, refers to agents which are involved in modulating (e.g., inhibiting, decreasing, increasing, promoting) apoptosis. Examples of apoptosis-modulating agents include proteins which comprise a death domain such as, but not limited to, Fas/CD95, TRAMP, 15 TNF RI, DRI, DR2, DR3, DR4, DR5, DR6, FADD, and RIP. Other examples of apoptosis-modulating agents include, but are not limited to, TNFa, Fas ligand, antibodies to Fas/CD95 and other TNF family receptors, TRAIL (also known as Apo2 Ligand or Apo2L/TRAIL), antibodies to TRAIL-Ri or TRAIL-R2, Bcl-2, p53, BAX, BAD, Akt, CAD, P13 kinase, PP1, and caspase proteins. Modulating 20 agents broadly include agonists and antagonists of TNF family receptors 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 Fas/CD95 ligand, a TNFR-1 ligand, or TRAIL. 25 [0049] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical 30 Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. [0050] The terms "pulsatile administration," "pulsatile dose administration" or "pulsatile dosing" as used herein, refer to intermittent (i.e., not continuous) administration of compounds having Formulae I-XXVIII, or pharmaceutically WO 2012/155066 PCT/US2012/037570 19 acceptable salts, solvates, or prodrugs thereof, to a patient. Pulsatile dose administration regimens useful in the present disclosure encompass any discontinuous administration regimen that provides a therapeutically effective amount of compounds having Formulae I-XXVIII, or pharmaceutically 5 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 continuous dosing regimens. Advantages of pulsatile dose administration of compounds having Formulae I-XXVIII, or pharmaceutically acceptable salts, solvates, or prodrugs 10 thereof, include, but are not limited to, improved safety, decreased toxicity, increased exposure, increased efficacy, and increased patient compliance. These advantages may be realized when compounds having Formulae I-XXVIII, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, are administered as a single agent or are administered in combination with one or more additional 15 anticancer agents. On the day that compounds having Formulae I-XXVIII, 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 20 acceptable salts, solvates, or prodrugs thereof, are administered once (QD) or twice (BID) on the day it is schedule to be administered [0051] 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., C 1
-C
1 8 means I to 18 25 carbons). In one embodiment, the alkyl is a CI-C1o alkyl. In another embodiment, the alkyl is a CI-C 6 alkyl. In another embodiment, the alkyl is a
C
1
-C
4 alkyl. In another embodiment, the alkyl is a CI-C 3 alkyl. In another embodiment, the alkyl is a C 2 -Cio alkyl. In another embodiment, the alkyl is a
C
3
-C
10 alkyl. In another embodiment, the alkyl is a C 3
-C
6 alkyl. Exemplary alkyl 30 groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, 4,4-dimethylpentyl, n-octyl, 2,2,4-trimethylpentyl, nonyl, decyl and the like.
WO 2012/155066 PCT/US2012/037570 20 [0052] The term "optionally substituted alkyl" as used herein by itself or part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from hydroxy (i.e., -OH), nitro (i.e., -NO 2 ), cyano (i.e., -CN), amino, optionally 5 substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,
-CO
2 R, -COR, -SO 2 Rd, -N(Re)CORf, -N(R )SO 2 R9 or -N(R e)C=N(Rh)-amino, wherein Re is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rd is optionally substituted alkyl, optionally 10 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 optionally substituted heteroaryl; R9 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Rh is hydrogen, -CN, 15 optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. In another embodiment, the substituents are selected from hydroxyl (i.e., a hydroxyalkyl, e.g., a monohydroxyalkyl or 20 dihydroxyalkyl), optionally substituted cycloalkyl (i.e., a (cycloalkyl)alkyl), optionally substituted heterocyclo (i.e., a (heterocyclo)alkyl), -CO 2 H, or amino (i.e., an aminoalkyl). Exemplary optionally substituted alkyl groups include
-CH
2 0CH 3 , -CH 2
CH
2
NH
2 , -CH 2
CH
2
NH(CH
3 ), -CH 2
CH
2 CN, -CH 2
CO
2 H,
-CH
2
CONH
2 , -CH 2
SO
2
CH
3 , -CH 2
CH
2
SO
2
CH
3 , -C(CH 3
)
2
CO
2 H, hydroxymethyl, 25 hydroxyethyl, hydroxypropyl, and the like. [00531 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 include -(CH 2 )-, -(CH 2
)
2 -, (CH 2
)
3 -, -(CH 2
)
4 -, and the like. 30 [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 optionally substituted C 1
-C
6 alkyl, optionally substituted WO 2012/155066 PCT/US2012/037570 21 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In one embodiment, the optionally substituted C 1
-C
6 alkyl is methyl. In one embodiment, the optionally substituted aryl is a phenyl optionally substituted with one or two halo groups. Exemplary optionally substituted alkylenyl groups 5 include -CH(CH 3 )-, -C(CH 3
)
2 -, -CH 2
CH(CH
3 )-, -CH 2
CH(CH
3
)CH
2 -,
-CH
2 CH(Ph)CH 2 -, -CH(CH 3
)CH(CH
3 )-, and the like. [0055] 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 10 haloalkyl groups include trifluoromethyl, -CH 2
CH
2 F and the like. [00561 The term "monohydroxyalkyl" as used herein by itself or part of another group refers to an alkyl as defined above having exactly one hydroxy substituent. Exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like. 15 [0057] The term "dihydroxyalkyl" 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 -CH 2
CH
2
CCH
3
(OH)CH
2 OH,
-CH
2
CH
2
CH(OH)CH(CH
3 )OH, -CH 2
(OH)CH
2 OH, -CH 2
CH(CH
2
OH)
2 ,
-CH
2
CH
2
CH(OH)C(CH
3
)
2 0H, -CH 2
CH
2
CCH
3
(OH)CH(CH
3 )OH, and the like, 20 including stereoisomers thereof. [0058] 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: OH OH OH OH OH OH OH OH OH OH 25 and the like, including stereoisomers thereof.
WO 2012/155066 PCT/US2012/037570 22 [00591 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 optionally substituted cycloalkyl (as defined below) substituent. Exemplary optionally substituted (cycloalkyl)alkyl groups include: and 5 OH
NH
2 NH Ns and the like, including stereoisomers thereof. [0060] 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) substituent. 10 [00611 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 optionally 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 15 an aryl(CI-C 4 alkyl). In another embodiment, the aryl(CI-C 4 alkyl) has two optionally substituted aryl substituents. In another embodiment, the aryl(CI-C 4 alkyl) has one optionally substituted aryl substituent. Exemplary aralkyl groups include, for example, benzyl, phenylethyl, (4-fluorophenyl)ethyl, phenylpropyl, diphenylmethyl (i.e., Ph 2 CH-), diphenylethyl (Ph 2
CHCH
2 -) and the like. 20 [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 containing one to three rings having from three to twelve carbon atoms (i.e., C 3
-C
12 cycloalkyl) or the number of carbons designated. In one embodiment, the cycloalkyl has one ring. In another 25 embodiment, the cycloalkyl is a C 3
-C
6 cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl and the like.
WO 2012/155066 PCT/US2012/037570 23 [00631 The term "optionally substituted cycloalkyl" as used herein by itself or part of another 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, optionally substituted alkyl, 5 haloalkyl, hydroxyalkyl, aminoalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,
-CO
2 R, -COR, -SO 2 R, -N(Re)CORf, -N(R )SO 2 R9 or -N(R e)C=N(Rh)-amino, 10 wherein Re, Rd, Re, Rf, R9, 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 optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is 15 substituted with one substituent. In another embodiment, the substituents are selected from hydroxy (i.e., a hydroxycycloalkyl, e.g., a monohydroxycycloalkyl or dihydroxycycloalkyl) or -CO 2 H. Exemplary optionally substituted cycloalkyl groups include: HO Ph CO2H 0 2 H OH O C0 2 H OH OH I and 20 and the like. [0064] The term "alkenyl" 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=CH 2 , -CH 2
CH=CH
2 , 25 CH 2
CH
2
CH=CH
2 , -CH 2
CH
2
CH=CHCH
3 and the like. [0065] 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 WO 2012/155066 PCT/US2012/037570 24 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, optionally substituted aryl, optionally 5 substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido. Exemplary optionally substituted alkenyl groups include -CH=CHPh, -CH 2 CH=CHPh and the like. [00661 The term "cycloalkenyl" as used herein by itself or part of another group refers to a cycloalkyl group as defined above containing one, two or three carbon 10 to-carbon double bonds. In one embodiment, the cycloalkenyl has one carbon-to carbon double bond. Exemplary cycloalkenyl groups include cyclopentene, cyclohexene and the like. [0067] The term "optionally substituted cycloalkenyl" as used herein by itself or part of another group means the cycloalkenyl as defined above is either 15 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, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, 20 aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido. [00681 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 alkynyl groups include -C--CH, -C--CCH 3 , -CH 2 C--CH, 25 CH 2
CH
2 C--CH and -CH 2
CH
2
C--CCH
3 . [00691 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, 30 hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, WO 2012/155066 PCT/US2012/037570 25 aralkyloxy, alkylthio, carboxamido or sulfonamido. Exemplary optionally substituted alkenyl groups include -C--CPh, -CH 2 C--CPh and the like. [0070] 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 5 carbon atoms (i.e., C 6
-C
14 aryl) such as phenyl (abbreviated as Ph), 1-naphthyl and 2-naphthyl and the like. [0071] 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 substituents independently selected from halo, nitro, 10 cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, -CONHSO 2 Me, -CO 2 R, -COR, -SO 2 Rd, 15 N(R e)CORf, -N(Re)SO2R9 or -N(R e)C=N(Rh)-amino, wherein R', Rd, R e, Rf, R9, 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 substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three 20 substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally 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 25 methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3 methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl and 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4 fluorophenyl, 4-CO 2 H-phenyl and the like. The term optionally substituted aryl 30 is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include WO 2012/155066 PCT/US2012/037570 26 and the like. [0072] 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 5 fourteen ring atoms (i.e., 5- to 14-membered heteroaryl) and one, two, three, or four heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. In one embodiment, 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 heteroaryl is a 10 5-membered heteroaryl. In another embodiment, the heteroaryl is a 6-membered heteroaryl. In another embodiment, the heteroaryl is a 6-membered heteroaryl having one or two nitrogen atoms. Exemplary heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 15 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, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl 20 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. [0073] The term "optionally 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 25 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 heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, 30 sulfonamido, -CO 2 R, -COR, -SO 2 Rd, -N(R e)CORf, -N(R e)S2Rg or -N(R e)C=N(Rh)-amino, wherein Re, Rd, Re, Rf, R9, and Rh are as defined above in WO 2012/155066 PCT/US2012/037570 27 connection with optionally substituted alkyl. In one embodiment, the optionally substituted heteroaryl has one substituent. In another embodiment, the substituent is an optionally substituted aryl, aralkyl, or optionally substituted alkyl. In another embodiment, the substituent is an optionally substituted phenyl. 5 Any available carbon or nitrogen atom may be substituted. Exemplary optionally substituted heteroaryl groups include Ph Ph SoPh O %Ph HN NN Ph HN N N N N N Ph Ph Ph Ph Ph s / HN HN N N N N N N Ph Ph Ph Ph /N NN HN HN -"N H / HN " 'N N N N and the like. [0074] The term "heterocyclo" as used herein by itself or part of another group 10 refers to saturated and partially unsaturated (containing one or two double bonds) cyclic groups containing one to three rings having from three to fourteen ring members (i.e., 3- to 14-membered 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 6-membered cyclic group containing 15 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 through a carbon or nitrogen atom. Exemplary heterocyclo groups include: WO 2012/155066 PCT/US2012/037570 28 N N N 0 ' N N S Sn - V- and and the like. [00751 The term "optionally substituted heterocyclo" as used herein by itself or part of another group means the heterocyclo as defined above is either 5 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 heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, 10 aralkyloxy, alkylthio, carboxamido, sulfonamido, -CO 2 R, -COR, -SO 2 Rd, -N(R e)CORf, -N(Re)SO2R9 or -N(R e)C=N(Rh)-amino, wherein Rc, Rd, R e, Rf, R9, and Rh are as defined above in connection with optionally substituted alkyl. Substitution may occur on any available carbon or nitrogen atom. Exemplary substituted heterocyclo groups include NN Ph 15 and the like. An optionally substituted heterocyclo may be fused to an aryl group to provide an optionally substituted aryl as described above. [00761 The term "alkoxy" as used herein by itself or part of another group refers to a haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, 20 optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. Exemplary alkoxy groups include methoxy, tert-butoxy,
-OCH
2
CH=CH
2 , -OCH 2
CH
2 OH, -OC(CH 3
)
2
CO
2 H, and the like. [0077] 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 25 aryloxy groups include phenoxy and the like. [0078] The term "aralkyloxy" as used herein by itself or part of another group refers to an aralkyl attached to a terminal oxygen atom. Exemplary aralkyloxy groups include benzyloxy and the like.
WO 2012/155066 PCT/US2012/037570 29 [00791 The term "alkylthio" as used herein by itself or part of another group refers to a haloalkyl, aralkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal sulfur atom. Exemplary alkyl groups include -SCH 3 and 5 the like. [0080] 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. [0081] The term "amino" as used herein by itself or part of another group refers 10 to a radical of formula -NRaRb wherein Ra and Rb are independently hydrogen, haloalkyl, aralkyl, optionally substituted alkyl, optionally 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 15 heterocyclo. Exemplary amino groups include -NH 2 , -N(H)CH 3 , -N(CH 3
)
2 ,
-N(H)CH
2
CH
3 , -N(CH 2
CH
3 ), -N(H)CH 2 Ph and the like. [0082] The term "carboxamido" as used herein by itself or part of another group refers to a radical of formula -CO-amino. Exemplary carboxamido groups include -CONH 2 , -CON(H)CH 3 , -CON(H)Ph, -CON(H)CH 2
CH
2 Ph, 20 CON(CH 3
)
2 , CON(H)CHPh 2 and the like. [00831 The term "sulfonamido" as used herein by itself or part of another group refers to a radical of formula -S0 2 -amino. Exemplary sulfonamido groups include -SO 2
NH
2 , -SO 2
N(H)CH
3 , -SO 2 N(H)Ph and the like. [0084] The term "about," as used herein, includes the recited number ± 10%. 25 Thus, "about 10" means 9 to 11. [0085] Certain of the compounds of the present disclosure may exist as stereoisomers, i.e., isomers that differ only in the spatial arrangement of atoms, including optical isomers and conformational isomers (or conformers). The disclosure includes all stereoisomers, both as pure individual stereoisomer 30 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.
WO 2012/155066 PCT/US2012/037570 30 [00861 The term "substantially free of' as used herein means that the compound comprises less than about 25% of other stereoisomers, e.g., diastereomers and/or enantiomers, as established using conventional analytical methods routinely used by those of skill in the art. In one embodiment, the amount of other 5 stereoisomers is less than about 24%, less than about 23%, less than about 22%, less than about 2 1%, less than about 2 0%, 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 10 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%. [0087] Stereoisomerically enriched compounds that contain about 95% or more of a desired stereoisomer, 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 15 pure stereoisomers." [0088] Stereoisomerically enriched compounds that contain about 99% or more of a desired stereoisomer are referred to herein as "pure" stereoisomers." The purity of any stereoisomerically enriched compound can be determined using conventional analytical methods such as, for example, normal phase HPLC, 20 reverse phase HPLC, chiral HPLC, and H and "C NMR. Compounds [0089] In one embodiment, compounds of Formula I are provided: 0 E R 2 Y R
R
3 b R 3 a X 0 R1e X OR0 Rid 25 wherein: la lbi R , R", RiC, and R" are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, WO 2012/155066 PCT/US2012/037570 31 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; 5 R 3 a 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; R 3 is selected from the group consisting of halo, optionally substituted 10 alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; or
R
3 a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl or a 3- to 9-membered optionally substituted heterocyclo; 15 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 R4 20 R 26 c is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, 5b 5 -S0 2
R
5 , and R; wherein R 4 and R 5 have the meanings as described below for Formula II; 25 or R26b and R 2 6 c taken together form a 4- to 9-membered optionally substituted heterocyclo; R 5 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl; 30 X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR; R' is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; WO 2012/155066 PCT/US2012/037570 32 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 acceptable salt, solvate, or prodrug thereof. 5 [0090] In another embodiment, compounds of Formula I are provided, wherein: la lbi R , R", RiC, and R" 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 cycloalkenyl, optionally 10 substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R
3 a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, 15 optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; R 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 20 substituted aryl, and optionally substituted heteroaryl; or
R
3 a and R 3 b taken together form a 3- to 9-membered 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 25 substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; R26b is selected from the group consisting of hydrogen and optionally substituted alkyl; R 26 is selected from the group consisting of hydrogen, optionally 30 substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, and -SO 2 R 5- WO 2012/155066 PCT/US2012/037570 33 or R26b and R26 taken together form a 4- to 9-membered optionally substituted heterocyclo; R 5 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally 5 substituted aryl, and optionally substituted heteroaryl; X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR"; R' is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; 10 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 acceptable salt, solvate, or prodrug thereof. [0091] In another embodiment, compounds of Formula I are provided, wherein: 15 Ria, R , R , and Rid 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 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; 20 R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R
3 a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl or a 3- to 9-membered optionally substituted heterocyclo; E is selected from the group consisting of -OR26a and -NR26bR26c. 25 R 26 a 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; 30 R 26 c is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, and-SO 2 R5b- WO 2012/155066 PCT/US2012/037570 34 wherein R 4 and R' have the meanings as described below for Formula II; or R and R 26 taken together form a 4- to 9-membered optionally substituted heterocyclo; R 5 is selected from the group consisting of optionally substituted alkyl, 5 optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl; X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR; R' is selected from the group consisting of hydrogen, optionally 10 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 acceptable salt, solvate, or prodrug thereof. 15 [0092] In another embodiment, compounds of Formula II are provided: R4 R 2 0 ,R 5 R la ,I Rlb R 3 b X 0 Rid wherein: la lb i R , R , RiC, and R" are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, 20 optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; R is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; 25 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; WO 2012/155066 PCT/US2012/037570 35 R 3 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; or 5 R 3 a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl;
R
4 is selected from the group consisting of hydrogen and optionally substituted alkyl;
R
5 is selected from the group consisting of:
W
1 7 / R 13
R
12 a R 18
R
17 a R17b/
R
23
R
22 a q R R 22 b aR 6 b R / ' R12b / r 22b -(CRW R 1 7 R and R 22 c N
R
8 a R 8 b R1 2 d R 14
R
19 OR21b R 2 2 d 10 R5-1 R5-2 R5-3 R5-4 wherein: each R 6 a and R 6 b is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; 15 R 7 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; R a and R'b are each independently selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; or 20 R 8 a and R'b taken together with the carbon that they are attached form a 3 to 8-membered optionally substituted cycloalkyl;
W
1 is selected from the group consisting of -OR 9 a and -NR 9 bR 9 ';
R
9 a is hydrogen; R9b is selected from the group consisting of hydrogen, optionally 25 substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, 9d 9eR9f. optionally substituted heteroaryl, -SO 2 R9', and -CONR R
R
9 ' is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or WO 2012/155066 PCT/US2012/037570 36 R 9 and R 9 ' 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; 5 R 9 e and R 9 f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or
R
9 e and R 9 f taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; W is selected from the group consisting of -OR4 and -NR'aR' I 10 with the proviso that when Wl is -OR9a and W2 is -OR 10 then at least one of R 7 , R 8 a, and R b is other than hydrogen; RIO is hydrogen; or one of R9a and RIO is hydrogen and the other is a metabolically cleavable group; 15 RIla is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SO 2 Rll, and -CONRlld Rle ; R is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, 20 and optionally substituted heteroaryl; or Ru 1 a and Ru b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; Rl" is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl; 25 R and R" lare each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or R and Rile together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; n is 1, 2, 3, 4, or 5; 30 each Ra 12 , R1 2 b, R1 2 c and R12d is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; WO 2012/155066 PCT/US2012/037570 37 R 4 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; Z is selected from the group consisting of -OR" and -NR 16aR 6; or Z and R14 taken together form a carbonyl, i.e., a C=O, group. 5 R 15 is selected from the group consisting of hydrogen and metabolically cleavable group;
R
16 a is selected from the group consisting of -SO 2 R1 6 ' and -CONR 16R 1e R 6b is selected from the group consisting of hydrogen and optionally substituted alkyl; 10 R 1 6 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R1 6 d and R 1e are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, 15 optionally substituted aryl, and optionally substituted heteroaryl; or R 1d and R1 6 e 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; 20 each R1 7 a, R 7 b, R 1 7 c and R 1 7 d is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R's is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R19 is selected from the group consisting of hydrogen, optionally 25 substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; R20 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl;
R
21 a and R are each hydrogen; or one of Ra 21 and R21b is hydrogen and the other is metabolically cleavable 30 group; q is 0, 1, 2, or 3; r is 1, 2, or 3; WO 2012/155066 PCT/US2012/037570 38 each R 22 a, R 2 2 b, R 22 c, and R 2 2 d is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; 5 R24 is selected from the group consisting of -SO 2
R
2 4 a and -CONR24b R24c
R
24 a is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R and R are each independently selected from the group consisting of 10 hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
R
24 b and R 24 c taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclo; s and t are each independently 1, 2, or 3; 15 X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, 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 hydrogen, optionally 20 substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and ~-- represents a single or a double bond, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0093] 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 enantiomers, 25 e.g., a racemic mixture. In another embodiment, the compound of Formula I or II is provided as a single stereoisomer. [0094] In another embodiment, compounds of Formula III are provided: o E R2 RiC R3b R1 i X O WO 2012/155066 PCT/US2012/037570 39 a lb le Id 2 3a 3 wherein Ri, R , R , R , R2, R , Rl , E, X, and Y have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0095] In another embodiment, compounds of Formula III are provided wherein 45 la lb le Id 2 3a 3b 4 5 5 E is NRR, and Ri, R , R , R , R, Ra, R , R, R, X, and Y have the meanings as described above for Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [00961 In another embodiment, compounds of Formula IV are provided: 0 E R 2
R
1 a Rib Nb R 3 b I R 3 a R1e x 0 Rid IV la lb le Id 2 3a 3 10 wherein Ri, R , R , R , R, Ra, RE , 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. [0097] In another embodiment, compounds of Formula IV are provided wherein 45 la lb le Id 2 3 3b 4 5 E is -NR4R , and R , R , R , R , R2, R3a, R3b, R4, R , X, and Y have the 15 meanings as described above for Formula II, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0098] In another embodiment, compounds of Formula V are provided: o E R 2 Ria Re /X O (R), Ric x 0 Rid i.e., R3a and R 3 b of Formula I are taken together form a 3- to 9-membered la lb le ld 2 20 optionally substituted cycloalkyl, wherein R , R , R , R , R , E, X, and Y have the meanings as described above for Formula I, u is 0, 1, 2, 3, 4, 5, or 6, v is 0, 1, 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 25 substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, WO 2012/155066 PCT/US2012/037570 40 optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0099] In another embodiment, compounds of Formula V are provided wherein E 45 la l Ic d 2 4 5 5 is NRR, and RR , R , R , R2, R4, R , X, and Y have the meanings as described above for Formula II, u is 0, 1, 2, 3, 4, 5, or 6, v is 0, 1, 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 alkynyl, 10 optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [00100] In another embodiment, compounds of Formula V are provided wherein u is 1, 2, 3, 4, 5, or 6, each R is independently (CI-C 4 )alkyl and v is 0, 1, or 2, or a 15 pharmaceutically acceptable salt, solvate, or prodrug thereof. [00101] In another embodiment compounds of Formula V are provided wherein v is 0 and u is 0, 1, 2, 3, 4, 5, or 6, , i.e., R a and R b of Formula I are taken together form a 3- to 9-membered unsubstituted cycloalkyl. [0100] In another embodiment compounds of Formula V are provided wherein v 20 is 0 and u is 2, 3, or 4, i.e., R3a and R of Formula I are taken together form a 5-, 6-, or 7-membered unsubstituted cycloalkyl. [0101] In another embodiment, compounds of any one of Formulae VI-XXI are provided: WO 2012/155066 PCT/US2012/037570 41 OgE O E O EO E R2 R2 R2 R2 Rla Rla R R1a -a- W R .1. lbYYY Y R R 3 b R R 3 b Rb .R 3 b Rib R 3 b
R
3 a 'R 3 a R 3 R3a Ric X O RCe X O R~e X Re X O R R a R R x;x- R~ ic x Ro )--0X 0- VI VII VIII IX O E O E O E O E R2 R2 R2b RR2 Rl a .,R R 1 a R Rlb a .. R Rlb a
R
3 a R3a 'R 3 a R3a R1 X R1 X O R1 X Rc X 0 Rl Rld Rld Rld O E O E O,,-E O E R2 R2 R 2 i 2
R
3
R
3 3 R3 R b R 3 b R b ~ 3 b b N. 3 b b 4 N " , Ri Y Ri R Ri Ri XIV XV XVI XVII 0 E O E 0 E R2 R2 R2 R2 F RlbRa '-Y Rla '-Y Rla Y We R Y R R 3 b Rb .R 3 b Rib Rib , 3b
R
3 a R 3 a 'R 3 a 3a R1 X R1c X O Rc X O R1c X0 Rid Rid Rid Rid XVIII XIX XX XXI l lb le Id 2 3a 3 wherein Ri, R , R , R , R2, R , Rl, E, X, and Y have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 5 [0102] In another embodiment, compounds of any one of Formulae VI-XXI are 4 l lb Ic d 2 3a 3b 4 5 provided, wherein E is NRRs, and Ria, R , Re, R , R2, Ra, R, R, R, X, and Y have the meanings as described above for Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0103] In another embodiment, compounds of any one of Formulae VI-XXI are 10 provided substantially free of one or more other stereoisomers. In another embodiment, compounds of any one of Formulae VI-XXI are substantially pure WO 2012/155066 PCT/US2012/037570 42 stereoisomers. In another embodiment, compounds of any one of Formulae VI-XXI are pure stereoisomers. [0104] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided 5 wherein: a) Rla, R l, Rle, and Rid are independently selected from the group consisting of hydrogen, fluoro, and chloro; b) Ria and Rid are hydrogen; R is selected from the group consisting of hydrogen and fluoro; and Ric is selected from the group consisting of fluoro and 10 chloro; c) R 2 is optionally substituted phenyl; d) R3a is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, and optionally substituted cycloalkyl; 15 e) R 3 b is selected from the group consisting of halo, optionally substituted alkyl, optionally substituted (cycloalkyl)alkyl, and optionally substituted cycloalkyl; f) R 3 a and R 3 b taken together form an optionally substituted 3- to 9-membered cycloalkyl; 20 g) E is -NR 4
R
5 and R 4 is hydrogen; h) X is NH; i) X is 0; j) X is S; k) Y is 0; 25 l) Y is S; m) Y is NH; or n) X and Y are NH; or any combination thereof. [0105] In another embodiment, compounds of any one of Formulae I-XXI, or a 30 pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR 4
R
5 , R 5 is R5-1; R 6 a and R 6 b are hydrogen; R 7 is CI-C 4 alkyl; R 8 a and R'b are hydrogen; W is -OR 4, R9 and R10 are hydrogen; and n is 2.
WO 2012/155066 PCT/US2012/037570 43 [01061 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 -NR 4
R
5 ; R 5 is R5-1; R 6 a and R 6 b are hydrogen; R 7 is CI-C 4 alkyl; R 8 a and R'b are hydrogen; W is -NR aR , R 9 is hydrogen; and n is 2. 5 [0107] 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 -NR 4
R
5 ; R 5 is R5-1; R6a and R 6 b are hydrogen; R 7 is CI-C 4 alkyl; R 8 a and R'b are hydrogen; W is -OR 4, one of R 9 and R 1 0 is hydrogen and the other is a metabolically cleavable group; and n is 2. 10 [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 -NR 4 R ; R is R5-2; Rua, R1 2 b, R 2 c, and R1 2 d are each hydrogen; R is hydrogen; Z is -OR 15 and R 15 is hydrogen; o is 1 or 2; and p is 1 or 2. [0109] In another embodiment, of any one of Formulae I-XXI, or a 15 pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, 5 512a 12b 12c 12d 13 wherein E is -NR 4 R ; R is R5-2; R , R , R , and R are each hydrogen; R is hydrogen; Z is -NR iaR 6b; o is 1 or 2; and p is 1 or 2. [0110] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, 5 512a 12b 12c 12d 13 20 wherein E is -NR 4 R ; R 5 is R5-2; R , R , R , and R are each hydrogen; R is hydrogen; Z is -OR 15 and R 15 a metabolically cleavable group; o is 1 or 2; and p is 1 or 2. [0111] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, 5 51a 1l 7 b 17c 17 25 wherein E is -NR 4
R
5 ; R is R5-3; R 1 a, R , R , and R 7d are each hydrogen; 18 19 20la l1b R , R , and R20 are hydrogen; Ra and R2 are hydrogen; and q and r are 1. [0112] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, 5 5 17a 1l 7 b 171d wherein E is -NR 4 R ; R is R5-3; R , R , R 7c, and R'd are each hydrogen; 18 19 2021a 21 30 R , R , and R20 are hydrogen; one of R and R 2 1b is hydrogen and the other is a metabolically cleavable group; and q and r are 1.
WO 2012/155066 PCT/US2012/037570 44 [01131 In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R2 is an optionally substituted aryl having the Formula R2-1:
R
25 d
R
25 c R25e
R
25 b R 25a R2-1 25a 25b 2c 5d 25e 5 and R , R , R25c, R25a, and R are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, optionally substituted alkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In one embodiment, R2a is selected from the group consisting of hydrogen and fluoro; R 2 5b is chloro; R 2 5 c is selected from the group consisting of 10 hydrogen and fluoro; and R 2 5 d and R 25 e are hydrogen. [0114] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R 2 is an optionally substituted pyridyl. [0115] In another embodiment, compounds of any one of Formulae I-XXI, or a 15 pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR4R5, R4 is hydrogen, and R is selected from the group consisting of: WO 2012/155066 PCT/US2012/037570 45
OR
9 a ORea NR 9 bR 9 4
OR
10 NR11aR11b OR 1 0
OR
15 R7 ' R7 R7 R5-8 R5-5 R5-6 R5-7 16aR16b NR1 6 aR1 6 b
OR
15 V NRl al bOR 15 R14"q R14 R14 R5-9 R5-1 0 R5-11 R5-12 NR1 6 aR1 6 b OR 15 NR1 6 aR16b , R 20 R14 R1g OR 2 1b R5-13 R5-14 R5-15 R5-16 /R20 24 R21a NR1 6 aRl 6 b and N'R24
R
1 9
OR
2 1b R5-18 R5-19 R5-17 including stereoisomers, e.g., enantiomers, thereof, wherein:
R
7 is optionally substituted C 1
-C
4 alkyl; R9a and R10 are each hydrogen; or 5 one of R 9 a and R 10 is hydrogen and the other is a metabolically cleavable group; R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, 9d 9eR9f. optionally substituted heteroaryl, -SO 2 R9', and -CONR R 10 R 9 ' is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 9 and R 9 ' taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; 15 R 9 d is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl; R9e and R9f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or WO 2012/155066 PCT/US2012/037570 46 R9' and R9f taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; RIa is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, 5 optionally substituted heteroaryl, -SO 2 R Il, and -CONR RIle ; Rll is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or RIa and Rulb taken together with the nitrogen atom to which they are 10 attached form a 4- to 8-membered optionally substituted heterocyclo; Rl" is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl; Rld and R" are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or 15 RIld and Rile taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; R 4 is selected from the group consisting of hydrogen, C 1
-C
4 alkyl, or
C
3
-C
6 cycloalkyl;
R
15 is hydrogen or a metabolically cleavable group; 20 Ri1a is selected from the group consisting of -SO 2 Ri 6 and -CONR 1dR Me R 6b is selected from the group consisting of hydrogen and optionally substituted alkyl; R 16 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally 25 substituted heteroaryl; R 1d and R Me are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 6 d and R Me taken together with the nitrogen atom to which they are 30 attached form a 4- to 8-membered heterocyclo; R19 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; WO 2012/155066 PCT/US2012/037570 47 R20 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; p21a p21b R and R are each hydrogen; or one of R 2 a and R 21 is hydrogen and the other is metabolically cleavable 5 group;
R
24 is selected from the group consisting of -SO 2
R
2 4 a and -CONR 2 4 bR 2 4 c.
R
24 a is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and 10 R 24 b and R 2 4 c are each independently selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R
24 b and R 24 c taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclo. 15 [01161 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 -NR 4
R
5 , R 4 is hydrogen, and R 5 is selected from the group consisting of R5-5, R5-6, R5-10, R5-11, R5-12, R5-13, and R5-14. [0117] In another embodiment, compounds of any one of Formulae I-XXI, or a 20 pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR 4
R
5 , R 4 is hydrogen, and R 5 is selected from the group consisting of R5-10 and R5-12 and R 14 is hydrogen or methyl and R 15 is hydrogen. [0118] In another embodiment, compounds of any one of Formulae I-XXI, or a 25 pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein E is -NR4R5, R4 is hydrogen, and R is selected from the group consisting of: OH OH OH OH OH/ OH OH OH
R
8 a R R8a OH OH /OH OH
R
7
R
8 b and H 3 0 R 8 b R aR 8 a WO 2012/155066 PCT/US2012/037570 48 wherein:
R
7 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; and R a and R b are each independently selected from the group consisting of 5 hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopropyl. [0119] 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 R is selected from the group consisting of: OH OH OH
NHSO
2 R11C /NHSO 2 R11C NHSO 2 RllC
R
8 a OH OH OH
NHSO
2 RllC / NHSO 2 R11C / NHSO 2
R
11 C
R
7 RbH 3 6 R 8 b
R
8 a R8a R8a
NHSO
2
R
9 d NHSO 2
R
9 d NHSO 2
R
9 d OH OH a OH NHSi 2
R
9 d NHS 2
R
9 d cyloro OH OH /OH O
R
7 a h is ad f th R 10 wherein: 8 R2R2
R
7 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; R Saand R b are each independently is selected from the group consisting 15 of hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopropyl;
R
9 d is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, and cyclopropyl; and WO 2012/155066 PCT/US2012/037570 49 R"' is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, and cyclopropyl. [0120] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, 5 wherein E is -NR4R5, R4 is hydrogen, and R is selected from the group consisting of: OH OH OH NHCONHR11d 4 - NHCONHR11d NHCONHRlId
R
8 a OH OH OH NHCONHRlld NHCONHR11d - NHCONHRlId R R 8 b H 8 b
R
8 a R8a R8a
NHCONHR
9 e
NHCONHR
9 e
NHCONHR
9 e /OH /,,OH z O R7 RRR 8a
NHCONHR
9 e NHCONHR 9 e NHCONHR 9 e /OH /OH - OH
H
7
R
8 b and HC 8 b R R 8 a R 8 a3 R 8 a wherein:
R
7 is selected from the group consisting of methyl, ethyl, propyl, 10 isopropyl, and cyclopropyl; R a and R b are each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopropyl; R9e is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, and cyclopropyl; and 15 RIld is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, and cyclopropyl. [0121] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, WO 2012/155066 PCT/US2012/037570 50 wherein E is -NR4R5, R4 is hydrogen, and R is selected from the group consisting of: 1 R14 , R14 OH OH OH OH 'OOH H OH H = R14 R 1 OH H OH OHI OH % -OH IIOH > H OH OH -OH SO H O 20 1 R0 OH OH IOH R an . R19 RR 1 9 OH R 19 H O .0OH -OH Q( 0H OH OH OH O OH OH H H
R
2 20 R 20 and ~ O
R
1 9 0R 9
OHR
1 9 HF9O wherein: 5 R 14 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; and
R
19 and R 20 are each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopropyl. [0122] In another embodiment, compounds of any one of Formulae I-XXI, or a 10 pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, WO 2012/155066 PCT/US2012/037570 51 wherein E is -NR4R , R4 is hydrogen, and R is selected from the group consisting of:
NHSO
2
R
6 c NHSO 2 R1 6 C NHSO 2 R1 6 C YN R14 z 16C NH02RS16R 6 C NHSO2R~e HORe NHSO2R~e
NHSO
2 R 1 6 C ,. NHSQ2R16C 16NHSOR1c R4R
NHSO
2 Rc16c NHSO2R16c NHSO2R16c
NHSO
2 R16C ,NHSO 2 R16C ,,
NHSO
2 R1 6 C NHSO 2 R16c j N HSO 2 R16C N S24 0 '.NSR 16
NH
2
R
6 NHS0 2 R
-
6 C and
NHSO
2 R1 6 C
NHSO
2 R1 6 C wherein: 5 R 14 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; and WO 2012/155066 PCT/US2012/037570 52 R 16 is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, and cyclopropyl. [0123] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, 5 wherein E is -NR4R , R4 is hydrogen, and R is selected from the group consisting of: 'R14 NHCONHR1 6 d &HCONHR1 6 d NHCONHRi 6 d R14 NHCONHRe NHCONHRiad NHCONHRiad NHCONHR 1 6 d , .. NHCQNHR16d N Hd R14 R NHCONHR16d ,4 NHCONHRi6d, NNHCONHR16d 14 R NHCONHR16d , NHCONHR16d , -NHCONHRi 6 d NHCONHR16dHd NHCONHR16d NHCONHR 16d 14 NHCONHRid ~NHCONHR 16d > NHCONHR 16d ***Q 14 NH 14 ONHONH 14 16dOHR6 / QR- and NHCONHR1 6 d NNHCONHRi6d wherein: WO 2012/155066 PCT/US2012/037570 53 R 4 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclopropyl; and R 1d is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, and cyclopropyl. 5 [0124] 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 -NR 4 R , R 4 is hydrogen, and R 5 is selected from the group consisting of: OH~ 'O H ,. ''OH ' 0 OH j 3 TIIIH3
HH
3 0 SH OH OH 'OH 6H 3
CH
3 O H , OH -OH Q-OH OH3 O OH OHOH "C/IOH OH OH OH OH 0H 'OH OH and AoOH V~HandV CH3 CH 3
CH
3
CH
3 10 [0125] 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 R is selected from the group consisting of: WO 2012/155066 PCT/US2012/037570 54
OR
15
'
1 OR15 OR15 and "OR15 R 14 ' R14 ' n14 R144 wherein: R 4 is selected from the group consisting of hydrogen and C 1
-C
4 alkyl; and
R
15 is hydrogen or a metabolically cleavable group. 5 [01261 In one embodiment, the metabolically cleavable group at R 15 is selected from the group consisting of: O R 2 9 a 0 N*,R29b and OR 3 0a
R
28 a R28b
OR
3 Ob wherein: each R 28 a and R 2 8 b is independently selected from the group consisting of 10 hydrogen, optionally substituted alkyl, and aralkyl;
R
29 a and R 29 are each selected from the group consisting of hydrogen and optionally substituted alkyl; v is 1, 2, 3, or 4; and R30a and R30b are each selected from the group consisting of hydrogen, 15 optionally substituted alkyl, aralkyl, optionally substituted aryl, and monovalent pharmaceutically acceptable cation; or taken together R 30 a and R 3 0b represent a divalent pharmaceutically acceptable cation or an optionally substituted alkylenyl. [0127] In another embodiment, the metabolically cleavable group at R 15 is the 20 residue of a natural or unnatural amino acid. In another embodiment, the metabolically cleavable group at R 15 is the residue of glycine, isoleucine alanine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, proline, serine, tyrosine, arginine, and histidine. 25 [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.
WO 2012/155066 PCT/US2012/037570 55 [0129] 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 0 and Y is NH. [0130] In another embodiment, compounds of any one of Formulae I-XXI, or a 5 pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided wherein X is S and Y is NH. [0131] 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 R 3 b are the same or different C 1
-C
10 alkyl. 10 [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 R 3 b are the same or different C 2
-C
10 alkyl. [0133] In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are 15 provided, wherein R3a and R 3 b are the same or different C 1
-C
6 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl. [0134] In another embodiment, compounds of any one of Formulae I-IV or VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are 20 provided, wherein R3a and R 3 b are the same or different C 2
-C
6 alkyl. [0135] 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 R 3 b are the same or different C 1
-C
4 alkyl. [0136] In another embodiment, compounds of any one of Formulae I-IV or 25 VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein R3a and R 3 b are the same or different C 2
-C
4 alkyl. [0137] 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 R 3 b are the same or different C 1
-C
3 alkyl. 30 [0138] 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 R 3 b are the same or different halo.
WO 2012/155066 PCT/US2012/037570 56 [01391 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 R 3 b are the same or different, and are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and neopentyl. 5 [0140] 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 R 3 b are the same or different, and are selected from the group consisting of ethyl, propyl, isopropyl, butyl, and neopentyl. [0141] In another embodiment, compounds of any one of Formulae I-IV or 10 VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R3a and R 3 b are fluoro. [0142] 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 R 3 b are the same, e.g., R3a is methyl and R 3 b is methyl, 3a3a 3b 3a i bp3b 15 R is ethyl and R 3 b is ethyl, R is propyl and R is propyl, etc. If R and R are the same, the carbon atom to which R 3 a and R 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 XII; Formula XIV and XVI; Formula XV and XXI; Formula XVII and XX; and Formula XVIII and XIX 20 represent equivalent isomers. [0143] 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 R 3 b are different, e.g., R 3 a is methyl and R 3 b is ethyl, R3a is methyl and R is neopentyl, R3a is ethyl and R is propyl, etc.. 25 [0144] 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 R 3 b are taken together to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring. In one embodiment, the optional substituent is a (CI-C 4 )alkyl. In another embodiment, 30 the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring is unsubstituted. [0145] In another embodiment, compounds of any one of Formulae I-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, WO 2012/155066 PCT/US2012/037570 57 wherein Ria and Rid are hydrogen, Rb and Ri" are each independently selected from the group consisting of hydrogen, chloro, and fluoro, and R2 is R2-1 wherein Raa, R 2b, R25c, R 25, and R e are each independently selected from the group consisting of hydrogen, chloro, and fluoro. 5 [0146] In another embodiment, compounds having any one of Formulae VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein: E is NR 4 R; ia ib ie id R , R , R , and R1 are each independently selected from the group 10 consisting of hydrogen, fluoro, and chloro; R is:
R
25 b
R
25 c R 2 5 a
R
2 5 d R 25e wherein: p25a, 25b R25 c 25d 5 Ra, R2, R2c, R2, and R are each independently selected from the 15 group consisting of hydrogen, fluoro, and chloro; R3a is Ci-C 6 alkyl; R3 is C1-C 4 alkyl; or R3a and R 3 b are taken together to form an optionally substituted 3- to 7-membered cycloalkyl; 20 R 4 is selected from the group consisting of hydrogen and optionally substituted C1-C 4 alkyl;
R
5 is selected from the group consisting of: I's OH 1'OH iI .OH and ,OH
R
14 R4 R4 R4 wherein: 25 R1 4 is selected from the group consisting of hydrogen and optionally substituted C1-C 4 alkyl; X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR; WO 2012/155066 PCT/US2012/037570 58 R' is selected from the group consisting of hydrogen and optionally substituted C 1
-C
4 alkyl; and R" is selected from the group consisting of hydrogen and optionally substituted C 1
-C
4 alkyl, 5 wherein the compounds are substantially free of one or more other stereoisomers. [0147] In another embodiment, compounds having any one of Formulae VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein: 10 E is NR 4 R ; Ria is hydrogen; R", R1, and Rid are each independently selected from the group consisting of hydrogen, fluoro, and chloro;
R
2 is:
R
25 b
R
25 c R 2 5 a
R
25 d 15 R25e wherein: p25a, 25b R25% R25d 25e Ra, R2, R2, R2, and R are each independently selected from the group consisting of hydrogen, fluoro, and chloro; R3a and R b are methyl; 20 or R3a and R 3 b taken together form a cyclopentyl, cyclohexyl, or cycloheptyl ring;
R
4 is hydrogen;
R
5 is selected from the group consisting of: OHOH H MOH e Me OOH 'OH OH and ,''OH Me Me ;and WO 2012/155066 PCT/US2012/037570 59 X and Y are NH, wherein the compounds are substantially free of one or more other stereoisomers. [0148] In another embodiment, compounds having any one of Formulae VI-XXI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, 5 wherein E is NR 4
R
5 , R 4 is hydrogen, and R 5 is selected from the group consisting of: >aOH - and
'
1 0 OH Me wherein the compound is substantially free of one or more other stereoisomers. [0149] In another embodiment, compounds having Formula VI, or a 10 pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein the compounds are substantially pure stereoisomers. [0150] In another embodiment, compounds having Formula XVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein the compounds are substantially pure stereoisomers. 15 [0151] In another embodiment, compounds having Formula XVI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, wherein the compounds are substantially pure stereoisomers. [0152] In another embodiment, compounds having Formula XVI, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are provided, 20 wherein: E is NR 4 R ;
R
4 is hydrogen; X and Y are NH;
R
3 a and R 3 b are methyl or ethyl, or 25 R3a and R 3 b taken together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring, each optionally substituted by one of more C 1
-C
4 alkyl groups; and R 5 is selected from the group consisting of: WO 2012/155066 PCT/US2012/037570 60 OH 'OH Me Me OH OH OH and OH Me Me wherein the compounds are substantially pure stereoisomers. [0153] In another embodiment, compounds of any one of Formulae VI-XXI are 26 a lb Ic d 2 3a 3b 26a provided, wherein E is -OR 2 6 a and Ria, R, R, R, R, Ra, R3 , R2, X, and Y 5 have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, R26a is hydrogen. [0154] In another embodiment, compounds of any one of Formulae VI-XXI are 26a la lb le Id 2 26a provided, wherein E is -OR ; R , R , R , R , R2, R a, X, and Y have the 10 meanings as described above for Formula I; and R3a and R 3b taken together form a 4- to 7-membered optionally substituted cycloalkyl or 4- to 7-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, R 2 6 a is hydrogen. In another embodiment, R3a and R taken together form a cyclobutyl, cyclopentyl, 15 cyclohexyl, cycloheptyl, or optionally substituted piperidinyl group. [0155] In another embodiment, compounds of any one of Formulae VI-XXI are provided, wherein E is -NR 26bR26c; Ra, R , R l, R , R2, R3a, R3' R26b, R26% , and Y have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 20 [0156] In another embodiment, compounds of any one of Formulae VI-XXI are provided, wherein E is -NR 26bR26c; Ra, R , R l, R I, R2, R21, R26, X, and Y have the meanings as described above for Formula I; and R3a and R 3 b taken together form a 4- to 7-membered optionally substituted cycloalkyl or 4- to 7-membered optionally substituted heterocyclo, or a pharmaceutically acceptable 25 salt, solvate, or prodrug thereof. [0157] In another embodiment, compounds of any one of Formulae VI-XXI are provided, wherein E is -NR 26bR26c; Ria, R 1, Re, RId, R2, R21, R26c X, and Y WO 2012/155066 PCT/US2012/037570 61 have the meanings as described above for Formula I; and R 3 a and R b taken together form a 4- to 7-membered optionally substituted cycloalkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0158] In another embodiment, compounds of any one of Formulae VI-XXI are 5 provided, wherein E is -NR R26c and Ria, R ,R , R I, R2, R26b, R6, X, and Y have the meanings as described above for Formula I, and R3a and R 3 b taken together form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0159] In another embodiment, compounds of any one of Formulae VI-XXI are 10 provided, wherein E is -NR R26c and Ria, R ,R , R I, R2, R26b, R6, X, and Y have the meanings as described above for Formula I, and R3a and R 3 b taken together form a 4- to 7-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0160] In another embodiment, compounds of any one of Formula VI-XXI are 15 provided, wherein E is -NR2 R26c and Ria, R ,R , R I, R2, R26b, R6, X, and Y have the meanings as described above for Formula I, and R3a and R 3 b taken together form a tetrahydropyranyl or optionally substituted piperidinyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0161] In another embodiment, compounds of any one of Formulae VI-XXI are 20 provided, wherein E is -NR26bR26c, and Ria, R ,R , R I, R2, R3a, R3b, X, and Y have the meanings as described above for Formula I, R26b is hydrogen, and R 2 6 c is optionally substituted cycloalkyl. In another embodiment, R 2 6 c is hydroxycycloalkyl. In another embodiment, R26c is cycloalkyl substituted with
-CO
2 H. 25 [0162] In another embodiment, compounds of any one of Formulae VI-XXI are provided, wherein E is -NR26bR26c, and Ria, R ,R , R I, R2, R3a, R3b, X, and Y have the meanings as described above for Formula I, R26b is hydrogen, and R26, is optionally substituted aryl. In another embodiment R 2 6 c is phenyl substituted with -CO 2 H. 30 [01631 In another embodiment, compounds of Formula XXII are provided: WO 2012/155066 PCT/US2012/037570 62 0 E R 2 R la Y Rib D I BA B--A R1 X 0 Rid HH wherein: la lb IC Id 2 Ri, R , R , R , R2, E, X, and Y have the meanings as described above for Formula I; 5 A is selected from the group consisting of CR 2 7 aR 2 7 b, 0, S, SO, SO 2 , and N28. 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 10 substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, sulfonamido, and -CO 2 R3; R27b is selected from the group consisting of hydrogen and optionally substituted alkyl; or R27a and R 2 7 b taken together form a 3- to 6-membered optionally 15 substituted cycloalkyl or 3- to 6-membered optionally substituted heterocyclo; R28 is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally 20 substituted heterocyclo, carboxamido, sulfonamido, amino, -CO 2
R
32 a, -COR 32 a,
-SO
2 R 32b, -N(R32c)COR 32, -N(R32c)SO 2 R3 and -N(R 32c)C=N(R )-amino; Rna is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; 25 R 32 b is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 32 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; WO 2012/155066 PCT/US2012/037570 63 R 32 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R is selected from the group consisting of optionally substituted alkyl, 5 optionally substituted aryl, and optionally substituted heteroaryl; and R is selected from the group consisting of hydrogen, -CN, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; B is -(CR 2aR29 10 D is -(CR30aR30 )x-; each R 2 9 a, R 2 9 b, R 3 0a, and R30b is independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, 15 optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido and sulfonamido; R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl; 20 w is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and xis 0, 1, 2, 3, 4, 5, 6, 7, or 8; with the proviso that the sum of w plus x is 1, 2, 3, 4, 5, 6, 7 or 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0164] In another embodiment, compounds of Formula XXII are provided as a 25 single stereoisomer, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0165] In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, and each R 29 a, R 29, R 30a, and R30b is independently hydrogen or (CI-C 4 )alkyl, or a pharmaceutically acceptable salt, 30 solvate, or prodrug thereof. [0166] In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, each R 2 9 a, R 2 9, R 30a, and R30b is WO 2012/155066 PCT/US2012/037570 64 independently hydrogen or (CI-C 4 )alkyl, and A is CR 2 7 aR 2 7 b, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0167] In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, each R 2 9 a, R 2 9, R 30a, and R30b is 27ap27b p27a 27b 5 independently hydrogen or (CI-C 4 )alkyl, A is CR2R2, and R and R are independently selected from the group consisting of hydrogen and alkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [01681 In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, each R 2 9 a, R 2 9 b, R 3 0a, and R 3 0b is 27ap27b p27a 27b 10 independently hydrogen or (CI-C 4 )alkyl, A is CR2R2, and R and R are hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [01691 In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, each R 2 9 a, R 2 9 , R a, and R 3 0b is independently hydrogen or (CI-C 4 )alkyl, and A is 0, or a pharmaceutically 15 acceptable salt, solvate, or prodrug thereof. [0170] In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, each R 2 9 a, R 2 96, R3 , and R30 is independently hydrogen or (CI-C 4 )alkyl, and A is SO 2 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 20 [0171] In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, each R 2 9 a, R 2 9 , R a, and R 3 0b is independently hydrogen or (CI-C 4 )alkyl, and A is NR 28 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0172] In another embodiment, compounds of Formula XXII are provided 29a 29b 30a 30 25 wherein w is 1, 2, or 3, x is 1, 2, or 3, R , R , R3, and R 3 Ob are hydrogen, and A is NR 2 8 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0173] In another embodiment, compounds of Formula XXII are provided wherein w is 1, 2, or 3, x is 1, 2, or 3, R 29, R29 , R 30 a, and R 3 0b are hydrogen, A is NR28, and R 2 8 is selected from the group consisting of hydrogen, optionally 30 substituted alkyl, carboxamido, sulfonamido, amino, -CO 2 R a, -CORna
-SO
2 R 32b, -N(R 3 2 c)COR32a, -N(R 32c)SO 2 R and -N(R32c)C=N(R )-amino, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
WO 2012/155066 PCT/US2012/037570 65 [0174] In another embodiment, compounds of Formula XXII are provided 29a 29b 30a 2 wherein w and x are 1, each R , R , R , and R 3 0b is hydrogen, A is NR28, and R28 is selected from the group consisting of hydrogen, optionally substituted alkyl, carboxamido, sulfonamido, -CO 2 Rna, -COR a, -SO 2 R32b, -N(R32c)COR32a 5 -N(R 32c)SO 2
R
3 2 e and -N(R 32 c)C=N(R 32 )-amino, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0175] In another embodiment, compounds of Formula XXII are provided wherein w and x are 2, each R 2a, R 29, R 30a, and R 3 0b is hydrogen, A is NR28, and R28 is selected from the group consisting of hydrogen, optionally substituted 10 alkyl, carboxamido, sulfonamido, -CO 2 Rna, -COR a, -SO 2 R32b, -N(R32c)COR32a -N(R 32c)SO 2
R
32 e and -N(R 32 c)C=N(R 32 )-amino, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0176] In another embodiment, compounds of Formula XXII are provided wherein w and x are 3, each R 2 9 a, R 29 b, R30a, and R 3 0b is hydrogen, A is NR 28 , and 15 R28 is selected from the group consisting of hydrogen, optionally substituted alkyl, carboxamido, sulfonamido, -CO 2 Rna, -COR a, -SO 2 R32b, -N(R32c)COR32a -N(R c)SO 2
R
32 e and -N(R 32 c)C=N(R 32 f)-amino, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0177] In another embodiment, compounds of Formula XXII are provided 26a 20 wherein E is -OR , or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0178] In another embodiment, compounds of Formula XXII are provided wherein E is -NR 26
R
26 c, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 25 [0179] In another embodiment, compounds of Formula XXIII are provided: 0 E R 2 Rla Rib A R1e X 0 Rid XXIII wherein R a, R l, R1, 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, 1, or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
WO 2012/155066 PCT/US2012/037570 66 [0180] In another embodiment, compounds of Formula XXIV are provided: R 2 R la Rib A z R1c X 0 Rild XXIV la lb ic Id 2 wherein Ri, R , 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 z 5 has the meaning as described above for Formula XXIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0181] In another embodiment, compounds of Formula XXV are provided: E R 2 R1b A z R1 X 0 Rid XXV la lb Ic C Id 2 wherein Ri, R , R , R , R2, E, X, and Y have the meanings as described above 10 for Formula I, A has the meaning as described above for Formula XXII, and z has the meaning as described above for Formula XXIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0182] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided, wherein E is -OR 2 6 a and R 26 a is hydrogen, or a pharmaceutically 15 acceptable salt, solvate, or prodrug thereof. [0183] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided, wherein E is -NR26b R 26c, 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 20 aralkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, R 26 c is a hydroxyalkyl, e.g., a monohydroxyalkyl or dihydroxyalkyl. In another embodiment, R26, is an optionally substituted (cycloalkyl)alkyl. In another embodiment, R 26 is a (heterocyclo)alkyl. In another embodiment, R 26 c is optionally substituted cycloalkyl. In another 25 embodiment, R 2 6 , is optionally substituted phenyl.
WO 2012/155066 PCT/US2012/037570 67 [0184] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CR 2aR27b, 0, or NR28, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0185] In another embodiment, compounds of any one of Formulae XXIII-XXV 27a 5 are provided wherein A is CHR , or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0186] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CHR 2 7 a and R 2 7 a is selected from the group consisting of hydrogen, hydroxy, amino, alkoxy, optionally substituted alkyl, haloalkyl, 10 substituted heteroaryl, carboxamido, sulfonamido, and -CO 2 H, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0187] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CH 2 or NR28, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 15 [0188] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CH 2 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0189] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is NR28, or a pharmaceutically acceptable salt, solvate, or 20 prodrug thereof. [0190] In another embodiment, compounds of any one of Formulae XXIII-XXV are provided wherein A is CH 2 and z is 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0191] In another embodiment, compounds of any one of Formulae XXIII-XXV 25 are provided wherein A is CH 2 , z is 1, E is -NR26bR26c , R26b is hydrogen, and R26, 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, solvate, or prodrug thereof. In another embodiment, R 26 c is optionally substituted cycloalkyl, e.g., a 30 hydroxycycloalkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, R 26 is optionally substituted aryl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another WO 2012/155066 PCT/US2012/037570 68 embodiment, R 26 c is optionally substituted heteroaryl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0192] In another embodiment, compounds of Formula XXVI are provided: H R2 NR 26, R Ra NH R1 N 0 Rild H xv R~e HXXVI 5 wherein R a, R , R I, R I, R2, and R 26c have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0193] In another embodiment, compounds of Formula XXVII are provided: NH R1 N 0 Rid H wherein R i, R , R I, R I, R2, and R 26c have the meanings as described above for 10 Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0194] In another embodiment, compounds of Formula XXVIII are provided: R 2 R~e R1 Ria N H R1 N 0 Rild H xvl R~e HXXVIII wherein R i, R , R I, R I, R2, and R 26C have the meanings as described above for Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 15 [0195] In another embodiment, compounds of any one of Formulae XXVI-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein: la lb IC id R , R , R , and R1 are independently selected from the group consisting of hydrogen, fluoro, and chloro; 20 R 2 is optionally substituted phenyl; and WO 2012/155066 PCT/US2012/037570 69 R26, is selected from the group consisting of optionally substituted (CI-C 4 ) alkyl, optionally substituted (C 4 -Cs) cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, and aralkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 5 [0196] 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 R 26 c is optionally substituted alkyl. In another embodiment, R 26 is hydroxyalkyl. In another embodiment, R 26c is dihydroxyalkyl. In another embodiment, R 26 is (heterocyclo)alkyl. 10 [0197] 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 R 26 c is optionally substituted cycloalkyl. In another embodiment, R 26c is hydroxycycloalkyl. In another embodiment, R26 is cycloalkyl substituted with -CO 2 H. 15 [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 R 26 is selected from the group consisting of: OH''OH Me OH OH OH OH .OH Me Me **** 0 2 N"a n d ,
CO
H C2 'nCO2H CO 2 H [0199] In another embodiment, compounds of any one of Formulae I or 20 III-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R 26 is optionally substituted aryl. In another embodiment,
R
2 6 c is optionally substituted phenyl. In another embodiment, R 2 6 c is phenyl substituted with one or two of the following groups: halo, cyano, hydroxy, alkyl, WO 2012/155066 PCT/US2012/037570 70 haloalkyl, alkoxy, carboxamido, sulfonamido, -CONHSO 2 Me, -CO 2 R, -COR',
-SO
2 R d, N(R e)CORf, -N(R )SO 2 R1 or -N(Re)C=N(Rh)-amino, wherein R', Rd, R , Rf, R9, and Rh are as defined above in connection with optionally substituted alkyl. In another embodiment, R 26 is phenyl substituted with one or two of the 5 following groups: halo, cyano, alkyl, haloalkyl, alkoxy, carboxamido, sulfonamido, -CO 2 R, or -SO 2 Rd, wherein R' and Rd are as defined above in connection with optionally substituted alkyl. In another embodiment, R 2 6 c is phenyl substituted with -CO 2 H. [0200] In another embodiment, compounds of any one of Formulae I or 10 III-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R 26 is selected from the group consisting of: WO 2012/155066 PCT/US2012/037570 71 0 0 0 0 OH NH 2 OH 0 0 0 OH NH 2
NH
2 N I H H OH OH H 2 I 01 0 0 0 OHI NNH2NHH2ICO2H 0 F F F CN 0 N ~N 01 0 00 ,,( N H2JK'N,,q N1 0" 0 1 0 0 0 0 OH OH '- NH 2 J)" 0 'OH O OH ~ - 0 -0 0'"IO 0-- O 0 0 0 0 0 0 0 0 0 'N H 2 - -- 'NH 2 ~ C 2
C[
2 H I o e d t m d a o f mr
HI
2 I or a C 2 , s ateop duH F F FF [02011 In another embodiment, compounds of any one of Formulae I or III-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodirug thereof are WO 2012/155066 PCT/US2012/037570 72 provided, wherein R 2 6 c is optionally substituted heteroaryl. In another embodiment, the optionally substituted heteroaryl is an optionally substituted furyl, thienyl, pyridyl, pyrimidyl, benzimidazolyl, benzthiazolyl, or indolyl, In another embodiment, R 26 is heteroaryl substituted with one or two of the 5 following groups: halo, cyano, hydroxy, alkyl, haloalkyl, alkoxy, carboxamido, sulfonamido, -CONHSO 2 Me, -CO 2 R, -COR, -SO 2 Rd, -N(R e)CORf, -N(R e)SO2R or -N(Re)C=N(Rh)-amino, wherein R, Rd, R, R9, and Rh are as defined above in connection with optionally substituted alkyl. In another embodiment, R 26c is heteroaryl substituted with one or two of the following 10 groups: halo, cyano, alkyl, haloalkyl, alkoxy, carboxamido, sulfonamido,
-CO
2 R', or -SO 2 Rd, wherein R and Rd are as defined above in connection with optionally substituted alkyl. In another embodiment, R 2 6 c is heteroaryl substituted with -CO 2 H. [0202] In another embodiment, compounds of any one of Formulae I or 15 III-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided, wherein R 26 is selected from the group consisting of: 0 0 0 H NH 2 OH , NH2 NH 0
"-NH
2 NH NH2 N H 2 C1 HO 2 C and N N F F [02031 In another embodiment, compounds of any one of Formulae I or III-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are 20 provided, wherein R 2 6 c is aralkyl. [0204] 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 R 2 6 c is selected from the group consisting of: WO 2012/155066 PCT/US2012/037570 73 00 0 0 00 OHNH2 OH I NH 2 OH OH OH NH2 1nd [0205] In another embodiment, compounds of any one of Formulae I or III-XXVIII are provided, wherein R 26, is selected from the group consisting of: OH CO2H O N O=S5=O CH3 CO2H N eb CO 2H CO2H CO2H CO2H N--N HO O- OOeHNand / NH 2 L' and NO' 5 [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, compounds of any one of Formulae XXVII or XXVIII are p u r e stereoisomers. 10 [0207] In another embodiment, compounds of Formula I are provided having the structure: WO 2012/155066 PCT/US2012/037570 74 H H1F 0 N - H1 1 F 0 N aH OH a OH NH NH NH I0 I0 c c1 ~N CII N H H H H H C1 F N / CIFO N IFO NOH NH "OH / NH OH / N I 0 0 0 ciq5 ~N ci1 N C11 HH H H H HC1F o CI1 FO0 NWV CI F 0CI, -O-/O - OH C1 - "-OH /NH NH N H 0 I 0 I 0 i N C11 CI NC1 NH H H HH H HI FONg-y C ON>~ CI1 FO0 N-O 4H NH N NH I0 I0 I0 c1 ~N ci5 N& HH H H H H C 1 F N CFO NCIF N aOH NH OH NH NH N or 10 I0 0 Ni c N ci H HH or stereoisomers thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof. 102081 In another embodiment, compounds of Formula I are provided having the 5 structure: WO 2012/155066 PCT/US2012/037570 75 H CI F CI F F CIFW)O / /H NH 'O NH O N~~ 0 I 0 CI , CI * N ci H H H HH H CI F O'-N%<0 CI FU o~N%.K C1 F 0 ,N O' H NH 'O NH OH NH F 0 F H1 CI N HI HHH H H H CI F 0 N %0. H, F NH 'OH NH 'O / O I 0 NN H %"N00 0 c1 HN C I N CI1 HH H H H H CI F 0 ,-.,N ."O CI ~ N C1 0 F 'F -0, NH NH -/NH~ 0 NH N or N I 00 I 0 H0C 0 0 c or pharmaceutically acceptable salts, solvates, or prodirugs thereof. 102091 In another embodiment, compounds of Formula I are provided having the structure: WO 2012/155066 PCT/US2012/037570 76 H H H C1 F 0 _,,N C1 F CI F NH NH NH I 0 I 0 0 c" ~N C11 NN H H C11 H H H H 0 F 0 ,N<CIFoNJ'I F 0 ~, 0 ,--OH NH / *NH NHNHN I 0 I 0 I Cj) ;N c1 a~ ci H H C"a H H H H CI F 0 ~~~ CI F -eNCF : %. NH OV~ H --F *OH NHF NH NH N.' 0 0 0 C1- N Nc I:!: 0 H H C1 HH H HI0 /N < CI F N C1 F 0 / NH NH NH 0 0 0, Kr 0 Cl-*O N CH 0NH H or pharmaceutically acceptable salts, solvates, or prodirugs thereof. 102101 In another embodiment, compounds of Formula I are provided having the structure: 0-1 0 .. OH o HN / '~ HN Cl NH C1 N NH C 1 NH FF F 0 I 0 0 H N C1 N H i" H H WO 2012/155066 PCT/US2012/037570 77 H H H o HF N OH CI F 0 - N OH C F O - '~jk~~~OH K2' / 2 "H NH N O N N O N N N "O I 0 I I N Ci FC I ON CI C H H H H H H CI F 0 N 0 ,H CI F CI / NH NH~ ~ ~NH Cl F F I - I I ci ) N c I H cij HH H H HH H 0ON ,-NO00N.. OH Y -0 cI NH F lN H F lN H F F F F F F F N F 0 - 0 0 ~c N N CIHH SOHN ''OH 0 NN CINH NH CI F 0 F 0~' F 0 I- 0 0N ci N ci N o H H ci N H OWHo H -N NO \v N-CH 3 ci / NH CINH CI NH F NH F NHF -I %W 0 ci -N cijC HH n ~H 0 H oH %11N-H3N-CH 3 ~- " ci - NH cl NH cl NH 0 F o N - F N Fo I 1= 0 1 Ci N ciN C N HH H WO 2012/155066 PCT/US2012/037570 78 0 0:= CH 3 S _CH3 O NH cI NH O 0 NH CI NH F N C 4 NH C O O NNH ciO N FHN C NH N H 0 H H 0 O~S~ 0 0 OH OH OH O H N - -N H NN O- O/ NH H O NH NH CI N CI CI / N H CI NH C O HH 0 0 0 ci" 0 NI O 0 0 0 OHHCi OH ~yH N-N H 0 N H 0 0 NH 0- cN H NH c NH NH NH FF F F ci N i ~ N ci N: H c H Hia 0 OH
N-HH
WO 2012/155066 PCT/US2012/037570 79 0 OH HO 0 HO0 C H 3 C H 3 0IN H N H NH NH /NH l cI "l NH 0 0 F CI HCI N 1 0 H ci - N H OH 0 0~< 0 O N N 0 NH 0 NH 0 NH /l NH clNH cI NH F Nz ,F %W 0 0 0 cI i Ncil:C SN H H H 0 0OH OH OH 0 NH 0 NH N 0 NH ci NH cl NH CI NH F F 0 I0 N 0 c N cI cil N H H H 00 0 OH OH ij11 OH I 0 NH 0H NHl c NH F NH - NH 0 F j H A-cN C I N H
H
WO 2012/155066 PCT/US2012/037570 80 0 OH 0 OH F F O NH 0 NH CI NH C NH F F 0 I 0 CI N CI N H or H or pharmaceutically acceptable salts, solvates, or prodrugs thereof. [0211] In another embodiment, compounds of Formula I are provided having the structure: H H H CI F O NK* j CI F O CI F 0 N - O',C H NH ''OH NH ''C2H NH CI N CI N CI N I 0 I 0 0 H H H H H CI F O N 'O CI F O N OH NH NH C I oor ci N H Ni H 5 or pharmaceutically acceptable salts, solvates, or prodrugs thereof. [0212] In another embodiment, the disclosure provides a method of preparing a compound having Formula XVI: OE R2 Ri b R 3 b R. ."IR R3a R~ / X O Ric x 0~ Rid xvi Ia lb Ic id 2 3a wherein Ri, R , R , R , R2, R , Rl, and E have the meanings as described 10 above for Formula I, and X and Y are NH. In another embodiment, E is -OR 26 a. In another embodiment, E is -NR 2 6 bR 26 c. In another embodiment, R 26 b is hydrogen, and R26c is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally WO 2012/155066 PCT/US2012/037570 81 substituted heteroaryl. In another embodiment, R a and R 3 b are taken together form an unsubstituted 4- to 8-membered cycloalkyl. [02131 In another embodiment, the method of preparing a compound having Formula XVI comprises allowing a compound having Formula VI: OE R2 |" '3a R1c XAO 5 Rid VI to isomerize to a compound having Formula XVI. [0214] In another embodiment, the method of preparing a compound having Formula XVI comprises dissolving a compound having Formula VI in a solvent or a mixture of solvents. 10 [0215] In another embodiment, the method of preparing a compound having Formula XVI comprises: [0216] a) dissolving a compound having Formula VI in a solvent or a mixture of solvents; and [0217] b) allowing the compound having Formula VI to isomerize to a 15 compound having Formula XVI. [0218] 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 20 b) isolating the compound 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 25 solvents; b) allowing the compound having Formula VI to isomerize to a compound having Formula XVI; and c) isolating the compound having Formula XVI substantially free from the compound having Formula VI, and one or more other stereoisomers.
WO 2012/155066 PCT/US2012/037570 82 [0219] In another embodiment, the solvent is selected from the group consisting of acetonitrile, methanol, ethyl acetate, and water, or a mixture thereof. [0220] In another embodiment, the isomerization 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 5 one embodiment, the isomerization is carried out at a pH of about 7. In one embodiment, the isomerization 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. [0221] In another embodiment, the isomerization is carried out in the presence of an acid, e.g., trifluoroacetic acid or acetic acid. 10 [0222] In one embodiment, the isomerization is carried out in the presence of a base, e.g., NaHCO 3 . [0223] 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 15 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. 20 [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 25 the chemical structure of Formula VI, the solvent(s), the temperature, and/or the pH. [0225] In certain aspects, the disclosure provides the following particular embodiments: [0226] I. A compound having Formula 11: WO 2012/155066 PCT/US2012/037570 83 R 4 R 2 0 ',R 5 Y R b R 3 b X 0 Rid wherein: la lb IC id R , R , R , and R1 are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, optionally substituted 5 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; 10 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; R3a is selected from the group consisting of halo, optionally substituted alkyl, 15 optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 3a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl; 20 R 4 is selected from the group consisting of hydrogen and optionally substituted
C
1
-C
6 alkyl;
R
5 is selected from the group consisting of: / R 13
R
12 a R 18
R
17 aR17b / 23 R22a
W
1
R
7 N/ ' R12b r / 2
R
22 b -(CR'aRob) W R 12 c z R 1 7 d R 21 and R 22 c N24
R
8 a R 8 b R1 2 d R 14
R
19 OR21b R 2 2 d R5-1 R5-2 R5-3 R5-4 WO 2012/155066 PCT/US2012/037570 84 wherein: each R 6 a and R 6 b is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl;
R
7 is selected from the group consisting of hydrogen, optionally 5 substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl;
R
8 a and R 8 b are each independently selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; or R a and R'b taken together with the carbon that they are attached form a 3 10 to 8-membered optionally substituted cycloalkyl; W is selected from the group consisting of -OR 9 a and -NR 9R9'
R
9 a is hydrogen; R9 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, 15 optionally substituted heteroaryl, -SO 2 R9', and -CONR R
R
9 ' is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 9 and R 9 ' taken together with the nitrogen atom to which they are 20 attached form a 4- to 8-membered optionally substituted heterocyclo;
R
9 d is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl; R9e and R9f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or 25 R 9 e and R 9 f taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; W is selected from the group consisting of -OR4 and -NR aR1 with the proviso that when W 1 is -OR 9 a and W 2 is -OR 1 0 then at least one of R 7 , R 8 a, and R b is other than hydrogen; 30 R 10 is hydrogen; or one of R 9 a and R 10 is hydrogen and the other is a metabolically cleavable group; WO 2012/155066 PCT/US2012/037570 85 Rua is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SO 2 R Il, and -CONR RIle ; R is selected from the group consisting of hydrogen, optionally 5 substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or Ru 1 a and Ru b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; Rl" is selected from the group consisting of optionally substituted alkyl 10 and optionally substituted cycloalkyl; R and R" are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; or Rld and R" taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo; 15 nis 1,2,3,4,or5; each R1 2 a, R1 2 b, R1 2 c and R12d is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; 20 R 14 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; Z is selected from the group consisting of -OR 15 and -NR1 6 aRi 6 b; or Z and R14 taken together form a carbonyl, i.e., a C=O, group.
R
15 is selected from the group consisting of hydrogen and metabolically 25 cleavable group; Ri1a is selected from the group consisting of -SO 2 Ri 6 and -CONR 1dR Me R 6 is selected from the group consisting of hydrogen and optionally substituted alkyl; R 1 6 is selected from the group consisting of optionally substituted alkyl, 30 optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; WO 2012/155066 PCT/US2012/037570 86 R 1d and R 16 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 1d and R1 6 e taken together with the nitrogen atom to which they are 5 attached form a 4- to 8-membered heterocyclo; o is 1, 2, or 3; p is 0, 1, 2, or 3; each Ra 17 , R 7 b, R 1 7 c and R 1 7 d is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; 10 R's is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl;
R
19 is selected from the group consisting of hydrogen, optionally substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl;
R
20 is selected from the group consisting of hydrogen, optionally 15 substituted C 1
-C
6 alkyl, and optionally substituted cycloalkyl; p2la p2lb R and R are each hydrogen; or one of R 21 and R 21 is hydrogen and the other is metabolically cleavable group; q is 0, 1, 2, or 3; 20 ris 1,2,or3; each R 2 2 a, R 22 b, R 22 c, and R 2 2 d is independently selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; R is selected from the group consisting of hydrogen and optionally substituted C 1
-C
6 alkyl; 25 R24 is selected from the group consisting of -SO 2
R
2 4 a and -CONR24b R24c R24a is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R
24 b and R 24 are each independently selected from the group consisting of 30 hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R24b and R 2 4 c taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclo; WO 2012/155066 PCT/US2012/037570 87 s and t are each independently 1, 2, or 3; X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR; R' is selected from the group consisting of hydrogen, optionally 5 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 acceptable salt, solvate, or prodrug thereof. 10 [0227] II. The compound of particular embodiment I having the formula: R 4 Ria Rib R 3 b I ~ R 3a R1 X 0 Rid or a pharmaceutically acceptable salt, solvate, or prodrug thereof [0228] III. The compound of particular embodiment II having formula: R4 N,5 R 2 R R la Y,, . 3b R 3a R1 X 0 15 Rid or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0229] IV. The compound of any one of particular embodiments 1-111, wherein: la lb ICd R , R , R , and Rid are each independently selected from the group consisting of hydrogen, fluoro, and chloro; 20 R 2 is optionally substituted aryl;
R
3 a is halo or C 1
-C
10 alkyl;
R
3 b is halo or C 1
-C
10 alkyl; or WO 2012/155066 PCT/US2012/037570 88 R3a and R 3b taken together form a 3- to 9-membered optionally substituted cycloalkyl;
R
4 is hydrogen; and X and Y are NH, 5 or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0230] V. The compound of particular embodiment IV, wherein: Ria and Rid are each hydrogen; b is selected from the group consisting of hydrogen and fluoro; and R" is selected from the group consisting of fluoro and chloro, 10 or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0231] VI. The compound of any one of particular embodiments I-V, wherein R2 is an optionally substituted aryl having Formula R2-1:
R
25 d
R
2 5 c R 25 e
R
25 b
R
25 a R2-1 wherein R a, R 25, R , R 25d, and R 25 e are each independently selected from the 15 group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, alkyl, or haloalkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0232] VII. The compound of particular embodiment VI, wherein: Ra is selected from the group consisting of hydrogen and fluoro; 20 R25b is chloro; R25c is selected from the group consisting of hydrogen and fluoro; and R25d and R are each hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0233] VIII. The compound of any one of particular embodiment I-VII, 25 wherein R 5 is selected from the group consisting of: WO 2012/155066 PCT/US2012/037570 89 9aOR 9 a NR 9 bR 9 c OP
OR
10 NRuIaR11b OR 10
OR
15 R7 R7 R7 R5-8 R5-5 R5-6 R5-7 NR16aR16 O "' NR1 6 aRI 6 b OR 15 ' R14 R R4 R5-9 R5-10 R5-11 R5-12 NR1 6 aR1 6 b OR 15 NR1 6 aR1 6 b R21 R R4 R19 OR 2 1b
R
1 9 R5-13 R5-14 R5-15 R5-16 NR21a and NR1 6 aR1 6 b
R
19
OR
2 1b R5-18 R5-17 or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0234] IX. The compound of particular embodiment VIII, wherein R 5 is selected from the group consisting of: OR 15
OR
15 and R 14 R 14 5 R5-10 R5-12 wherein:
R
1 4 is hydrogen or C 1
-C
4 alkyl; and
R
15 is hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 10 [0235] X. The compound of any one of particular embodiments I-IX, wherein R 3 a and R 3 b are each independently C 1
-C
6 alkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0236] XI. The compound of any one of particular embodiments I-IX, wherein R3a and R 3 b are taken together to form an optionally substituted WO 2012/155066 PCT/US2012/037570 90 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0237] XII. The compound of any one of particular embodiments I-XI, wherein R 5 is selected from the group consisting of: "OH N 1 2 ~ OH , III~iOH , OH , H 3
H
3 OIHO H3C O ~tii14.... OHS 5O'OH OH a OH or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0238] XIII. A compound selected from the group consisting of: H H H C F O H''OH F O NF'''OH O 'O H NH NH
N
0 0 H H H H'F Oz CI F _ H 0 10 CI F/' 0 N"'OH'O NH NH C1 and ci Hi C N H H or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 10 [0239] XIV. A pharmaceutical composition comprising the compound of any one of particular embodiments I-VIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. [0240] XV. A method of treating a patient comprising administering to the patient a therapeutically effective amount of the compound of any one of 15 particular embodiments I-VIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the patient has a hyperproliferative disease. [0241] XVI. A method of treating a patient comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of particular embodiment XIV, wherein the patient has a hyperproliferative disease.
WO 2012/155066 PCT/US2012/037570 91 [0242] XVII. The method of particular embodiments XV or XVI, wherein the hyperproliferative disease is cancer. [0243] XVIII. The method of particular embodiments XV or XVI, wherein cells of the hyperproliferative disease express functional p53. 5 [0244] XIX. The method of particular embodiment XVII, further comprising administering to the patient one or more anticancer agents. [0245] XX. The method of particular embodiment XIX, wherein the anticancer agent is a chemotherapeutic agent. [0246] XXI. The method of particular embodiment XIX, wherein the anticancer 10 agent is radiation therapy. [0247] XXII. A method of treating a patient, wherein the patient has a hyperproliferative disorder and is being treated with an anticancer agent, comprising administering to the patient a compound of any one of particular embodiments I-XIII, or a pharmaceutically acceptable salt, solvate, or prodrug 15 thereof. [0248] XXIII. The method of particular 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. 20 [0249] XXIV. The method of particular embodiment XXII, wherein cells of the hyperproliferative disorder express functional p53. [0250] XXV. A kit comprising a compound of any one of particular embodiments I-XIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and instructions for administering the compound to a patient having a 25 hyperproliferative disease. [0251] XXVI. The kit of particular embodiment XXV, wherein the hyperproliferative disease is cancer. [0252] XXVII. The kit of particular embodiment XXVI, further comprising one or more anticancer agents. 30 [0253] XXVIII. The kit of particular embodiment XXVII, wherein the instructions direct co-administration of the compound together with the one or more anticancer agents. [0254] XXIX. A compound having Formula I: WO 2012/155066 PCT/US2012/037570 92 0 E R 2 Ria Rlb R 3 b RiC X R 3 a R~c x 0 R3 Rid wherein: la lb IC id R , R , R , and R1 are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, alkoxy, aryloxy, 5 optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido;
R
2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; 10 R 3 a 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; R3a is selected from the group consisting of halo, optionally substituted 15 alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; or R3a and R 3b taken together form a 3- to 9-membered optionally substituted cycloalkyl or a 3- to 9-membered optionally substituted heterocyclo; 20 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 25 substituted C 1
-C
6 alkyl; R 26 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, and -SO 2
R
5 b; or WO 2012/155066 PCT/US2012/037570 93 R26b and R 26 c taken together form a 4- to 9-membered optionally substituted heterocyclo; X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR; 5 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 hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; and ~--- represents a single or a double bond, 10 or a pharmaceutically acceptable salt thereof. [0255] XXX. The compound of particular embodiment XXIX having Formula III: 0 E R2 R 1b R 3 b RiF R 3 a X 0 or a pharmaceutically acceptable salt thereof. 15 [0256] XXXI. The compound of particular embodiment XXX having Formula VI: OE R2 R l l R 3b R3a R1c X O Rid V1, or a pharmaceutically acceptable salt thereof. 20 [0257] XXXII. The compound of particular embodiment XXX having Formula XVI: WO 2012/155066 PCT/US2012/037570 94 OE R 2 Ra Rib 3b
R
3 a R1e / X 0 Rid XVI, or a pharmaceutically acceptable salt thereof [0258] XXXIII. The compound of any one of particular embodiments XXIX-XXXII, wherein: 5 E is -NRK R26c.
R
2 is optionally substituted aryl;
R
3 a is halo or C 1
-C
10 alkyl;
R
3 b is halo or C 1
-C
10 alkyl; or
R
3 a and R 3 b taken together form a 3- to 9-membered optionally substituted 10 cycloalkyl or a 3- to 9-membered optionally substituted heterocyclo;
R
26 b is hydrogen; and X and Y are NH, or a pharmaceutically acceptable salt thereof. [0259] XXXIV. The compound of any one of particular embodiments 15 XXIX-XXXIII, wherein R3a and R 3 b are each independently C 1
-C
10 alkyl. [0260] XXXV. The compound of any one of particular embodiments XXIX-XXXIII, wherein R 3 a and R 3 b taken together form a 4- to 8-membered optionally substituted cycloalkyl or a 4- to 8-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt thereof. 20 [0261] XXXVI. The compound of particular embodiment XXXV, wherein
R
3 a and R 3 b taken together form a 6-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt thereof. [0262] XXXVII. The compound of particular embodiment XXXVI, wherein R3a and R3b taken together form an optionally substituted piperidine or a 25 tetrahydropyran. [0263] XXXVIII. The compound of particular embodiment XXXV, wherein R3a and R 3 b taken together form a 4- to 8-membered optionally substituted cycloalkyl, or a pharmaceutically acceptable salt thereof.
WO 2012/155066 PCT/US2012/037570 95 [0264] XXXIX. The compound of particular embodiment XXXVIII, wherein R3a and R are taken together to form an unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring, or a pharmaceutically acceptable salt thereof. 5 [0265] XL. The compound of any one of particular embodiments XXIX-XXXIX, wherein: Ria and Rid are each hydrogen; b is selected from the group consisting of hydrogen and fluoro; and R" is selected from the group consisting of fluoro and chloro; 10 or a pharmaceutically acceptable salt thereof. [0266] XLI. The compound of any one of particular embodiments XXIX-XL, wherein R2 is optionally substituted aryl having Formula R2-1:
R
25 d
R
25 c R25e
R
2 5 b R 25a R2-1 wherein R a, R 25, R , R 25d, and R 25 e are each independently selected from the 15 group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, alkyl, or haloalkyl, or a pharmaceutically acceptable salt thereof. [0267] XLII. The compound of any one of particular embodiments XXIX-XL, wherein R 2 is optionally substituted pyridyl, or a pharmaceutically acceptable salt 20 thereof. [0268] XLIII. The compound of particular embodiment XXIX having Formula XXVI H R2 NR 26, R la NH R b R1 N 0 R ld H XXVI or a pharmaceutically acceptable salt thereof. 25 [0269] XLIV. The compound of particular embodiment XLIII having Formula XXVII: WO 2012/155066 PCT/US2012/037570 96 R2 R26 Ria Rib NH R1c N O R ld H XXVII or a pharmaceutically acceptable salt thereof. [0270] XLV. The compound of particular embodiment XLIII having Formula XXVIII: I 26c R 2 R R Ra NH R1c N 0 5 1l H XXVIII, or a pharmaceutically acceptable salt thereof. [0271] XLVI. The compound of any one of particular embodiments XXIX-XLV, wherein R 26 is optionally substituted alkyl, or a pharmaceutically acceptable salt thereof. 10 [0272] XLVII.The compound of particular embodiment XLVI, wherein the optionally substituted alkyl is substituted with an optionally substituted cycloalkyl, or a pharmaceutically acceptable salt thereof. [0273] XLVIII. The compound of particular embodiment XLVI, wherein the optionally substituted alkyl is substituted with an optionally substituted 15 heteroaryl, or a pharmaceutically acceptable salt thereof. [0274] XLIX. The compound of any one of claims XXIX-XLV, wherein R26, is aralkyl, or a pharmaceutically acceptable salt thereof. [0275] L. The compound of any one of particular embodiments XXIX-XLV, wherein R 26 c is optionally substituted cycloalkyl, or a pharmaceutically 20 acceptable salt thereof. [0276] LI. The compound particular embodiment L, wherein R26, is hydroxycycloalkyl, or a pharmaceutically acceptable salt thereof.
WO 2012/155066 PCT/US2012/037570 97 [02771 LII. The compound of particular embodiment L, wherein the optionally substituted cycloalkyl is substituted with at least one -CO 2 H, or a pharmaceutically acceptable salt thereof. [0278] LIII. The compound of particular embodiment L, wherein R26, is 5 selected from the group consisting of: OH ' I 'OH OH , H NI1IOH OH H 3 C H 3 C OH 'OH OH .. OH OH ' OH H3 'CH3 ' CH3CH
CO
2 H '
CO
2 H
CO
2 H TI, ICO 2 H
H
3 C H 3 C
CO
2 - CO 2 H and '''CO 2 H
'
C
O2HH 3
CH
3 or a pharmaceutically acceptable salt thereof. [0279] LIV. The compound of any one of particular embodiment XXIX-XLV, wherein R 26 is optionally substituted heterocyclo, or a pharmaceutically 10 acceptable salt thereof. [0280] LV. The compound of any one of particular embodiment XXIX-XLV, wherein R 26 c is optionally substituted aryl, or a pharmaceutically acceptable salt thereof. [0281] LVI. The compound of particular embodiment LV, wherein R26, is 15 optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. [0282] LVII. The compound of particular embodiment LVI, wherein the optionally substituted phenyl is substituted with at least one -CO 2 H, or a pharmaceutically acceptable salt thereof.
WO 2012/155066 PCT/US2012/037570 98 [0283] LVIII. The compound of any one of particular embodiments XXIX-XLV, wherein R26 is optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof. [0284] LIX. The compound of particular embodiment LVIII, wherein R26, is 5 optionally substituted pyridyl, or a pharmaceutically acceptable salt thereof. [0285] LX. A compound selected from the group consisting of: 0 0 HN S 0 C1,e NH CI NH C I NH I C I N I N H H H H H NH H ~ "O NH CI N O CI O CI N O H H H H H C 0 N CI F F C 0 F C 1 H N "H N O FF C I NI N 0 ci O ON C I C IN H HH H HH CI F\/ ci N H FNH FNH F 'N;Z ' FWNz" F F ci , N ci ~ NC1 N H H H OC1 NH~ OH C1 N H oC H F~ 1 F NH F NHF N 0 0 F I H5 O I 0 H OH N N1HO -N 0N H H Ci N
H
WO 2012/155066 PCT/US2012/037570 99 0 N H 0 N 0 N-CH3 .... N-C H3 N O ~N-NH/ CI NH cI NH CI NH F N H F N H F ,- ' I - -No 0 I0 C H CI H NH H /N-CH3 - N-CH 3 - N-CH 3 CI NH c NH c NH 0 F N- F N- F N CI CIj:C CI O O= CH3 n 0 I O -CH3 NH CI NH O O NH CI NH N NH 0 0 0zK O=s N --- OHOH NH NH O NH F O- NH F CI NH HF 0 CI N HF, IO HH H0 0 cC N H H 0=sS OH ~ OH NN 0 NH0-N clN lNH O. NH NH F F I 0!; l HN C HCl "a N WO 2012/155066 PCT/US2012/037570 100 O OH N-N HO 0 0~NH H 0 N 0 NH NH cI cI N NH NH F F F 0 I I 0' I0 ci H ci i::N ci~ N H H 0 OH HO 0 HO Hjo
H
3 Zo
CH
3 I ~N0 NNHN NH /NH .~ N CI / NH I00 F Ni N 0 H lH cil N~ H 0OH 0 0 r NN 0 N H 0V

ci I NH cIN H F0 0 0 0i I 0L ci N H IN H 0. OHH O ~H F N 0 0 NH00 H H H WO 2012/155066 PCT/US2012/037570 101 O00 OH OH OH O0NH O NH NH C1 O CI NH F NH - NH O F F ci ' N C1 H I I H H 0 OH 0 OH F F O NH 0 NH Cl NH NH F F Cl N CI N H and H or a pharmaceutically acceptable salt thereof. [02861 LXI. A compound selected from the group consisting of: H H H CI F 0_j,,% 'CI F 0- N0 CI F o0_N.0 NH /OH NH 'C2H ' 2 H C1 Nci (-:N C I N H H H H H CI F oNy~ CI 'F0 N 0H NH / NH and ci N N 0 5 or a pharmaceutically acceptable salt thereof. [0287] LXII. The compound of particular embodiment XXIX, wherein E is 26a -OR , or a pharmaceutically acceptable salt thereof. [0288] LXIII. The compound of particular embodiment LXII, wherein R 26 a is hydrogen, or a pharmaceutically acceptable salt thereof.
WO 2012/155066 PCT/US2012/037570 102 [0289] 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 carrier. [0290] LXV. A method of treating a patient comprising administering to the 5 patient a therapeutically effective amount of the compound of any one of particular embodiments XXIX-LXI, or a pharmaceutically acceptable salt thereof, wherein the patient has a hyperproliferative disease. [0291] LXVI. The method of particular embodiment LXV, wherein the hyperproliferative disease is cancer. 10 [0292] LXVII.The method of particular embodiment LXVI, wherein the cancer is selected from the group consisting of melanoma, lung cancer, sarcoma, colon cancer, prostate cancer, choriocarcinoma, breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymphoma, multiple myeloma, and leukemia. 15 [0293] LXVIII. The method of particular embodiment LXVII, wherein the cancer is selected from the group consisting of liposarcoma and melanoma. [0294] LXIX. A kit comprising a compound of any one of particular embodiments XXIX-LXI, or a pharmaceutically acceptable salt, thereof, and instructions for administering the compound to a patient having a 20 hyperproliferative disease. [0295] LXX. The kit of particular embodiment LXIX, wherein the hyperproliferative disease is cancer. [0296] LXXI. A method of preparing a compound having Formula XVI: OE R2 R1 % R 3a RiC / X O R i xvi0 R ld XVI, 25 comprising: a) allowing a compound of particular embodiment XXXI to isomerize; and b) isolating the compound having Formula XVI substantially free from the compound of claim 3, WO 2012/155066 PCT/US2012/037570 103 wherein X and Y are NH. [0297] LXXII.The method of particular embodiment LXXI, wherein E is -OR 2 6 a. [0298] LXXIII. The method of particular embodiment LXXI, wherein E is -NR26bR26c 5 [0299] LXXIV. The method of any one of particular embodiments LXXI-LXXIII, wherein R3a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl. [03001 The compounds provided herein will be better understood in connection with the following synthetic schemes which illustrate the methods by which the 10 compounds provided 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. 15 [03011 Compounds of Formula III wherein Y is NH and E is -NR 2 6 cR 26 c can be synthesized as described in Schemes 2 and 3. Scheme 2 Ra R2 H O O 1lb + R3a N Molecular Sieve 4A R2 Ri+ R + R 1 a N R X O R 3 b O PhMe, reflux, 12 h Rib R 3 b RId RIc X RId 0 NR 2 6 bR 2 6 c
HNR
2 6 bR 2 6 C 0 NR 26 bR 26 C CAN 2.5 equiv R2 Rla R2 N OH THF/H 2 0 R 1 a NHR 3 b THF, rt, 12h Rib R 3 b Rib R 3a or Pb(OAC) 4 1 O R1 / X RIe X Rld RId Formula Ill (wherein Y is NH and E is NR 2 6 bR 2 6 c) 20 WO 2012/155066 PCT/US2012/037570 104 Scheme 3 R2 o OtBu Rib + 3a H Molecular Sieve 4A R 2 ,R + R + KN'R ' R 1 a N 1 X O3b PhMe, reflux, 12 h Rib R 3 b Ric x O-1-R 3b C0 2 tBu R I ~ Rld R 1 c X O Rid O OH O NR26bR26c R2 ,R HNR 26 bR 26 C R 2 ,R Ria N R 3 b HOBt/EDC HCI Ria N 3 b
TFA/CH
2 Cl 2 Rib b 3 a R R3a iPr2NEt Rb R3a R1c X R1c X Rld Rid O NR26bR26c R2 NBS, THF/H- 2 0 Ria NH N Rib R 3 b R = hydrogen, p-OMeBn-, Bn-, Me or DDQ, THF/H 2 0 R 3 a or other alkyl group (when R not H) R1c X O Rid Formula Ill (wherein Y is NH and E is NR 26 bR 26 c) [03021 Compounds of Formula III can be separated by chiral resolution methods well known in the art, e.g., chiral column chromatography, to give compounds of 5 Formulae VI-XXI. Suitable chiral columns for use in chiral resolutions include, 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 example, compounds of Formula VI, 26b 26, 10 wherein Y is NH and E is NR R , can be synthesized by using a asymmetric 1,3-dipolar cycloaddition as the key step as previously described (See U.S. Patent Nos. 7,759,383 B2 and 7,737,174 B2, and Ding et al., J Am. Chem. Soc. 127:10130-10131 (2005)). Compounds of Formula VI can undergo isomerization in solution to give compounds of Formula XVI. 15 WO 2012/155066 PCT/US2012/037570 105 Scheme 4 MeO OMe O O Ph R .R 3 b -P Rla R 2 O O MgBr 2 OEt 2 Ria R 2 N Ph +Ri1b / + 1: --------- R1 b ,R 3 a O RN THF . R 1 0 HI X I
R
3 A R 3 b R1c X R1c X Rid Rid O'- NR 2 6 bR 2 6 c
O-NR
2 6 bR 26 C Ph R2 R2 N O H CAN R1a NH 3b
HNR
2 bR 2 6 c Ria R Ph CH 3
CN/H
2 0 R -3a R- 'R 3 a | THF '0 R1c X R1c X Rid Rid Formula VI (wherein Y is NH) O NR 2 6 bR 26 C R 2 Ria NH 3 rearrangement R 3b R1c X Rid Formula XVI (wherein Y is NH) [03031 Without intending to be bound by theory, the isomerization of Formula VI to Formula XVI may involve formation of the imine intermediate shown in 5 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 compounds of Formula XVI may be improved when R3a and R3a are the same, e.g., R3a and R are methyl, R3a and RSb taken together form a cyclohexyl ring, because the 2' position of the pyrrolidine 10 ring is not an asymmetric center, and the number of possible isomerization products of Formula VI is reduced. General methods to prepare compounds provided in the present disclosure are shown in Schemes 4-8. 15 WO 2012/155066 PCT/US2012/037570 106 Scheme 5 R 26 b
R
26 b R R 2 b Ria NHiNb Rib NHR 3 b isomerization R 2-R 3 R3a 1c R Ric X 2 O Ric RId 1 Rid Formula XVI Formula VI (wherein Y = N H) (wherein Y = NH)
R
2 6 b ON, 26c, R 2 R Ria Rib Rb R 3b Ric X OH Rid mine intermediate Scheme 6 0 Ph OH 0 R R Ph 1. LiOH, 1:1 O OHOHPh O OH R2 Ph THF:H2O 2 Ph 1:1 CH 3 CN: R NH R1a N R3b RT, 1h Rla R N R3b H2O, CAN Ra NR3b Rib Rb R Rib RaRib RTa 30~ 3a RI . R 2. Sat. NH 4 C R R RT 30 min R R Ric X Ric X Ric X Rid Rid Rid Formula VI O OH O NR 2 bR 2 c (E is-OH) AGE in 1:1 DCM, EDCI 2 NH3b HOBt, DIEA R N RiH:20a RiaN.' NH Rb 2 d Rib R 3 a HNR 2 6 bR 2 6 c Ri R 3 a Ric X RT overnight Ric ) x Rid Rid Formula XVI Formula XVI 5 (E is -OH) (E is -NR 26 bR 26 c) 10 WO 2012/155066 PCT/US2012/037570 107 Scheme 7 0 Ria NH + O methanol, R2 R NH + 0 + R piperidlne HN30 RN Ri R overnight i R' Ph RIc Rib Rid Ph RIc
R
2 6 c OH O Ph O NH- Ph R2 R2 101Ra N Ph R26cNH2, THF ,lRa N Ph Toluene:THF Rib RN h RiN reflux, overnight reflux, 3h Ri N Rio N Rid H Rid H ;N-R26c \- 26c R2 - R2 CAN, 1:1 Ria NH AGE, 1:1 Ria NH
CH
3
CN/H
2 0 R: 15 min 10% TFA 0 Ri Ric N Rid Rid Formula XXVII Formula XXVII Scheme 8 00 Ph R OMe Ph 0 2\/~P 2\-OMe
R
1 a N Ph R 1 a N Ph R 1 a NH Rib
H
2
SO
4 conc. Rib CAN, 1:1 Rib Re N O MeOH, 501C R NO
CH
3
CN/H
2 0 R Ro N MH,0C Rioc N 15min Ric N Rid H Rid H Rid H 0 H O 2....N-R26c Ra NH R 26 oNH 2 , 1bRib N LiOH.H 2 0 Rib Amide coupling 1:1 THF/H 1 0 Hi ' 2 Ri c conditions Rio R N Rid HRi 5 Formula XXVIII Methods [03041 The present disclosure contemplates that exposure of animals suffering from cancer to therapeutically effective amounts of drug(s) (e.g., small molecules) that increase the function(s) of p53 and p53-related proteins (e.g., WO 2012/155066 PCT/US2012/037570 108 p63, p73) inhibits the growth of cancer cells or supporting cells. The compounds provided herein inhibit the interaction between p53 or p53-related proteins and MDM2 or MDM2-related proteins (e.g., MDMX). Inhibiting the interaction between p53 or p53-related proteins and MDM2 or MDM2-related proteins 5 inhibits the growth of cancer cells or supporting cells and/or renders such cells as a population more susceptible to the cell death-inducing activity of cancer therapeutic drugs or radiation therapies. In one embodiment, the inhibitors provided herein prolong the half-life of p53 by interfering with the p53-MDM2 interaction that would normally promote degradation of p53. The compounds 10 provided herein satisfy an unmet need for the treatment 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 15 therapies (combination therapies), so as to render a greater proportion of the cancer cells or supportive cells susceptible to executing the apoptosis program compared to the corresponding proportion of cells in an animal treated only with the cancer therapeutic drug or radiation therapy alone. [0305] In one embodiment, treatment of patients with a therapeutically effective 20 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, because the compounds provided herein can lower the apoptotic threshold of cells that express p53 or p53-related protein, 25 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 30 tolerable, dose of an anticancer drug and/or radiation to produce 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 WO 2012/155066 PCT/US2012/037570 109 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 activities of p53 and p53-related proteins, the exposure of cancer cells and supporting cells to 5 therapeutically effective amounts of these compounds can be temporally linked to coincide with the attempts of cells to execute the apoptosis program in response to the anticancer drug or radiation therapy. Thus, in one embodiment, administering the compounds or pharmaceutical compositions provided herein in combination with other known anticancer drugs provides especially efficacious 10 therapeutic practices. [0306] In one embodiment, the inhibitors 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 15 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 proteins) while having no or less effect on cancer cells comprising mutated, deleted, or otherwise non- or less functional p53 (and/or mutated, 20 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 without increasing the toxic side effects of such treatment when administered in combination with inhibitors provided herein. 25 [0307] Also provided herein are methods of using compounds having Formulae I-XXVIII for sensitizing cells to additional agent(s), such as inducers of senescence, 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 30 chemotherapeutic agents. In one embodiment, methods of rendering a normal cell resistant to chemotherapeutic agents or treatments comprises 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 WO 2012/155066 PCT/US2012/037570 110 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 5 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, without limitation, mucositis, stomatitis, xerostomia, gastrointestinal disorders, and alopecia. 10 [03081 Compounds having Formulae I-XXVIII are useful for the treatment, amelioration, or prevention of disorders, such as those responsive 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 15 characterized by resistance to cancer therapies (e.g., those cancer cells which are chemoresistant, radiation resistant, hormone resistant, and the like). In another 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., 20 non-hyperproliferative) cells from the toxic side effects of chemotherapeutic agents and treatments by the induction of cell cycle arrest in those cells. [03091 In one embodiment, compounds having Formulae I-XXVIII induce cell cycle arrest and/or apoptosis and also potentiate the induction of cell cycle arrest and/or apoptosis either alone or in response to additional apoptosis induction 25 signals. Therefore, it is contemplated that these compounds sensitize 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 p53-related 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 30 the induction 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.
WO 2012/155066 PCT/US2012/037570 111 [03101 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, 5 TNF RI, DRI, DR2, DR3, DR4, DR5, DR6, FADD, RIP, TNFa, Fas ligand, TRAIL, antibodies to TRAIL-Ri or TRAIL-R2, Bcl-2, p53, BAX, BAD, Akt, CAD, P13 kinase, PP1, and caspase proteins. Other agents involved in the initiation, decision and degradation phase of apoptosis are also included. Examples of apoptosis-modulating agents include agents, the activity, presence, 10 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-1 ligand, or TRAIL. [0311] In one embodiment, the compounds, compositions, and methods provided 15 herein are used to treat diseased cells, tissues, organs, or pathological conditions and/or disease states in an animal (e.g., a mammalian patient including, but not limited to, humans and veterinary animals). In this regard, various diseases and pathologies are amenable to treatment or prophylaxis using the present methods and compositions. A non-limiting exemplary list of these diseases and conditions 20 includes, but is not limited to, breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell 25 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, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic 30 insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia (CLL) including B-CLL, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic WO 2012/155066 PCT/US2012/037570 112 leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, sarcoma such as liposarcoma malignant fibrous histiocytoma, osteosarcoma, Ewing's sarcoma, leiomyosarcoma, and rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's 5 lymphoma, soft-tissue sarcomas such as lipoma, and malignant Schwannoma, 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 10 metastatic. In another embodiment, the cancer cells being treated are resistant to other anticancer agents. [0312] In one embodiment, the compounds, compositions, and methods provided herein are used to treat cancers that express functional or wild type p53 or p53-related proteins. In one embodiment, the compounds, compositions, and 15 methods provided herein are used to treat cancers that express elevated levels of MDM2 or MDM2-related proteins. [03131 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 20 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, 25 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. [0314] In one embodiment, the compounds, compositions, and methods provided here can be used to treat a patient having melanoma, lung cancer, sarcoma, colon 30 cancer, prostate cancer, choriocarcinoma, breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymphoma, multiple myeloma, or leukemia. [0315] In one embodiment, the compounds, compositions, and methods provided here can be used to treat a patient having liposarcoma or melanoma.
WO 2012/155066 PCT/US2012/037570 113 [03161 In one embodiment, infections suitable for treatment with the compounds, compositions, and methods provided herein include, but are not limited to, infections caused by viruses, bacteria, fungi, mycoplasma, prions, and the like. [0317] A further aspect of the present disclosure is to provide the use of a 5 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. [03181 A further aspect of the present disclosure is to provide a compound 10 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. [0319] In one embodiment, methods are provided for administering an effective amount of a compound having Formulae I-XXVIII in combination with at least 15 one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosis-modulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, and/or radiotherapies). In one embodiment, the additional therapeutic agent(s) is an anticancer agent. 20 [0320] A number of suitable therapeutic or anticancer agents are contemplated for use in the methods provided herein. 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); polypeptides (e.g., enzymes and antibodies); biological mimetics (e.g., 25 gossypol or BH3 mimetics); agents that bind (e.g., oligomerize or complex) with a Bcl-2 family protein such as Bax; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins), toxins; radionuclides; biological response modifiers (e.g., interferons 30 (e.g., IFN-a) and interleukins (e.g., IL-2)); adoptive 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; angiogenesis inhibitors; proteosome inhibitors: WO 2012/155066 PCT/US2012/037570 114 NF-KB modulators; anti-CDK compounds; HDAC inhibitors; and the like. Numerous other examples of therapeutic agents such as chemotherapeutic compounds and anticancer therapies suitable for co-administration with the disclosed compounds are known to those skilled in the art. 5 [0321] In one embodiment, anticancer agents comprise agents that induce or stimulate apoptosis. Agents that induce or stimulate apoptosis include, for example, agents that interact with or modify DNA, such as by intercalating, cross-linking, alkylating, or otherwise damaging or chemically modifying DNA. Agents that induce apoptosis include, but are not limited to, radiation (e.g., X 10 rays, gamma rays, UV); tumor necrosis factor (TNF)-related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, antibodies to TRAIL-Ri or TRAIL-R2); kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitor. Additional anticancer agents include: vascular growth factor receptor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) 15 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., raloxifene and tamoxifen); anti-androgens (e.g., flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and 20 corticosteroids); cyclooxygenase 2 (COX-2) inhibitors (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, 25 oxyphenbutazone, PEDIAPRED, phenylbutazone, PLAQUENIL, prednisolone, prednisone, PRELONE, and TANDEARIL); and cancer chemotherapeutic drugs (e.g., irinotecan (CAMPTOSAR), CPT-11, fludarabine (FLUDARA), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP-16, cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, gemcitabine, bortezomib, 30 gefitinib, bevacizumab, TAXOTERE or TAXOL); cellular signaling molecules; ceramides and cytokines; staurosporine, and the like. [0322] In one embodiment, the compositions and methods provided herein include one or more compounds provided herein and at least one WO 2012/155066 PCT/US2012/037570 115 anti-hyperproliferative or anticancer agent, e.g., alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and/or animal derived compounds). [0323] Alkylating agents suitable for use in the present compositions and 5 methods include, but are not limited to: 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysin); 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 10 CCNU); and streptozocin (streptozotocin)); and 5) triazenes (e.g., dacarbazine (DTIC; dimethyltriazenoimid-azolecarboxamide). [0324] In one embodiment, antimetabolites suitable for use in the present compositions and methods include, but are not limited to: 1) folic acid analogs (e.g., methotrexate (amethopterin)); 2) pyrimidine analogs (e.g., fluorouracil (5 15 fluorouracil; 5-FU), floxuridine (fluorode-oxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (e.g., mercaptopurine (6 mercaptopurine; 6-MP), thioguanine (6-thioguanine; TG), and pentostatin (2' deoxycoformycin)). [0325] In one embodiment, chemotherapeutic agents suitable for use in the 20 present compositions and methods include, but are not limited to: 1) vinca alkaloids (e.g., vinblastine (VLB), vincristine); 2) epipodophyllotoxins (e.g., etoposide and teniposide); 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)); 4) enzymes (e.g., L 25 asparaginase); 5) biological response modifiers (e.g., interferon-alfa); 6) platinum coordinating complexes (e.g., cisplatin (cis-DDP) and carboplatin); 7) anthracenediones (e.g., mitoxantrone); 8) substituted ureas (e.g., hydroxyurea); 9) methylhydrazine derivatives (e.g., procarbazine (N-methylhydrazine; MIH)); 10) adrenocortical suppressants (e.g., mitotane (o,p'-DDD) and aminoglutethimide); 30 11) adrenocorticosteroids (e.g., prednisone); 12) progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate); 13) estrogens (e.g., diethylstilbestrol and ethinyl estradiol); 14) antiestrogens (e.g., tamoxifen); 15) androgens (e.g., testosterone propionate and WO 2012/155066 PCT/US2012/037570 116 fluoxymesterone); 16) antiandrogens (e.g., flutamide): and 17) gonadotropin releasing hormone analogs (e.g., leuprolide). [0326] Any anticancer agent that is routinely used in a cancer therapy context finds use in the compositions and methods of the present disclosure. For 5 example, the U.S. 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 U.S. Those skilled in the art will appreciate that the "product labels" required on all U.S. approved 10 chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents. Table 1 Aldesleukin Proleukin (des-alanyl-1, serine-125 human interleukin-2) Alemtuzumab Camp ath (IgGl anti CD52 antibody) Alitretinoin Panretin (9-cis-retinoic acid) Allopurinol Zyloprim (1,5-dihydro-4 H -pyrazolo[3,4-d]pyrimidin-4-one monosodium salt) Altretamine Hexalen (N,N,N',N',N",N",- hexamethyl-1,3,5-triazine-2, 4, 6-triamine) Amifostine Ethyol (ethanethiol, 2-[(3-aminopropyl)amino]-, dihydrogen phosphate (ester)) Anastrozole Arimidex (1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(lH-1,2,4 triazol-1-ylmethyl)) Arsenic trioxide Trisenox Asparaginase Elspar (L-asparagine amidohydrolase, type EC-2) BCG Live TICE BCG lyophilizedd preparation of an attenuated strain of Mycobacterium bovis (Bacillus Calmette-Gukin [BCG], substrain Montreal) bexarotene capsules Targretin (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-napthalenyl) ethenyl] benzoic acid) bexarotene gel Targretin Bleomycin Blenoxane (cytotoxic glycopeptide antibiotics produced by Streptomyces verticillus; bleomycin A 2 and bleomycin B 2 ) Capecitabine Xeloda (5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine) Carboplatin Paraplatin (platinum, diammine [1,1-cyclobutanedicarboxylato(2-)-O, 0']-,(SP 4-2)) Carmustine BCNU, BiCNU WO 2012/155066 PCT/US2012/037570 117 (1,3 -bis(2-chloroethyl)- 1 -nitrosourea) Carmustine with Polifeprosan 20 Implant Gliadel Wafer Celecoxib Celebrex (as 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide) Chlorambucil Leukeran (4-[bis(2chlorethyl)amino]benzenebutanoic acid) Cisplatin Platinol (PtCl 2
H
6
N
2 ) Cladribine Leustatin, 2-CdA (2-chloro-2'-deoxy-b-D-adenosine) Cyclophosphamide Cytoxan, Neosar (2-[bis(2-chloroethyl)amino] tetrahydro-2H-13,2-oxazaphosphorine 2-oxide monohydrate) Cytarabine Cytosar-U (1-b-D-Arabinofuranosylcytosine, C 9
H
13
N
3 0 5 ) cytarabine liposomal DepoCyt Dacarbazine DTIC-Dome (5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide (DTIC)) Dactinomycin, actinomycin D Cosmegen (actinomycin produced by Streptomyces parvullus, C 62
H
86
N
12 0 16 ) Darbepoetin alfa Aranesp (recombinant peptide) daunorubicin liposomal DanuoXome ((8S-cis)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-4-L-lyxo hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1 methoxy-5,12-naphthacenedione hydrochloride) Daunorubicin HCl, daunomycin Cerubidine ((1 S,3 S )-3-Acetyl-1,2,3,4,6,1 1-hexahydro-3,5,12-trihydroxy-10 methoxy-6, 11 -dioxo-1 -naphthacenyl 3-amino-2,3,6-trideoxy-(alpha) L- lyxo -hexopyranoside hydrochloride) Denileukin diftitox Ontak (recombinant peptide) Dexrazoxane Zinecard ((S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione) Docetaxel Taxotere ((2R,3 S)-N-carboxy-3 -phenylisoserine, N-tert-butyl ester, 13-ester with 5b-20-epoxy-12a,4,7b,10b,13a-hexahydroxytax- 11-en-9-one 4 acetate 2-benzoate, trihydrate) Doxorubicin HCl Adriamycin, Rubex (8S,10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy] -8-glycolyl-7,8,9,10-tetrahydro-6,8, 11- trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride) doxorubicin Adriamycin PFS Intravenous injection doxorubicin liposomal Doxil dromostanolone propionate Dromostanolone (17b-Hydroxy-2a-methyl-5a-androstan-3 -one propionate) dromostanolone propionate Masterone injection Elliott's B Solution Elliott's B Solution Epirubicin Ellence ((8S-cis)-10-[(3-amino-2,3,6-trideoxy-a-L-arabino hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8 (hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride) Epoetin alfa Epogen (recombinant peptide) Estramustine Emcyt WO 2012/155066 PCT/US2012/037570 118 (estra-1,3,5(10)-triene-3,17-diol(17(beta))-, 3-[bis(2 chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate, or estradiol 3-[bis(2-chloroethyl)carbamate] 17 (dihydrogen phosphate), disodium salt, monohydrate) Etoposide phosphate Etopophos (4'-Demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-(beta)-D glucopyranoside], 4'-(dihydrogen phosphate)) etoposide, VP-16 Vepesid (4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-(beta)-D glucopyranoside]) Exemestane Aromasin (6-methylenandrosta-1,4-diene-3, 17-dione) Filgrastim Neupogen (r-metHuG-CSF) floxuridine (intraarterial) FUDR (2'-deoxy-5-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-1,3,5 (10)- triene-3,17-beta-diol) Gemcitabine Gemzar (2'-deoxy-2', 2'-difluorocytidine monohydrochloride (b-isomer)) Gemtuzumab Ozogamicin Mylotarg (anti-CD33 hP67.6) Goserelin acetate Zoladex Implant Hydroxyurea Hydrea Ibritumomab Tiuxetan Zevalin (immunoconjugate resulting from a thiourea covalent bond between the monoclonal antibody Ibritumomab and the linker-chelator tiuxetan [N-[2-bis(carboxymethyl)amino]-3-(p isothiocyanatophenyl)- propyl]-[N-[2-bis(carboxymethyl)amino]-2 (methyl) -ethyl]glycine) Idarubicin Idamycin (5, 12-Naphthacenedione, 9-acetyl-7-[(3-amino-2,3,6-trideoxy (alpha)-L- lyxo -hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11 trihydroxyhydrochloride, (7S- cis )) Ifosfamide IFEX (3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2 oxazaphosphorine 2-oxide) Imatinib Mesilate Gleevec (4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3 pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate) Interferon alfa-2a Roferon-A (recombinant peptide) Interferon alfa-2b Intron A (Lyophilized (recombinant peptide) Betaseron) Irinotecan HCl Camptosar ((4S)-4,11-diethyl-4-hydroxy-9-[(4- piperi dinopiperidino)carbonyloxy]-1H-pyrano[3', 4': 6,7] indolizino[1,2-b] quinoline-3,14(4H, 12H) dione hydrochloride trihydrate) Letrozole Femara (4,4'-(1H-1,2,4 -Triazol-1-ylmethylene) dibenzonitrile) Leucovorin Wellcovorin, WO 2012/155066 PCT/US2012/037570 119 (L-Glutamic acid, N[4[[(2amino-5-formyll,4,5,6,7,8 hexahydro4oxo- Leucovorin 6-pteridinyl)methyl]amino]benzoyl], calcium salt (1:1)) Levamisole HCl Ergamisol ((-)-( S)-2,3,5, 6-tetrahydro-6-phenylimidazo [2,1-b] thiazole monohydrochloride CI H 12
N
2 S-HCl) Lomustine CeeNU (1 -(2-chloro-ethyl)-3-cyclohexyl- 1 -nitrosourea) Meclorethamine, nitrogen mustard Mustargen (2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride) Megestrol acetate Megace 17a( acetyloxy)- 6- methylpregna- 4,6- diene- 3,20- dione Melphalan, L-PAM Alkeran (4-[bis(2-chloroethyl) amino]-L-phenylalanine) Mercaptopurine, 6-MP Purinethol (1,7-dihydro-6 H -purine-6-thione monohydrate) Mesna Mesnex (sodium 2-mercaptoethane sulfonate) Methotrexate Methotrexate (N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L glutamic acid) Methoxsalen Uvadex (9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one) Mitomycin C Mutamycin mitomycin C Mitozytrex Mitotane Lysodren (1,1 -dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane) Mitoxantrone Novantrone (1,4-dihydroxy-5,8-bis[[2- [(2-hydroxyethyl)amino]ethyl]amino] 9,10-anthracenedione dihydrochloride) Nandrolone phenpropionate Durabolin-50 Nofetumomab Verluma Oprelvekin Neumega (IL-li) Oxaliplatin Eloxatin (cis-[(lR,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O'] platinum) Paclitaxel TAXOL (58, 20-Epoxy-1,2a, 4,78, 10B, 13a-hexahydroxytax-1 1-en-9-one 4,10-diacetate 2- benzoate 13-ester with (2R, 3 S)- N-benzoyl-3 phenylisoserine) Pamidronate Aredia (phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD)) Pegademase Adagen (Pegademase ((monomethoxypolyethylene glycol succinimidyl) 11 - 17 -adenosine Bovine) deaminase) Pegaspargase Oncaspar (monomethoxypolyethylene glycol succinimidyl L-asparaginase) Pegfilgrastim Neulasta (covalent conjugate of recombinant methionyl human G-CSF (Filgrastim) and monomethoxypolyethylene glycol) Pentostatin Nipent Pipobroman Vercyte Plicamycin, Mithramycin Mithracin WO 2012/155066 PCT/US2012/037570 120 (antibiotic produced by Streptomyces plicatus) Porfimer sodium Photofrin Procarbazine Matulane (N-isopropyl-g-(2-methylhydrazino)-p-toluamide monohydrochloride) Quinacrine Atabrine (6-chloro-9-( 1 -methyl-4-diethyl-amine) butylamino-2 methoxyacridine) Rasburicase Elitek (recombinant peptide) Rituximab Rituxan (recombinant anti-CD20 antibody) Sargramostim Prokine (recombinant peptide) Streptozocin Zanosar (streptozocin 2 -deoxy - 2 -[[(methylnitrosoamino)carbonyl]amino] a(and b ) - D - glucopyranose and 220 mg citric acid anhydrous) Talc Sclerosol (Mg 3 Si 4 Oo (OH) 2 ) Tamoxifen Nolvadex ((Z)2-[4-(1,2-diphenyl- 1 -butenyl) phenoxy]-N, N dimethylethanamine 2-hydroxy-1,2,3- propanetricarboxylate (1:1)) Temozolomide Temodar (3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8 carboxamide) teniposide, VM-26 Vumon (4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-2- thenylidene-(beta) D-glucopyranoside]) Testolactone Teslac (13-hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid [dgr ] lactone) Thioguanine, 6-TG Thioguanine (2-amino-1,7-dihydro-6 H - purine-6-thione) Thiotepa Thioplex (Aziridine, 1,1', 1 "-phosphinothioylidynetris-, or Tris (1 -aziridinyl) phosphine sulfide) Topotecan HCl Hycamtin ((S)-10-[(dimethylamino) methyl]-4-ethyl-4,9-dihydroxy-1H pyrano[3', 4': 6,7] indolizino [1,2-b] quinoline-3,14-(4H,12H)-dione monohydrochloride) Toremifene Fareston (2-(p-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]-phenoxy)-N,N dimethylethylamine citrate (1:1)) Tositumomab, 1131 Tositumomab Bexxar (recombinant murine immunotherapeutic monoclonal IgG 2 . lambda anti-CD20 antibody (1131 is a radioimmunotherapeutic antibody)) Trastuzumab Herceptin (recombinant monoclonal IgGi kappa anti-HER2 antibody) Tretinoin, ATRA Vesanoid (all-trans retinoic acid) Uracil Mustard Uracil Mustard Capsules Valrubicin, N-trifluoroacetyladriamycin- 14-valerate Valstar ((2S-cis)-2- [1,2,3,4,6,11 -hexahydro-2,5,12-trihydroxy-7 methoxy 6,11 -dioxo-[[4 2,3,6-trideoxy-3 - [(trifluoroacetyl)-amino-a-L-lyxo hexopyranosyl]oxyl] -2 -naphthacenyl] -2-oxoethyl pentanoate) WO 2012/155066 PCT/US2012/037570 121 Vinblastine, Leurocristine Velban
(C
4 6
H
56
N
4 0 1 o-H 2
SO
4 ) Vincristine Oncovin
(C
4 6
H
56
N
4 0 1 o-H 2
SO
4 ) Vinorelbine Navelbine (3' ,4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3 dihydroxybutanedioate (1:2)(salt)]) Zoledronate, Zoledronic acid Zometa ((1 -Hydroxy-2-imidazol-1 -yl-phosphonoethyl) phosphonic acid monohydrate) [03271 Anticancer agents further include compounds which have been identified to have anticancer activity. Examples include, but are not limited to, 3-AP, 12-0 tetradecanoylphorbol- 13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT 5 751, ADI-PEG 20, AE-941, AG-013736, AGRO100, alanosine, AMG 706, antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BGOOOO1, bicalutamide, BMS 247550, bortezomib, bryostatin-1, buserelin, calcitriol, CCI-779, CDB-2914, cefixime, cetuximab, CGO070, cilengitide, 10 clofarabine, combretastatin A4 phosphate, CP-675,206, CP-724,714, CpG 7909, curcumin, decitabine, DENSPM, doxercalciferol, E7070, E7389, ecteinascidin 743, efaproxiral, eflornithine, EKB-569, enzastaurin, erlotinib, exisulind, fenretinide, flavopiridol, fludarabine, flutamide, fotemustine, FR901228, G17DT, galiximab, gefitinib, genistein, glufosfamide, GTI-2040, histrelin, HKI-272, 15 homoharringtonine, HSPPC-96, hul4.18-interleukin-2 fusion protein, HuMax CD4, iloprost, imiquimod, infliximab, interleukin-12, IPI-504, irofulven, ixabepilone, lapatinib, lenalidomide, lestaurtinib, leuprolide, LMB-9 immunotoxin, lonafamib, luniliximab, mafosfamide, MB07133, MDX-010, MLN2704, monoclonal antibody 3F8, monoclonal antibody J591, motexafin, 20 MS-275, MVA-MUCl-IL2, nilutamide, nitrocamptothecin, nolatrexed dihydrochloride, nolvadex, NS-9, 06-benzylguanine, oblimersen sodium, ONYX-015, oregovomab, OSI-774, panitumumab, paraplatin, PD-0325901, pemetrexed, PHY906, pioglitazone, pirfenidone, pixantrone, PS-341, PSC 833, PXD101, pyrazoloacridine, R115777, RADOO, ranpirnase, rebeccamycin 25 analogue, rhuAngiostatin protein, rhuMab 2C4, rosiglitazone, rubitecan, S-1, S 8184, satraplatin, SB-, 15992, SGN-0010, SGN-40, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, talabostat, WO 2012/155066 PCT/US2012/037570 122 talampanel, tariquidar, temsirolimus, TGFa-PE38 immunotoxin, thalidomide, thymalfasin, tipifarnib, tirapazamine, TLK286, trabectedin, trimetrexate glucuronate, TroVax, UCN-1, valproic acid, vinflunine, VNP40101M, volociximab, vorinostat, VX-680, ZD1839, ZD6474, zileuton, and zosuquidar 5 trihydrochloride. [0328] For a more detailed description of anticancer agents and other therapeutic agents, those skilled in the art are referred to any number of instructive manuals including, but not limited to, the Physician's Desk Reference and to Goodman and Gilman's "Pharmaceutical Basis of Therapeutics" tenth edition, Eds. 10 Hardman et al., 2002. [0329] 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 15 dose of radiation to an animal. For example, the animal may receive photon radiotherapy, particle 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 radiation is delivered using a gamma knife. 20 [03301 The source of radiation can be external or internal to the animal. External radiation therapy is most common and involves directing a beam of high-energy 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 25 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 following treatment, 30 or left in the body inactive. Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmunotherapy, and the like.
WO 2012/155066 PCT/US2012/037570 123 [03311 The animal may optionally receive radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (IudR), nitroimidazole, 5-substituted-4-nitroimidazoles, 2H-isoindolediones, [[(2 bromoethyl)-amino]methyl]-nitro- 1 H-imidazole- 1-ethanol, nitroaniline 5 derivatives, DNA-affinic hypoxia selective cytotoxins, halogenated DNA ligand, 1,2,4 benzotriazine oxides, 2-nitroimidazole derivatives, fluorine-containing nitroazole derivatives, benzamide, nicotinamide, acridine-intercalator, 5 thiotretrazole derivative, 3-nitro- 1,2,4-triazole, 4,5-dinitroimidazole derivative, hydroxylated texaphrins, cisplatin, mitomycin, tiripazamine, nitrosourea, 10 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-i, IL-6, and the like). Radiosensitizers enhance the killing of tumor cells. Radioprotectors protect 15 healthy tissue from the harmful effects of radiation. [0332] Any type of radiation can be administered to an animal, so long as the dose of radiation is tolerated by the animal without unacceptable negative side effects. Suitable types of radiotherapy include, for example, ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) or particle beam 20 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 effects of radiation can be at least partially controlled by the clinician. In one embodiment, 25 the dose of radiation is fractionated for maximal target cell exposure and reduced toxicity. [0333] In one embodiment, the total dose of radiation administered 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 30 Gy, 55 Gy, or 60 Gy) are administered over the course of treatment. While in some embodiments a complete dose of radiation 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 WO 2012/155066 PCT/US2012/037570 124 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). Accordingly, 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). 5 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 desirably is administered on 5 consecutive days, and not administered on 2 days, for each week of treatment, 10 thereby allowing 2 days of rest per week. However, radiation can be administered 1 day/week, 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, radiation is initiated in week 1 or week 15 2, and is administered for the remaining duration of the therapeutic period. For example, radiation 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 20 not intended, however, to limit the methods provided herein. [0334] 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 microbial organisms may be used, as well as any agent contemplated to have such activities. Antimicrobial 25 agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g., defensins), antisense nucleic acids, membrane disruptive agents and the like, used alone or in combination. Indeed, any type of antibiotic may be used including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like. 30 [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 Formulae I-XXVIII and one or more additional therapeutic WO 2012/155066 PCT/US2012/037570 125 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 different concentrations, by different administration routes, etc. In one embodiment, the compound having Formulae I-XXVIII is administered prior 5 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 10 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 different 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 15 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. [03361 In one embodiment, a method of treating, preventing, or ameliorating cancer in a patient is provided, wherein the method comprises pulsatile 20 administration to the patient a therapeutically effective amount of a compound having Formulae I-XXVIII, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0337] In one embodiment, the pharmaceutical compositions provided herein comprise one or more compounds having Formulae I-XXVIII in an amount 25 which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, 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 30 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 2012/155066 PCT/US2012/037570 126 suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, or from about 0.01 to about 5 mg/kg. [0338] The unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of the compound. The unit dose may be 5 administered 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 solvates. [0339] 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 10 is present at a concentration of about 0.07-1.0 mg/ml, for example, about 0.1-0.5 mg/ml, and in one embodiment, about 0.4 mg/ml. [0340] 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 embodiment, the pharmaceutical composition 15 comprises one or more pharmaceutically acceptable carriers, excipients, and/or auxiliaries. 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 20 which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from 25 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. [0341] The pharmaceutical compositions provided herein may be administered to any patient which may experience the beneficial effects of compounds having 30 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).
WO 2012/155066 PCT/US2012/037570 127 [0342] Compounds having Formulae I-XXVIII and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, 5 intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent 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. 10 [0343] The pharmaceutical compositions and preparations provided herein are manufactured by means of conventional mixing, 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, 15 after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. [0344] Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen 20 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 polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl 25 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 example, 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 gastric 30 juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, WO 2012/155066 PCT/US2012/037570 128 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. 5 [0345] Other pharmaceutical preparations which can be used orally include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain 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 10 stearate and, optionally, stabilizers. In soft capsules, 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. [03461 Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the 15 active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. 20 [0347] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, 25 or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers. 30 [0348] The topical compositions provided herein are formulated in one embodiment as oils, creams, 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 WO 2012/155066 PCT/US2012/037570 129 molecular weight alcohol (greater than C 12 ). The carriers may be those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers can be employed in 5 these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762. [0349] Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which 10 includes about 30% almond oil and about 70% white soft paraffin by weight. Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol. [0350] The following examples are illustrative, but not limiting, of the 15 compounds, compositions, and methods provided herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the methods, compounds, and compositions provided herein. 20 EXAMPLE 1 Synthesis of Compound Example No. 3 Scheme 7 0 0 | methanol, NH + N - NH piperidine CI F overnight CI CI CI 1 2 3 25 [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.
WO 2012/155066 PCT/US2012/037570 130 Scheme 8 0 Ph / O O O 10:1 OO P ---- O Toluene:THF CI NPh NH + + N C F HN Ph reflux, 3h F y Ph I N-O CI H 3 4 5a=CH 2 6a=CH 2 5b = CF 2 6b = CF 2 5c=O 6c=O 5d = NBoc 6d = NBoc 5e= NMe 6e= NMe 5f= NAc 6f= NAc [0352] 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 5 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 product (30-50% yield) as a solid. Scheme 9 OH OH 00 Ph 0 NH 0 h CI N Ph CI Ph N NH 2 N CAN, 1:1 CI -- O e lux CO
CH
3
CN/H
2 0 ci - N C 1 N H H 6a 7 O\- N c "'OH - O N.K 'OH CI NH isomerize CI NH F F --O MeOH/H 2 0 0 CI N 10%TFA, 2d I N H H 8 Compound Example No. 3 10 [0353] Trans-4-aminocyclohexanol (1.8 g, 15.6 mmol) was added to a solution of intermediate 6a (1.0 g, 1.56 mmol), dissolved in THF (30 mL), and refluxed overnight. The solvent was removed and the crude product was purified by WO 2012/155066 PCT/US2012/037570 131 column chromatography to give 0.568 g of intermediate 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 saturated sodium bicarbonate, extracted with ethyl 5 acetate, dried over sodium sulfate, and filtered through celite. The solvent was removed 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 10 methanol/water, purified by preparative HPLC, and lyophilized to give Compound Example No. 3 (as the TFA salt) as a white powder. H NMR (300 MHz, CD 3 0D) 3 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 15 = 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 20 Synthesis of Compound Example No. 22 Scheme 10 O 0 Ph 0 OMe h CI N "Ph CI N Ph 1:1 CH 3 CN:
H
2
SO
4 conc. H 2 0, CAN F F O MeOH, 50'C RT, 30 min CI N CI N H H 6a 11 O) OMe OH CI ci NH F NiOH.H 2 0 CI NH 1:1 THF/H 2 0 , CI N 0 H CI N H 12 13 WO 2012/155066 PCT/US2012/037570 132 [0354] Concentrated sulfuric acid (2 mL) was added to a solution of intermediate 6a (3.65 g, 5.69 mmol) dissolved in methanol (50 mL), and the resulting solution was heated to 50'C for 5 hours. The methanol was removed by evaporation, and the resulting concentrate was cooled to 0C and slowly neutralized with a 5 solution of saturated 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. [0355] Intermediate 11 (2.20 g, 3.25 mmol) was dissolved in acetonitrile (25 mL) 10 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 solvent 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 15 a solid. [0356] The methyl ester intermediate 12 (1.43 g, 3.0 mmol) was dissolved in THF (20 mL) and LiOH.H 2 0 (377 mg, 9.0 mmol) was added, followed by water (20 mL). After 2 hours, the reaction was quenched with water and saturated ammonium chloride, and the aqueous layer was extracted with ethyl acetate. The 20 ethyl acetate solution was dried over sodium sulfate, filtered, and concentrated to produce the carboxylic acid intermediate 13 as an off white solid. The acid was used without further purification. ESI-MS m/z 463.17 (M+H). 25 30 WO 2012/155066 PCT/US2012/037570 133 Scheme 11 OOH 1. CICH 2
CH
2 CI, CI NH + H 2 N O CDl, 500C F +-2 C I O OMe 2. aniline, reflux H 13 14 0 HN 0 -CmuOMe E HN Ci D ( NH LiOH.H 2 0 L, m OH F NaOH NH I0 1:1 THF/H 2 0 ci N N H 15 Compound Example No. 22 103571 CDI (525 mg, 3.24 mmol), DIEA (0.94 1 mL, 5.4 mmol), and DMAP (catalytic) were added to a solution of carboxylic acid intermediate 13 (500 mg, 5 1.08 mmol) dissolved in 1,2-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 reaction was heated to reflux. After heating overnight, the solvent was removed and the crude product was purified by column chromatography to give 265 mg (41% yield) of intermediate 15 as a 10 white solid. [0358] The resulting methyl ester intermediate 15 (265 mg, 0.44 mmol) was dissolved in THF (10 mL) then LiOH.H 2 0 (56 mg, 1.33 mmol), NaOH (53 mg, 1.33 mmol), and H 2 0 were added. After 2 hours, 3 mL of TFA was added, stirred briefly, and the solvent was evaporated. The resulting oil was re-dissolved 15 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. H NMR (300 MHz, CD 3 0D) 3 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 20 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, WO 2012/155066 PCT/US2012/037570 134 1H), 2.08-1.85 (m, 3H), 1.78 (d, J = 11.8 Hz, 2H), 1.54 (q, J = 14.2 Hz, 1H), 1.32-1.10 (m, 2H); ESI-MS m/z 582.17 (M+H). EXAMPLE 3 Synthesis of Compound Example No. 23 5 Scheme 12 OOH o HN S, '0 ~ .HCI 0CM, EDGI N CI NH HC HOBt, DIEA, CI NH F ODMAP (cat) N F O RT overnight I 0 ci - N CI N H H 13 16 Compound Example No. 23 [0359] 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, 10 4-aminotetrahydro-2H-thiopyran- 1,1-dioxide hydrochloride (24 mg, 0.13 mmol) and a catalytic 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 15 mg of Compound Example No. 23 (as the TFA salt) as a white powder. 1H NMR (300 MHz, CD 3 0D) 3 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, 20 1OH), 1.52 (q, J = 13.9 Hz, 1H), 1.3 1-1.11 (m, 2H); ESI-MS m/z 594.50 (M+H). EXAMPLE 4 Synthesis of Compound Example 24 25 WO 2012/155066 PCT/US2012/037570 135 Scheme 13 O OH DCM, EDCI CI NH HMe HOBt, D EA, F +' ~ - OM e DMAP (cat) O RT overnight ci N H 13 17 O HNH N '" H.. He CI / LiOH.H 2 0 CI - NH N H F 1:1 THF/H 2 0 F CI O ci N H H 18 Compound Example No. 24 [03601 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 5 13 (30 mg, 0.065 mmol) dissolved in DCM. After 10 minutes, methyl trans-4 aminocyclohexanecarboxylate hydrochloride (25 mg, 0.13 mmol) and a catalytic amount of DMAP were added. After stirring overnight, the solvent was removed and the crude product was purified by column chromatography to give the 30 mg of intermediate 18 as a white solid. 10 [0361] Methyl ester intermediate 18 (30 mg, 0.05 mmol) was dissolved in THF (1 mL) then LiOH.H 2 0 (6.2 mg, 0.15 mmol) and H 2 0 were added. After 2 hours, 0.5 mL of TFA was added, and the solvent was evaporated. The oil was re dissolved in 3:1 methanol/water with 10% TFA, purified by preparative HPLC, and lyophilized to give 20 mg of Compound Example No. 24 (as the TFA salt) as 15 a white powder. H NMR (300 MHz, CD 3 0D) 3 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), 20 1.32-1.11 (m, 3H), 0.99-0.82 (m, 1H) ESI-MS m/z 588.33 (M+H).
WO 2012/155066 PCT/US2012/037570 136 EXAMPLE 5 [0362] The following compounds were prepare using methodology described in Examples 1-4. Unless otherwise indicated, each Compound Example was purified by reverse phase HPLC and isolated as the TFA salt. Unless otherwise 5 indicated, all H NMR chemical shifts reported herein are denoted by the delta (6) scale. [0363] Compound Example No. 1: H CI F OzN:'''O / NH "'OH NH CI N H [0364] 1 H NMR (300 MHz, MeOH-d 4 ): 8.14 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 10 Hz, 1H), 7.51 (dd, J = 1.9, 8.1 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.17 (dd, J = 1.9, 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 15 (M+Na). [0365] Compound Example No. 2: H CI F O N '''OH NH C1 0 ci ' N H [0366] 1 H NMR (300 MHz, MeOH-d 4 ): 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, 20 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). 25 WO 2012/155066 PCT/US2012/037570 137 [03671 Compound Example No. 4: H CI F O N NH I 0 cl N H [0368] 1 H NMR (300 MHz, MeOH-d 4 ): 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), 5 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). 10 [0369] Compound Example No. 5: H CI F O N '''OH NH CI N H [0370] IH NMR (300 MHz, MeOH-d 4 ): 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 15 (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)+. [0371] Compound Example No. 6: c O NH F I 0 Cl N H 20 [0372] ESI-MS m/z 563.67 (M+H) .
WO 2012/155066 PCT/US2012/037570 138 [03731 Compound Example No. 7: H 0 N N 0 Cl NH F FF Cl N F CII H [0374] The title compound was prepared as described in EXAMPLE 1 using intermediate 6b and 2-morpholinoethanamine (2 equivalents) at room 5 temperature. 1H NMR (300 MHz, CD 3 0D) 3 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); ESI-MS m/z 611.25 (M+H). [0375] Compound Example No. 8: H O N , N 0 Cl NH F F F -. , F /-O 10 H [0376] The title compound was prepared as described in Example 1 using intermediate 6b and 2-morpholinoethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD 3 0D) 3 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 15 (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). [0377] Compound Example No. 9: O 'OH Cl NH F F H [0378] The title compound was prepared as described in EXAMPLE 1 using 20 intermediate 6b. 1 H NMR (300 MHz, CD 3 0D) 3 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), WO 2012/155066 PCT/US2012/037570 139 7.16-7.05 (m, 2H), 6.78 (d, J = 1.9 Hz, 1H), 4.77 (d, J = 10.3 Hz, 1H), 3.70-3.41 (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)+. [03791 Compound Example No. 10: vN ''OH CI NH F 0 | -O CI N 5 H [0380] The title compound was prepared as described in Example 1 using intermediate 6c. 1 H NMR (300 MHz, CD 3 0D) 3 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), 4.12-3.80 (m, 3H), 3.76-3.48 (m, 3H), 2.25 10 0.94 (m, 12H); ESI-MS m/z 562.92 (M+H). [0381] Compound Example No. 11: N 'OH CI NH F 0 [0382] The title compound was prepared as described in EXAMPLE 1 using intermediate 6c. 1 H NMR (300 MHz, CD 3 0D) 3 ppm 8.19 (d, J = 7.9 Hz, 1H), 15 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, 20 1H); ESI-MS m/z 562.67 (M+H). 25 WO 2012/155066 PCT/US2012/037570 140 [03831 Compound Example No. 12: 0 H_ -N 0 N 0 CI NH F N N 0 H [0384] The title compound was prepared as described in Example 1 using intermediate 6c, and 2-morpholinoethanamine (2 equivalents) at room 5 temperature. 1H NMR (300 MHz, CD 3 0D) 3 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), 2.17-2.04 (m, 1H), 1.96-1.80 (m, 1H), 1.50-1.34 (m, 1H); ESI-MS m/z 577.75 (M+H). 10 [0385] Compound Example No. 13: ... O CH3 CI NH F NH |-O CI1 N H [0386] The title compound was prepared as described in EXAMPLE 1 using intermediate 6d and methyl amine (2 equivalents) at room temperature. H NMR (300 MHz, CD 3 0D) 3 ppm 8.10 (s, 1H), 7.27-7.15 (m, 3H), 7.00-6.89 (m, 2H), 15 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). [0387] Compound Example No. 14: O-CH3 F N H 1 0 Cl1 N N
H
WO 2012/155066 PCT/US2012/037570 141 [03881 The title compound was prepared as described in EXAMPLE 1 using intermediate 6d and methyl amine (2 equivalents) at room temperature. H NMR (300 MHz, CD 3 0D) 3 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 5 (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), 2.10-1.88 (m, 2H), 1.50-1.26 (m, 1H); ESI-MS m/z 477.17 (M+H). [0389] Compound Example No. 15: 0 H _ N 0 Cl NH Cl N H 10 [0390] The title compound was prepared as described in EXAMPLE 1 using intermediate 6a and 2-morpholinoethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD 3 0D) 3 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), 5.02 (d, J = 10.3 Hz, 1H), 4.80 (d, J = 10.5 Hz, 1H), 3.94-3.80 (m, 4H), 3.61 (t, J 15 = 6.2 Hz, 2H), 3.29-3.17 (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 (M+H). [0391] Compound Example No. 16: OI _CH3 Cl NH F N H [0392] The title compound was prepared as described in EXAMPLE 1 using 20 intermediate 6e and methyl amine (2 equivalents) at room temperature. H NMR (300 MHz, CD 3 0D) 3 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, WO 2012/155066 PCT/US2012/037570 142 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). [0393] Compound Example No. 17: ON-CH3 CI NH F
N
CI N H 5 [0394] The title compound was prepared as described in EXAMPLE 1 using intermediate 6e and methyl amine (2 equivalents) at room temperature. H NMR (300 MHz, CD 3 0D) 3 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, 10 J= 12.5 Hz, 1H), 3.52-3.40 (m, 2H), 3.24-3.12 (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) [0395] Compound Example No. 18: CI NH F N CI N H 15 [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) [0397] Compound Example No. 19: O -CH3 CI NH 0 C N N 1 0
H
WO 2012/155066 PCT/US2012/037570 143 [03981 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). [0399] Compound Example No. 20: 0 - O-NH Ci 1 NH F O N0 C NH 5 H [0400] The title compound was prepared as described in EXAMPLE 1 using intermediate 6a and 2-(methylsulfonyl)ethanamine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD 3 0D) 3 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, 10 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) [0401] Compound Example No. 21:
CH
3 O NH Cl NH F I 0 Cl N H 15 [0402] The title compound was prepared as described in EXAMPLE 1 using intermediate 6a and methyl amine (2 equivalents) at room temperature. 1H NMR (300 MHz, CD 3 0D) 3 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, 20 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 2012/155066 PCT/US2012/037570 144 [0403] Compound Example No. 25: 0 11 N O NH C1 NH F CI 0 ci 'N H [0404] The title compound was prepared using 1-(2 (methylsulfonyl)ethyl)piperidin-4-amine hydrochloride. 1 H NMR (300 MHz, 5 CD 3 0D) 3 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 10 (M+H)+. [0405] Compound Example No. 26: O O OH Ci NH F Cl H' I 0 Cl N H [0406] Intermediate 13 (see EXAMPLE 3) was dissolved in 3:1 methanol/water, treated with 10% TFA, and purified by preparative HPLC to give the title 15 compound as the TFA salt. 1H NMR (300 MHz, CD 3 0D) 3 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). 20 WO 2012/155066 PCT/US2012/037570 145 [04071 Compound Example No. 27: 0 OH O ONH Cl NH F jI 0 Cl N H [0408] The title compound was prepared using methyl 4-aminobutanoate hydrochloride. 'H NMR (300 MHz, CD 3 0D) 3 ppm 7.64 (t, J = 7.1 Hz, 1H), 5 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). 10 [0409] Compound Example No. 28: 0 OH O NH CI NH F CI N H [0410] The title compound was prepared using methyl trans-4 (aminomethyl)cyclohexanecarboxylate hydrochloride. 1 H NMR (300 MHz,
CD
3 0D) 3 ppm 8.36-8.26 (m, 1H), 7.67 (t, J = 6.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 15 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). [0411] Compound Example No. 29: WO 2012/155066 PCT/US2012/037570 146 0 OH OI N H F 0 C aN H H [0412] The title compound was prepared using methyl 4-(aminomethyl)benzoate hydrochloride. 1 H NMR (300 MHz, CD 3 0D) 3 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), 5 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). 10 [0413] Compound Example No. 30: 0 O=S'' II O NH Cl1 NH F I "" 0 cl N H [0414] The title compound was prepared using methanesulfonamide. 1H NMR (300 MHz, CD 3 0D) 3 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, 15 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). 20 WO 2012/155066 PCT/US2012/037570 147 [04151 Compound Example No. 31: 0 OH 0~ O 0 ,NH C1 NH F I 0 ci N H [0416] The title compound was prepared using methyl 4-amino-3 methoxybenzoate. 1H NMR (300 MHz, CD 3 0D) 3 ppm 8.26 (d, J = 8.6 Hz, 1H), 5 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)+. 10 [0417] Compound Example No. 32: N-N N 0 NH H C1 NH F N 0 C1 N H [0418] The title compound was prepared using (lH-tetrazol-5-yl)methanamine hydrochloride. 1 H NMR (300 MHz, CD 3 0D) 3 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, 15 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). 20 WO 2012/155066 PCT/US2012/037570 148 [0419] Compound Example No. 33: HO O -NH C1 NH F CI 0 H [0420] The title compound was prepared using (1s,3s)-3-(tert butyldimethylsilyloxy)-3-methylcyclobutanamine. H NMR (300 MHz, CD 3 0D) 5 3 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, 10 3H), 1.27-1.07 (m, 2H); ESI-MS m/z 546.67 (M+H). [0421] Compound Example No. 34 HO CH3 O O NH NH Ci I N H [0422] IH NMR (300 MHz, CD 3 0D) 3 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, 15 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), 1.62-1.40 (m, 7H), 1.40-1.08 (m, 2H); ESI-MS m/z 560.58 (M+H). 20 WO 2012/155066 PCT/US2012/037570 149 [0423] Compound Example No. 35 HO 0 CH3 N O NH NH C 1 0 cl N H [0424] H NMR (300 MHz, CD 3 OD) 3 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, 5 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), 1.32-1.08 (m, 2H); ESI-MS m/z 561.33 (M+H). [0425] Compound Example No. 36 O OH NN O NH Cl 1 NH F C 0 Ci 11 N H [0426] The title compound was prepared using methyl 5-aminopicolinate. 10 1 H NMR (300 MHz, CD 3 0D) 3 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), 5.30 (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, 15 1H), 1.32-1.11 (m, 2H); ESI-MS m/z 583.96 (M+H). 20 WO 2012/155066 PCT/US2012/037570 150 [04271 Compound Example No. 37 OH 0 N O ONH C 1 NH F I 0 Cl N H [0428] The title compound was prepared using methyl 2-(4-aminopiperidin-1 yl)acetate hydrochloride. 1 H NMR (300 MHz, CD 3 0D) 3 ppm 7.66 (t, J = 7.1 Hz, 5 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), 3.79-3.39 (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); ESI-MS m/z 603.67 (M+H). 10 [0429] Compound Example No. 38 0 N 0 NH F I 0 Cl N H [0430] The title compound was prepared using tert-butyl 3-aminoazetidine-1 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, 15 DIEA, and DMAP(catalytic) in DCM. After stirring 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. 1 H NMR (300 MHz, CD 3 0D) 3 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 WO 2012/155066 PCT/US2012/037570 151 (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). 5 [0431] Compound Example No. 39 O NH Cl- NH F I 1! 0 Cl N H [0432] The title compound was prepared using methyl trans-3 aminocyclobutanecarboxylate hydrochloride. 1 H NMR (300 MHz, CD 3 0D) 3 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, 10 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), 2.29-2.08 (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). [0433] Compound Example No. 40 O OH -O NH C NH F I 0 Cl N 15 H [0434] IH NMR (300 MHz, CD 3 0D) 3 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), 2.41-2.29 (m, 1H), 20 2.20 (d, J = 15.3 Hz, 1H), 2.03-1.12 (m, 16H); ESI-MS m/z 588.50 (M+H).
WO 2012/155066 PCT/US2012/037570 152 [04351 Compound Example No. 41 OH O 0 <NH c NH F I 0 Cl N H [0436] 1 H NMR (300 MHz, CD 3 0D) 3 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, 5 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). [0437] Compound Example No. 42 OH N O NH c l NH I 0 cl N 10 H [0438] IH NMR (300 MHz, CD 3 0D) 3 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), 3.50-3.36 (m, 1H), 2.83 (d, J = 12.5 Hz, 1H), 2.17 (d, 15 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). 20 WO 2012/155066 PCT/US2012/037570 153 [0439] Compound Example No. 43 0 OH O NH c N H F I ": " 0 cil N H [0440] H NMR (300 MHz, CD 3 0D) 6 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, 5 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). [0441] Compound Example 44 0 OH O N H Cl1 N H [0443] Compound Example No. 45 O OH O N H Cl -, N H F I -0 Cl N 1 CoH E OH O WO 2012/155066 PCT/US2012/037570 154 [0444] H NMR (300 MHz, CD 3 0D) 3 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, 5 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). [04451 Compound Example No. 46 O OH F Cl NH ci N H F I 0 Cl - N H [0446] 1 H NMR (300 MHz, CD 3 0D) 3 ppm 7.90 (t, J = 8.4 Hz, 1H), 7.74-7.61 10 (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), 2.94-2.84 (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). 15 [0447] Compound Example No. 47 O OH F O NH Ci NH F ~N I N ci N H [0448] IH NMR (300MHz, CD 3 0D) 3 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, 20 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), WO 2012/155066 PCT/US2012/037570 155 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)+. EXAMPLE 6 5 Fluorescence-polarization MDM2 binding assay [0449] The binding affinity of the MDM2 inhibitors disclosed herein was determined using a fluorescence polarization-based (FP-based) binding assay using a recombinant human His-tagged MDM2 protein (residues 1-118) and a fluorescently tagged p53-based peptide. 10 [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 protein was determined from the saturation curve. MDM2 protein was serially double diluted in a Dynex 96-well, 15 black, round-bottom plate, and the PMDM6-F peptide was added at InM concentration. The assay was performed in the buffer: 100 mM potassium phosphate, pH 7.5; 100 pg/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 U.S. Inc., Research Triangle Park, 20 NC). The IC 50 value was obtained by fitting the mP values in a sigmoidal dose response curve (variable slope) with a non-linear regression, and was determined to be 1.40 nM ± 0.25. The Kd value was calculated using the equation: Kd value = IC 50 - LO/2. LO/2 is the concentration of the free ligand (PMDM6-F). Since PMDM6-F was used at a final concentration of InM, LO/2 was 0.5 nM. 25 [0451] Dose-dependent, competitive binding experiments were performed with serial dilutions of a tested compound in DMSO. A 5 pL sample of the tested compound and pre-incubated MDM2 protein (10 nM) and PMDM6-F peptide (1 nM) in the assay buffer (100 mM potassium phosphate, pH 7.5; 100 pg/mL bovine gamma globulin; 0.02% sodium azide, 0.01% Triton X-100), were added 30 in a Dynex 96-well, black, round-bottom plate to produce a final volume of 125 pL. 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 WO 2012/155066 PCT/US2012/037570 156
IC
50 values, i.e., the inhibitor 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 results of this assay are present in Table 2. 5 EXAMPLE 7 Cell growth assay [0452] Isogenic HCT-1 16 colon cancer cell lines were a kind gift from Prof. Bert Vogelstein (Johns Hopkins, Baltimore, MD) and were maintained in McCoy's 5A 10 medium containing 10% FBS. The SJSA-1 cell lines were obtained from ATCC, (Manassas, VA) and were maintained in RPMI-1640 medium containing 10% FBS. [0453] Cells were seeded in 96-well flat bottom cell culture plates at a density of 2-3x 103 cells/well with compounds and incubated for 4 days. The rate of cell 15 growth inhibition after treatment with increasing concentrations of the tested compounds was determined by WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4 nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (Dojindo Molecular Technologies Inc., Gaithersburg, Maryland). WST-8 was added at a final concentration of 10% to each well, and then the plates were incubated at 20 37 0 C for 2-3 hrs. The absorbance of the samples was measured at 450 nm using a TECAN ULTRA Reader. The concentration of the compounds that inhibited cell growth by 50% (IC 50 ) was calculated by comparing absorbance in the untreated cells and the cells treated with the compounds using the GraphPad Prism software (GraphPad Software, La Jolla, CA 92037, USA). The results of 25 this assay are presented in Table 2 and Fig. 1 and Fig. 2. Table 2 Binding affinities to MDM2 (1-118) Compound Number
IC
50 Ki (nM) HCT116 HCT116 SJSA-1 (nM) p53 WT p53 KO 1 201 26.4 1.8 > 30 2.3 2 41.8 4.6 0.4 >30 0.5 3 19.3±5.2 1.5±0.7 0.12 24 0.33 4 15.6±2.2 1.0±0.3 7.3 48 1.9 5 >10,000 6 <1,000 WO 2012/155066 PCT/US2012/037570 157 7 <1,000 <5 8 <5,000 <5 9 <100 <1 10 <5,000 <5 11 <5,000 <5 12 <5,000 <10 13 >10,000 >10 14 >10,000 >10 15 <100 <3 16 >5,000 17 >5,000 18 >5,000 19 >1,000 20 <100 21 <100 <5 22 <100 <1 23 <100 <3 24 <100 <1 25 <100 <1 26 <500 <30 27 <100 <5 28 <100 <5 29 <100 30 <500 <10 31 <100 <1 32 <100 33 <100 <1 34 >10,000 35 >10,000 36 <100 <1 37 <100 38 <100 <1 39 <100 <1 40 <100 41 <100 42 <1,000 43 <100 EXAMPLE 8 In vivo efficacy studies using SJSA-xenograft models [0454] SJSA-1 (osteosarcoma) tumor cells were harvested with Trypsin (0.05%) 5 EDTA (0.53 mM) (GIBCOT
M
, Invitrogen Corp.), growth medium was added, and the cells were placed on ice. A cell sample was mixed 1:1 with Trypan Blue (GIBCOTM, Invitrogen Corp.) and counted on a hemocytometer to determine the WO 2012/155066 PCT/US2012/037570 158 number of live/dead cells. Cells were washed once with IX 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 5 mg/ml. SJSA-1 tumors were inoculated into C.B-17 SCID mice at 5 x 106 cells in 0. 1ml with Matrigel. Cells were injected s.c. into the flank region of each mouse using a 27 gauge needle. [0455] The size of tumors growing in the mice was measured in two dimensions using calipers. Tumor volume (mm 3 ) = (AxB 2 )/2 where A and B are the tumor 10 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 Compound Example Nos. 22 and 24 are 15 shown in Fig. 3. [0456] Suitable vehicles for in vivo administration of the compounds provided 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. 20 EXAMPLE 9 Stability of Compounds in Solution [0457] The stability of Compound Example Nos. 3, 22, 24, and 39, and MI-77301 (See U.S. Patent Appl. Pub. No. 2011/0112052 A2) were determined 25 in 1:1 MeOH:H 2 0 (Fig. 4) and 1:1 CH 3
CN:H
2 0 (Fig. 5) using ultra performance liquid chromatography. In both solvent systems, Compound Example Nos. 3, 22, 24, and 39 were more stable than MI-77301. [0458] The stability of Compound Example Nos. 10 and 11 were determined in 1:1 MeOH:H 2 0 with 10% TFA added using ultra performance liquid 30 chromatography (Fig. 6). Compound Example No. 10 is converted into Compound Example No. 11 under these conditions. [0459] 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 WO 2012/155066 PCT/US2012/037570 159 be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the compounds, methods, and compositions provided herein or any embodiment thereof. All patents, patent applications, and publications cited herein are fully incorporated by reference 5 herein in their entirety.

权利要求:
Claims (46)
[1] 1. A compound having Formula I: 0 E R
[2] 2 R Y R1b R 3 b Ri 'X 0 Rid wherein: la lb le id 5 R , R , R , and R1 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 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, and sulfonamido; 10 R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R a 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 15 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; or 20 R3a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl or a 3- to 9-membered optionally substituted heterocyclo; E is selected from the group consisting of -OR 2 6 a and -NR 2 6 bR 2 6 c; R26a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 25 R26b is selected from the group consisting of hydrogen and optionally substituted C 1 -C 6 alkyl; WO 2012/155066 PCT/US2012/037570 161 R26, is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, and -SO 2 R 5; or R2 and R taken together form a 4- to 9-membered optionally substituted 5 heterocyclo; X is selected from the group consisting of 0, S, and NR'; Y is selected from the group consisting of 0, S, and NR"; R' is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, and optionally substituted cycloalkyl; 10 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 acceptable salt thereof. 15 2. The compound of claim 1 having Formula III: o E R 2 Rla Rib N R3b R 3 a R~eX O Ric x 0 or a pharmaceutically acceptable salt thereof.
[3] 3. The compound of claim 2 having Formula VI: 20 R 2 Ria Rib R 3 b cR3a Re X O Rid V1, or a pharmaceutically acceptable salt thereof.
[4] 4. The compound of claim 2 having Formula XVI: 25 WO 2012/155066 PCT/US2012/037570 162 OZ . E R 2 F Ria Ri . . .aR' 4x R 3a Rid XVI, or a pharmaceutically acceptable salt thereof
[5] 5. The compound of any one of claims 1-4, wherein: 5 E is -NR26 R26c. R2 is optionally substituted aryl; R 3 a is halo or C 1 -C 10 alkyl; R 3 b is halo or C 1 -C 10 alkyl; or R 3a and R 3 b taken together form a 3- to 9-membered optionally substituted 10 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. 15
[6] 6. The compound of any one of claims 1-5, wherein R3a and R 3 b are each independently C 1 -C 10 alkyl, or a pharmaceutically acceptable salt thereof.
[7] 7. The compound of any one of claims 1-5, wherein R3a and R 3 b taken together form a 4- to 8-membered optionally substituted cycloalkyl or a 4- to 8-membered optionally 20 substituted heterocyclo, or a pharmaceutically acceptable salt thereof.
[8] 8. The compound of claim 7, wherein R 3 a and R 3 b taken together form a 6-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt thereof. 25
[9] 9. The compound of claim 8, wherein R 3 a and R 3 b taken together form an optionally substituted piperidine or a tetrahydropyra, or a pharmaceutically acceptable salt thereof. WO 2012/155066 PCT/US2012/037570 163
[10] 10. The compound of claim 7, wherein R 3 a and R 3 b taken together form a 4- to 8-membered optionally substituted cycloalkyl, or a pharmaceutically acceptable salt thereof. 5
[11] 11. The compound of claim 10, wherein R3a and R 3b are taken together to form an unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring, or a pharmaceutically acceptable salt thereof.
[12] 12. The compound of any one of claims 1-11, wherein: 10 Ria and Rld are each hydrogen; R bis selected from the group consisting of hydrogen and fluoro; and R" is selected from the group consisting of fluoro and chloro, or a pharmaceutically acceptable salt thereof. 15
[13] 13. The compound of any one of claims 1-12, wherein R 2 is optionally substituted aryl having Formula R2- 1: R 25 d R 25 c R25e R 25 b R 25a R2-1 wherein R 2, R , R 2 R25 , and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, alkyl, or 20 haloalkyl, or a pharmaceutically acceptable salt thereof.
[14] 14. The compound of any one of claims 1-12, wherein R 2 is optionally substituted pyridyl, or a pharmaceutically acceptable salt thereof. 25
[15] 15. The compound of claim 1 having Formula XXVI H R2 NR 26, R ia NH R1 N 0 R ld H XXVI, WO 2012/155066 PCT/US2012/037570 164 or a pharmaceutically acceptable salt thereof.
[16] 16. The compound of claim 15 having Formula XXVII: NH R1c N 0 5 1 d H XXVII, or a pharmaceutically acceptable salt thereof.
[17] 17. The compound of claim 15 having Formula XXVIII: R Rla NH R1 c N 0 R ld H XXVIII, 10 or a pharmaceutically acceptable salt thereof.
[18] 18. The compound of any one of claims 1-17, wherein R 26 c is optionally substituted alkyl, or a pharmaceutically acceptable salt thereof. 15
[19] 19. The compound of claim 18, wherein the optionally substituted alkyl is substituted with an optionally substituted cycloalkyl, or a pharmaceutically acceptable salt thereof.
[20] 20. The compound of claim 18, wherein the optionally substituted alkyl is substituted with an optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof. 20
[21] 21. The compound of any one of claims 1-17, wherein R 2 6 c is aralkyl, or a pharmaceutically acceptable salt thereof. WO 2012/155066 PCT/US2012/037570 165
[22] 22. The compound of any one of claims 1-17, wherein R 26 c is optionally substituted cycloalkyl, or a pharmaceutically acceptable salt thereof.
[23] 23. The compound claim 22, wherein R 26 c is hydroxycycloalkyl, or a 5 pharmaceutically acceptable salt thereof.
[24] 24. The compound of claim 22, wherein the optionally substituted cycloalkyl is substituted with at least one -CO 2 H, or a pharmaceutically acceptable salt thereof. 10
[25] 25. The compound of claim 22, wherein R26c is selected from the group consisting of: OH OH OH , ' H 3 C H 3 C >Li OH OH 'OH HOH CH 3 CO2H ''CO 2 H CO2H ,-CO2H CO 2 HH 3 6 H 3 C CO 2 H and '''CO 2 H CO 2 H 'CO 2 H 'H 3 CH 3 or a pharmaceutically acceptable salt thereof.
[26] 26. The compound of any one of claims 1-17 wherein R 2 6 c is optionally substituted 15 heterocyclo, or a pharmaceutically acceptable salt thereof.
[27] 27. The compound of any one of claims 1-17, wherein R 26 is optionally substituted aryl, or a pharmaceutically acceptable salt thereof. WO 2012/155066 PCT/US2012/037570 166
[28] 28. The compound of claim 27, wherein R 2 6 c is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof.
[29] 29. The compound of claim 28, wherein the optionally substituted phenyl is 5 substituted with at least one -CO 2 H, or a pharmaceutically acceptable salt thereof.
[30] 30. The compound of any one of claims 1-17, wherein R 26 c is optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof. 10
[31] 31. The compound of claim 30, wherein R26c is optionally substituted pyridyl, or a pharmaceutically acceptable salt thereof.
[32] 32. A compound selected from the group consisting of: O N OH O N OH o HN CI NH CI NH CI NH F F F F O CI NH NH, NH I !5 0'". 0 CI N C N C 1 N H H H H H 0 N_ .. CI F 0 NC1F N c i - K X O H /ON S1N H N HNH F % 0 ci -~N Ci I N i H H H F H HH CIF 0 -N 0 2 "O NI F-N/- N H /NH' " NH I 1 0 ci" ci1' Ci H H H WO 2012/155066 PCT/US2012/037570 167 H H H O N N O O N N N "OH cI NH F CI NH F CI NH F F F F F F F C I N C I N H ci CI NNOH H H ,H NH 3 O H 3 rN O H N CI-N 0 H_ NH N C N-CH3 N-CH3N-CH cI NH NH NH O 'F N CI N CI N I H H Hl H H 0 HIN O CH3 O NH C NH OO NHCI NH HH F NH F NH FN I I0 I 0 c N ci,: 1 Hl ci H H n i-H 3 H oH %- H ~NCH 3 N CH ci NH cl NH cl NH 0 c- N N Hl cljC:N cl N HH H 0 0- HO~zH 3 N CH3 CONH clNH 0 -N H ci-' NH cI N NH 0 H 0 ji 0 H Ci N H WO 2012/155066 PCT/US2012/037570 168 0 O=s' 0 N 0 OH OH CI NH O NH O NH cI NH /l1 & 0 NH CI NH ci N HI F O CI 0 O H 0i ci N H 0 0 0 OH OH O0S 0 NH NH O HHO N NH CI NH CN H NH CI NH O CH O F F O O 0 CH0 H O N N 0 cl H C H H O OH N-N HO K" N % 0 NH H NH 0 NH OC CNH O Cl NH clNH NH F F F 0 I 0 0 0H ClN ci~ N H H 0 OH OH 3 H 3 N N NHN NH /NH .~N l l cl / NH HI Hl NlI H WO 2012/155066 PCT/US2012/037570 169 OH O 0,OH N N ~0 NH 0 NH~ H H NH NH C1 NH CI NHN O 0O OO H H HI OH O OH OH OH 0 NH O0 NH C NH NH F F Cla N CI N 0 0 0 OH OHH OH H H a H o acH x 'Nn 01 N H N NH NH CI 0 F VF II " N NII H H 0 OH 0 OH o F 0 NH 0 \-NH 1N H 1N H F F N N 0 C1 H and C'a H or a pharmaceutically acceptable salt thereof. WO 2012/155066 PCT/US2012/037570 170
[33] 33. A compound selected from the group consisting of: H H H CI F O NKj CI F 0 N CI F O NK0 NH NH 'C2H NH 'C2H I N I N C I H H H H H CI F 0 N ''C 2 H CI F O N OH NH NH I 0 and 0 c N H c1 N or a pharmaceutically acceptable salt thereof. 5
[34] 34. The compound of claim 1, wherein E is -OR 26 a, or a pharmaceutically acceptable salt thereof.
[35] 35. The compound of claim 34, wherein R 2 6 a is hydrogen, or a pharmaceutically 10 acceptable salt thereof.
[36] 36. A pharmaceutical composition comprising the compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15
[37] 37. A method of treating a patient comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein the patient has a hyperproliferative disease. 20
[38] 38. The method of claim 37, wherein the hyperproliferative disease is cancer.
[39] 39. The method of claim 38, wherein the cancer is selected from the group consisting of melanoma, lung cancer, sarcoma, colon cancer, prostate cancer, choriocarcinoma, WO 2012/155066 PCT/US2012/037570 171 breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymphoma, multiple myeloma, and leukemia.
[40] 40. The method of claim 39, wherein the cancer is selected from the group consisting 5 of liposarcoma and melanoma.
[41] 41. A kit comprising a compound of any one of claims 1-33, or a pharmaceutically acceptable salt, thereof, and instructions for administering the compound to a patient having a hyperproliferative disease. 10
[42] 42. The kit of claim 41, wherein the hyperproliferative disease is cancer.
[43] 43. A method of preparing a compound having Formula XVI: OE R 2 Ria RiR3b R 3 a R~ / X O Rid XVI, 15 comprising: a) allowing a compound of claim 3 to isomerize; and b) isolating the compound having Formula XVI substantially free from the compound of claim 3, wherein X and Y are NH. 20
[44] 44. The method of claim 43, wherein E is -OR 26 a
[45] 45. The method of claim 43, wherein E is -NR 26bR26c 25
[46] 46. The method of any one of claims 43-45, wherein R3a and R 3 b taken together form a 3- to 9-membered optionally substituted cycloalkyl.

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法律状态:
2014-01-23| PC1| Assignment before grant (sect. 113)|Owner name: THE REGENTS OF THE UNIVERSITY OF MICHIGAN Free format text: FORMER APPLICANT(S): AGUILAR, ANGELO; GARCIA-ECHEVERRIA, CARLOS; SUN, WEI; WANG, SHAOMENG; SANOFI; THE REGENTS OF THE UNIVERSITY OF MICHIGAN |

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2014-03-06| TH| Corrigenda|Free format text: IN VOL 28 , NO 3 , PAGE(S) 398 UNDER THE HEADING ASSIGNMENTS BEFORE GRANT, SECTION 113 - 2012 UNDERTHE NAME THE REGENTS OF THE UNIVERSITY OF MICHIGAN, APPLICATION NO. 2012253339, UNDER INID (71) ADD CO-APPLICANT SANOFI |

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2016-07-28| FGA| Letters patent sealed or granted (standard patent)|

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US201161484986P| true| 2011-05-11|2011-05-11||

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