USOO8883832B2

(12) United States Patent (10) Patent No.: US 8,883,832 B2 Shallwitz et al. (45) Date of Patent: *Nov. 11, 2014

(54) COMPOUNDS, COMPOSITIONS, AND (2013.01); C07D 277/60 (2013.01); A61 K METHODS FOR PREVENTING METASTASS 31/538 (2013.01); A61K 31/428 (2013.01); OF CANCER CELLS A61K 45/06 (2013.01); A61 K3I/7068 (2013.01) (71) Applicant: Aerpio Therapeutics Inc., Cincinnati, USPC ...... 514/365: 514/254.02: 514/342 OH (US) (58) Field of Classification Search (72) Inventors: Robert Shalwitz, Bexley, OH (US); None Kevin Gene Peters, Cincinnati, OH See application file for complete search history. (US) (56) References Cited (73) Assignee: Aerpio Therapeutics Inc., Cincinnati, OH (US) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 4,673,641 A 6/1987 George et al. 5,424,398 A 6/1995 Middeldorp et al. patent is extended or adjusted under 35 5,585,089 A 12/1996 Queen et al. U.S.C. 154(b) by 0 days. 5,688,781 A 1 1/1997 Siegallet al. 5,807,819 A 9/1998 Cheng et al. This patent is Subject to a terminal dis 5,994,128 A 11/1999 Fallaux et al. claimer. 6,033,908 A 3/2000 Bout et al. 6,342,219 B1 1/2002 Thorpe et al. (21) Appl. No.: 13/783,311 6,589,758 B1 7, 2003 Zhu 6,596,772 B1 7/2003 Huang et al. (22) Filed: Mar. 3, 2013 7,226,755 B1 6/2007 Peters et al. 7,507,568 B2 3/2009 Evdokimov 7,588,924 B2 9, 2009 Evdokimov et al. (65) Prior Publication Data 7,589,212 B2 9/2009 Gray et al. US 2014/0249100A1 Sep. 4, 2014 7,622,593 B2 11/2009 Gray et al. 7,795,444 B2 9/2010 Gray et al. 8, 106,078 B2 1/2012 Gray et al. Related U.S. Application Data 8,188,125 B2 5/2012 Gray et al. 8,258,311 B2 9/2012 Gray et al. (63) Continuation of application No. 12/677.550, filed as 8.329,916 B2 12/2012 Amarasinghe et al. application No. PCT/US2010/020822 on Jan. 12, 8.338,615 B2 12/2012 Gray et al. 2010, now Pat. No. 8,569,348. 2004O1671.83 A1 8/2004 Klopfenstein et al. 2004/0204863 A1 10/2004 Kim et al. (60) Provisional application No. 61/223.260, filed on Jul. 6, 2007/02991 16 A1 12/2007 Gray 2009. 2008.0004267 A1 1/2008 Gray 2008/0076764 A1 3/2008 Peters et al. 2008. O1086.31 A1 5/2008 Gray et al. (51) Int. Cl. 2009/0227639 A1 9/2009 Gray et al. AOIN 43/78 (2006.01) A6 IK3I/425 (2006.01) (Continued) A6 IK3I/427 (2006.01) A6 IK3I/53 (2006.01) FOREIGN PATENT DOCUMENTS CO7D 417/04 (2006.01) WO WOOOf 65085 11, 2000 C07D 277/64 (2006.01) WO WOOOf 65088 A1 11, 2000 CO7D 417/4 (2006.01) WO WOO2,26774 A1 4/2002 C07D 277/28 (2006.01) C07D 417/12 (2006.01) OTHER PUBLICATIONS A 6LX3L/2197 (2006.01) A6 IK3I/4245 (2006.01) Altschulet al., “Gapped BLAST and PSI-BLAST: A New Generation A6 IK3I/433 (2006.01) of Protein Database Search Programs.” Nucleic Acids Res., A6 IK3I/4439 (2006.01) 25(27).3389-3402 (1997). A6 IK3I/426 (2006.01) (Continued) C07D 277/60 (2006.01) A6 IK3I/538 (2006.01) A6 IK3I/428 (2006.01) Primary Examiner — Patrick Lewis A6 IK 45/06 (2006.01) (74) Attorney, Agent, or Firm — Richard S. Echler A6 IK3I/7068 (2006.01) (52) U.S. Cl. CPC ...... C07D 277/28 (2013.01); A61K3I/427 (57) ABSTRACT (2013.01); A61 K3I/513 (2013.01); C07D Disclosed are methods for preventing metastasis of cancer 417/04 (2013.01); C07D 277/64 (2013.01); cells. The disclosed compounds can be used to prevent the C07D 417/14 (2013.01); C07D 417/12 spread of tumor or other types of cancer cells. (2013.01); A61 K3I/497 (2013.01); A61 K 3 1/4245 (2013.01); A61 K31/433 (2013.01): A61 K3I/4439 (2013.01); A61 K3I/426 52 Claims, 5 Drawing Sheets US 8,883,832 B2 Page 2

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xxxyyxxx-xxxxxxxxxxxxx S sexyyxxS s leys of s US 8,883,832 B2 1. 2 COMPOUNDS, COMPOSITIONS, AND the initial tumor can grow to a size that adversely effects organ METHODS FOR PREVENTING METASTASS function at the primary site and in nearby tissues. Metastases OF CANCER CELLS of the primary tumor are also more likely if the primary tumors growth is uncontrolled. There is a need for methods PRIORITY of slowing or preventing tumor growth. This application is a Continuation Application of U.S. SUMMARY patent application Ser. No. 12/677.550, filed Dec. 1, 2010, which is a National Stage Entry under 35 U.S.C. S371 of Disclosed herein are compounds, compositions, and meth International Application PCT/US2010/020822, filed Jan. 10 ods for preventing metastasis of cancer cells. Further dis 12, 2010, which claims the benefit of Provisional Application closed are compounds, compositions, and methods that can Ser. No. 61/223,260 filed on Jul. 6, 2009, the entire disclo be used for treating cancer, including combination therapy sures of which applications are incorporated herein by refer compositions wherein the disclosed compounds are com CCC. bined with one or more cancer treatment drugs or other che 15 motherapeutic agents. FIELD Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the Disclosed are compounds that can prevent the metastasis of description, or may be learned by practice of the aspects cancerous tumors and/or reduce tumor growth. Further dis described below. The advantages described below will be closed are compositions, especially pharmaceutical compo realized and attained by means of the elements and combina sitions for preventing metastasis of malignant tumors and tions particularly pointed out in the appended claims. It is to reducing tumor growth. Included within the compositions are be understood that both the foregoing general description and combined therapy compositions for use in treating cancer. the following detailed description are exemplary and Still further disclosed are methods for preventing metastasis explanatory only and are not restrictive. of cancerous tumors and other cancer cells. As such, the 25 disclosed compounds can be used to aid in the prevention of BRIEF DESCRIPTION OF THE FIGURES cancerous growth in a Subject having cancer or diagnosed with cancer. FIG. 1 depicts a graph showing the increase in tumor Vol ume with time of renal cell carcinoma tumors (Renca) in BACKGROUND 30 mice; vehicle control (D); 100,000 IU/dose of IL-2 twice daily (()); 40 mg/kg of D91 twice daily (A): 100,000 IU/dose One of the most frightening aspects of cancer is its ability of IL-2 and 40 mg/kg of D91 twice daily (O). to spread, or metastasize. Initially, cancer cells are found FIG. 2 is a histogram of the volume of renal cell carcinoma grouped together thereby forming one or more tumors. tumors (Renca) in mice at day 25; vehicle control (A): 40 After formation of the primary tumor, cancer cells can gain 35 mg/kg of D91 twice daily (B): 100,000 IU/dose of IL-2 twice the ability to separate from the original tumor and travel to daily (C); 100,000 IU/dose of IL-2 and 40 mg/kg of D91 other areas of the body. Lung cancer cells that take up in the twice daily (D). liver and form tumors are still lung cancer cells. Thus, the FIG.3 depicts a graph showing the increase in tumor Vol propensity for one particular form of cancer to metastasize is ume with time of B16 melanoma tumors in mice; vehicle dependent on many factors, including type of cancer; how 40 control (D): 300,000 IU/dose of IL-2 twice daily (()); 300, ever, the overall process of how cells begin the process of 000 IU/dose of IL-2 and 40 mg/kg of D91 twice daily (O). metastasis is still not completely understood. FIG. 4 depicts histogram of the volume of B16 melanoma If a single localized tumor is discovered before it has had a tumors in mice at day 22; vehicle control (A): 300,000 chance to metastasize, then the prognosis of patient Survival is IU/dose of IL-2 twice daily (B): 300,000 IU/dose of IL-2 and higher. This is because the tumor can be effectively excised or 45 40 mg/kg of D91 twice daily (C). destroyed by radiation or chemotherapy. There is, therefore, a FIG.5 depicts a graph of the body weight of mice with B16 difference between tumor growth and metastasis of the tumor melanoma tumors; vehicle control (D); 100,000 IU/dose of cells; the first does not always lead to the other. Cancers that IL-2 twice daily (()); 300,000 IU/dose of IL-2 twice daily have metastasized, however, are difficult to cure because the (A): 100,000 IU/dose of IL-2 and 40 mg/kg of D91 twice daily extent to which they have spread throughout the body is 50 (O); and 300,000 IU/dose of IL-2 and 40 mg/kg of D91 twice Sometimes not discernable. daily (). In order to metastasize, a cancer cell must breakaway from FIG. 6 depicts a graph showing the increase in tumor Vol its tumor and invade either the circulatory or lymph system. ume with time of B16 melanoma tumors in mice; vehicle The free cells are then carried to a new location where they control (D); 100,000 IU/dose of IL-2 twice daily (()); and establish themselves. Although the body has natural safe 55 100,000 IU/dose of IL-2 and 40 mg/kg of D91 twice daily guards that prevent cell from Surviving after being detached (O). from their natural location, some cancer cells have the ability FIG. 7 depicts histogram of the volume of B16 melanoma to over come these safeguards. Therefore, if metastasis is tumors in mice at day 22; vehicle control (A): 100,000 stopped or significantly reduced, the extent of cancer can be IU/dose of IL-2 twice daily (B); and 100,000 IU/dose of IL-2 determined and Subsequently treated. As such, a follow up 60 and 40 mg/kg of D91 twice daily (C). treatment to cancer therapy wherein a tumor has been excised FIG. 8 depicts a graph showing the increase in tumor Vol or radiation/chemotherapy has been used, would be the treat ume with time of B16 melanoma tumors in mice; vehicle ment of the patient to an anti-metastasizing agent. There is a control (); and 40 mg/kg of D91 twice daily (O). long felt need for methods of preventing cancer cell metasta FIG.9 depicts the size of pancreatic tumors orthotopically S1S. 65 implanted in NCr nu/nu mice: vehicle control (()); 100 The growth of primary tumors also presents a challenge to mg/kg gemcitabine, i.p. twice weekly (X); 150 mg/kg gem treatment. If the growth of a primary tumor goes unchecked, citabine, i.p. twice weekly (D); 20 mg/kg D91 twice daily US 8,883,832 B2 3 4 (O); 100 mg/kg gemcitabine, i.p. twice weekly and 20 mg/kg As used herein, the terms “manage.” “managing and D91 twice daily (*); and 150 mg/kg gemcitabine, i.p. twice “management” refer to the beneficial effects that a subject weekly and 20 mg/kg D91 twice daily (A). derives from administration of a prophylactic or therapeutic agent, which does not result in a cure of the disease or dis DETAILED DESCRIPTION eases. In certain embodiments, a Subject is administered one or more prophylactic or therapeutic agents to “manage' a In this specification and in the claims that follow, reference disease so as to prevent the progression or worsening of the will be made to a number of terms, which shall be defined to disease or diseases. have the following meanings: As used herein, the terms “prevent”, “preventing and All percentages, ratios and proportions herein are by 10 “prevention” refer to the methods to avert or avoid a disease or weight, unless otherwise specified. All temperatures are in disorder or delay the recurrence or onset of one or more degrees Celsius (°C.) unless otherwise specified. symptoms of a disorder in a subject resulting from the admin By “pharmaceutically acceptable' is meant a material that istration of a prophylactic agent. is not biologically or otherwise undesirable, i.e., the material As used herein, the term “in combination” refers to the use can be administered to an individual along with the relevant 15 of more than one prophylactic and/or therapeutic agents. The active compound without causing clinically unacceptable use of the term “in combination' does not restrict the order in biological effects or interacting in a deleterious manner with which prophylactic and/or therapeutic agents are adminis any of the other components of the pharmaceutical composi tered to a subject with a disorder, e.g., hyperproliferative cell tion in which it is contained. disorder, especially cancer. A first prophylactic ortherapeutic Throughout the description and claims of this specification agent can be administered prior to (e.g., 1 minute, 5 minutes, the word “comprise' and other forms of the word, such as 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, “comprising and "comprises.” means including but not lim 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 ited to, and is not intended to exclude, for example, other week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, additives, components, integers, or steps. or 12 weeks before), concomitantly with, or Subsequent to As used in the description and the appended claims, the 25 (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 min singular forms “a” “an.” and “the include plural referents utes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 unless the context clearly dictates otherwise. Thus, for hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, example, reference to “a composition' includes mixtures of 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the adminis two or more Such compositions, reference to “a phenylsul tration of a second prophylactic or therapeutic agent to a famic acid includes mixtures of two or more such phenyl 30 subject which had, has, or is susceptible to a disorder. The sulfamic acids, reference to “the compound includes mix prophylactic or therapeutic agents are administered to a Sub tures of two or more such compounds, and the like. ject in a sequence and within a time interval such that the "Optional' or “optionally’ means that the subsequently agent of the present disclosure can act together with the other described event or circumstance can or cannot occur, and that agent to provide an increased benefit than if they were admin the description includes instances where the event or circum 35 istered otherwise. Any additional prophylactic or therapeutic stance occurs and instances where it does not. agent can be administered in any order with the other addi Ranges can be expressed herein as from “about one par tional prophylactic or therapeutic agents ticular value, and/or to “about another particular value. As used herein, the terms “administer' when used to When Such a range is expressed, another aspect includes from describe the dosage of a compound, means a single dose or the one particular value and/or to the other particular value. 40 multiple doses of the compound. Similarly, when values are expressed as approximations, by As used herein, the term "cancer treatment’ means any use of the antecedent “about it will be understood that the treatment for cancer known in the art including, but not lim particular value forms another aspect. It will be further under ited to, chemotherapy and radiation therapy. stood that the endpoints of each of the ranges are significant As used herein, “tumor cells' means both cells derived both in relation to the other endpoint, and independently of 45 from tumors, including malignant tumors, and cells immor the other endpoint. It is also understood that there are a talized in vitro. "Normal” cells refer to cells with normal number of values disclosed herein, and that each value is also growth characteristics that do not show abnormal prolifera herein disclosed as “about that particular value in addition to tion. the value itself. For example, if the value “10 is disclosed, As used herein, the terms “an individual identified as hav then “about 10' is also disclosed. It is also understood that 50 ing cancer and "cancer patient” are used interchangeably when a value is disclosed, then “less than or equal to the and are meant to refer to an individual who has been diag value, “greater than or equal to the value.” and possible ranges nosed as having cancer. There are numerous well known between values are also disclosed, as appropriately under means for identifying an individual who has cancer. In some stood by the skilled artisan. For example, if the value “10 is embodiments, a cancer diagnosis is made or confirmed using disclosed, then “less than or equal to 10” as well as “greater 55 PET imaging. Some embodiments of the present disclosure than or equal to 10” is also disclosed. It is also understood that comprise the step of identifying individuals who have cancer. throughout the application data are provided in a number of As used herein, the term “therapeutically effective different formats and that this data represent endpoints and amount' is meant to refer to an amount of an active agent or starting points and ranges for any combination of the data combination of agents effective to ameliorate or prevent the points. For example, if a particular data point “10 and a 60 symptoms, shrink tumor size, or prolong the Survival of the particular data point “15” are disclosed, it is understood that patient being treated. Determination of a therapeutically greater than, greater than or equal to, less than, less than or effective amount is well within the capabilities of those equal to, and equal to 10 and 15 are considered disclosed as skilled in the art, especially in light of the detailed disclosure well as between 10 and 15. It is also understood that each unit provided herein. between two particular units are also disclosed. For example, 65 As used herein the term “inhibit or “inhibiting refers to a if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also statistically significant and measurable reduction in activity, disclosed. preferably a reduction of at least about 10% versus control, US 8,883,832 B2 5 6 more preferably a reduction of about 50% or more, still more inorganic atom comprising salts, interalia, carboxylate salts, preferably a reduction of about 80% or more. quaternary ammonium salts. Within the broad meaning of the As used herein the term “increase' or "enhancing refers to term “hydrocarby1 are the classes “acyclic hydrocarbyl and a statistically significant and measurable increase in activity, “cyclic hydrocarbyl which terms are used to divide hydro preferably an increase of at least about 10% versus control, carbyl units into cyclic and non-cyclic classes. more preferably an increase of about 50% or more, still more As it relates to the following definitions, “cyclic hydrocar preferably an increase of about 80% or more. by1' units can comprise only carbon atoms in the ring (i.e., The term “prevent or “preventing when used in relation carbocyclic and aryl rings) or can comprise one or more to a condition, such as a local recurrence (e.g., pain), a disease heteroatoms in the ring (i.e., heterocyclic and heteroaryl Such as cancer, a syndrome complex Such as heart failure or 10 rings). For “carbocyclic” rings the lowest number of carbon any other medical condition, is well understood in the art, and atoms in a ring are 3 carbon atoms; cyclopropyl. For “aryl includes administration of a composition which reduces the rings the lowest number of carbonatoms in a ring are 6 carbon frequency of, or delays the onset of symptoms of a medical atoms; phenyl. For "heterocyclic rings the lowest number of condition in a Subject relative to a subject which does not carbon atoms in a ring is 1 carbon atom; diazirinyl. Ethylene receive the composition. Thus, prevention of cancer includes, 15 oxide comprises 2 carbon atoms and is a Cheterocycle. For for example, reducing the number of detectable cancerous "heteroaryl rings the lowest number of carbon atoms in a growths in a population of patients receiving a prophylactic ring is 1 carbon atom; 1,2,3,4-tetrazolyl. The following is a treatment relative to an untreated control population, and/or non-limiting description of the terms “acyclic hydrocarbyl delaying the appearance of detectable cancerous growths in a and “cyclic hydrocarbyl as used herein. treated population versus an untreated control population, A. Substituted and unsubstituted acyclic hydrocarbyl: e.g., by a statistically and/or clinically significant amount. For the purposes of the present disclosure the term “sub Prevention of an infection includes, for example, reducing the stituted and unsubstituted acyclic hydrocarby1' encom number of diagnoses of the infection in a treated population passes 3 categories of units: Versus an untreated control population, and/or delaying the 1) linear or branched alkyl, non-limiting examples of which onset of symptoms of the infection in a treated population 25 include, methyl (C), ethyl (C), n-propyl (C), iso-propyl Versus an untreated control population. Prevention of pain (C), n-butyl (C), sec-butyl (C), iso-butyl (C), tert-butyl includes, for example, reducing the magnitude of, or alterna (C), and the like; substituted linear or branched alkyl, tively delaying, pain sensations experienced by Subjects in a non-limiting examples of which includes, hydroxymethyl treated population versus an untreated control population. (C), chloromethyl (C), trifluoromethyl (C), aminom The terms “treatment”, “treating, “treat’, and the like, 30 ethyl (C), 1-chloroethyl (C), 2-hydroxyethyl (C), 1,2- refer to obtaining a desired pharmacologic and/or physiologic difluoroethyl (C), 3-carboxypropyl (C), and the like. effect. The effect may be prophylactic interms of completely 2) linear or branched alkenyl, non-limiting examples of or partially preventing a disease or symptom thereof and/or which include, ethenyl (C), 3-propenyl (C), 1-propenyl may be therapeutic in terms of a partial or complete cure for (also 2-methylethenyl) (C), isopropenyl (also 2-methyl a disease and/or adverse affect attributable to the disease. 35 ethen-2-yl) (C), buten-4-yl (C), and the like; substituted “Treatment, as used herein, covers any treatment of a disease linear or branched alkenyl, non-limiting examples of in a mammal, particularly in a human, and includes: (a) pre which include, 2-chloroethenyl (also 2-chlorovinyl) (C), venting the disease from occurring in a subject which may be 4-hydroxybuten-1-yl (C), 7-hydroxy-7-methyloct-4-en predisposed to the disease but has not yet been diagnosed as 2-yl (C), 7-hydroxy-7-methyloct-3,5-dien-2-yl (C), and having it; (b) inhibiting the disease, i.e., arresting its devel 40 the like. opment; and (c) relieving the disease, i.e., causing regression 3) linear or branched alkynyl. non-limiting examples of of the disease and/or relieving one or more disease symptoms. which include, ethynyl (C), prop-2-ynyl (also propargyl) “Treatment' is also meant to encompass delivery of an agent (C), propyn-1-yl (C), and 2-methyl-hex-4-yn-1-yl (C7); in order to provide for a pharmacologic effect, even in the Substituted linear or branched alkynyl, non-limiting absence of a disease or condition. For example, “treatment' 45 examples of which include, 5-hydroxy-5-methylhex-3- encompasses delivery of a receptor modulator that can pro ynyl (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (Cs), 5-hy vide for enhanced or desirable effects in the subject (e.g., droxy-5-ethylhept-3-ynyl (C), and the like. reduction of pathogen load, beneficial increase in a physi B. Substituted and unsubstituted cyclic hydrocarbyl: ological parameter of the Subject, reduction of disease symp For the purposes of the present disclosure the term “sub toms, etc.). 50 stituted and unsubstituted cyclic hydrocarbyl encom Throughout this application, various publications are ref passes 5 categories of units: erenced. The disclosures of these publications in their entire 1) The term “carbocyclic” is defined hereinas “encompassing ties are hereby incorporated by reference into this application rings comprising from 3 to 20 carbon atoms, wherein the in order to more fully describe the state of the art to which this atoms which comprise said rings are limited to carbon pertains. The references disclosed are also individually and 55 atoms, and further each ring can be independently Substi specifically incorporated by reference herein for the material tuted with one or more moieties capable of replacing one or contained in them that is discussed in the sentence in which more hydrogen atoms. The following are non-limiting the reference is relied upon examples of “substituted and unsubstituted carbocyclic The following chemical hierarchy is used throughout the rings' which encompass the following categories of units: specification to describe and enable the scope of the present 60 i) carbocyclic rings having a single Substituted or unsub disclosure and to particularly point out and distinctly claim stituted hydrocarbon ring, non-limiting examples of the units which comprise the compounds of the present dis which include, cyclopropyl (C), 2-methyl-cyclopropyl closure, however, unless otherwise specifically defined, the (C), cyclopropenyl (C), cyclobutyl (C), 2,3-dihy terms used herein are the same as those of the artisan of droxycyclobutyl (C), cyclobutenyl (C), cyclopentyl ordinary skill. The term “hydrocarbyl stands for any carbon 65 (Cs), cyclopentenyl (Cs), cyclopentadienyl (Cs), cyclo atom-based unit (organic molecule), said units optionally hexyl (C), cyclohexenyl (C), cycloheptyl (C7), containing one or more organic functional group, including cyclooctanyl (Cs), 2,5-dimethylcyclopentyl (Cs), 3.5- US 8,883,832 B2 7 8 dichlorocyclohexyl (C), 4-hydroxycyclohexyl (C), which comprises a heteroatom is an aromatic ring.” The and 3,3,5-trimethylcyclohex-1-yl (C). following are non-limiting examples of “substituted and ii) carbocyclic rings having two or more Substituted or unsubstituted heterocyclic rings' which encompass the unsubstituted fused hydrocarbon rings, non-limiting following categories of units: examples of which include, octahydropentalenyl (Cs), i) heteroaryl rings containing a single ring, non-limiting octahydro-1H-indenyl (C), 3a,4,5,6,7,7a-hexahydro examples of which include, 1.2.3,4-tetrazolyl (C), 1.2, 3H-inden-4-yl (C), decahydroaZulenyl (C). 3triazolyl (C), 1.2.4 triazolyl (C), triazinyl (C), iii) carbocyclic rings which are substituted or unsubstituted thiazolyl (C), 1H-imidazolyl (C), oxazolyl (C), isox bicyclic hydrocarbon rings, non-limiting examples of azolyl (C), isothiazolyl (C), furanyl (C), thiophenyl which include, bicyclo-2.1.1 hexanyl, bicyclo[2.2.1 10 heptanyl, bicyclo[3.1.1 heptanyl, 1,3-dimethyl2.2.1 (C), pyrimidinyl (C), 2-phenylpyrimidinyl (C), heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3 pyridinyl (Cs), 3-methylpyridinyl (Cs), and 4-dimethy undecanyl. laminopyridinyl (Cs) 2) The term “aryl is defined herein as “units encompassing at ii) heteroaryl rings containing 2 or more fused rings one of least one phenyl or naphthyl ring and wherein there are no 15 which is a heteroaryl ring, non-limiting examples of heteroaryl or heterocyclic rings fused to the phenyl or which include: 7H-purinyl (Cs), 9H-purinyl (Cs), naphthyl ring and further each ring can be independently 6-amino-9H-purinyl (Cs), 5H-pyrrolo 3,2-dipyrimidi Substituted with one or more moieties capable of replacing nyl (C), 7H-pyrrolo2,3-dipyrimidinyl (C), pyrido2. one or more hydrogen atoms. The following are non 3-dipyrimidinyl (C7), 2-phenylbenzodthiazolyl (C7), limiting examples of “substituted and unsubstituted aryl 1H-indolyl (Cs), 4,5,6,7-tetrahydro-1-H-indolyl (Cs), rings' which encompass the following categories of units: quinoxalinyl (Cs), 5-methylduinoxalinyl (Cs), i) C or Co. Substituted or unsubstituted aryl rings; phenyl quinazolinyl (Cs), quinolinyl (C), 8-hydroxy-quinoli and naphthyl rings whether substituted or unsubstituted, nyl (C), and isoquinolinyl (C). non-limiting examples of which include, phenyl (C), 5) C-C tethered cyclic hydrocarbyl units (whether carbocy naphthylen-1-yl (Co.), naphthylen-2-yl (Co), 4-fluo 25 clic units, C or Co aryl units, heterocyclic units, or het rophenyl (C), 2-hydroxyphenyl (C), 3-methylphenyl eroaryl units) which connected to another moiety, unit, or (C), 2-amino-4-fluorophenyl (C), 2-(N,N-diethy core of the molecule by way of a C-C alkylene unit. lamino)phenyl (C), 2-cyanophenyl (C), 2,6-di-tert-bu Non-limiting examples of tethered cyclic hydrocarbyl tylphenyl (C), 3-methoxyphenyl (C), 8-hydroxynaph units include benzyl C-(Ce) having the formula: thylen-2-yl (C), 4.5-dimethoxynaphthylen-1-yl (C), 30 and 6-cyano-naphthylen-1-yl (Co). ii) C or Caryl rings fused with 1 or 2 saturated rings to afford Cs-Coring systems, non-limiting examples of which include, bicyclo4.2.0 octa-1,3,5-trienyl (Cs), and indanyl (C). 35 3) The terms "heterocyclic” and/or "heterocycle are defined herein as “units comprising one or more rings having from wherein R is optionally one or more independently chosen 3 to 20 atoms wherein at least one atom in at least one ring substitutions for hydrogen. Further examples include other is a heteroatom chosen from nitrogen (N), oxygen (O), or aryl units, interalia, (2-hydroxyphenyl)hexyl C-(Ce); naph sulfur (S), or mixtures of N, O, and S, and wherein further 40 thalen-2-ylmethyl C-(Ce), 4-fluorobenzyl C-(Ce), 2-(3- the ring which contains the heteroatom is also not an aro hydroxyphenyl)ethyl C-(Ce), as well as Substituted and matic ring.” The following are non-limiting examples of unsubstituted C-C alkylenecarbocyclic units, for example, “substituted and unsubstituted heterocyclic rings” which cyclopropylmethyl C-(C), cyclopentylethyl C-(Cs), cyclo encompass the following categories of units: hexylmethyl C-(Ce). Included within this category are Sub i) heterocyclic units having a single ring containing one or 45 stituted and unsubstituted C-C alkylene-heteroaryl units, more heteroatoms, non-limiting examples of which for example a 2-picolyl C-(Ce) unit having the formula: include, diazirinyl (C), aziridinyl (C), urazolyl (C), aZetidinyl (C), pyrazolidinyl (C), imidazolidinyl (C), oxazolidinyl (C), isoxazolinyl (C), thiazolidinyl (C), isothiazolinyl (C), oxathiazolidinonyl (C), oxazolidi 50 nonyl (C), hydantoinyl (C), tetrahydrofuranyl (C), pyrrolidinyl (C), morpholinyl (C), piperazinyl (C), --K Ra piperidinyl (C), dihydropyranyl (Cs), tetrahydropyra nyl (Cs), piperidin-2-onyl (valerolactam) (Cs), 2.3.4.5- wherein R is the same as defined above. In addition, C-C, tetrahydro-1H-azepinyl (C), 2,3-dihydro-1H-indole 55 tethered cyclic hydrocarbyl units include C-C alkylenehet (Cs), and 1,2,3,4-tetrahydroquinoline (C). erocyclic units and alkylene-heteroaryl units, non-limiting ii) heterocyclic units having 2 or more rings one of which examples of which include, aziridinylmethyl C-(C) and is a heterocyclic ring, non-limiting examples of which oxazol-2-ylmethyl C-(C). include hexahydro-1H-pyrrolizinyl (C7), 3a,4,5,6,7,7a For the purposes of the present disclosure carbocyclic rings hexahydro-1H-benzodimidazolyl (C7), 3a,4,5,6,7,7a 60 are from C to Co., aryl rings are C or Co.; heterocyclic rings hexahydro-1H-indolyl (Cs), 1,2,3,4-tetrahydroquinoli are from C to Co.; and heteroaryl rings are from C to C. nyl (Co), and decahydro-1H-cyclooctablpyrrolyl (Co). For the purposes of the present disclosure, and to provide 4) The term "heteroaryl' is defined herein as “encompassing consistency in defining the present disclosure, fused ring one or more rings comprising from 5 to 20 atoms wherein units, as well as spirocyclic rings, bicyclic rings and the like, at least one atom in at least one ring is a heteroatom chosen 65 which comprise a single heteroatom will be characterized and from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of referred to herein as being encompassed by the cyclic family N, O, and S, and wherein further at least one of the rings corresponding to the heteroatom containing ring, although US 8,883,832 B2 10 the artisan may have alternative characterizations. For i) C-C linear, branched, or cyclic alkyl, alkenyl, and example, 1,2,3,4-tetrahydroquinoline having the formula: alkynyl: methyl (C), ethyl (C), ethenyl (C), ethynyl (C), n-propyl (C), iso-propyl (C), cyclopropyl (C), 3-propenyl (C), 1-propenyl (also 2-methylethenyl) (C), isopropenyl (also 2-methylethen-2-yl) (C), prop 2-ynyl (also propargyl) (C), propyn-1-yl (C), n-butyl (C), sec-butyl (C), iso-butyl (C), tert-butyl (C), N H cyclobutyl (C), buten-4-yl (C), cyclopentyl (Cs), cyclohexyl (C); 10 ii) Substituted or unsubstituted C or Co aryl; for example, is, for the purposes of the present disclosure, considered a phenyl, naphthyl (also referred to herein as naphthylen heterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine 1-yl (Co) or naphthylen-2-yl (Co)); having the formula: iii) substituted or unsubstituted C or Co alkylenearyl; for example, benzyl, 2-phenylethyl, naphthylen-2-ylm 15 ethyl: iv) substituted or unsubstituted C-C heterocyclic rings: as described herein below: V) Substituted or unsubstituted C-C heteroaryl rings; as described herein below: is, for the purposes of the present disclosure, considered a vi) -(CR'R'')OR'; for example, OH, heteroaryl unit. When a fused ring unit contains heteroatoms —CHOH, - OCH, -CHOCH, OCHCH in both a saturated ring (heterocyclic ring) and an aryl ring —CHOCHCH –OCHCHCH and (heteroaryl ring), the aryl ring will predominate and deter —CHOCHCHCH: mine the type of category to which the ring is assigned herein vii)-(CR'R''),C(O)R'; for example, COCH, for the purposes of describing the present disclosure. For 25 - CH-COCH, -COCHCH, -CHCOCHCH example, 1.2.3,4-tetrahydro-1.8naphthpyridine having the - COCHCHCH, and -CHCOCHCHCH: formula: viii) - (CR'R''),C(O)OR'; for example, —COCH, —CHCOCH, —COCHCH —CH2COCHCH —COCH2CHCH and 30 N -CHCOCHCHCH: n ix) (CR'R''),C(O)N(R'); for example, CONH, CHCONH CONHCH, 21 -CHCONHCH, CONCCH), and -CHCON (CH3)2. 35 x) –(CR'R'')N(R''); for example, NH, is, for the purposes of the present disclosure, considered a - CH-NH, -NHCH, -CH-NHCH, -N(CH), heteroaryl unit. and —CHN(CH), The term “substituted” is used throughout the specifica Xi) halogen; —F. —Cl. —Br, and —I: tion. The term “substituted” is applied to the units described xii) (CR02R 102h)CN: herein as “substituted unit or moiety is a hydrocarbyl unit or 40 xiii) (CR102 RO)NO; moiety, whether acyclic or cyclic, which has one or more xiv) —CHX; wherein X is halogen, the index j is an hydrogenatoms replaced by a Substituent or several Substitu integer from 0 to 2, j+k=3; for example, —CHF, ents as defined herein below.” The units, when substituting for —CHF, —CF, —CCls, or —CBr; hydrogenatoms are capable of replacing one hydrogenatom, xv) (CR'R''),SR'; SH, CHSH, SCH, two hydrogen atoms, or three hydrogen atoms of a hydrocar 45 —CHSCH. —SCHs and —CH2SCHs. byl moiety at a time. In addition, these Substituents can xvi) - (CR'R'')SOR'; for example, SOH, replace two hydrogen atoms on two adjacent carbons to form —CHSOH, —SOCH, —CHSOCH, said Substituent, new moiety, or unit. For example, a Substi —SOCHs, and —CHSOCHs; and tuted unit that requires a single hydrogen atom replacement xvii) -(CR'R'')SOR'; for example, -SOH, includes halogen, hydroxyl, and the like. A two hydrogen 50 —CHSOH, —SOCH, —CHSOCH, atom replacement includes carbonyl, oximino, and the like. A —SOCHs, and —CHSOCHs. two hydrogen atom replacement from adjacent carbon atoms wherein each R' is independently hydrogen, substituted or includes epoxy, and the like. Three hydrogen replacement unsubstituted C-C linear, branched, or cyclic alkyl, phenyl, includes cyano, and the like. The term substituted is used benzyl, heterocyclic, or heteroaryl; or two R' units can be throughout the present specification to indicate that a hydro 55 taken togetherto formaring comprising 3-7 atoms; R'' and carbyl moiety, interalia, aromatic ring, alkyl chain; can have R'' are each independently hydrogen or C-C linear or one or more of the hydrogenatoms replaced by a Substituent. branched alkyl; the index “a” is from 0 to 4. When a moiety is described as “substituted any number of For the purposes of the present disclosure the terms “com the hydrogenatoms may be replaced. For example, 4-hydrox pound,” “analog, and “composition of matter stand equally yphenyl is a “substituted aromatic carbocyclic ring (aryl 60 well for each other and are used interchangeably throughout ring)”, (N,N-dimethyl-5-amino)octanyl is a “substituted Cs the specification. The disclosed compounds include all enan linear alkyl unit, 3-guanidinopropyl is a 'substituted Clinear tiomeric forms, diastereomeric forms, salts, and the like. alkyl unit,” and 2-carboxypyridinyl is a “substituted het The compounds disclosed herein include all salt forms, for eroaryl unit.” example, salts of both basic groups, interalia, amines, as well The following are non-limiting examples of units which 65 as salts of acidic groups, inter alia, carboxylic acids. The can Substitute for hydrogen atoms on a carbocyclic, aryl, following are non-limiting examples of anions that can form heterocyclic, or heteroaryl unit: salts with protonated basic groups: chloride, bromide, iodide, US 8,883,832 B2 11 Sulfate, bisulfate, carbonate, bicarbonate, phosphate, for mate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, Succinate, tartrate, fumarate, citrate, and the like. The following are non-limiting examples of cations that can form salts of acidic groups: ammonium, Sodium, lithium, potassium, calcium, magnesium, bismuth, lysine, and the like. wherein R and Rare each independently chosen from: The disclosed compounds have Formula (I): i) hydrogen; 10 ii) substituted or unsubstituted C-C linear, branched, or cyclic alkyl; (I) iii) substituted or unsubstituted C-C linear, branched, or R cyclic alkenyl; O. O \/ N iv) substituted or unsubstituted C-C linear or branched HO1 H1NZ 15 alkynyl: V) Substituted or unsubstituted C or Co aryl; H vi) substituted or unsubstituted C-C heteroaryl; vii) substituted or unsubstituted C-C heterocyclic; or viii) RandR can be taken together to form a saturated or wherein the carbon atom having the amino unit has the (S) unsaturated ring having from 5 to 7 atoms; wherein from Stereochemistry as indicated in the following formula: 1 to 3 atoms can optionally be heteroatoms chosen from oxygen, nitrogen, and Sulfur. The following are non-limiting examples of units that can substitute for one or more hydrogen atoms on the RandR 25 units. The following substituents, as well as others notherein described, are each independently chosen: i) C-C linear, branched, or cyclic alkyl, alkenyl, and alkynyl: methyl (C), ethyl (C), ethenyl (C), ethynyl 30 (C), n-propyl (C), iso-propyl (C), cyclopropyl (C), 3-propenyl (C), 1-propenyl (also 2-methylethenyl) The units which comprise Rand Z can comprise units having (C), isopropenyl (also 2-methylethen-2-yl) (C), prop any configuration, and, as such, the disclosed compounds can 2-ynyl (also propargyl) (C), propyn-1-yl (C), n-butyl be single enantiomers, diastereomeric pairs, or combinations thereof. In addition, the compounds can be isolated as salts or (C), sec-butyl (C), iso-butyl (C), tert-butyl (C), 35 cyclobutyl (C), buten-4-yl (C), cyclopentyl (Cs), hydrates. In the case of salts, the compounds can comprises cyclohexyl (C); more than one cation or anion. In the case of hydrates, any ii) Substituted or unsubstituted C or Co aryl; for example, number of water molecules, or fractional part thereof (for phenyl, naphthyl (also referred to herein as naphthylen example, less than 1 water molecule present for each mol 1-yl (Co) or naphthylen-2-yl (Co)); ecule of analog) can be present. 40 iii) substituted or unsubstituted C or Co alkylenearyl; for R Units example, benzyl, 2-phenylethyl, naphthylen-2-ylm R is a substituted or unsubstituted thiazolyl unit having the ethyl: formula: iv) Substituted or unsubstituted C-C heterocyclic rings; as described herein; 45 V) Substituted or unsubstituted C-C heteroaryl rings; as described herein; vi) (CR21R21), OR20. for example, OH, -CHOH, —OCH, —CHOCH, –OCHCH —CHOCHCH –OCHCHCH and --CC - - K - 50 —CHOCH2CHCH: vii) (CR2R31),C(OR3, for example, —COCH, - CH-COCH, -COCHCH, -CHCOCHCH Kr - COCHCHCH, and -CHCOCHCHCH: viii)–(CR'R''),C(O)OR; for example, CO.CH, 55 —CH2COCH, COCHCH. —CH2COCHCH R. R. and Rare substituent groups that can be indepen —COCHCHCH, and —CHCOCHCHCH: dently chosen from a wide variety of non-carbon atom con X) —(CR'R'').cox."); for example, —CONH2, taining units (for example, hydrogen, hydroxyl, amino, halo CHCONH CONHCH, CHCONHCH gen, nitro, and the like) or organic Substituent units, such as —CON(CH), and —CH2CONCCH): substituted and unsubstituted acyclic hydrocarbyl and cyclic 60 x) (CR'R'')N(R); for example, NH, hydrocarbyl units as described herein. The carbon comprising —CH-NH, -NHCH, —CH-NHCH, -N(CH), and —CHN(CH), units can comprise from 1 to 12 carbon atoms, or 1 to 10 Xi) halogen; —F. —Cl. —Br, and —I: carbon atoms, or 1 to 6 carbon atoms. xii) (CRR)CN: An example of compounds of Formula (I) include com 65 xiii) (CRR).N.O.; pounds wherein R units are thiazol-2-yl units having the xiv)-(CH,X),CHX; wherein X is halogen, the index.j formula: is an integer from 0 to 2.j+k 3, the index' is an integer US 8,883,832 B2 13 14 from 0 to 2, '+k'=2, the index h is from 0 to 6; for A yet further example of compounds of Formula (I), R example, —CHF, —CF, —CHCF. —CHFCF, units include units wherein R is hydrogen and R is phenyl or —CC1s, or—CBr; substituted phenyl, wherein non-limiting examples of R xv) (CRR),SR, SH, CH, SH, —SCH, units include phenyl, 3,4-dimethylphenyl, 4-tert-butylphe —CHSCH. —SCHs and —CHSCHs. nyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluo xvi.) (CR2R31). SOR20. for example, —SOH, romethyl)phenyl, 4-methoxyphenyl, 4-(difluoromethoxy) —CHSOH, —SOCH, —CHSOCH, phenyl, 4-(trifluoromethoxy)phenyl, 3-chloropheny, —SOCHs, and —CHSOCHs; and 4-chlorophenyl, and 3,4-dichlorophenyl, which when incor xvii) (CR2R31)SO, R20; for example, —SOH, porated into the definition of Raffords the following R units —CHSOH, —SOCH, —CHSOCH, 10 4-phenylthiazol-2-yl, 3,4-dimethylphenylthiazol-2-yl, —SOCHs, and —CHSOCHs. 4-tert-butylphenylthiazol-2-yl 4-cyclopropylphenylthiazol wherein each R" is independently hydrogen, substituted or 2-yl 4-diethylaminophenylthiazol-2-yl 4-(trifluoromethyl) unsubstituted C-C linear, branched, or cyclic alkyl, phenyl, phenylthiazol-2-yl 4-methoxyphenylthiazol-2-yl 4-(difluo benzyl, heterocyclic, or heteroaryl; or two R' units can be romethoxy)phenylthiazol-2-yl, 4-(trifluoromethoxy) taken together to form a ring comprising 3-7 atoms; R" and 15 phenylthiazol-2-yl, 3-chlorophenylthiazol-2-yl, R" are each independently hydrogen or C-C linear or 4-chlorophenylthiazol-2-yl, and 3,4-dichlorophenylthiazol branched alkyl; the index p is from 0 to 4. 2-yl. An example of compounds of Formula (I) includes R units A still further example of compounds of Formula (I) includes R units wherein R is chosen from hydrogen, methyl, having the formula: ethyl, n-propyl, and iso-propylandR is phenyl or substituted phenyl. A non-limiting example of a R unit according to the N R2 fifth aspect of the first category of R units includes 4-methyl 5-phenylthiazol-2-yl and 4-ethyl-5-phenylthiazol-2-yl. 25 Another further example of compounds of Formula (I) --CCS H includes R units wherein R is hydrogen and R is a substi tuted or unsubstituted heteroaryl unit chosen from 1,2,3,4- tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, 1.2.3 triazol-4-yl, 1.2.3 wherein R is hydrogen and R is a unit chosen from methyl triazol-5-yl, 1.2.4 triazol-4-yl, 1.2.4 triazol-5-yl, imidazol (C), ethyl (C), n-propyl (C), iso-propyl (C), n-butyl (C), 2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, sec-butyl (C), iso-butyl (C), tert-butyl (C), n-pentyl (Cs), 30 oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isox 1-methylbutyl (Cs), 2-methylbutyl (Cs), 3-methylbutyl (Cs), azol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1.3, cyclopropyl (C), n-hexyl (C), 4-methylpentyl (C), and 4oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, cyclohexyl (C). thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5- Another example of compounds of Formula (I) include R y1, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,4thiadiazol units having the formula: 35 3-yl, 1,2,4thiadiazol-5-yl, and 1,3,4thiadiazol-2-yl. Further non-limiting example of compounds of Formula (I) includes R units wherein R is substituted or unsubstituted N R2 thiophen-2-yl, for example thiophen-2-yl, 5-chlorothiophen 40 2-yl, and 5-methylthiophen-2-yl. A still further example of compounds of Formula (I) --CCS R3 includes R units wherein R is substituted or unsubstituted thiophen-3-yl, for example thiophen-3-yl, 5-chlorothiophen wherein R is a unit chosen from methyl (C), ethyl (C), 3-yl, and 5-methylthiophen-3-yl. n-propyl (C), iso-propyl (C), n-butyl (C), sec-butyl (C), 45 Another example of compounds of Formula (I) includes R iso-butyl (C), and tert-butyl (C); and R is a unit chosen units wherein RandR are taken together to form a saturated from methyl (C) or ethyl (C). Non-limiting examples of this or unsaturated ring having from 5 to 7 atoms. Non-limiting aspect of R includes 4,5-dimethylthiazol-2-yl 4-ethyl-5-me examples of the sixth aspect of the first category of R units thylthiazol-2-yl 4-methyl-5-ethylthiazol-2-yl, and 4,5-dieth include 5,6-dihydro-4H-cyclopentadthiazol-2-yland 4,5,6, ylthiazol-2-yl. 50 7-tetrahydrobenzodthiazol-2-yl. A further example of compounds of Formula (I) includes R Further examples of compounds of Formula (I) include R units wherein R is hydrogen andR is a substituted alkyl unit, units that are thiazol-4-yl units having the formula: said Substitutions chosen from: i) halogen: —F. —Cl, —Br, and —I: ii) —N(R'); and 55 iii) OR'': wherein each R'' is independently hydrogen or C-C linear or branched alkyl. Non-limiting examples of units that can be C - K. a substitute for a R or Rhydrogen atom on R units include —CHF, —CHF, —CF, —CHCF, —CH2CHCF, 60 wherein R is a unit chosen from: —CHCl, -CHOH, -CHOCH, -CHCH-OH, i) hydrogen; —CHCHOCH, -CH-NH, -CH-NHCH, -CHN ii) substituted or unsubstituted C-C linear, branched, or (CH), and —CH-NH(CHCH). cyclic alkyl; Further non-limiting examples of units that can be a Sub iii) substituted or unsubstituted C-C linear, branched, or stitute for a R or R hydrogen atom on R units include 65 cyclic alkenyl; 2,2-difluorocyclopropyl, 2-methoxycyclohexyl, and 4-chlo iv) substituted or unsubstituted C-C linear or branched rocyclohexyl. alkynyl: US 8,883,832 B2 15 16 V) Substituted or unsubstituted C or Co aryl; A further example of compounds of Formula (I) includes R vi) substituted or unsubstituted C-C heteroaryl; or units wherein R is a unit chosen from methyl (C), ethyl (C), vii) substituted or unsubstituted C-C heterocyclic. n-propyl (C), iso-propyl (C), n-butyl (C), sec-butyl (C), The following are non-limiting examples of units that can iso-butyl (C), and tert-butyl (C). Non-limiting examples of substitute for one or more hydrogen atoms on the R units. 5 this aspect of R includes 2-methylthiazol-4-yl, 2-ethylthi The following substituents, as well as others not herein azol-4-yl, 2-(n-propyl)thiazol-4-yl, and 2-(iso-propyl)thia described, are each independently chosen: Zol-4-yl. i) C-C linear, branched, or cyclic alkyl, alkenyl, and A still further example of compounds of Formula (I) alkynyl: methyl (C), ethyl (C), ethenyl (C), ethynyl includes R units wherein R is substituted or unsubstituted (C), n-propyl (C), iso-propyl (C), cyclopropyl (C), 10 phenyl, non-limiting examples of which include phenyl, 3-propenyl (C), 1-propenyl (also 2-methylethenyl) 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methox (C), isopropenyl (also 2-methylethen-2-yl) (C), prop yphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 2-ynyl (also propargyl) (C), propyn-1-yl (C), n-butyl 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-meth (C), sec-butyl (C), iso-butyl (C), tert-butyl (C), 15 ylphenyl, and 4-methoxyphenyl. cyclobutyl (C), buten-4-yl (C), cyclopentyl (Cs), Yet further example of compounds of Formula (I) includes cyclohexyl (C); Runits wherein R is substituted or unsubstituted heteroaryl, ii) Substituted or unsubstituted C or Caryl; for example, non-limiting examples of which include thiophen-2-yl, phenyl, naphthyl (also referred to herein as naphthylen thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2.5- 1-yl (Co) or naphthylen-2-yl (Co)); dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl 4-ethylthi iii) substituted or unsubstituted C or Co alkylenearyl; for azol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and 3-me example, benzyl, 2-phenylethyl, naphthylen-2-ylm thyl-1,2,4-oxadiazol-5-yl. ethyl: Another example of 5-member ring R units includes sub iv) Substituted or unsubstituted C-C heterocyclic rings; stituted or unsubstituted imidazolyl units having the formula: as described herein below: 25 V) Substituted or unsubstituted C-C heteroaryl rings; as described herein below: N R2 N R4 vi) (CR21R21), OR20. for example, OH, -CHOH, —OCH, —CHOCH, –OCHCH 30 N 3 NH —CHOCHCH –OCHCHCH and H R —CHOCH2CHCH: vii) (CRR),C(O)R’; for example, COCH, -CHCOCH, -COCHCH, -CHCOCHCH One example of imidazolyl Runits includes imidazol-2-yl - COCHCHCH, and -CHCOCHCHCH: units having the formula: viii)–(CR'R''),C(O)CR; for example, CO.CH, 35 —CH2COCH, —COCHCH. —CH2COCHCH —COCH2CHCH, and —CH2COCHCHCH: xi)–(CR'R''),C(O)N(R°); for example, CONH, CHCONH CONHCH, CHCONHCH —CON(CH), and —CHCON(CH): 40 x) —(CR'R'')N(R'); for example, NH, —CH-NH, -NHCH, —CH-NHCH, -N(CH), and —CHN(CH), wherein R and Rare each independently chosen from: Xi) halogen; —F. —Cl. —Br, and —I: i) hydrogen; xii)–(CRR)CN: 45 ii) substituted or unsubstituted C-C linear, branched, or xiii)–(CRR).NO.; cyclic alkyl; xiv)-(CH,X),CHX; wherein X is halogen, the index.j iii) substituted or unsubstituted C-C linear, branched, or is an integer from 0 to 2.j+k 3, the index' is an integer cyclic alkenyl; from 0 to 2, '+k'=2, the index h is from 0 to 6; for iv) substituted or unsubstituted C-C linear or branched example, —CHF, —CHF, —CF, —CH2CF, 50 alkynyl: —CHFCF —CC1, or—CBr: V) Substituted or unsubstituted C or Co aryl; xv) (CRR),SR, SH, CH, SH, —SCH, vi) substituted or unsubstituted C-C heteroaryl; —CHSCH. —SCHs and —CH2SCHs. vii) substituted or unsubstituted C-C heterocyclic; or xvi) —(CR'R''),SO.R’’; for example, -SO.H. viii) RandR can be taken together to form a saturated or —CHSOH, —SOCH, —CHSOCH, 55 unsaturated ring having from 5 to 7 atoms; wherein from —SOCHs, and —CHSOCHs; and 1 to 3 atoms can optionally be heteroatoms chosen from xvii) (CR2R31)SO, R20; for example, —SOH, oxygen, nitrogen, and Sulfur. —CHSOH, —SOCH, —CHSOCH, The following are non-limiting examples of units that can —SOCHs, and —CHSOCHs. substitute for one or more hydrogen atoms on the RandR wherein each R" is independently hydrogen, substituted or 60 units. The following substituents, as well as others notherein unsubstituted C-C linear, branched, or cyclic alkyl, phenyl, described, are each independently chosen: benzyl, heterocyclic, or heteroaryl; or two R' units can be i) C-C linear, branched, or cyclic alkyl, alkenyl, and taken together to form a ring comprising 3-7 atoms; R" and alkynyl: methyl (C), ethyl (C), ethenyl (C), ethynyl R" are each independently hydrogen or C-C linear or (C), n-propyl (C), iso-propyl (C), cyclopropyl (C), branched alkyl; the index p is from 0 to 4. 65 3-propenyl (C), 1-propenyl (also 2-methylethenyl) An example of compounds of Formula (I) includes R units (C), isopropenyl (also 2-methylethen-2-yl) (C), prop wherein R is hydrogen. 2-ynyl (also propargyl) (C), propyn-1-yl (C), n-butyl US 8,883,832 B2 17 18 (C), sec-butyl (C), iso-butyl (C), tert-butyl (C), (C), iso-propyl (C), n-butyl (C), Sec-butyl (C), iso-butyl cyclobutyl (C), buten-4-yl (C), cyclopentyl (Cs), (C), and tert-butyl (C); and R is a unit chosen from methyl cyclohexyl (C); (C) or ethyl (C). Non-limiting examples of this aspect of R ii) Substituted or unsubstituted C or Co aryl; for example, includes 4,5-dimethylimidazol-2-yl 4-ethyl-5-methylimida phenyl, naphthyl (also referred to herein as naphthylen Zol-2-yl 4-methyl-5-ethylimidazol-2-yl, and 4,5-diethylimi 1-yl (Co) or naphthylen-2-yl (Co)); dazol-2-yl. iii) substituted or unsubstituted C or Co alkylenearyl; for An example of R units includes compounds wherein R is example, benzyl, 2-phenylethyl, naphthylen-2-ylm hydrogen and R is a substituted alkyl unit chosen, said sub ethyl; stitutions chosen from: iv) Situted or unsubstituted C-C heterocyclic rings: 10 i) halogen: —F. —Cl. —Br, and —I: as described herein; ii) - N(R'); and V) Substituted or unsubstituted C-C heteroaryl rings; as iii) OR'': described herein; wherein each R'' is independently hydrogen or C-C linear vi)–(CR'R''), OR: for example, OH, CH-OH, or branched alkyl. —OCH, —CHOCH, –OCHCH 15 Non-limiting examples of units comprising this embodi —CHOCHCH –OCHCHCH and ment of R includes: —CHF, —CHF, —CF, —CHCF, —CHOCHCHCH: —CHCl, -CHOH, -CHOCH, -CHCH-OH, vii) -(CR'R''),C(O)R’; for example, COCH, - CHCHOCH, -CH-NH, -CH-NHCH, CHN - CH-COCH, -COCHCH, -CHCOCHCH (CH), and —CH-NH(CH2CH). - COCHCHCH, and -CHCOCHCHCH: A yet further example of R units include units wherein R viii) —(CR'R''), C(O)OR; for example, -COCH, is hydrogen and R is phenyl. —CHCOCH, —COCHCH, —CHCOCHCH A still further example of Runits include units wherein R —COCH2CHCH, and —CH2COCHCHCH: is hydrogen and R is a heteroaryl unit chosen from 1,2,3,4- xii) -(CR'R''), C(O)N(R'); for example, tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, 1.2.3 triazol-4-yl, 1.2.3 - CONH2, -CHCONH2, CONHCH, 25 triazol-5-yl, 1.2.4 triazol-4-yl, 1.2.4 triazol-5-yl, imidazol -CHCONHCH – CONCCH), and -CHCON 2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, (CH), oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isox x) (CR'R'')N(R'); for example, NH, azol-5-yl, 1.2.4 oxadiazol-3-yl, 1.2.4 oxadiazol-5-yl, 1.3, —CH-NH, -NHCH, —CH-NHCH, -N(CH), 4oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, and —CHN(CH), 30 thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5- Xi) halogen; —F. —Cl. —Br, and —I: y1, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,4thiadiazol xii) (CRR). CN: 3-yl, 1,2,4thiadiazol-5-yl, and 1,3,4thiadiazol-2-yl. xiii) (CRR) NO; Z Units xiv)-(CH,X),CHX; wherein X is halogen, the index.j Z is a unit having the formula: is an integer from 0 to 2.j+k 3, the index' is an integer 35 from 0 to 2, '+k'=2, the index h is from 0 to 6; for example, —CHF, —CHF, —CF, —CH2CF, R" is chosen from: —CHFCF —CC1, or—CBr: i) hydrogen; xv) (CRR). SR20, SH, CHSH, —SCH, ii) hydroxyl; —CHSCH. —SCHs and —CHSCHs; 40 iii) amino; xvi) -(CRR). SOR: for example, -SOH, iv) substituted or unsubstituted C-C linear, branched or —CHSOH, —SOCH, —CHSOCH, cyclic alkyl; —SOCHs, and —CHSOCHs; and v) substituted or unsubstituted C-C linear, branched or xvii) -(CR'R''). SOR: for example, SOH, cyclic alkoxy; —CHSOH, —SOCH, —CHSOCH, 45 vi) Substituted or unsubstituted C or Co aryl; —SOCHs, and —CHSOCHs. vii) Substituted or unsubstituted C-C heterocyclic rings; wherein each R" is independently hydrogen, substituted or O unsubstituted C-C linear, branched, or cyclic alkyl, phenyl, viii) substituted or unsubstituted C-C heteroaryl rings. benzyl, heterocyclic, or heteroaryl; or two R' units can be The following are non-limiting examples of units that can taken together to form a ring comprising 3-7 atoms; R" and 50 substitute for one or more hydrogen atoms on the R' units. R" are each independently hydrogen or C-C linear or The following substituents, as well as others not herein branched alkyl; the index p is from 0 to 4. described, are each independently chosen: One example of R units includes compounds wherein R i) C-C linear, branched, or cyclic alkyl, alkenyl, and units have the formula: alkynyl: methyl (C), ethyl (C), ethenyl (C), ethynyl 55 (C), n-propyl (C), iso-propyl (C), cyclopropyl (C), 3-propenyl (C), 1-propenyl (also 2-methylethenyl) (C), isopropenyl (also 2-methylethen-2-yl) (C), prop N R2 2-ynyl (also propargyl) (C), propyn-1-yl (C), n-butyl (C), sec-butyl (C), iso-butyl (C), tert-butyl (C), - KCN H 60 cyclobutyl (C), buten-4-yl (C), cyclopentyl (Cs), cyclohexyl (C); ii) Substituted or unsubstituted C or Co aryl; for example, wherein R is hydrogen and R is a unit chosen from methyl phenyl, naphthyl (also referred to herein as naphthylen (C), ethyl (C), n-propyl (C), iso-propyl (C), n-butyl (C), 1-yl (Co) or naphthylen-2-yl (Co)); sec-butyl (C), iso-butyl (C), and tert-butyl (C). 65 iii) substituted or unsubstituted C or Co alkylenearyl; for Another example of R units includes compounds wherein example, benzyl, 2-phenylethyl, naphthylen-2-ylm R is a unit chosen from methyl (C), ethyl (C2), n-propyl ethyl: US 8,883,832 B2 19 20 iv) Substituted or unsubstituted C-C heterocyclic rings; dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2.3, as described herein; 4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6- V) Substituted or unsubstituted C-C heteroaryl rings; as trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5- described herein; trichlorophenyl, and 2,4,6-trichlorophenyl. vi)–(CR'R''), OR; for example, OH, -CH-OH, —OCH, —CHOCH, –OCHCH A yet further example of R' units includes substituted C. —CHOCHCH –OCHCHCH and aryl units chosen from 2-methylphenyl, 3-methylphenyl, —CHOCH2CHCH: 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, vii) -(CR'R''),C(OR; for example, COCH, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphe - CH-COCH, -COCHCH, -CHCOCHCH 10 nyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2.3,6-tri - COCHCHCH, and -CHCOCHCHCH: methylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, viii)–(CR'R''),C(O)CR; for example, COCH, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphe —CH2COCH, —COCHCH. —CH2COCHCH nyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, —COCHCHCH, and —CHCOCHCHCH: 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, xiii) -(CR'R''),C(O)N(R); for example, 15 2.3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphe —CONH, -CHCONH, CONHCH, nyl, 2-isopropylphenyl, 3-isopropylphenyl, and 4-isopropy -CHCONHCH – CONCCH), and -CHCON lphenyl. (CH3)2. Another still further example of R' units includes substi x) —(CR'R'')N(R); for example, NH, tuted Caryl units chosen from 2-aminophenyl, 2-(N-methy - CH-NH, -NHCH, -CH-NHCH, -N(CH), lamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N-ethy and —CHN(CH): lamino)phenyl, 2-(N,N-diethylamino)phenyl, Xi) halogen; —F. —Cl. —Br, and —I: 3-aminophenyl, 3-(N-methylamino)phenyl, 3-(N,N-dim xii) (CRRI)CN: ethylamino)phenyl, 3-(N-ethylamino)phenyl, 3-(N,N-di xiii)–(CR'R''NO.; ethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phe xiv)-(CH,X),CHX; wherein X is halogen, the index.j 25 is an integer from 0 to 2.j+k 3, the index' is an integer nyl, 4-(N,N-dimethylamino)phenyl, 4-(N-ethylamino) from 0 to 2, '+k'=2, the index h is from 0 to 6; for phenyl, and 4-(N,N-diethylamino)phenyl. example, —CHF, —CHF, —CF, —CHCF, R" can comprise heteroaryl units. Non-limiting examples —CHFCF —CC1, or—CBr: of heteroaryl units include: XV) (CR3 R31). SR30: -SH, -CHSH, —SCH, 30 —CHSCH. —SCHs and —CH2SCHs. xvi) -(CR'R''),SO.R; for example, -SO.H. —CHSOH, —SOCH, —CHSOCH, H —SOCHs, and —CHSOCHs; and NN NNN xvii) —(CR'R'')SO, R; for example, -SO,H, 35 N Q —CHSOH, —SOCH, —CHSOCH, 2N. N-N: —SOCHs, and —CHSOCHs. ii) wherein each R" is independently hydrogen, substituted or H unsubstituted C-C linear, branched, or cyclic alkyl, phenyl, t NNN. benzyl, heterocyclic, or heteroaryl; or two R' units can be 40 taken together to form a ring comprising 3-7 atoms; R" and 2N N R'' are each independently hydrogen or C-C linear or branched alkyl; the index q is from 0 to 4. One example of R' units includes substituted or unsubsti tuted phenyl (Caryl) units, wherein each Substitution is 45 independently chosen from: halogen, C-C linear, branched alkyl, or cyclic alkyl, -OR'', CN, N(R''), —COR'', iii) C(O)N(R'), NR''C(O)R'', NO, and SOR'': each R'' is independently hydrogen; substituted or unsubsti 50 tuted C-C linear, branched, cyclic alkyl, alkenyl, or alkynyl: H substituted or unsubstituted phenyl or benzyl; or two R' iv) units can be taken together to form a ring comprising from 3-7 H atOmS. Another example of R' units includes substituted Caryl N s 7 NH; units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 55 N le 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3.5- difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlo v) rophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3.5- N O dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, | / h 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 60 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethox \, - N N yphenyl, and 3.5-dimethoxyphenyl. vi) A further example of R' units includes substituted or unsubstituted Caryl units chosen from 2,4-difluorophenyl, s 7 O 9NN 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophe 65 M : N nyl, 2,3,5-trifluorophenyl, 2.3,6-trifluorophenyl, 2,4,5-trif N-O le N luorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 2.5- US 8,883,832 B2 21 22 -continued A further example of R' includes phenyl and benzyl units substituted by an amide unit having the formula —NHC(O) s O-N N: vii) R; R is chosen from methyl, methoxy, ethyl, ethoxy, tert butyl, and tert-butoxy. N-5 VJ A yet further example of R' includes phenyl and benzyl O viii) units substituted by one or more fluoro or chloro units. L Units L is a linking unit which is present when the index n is equal

N -N: 10 to 1, but is absent when the index n is equal to 0. L. units have ix) the formula: O / O; --K - { D wherein Q and Q are each independently: - { - {D X) 15 v) - NHC(O)NH : xi) vi) - NHC(O)O : N- - C - { h vii) - C(O)O : xii) 25 xi) —SO :

xiv) - NHC(=NH) ; or xiii) 30 xv) - NHC(=NH)NH-. N When the index y is equal to 1, Q is present. When the index SNN. and y is equal to 0, Q is absent. N s \! When the index Z is equal to 1, Q' is present. When the index N-S N Z is equal to 0, Q" is absent. xiv) R" and Rare each independently: 35 i) hydrogen; ii) hydroxy: KhN-N. iii) halogen; iv) C-C substituted or unsubstituted linear or branched alkyl; or R" heteroaryl units can be substituted or unsubstituted. 40 Non-limiting examples of units that can substitute for hydro V) a unit having the formula: gen include units chosen from: i) C-C linear, branched, and cyclic alkyl, ii) substituted or unsubstituted phenyl and benzyl: wherein R'' and R'' are each independently: iii) substituted of unsubstituted C-C heteroaryl; 45 i) hydrogen; or ii) substituted or unsubstituted C-C linear, branched, or v) NHC(O)R’; cyclic alkyl. R is: wherein R is C-C linear and branched alkyl: C-C linear i) hydrogen; and branched alkoxy; or -NHCHC(O)R': R' is chosen ii) substituted or unsubstituted C-C linear, branched, or from hydrogen, methyl, ethyl, and tert-butyl. 50 cyclic alkyl; An example of R' relates to units substituted by an alkyl iii) Substituted or unsubstituted C or Co aryl; unit chosen from methyl, ethyl, n-propyl, iso-propyl. n-butyl, iv) substituted or unsubstituted C-C heteroaryl; or iso-butyl, sec-butyl, and tert-butyl. v) substituted or unsubstituted C-C heterocyclic. Another example of R' includes units that are substituted R" and Rare each independently: by substituted or unsubstituted phenyl and benzyl, wherein 55 i) hydrogen; or the phenyl and benzyl substitutions are chosen from one or ii) C-C linear or branched alkyl. O The indices t, w and X are each independently from 0 to 4. i) halogen; The following are non-limiting examples of units that can ii) C-C alkyl; substitute for one or more hydrogen atoms on R. R. R', iii) C-C alkoxy; 60 R', and R units. The following substituents, as well as iv) - COR''; and others notherein described, are each independently chosen: v) NHCOR': i) C-C linear, branched, or cyclic alkyl, alkenyl, and wherein R'' and R'' are each independently hydrogen, alkynyl: methyl (C), ethyl (C), ethenyl (C), ethynyl methyl, or ethyl. (C), n-propyl (C), iso-propyl (C), cyclopropyl (C), Another example of R' relates to phenyl and benzyl units 65 3-propenyl (C), 1-propenyl (also 2-methylethenyl) substituted by a carboxy unit having the formula—C(O)R’; (C), isopropenyl (also 2-methylethen-2-yl) (C), prop R is chosen from methyl, methoxy, ethyl, and ethoxy. 2-ynyl (also propargyl) (C), propyn-1-yl (C), n-butyl US 8,883,832 B2 23 24 (C), sec-butyl (C), iso-butyl (C), tert-butyl (C), wherein R is: cyclobutyl (C), buten-4-yl (C), cyclopentyl (Cs), i) hydrogen; cyclohexyl (C); ii) Substituted or unsubstituted C or Co aryl; for example, ii) methyl: phenyl, naphthyl (also referred to herein as naphthylen iii) ethyl: 1-yl (Co) or naphthylen-2-yl (Co)); iv) isopropyl; iii) substituted or unsubstituted C or Co alkylenearyl; for example, benzyl, 2-phenylethyl, naphthylen-2-ylm V) phenyl: ethyl: vi) benzyl; iv) Substituted or unsubstituted C-C heterocyclic rings; 10 vii) 4-hydroxybenzyl: as described herein below: viii) hydroxymethyl; or V) Substituted or unsubstituted C-C heteroaryl rings; as described herein below: iX) 1-hydroxyethyl. vi)–(CR'R''), OR; for example, OH, -CHOH, 15 When the index X is equal to 1, this embodiment provides the —OCH, —CHOCH, –OCHCH following non-limiting examples of L units: —CHOCHCH –OCHCHCH and

—CHOCHCHCH: vii) -(CR'R''),C(O)R'; for example, COCH, - CH-COCH, -COCHCH, -CHCOCHCH - COCHCHCH, and -CHCOCHCHCH: viii) - (CR'R''),C(O)OR'; for example, COCH, —CH2COCH, —COCHCH. —CH2COCHCH —COCHCHCH, and —CHCOCHCHCH: xiv) (CR'R''),C(O)N(R'); for example, 25 CONH, -CHCONH, CONHCH, -CHCONHCH – CONCCH), and -CHCON (CH3)2. x) –(CR'R'')N(R'); for example, NH, - CH-NH, -NHCH, -CH-NHCH, -N(CH), 30 and —CH2NCCH), Xi) halogen; —F. —Cl. —Br, and —I: xii) (CRR). CN: xiii) (CR'R''). NO; xiv)-(CH,X),CHX; wherein X is halogen, the index.j 35 is an integer from 0 to 2.j+k 3, the index' is an integer from 0 to 2, '+k'=2, the index h is from 0 to 6; for example, —CHF, —CHF, —CF, —CH2CF, —CHFCF —CC1, or—CBr: 40 xv) (CRR), SR, SH, CHSH, —SCH, —CHSCH. —SCHs and —CH2SCHs. xvi) -(CR'R''). SOR: for example, -SOH, —CHSOH, —SOCH, —CHSOCH, —SOCHs, and —CHSOCHs; and xvii) -(CR'R''), SOR: for example, SOH, 45 —CHSOH, —SOCH, —CHSOCH, —SOCHs, and —CHSOCHs. wherein each R" is independently hydrogen, substituted or unsubstituted C-C linear, branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R' units can be 50 taken together to form a ring comprising 3-7 atoms; R'' and R'' are each independently hydrogen or C-C linear or branched alkyl; the index r is from 0 to 4. One aspect of L units relates to units having the formula: 55 wherein R is hydrogen, substituted or unsubstituted C-C, alkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; and the index X is 1 or 2. One 60 embodiment relates to linking units having the formula: i) - C(O)C(RH)|NHC(O)O : ii) –C(O)IC(RH)(CHNHC(O)O : ii) - C(O)ICHC(RH)|NHC(O)O : iv) - C(O)C(RH)NHC(O) ; 65 v) - C(O)C(RH)|CH-NHC(O) ; or vi) - C(O)CHC(RH)|NHC(O) ; US 8,883,832 B2 25 26 When the index X is equal to 2, this embodiment provides A still further embodiment of L units includes units having the following non-limiting examples of L units: the formula:

wherein R* and Rare hydrogen and the index w is equal to 0, 1 or 2; said units chosen from: ii) - C(O)NH-; ii) - C(O)NHCH ; and 10 iii) –C(O)NHCHCH-.

A yet still further example of Lunits includes units having the formula:

15 - SOC(RR) ; wherein Rand Rare hydrogen or methyl and the index w is equal to 0, 1 or 2; Said units chosen from: i) —SO : ii) —SOCH2—, and iii)—SOCH2CH2—. Vascular Leakage Control The disclosed compounds (analogs) are arranged into sev 25 eral Categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not Another embodiment ofL units includes units wherein Q is expressly exampled herein. The arrangement into categories —C(O)—, the indices X and Zare equal to 0, w is equal to 1 or 2, a first R' unit chosen from phenyl, 2-fluorophenyl, 3-fluo does not imply increased or decreased efficacy for any of the rophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluo compositions of matter described herein. rophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophe 30 A described herein above the disclosed compounds include nyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4- all pharmaceutically acceptable salt forms. A compound hav dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, ing the formula: 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl; a second 35 R" unit is hydrogen and R'units are hydrogen. For example a linking unit having the formula: S S

40 4.X-O N C-CH-CH

45 roH "n ''', OCH3. O1. OCH A further example of this embodiment of L includes a first R" unit as depicted herein above that is a substituted or 50 can form salts, for example, a salt of the Sulfamic acid: unsubstituted heteroaryl unit as described herein above. A yet further example of this embodiment of L includes units having the formula: C(O)IC(RoR) ; 55 wherein R* and Rare hydrogen and the index w is equal to S S 1 or 2; said units chosen from: CX-O . Another embodiment of L units includes units having the 60 formula: e-n 1N O wherein R* and Rare hydrogen and the index X is equal to N. h COO 1 or 2; said units chosen from: 65 O1. OCH

US 8,883,832 B2 29 30 -continued -continued S

NH2 N

HN O HN O or "Ne ON O CH O CH2 H CH 3

Reagents and conditions; (b) Lawesson's reagent, THF, rt, 3 hr, S 15 4 t

S. Y / N OnHN NH2O O O orn- in \/ Orc CH O CH e- SN O NH GE) ls <. N O CH2 HC H CH 2 25 O

--

5 30 Reagents and conditions: (e) (i) H2:PdC, MeOH; (ii)SO3-pyridine, NH4OH:rt, 2 hr.

SS. Y / N Example 1 NHHBr 35 ON 4-(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phe Reagents and conditions; (c) CH3CN; reflux, 3 hr. nylpropanamido-2-(4-ethylthiazol-2-yl) ethylphenylsulfamic acid (5) 40 Preparation of 1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl carbamic acid tert-butyl ester (1): To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propi SS Y / N -e- onic acid and N-methylmorpholine (1.1 mL, 9.65 mmol) in 45 DMF (10 mL) is added dropwise iso-butyl chloroformate NH2 (1.25 mL, 9.65 mmol). The mixture is stirred at 0°C. for 20 ON minutes after which NH (g) is passed through the reaction mixture for 30 minutes at 0° C. The reaction mixture is concentrated and the residue dissolved in EtOAc, washed 50 successively with 5% citric acid, water, 5% NaHCO, water and brine, dried (NaSO), filtered and concentrated in vacuo 1 N to a residue that is triturated with a mixture of EtOAc/petro Y / leum ether to provide 2.2 g (74%) of the desired product as a N white solid. HN O 55 Preparation of 2-(4-nitrophenyl)-1-(S)-thiocarbamoyl ON O CH ethylcarbamic acid tert-butyl ester (2): To a solution of 1 (S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-bu --- CH2 tyl ester, 1 (0.400 g, 1.29 mmol) in THF (10 mL) is added H CH 3 Lawesson’s reagent (0.262 g. 0.65 mmol). The reaction mix 60 ture is stirred for 3 hours and concentrated to a residue which is purified over silica to provide 0.350 g (83%) of the desired product. "H NMR (300 MHz, CDC1) & 8.29 (s, 1H), 8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d. J=8.4 Hz, 2H), 5.70 (d. 4 J=7.2 Hz, 1H), 4.85 (d. J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 65 1.21 (s, 9H). Reagents and conditions; (d) Boc-Phe, EDCL, HOBt, DIPEA, DMF, rt, 18 hr. Preparation of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophe nyl)ethyl amine (3): A mixture of 2-(4-nitrophenyl)-1-(S)- US 8,883,832 B2 31 32 thiocarbamoylethyl-carbamic acid tert-butyl ester, 2, (0.245 4-(S)-2-(R)-2-(tert-butoxycarbonylamino)-3-phenyl g, 0.753 mmol), 1-bromo-2-butanone (0.125 g, 0.828 mmol) propanamido)-2-(4-ethylthiazol-2-yl)ethylphenylsulfamic in CHCN (5 mL) is refluxed 3 hours. The reaction mixture is acid: "H NMR (CDOD): 8 7.22-7.02 (m, 10H), 5.39 (s, 1H), cooled to room temperature and diethyl ether is added to the 4.34 (s, 1H), 3.24-2.68 (m, 6H), 1.37 (s, 9H), 1.30 (t, 3H, solution and the precipitate which forms is removed by filtra J=7.5 Hz). tion. The solid is dried under vacuum to afford 0.242 g (90% Another embodiment of this aspect of Category Irelates to yield) of the desired product. ESI+ MS 278 (M+1). inhibitors having the formula: Preparation of {1-1-(4-ethylthiazol-2-yl)-2-(4-nitrophe nyl)ethylcarbamoyl-2-phenylethylcarbamic acid tert-butyl ester (4): To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4- 10 R nitrophenyl)ethyl amine hydrobromide, 3, (0.393 g, 1.1 O O R5a H mmol), (S)-(2-tert-butoxycarbonylamino)-3-phenylpropi \/ N o, onic acid (0.220g. 0.828 mmol) and 1-hydroxybenzotriazole HO1 s H1 r NA-en H O O (HOBt) (0.127 g., 0.828 mmol) in DMF (10 mL) at 0°C., is 15 CH3 added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.159 g, 0.828 mmol) followed by diisopropylamine wherein R units and R units further described in Table II. (0.204 g, 1.58 mmol). The mixture is stirred at 0°C. for 30 minutes then at room temperature overnight. The reaction TABLE II mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% No. R RSG aqueous NaHCO, water and brine, and dried over NaSO. B26 thiazol-2-yl (S)-benzy The solvent is removed in vacuo to afford 0.345 g of the B27 4-methylthiazol-2-yl (S)-benzy desired product which is used without further purification. B28 4-ethylthiazol-2-yl (S)-benzy 25 B29 4-propylthiazol-2-yl (S)-benzy LC/MS ESI+ 525 (M+1). B30 4-iso-propylthiazol-2-yl (S)-benzy Preparation of 4-(S)-2-(S)-2-(tert-butoxycarbony B31 4-cyclopropylthiazol-2-yl (S)-benzy lamino)-3-phenylpropanamido-2-(4-ethylthiazol-2-yl) B32 4-butylthiazol-2-y (S)-benzy B33 4-tert-butylthiazol-2-yl (S)-benzy ethylphenylsulfamic acid ammonium salt (5): 1-1-(4-eth B34 4-cyclohexylthiazol-2-yl (S)-benzy ylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl-2- B35 4-(2.2.2-trifluoroethyl)thiazol-2-yl (S)-benzy phenylethylcarbamic acid tert-butyl ester, 4, (0.345 g) is 30 B36 4-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzy B37 4-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzy dissolved in MeCH (4 mL). A catalytic amount of Pd/C (10% B38 4-(methoxymethyl)thiazol-2-yl (S)-benzy w/w) is added and the mixture is stirred under a hydrogen B39 4-(carboxylic acid ethyl ester)thiazol-2-yl (S)-benzy atmosphere 2 hours. The reaction mixture is filtered through B40 4,5-dimethylthiazol-2-yl (S)-benzy a bed of CELITETM and the solvent is removed under reduced B41 4-methyl-5-ethylthiazol-2-yl (S)-benzy pressure. The crude product is dissolved in pyridine (12 mL) 35 B42 4-phenylthiazol-2-yl (S)-benzy B43 4-(4-chlorophenyl)thiazol-2-yl (S)-benzy and treated with SO-pyridine (0.314 g). The reaction is B44 4-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzy stirred at room temperature for 5 minutes after which a 7% B45 4-methyl-5-phenylthiazol-2-yl (S)-benzy solution of NHOH (50 mL) is added. The mixture is then B46 4-(thiophen-2-yl)thiazol-2-yl (S)-benzy concentrated and the resulting residue is purified by reverse B47 4-(thiophen-3-yl)thiazol-2-yl (S)-benzy 40 B48 4-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzy phase chromatography to afford 0.222 g of the desired prod B49 5,6-dihydro-4H-cyclopentadthiazol-2-yl (S)-benzy uct as the ammonium salt. "H NMR (CDOD): 8 7.50-6.72 BSO 4,5,6,7-tetrahydrobenzodthiazol-2-yl (S)-benzy (m. 10H), 5.44-5.42 (d. 1H, J=6.0Hz), 4.34 (s, 1H), 3.34-2.79 (m, 4H), 2.83-2.76(q,2H, J=7.2 Hz), 1.40 (s.9H), 1.31 (t,3H, J=7.5 Hz). The compounds of this embodiment can be prepared The disclosed inhibitors can also be isolated as the free 45 according to the procedure outlined above in Scheme I and acid. A non-limiting example of this procedure is described described in Example 1 by substituting the appropriate Boc herein below in Example 4. B-amino acid for (S)-(2-tert-butoxycarbonylamino)-3-phe The following is a non-limiting example of compounds nylpropionic acid in step (d). encompassed within this embodiment of the first aspect of The following are non-limiting examples of compounds Category I of the present disclosure. 50 according to this embodiment.

55 S. Y / O O N O O N \/ HN O \/ HN O HO1 NN O CH HO1 SN H CH3 H ls 60 N O w N -- CH3 w CH3 H CH O CH3

65

US 8,883,832 B2 35 36 -continued -continued S

NX-K y O O Br \/ HN O G1N O CH NH4GE) H ls ON N O CH 10 H CH

15 9 Reagents and conditions; (b) 48% HBr, THF: 0°C., 1.5 hr. Reagents and conditions; (d) (i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH:rt, 12 hr.

Example 2 Br 4-(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phe HN O nylpropanamido-2-(2-phenylthiazol-4-yl)phenylsul famic acid (9) or "NY 25 O CH3 Preparation of (S)-3-diazo-1-(4-nitrobenzyl)-2-oxo-pro pyl-carbamic acid tert-butyl ester (6): To a 0°C. solution of H3CK. 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propi 7 30 onic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added drop wise triethylamine (0.61 mL, 4.4 mmol) followed by iso butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0° C. for 20 minutes and filtered. The filtrate is treated with an ether solution of diazomethane (~16 mmol) at 0°C. The reaction mixture is stirred at room tem perature for 3 hours then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed successively with water and brine, dried (NaSO), filtered and concentrated. ON O The residue is purified over silica (hexane/EtOAc 2:1) to 40 afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. "H NMR (300 MHz, CDC1) & 8.16 (d. J=8.7 Hz, 2H), 7.39 (d. J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d. J=6.3 HZ, 1H), 4.49 (s.1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd. J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H). 45 Preparation of (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)- 3-oxobutan-2-ylcarbamate (7): To a 0°C. solution of (S)-3- 8 diazo-1-(4-nitrobenzyl)-2-oxo-propyl-carbamic acid tert Reagents and conditions; (c) (i) thiobenzamide, CH3CN; reflux, 2 hr., (ii) Boc-Phe, butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is added HOBt, DDPEA, DMFrt, 18 hr. dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours then the reaction is quenched at 0°C. with sat. NaCO. The mixture is extracted with EtOAc (3x25 mL) and the combined organic extracts are washed with brine, dried (NaSO), filtered and concentrated to obtain 0.400 g of the product which is used in the next step N without further purification. H NMR (300 MHz, CDC1) & 8.20 (d. J=8.4 Hz, 2H), 7.39 (d. J=8.4 Hz, 2H), 5.06 (d. J=7.8 HN O HZ, 1H), 4.80 (q, J–6.3 Hz, 1H), 4.04 (s. 2H), 1.42 (s, 9H). ON O CH Preparation of tert-butyl (S)-1-(S)-2-(4-nitrophenyl)-1-(2- phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2- --- 60 ylcarbamate (8): A mixture of thiobenzamide (0.117 g. 0.85 H CH mmol) and (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-ox obutan-2-ylcarbamate, 7, (0.300 g, 0.77 mmol) in CHCN (4 mL) is refluxed 2 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to precipitate the 65 intermediate 2-(nitrophenyl)-(S)-1-(4-phenylthiazol-2-yl) 8 ethylamine which is isolated by filtration as the hydrobro mide salt. The hydrobromide salt is dissolved in DMF (3 mL) US 8,883,832 B2 37 38 together with diisoproylethylamine (0.42 mL, 2.31 mmol), TABLE IV 1-hydroxybenzotriazole (0.118 g. 0.79 mmol) and (S)-(2- tert-butoxycarbonyl-amino)-3-phenylpropionic acid (0.212 No. R RSG g, 0.80 mmol). The mixture is stirred at 0°C. for 30 minutes then at room temperature overnight. The reaction mixture is D76 thiazol-4-yl (S)-benzy diluted with water and extracted with EtOAc. The combined D77 2-methylthiazol-4-yl (S)-benzy D78 2-ethylthiazol-4-yl (S)-benzy organic phase is washed with 1 Naqueous HCl, 5% aqueous D79 2-propylthiazol-4-yl (S)-benzy NaHCO, water and brine, and dried over NaSO. The sol D80 2-iso-propylthiazol-4-yl (S)-benzy vent is removed in vacuo to afford 0.395 g (90% yield) of the 10 D81 2-cyclopropylthiazol-4-yl (S)-benzy desired product which is used without further purification. D82 2-butylthiazol-4-y (S)-benzy LC/MS ESI+ 573 (M+1). D83 2-tert-butylthiazol-4-yl (S)-benzy Preparation of (4-((S)-2-((S)-2-((tert-Butoxycarbonyl) D84 2-cyclohexylthiazol-4-yl (S)-benzy D85 2-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzy amino)-3-phenylpropan-amido)-2-(2-phenylthiazol-4-yl) D86 2-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzy ethyl)phenyl)sulfamic acid (9): tert-butyl (S)-1-(S)-2-(4-ni 15 D87 2-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzy trophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3- D88 2-phenylthiazol-4-yl (S)-benzy phenylpropan-2-ylcarbamate, 8, (0.360 g) is dissolved in D89 2-(4-chlorophenyl)thiazol-4-yl (S)-benzy MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is D90 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzy added and the mixture is stirred under a hydrogen atmosphere D91 2-(thiophen-2-yl)thiazol-4-yl (S)-benzy 12 hours. The reaction mixture is filtered through a bed of D92 2-(thiophen-3-yl)thiazol-4-yl (S)-benzy CELITETM and the solvent is removed under reduced pres D93 2-(3-chlorothiophen-2-yl)thiazol-4-yl (S)-benzy D94 2-(3-methylthiophen-2-yl)thiazol-4-yl (S)-benzy sure. The crude product is dissolved in pyridine (12 mL) and D95 2-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzy treated with SO-pyridine (0.296 g). D96 2-(furan-2-yl)thiazol-4-yl (S)-benzy The reaction is stirred at room temperature for 5 minutes 25 D97 2-(pyrazin-2-yl)thiazol-4-yl (S)-benzy after which a 7% solution of NH-OH (10 mL) is added. The D98 2-(2-methyl)pyridin-5-ylthiazol-4-yl (S)-benzy mixture is then concentrated and the resulting residue is puri D99 2-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzy fied by reverse phase chromatography to afford 0.050 g of the D100 2-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzy desired product as the ammonium salt. H NMR (300 MHz, MeOH-d) & 8.20 (d. J=8.1 Hz, 1H), 7.96-7.99 (m. 2H), 30 7.48-7.52 (m, 3H), 7.00-7.23 (m, 7H), 6.89 (s, 1H), 5.28 (q, The compounds encompassed within the second aspect of J=7.5 Hz, 1H), 4.33 (t, J=6.6 Hz, 1H), 3.09-3.26 (m, 2H), 3.34 Category II of the present disclosure can be prepared by the (dd, J=13.2and8.4 Hz, 1H), 2.82 (dd, J–13.2and8.4 Hz, 1H), procedure outlined in Scheme III and described in Example 3 1.38 (s, 9H). herein below. The first aspect of Category II of the present disclosure 35 relates to compounds wherein R is a substituted or unsubsti Scheme III tuted thiazol-4-yl unit having the formula: O

40 Br

S X-R' HN O N O O O or - NY VA N SS ls O CH Ho-1'N C(RdR s -CH 45 r CH3 H O H HC

7 one embodiment of which relates to inhibitors having the 50 formula: SX / N

HN O y 55 ON O \ { N ls O1 CH3 O O R5a O H HO1\/ H1 N ls --"CH 60

H O H

12 wherein R units are thiazol-4-yl units, that when substituted, 65 Reagents and conditions: (a)(i) propanethioamide, CH3CN; reflux, 2 hr. are substituted with R units. R and R units are further (ii) Boc-Phe, HOBt, DIPEA, DMF; rt, 18 hr. described in Table IV. US 8,883,832 B2 39 40 -continued Preparation of 4-((S)-2-((S)-2-(methoxycarbonylamino)- 3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenyl SX / sulfamic acid ammonium salt (13): tert-Butyl (S)-1-(S)-2-(4- N nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3- phenylpropan-2-ylcarbamate, 12, (0.300 g) is dissolved in HN O ON O MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere N ls O -CH3 18 hours. The reaction mixture is filtered through a bed of H 10 CELITETM and the solvent is removed under reduced pres sure. The crude product is dissolved in pyridine (12 mL) and treated with SO-pyridine (223 mg, 1.40 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% 15 solution of NHOH (12 mL) is added. The mixture is then 12 concentrated and the resulting residue is purified by reverse phase chromatography to afford 25 mg of the desired product as the ammonium salt. "H NMR (300 MHz, MeOH-da) & 7.14-7.24 (m, 6H), 6.97-7.0 (m, 4H), 6.62 (s, 1H), 5.10-5.30 X / (m. 1H), 4.36 (t, J=7.2 Hz, 1H), 3.63 (s.3H), 3.14 (dd, J=13.5 O O and 6.3 Hz, 1H), 2.93-3.07 (m, 5H), 2.81 (dd, J=13.5 and 6.3 V/ HZ, 1H), 1.39 (t, J=7.8 Hz, 3H). S HN O HO1 NN O In anotheriteration of the process of the present disclosure, or 25 compound 13, as well as the other analogs which comprise H ls CH3 N o1 the present disclosure, can be isolated as the free acid by H adapting the procedure described herein below.

30

13 Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH:rt, 18 hr. 35 SX / N -e- HN O Example 3 ON O 4-(S)-2-(S)-2-(Methoxycarbonylamino)-3-phenyl 40 N l o1 CH3 propanamido-2-(2-ethylthiazol-4-yl) H ethylphenylsulfamic acid (13) Preparation of methyl (S)-1-(S)-1-(2-ethylthiazole-4-yl)- 2-(4-nitrophenyl)-ethylamino-1-oxo-3-phenylpropane-2- 45 ylcarbamate (12): A mixture of propanethioamide (69 mg, 0.78 mmol) and (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3- 12 oxobutan-2-ylcarbamate, 7, (0.300 g, 0.77 mmol) in CHCN (4 mL) is refluxed for 2 hours. The reaction mixture is cooled 50 to room temperature and diethyl ether is added to precipitate the intermediate 2-(nitrophenyl)-(S)-1-(4-ethylthiazol-2-yl) SX / ethylamine which is isolated by filtration as the hydrobro N mide salt. The hydrobromide salt is dissolved in DMF (8 mL) 55 HN O together with diisoproylethylamine (0.38 mL, 2.13 mmol), HN O 1-hydroxybenzotriazole (107 mg, 0.71 mmol) and (S)-(2- methoxycarbonyl-amino)-3-phenylpropionic acid (175 mg. N lso1 CH3 0.78 mmol). The mixture is stirred at 0°C. for 30 minutes then H at room temperature overnight. The reaction mixture is 60 diluted with water and extracted with EtOAc. The combined organic phase is washed with 1N aqueous HCl, 5% aqueous NaHCO, water and brine, and dried over NaSO. The sol 12a vent is removed in vacuo to afford 0.300 g (81% yield) of the 65 desired product which is used without further purification. Reagents and conditions: (a) H2:PdC, MeOH: rt, 40 hr. LC/MS ESI+ MS 483 (M+1). US 8,883,832 B2 41 42 -continued herein above. Acetonitrile (50 mL, 5 mL/g) is added and the yellow Suspension is stirred at room temperature. A second 3-necked 500 mL RBF is charged with SOspyr (5.13 g, 32.2 SX / mmol. 1.4 eq) and acetonitrile (50 mL 5 mL/g) and the white N Suspension is stirred at room temperature. Both Suspensions HN O are gently heated until the reaction solution containing 1-2- HN O (S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-car bamoyl-2-phenylethyl-carbamic acid methyl ester CH N - O - becomes red-orange in color (typically for this example about H 10 44° C.). This Substrate containing solution is poured in one portion into the stirring suspension of SOspyr at 35°C. The resulting opaque mixture (39°C.) is stirred vigorously while allowed to slowly cool to room temperature. After stirring for 45 min, the reaction is determined to be complete by HPLC. 15 H2O (200 mL. 20 mL/g) is added to the orange suspension to 12a provide a yellow-orange homogeneous solution having a pH of approximately 2.4. Concentrated HPO is added slowly over 12 minutes to lower the pH to approximately 1.4. During X / this pH adjustment, an off-white precipitate is formed and the O O V/ solution is stirred at room temperature for 1 hr. The suspen S HN O sion is filtered and the filter cake is washed with the filtrate. HO1 NN or O The filter cake is air-dried on the filter overnight to afford H ls CH 10.89 g (89% yield) of the desired product as a tan solid. N o1 The following are further non-limiting examples of the H 25 second aspect of Category II of the present disclosure.

S

13 30 X O O N Reagents and conditions; (b) SO3-pyridine, CH3CN; heat, 45 min. \/ HN O HO1 SN O

35 Example 4 N l OCH H 4-((S)-2-((S)-2-(Methoxycarbonylamino)-3-phenyl propanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenyl sulfamic acid Free Acid Form(13) 40 Preparation of 1-2-(S)-(4-(S)-aminophenyl)-1-(2-eth ylthiazol-4-yl)ethyl-carbamoyl-2-phenylethyl-carbamic 4-(S)-2-(S)-2-(Methoxycarbonylamino)-3-phenylpro acid methyl ester (12a): A Parr hydrogenation vessel is panamido-2-(2-methylthiazol-4-yl)ethylphenylsulfamic charged with tert-butyl (S)-1-(S)-2-(4-nitrophenyl)-1-(2-eth 45 acid: "H NMR (300 MHz, MeOH-d) & 8.15 (d. J=8.4 Hz, ylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcar 1H), 7.16-7.25 (m, 5H), 6.97-7.10 (m, 4H), 6.61 (s, 1H), bamate, 12, (18.05 g, 37.4 mmol, 1.0 eq) and Pd/C (10% Pd 5.00-5.24 (m, 1H), 4.36 (t, J–7.2 Hz, 1H), 3.64 (s. 2H), on C, 50% wet, Degussa-type E101 NE/W, 2.68 g. 15 wt %) 3.11-3.19 (s, 1H), 2.92-3.04 (s. 2H), 2.81 (dd, J=13.5 and 8.1 as solids. MeOH (270 mL, 15 mL/g) is added to provide a HZ, 1H), 2.75 (s.3H). Suspension. The vessel is put on a Parr hydrogenation appa 50 ratus. The vessel is submitted to a fill/vacuum evacuate pro S cess with N. (3x20 psi) to inert, followed by the same proce dure with H. (3x40 psi). The vessel is filled with H and the M w vessel is shaken under 40 psi H, for ~40 hr. The vessel is O O N evacuated and the atmosphere is purged with N (5x20 psi). 55 An aliquot is filtered and analyzed by HPLC to insure com \/ HN O plete conversion. The Suspension is filtered through a pad of HO1 SN O celite to remove the catalyst, and the homogeneous yellow filtrate is concentrated by rotary evaporation to afford 16.06 g H s (95% yield) of the desired productasatan solid, which is used 60 without further purification. Preparation of 4-((S)-2-((S)-2-(methoxycarbonyl)-3-phe nylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsul famic acid (13): A 100 mL RBF is charged with 1-2-(S)- (4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl 65 carbamoyl-2-phenylethyl-carbamic acid methyl ester, 12a, 4-(S)-2-(2-Ethylthiazole-4-yl)-2-(S)-2-(methoxycarbo (10.36 g. 22.9 mmol. 1.0 eq) prepared in the step described nylamino)-3-phenylpropan-amidolethylphenylsulfamic

US 8,883,832 B2 49 50 Example 5 S \ / S 4-(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2- s le (4-ethylthiazol-2-yl)ethylphenylsulfamic acid (15) 5 W HN O Preparation of (S)-2-acetamido-N-(S)-1-(4-ethylthi HO1 NN O azol-2-yl)-2-(4-nitrophenyl)-ethyl-3-phenylpropanamide H ls (14): To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitro N CH3 phenyl)ethylamine hydrobromide, 3, (0.343 g, 0.957 mmol), 10 H N-acetyl-L-phenylalanine (0.218 g), 1-hydroxybenzotriazole (HOBt) (0.161 g), diisopropyl-ethylamine (0.26 g), in DMF (10 mL) at 0°, is added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) (0.201 g). The mixture is stirred at 0°C. for 30 minutes then at room temperature overnight. The reac 15 tion mixture is diluted with water and extracted with EtOAc. 4-(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-4- The combined organic phase is washed with 1 Naqueous HCl, (thiophen-3-yl)thiazol-2-yl)ethyl)phenylsulfamic acid: "H 5% aqueous NaHCO, water and brine, and dried over NMR (300 MHz, CDOD): 8 8.58 (d. J=8.1 Hz, 1H), 7.83 NaSO. The solvent is removed in vacuo to afford 0.313 g 7.82 (m. 1H), 7.57-746 (m, 3H), 7.28-6.93 (m. 11H), 5.54 (70% yield) of the desired product which is used without 5.43 (m, 1H), 4.69-4.55 (m, 2H), 3.41-3.33 (m, 1H), 3.14 further purification. LC/MS ESI+ 467 (M+1). 3.06 (3H), 2.86-2.79 (m, 1H), 1.93 (s.3H). The first aspect of Category IV of the present disclosure Preparation of 4-((S)-2-((S)-2-acetamido-3-phenylpro relates to compounds wherein R is a substituted or unsubsti panamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic acid tuted thiazol-2-yl unit having the formula: (15): (S)-2-Acetamido-N-(S)-1-(4-ethylthiazol-2-yl)-2- 25 (4-nitrophenyl)ethyl-3-phenylpropanamide, 14, (0.313 g) is dissolved in MeCH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 2 hours. The reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced 30 pressure. The crude product is dissolved in pyridine (12 mL) R A” S O CH3 and treated with SO-pyridine (0.320 g). The reaction is HO1NS H1 N CRsaR5b( kn l O CH3 stirred at room temperature for 5 minutes after which a 7% CH H O H solution of NHOH (30 mL) is added. The mixture is then 35 concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.215 g of the desired prod one embodiment of which relates to inhibitors having the uct as the ammonium salt. H NMR (CDOD): 8 7.23-6.98 formula: (m. 10H), 5.37 (t, 1H), 4.64 (t, 1H, J–6.3 Hz), 3.26-2.74 (m, 40 6H), 1.91 (s.3H), 1.29 (t, 3H, J=7.5 Hz). R2 The following are further non-limiting examples of com pounds encompassed within Category III of the present dis R3 closure. N N \ S 45 O O R5a O CH3

HO1 NN H N O CH3 S CH N H O H O O 50 \/ HN O HO1 SN O wherein Runits and R units further described in Table VI.

CH TABLE VI N 55 No. R RSG F126 thiazol-2-yl hydrogen F127 4-methylthiazol-2-yl hydrogen F128 4-ethylthiazol-2-yl hydrogen F129 4-propylthiazol-2-yl hydrogen 60 F130 4-iso-propylthiazol-2-yl hydrogen F131 4-cyclopropylthiazol-2-yl hydrogen 4-(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4- F132 4-butylthiazol-2-yl hydrogen tert-butylthiazol-2-yl)ethylphenylsulfamic acid: "H NMR F133 4-tert-butylthiazol-2-yl hydrogen F134 4-cyclohexylthiazol-2-yl hydrogen (300 MHz, CDOD): 8 7.22-7.17 (m, 5H), 7.06 (dd, J=14.1, F135 4,5-dimethylthiazol-2-yl hydrogen 8.4 Hz, 4H), 6.97 (d. J=0.9 Hz, 1H), 5.39 (dd, J=8.4, 6.0 Hz, 65 F136 4-methyl-5-ethylthiazol-2-yl hydrogen 1H), 4.65 (t, J=7.2 Hz, 1H), 3.33-3.26 (m. 1H), 3.13-3.00 (m, F137 4-phenylthiazol-2-yl hydrogen 3H), 2.80 (dd, J=13.5, 8.7 Hz, 1H), 1.91 (s.3H), 1.36 (s.9H). US 8,883,832 B2 52 TABLE VI-continued -continued

No. R R5a

5 SS. Y / F138 thiazol-2-yl (S)-iso-propy O O N F139 4-methylthiazol-2-yl (S)-iso-propy \/ HN O F140 4-ethylthiazol-2-yl (S)-iso-propy HO1 NN O CH3 F141 4-propylthiazol-2-yl (S)-iso-propy 10 H3C F142 4-iso-propylthiazol-2-yl (S)-iso-propy N O CH3 F143 4-cyclopropylthiazol-2-yl (S)-iso-propy H CH F144 4-butylthiazol-2-yl (S)-iso-propy CH3 F145 4-tert-butylthiazol-2-yl (S)-iso-propy 17 15 F146 4-cyclohexylthiazol-2-yl (S)-iso-propy Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH, F147 4,5-dimethylthiazol-2-yl (S)-iso-propy rt, 2 hr., F148 4-methyl-5-ethylthiazol-2-yl (S)-iso-propy F149 4-phenylthiazol-2-yl (S)-iso-propy F150 4-(thiophen-2-yl)thiazol-2-yl (S)-iso-propy 2O Example 6 The compounds encompassed within Category IV of the present disclosure can be prepared by the procedure outlined 25 4-(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-meth in Scheme V and described in Example 6 herein below. ylbutanamido-2-(4-ethylthiazol-2-yl) ethylphenylsulfamic acid (17)

Scheme V Preparation of tert-butyl (S)-1-(S)-(4-ethylthiazol-2-yl)- 30 2-(4-nitrophenyl)ethylaminol-3-methyl-1-oxobutan-2-yl carbamate (16): To a solution of 1-(S)-(4-ethylthiazol-2-yl)- Ss Y / 2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.200 g, 0.558 mmol), (S)-(2-tert-butoxycarbonylamino)-3-methyl NH2 butyric acid (0.133 g) and 1-hydroxybenzotriazole (HOBt) ON 35 (0.094 g) in DMF (5 mL) at 00, is added 1-(3-dimethylami 3 nopropyl)-3-ethylcarbodiimide (EDCI) (0.118 g) followed by diisopropylamine (0.151 g). The mixture is stirred at 0°C. for 30 minutes then at room temperature overnight. The reac 40 tion mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, SS. Y / N 5% aqueous NaHCO, water and brine, and dried over NaSO. The solvent is removed in vacuo to afford 0.219 g (82% yield) of the desired product which is used without ON OnO O CH3 45 further purification. LC/MS ESI+ 477 (M+1). Preparation of 4-(S)-2-(S)-2-(tert-butoxycarbony is-s-s-sN O CH3 H CH lamino)-3-methylbutanamido-2-(4-ethylthiazol-2-yl) CH 3 50 ethylphenylsulfamic acid (17): tert-Butyl (S)-1-(S)-(4-eth 16 ylthiazol-2-yl)-2-(4-nitrophenyl)ethylaminol-3-methyl-1- Reagents and conditions: (a) Boc-Val; EDCL, HOBt, DDPEA, DMF; rt, 18 hr. oxobutan-2-ylcarbamate, 16, (0.219 g) is dissolved in MeCH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 2 hours. S Y / 55 The reaction mixture is filtered through a bed of CELITETM S. and the solvent is removed under reduced pressure. The crude N product is dissolved in pyridine (5 mL) and treated with SO-pyridine (0.146 g). The reaction is stirred at room tem ON OrO O CH3 e 60 perature for 5 minutes after which a 7% solution of NHOH (30 mL) is added. The mixture is then concentrated and the HC N ls O-- CH3 resulting residue is purified by reverse phase chromatography H CH CH to afford 0.148g of the desired product as the ammonium salt. 65 H NMR (CDOD): 87.08 (s, 4H), 7.02 (s, 1H), 5.43 (s, 1H), 16 3.85 (s, 1H), 3.28-2.77 (m, 4H), 1.94 (s, 1H), 1.46 (s, 9H), 1.29 (s.3H, J=7.3 Hz), 0.83 (s, 6H).

US 8,883,832 B2 70 and extracted with EtOAc. The combined organic phase is Scheme VII washed with 1N aqueous HCl, 5% aqueous NaHCO, water and brine, and dried over NaSO. The solvent is removed in 1 N vacuo to afford 0.260 g (60% yield) of the desired product S. Y / -as which is used without further purification. ESI+ MS 396 N (M+1). Preparation of 4-2-(S)-(4-ethylthiazol-2-yl)-2-(2-phe NH2-HBr nylacetylamido)ethyl-phenylsulfamic acid (21): N-1-(4- ON ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl)-2-phenyl-aceta 10 3 mide, 20, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred S y / under a hydrogen atmosphere 18 hours. The reaction mixture S. N is filtered through a bed of CELITETM and the solvent is 15 removed under reduced pressure. The crude product is dis HN O solved in pyridine (12 mL) and treated with SO-pyridine ON (0.177 g, 1.23). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NHOH (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.136 g of the desired product as the ammonium salt. H 2O NMR (CDOD) & 8.60 (d. 1H, J=8.1 Hz), 7.33-7.23 (m, 3H), Reagents and conditions: (a) CHCO2H, EDCI, HOBt, DIPEA, DMF; 7.16-7.00 (m, 6H), 5.44-5.41 (m. 1H), 3.28 (1H, A of ABX, rt, 18 hr, obscured by solvent), 3.03 (1H, B of ABX, J=14.1, 9.6 Hz), 25 2.80 (q, 2H, J=10.5, 7.8 Hz) 1.31 (t, 3H, J=4.6 Hz). The following are non-limiting examples of the first aspect SS Y / N of Category V of the present disclosure.

HN O ON 30 Y / O. O N \/ HN O 35 HO1 SN 2O S y / S. O O N 40 \/ HN O HO1 NN (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)ac H etamido)ethyl)phenylsulfamic acid: "H NMR (CDOD) 8 8.65 (d. 1H, J=8.4 Hz), 7.29-7.15 (m, 1H), 7.13-7.03 (m, 7H), 45 5.46-5.42 (m, 1H), 3.64-3.51 (m, 2H), 3.29 (1H), 3.04 (1H, B of ABX, J=13.8, 9.6 Hz), 2.81 (q, 2H, J=15.6, 3.9 Hz), 1.31 (t, 21 3H, J=7.8 Hz). F NMR (CDOD) & 43.64. Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NHOH, rt, 18 hr. 50

Example 8 O. O N \/ HN O {4-2-(S)-(4-Ethylthiazol-2-yl)-2-(2-phenylacetyla 55 mido)ethylphenylsulfamic acid (21) HO1 SN Preparation of N-1-(4-ethylthiazol-2-yl)-2-(4-nitrophe nyl)ethyl)-2-phenyl-acetamide (20): To a solution of 1-(S)- (4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydro 60 bromide, 3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and 1-hydroxybenzotriazole (HOBt) (0.094 g, (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)ac 0.70 mmol) in DMF (10 mL) at 00, is added 1-(3-dimethy etamido)ethyl)phenylsulfamic acid: "H NMR (CDOD) & laminopropyl)-3-ethylcarbodiimide (EDCI) (0.268 g, 1.4 8.74 (d. 1H, J=8.4Hz), 7.32(q, 1H, J=6.6, 14.2 Hz), 7.10-6.91 mmol) followed by triethylamine (0.60 mL, 4.2 mmol). The 65 (m,8H), 5.47-5.40 (m, 1H), 3.53 (s.2H), 3.30 (1H), 3.11 (1H, mixture is stirred at 0°C. for 30 minutes then at room tem B of ABX, J=9.6, 14.1 Hz), 2.80 (q, 2H, J=6.6, 15.1 Hz), 1.31 perature overnight. The reaction mixture is diluted with water (t,3H, J=7.8 Hz). 'F NMR & 47.42.

US 8,883,832 B2 83 NMR (CDOD): 8 7.98-7.95 (m, 2H), 7.48-7.46 (m, 3H), TABLE XI-continued 7.23 (s, 1H), 7.09-7.05 (m, 4H), 5.33 (t, 1H, J–7.2 Hz), 3.33-3.06 (m, 2H), 2.35 (s.3H). No. R2 R3 RSG 5 K491 ethyl hydrogen 4-chlorophenyl S K492 ethyl hydrogen 3,4-dichlorophenyl K493 ethyl hydrogen 2-methoxyphenyl K494 ethyl hydrogen 3-methoxyphenyl O. O O-()N K495 ethyl hydrogen 4-methoxyphenyl \/ HN O 10 HO1 SN O The compounds encompassed within the third aspect of O Category V of the present disclosure can be prepared by the N procedure outlined in Scheme IX and described in Example N-- 15 10 herein below.

4-(S)-2-[2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetamido Scheme IX 2-2-(thiophen-2-yl)thiazol-4-yl)ethylphenylsulfamic acid: H NMR (CDOD) & 7.62 (d. 1H, J=3 Hz), 7.58 (d. 1H, 2O S Y / J=15.6Hz), 7.27 (s, 1H), 7.16 (t, 1H, J=1.5 Hz), 5.42-5.32 (m, S. 1H), 4.31 (d. 1H, J=15.6 Hz), 3.91 (d. 1H, J=15.9 Hz), 3.60 N -e- 3.50 (m, 4H), 3.30-3.23 (m, 2H), 2.98 (1H, B of ABX, J=9.9, 13.8 Hz), 1.21 (t, 3H, J=6.9 Hz). NHHBr ON The third aspect of Category V of the present disclosure 25 S relates to compounds having the formula: 3 S. Y / N

HN O 30 ON CCC 35

25 Reagents and conditions: (a) diphenylpropionic acid, EDCI, HOBt, TEA, DMF; 0° C. tort, 18 hr. wherein the linking unit L comprises a phenyl unit, said 40 S Y / linking group having the formula: S. N R" is hydrogen, R is phenyl, R is phenyl or substituted HN O phenyland non-limiting examples of the units R. R. and R' are further exemplified herein below in Table XI. TABLE XI as O2N CCC No. R3 RSG 50 25 K472 methyl ny rogen phenyl K473 methyl ny rogen 2-fluorophenyl K474 methyl ny rogen 3-fluorophenyl K475 methyl ny rogen 4-fluorophenyl y / K476 methyl ny rogen 3,4-difluorophenyl N K477 methyl ny rogen 2-chlorophenyl K478 methyl ny rogen 3-chlorophenyl 55 W HN O K479 methyl ny rogen 4-chlorophenyl HO1 NN K48O methyl ny rogen 3,4-dichlorophenyl H K481 methyl ny rogen 2-methoxyphenyl K482 methyl ny rogen 3-methoxyphenyl K483 methyl ny rogen 4-methoxyphenyl K484 ethyl ny rogen phenyl K485 ethyl ny rogen 2-fluorophenyl 60 CO K486 ethyl ny rogen 3-fluorophenyl K487 ethyl ny rogen 4-fluorophenyl 26 K488 ethyl ny rogen 3,4-difluorophenyl Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, K489 ethyl ny rogen 2-chlorophenyl 65 NH4OH:rt, 18 hr. K490 ethyl ny rogen 3-chlorophenyl US 8,883,832 B2 85 86 Example 10 -continued (S)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthi azol-2-yl)ethyl)-phenylsulfamic acid (26) O O Preparation of (S) N-1-(4-ethylthiazol-2-yl)-2-(4-nitro phenyl)ethyl-2,3-diphenyl-propanamide (25): To a solution OCH -e- OH of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.95 g, 2.65 mmol), diphenylpropionic HCO HCO acid (0.60 g, 2.65 mmol) and 1-hydroxybenzotriazole 10 (HOBt) (0.180g, 1.33 mmol) in DMF (10 mL) at 00, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) 27 28 (0.502g, 2.62 mmol) followed by triethylamine (1.1 mL, 7.95 Reagents and conditions; (b)NaOH, THF/MeOH: rt, 18 hr. mmol). The mixture is stirred at 0°C. for 30 minutes then at 15 room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO, Example 11 water and brine, and dried over NaSO. The solvent is removed in vacuo to afford 0.903 g (70% yield) of the desired 2-(2-Methoxyphenyl)-3-phenylpropanoic acid (28) product which is used without further purification. Preparation of (S)-4-(2-(2,3-diphenylpropanamido)-2-(4- Preparation of methyl 2-(2-methoxyphenyl)-3-phenylpro ethylthiazol-2-yl)ethyl)phenylsulfamic acid (26) (S) N-1- panoate (27): A 500 mL round-bottom flask is charged with (4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl-2,3-diphenyl methyl 2-(2-methoxyphenyl)acetate (8.496 g. 47 mmol. 1 eq) propanamide, 25, (0.903 g) is dissolved in MeOH (10 mL). A 25 and THF (200 mL). The homogeneous mixture is cooled to 0° catalytic amount of Pd/C (10% w/w) is added and the mixture C. in an ice bath. Lithium diisopropyl amide (23.5 mL of a is stirred under a hydrogen atmosphere 18 hours. The reaction 2.0M solution in heptane/THF) is added, maintaining a tem mixture is filtered through a bed of CELITETM and the solvent perature less than 3°C. The reaction is stirred 45 minutes at is removed under reduced pressure. The crude product is this reduced temperature. Benzyl bromide (5.6 mL, 47 mmol. dissolved in pyridine (30 mL) and treated with SO-pyridine 30 1 eq) is added dropwise. The reaction is allowed to gradually (0.621 g). The reaction is stirred at room temperature for 5 warm to room temperature and is stirred for 18 hours. The reaction is quenched with 1 NHCl and extracted 3 times with minutes after which a 7% solution of NH-OH is added. The equal portions of EtOAc. The combined extracts are washed mixture is then concentrated and the resulting residue is puri with HO and brine, dried over NaSO, filtered, and concen fied by reverse phase chromatography to afford 0.415 g of the 35 trated. The residue is purified over silica to afford 4.433 g desired product as the ammonium salt. "H NMR (CDOD) 8 (35%) of the desired compound. ESI+ MS 293 (M+Na). 8.59-8.52 (m, 1H), 7.37-704 (m, 9H), 6.97-6.93 (m, 1H), Preparation of 2-(2-methoxyphenyl)-3-phenylpropanoic 6.89-6.85 (m, 2H), 5.36-5.32 (m, 1H), 3.91-3.83 (m. 1H), acid (28): Methyl 2-(2-methoxyphenyl)-3-phenylpropanoate 3.29 (1H, A of ABX, obscured by solvent), 3.15 (1H, B of (4.433 g, 16 mmol. 1 eq) is dissolved in 100 mL of a 1:1 (v:v) ABX, J–5.4, 33.8 Hz), 2.99-2.88 (m, 2H), 2.81-2.69 (m, 2H), 40 mixture of THF and methanol. Sodium hydroxide (3.28 g. 82 1.32-1.25 (m, 3H). mmol. 5 eq) is added and the reaction mixture is stirred 18 The precursors of many of the Zunits which comprise the hours at room temperature. The reaction is then poured into HO and the pH is adjusted to 2 via addition of 1N HC1. A third aspect of Category V are not readily available. The white precipitate forms which is removed by filtration. The following procedure illustrates an example of the procedure resulting solution is extracted with 3 portion of diethyl ether. which can be used to provide different R units according to 45 The extracts are pooled, washed with H2O and brine, dried the present disclosure. Using the procedure outlined in over NaSO filtered, and concentrated in vacuo. The result Scheme X and described in Example 11 the artisan can make ing residue is purified over silica to afford 2.107 g (51%) of modifications without undue experimentation to achieve the the desired compound. ESI-MS 255 (M-1), 211 (M-COH). R" units encompassed by the present disclosure. Intermediate 28 can be carried forward according to the 50 procedure outlined in Scheme IX and described in Example 10 to produce the following compound according to the third Scheme X aspect of Category V.

O O O)-N O OCH VS A” HCO OCH HO1 n N 60 H3CO O

OCH 27 65 Reagents and conditions: (a) benzyl bromide, LDA, THF: 0°C. tort 18 hr. (S)-4-2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)- 3-phenylpropanamido-ethylphenylsulfamic acid: "H NMR

US 8,883,832 B2 89 90 -continued NaSO. The solvent is removed in vacuo to afford 0.169 g (31% yield) of the desired product which is used without further purification. SS. Y / N Preparation of N—(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitro phenyl)ethyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenyl HN O propanamide (30): Ethyl 2-benzyl-3-((S)-1-(4-ethylthiazol ON 2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium O carbonate (80 mg) and acetamide oxime (43 mg) are added. 10 and treated with 80 mg potassium carbonate and 43 mg aceta mide oxime at reflux. The reaction mixture is cooled to room )- N temperature, filtered and concentrated. The residue is chro HC matographed oversilicato afford 0.221 g (94%) of the desired 30 product as a yellow oil. Reagents and conditions; (b) CH3C(NOH)NH2. K2CO3, toluene; reflux, 18 hr 15 Preparation of 4-(S)-2-(4-ethylthiazol-2-yl)-2-[2-(3-me thyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido ethylphenylsulfamic acid (31): N-(S)-1-(4-ethylthiazol 2-yl)-2-(4-nitrophenyl)ethyl-2-(3-methyl-1,2,4-oxadiazol 5-yl)-3-phenylpropanamide, 30, (0.221 g) and tin (II) chloride (507 mg, 2.2 mmol) are dissolved in EtOH (25 mL) or -3- and the solution is brought to reflux 4 hours. The solvent is removed in vacuo and the resulting residue is dissolved in EtOAc. A saturated solution of NaHCO (50 mL) is added and the Solution is stirred 1 hour. The organic layer is sepa 25 rated and the aqueous layer extracted twice with EtOAc. The combined organic layers are dried (Na2SO4), filtered and )- concentrated to a residue which is dissolved in pyridine 30 (0.143 g) and treated with SO-pyridine (0.143 g). The reac tion is stirred at room temperature for 5 minutes after which a 30 7% solution of NH-OH is added. The mixture is then concen Y / trated and the resulting residue is purified by reverse phase N chromatography to afford 0.071 g of the desired product as V/ the ammonium salt. "H NMR (CDOD): 8 7.29-6.87 (n, 10H), 5.38–5.30 (m, 1H), 4.37-4.30 (m. 1H), 3.42-2.74 (m, H 35 6H), 2.38-2.33 (m, 3H), 1.34-1.28 (m, 3H). Category VI of the present disclosure relates to 2-(thiazol N^O 2-yl) compounds having the formula: )- 40 C

31 Reagents and conditions; (c) (i) tin (II) chloride, EtOH; (ii) SO3-pyridine, NH4OH:rt, 18 hr. 45

Example 12 4-(S)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4- 50 oxadiazol-5-yl)-3-phenylpropanamido wherein R', R, R, and L are further defined herein in Table ethylphenylsulfamic acid (31) XIII herein below. TABLE XIII Preparation of ethyl-2-benzyl-3-(S)-1-(4-ethylthiazol-2- 55 yl)-2-(4-nitrophenyl)-ethylamino-3-oxopropanoate (29): To No. R2 R3 RI a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl) MS21 ethyl hydrogen thiophen-2-yl ethyl amine hydrobromide, 3, (0.406 g, 1.13 mmol), 2-ben MS22 ethyl hydrogen thiazol-2-yl Zyl-3-ethoxy-3-oxopropanoic acid (0.277 g) and 1-hydroxy MS23 ethyl hydrogen oxazol-2-yl MS24 ethyl hydrogen isoxazol-3-yl benzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF (10 mL) 60 MS25 ethyl hydrogen imidazol-2-yl at 0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodi MS26 ethyl hydrogen isoxazol-3-yl imide (EDCI) (0.240 g, 1.25 mmol) followed by diisopropy M527 ethyl hydrogen oxazol-4-yl MS28 ethyl hydrogen isoxazol-4-yl lethylamine (DIPEA) (0.306 g). The mixture is stirred at 0°C. MS29 ethyl hydrogen thiophen-4-yl for 30 minutes then at room temperature overnight. The reac MS30 ethyl hydrogen thiazol-4-yl tion mixture is diluted with water and extracted with EtOAc. 65 MS31 ethyl methyl methyl The combined organic phase is washed with 1 Naqueous HCl, MS32 ethyl methyl ethyl 5% aqueous NaHCO, water and brine, and dried over US 8,883,832 B2 91 92 TABLE XIII-continued -continued No. R2 R3 RI y / M533 ethyl methyl propyl O O N O MS34 ethyl methyl iso-propy \/ HN M535 ethyl methyl butyl HO1 NN MS36 ethyl methyl phenyl H M537 ethyl methyl benzyl O MS38 ethyl methyl 2-fluorophenyl 33 MS39 ethyl methyl 3-fluorophenyl 10 MS40 ethyl methyl 4-fluorophenyl Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH. MS41 phenyl hydrogen methyl MS.42 phenyl hydrogen ethyl MS43 phenyl hydrogen propyl MS44 phenyl hydrogen iso-propy 15 Example 13 MS45 phenyl hydrogen butyl MS46 phenyl hydrogen phenyl (S)-4-2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbu MS47 phenyl hydrogen benzyl tanamido)ethyl-phenylsulfamic acid (33) MS48 phenyl hydrogen 2-fluorophenyl MS49 phenyl hydrogen 3-fluorophenyl Preparation of (S) N-1-(4-ethylthiazol-2-yl)-2-(4-nitro M550 phenyl hydrogen 4-fluorophenyl phenyl)ethyl-4-oxo-4-phenylbutanamide (32): 3-Benzoyl M551 hiophen-2-yl hydrogen methyl propionic acid (0.250 g) is dissolved in CHCl (5 mL), M552 hiophen-2-yl hydrogen ethyl N-methyl imidazole (0.333 mL) is added and the resulting M553 hiophen-2-yl hydrogen propyl solution is cooled to 0°C. after which a solution of thionyl MSS4 hiophen-2-yl hydrogen iso-propy 25 M555 hiophen-2-yl hydrogen butyl chloride (0.320 g) in CHCl (2 mL) is added dropwise. After M556 hiophen-2-yl hydrogen phenyl 0.5 hours (S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)etha M557 hiophen-2-yl hydrogen benzyl namine, 3, (0.388 g) is added. The reaction is stirred for 18 M558 hiophen-2-yl hydrogen 2-fluorophenyl hours at room temperature and then concentrated in vacuo. M559 hiophen-2-yl hydrogen 3-fluorophenyl The resulting residue is dissolved in EtOAc and washed with MS60 hiophen-2-yl hydrogen 4-fluorophenyl 30 1N HCl and brine. The solution is dried over NaSO filtered, and concentrated and the crude material purified over silica to afford 0.415 g of the desired product. The compounds encompassed within Category VI of the Preparation of (S)-4-2-(4-ethylthiazol-2-yl)-2-(4-oxo-4- present disclosure can be prepared by the procedure outlined phenylbutanamido)-ethylphenylsulfamic acid (33): (S) N 35 1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl-2,3-diphe in Scheme XII and described in Example 13 herein below. nyl-propanamide, 32, (0.2g) is dissolved in MeCH (15 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The Scheme VI reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure. The crude 40 product is dissolved in pyridine (5 mL) and treated with SS. Y / SO-pyridine (0.153 g). The reaction is stirred at room tem N -e- perature for 5 minutes after which a 7% solution of NH-OH is added. The mixture is then concentrated and the resulting NHHBr residue is purified by reverse phase chromatography to afford ON 45 0.090 g of the desired product as the ammonium salt. "H 3 NMR (CDOD) & 8.68 (d. 1H, J=8.2 Hz), 8.00 (d. 2H, J=7.2 Hz), 7.80-7.50 (m, 3H), 7.12 (s, 4H), 7.03 (s, 1H), 5.46-5.38 (m. 1H), 3.29-3.14 (m, 2H), 3.06-2.99 (m, 2H), 2.83 (q, 2H, SS Y / N O J=7.5 Hz), 2.69-2.54 (m, 2H), 1.33 (t, 3H, J–7.5 Hz). 50 The following are non-limiting examples of compounds HN encompassed within Category II of the present disclosure. ON The intermediate nitro compounds of the following can be prepared by coupling the appropriate 4-oxo-carboxcylic acid O with intermediate 3 under the conditions described herein 32 55 above for the formation of intermediate 4 of scheme I. Reagents and conditions: (a) 3-benzoylpropionic acid, SOCl2, N-Methyl imidazole, CH2Cl2; rt, 18 hr.

O)-N S Y / O. O 60 s O V/ -e- S HN O HN HO1 SN O ON O 65 32

US 8,883,832 B2 95 96 The first aspect of Category VII of the present disclosure -continued relates to 2-(thiazol-2-yl) compounds having the formula:

ON r 10 H1 NR

O

15 wherein non-limiting examples of R', R, and Rare further HO1 S NN HN O described herein below in H N TABLE XIV H1 35 No. R2 R3 R Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH. NS61 methyl hydrogen phenyl N562 methyl hydrogen benzyl N563 methyl hydrogen 2-fluorophenyl NS64 methyl hydrogen 3-fluorophenyl N565 methyl hydrogen 4-fluorophenyl 25 NS66 methyl hydrogen 2-chlorophenyl Example 14 N567 methyl hydrogen 3-chlorophenyl NS68 methyl hydrogen 4-chlorophenyl N569 ethyl hydrogen phenyl (S)-4-(2-(3-Benzylureido)-2-(4-ethylthiazol-2-yl) N570 ethyl hydrogen benzyl ethyl)phenylsulfamic acid (35) N571 ethyl hydrogen 2-fluorophenyl 30 N572 ethyl hydrogen 3-fluorophenyl N573 ethyl lydrogen 4-fluorophenyl Preparation of (S)-1-benzyl-3-1-(4-ethylthiazol-2-yl)-2- N574 ethyl hydrogen 2-chlorophenyl N575 ethyl hydrogen 3-chlorophenyl (4-nitrophenyl)ethylurea (34): To a solution of 1-(S)-(4-eth N576 ethyl hydrogen 4-chlorophenyl ylthiazol-2-yl)-2-(4-nitrophenyl)ethylamine hydrobromide, N577 thiene-2-yl hydrogen phenyl 35 3, (0.360 g, 1 mmol) and EtN (0.42 mL, 3 mmol) in 10 mL N578 thiene-2-yl hydrogen benzyl N579 thiene-2-yl hydrogen 2-fluorophenyl CHCl is added benzyl isocyanate (0.12 mL, 1 mmol). The N58O thiene-2-yl hydrogen 3-fluorophenyl mixture is stirred at room temperature for 18 hours. The NS81 thiene-2-yl hydrogen 4-fluorophenyl product is isolated by filtration to afford 0.425 g (96% yield) N582 thiene-2-yl hydrogen 2-chlorophenyl N583 thiene-2-yl hydrogen 3-chlorophenyl of the desired product which is used without further purifica NS84 thiene-2-yl hydrogen 4-chlorophenyl 40 tion. Preparation of (S)-4-(2-(3-benzylureido)-2-(4-ethylthi azol-2-yl)ethyl)phenylsulfamic acid (35): (S)-1-benzyl-3-1- The compounds encompassed within Category VII of the (4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylurea, 34 (0.425 present disclosure can be prepared by the procedure outlined g) is dissolved in MeCH (4 mL). A catalytic amount of Pd/C in Scheme XIII and described in Example 14 herein below. 45 (10% w/w) is added and the mixture is stirred under a hydro gen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITETM and the solvent is removed under Scheme XIII reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO-pyridine (0.220g). The reac $1 N 50 tion is stirred at room temperature for 5 minutes after which a S 7% solution of NH-OH is added. The mixture is then concen N trated and the resulting residue is purified by reverse phase NHHBr chromatography to afford 0.143 g of the desired product as ON the ammonium salt. "H NMR (CDOD) & 7.32-7.30 (m. 2H), 55 7.29-7.22 (m,3H), 7.12-7.00 (m, 4H), 6.84 (d. 1H, J–8.1 Hz), 3 S y / 5.35-5.30 (m, 1H), 4.29 (s. 2H), 3.27-3.22 (m,3H), 3.11-3.04 S. (m,3H), 2.81 (q, 2H, J=10.2, 13.0 Hz), 1.31 (t,3H, J–4.5Hz). N The following is a non-limiting examples of compounds 60 encompassed within the first aspect of Category VII of the ON present disclosure. N 4-(S)-2-(2-Ethylthiazol-4-yl)-2-(3-(R)-methoxy-1-oxo H1 CO 3-phenylpropan-2-yl)ureidolethylphenylsulfamic acid: "H 34 NMR (CDOD) & 7.36-7.26 (m, 3H), 7.19-7.17 (m, 2H), Reagents and conditions: (a) benzyl isocryanate, TEA, CH2Cl2; rt, 18 hr, 65 7.10-7.06 (m, 2H), 6.90-6.86 (m, 3H), 5.12-5.06 (m, 1H), 4.60-4.55 (m. 1H), 3.69 (s.3H)3.12-2.98 (m, 6H), 1.44-1.38 (m, 3H).

US 8,883,832 B2 101 102 -continued -continued S S S

X-O NaO1\,& NX-CH, V/ s 40 HO1 S n N HNN '- Reagents and conditions: (a)Na2SO3.H2O; microwave (a 200°C., 20 min. H sO S

10 S M NaO1Yu NX-in 40 39 S Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH. S A 15 C1YU NX-CH 41 Reagents and conditions; (b) PCls, POCl3: 50° C., 3 hrs. Example 16 {4-(S)-2-Phenylmethanesulfonylamino-2-(2- thiophen-2-ylthiazol-4-yl)ethylphenylsulfamic acid Example 17 (39) (2-Methylthiazol-4-yl)methanesulfonyl chloride (41) Preparation of (S) N-(2-(4-nitrophenyl)-1-(2-(thiophen 25 2-yl)thiazol-4-yl)ethyl-1-phenylmethanesulfonamide (38): Preparation of sodium (2-methylthiazol-4-yl)methane To a suspension of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthi sulfonate (40): 4-Chloromethyl-2-methylthiazole (250 mg. azol-4-yl)ethylamine, 8, (330 mg. 0.80 mmol) in CHCl2 (6 1.69 mmol) is dissolved in HO (2 mL) and treated with mL) at 0°C. is added diisopropylethylamine (0.30 mL, 1.6 sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is mmol) followed by phenylmethanesulfonyl chloride (167 30 subjected to microwave irradiation for 20 minutes at 200° C. mg, 0.88 mmol). The reaction mixture is stirred at room The reaction mixture is diluted with HO (30 mL) and washed temperature for 14 hours. The mixture is diluted with CHCl, with EtOAc (2x25 mL). The aqueous layer is concentrated to and washed with sat. NaHCOs followed by brine, dried afford 0.368g of the desired product as a yellow solid. LC/MS (NaSO), filtered and concentrated in vacuo. The resulting ESI+ 194 (M+1, free acid). residue is purified over silica to afford 210 mg of the desired 35 Preparation of (2-methylthiazol-4-yl)methanesulfonyl product as a white Solid. chloride (41): Sodium (2-methylthiazol-4-yl)methane sulfonate, 40. (357 mg, 1.66 mmol) is dissolved in phospho Preparation of{4-(S)-2-phenylmethanesulfonylamino-2- rous oxychloride (6 mL) and is treated with phosphorous (2-thiophen-2-ylthiazol-4-yl)ethylphenylsulfamic acid pentachloride (345 mg, 1.66 mmol). The reaction mixture is (39): (S) N-(2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thia 40 stirred at 50° C. for 3 hours, then allowed to cool to room zol-4-yl)ethyl-1-phenylmethanesulfonamide, 38, (210 mg. temperature. The solvent is removed under reduced pressure 0.41 mmol) is dissolved in MeOH (4 mL). A catalytic amount and the residue is re-dissolved in CHCl (40 mL) and is of Pd/C (10% w/w) is added and the mixture is stirred under washed with sat. NaHCO and brine. The organic layer is a hydrogen atmosphere 18 hours. The reaction mixture is dried over MgSO filtered, and the solvent removed in vacuo filtered through a bed of CELITETM and the solvent is 45 to afford 0.095g of the desired product as a brown oil. LC/MS removed under reduced pressure. The crude product is dis ESI+ 211 (M-1). Intermediates are obtained in sufficient solved in pyridine (12 mL) and treated with SO-pyridine purity to be carried forward according to Scheme IX without (197 mg, 1.23 mmol). The reaction is stirred at room tem the need for further purification. perature for 5 minutes after which a 7% solution of NH-OH is added. The mixture is then concentrated and the resulting 50 residue is purified by reverse phase chromatography to afford 0.060 g of the desired product as the ammonium salt. "H NMR (300 MHz, MeOH-d) & 7.52-7.63 (m, 6.70-728 (m, 11H), 4.75 (t, J=7.2 Hz, 1H), 3.95-4.09 (m, 2H), 3.20 (dd, J=13.5 and 7.8 Hz, 1H), 3.05 (dd, J=13.5 and 7.8 Hz, 1H). 55 1013770 Intermediates for use in Step (a) of Scheme XV can be conveniently prepared by the procedure outlined herein below in Scheme XVI and described in Example 17. 60

Scheme XVI (S)-(4-(2-((2-Methylthiazol-4-yl)methylsulfonamido)-2- S (2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenyl)sulfamic 65 acid: "H NMR (CDOD): 87.71-7.66 (m, 2H), 7.27-7.10 (m, UX-e- 7H), 4.87 (t, 1H, J–7.3 Hz), 4.30-4.16 (q, 2H, J=13.2 Hz), 3.34-3.13 (m, 2H), 2.70 (s.3H).

US 8,883,832 B2 107 108 unit for R' can be prepared by the procedure outlined in -continued Scheme XVII and described herein below in Example 18. S

O)-()N Scheme XVII O HN S ON Br S NH2 DXN 10 H3COC HN O -- He 44 or - NY S O CH X- y yC. O O N 15 H3C 7 \/ HN S S HO1 SN X2 H3COC N N 45 Reagents and conditions; (d) (i) SnCl2-2H2O, EtOH: reflux, 4 hours (ii) SO3-pyridine, NH2-HBr ON NH4OH. 42 Reagents and conditions: (a) CH3CN, reflux; 24 hr, 25 Example 18 (S)-4-(2-(2-Phenylthiazol-4-yl)-2-(4-(methoxycarbo S C nyl)thiazole-5-ylamino)ethyl)phenylsulfamic acid N -e- 30 (45) NH2 ON Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol 4-yl)ethanamine hydrobromide salt (42): A mixture of (S)- 42 tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcar S 35 bamate, 7, (1.62 g, 4.17 mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CHCN (5 mL) is refluxed for 24 hours. The O)N () reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which NCS forms is collected by filtration. The solid is dried under ON 40 vacuum to afford 1.2 g (67% yield) of the desired product. 43 LC/MS ESI+ 326 (M+1). Reagents and conditions; (b) thiophosgene, CaCO3, Preparation of (S)-4-(1-isothiocyanato-2-(4-nitrophenyl) ethyl)-2-phenylthiazole (43): To a solution of (S)-2-(4-nitro phenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide 45 salt, 42, (726 mg, 1.79 mmol) and CaCO (716 mg, 7.16 mmol) in HO (2 mL) is added CC1 (3 mL) followed by N -- thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at NCS room temperature for 18 hours then diluted with CHC1 and ON water. The layers are separated and the aqueous layer 50 extracted with CHC1. The combined organic layers are 43 washed with brine, dried (NaSO) and concentrated in vacuo COCH to a residue which is purified over silica (CHCl) to afford l He 480 mg (73%) of the desired product as a yellow solid. "H NC NMR (300 MHz, CDC1) & 8.15 (d. J=8.7 Hz, 2H), 7.97-7.99 S 55 (m. 2H), 743-7.50 (m, 3H), 7.34 (d. J=8.7 Hz, 2H), 7.15 (d. J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 HZ, 1H), 3.46 (dd, J=13.8 and 6.0 Hz). O)N () Preparation of (S)-methyl 5-1-(2-phenylthiazol-4-yl)-2- (4-nitrophenyl)-ethylaminothiazole-4-carboxylate (44): To HN S 60 a suspension of potassium tert-butoxide (89 mg, 0.75 mmol) in THF (3 mL) is added methyl isocyanoacetate (65uL, 0.68 ON D X mmol) followed by (S)-2-phenyl-4-(1-isothiocyanato-2-(4- H3COC N nitrophenyl)ethyl)thiazole, 43, (250 mg. 0.68 mmol). The 44 reaction mixture is stirred at room temperature for 2 hours Reagents and conditions; (c)KOtBu, THF:rt, 2 hr. 65 then poured into sat. NaHCO. The mixture is extracted with EtOAc (3x25 mL) and the combined organic layers are washed with brine and dried (NaSO) and concentrated in US 8,883,832 B2 109 vacuo. The crude residue is purified over silica to afford 323 -continued mg (~100% yield) of the desired product as a slightly yellow O solid. "H NMR (300 MHz, CDC1) & 8.09-8.13 (m, 2H), Br 7.95-798 (m,3H), 7.84 (d. J=1.2 Hz, 1H), 7.44-7.50 (m, 3H), -b- 7.28-7.31 (m, 2H), 7.96 (d. J=0.6 Hz, 1H), 4.71-4.78 (m, 1H), 3.92 (s, 3H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.45 (dd. J=13.8 and 6.0 Hz, 1H). H3CO Preparation of (S)-4-(2-(2-phenylthiazol-4-yl)-2-(4- (methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsul famic acid (45): (S)-methyl 5-1-(2-phenylthiazol-4-yl)-2-(4- 10 nitrophenyl)-ethylaminothiazole-4-carboxylate, 44 (323 N mg, 0.68 mmol) and tin(II) chloride (612 mg, 2.72 mmol) are HN S dissolved in EtOH and the solution is brought to reflux. The Solvent is removed in vacuo and the resulting residue is dis 15 solved in EtOAc. A saturated solution of NaHCO is added N / and the Solution is stirred 1 hour. The organic layer is sepa rated and the aqueous layer extracted twice with EtOAc. The combined organic layers are dried (Na2SO4), filtered and concentrated to a residue which is dissolved in pyridine (10 mL) and treated with SO-pyridine (130 mg,0.82 mmol). The HCO reaction is stirred at room temperature for 5 minutes after 48 which a 7% solution of NH-OH is added. The mixture is then Reagents and conditions; (b) CHCN, reflux, 24hr. concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.071 g of the desired prod 25 S uct as the ammonium salt "H NMR (300 MHz, MeOH-d) & 7.97-8.00 (m,3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7.03-7.13 N (m, 4H), 4.74 (t, J=6.6 Hz, 1H), 3.88 (s.3H), 3.28-3.42 (m, 2H). HN S Compounds according to the first aspect of Category IX 30 ON s -e- which comprise a substituted or unsubstituted thiazol-2-yl N / unit for R' can be prepared by the procedure outlined in Scheme XVIII and described herein below in Example 19. Intermediate 46 can be prepared according to Scheme II and Example 2 by Substituting cyclopropane-carbothioic acid 35 amide for thiophen-2-carbothioic acid amide. H3CO 48 Scheme XVIII 40 1 N O O N -e- \/ HN S 45 HO1 n N NH2-HBr ON N 46

50 N

HN NH2 HCO 49 S 55 Reagents and conditions; (c) (i) H2:PdC, MeOH; (ii)SO3-pyridine, NH4OH. 47 Reagents and conditions: (a)thiophosgene, CaCO3, CC14H2O; rt, 18 hr, S Example 19 60 N 4-(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[4-(3-meth -- oxyphenyl)thiazol-2-ylaminolethylphenylsulfamic HN NH2 acid (50)

S 65 Preparation of (S)-1-(1-(2-cyclopropylthiazol-4-yl)-2-(4- 47 nitrophenyl)ethyl)-thiourea (47): To a solution of (S)-1-(2- cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethan-amine

US 8,883,832 B2 117 118 -continued -continued O S Br M N 5 HN O HN --

ON Y ON S- S CH3 O CH NN,M 10 54 HC S 51 Reagents and conditions; (b) 48% HBr, THF: 0°C., 1.5 hr. NX- y O O O 15 Br \/ HN S NH2 HO1 NN S H X-CH N-N- N ON N. -- He 55 Reagents and conditions: (f)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH. "SkCH3 HC 51 Example 20 25 (S)-4-(2-(5-Methyl-1,3,4-thiadiazol-2-ylamino)-2-(2- N C phenylthiazol-4-yl)ethyl)phenylsulfamic acid (55) Preparation of 3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl ON 30 carbamic acid tert-butyl ester (50): To a 0° C. solution of 52 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propi Reagents and conditions; (c) CH3CN; reflux 2 hr. onic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added drop wise triethylamine (0.61 mL, 4.4 mmol) followed by iso 35 butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0°C. for 20 minutes then filtered. The N s filtrate is treated with an ether solution of diazomethane (~16 NH2 mmol) at 0°C. The reaction mixture is stirred at room tem ON perature for 3 hours and concentrated. The residue is dis 52 40 solved in EtOAc and washed successively with water and brine, dried (NaSO), filtered and concentrated in vacuo. The resulting residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a N slightly yellow solid. "H NMR (300 MHz, CDC1) & 8.16 (d. NCS 45 J=8.7 Hz, 2H), 7.39 (d. J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d. ON J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 53 3.06 (dd, J=13.5 and 6.9 HZ, 1H), 1.41 (s, 9H). Reagents and conditions; (d) thiophosgene, CaCO3, CC14H2O; rt, 18 hr, Preparation of 3-bromo-1-(4-nitro-benzyl)-2-oxo-pro S pyl-carbamic acid tert-butyl ester (51): To a 0°C. solution of 50 3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl-carbamic acid tert-butyl ester, 50, (0.350 g, 1.04 mmol) in THF (5 mL) is / -e- added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The NCS reaction mixture is stirred at 0°C. for 1.5 hours and quenched ON 55 at 0° C. with saturated aqueous NaCO. The mixture is 53 S extracted with EtOAc (3x25 mL) and the combined organic extracts are washed with brine, dried (NaSO), filtered and 2 concentrated in vacuo to afford 0.400g of the desired product N that is used in the next step without further purification. "H 60 NMR (300 MHz, CDC1,) & 8.20 (d. J=8.4 Hz, 2H), 7.39 (d. HN S ON J=8.4 Hz, 2H), 5.06 (d. J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s. 2H), 1.42 (s, 9H). O)-cis Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol 5 4 4-yl)ethanamine hydrobromide salt (52): A mixture of Reagents and conditions: (e) (i) CH3C(O)NHNH2, EtOH: reflux, 2 hr., (ii) POCl3, 65 3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl-carbamic acid rt 18 hr 50°C, 2 hr. tert-butyl ester, 51 (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol), in CHCN (5 mL) is refluxed for 24 US 8,883,832 B2 119 120 hours. The reaction mixture is cooled to room temperature -continued and diethyl ether (50 mL) is added to the solution and the precipitate that forms is collected by filtration. The solid is dried under vacuum to afford 1.059 g (63%) of the desired product. ESI+ MS 326 (M+1). O) { Preparation of (S)-4-1-isothiocyanato-2-(4-nitrophenyl)- ethyl-2-phenylthiazole (53): To a solution of (S)-2-(4-nitro ON phenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide N salt, 52, (2.03 g, 5 mmol) and CaCO (1 g, 10 mmol) in NH2 CCl/water (10:7.5 mL) is added thiophosgene (0.46 mL, 6 10 56 mmol). The reaction is stirred at room temperature for 18 Reagents and conditions: (a)thiophosgene, CaCO3, CC14H2O; rt, 18 hr, hours then diluted with CHC1 and water. The layers are separated and the aqueous layer extracted with CHCl2. The combined organic layers are washed with brine, dried 15 (NaSO4) and concentrated in vacuo to a residue that is puri fied over silica (CH,Cl) to afford 1.71 g (93% yield) of the desired product. ESI+ MS 368 (M+1). Preparation of (S)-5-methyl-N-2-(4-nitrophenyl)-1-(2- ON orN -- phenylthiazol-4-yl)ethyl-1,3,4-thiadiazol-2-amine (54): A NH2 Solution of (S)-4-1-isothiocyanato-2-(4-nitrophenyl)-ethyl 56 2-phenylthiazole, 53, (332 mg, 0.876 mmol) and acetic hydrazide (65 mg. 0.876 mmol) in EtOH (5 mL) is refluxed for 2 hours. The solvent is removed under reduced pressure, the residue is dissolved in POCl (3 mL) and the resulting 25 solution is stirred at room temperature for 18 hours after which the solution is heated to 50° C. for 2 hours. The solvent CH is removed in vacuo and the residue is dissolved in EtOAc (40 mL) and the resulting solution is treated with 1N NaOH until OCH the pH remains approximately 8. The solution is extracted 30 with EtOAc. The combined aqueous layers are washed with EtOAc, the organic layers combined, washed with brine, dried over MgSO, filtered, and concentrated in vacuo to afford 0.345 g (93% yield) of the desired product as a yellow solid. 'HNMR (CDC1,)8.09 (d. J=8.4 Hz, 2H), 7.91 (m, 2H), 35 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H), 3.59 (m, 2H), 2.49 X-O (s, 3H). ESI+ MS 424 (M+1). Preparation of (S)-4-2-(5-methyl-1,3,4-thiadiazol-2- ylamino)-2-(2-phenylthiazol-4-yl)ethylphenylsulfamic acid ON or (55): (S)-5-Methyl-N-2-(4-nitrophenyl)-1-(2-phenylthi 40 N / azol-4-yl)ethyl-1,3,4-thiadiazol-2-amine, 54, (0.404 g. 0.954 mmol) is dissolved in MeOH (5 mL). Pd/C (50 mg, 10% w/w) is added and the mixture is stirred under a hydro gen atmosphere until the reaction is judged to be complete. The reaction mixture is filtered through a bed of CELITETM 45 and the solvent removed under reduced pressure. The crude HCO product is dissolved in pyridine (4 mL) and treated with 57 SO-pyridine (0.304 g, 1.91 mmol). The reaction is stirred at Reagents and conditions; (b) CHCN, reflux, 5 hours room temperature for 5 minutes after which a 7% solution of NH-OH (50 mL) is added. The mixture is then concentrated 50 and the resulting residue is purified by reverse phase prepara tive HPLC to afford 0.052 g (11% yield) of the desired prod uct as the ammonium salt. H NMR (CDOD): 8 8.00-7.97 (m. 2H), 7.51-7.47 (m, 3H), 7.23 (s, 1H), 7.11-7.04 (q, 4H, J=9.0 Hz), 5.18 (t, 1H, J–7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 55 3H). ESI-MS 472 (M-1). Scheme XX or O S S - - - 60 NX-O N -e- NH2-HBr ON 65 57 US 8,883,832 B2 121 122 -continued unit for R' can be prepared by the procedure outlined in S S Scheme XXI and described herein below in Example 22. Intermediate 39 can be prepared according to Scheme XVII X-O and Example 18. V A” Ho-1N N "N- S Scheme XXI N / S 10

N -e-

NCS HCO ON 15 53 58 Reagents and conditions; (c) (i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH: rt, 18 hr.

N Example 21 HN N 4-(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)- ON N 2-2-(thiophen-2-yl)thiazol-4-yl) O / ethylphenylsulfamic acid (58) 25 Preparation of (S)-1-1-(thiophen-2-ylthiazol-4-yl)-2-(4- nitrophenyl)ethyl-thiourea (56): To a solution of (S)-2-(4- nitrophenyl)-1-(thiophen-2-ylthiazol-4-yl)ethanamine HCO hydrobromide salt, 8, (1.23g, 2.98 mmol) and CaCO (0.597 30 g, 5.96 mmol) in CCl/water (10 mL/5 mL) is added thio 60 phosgene (0.412 g, 3.58 mmol). The reaction is stirred at Reagents and conditions: (a) 1-azido-1-(3-methoxyphenyl)ethanone, PPh3, dioxane, room temperature for 18 hours then diluted with CHC1 and 90° C. 20 minutes, water. The layers are separated and the aqueous layer extracted with CHC1. The combined organic layers are 35 washed with brine, dried (NaSO) and concentrated in vacuo to a residue which is Subsequently treated with ammonia (0.5M in 1,4-dioxane, 29.4 mL, 14.7 mmol) which is purified over silica to afford 0.490 g of the desired product as a 40 orX-() red-brown solid. ESI+ MS 399 (M+1). Preparation of 4-(2-methoxyphenyl)-N-(S)-2-(4-nitro ON r) phenyl)-1-2-(thiophen-2-yl)thiazol-4-yl)ethylthiazol-2- amine (57): (S)-1-1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitro phenyl)ethyl-thiourea, 56, (265 mg 0.679 mmol) is treated with bromo-2'-methoxyacetophenone (171 mg, 0.746 mmol) 45 to afford 0.221 g of the product as a yellow solid. ESI+ MS 521 (M+1). H3CO Preparation on 4-(S)-2-[4-(2-methoxyphenyl)thiazol-2- 60 ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl S ethylphenylsulfamic acid (58): 4-(2-methoxyphenyl)-N- 50 (S)-2-(4-nitrophenyl)-1-2-(thiophen-2-yl)thiazol-4-yl) ethylthiazol-2-amine, 57. (0.229 g) is dissolved in 12 mL O O O)N () MeOH. A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere for 18 \/ HN hours. The reaction mixture is filtered through a bed of 55 HO1 NNH N CELITETM and the solvent is removed under reduced pres b. M sure. The crude product is dissolved in 6 mL pyridine and treated with SO-pyridine (140 mg). The reaction is stirred at room temperature for 5 minutes after which 10 mL of a 7% solution of NH-OH is added. The mixture is then concen 60 trated and the resulting residue is purified by reverse-phase chromatography to afford 0.033 g of the desired product as HCO the ammonium salt. HMRCDOD): 8 7.96-7.93 (m. 1H), 61 7.60-7.55 (m, 2H), 7.29-7.23 (m, 1H), 7.18-6.95 (m, 9H), Reagents and conditions; (b)(i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH:rt, 18 hr. 5.15 (t, 1H, J=6.9 Hz), 3.90 (s, 3H), 3.35-3.24 (m, 2H). 65 Compounds according to the second aspect of Category IX which comprise a substituted or unsubstituted oxazol-2-yl

US 8,883,832 B2 131 132 -continued atmosphere 18 hours. The reaction mixture is filtered through O S a bed of CELITETM and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) X-O and treated with SO-pyridine (0.157 g). The reaction is stirred at room temperature for 5 minutes after which a 7% HN O -e- solution of NH-OH is added. The mixture is then concen ON trated and the resulting residue can be purified by reverse C phase chromatography to afford the desired product as the ammonium salt. 10 The second aspect of Category X of the present disclosure relates to compounds having the formula: 63 O S 15

\/ HN O Y-R HO1 NN H O. O O C V/ Ho-1N H1NR, h 64 25 Reagents and conditions; (c) (i) H2:PdC, MeOH; (ii) SO3-pyridine, NH4OH, rt, 18 hr. wherein R' is aryland R and Rare further described herein below in Table XX.

TABLE XX Example 23 30 4-(S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2- No. R2 R3 R (thiophen-2-yl)oxazol-4-yl)ethyl)phenylsulfamic acid (64) T833 methyl hydrogen phenyl 35 Preparation of (S)-2-(4-nitrophenyl)-1-(thiophen-2-yl) T834 methyl hydrogen benzyl oxazol-4-yl)ethanamine hydrobromide salt (62): A mixture T835 methyl hydrogen 2-fluorophenyl of (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2- T836 methyl hydrogen 3-fluorophenyl ylcarbamate, 7, (38.7g, 100 mmol), and thiophen-2-carboxa T837 methyl hydrogen 4-fluorophenyl mide (14g, 110 mmol) (available from Alfa Aesar) in CHCN 40 T838 methyl hydrogen 2-chlorophenyl (500 mL) is refluxed for 5 hours. The reaction mixture is T839 methyl hydrogen 3-chlorophenyl cooled to room temperature and diethyl ether (200 mL) is T840 methyl hydrogen 4-chlorophenyl added to the solution. The precipitate which forms is col lected by filtration. The solid is dried under vacuum to afford T841 ethyl hydrogen phenyl the desired product which can be used for the next step with 45 T842 ethyl hydrogen benzyl out purification. T843 ethyl hydrogen 2-fluorophenyl Preparation of 2-(3-chlorophenyl)-N-(S)-2-(4-nitrophe T844 ethyl hydrogen 3-fluorophenyl nyl)-1-2-(thiophen-2-yl)oxazol-4-yl)ethyl)acetamide (63): To a solution of (S)-2-(4-nitrophenyl)-1-(thiophen-2-yl)ox T845 ethyl hydrogen 4-fluorophenyl T846 ethyl hydrogen 2-chlorophenyl azol-4-yl)ethanamine HBr, 47. (3.15 g, 10 mmol) 3-chlo 50 rophenyl-acetic acid (1.70 g, 10 mmol) and 1-hydroxybenzo T847 ethyl hydrogen 3-chlorophenyl triazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 mL) at 0°C., T848 ethyl hydrogen 4-chlorophenyl is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide T849 thien-2-yl hydrogen phenyl (EDCI) (1.90 g, 10 mmol) followed by triethylamine (4.2 mL, T850 thien-2-yl hydrogen benzyl 30 mmol). The mixture is stirred at 0°C. for 30 minutes then 55 at room temperature overnight. The reaction mixture is T851 thien-2-yl hydrogen 2-fluorophenyl diluted with water and extracted with EtOAc. The combined T852 thien-2-yl hydrogen 3-fluorophenyl organic phase is washed with 1N aqueous HCl, 5% aqueous T853 thien-2-yl hydrogen 4-fluorophenyl NaHCO, water and brine, and dried over NaSO. The sol T854 thien-2-yl hydrogen 2-chlorophenyl vent is removed in vacuo to afford the desired product which 60 T855 thien-2-yl hydrogen 3-chlorophenyl is used without further purification. Preparation of ((S)-2-(2-(3-chlorophenyl)acetamido)-2- T856 thiene-2-yl hydrogen 4-chlorophenyl (2-(thiophen-2-yl)oxazol-4-yl)ethyl)phenylsulfamic acid (64): 2-(3-chlorophenyl)-N-(S)-2-(4-nitrophenyl)-1-(2- (thiophen-2-yl)oxazol-4-yl)ethyl)acetamide, 63, (3 g) is dis 65 Compounds according to the second aspect of Category X solved in MeOH (4 mL). A catalytic amount of Pd/C (10% can be prepared by the procedure outlined in Scheme XXIII w/w) is added and the mixture is stirred under a hydrogen and described herein below in Example 24. US 8,883,832 B2 133 134 -continued Scheme XXIII O Ny / V / HO1. S n N HN O ON N. -- O K.CH 10 CH 67 Reagents and conditions; (c) (i) H2:PdC, MeOH; (ii)SO3-pyridine, NH4OH, rt, 18 hr. 15

Example 24 {4-2-(S)-(4-Ethyloxazol-2-yl)-2-phenylacetylami N noethyl-phenylsulfamic acid (67)

NH2-HBr Preparation of (S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophe ON nyl)ethanamine (65): A mixture of 1-(S)-carbamoyl-2-(4- 65 25 nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1 (10 g, Reagents and conditions: (a) CH3CN; reflux, 2 hr. 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1 mL, 36 mmol) in CHCN (500 mL) is refluxed for 18 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms 30 is removed by filtration and is used without further purifica S. Y / tion. N Preparation of N-1-(4-ethyloxazol-2-yl)-2-(4-nitrophe NH2-HBr nyl)ethyl)-2-phenyl-acetamide (66): To a solution of (S)-1- ON (4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine, 65, (2.9 65 35 g, 11 mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hy droxybenzotriazole (HOBt) (0.94g, 7.0 mmol) in DMF (100 mL) at 0°C., is added 1-(3-dimethylamino-propyl)-3-ethyl S. carbodiimide (EDCI) (2.68 g. 14 mmol) followed by triethy NY / lamine (6.0 mL, 42 mmol). The mixture is stirred at 0°C. for 40 30 minutes then at room temperature overnight. The reaction HN O mixture is diluted with water and extracted with EtOAc. The ON combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO, water and brine, and dried over NaSO. The solvent is removed in vacuo to afford the desired product 45 which is used without further purification. Preparation of 4-2-(S)-(4-ethyloxazol-2-yl)-2-pheny 66 lacetylaminoethyl-phenylsulfamic acid (67): N-1-(4- ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl-2-phenyl-aceta mide, 66, (0.260 g) is dissolved in MeOH (4 mL). A catalytic 50 amount of Pd/C (10% w/w) is added and the mixture is stirred Reagents and conditions; (b) CHCO2H, EDCL, HOBt, DDPEA, DMF; rt, 18 hr. under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure. The crude product is dis solved in pyridine (12 mL) and treated with SO-pyridine 55 (0.177 g, 1.23). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH-OH (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford the desired product as the ammonium salt. ON 60 Methods The disclosed compounds can be used to prevent, abate, minimize, control, and/or lessen tumor metastasis in humans 65 and animals. The disclosed compounds can also be used to 66 slow the rate of primary tumor growth. The disclosed com pounds when administered to a subject in need of treatment US 8,883,832 B2 135 136 can be used to stop the spread of cancer cells. As such, the Cancer. Non-Small Cell: Lung Cancer, Small Cell; Lym compounds disclosed herein can be administered as part of a phoma, AIDS-Related; Lymphoma, Burkitt; Lymphoma, combination therapy with one or more drugs or other phar Cutaneous T-Cell; Lymphoma, Hodgkin, Lymphoma, Non maceutical agents. When used as part of the combination Hodgkin; Lymphoma, Primary Central Nervous System; therapy, the decrease in metastasis and reduction in primary 5 Macroglobulinemia, Waldenström; Malignant Fibrous His tumor growth afforded by the disclosed compounds allows tiocytoma of Bone and Osteosarcoma; Medulloblastoma; for a more effective and efficient use of any pharmaceutical or Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Car drug therapy being used to treat the patient. In addition, cinoma; Mesothelioma; Metastatic Squamous Neck Cancer control of metastasis by the disclosed compound affords the with Occult Primary: Mouth Cancer; Multiple Endocrine Subject a greater ability to concentrate the disease in one 10 Neoplasia Syndrome, (Childhood); Multiple Myeloma/ location. Plasma Cell Neoplasm: Mycosis Fungoides; Myelodysplas Disclosed herein are methods for preventing metastasis of malignant tumors or other cancerous cells as well as to reduce tic Syndromes: Myelodysplastic/Myeloproliferative Dis the rate of tumor growth. The methods comprise administer eases; Myelogenous Leukemia, Chronic; Myeloid Leukemia, ing an effective amount of one or more of the disclosed 15 Adult Acute; Myeloid Leukemia, Childhood Acute; compounds to a subject diagnosed with a malignant tumor or Myeloma, Multiple; Myeloproliferative Disorders, Chronic; cancerous cells or to a Subject having a tumor or cancerous Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal cells. Cancer; Neuroblastoma; Non-Small Cell Lung Cancer; Oral Further disclosed herein is the use of the disclosed com Cancer; Oral Cavity Cancer; Oropharyngeal Cancer; pounds for making a medicament for preventing metastasis of Osteosarcoma and Malignant Fibrous Histiocytoma of Bone: malignant tumors or other cancerous cells and for slowing Ovarian Cancer: Ovarian Epithelial Cancer: Ovarian Germ tumor growth. Cell Tumor; Ovarian Low Malignant Potential Tumor; Pan The following are non-limiting examples of cancers that creatic Cancer; Pancreatic Cancer, Islet Cell Tumors; Papil can be treated by the disclosed methods and compositions: lomatosis; Parathyroid Cancer; Penile Cancer; Pharyngeal Acute Lymphoblastic; Acute Myeloid Leukemia; Adrenocor 25 Cancer; Pheochromocytoma; Pineal Parenchymal Tumors of tical Carcinoma; Adrenocortical Carcinoma, Childhood; Intermediate Differentiation; Pineoblastoma and Supratento Appendix Cancer; Basal Cell Carcinoma; Bile Duct Cancer, rial Primitive Neuroectodermal Tumors; Pituitary Tumor; Extrahepatic; Bladder Cancer; Bone Cancer; Osteosarcoma Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary and Malignant Fibrous Histiocytoma; Brain Stem Glioma, Blastoma; Primary Central Nervous System Lymphoma; Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem 30 Glioma, Childhood; Brain Tumor, Central Nervous System Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Atypical Teratoid/Rhabdoid Tumor, Childhood: Central Ner Renal Pelvis and Ureter, Transitional Cell Cancer; Respira vous System Embryonal Tumors; Cerebellar Astrocytoma; tory Tract Carcinoma Involving the NUT Gene on Chromo Cerebral Astrocytoma/Malignant Glioma; Craniopharyn some 15: Retinoblastoma; Rhabdomyosarcoma; Salivary gioma: Ependymoblastoma; Ependymoma; Medulloblas 35 Gland Cancer, Sarcoma, Ewing Family of Tumors; Sarcoma, toma; Medulloepithelioma; Pineal Parenchymal Tumors of Kaposi; Sarcoma, Soft Tissue: Sarcoma, Uterine; Sézary Intermediate Differentiation; Supratentorial Primitive Neu Syndrome: Skin Cancer (Nonmelanoma); Skin Cancer roectodermal Tumors and Pineoblastoma; Visual Pathway (Melanoma); Skin Carcinoma, Merkel Cell: Small Cell Lung and Hypothalamic Glioma; Brain and Spinal Cord Tumors; Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Squa Breast Cancer; Bronchial Tumors; Burkitt Lymphoma; Car 40 mous Cell Carcinoma, Squamous Neck Cancer with Occult cinoid Tumor; Carcinoid Tumor, Gastrointestinal; Central Primary, Metastatic; Stomach (Gastric) Cancer; Supratento Nervous System Atypical Teratoid/Rhabdoid Tumor; Central rial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Nervous System Embryonal Tumors; Central Nervous Sys Cutaneous; Testicular Cancer; Throat Cancer; Thymoma and tem. Lymphoma; Cerebellar Astrocytoma; Cerebral Astrocy Thymic Carcinoma; Thyroid Cancer; Transitional Cell Can toma/Malignant Glioma, Childhood; Cervical Cancer; Chor 45 cer of the Renal Pelvis and Ureter; Trophoblastic Tumor, doma, Childhood; Chronic Lymphocytic Leukemia; Chronic Gestational; Urethral Cancer, Uterine Cancer, Endometrial; Myelogenous Leukemia; Chronic Myeloproliferative Disor Uterine Sarcoma; Vaginal Cancer; Vulvar Cancer; Walden ders; Colon Cancer, Colorectal Cancer, Craniopharyngioma; ström Macroglobulinemia; and Wilms Tumor. Cutaneous T-Cell Lymphoma; Esophageal Cancer, Ewing In Vivo Anti-Metastasis Study Family of Tumors: Extragonadal Germ Cell Tumor; Extrahe 50 A total of 50 NCr nu/nu male mice aged 5-6 weeks were patic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; selected for the following in vivo test. H460-GFP human Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric tumor cells were grown Subcutaneously in NCr nu/nu male (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Gas mice after which the resulting tumors were harvested. Sub trointestinal Stromal Tumor (GIST); Germ Cell Tumor, sequent to harvesting, recipient NCr nu/nu mice of this study Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell 55 had tumor fragments transplanted by Surgical orthotopic Tumor, Ovarian: Gestational Trophoblastic Tumor; Glioma: implantation (SOI). Each animal was anesthetized is iso Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral furane and the Surgical area was sterilized with iodine and Astrocytoma; Glioma, Childhood Visual Pathway and Hypo alcohol. A transverse incision approximately 1.5 cm long was thalamic: Hairy Cell Leukemia; Head and Neck Cancer; made in the left chest wall of the mice using a pair of Surgical Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans 60 Scissors. An intercostal incision was made between the third Cell; Hodgkin Lymphoma; Hypopharyngeal Cancer, Hypo and the fourth costa and the left lung was exposed. Two pieces thalamic and Visual Pathway Glioma: Intraocular Melanoma; of H460-GFP tumor fragments were transplanted to the sur Islet Cell Tumors; Kidney (Renal Cell) Cancer; Langerhans face of the lung with 8-0 surgical nylon suture. The chest wall Cell Histiocytosis; Laryngeal Cancer, Leukemia, Acute Lym was closed with 6-0 silk suture. The lung was re-inflated by phoblastic: Leukemia, Acute Myeloid; Leukemia, Chronic 65 the intrathoracic puncture using 3 cc syringe with 25 G1/2 Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, needle to draw out the remaining air in the chest cavity. The Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer; Lung chest wall was closed with 6-0 surgical silk sutures. All pro US 8,883,832 B2 137 138 cedures of the operation described above were performed body weights during the study were consistent over each with a 7x magnification microscope (Olympus) under HEPA group and did not show any effects due to the choice of filtered laminar flow hoods. treatment. The treated mice were divided into five groups containing As depicted in FIG. 6, treatment with a low dose of IL-2 in ten mice each. Group I (Control) received 100 uL the drug 5 combination with a high dose of D91 (O) significantly vehicle twice daily for 15 days. Group II received 15 mg/kg of reduced tumor volume versus control (D), whereas low dose taxol intravenously at days 6, 9, 12, and 15. Group III received of IL-2 (()) alone did not show measurable tumor volume 15 mg/kg of taxol intravenously at days 6, 9, 12, and 15 and 15 reduction at the termination of the study on day 22. FIG. 7 is mg/kg of 4-(S)-2-(S)-2-(methoxycarbonylamino)-3-phe a histogram representing the tumor Volume of animals receiv nyl-propanamido)-2-[2-(thiophen-2-yl)thiazol-4-yl 10 ing control (A), low dose IL-2 (B), and low dose IL-2/high dose D91 (C). FIG. 8 shows the effectiveness of treatments ethylphenylsulfamic acid, D91, (Test Compound) twice per with 40 mg/kg b.i.d. D91 (O) versus vehicle control (D) on day from day 3 to day 15. Group IV received 10 mg/kg of B16 melanoma tumor volume. taxol intravenously at days 6, 9, 12, and 15 and 15 mg/kg of Renal Cell Carcinoma the Test Compound twice per day from day 3 to day 15. Group 15 The effectiveness of the disclosed compounds as a treat V received 15 mg/kg of the Test Compound twice per day ment against renal cell carcinoma was studied. Balb/c mice from day 3 to day 15. All animals were sacrificed on day 28. (6-8 weeks-old, female, Taconic Farm) were inoculated with Each animal was checked twice a week for primary tumor Renca renal cancer cells (5x10 cells/site). On day 4 post and metastasis via GFP open imaging of the mediastinal inoculation, the mice were randomly divided into 4 groups (4 lymph nodes. No metastasis was found on any other organs. mice/group) and treated (5 day/week, M-F) with vehicle con Six mice from the control group died before the end of the trol (bid, i.p.), IL-2 (100,000 IU/mouse, bid, i.p.), D91 (40 study, but were evaluated for tumor and/or cellular metastasis. mg/kg, bid, s.c., administered 30 minutes prior to IL-2) or the Table XXI below summarizes the results of this in vivo combination. Tumor volumes were recorded. metastasis study. As depicted in FIG. 1 and FIG. 2, 4-(S)-2-(S)-2-(meth 25 oxycarbonylamino)-3-phenyl-propanamido)-2-2- TABLE XXI (thiophen-2-yl)thiazol-4-yl)ethylphenylsulfamic acid, D91, Mouse No. Group I Group II Group III Group IV Group V significantly redcued renal tumor growth and was as effective Evidence of Metastasis as IL-2 in reducing tumor Volume. In addition, the combina tion of D91 and IL-2 further reduced tumor volume. 1 Yes No No No No 30 Pancreatic Cancer 2 Yes No No Yes Yes 3 No Yes No No No Pancreatic cancer is a malignant neoplasm of the pancreas. 4 Yes No No No No Each year in the United States, about 42,000 individuals are 5 Yes No No No No diagnosed with this condition and 35,000 die from the disease 6 Yes No No No Yes 7 Yes No No No No (“Pancreatic Cancer National Cancer Institute, U.S. 35 8 No No No No No National Institutes of Health' (2009)). The prognosis is rela 9 Yes No No Yes No tively poor but has improved; the three-year survival rate is 10 Yes No No No No now about thirty percent, but less than 5 percent of those # mice with 8 1 O 2 2 diagnosed are still alive five years after diagnosis. Complete metastases remission is still rather rare (Ghaneh Pet al., (August 2007). 40 “Biology and management of pancreatic cancer. Gut 56 (8): In Vivo Anticancer Studies 1134-52). B16 Melanoma The effectiveness of the disclosed compounds as a treat The effectiveness of the disclosed compounds as a treat ment for pancreatic cancer was investigated. 60 NCr nu/nu ment for melanoma was studied. C57BL/6 mice (6-8 weeks males, 5-6 weeks old were transplanted by Surgical orthotopic old, female, Taconic Farm) were inoculated with B16 mela 45 implantation (SOI) using MiaPaca-2-RFP tumor fragments noma cells (5x10" cells/site, s.c.). On day 4 post-inoculation, harvested from Stock animals. The animals were anesthetized the mice (5/group) were treated (5 day/week, M-F) with with isoflurane and the Surgical area was sterilized using vehicle control (bid, i.p.), low dose of IL-2 (100,000 iodine and alcohol. An incision approximately 1.5 cm long IU/mouse, bid, i.p.), high dose of IL-2 (300,000 IU/mouse, was made in the left upper abdomen of the nude mouse using bid, i.p.), or their combinations with D91 (40 mg/kg, bid, s.c., 50 a pair of Surgical Scissors. The pancreas was exposed, and administered 30 minutes prior to IL-2). Tumor volumes were then two pieces of the MiaPaca-2-RFP tumor fragments of recorded. In a separate experiment, mice similarly inoculated 2mm were transplanted to the mouse pancreas with 8-0 sur with B16 melanoma cells were treated (5 day/week, M-F) gical Sutures (nylon) after the capsule of the transplantation with vehicle control (bid, i.p.), IL-2 (300,000 IU/mouse, bid, site had been stripped. The abdomen was closed with 6-0 i.p.), high dose of D91 (40 mg/kg, bid, s.c.), low dose of D91 55 Surgical Sutures (silk). All procedures of the operation (10 mg/kg, bid, s.c.) or the combination of IL-2 (300,000 described above were performed with a 7x magnification IU/mouse, bid, i.p.) with low dose of D91 (10 mg/kg, bid, s.c., microscope (Olympus) under HEPA filtered laminar flow administered 30 minutes prior to IL-2). Tumor volumes were hoods. recorded. Dosing of the animals began three days following tumor As depicted in FIG. 3, although the high dose of IL-2 (()) 60 implantation. The high dose of gemcitabine was 150 mg/kg. reduced tumor Volume as expected versus control (D), treat The low dose of gemcitabine was 100 mg/kg. D91 was given ment with high dose of IL-2 in combination with high dose of at 20 mg/kg. Gemcitabine was give i.p. whereas D91 was D91 (O) significantly reduced tumor volume as compared to given s.c. high dose of IL-2 (Q) alone. FIG. 4 is a histogram represent The animals were divided into the following groups often ing the tumor Volume of animals receiving control (A), high 65 animals each as depicted in Table XXII. As indicated in Table dose IL-2 (B), and high dose IL-2/high dose D91 (C). The XXII, D91 was administered twice daily whereas gemcitab data depicted in FIG. 5 indicate that the increase in animal ine was given twice weekly. US 8,883,832 B2 139 140 TABLE XXII Another aspect relates a composition comprising: a) an effective amount of one or more compounds dis Group Agent Dose Schedule closed herein; and 1 vehicle 100 L b.i.d b) an effective amount of one or chemotherapeutic agents; 2 gemcitabine 150 mg/kg Twice weekly 5 wherein the disclosed compounds and the chemotherapeu 3 gemicitabine + 150 mg/kg + Twice weekly + tic agents can be administered together or in any order. D91 20 mg/kg b.i.d. 4 gemcitabine 100 mg/kg Twice weekly One embodiment relates to a compostion comprising: 5 gemicitabine + 100 mg/kg + Twice weekly + a) an effective amount of one or more compounds dis D91 20 mg/kg b.i.d. closed herein; and 6 D91 20 mg/kg b.i.d 10 b) an effective amount of taxol; wherein the disclosed compounds and taxol can be admin As depicted in FIG. 9, D91 given at 20 mg/kg showed a istered together or in any order. significant reduction in pancreatic tumor Volume at day 28 Another embodiment relates to a composition comprising: (O). In addition the combination of low dose gemcitabine a) an effective amount of one or more compounds dis and 20 mg/kg D91 (*) showed a greater reduction in tumor 15 closed herein; and volume than either low dose gencitabine (X) or D91 alone b) an effective amount of gemcitabine; (O). wherein the disclosed compounds and gemcitabine can be Disclosed herein is a method for treating carcinoma in a administered together or in any order. Subject, comprising administering to the Subject having a A further embodiment relate to a composition comprising: carcinoma an effective amount of one or more of the disclosed a) an effective amount of one or more compounds dis compounds. closed herein; and b) an effective amount of erlotinib; Also disclosed herein is a method for treating a subject wherein the disclosed compounds and erlotinib can be diagnosed with cancer, comprising administering to the Sub administered together or in any order. ject an effective amount of one or more of the disclosed 25 A yet further embodiment relate to a composition compris compounds. ing: Further disclosed herein is a method for treating carcinoma a) an effective amount of one or more compounds dis in a subject, comprising administering to the Subject having a closed herein; and carcinoma a composition comprising: b) an effective amount of doxil; a) an effective amount of one or more of the disclosed 30 wherein the disclosed compounds and doxil can be admin compounds; and istered together or in any order. b) an effective amount of an anticancer drug. A still further embodiment relate to a composition com Still further disclosed herein is a method for treating car prising: cinoma in a Subject, comprising administering to the Subject a) an effective amount of one or more compounds dis having a carcinoma a composition comprising: 35 closed herein; and a) an effective amount of one or more of the disclosed b) an effective amount of irinortecan; compounds; and wherein the disclosed compounds and irinortecan can be b) an effective amount of a compound that inhibits tumor administered together or in any order. growth. A still yet further embodiment relate to a composition Yet further disclosed herein is a method for treating a 40 comprising: Subject diagnosed with cancer, comprising administering to a) an effective amount of one or more compounds dis the Subject diagnosed with cancer a composition comprising: closed herein; and a) an effective amount of one or more of the disclosed b) an effective amount of bevacizumab: compounds; and wherein the disclosed compounds and bevacizumab can be 45 administered together or in any order. b) an effective amount of an anticancer drug. A “chemotherapeutic agent' or “chemotherapeutic com Still yrt further disclosed herein is a method for treating a pound is a chemical compound useful in the treatment of Subject diagnosed with cancer, comprising administering to cancer. Chemotherapeutic cancer agents that can be used in the Subject diagnosed with cancer a composition comprising: combination with those disclosed herein include, but are not a) an effective amount of one or more of the disclosed 50 limited to, mitotic inhibitors (vinca alkaloids). These include compounds; and Vincristine, vinblastine, vindesine and NavelbineTM (vinorel b) an effective amount of a compound that inhibits tumor bine-5'-noranhydroblastine). In yet other embodiments, che growth. motherapeutic cancer agents include topoisomerase I inhibi tors, such as camptothecin compounds. As used herein, Compositions 55 “camptothecin compounds’ include CamptosarTM (irinote can HCL), HycamtinTM (topotecan HCL) and other com pounds derived from camptothecin and its analogues. Disclosed herein are compositions which can be used to Another category of chemotherapeutic cancer agents that prevent metastasis of cancer cells in a Subject, the composi may be used in the methods and compositions of the present tions comprising an effective amount of one or more of the 60 disclosure are podophyllotoxin derivatives, such as etopo compounds disclosed herein. Further disclosed herein are side, teniposide and mitopodozide. The present disclosure compositions that can be used to treat tumors in a human or further encompasses other chemotherapeutic cancer agents other mammal. known as alkylating agents, which alkylate the genetic mate One aspect relates to a composition comprising: rial in tumor cells. These include without limitation cisplatin, a) an effective amount of one or more compounds dis 65 cyclophosphamide, nitrogen mustard, trimethylene thiophos closed herein; and phoramide, carmustine, buSulfan, chlorambucil, bellustine, b) one or more pharmaceutically acceptable ingredients. uracil mustard, chlomaphazin, and dacarbazine. The present US 8,883,832 B2 141 142 disclosure encompasses antimetabolites as chemotherapeutic cin; enloplatin; enpromate; epipropidine; epirubicin agents. Examples of these types of agents include cytosine hydrochloride; erbulozole; esorubicin hydrochloride; estra arabinoside, fluorouracil, methotrexate, mercaptopurine, mustine; estramustine phosphate Sodium; etanidazole; etopo azathioprime, and procarbazine. An additional category of side, etoposide phosphate; etoprine; fadrozole hydrochlo chemotherapeutic cancer agents that may be used in the meth ride; fazarabine; fenretinide; floxuridine; fludarabine ods and compositions of the present disclosure include anti phosphate; fluorouracil; fluorocitabine; fosquidone; fostrie biotics. Examples include without limitation doxorubicin, cin Sodium; gemcitabine; gemcitabine hydrochloride; bleomycin, dactinomycin, daunorubicin, mithramycin, mito hydroxyurea; idarubicin hydrochloride; ifosfamide: ilmofos mycin, mytomycin C, and daunomycin. There are numerous ine; interleukin II (including recombinant interleukin II, or liposomal formulations commercially available for these 10 rIL2), interferon alfa-2a: interferon alfa-2b; interferon alfa compounds. The present disclosure further encompasses n1; interferon alfa-n3; interferon beta-Ia; interferon gamma-I other chemotherapeutic cancer agents including without limi b; iproplatin: irinotecan hydrochloride; lanreotide acetate; tation anti-tumor antibodies, dacarbazine, azacytidine, amsa letrozole; leuprolide acetate; liarozole hydrochloride; lometr crine, melphalan, ifosfamide and mitoxantrone. exol Sodium, lomustine; losoxantrone hydrochloride; maso The disclosed compounds herein can be administered 15 procol; maytansine; mechlorethamine hydrochloride; mege alone or in combination with other anti-tumor agents, includ strol acetate; melengestrol acetate; melphalan; menogaril; ing cytotoxic/antineoplastic agents and anti-angiogenic mercaptopurine; methotrexate; methotrexate sodium; meto agents. Cytotoxic/anti-neoplastic agents are defined as agents prine; meturedepa; mitindomide; mitocarcin, mitocromin: which attack and kill cancer cells. Some cytotoxic/anti-neo mitogillin, mitomalcin, mitomycin; mitosper, mitotane; plastic agents are alkylating agents, which alkylate the mitoxantrone hydrochloride; mycophenolic acid; nocoda genetic material in tumor cells, e.g., cis-platin, cyclophospha Zole: nogalamycin; ormaplatin: Oxisuran, paclitaxel; pegas mide, nitrogen mustard, trimethylene thiophosphoramide, pargase; peliomycin; pentamustine; peplomycin Sulfate; per carmustine, buSulfan, chlorambucil, bellustine, uracil mus fosfamide; pipobroman; piposulfan, piroXantrone tard, chlomaphazin, and dacabazine. Other cytotoxic/anti hydrochloride; plicamycin; plomestane; porfimer Sodium; neoplastic agents are antimetabolites for tumor cells, e.g., 25 porfiromycin; prednimustine; procarbazine hydrochloride; cytosine arabinoside, fluorouracil, methotrexate, mercap puromycin; puromycin hydrochloride; pyrazofurin: ribo topuirine, azathioprime, and procarbazine. Other cytotoxic/ prine; rogletimide: Safingol; Safingol hydrochloride: Semus anti-neoplastic agents are antibiotics, e.g., doxorubicin, bleo tine; simtraZene; sparfosate Sodium; sparsomycin; Spiroger mycin, dactinomycin, daunorubicin, mithramycin, manium hydrochloride; spiromustine; spiroplatin: mitomycin, mytomycin C, and daunomycin. There are 30 streptonigrin: Streptozocin, Sulofenur; talisomycin; tecogalan numerous liposomal formulations commercially available for Sodium, tegafur, teloxantrone hydrochloride; temoporfin; these compounds. Still other cytotoxic/anti-neoplastic agents teniposide; teroxirone; testolactone; thiamiprine; thiogua are mitotic inhibitors (vinca alkaloids). These include Vinc nine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; ristine, vinblastine and etoposide. Miscellaneous cytotoxic/ trestolone acetate; triciribine phosphate; trimetrexate; trime anti-neoplastic agents include taxol and its derivatives, L-as 35 trexate glucuronate; triptorelin; tubulozole hydrochloride; paraginase, anti-tumor antibodies, dacarbazine, azacytidine, uracil mustard; uredepa; vapreotide; verteporfin, vinblastine amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, sulfate; Vincristine sulfate; Vindesine; vindesine sulfate; Vine and vindesine. pidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Anti-angiogenic agents are well known to those of skill in vinorelbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; the art. Suitable anti-angiogenic agents for use in the methods 40 Vorozole; Zeniplatin: Zinostatin: Zorubicin hydrochloride. and compositions of the present disclosure include anti Other anti-cancer drugs include, but are not limited to: VEGF antibodies, including humanized and chimeric anti 20-epi-1.25 dihydroxyvitamin D3; 5-ethynyluracil; abirater bodies, anti-VEGF aptamers and antisense oligonucleotides. one; aclarubicin; acylfulvene; adecypenol; adoZelesin; Other known inhibitors of angiogenesis include angiostatin, aldesleukin; ALL-TK antagonists; altretamine; ambamus endostatin, interferons, interleukin 1 (including C. and B) 45 tine; amidox; amifostine; aminolevulinic acid; amrubicin; interleukin 12, retinoic acid, and tissue inhibitors of metallo amsacrine; anagrelide; anastrozole; andrographolide; angio proteinase-1 and -2. (TIMP-1 and -2). Small molecules, genesis inhibitors; antagonist D; antagonist G, antarelix; anti including topoisomerases such as razoxane, a topoisomerase dorsalizing morphogenetic protein-1, antiandrogen, prostatic II inhibitor with anti-angiogenic activity, can also be used. carcinoma; antiestrogen; antineoplaston; antisense oligo Other anti-cancer agents that can be used in combination 50 nucleotides; aphidicolin glycinate; apoptosis gene modula with the disclosed compounds include, but are not limited to: tors; apoptosis regulators; apurinic acid; ara-CDP-DL acivicin; aclarubicin; acodazole hydrochloride; acronine; PTBA, arginine deaminase; asulacrine; atamestane; adoZelesin; aldesleukin; altretamine; ambomycin; amet atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza antrone acetate; aminoglutethimide; amsacrine; anastroZole; setron; azatoxin; azatyrosine; baccatin III derivatives; bal anthramycin; asparaginase; asperlin; azacitidine; azetepa; 55 anol; batimastat; BCR/ABL antagonists; benzochlorins; ben aZotomycin; batimastat; benzodepa; bicalutamide; bisant Zoylstaurosporine; beta lactam derivatives; beta-alethine; rene hydrochloride; bisnafide dimesylate; bizelesin; bleomy betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta cin Sulfate; brequinar Sodium; bropirimine; buSulfan, cacti mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene nomycin; calusterone; caracemide; carbetimer; carboplatin: A: bizelesin; breflate; bropirimine; budotitane; buthionine carmustine; carubicin hydrochloride; carZelesin; cedefingol; 60 Sulfoximine; calcipotriol; calphostin C; camptothecin deriva chlorambucil; cirolemycin; cisplatin: cladribine; crisinatol tives; canarypox IL-2; capecitabine; carboxamide-amino mesylate; cyclophosphamide; cytarabine; dacarbazine, dac triazole; carboxyamidotriazole; CaRest M3; CARN 700; car tinomycin; daunorubicin hydrochloride; decitabine; dexor tilage derived inhibitor; carZelesin; casein kinase inhibitors maplatin; deZaguanine; deZaguanine mesylate; diaziquone; (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns: docetaxel: doxorubicin; doxorubicin hydrochloride; drolox 65 chloroquinoxaline Sulfonamide; cicaprost, cis-porphyrin, ifene; droloxifene citrate; dromostanolone propionate; dua cladribine; clomifene analogues; clotrimazole; collismycin Zomycin; edatrexate; eflornithine hydrochloride; elsamitru A. collismycin B; combretastatin A4, combretastatin ana US 8,883,832 B2 143 144 logue; conagenin, crambescidin 816; crisinatol; cryptophycin phatase inhibitors; purine nucleoside phosphorylase inhibi 8, cryptophycin A derivatives; curacin A; cyclopentan tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin thraquinones; cycloplatam, cypemycin; cytarabine ocfosfate; polyoxyethylene conjugate; raf antagonists; raltitrexed: cytolytic factor, cytostatin; dacliximab, decitabine; dehy ramosetron; ras farnesyl protein transferase inhibitors; ras drodidemnin B; deslorelin; dexamethasone; dexifosfamide: inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe dexraZoxane; dexVerapamil; diaziquone; didemnin B; didox; nium Re 186 etidronate; rhizoxin: ribozymes: RII retinamide: diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol. rogletimide; rohitukine; romurtide; roquinimex: rubiginone 9-; dioxamycin; diphenyl spiromustine; docetaxel; B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A: docosanol; dolasetron: doxifluridine; droloxifene; dronab Sargramostim; Sdi 1 mimetics; Semustine; senescence inol; duocarmycin SA; ebselen; ecomustine: edelfosine; 10 edrecolomab: eflornithine; elemene; emitefur; epirubicin; derived inhibitor 1; sense oligonucleotides; signal transduc epristeride; estramustine analogue; estrogen agonists; estro tion inhibitors; signal transduction modulators; single chain gen antagonists; etanidazole; etoposide phosphate; exemes antigen binding protein; sizofuran; Sobuzoxane, Sodium tane; fadrozole; faZarabine; fenretinide; filgrastim; finas borocaptate; sodium phenylacetate; solverol; somatomedin teride; flavopiridol; flezelastine; fluasterone; fludarabine; 15 binding protein; Sonermin; sparfosic acid; spicamycin D; fluorodaunorunicin hydrochloride; forfenimex; formestane: spiromustine; splenopentin; spongistatin 1; squalamine; stem fostriecin, fotemustine; gadolinium texaphyrin; gallium cell inhibitor; stem-cell division inhibitors; stipiamide: nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit stromelysin inhibitors; Sulfinosine; Superactive vasoactive abine; glutathione inhibitors; hepsulfam; heregulin; hexam intestinal peptide antagonist; Suradista; Suramin; Swainso ethylene bisacetamide; hypericin; ibandronic acid; idarubi nine; synthetic glycosaminoglycans; tallimustine; tamoxifen cin; idoxifene; idramantone, ilmofosine; illomastat; methiodide; tauromustine; tazarotene; tecogalan Sodium; imidazoacridones; imiquimod; immunostimulant peptides; tegafur, tellurapyrylium; telomerase inhibitors; temoporfin; insulin-like growth factor-1 receptor inhibitor; interferon temozolomide; teniposide; tetrachlorodecaoxide; tetraZom agonists; interferons; interleukins; iobenguane; iododoxoru ine; thaliblastine; thiocoraline; thrombopoietin; thrombopoi bicin; ipomeanol, 4-, iroplact; irsogladine; isobengaZole; iso 25 etin mimetic; thymalfasin; thymopoietin receptor agonist; homohalicondrin B; itasetron; jasplakinolide; kahalalide F: thymotrinan; thyroid stimulating hormone; tin ethyl etiopur lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; purin; tirapazamine; titanocene bichloride; topsentin; lentinan Sulfate; leptolstatin; letrozole; leukemia inhibiting toremifene; totipotent stem cell factor; translation inhibitors: factor, leukocyte alpha interferon; leuprolide+estrogen tretinoin; triacetyluridine; triciribine; trimetrexate; triptore progesterone; leuprorelin; levamisole; liarozole; linear 30 polyamine analogue; lipophilic disaccharide peptide; lipo lin; tropisetron; turosteride; tyrosine kinase inhibitors; tyr philic platinum compounds; lissoclinamide 7: lobaplatin: phostins; UBC inhibitors: ubenimex; urogenital sinus-de lombricine; lometrexol; lonidamine; losoxantrone; lovasta rived growth inhibitory factor; urokinase receptor tin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; antagonists; vapreotide; variolin B; vector system, erythro lytic peptides; maitansine; mannostatin A; marimastat; maso 35 cyte gene therapy; velaresol; Veramine; Verdins; verteporfin; procol; maspin; matrilysin inhibitors; matrix metalloprotein Vinorelbine; Vinxaltine; vitaxin; Vorozole; Zanoterone; Zeni ase inhibitors; menogaril; merbarone; meterelin; methioni platin: Zilascorb; and Zinostatin stimalamer. In one embodi nase; metoclopramide: MIF inhibitor; mifepristone; ment, the anti-cancer drug is 5-fluorouracil, taxol, or leucov miltefosine; mirimostim; mismatched double stranded RNA; orin. mitoguaZone, mitolactol; mitomycin analogues; mitonafide; 40 The term “effective amount” as used herein means “an mitotoxin fibroblast growth factor-Saporin; mitoxantrone; amount of one or more phenylsulfamic acids, effective at mofarotene; molgramostim; monoclonal antibody, human dosages and for periods of time necessary to achieve the chorionic gonadotrophin, monophosphoryl lipid A+myobac desired or therapeutic result. An effective amount may vary terium cell wall sk; mopidamol; multiple drug resistance gene according to factors known in the art, such as the disease state, inhibitor, multiple tumor Suppressor 1-based therapy; mus 45 age, sex, and weight of the human or animal being treated. tard anticancer agent; mycaperoxide B; mycobacterial cell Although particular dosage regimes may be described in wall extract; myriaporone; N-acetyldinaline; N-substituted examples herein, a person skilled in the art would appreciated benzamides; nafarelin; nagreStip; naloxone-pentazocine; that the dosage regime may be altered to provide optimum napavin; naphterpin, nartograstim; nedaplatin: nemorubicin; therapeutic response. Thus, it is not possible to specify an neridronic acid; neutral endopeptidase; nilutamide; nisamy 50 exact “effective amount.” For example, several divided doses cin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; may be administered daily or the dose may be proportionally O6-benzylguanine; octreotide; okicenone; oligonucleotides; reduced as indicated by the exigencies of the therapeutic onapristone; ondansetron; ondansetron; oracin; oral cytokine situation. In addition, the compositions of the present disclo inducer, ormaplatin: osaterone; Oxaliplatin, oxaunomycin; Sure can be administered as frequently as necessary to achieve paclitaxel; paclitaxel analogues; paclitaxel derivatives; 55 a therapeutic amount. palauamine; palmitoylrhizoxin; pamidronic acid; panax While particular embodiments of the present disclosure ytriol; panomifene; parabactin; paZelliptine; pegaspargase; have been illustrated and described, it would be obvious to peldesine; pentosan polysulfate sodium; pentostatin: pentro those skilled in the art that various other changes and modi Zole; perflubron; perfosfamide; perillyl alcohol; phenazino fications can be made without departing from the spirit and mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo 60 scope of the disclosure. It is therefore intended to cover in the carpine hydrochloride; pirarubicin; piritrexim; placetin A; appended claims all such changes and modifications that are placetin B; plasminogen activator inhibitor, platinum com within the scope of this disclosure. plex; platinum compounds; platinum-triamine complex; por fimer Sodium; porfiromycin; prednisone; propyl bis-acri What is claimed is: done; prostaglandin J2, proteasome inhibitors; protein 65 1. A method for treating a Subject with cancer, comprising A-based immune modulator, protein kinase C inhibitor, pro administering to the Subject and effective amount of a tein kinase C inhibitors, microalgal; protein tyrosine phos compound having the formula: US 8,883,832 B2 145 146 xii) - C(=NH)–: R xiii) –C(=NH)NH-; xiv) - NHC(=NH) ; or W N xv) - NHC(=NH)NH : HO1 NN H1NZ R" and Rare each independently: i) hydrogen; h ii) hydroxy: iii) halogen; wherein R is a substituted or unsubstituted thiazolyl unit iv) C-C substituted or unsubstituted linear or branched having the formula: 10 alkyl; or V) a unit having the formula:

R" and R'' are each independently: 15 i) hydrogen; or --CC - k ii) substituted or unsubstituted C-C linear, branched, or cyclic alkyl; R is: i) hydrogen; Kr ii) substituted or unsubstituted C-C linear, branched, or cyclic alkyl; R. R. and Rare each independently: iii) Substituted or unsubstituted C or Co aryl; i) hydrogen; iv) substituted or unsubstituted C-C heteroaryl; or v) substituted or unsubstituted C-C heterocyclic; ii) substituted or unsubstituted C-C linear, branched, or 25 R" and Rare each independently: cyclic alkyl; i) hydrogen; or iii) substituted or unsubstituted C-C linear, branched, or cyclic alkenyl; ii) C-C linear or branched alkyl: iv) substituted or unsubstituted C-C linear or branched the index n is 0 or 1; the indices t, w and X are each alkynyl: independently from 0 to 4; the indices y and Z are each 30 independently 0 or 1; or V) substituted or unsubstituted C or Co aryl; a pharmaceutically acceptable salt thereof. vi) substituted or unsubstituted C-C heteroaryl; 2. The method according to claim 1, further comprising vii) substituted or unsubstituted C-C heterocyclic; or administering one or more chemotherapeutic agents. viii) RandR can be taken together to form a saturated or 3. The method according to claim 2, wherein the chemo unsaturated ring having from 5 to 7 atoms; wherein from 35 therapeutic agent is chosen from Vincristine, vinblastine, Vin 1 to 3 atoms can optionally be heteroatoms chosen from desine, Vinorelbine-5'-noranhydroblastine, irinotecan, topo oxygen, nitrogen, and Sulfur, tecan, cisplatin, cyclophosphamide, nitrogen mustard, Z is a unit having the formula: trimethylene thiophosphoramide, carmustine, buSulfan, chlorambucil, bellustine, chlomaphazin, dacarbazine, 40 cytosine arabinoside, fluorouracil, methotrexate, mercap R" is chosen from: topurine, azathioprime, procarbazine, doxorubicin, bleomy i) hydrogen; cin, dactinomycin, daunorubicin, mithramycin, mitomycin, ii) hydroxyl: mytomycin C, daunomycin, azacytidine, amsacrine, mel iii) amino; phalan, ifosfamide, mitoxantrone, cis-platin, etoposide, iv) substituted or unsubstituted C-C linear, branched or 45 taxol, acivicin; aclarubicin; acodazole hydrochloride; acro cyclic alkyl; nine; adoZelesin; aldesleukin; altretamine; ambomycin; v) substituted or unsubstituted C-C linear, branched or ametantrone acetate; aminoglutethimide; anastroZole; cyclic alkoxy; anthramycin; asperlin; azacitidine; azetepa; azotomycin; vi) Substituted or unsubstituted C or Co aryl; batimastat; benzodepa; bicalutamide; bisantrene hydrochlo vii) Substituted or unsubstituted C-C heterocyclic rings; 50 ride; bisnafide dimesylate; bizelesin; brequinar Sodium; O bropirimine: cactinomycin; calusterone; caracemide; carbe viii) substituted or unsubstituted C-C heteroaryl rings: timer; carboplatin: carubicin hydrochloride; carzelesin; L is a linking unit having the formula: cedefingol; cirolemycin; cladribine; crisinatol mesylate; cyt arabine; decitabine; dexormaplatin; deZaguanine; diazi -(QIC(RR).IQLIC(RR), 55 quone; docetaxel; droloxifene; duaZomycin; ediatrexate; eflo Q and Q are each independently: rnithine hydrochloride; elsamitrucin; enloplatin; enpromate; i) —C(O) ; epipropidine; epirubicin hydrochloride; erbulozole; esorubi ii) -NH ; cin hydrochloride; estramustine; etanidazole; etoprine; fadro iii) - C(O)NH-; Zole hydrochloride; fazarabine; fenretinide; floxuridine; flu iv) - NHC(O)–: 60 darabine phosphate; fluorocitabine; fosquidone; fostriecin v) - NHC(O)NH ; Sodium; gemcitabine; hydroxyurea; idarubicin hydrochlo vi) - NHC(O)O : ride; ilmofosine; interleukin II interferon alfa-2a: interferon vii) - C(O)O : alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon viii) –C(O)NHC(O)–: beta-Ia; interferon gamma-Ib, iproplatin: lanreotide acetate; iX) —O—; 65 letrozole; leuprolide acetate; liarozole hydrochloride; lometr exol Sodium, lomustine; losoxantrone hydrochloride; maso Xi)—SO : procol; maytansine; mechlorethamine hydrochloride; mege US 8,883,832 B2 147 148 strol acetate; melengestrol acetate; menogaril; metoprine; 16. The method according to claim 1, wherein R is sub meturedepa; mitindomide; mitocarcin, mitocromin, mitogil stituted or unsubstituted phenyl and R is hydrogen. lin, mitomalcin, mitosper, mitotane; mycophenolic acid; 17. The method according to claim 1, wherein R is sub nocodazole; nogalamycin; ormaplatin, oxiSuran, paclitaxel; stituted or unsubstituted heteroaryland R is hydrogen. pegaspargase; peliomycin; pentamustine; peplomycin Sul 18. The method according to claim 1, wherein R is a fate; perfosfamide; pipobroman; piposulfan, piroXantrone heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tet hydrochloride; plicamycin; plomestane; porfimer Sodium; razol-5-yl, 1.2.3 triazol-4-yl, 1.2.3 triazol-5-yl, 1.2.4 tria porfiromycin; prednimustine; puromycin; pyrazofurin: ribo Zol-4-yl, 1.2.4 triazol-5-yl, imidazol-2-yl, imidazol-4-yl, prine; rogletimide; Safingol: Semustine; simtraZene; sparfos pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5- 10 yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1.2.4 oxadia ate Sodium; sparsomycin; Spirogermanium hydrochloride; Zol-3-yl, 1.2.4 oxadiazol-5-yl, 1.3.4oxadiazol-2-yl, furan spiromustine; spiroplatin: Streptonigrin: Streptozocin, 2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3- Sulofenur; talisomycin; tecogalan Sodium, tegafur, telox yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, antrone hydrochloride; temoporfin, teniposide; teroxirone; thiazol-5-yl, 1,2,4thiadiazol-3-yl, 1,2,4thiadiazol-5-yl, or testolactone; thiamiprine; thioguanine; thiotepa, tiazofurin; 15 1,3,4thiadiazol-2-yl. tirapazamine; toremifene citrate; trestolone acetate; tricirib 19. The method according to claim 1, wherein R is ine phosphate; trimetrexate; triptorelin; tubulozole hydro thiophen-2-yl or thiophen-3-yl. chloride; uredepa; vapreotide; verteporfin; vinepidine Sul 20. The method according to claim 1, wherein R has the fate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinrosidine formula: Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin: Zinostatin: and Zorubicin hydrochloride. 4. The method according to claim 2, wherein the chemo therapeutic agent is chosen from taxol. IL-2, gemcitabine, erlotinib, doxil, irinortecan, and bevacizumab. 5. The method according to claim 2 wherein the compound 25 is administered prior to administration of the chemotherapeu tic agent. 21. The method according to claim 1, wherein R is hydro 6. The method according to claim 2 wherein the compound gen or Substituted or unsubstituted C-C linear, branched, or is administered together with each administration of the che cyclic alkyl. motherapeutic agent. 30 22. The method according to claim 1, wherein R is chosen 7. The method according to claim 2, wherein the compound from methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-butyl, is administered each time the chemotherapeutic agent is sec-butyl, and tert-butyl; and R is hydrogen. administered and between administrations of the chemo 23. The method according to claim 1, wherein R is sub therapeutic agent. stituted or unsubstituted phenyl and R is hydrogen. 8. The method according to claim 1, wherein the method 35 24. The method according to claim 1, wherein Risan alkyl further comprises radiation therapy. unit wherein one or more hydrogenatoms are Substituted with 9. The method according to claim8, wherein the compound one or more substitutions chosen from: is administered at the time of radiation therapy. i) halogen; 10. The method according to claim 8, wherein the com ii) - N(R'); and pound is administered prior to the onset of radiation therapy. 40 iii) —OR': 11. The method according to claim 8, wherein the com wherein each R'' is independently hydrogen or C-C lin pound is administered after radiation therapy. ear or C-C branched alkyl. 12. The method according to claim 8, wherein the com 25. The method according to claim 1, wherein R is sub pound is administered at the time of each radiation therapy stituted or unsubstituted heteroaryl. and between each Subsequent administration of radiation 45 26. The method according to claim 1, wherein R is a therapy. heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tet 13. The method according to claim 1, wherein R has the razol-5-yl, 1.2.3 triazol-4-yl, 1.2.3 triazol-5-yl, 1.2.4 tria formula: Zol-4-yl, 1.2.4 triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5- 50 yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1.2.4 oxadia N R2 Zol-3-yl, 1.2.4 oxadiazol-5-yl, 1.3.4oxadiazol-2-yl, furan 2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3- yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, S R3. thiazol-5-yl, 1.2.4thiadiazol-3-yl, 1,2,4thiadiazol-5-yl, --CC 55 and 1,3,4thiadiazol-2-yl. 27. The method according to claim 1, wherein R is 14. The method according to claim 1, wherein R is chosen thiophen-2-yl or thiophen-3-yl. from methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-butyl, 28. The method according to claim 1, wherein R' is hydro sec-butyl, and tert-butyl; and R is hydrogen. gen, methyl, ethyl, tert-butyl, or methyl substituted with phe 15. A method according to claim 1, wherein R is an alkyl 60 nyl. unit wherein one or more hydrogenatoms are Substituted with 29. The method according to claim 1, wherein L has the one or more substitutions chosen from: formula: i) halogen; ii) —N(R'); and C(O)IC(RR)NHC(O) iii) OR'': 65 R" is hydrogen, substituted or unsubstituted phenyl, and wherein each R'' is independently hydrogen or C-C lin substituted or unsubstituted heteroaryl; the index X is 1 ear or branched alkyl. or 2. US 8,883,832 B2 149 150 30. The method according to claim 1, wherein L has the formula chosen from:

10 wherein R is: i) hydrogen; wherein R is methyl or ethyl, R is hydrogen, R is chosen ii) methyl; from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluo iii) ethyl; 15 rophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3.5- difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, iv) isopropyl; 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophe V) phenyl: nyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydrox vi) benzyl: yphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-meth Oxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, vii) 4-hydroxybenzyl; 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-methyl viii) hydroxymethyl; or 1,2,4-oxadiazol-5-yl, thiophen-2-yl, thiophen-3-yl, ix) 1-hydroxyethyl. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, Oxazol-4-yl, oxazol-5-yl, or isoxazol-3-yl. 31. The method according to claim 1, wherein R' is chosen 25 38. The method according to claim 1, wherein the com from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophe pound has the formula: nyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophe nyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2.3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 30 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2.3- dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5-dimethox yphenyl. 32. The method according to claim 1, wherein R is methyl 35 or ethyl, R is hydrogen, and L has the formula C(O) CH2—. 33. The method according to claim 1, wherein R is methyl wherein R is methyl, ethyl, phenyl, or thiophen-2-yl, R' or ethyl, R is hydrogen, and L has the formula C(O) 40 is chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, CHCH . 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 34. The method according to claim 3, wherein R' is a 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, substituted or unsubstituted heteroaryl unit, said substitutions 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophe chosen from: nyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydrox 45 yphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-meth i) C-C linear, C-C branched, and C-C cyclic alkyl; Oxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, ii) substituted or unsubstituted phenyl and benzyl: 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-methyl 1,2,4-oxadiazol-5-yl, thiophen-2-yl, thiophen-3-yl, iii) substituted of unsubstituted heteroaryl; thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, iv) –C(O)R’; or 50 Oxazol-4-yl, oxazol-5-yl, or isoxazol-3-yl. v) NHC(O)R’; 39. The method according to claim 1, wherein the com R is C-C linear or C-C branched alkyl: C-C linear or pound has the formula: C-C branched alkoxy; or -NHCHC(O)R': R' is chosen from hydrogen, methyl, ethyl, or tert-butyl. 55 35. The method according to claim 1, wherein R' is a heteroaryl unit substituted by an alkyl unit chosen from methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-butyl, sec butyl, or tert-butyl. 60 36. The method according to claim 1, wherein R' is a heteroaryl unit substituted by a carboxy unit having the for mula - NHC(O)R’: R is chosen from methyl, methoxy, ethyl, ethoxy, tert-butyl, and tert-butoxy. 65 37. The method according to claim 1, wherein the com wherein R is chosen from methyl, ethyl, phenyl, and pound has the formula: thiophen-2-yl, R is hydrogen or methyl; R' is chosen US 8,883,832 B2 151 152 from phenyl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, iv) pyrrol-2-yl and pyrrol-3-yl having the respective for thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, mulae: oxazol-5-yl, and isoxazol-3-yl. 40. The method according to claim 1, wherein the com pound has the formula: --K - {D" 10 V) oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl having the respective formulae:

H1 NR 15 O - O - C - Cl wherein R and R are each independently hydrogen, methyl or ethyl; R' is chosen from phenyl, 2-fluorophe vi) isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl having nyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophe the respective formulae: nyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlo rophenyl, 3-chlorophenyl, 4-chlorophenyl, 2.3- dichlorophenyl, 3,4-dichlorophenyl, 3,5- 25 dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4- - C - {J. --K) dimethoxyphenyl, and 3,5-dimethoxyphenyl. 30 41. The method according to claim 1, wherein R' is a vii) (1,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl hav substituted or unsubstituted heteroaryl unit chosen from: ing the respective formulae: i) 1,2,3,4-tetrazol-1-yland 1,2,3,4-tetrazol-5-yl having the respective formulae: 35 N O NN. H K /NN: NNN. N-O N \ NeN N-N 40 viii) (1,3,4-oxadiazol-2-yl having the formula: ii) 1.2.3 triazol-4-yl, 1.2.3 triazol-5-yl, 1.2.4 triazol-4- y1, and 1.2.4 triazol-5-yl having the respective formu lae: 45 KhN-N:

iX) furan-2-yl and furan-3-yl having the respective formu t NN. lae: N2 N N 50 H NN; NNN. 55 --K - {D iii) imidazol-2-yl and imidazol-4-yl having the respective X) thiophen-2-yl and thiophen-3-yl having the respective formulae: formulae: 60 - O --O" 65 - { - {D

US 8,883,832 B2 159 160 (S)-4-2-[2-(tert-Butoxycarbonyl)acetamide-2-(4-eth 47. The method according to claim 1, wherein the com ylthiazol-2-yl)ethylphenyl-sulfamic acid; pound has the formula: (S)-4-2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyl) acetamidolethylphenyl-sulfamic acid; 4-(S)-2-(4-Ethylthiazol-2-yl)-2-(S)-2-(methoxycarbo 5 nyl)-3-methylbutanamido-ethylphenylsulfamic acid; 4-(S)-2-(S)-2-(tert-Butoxycarbonyl)-4-methylpentana mido-2-(4-ethylthiazol-2-yl)ethylphenylsulfamic V / acid; S O 4-(S)-2-(4-Ethylthiazol-2-yl)-2-(S)-2-(methoxycarbo 10 HO1 n N O nyl)-4-methylpentan-amidolethylphenylsulfamic acid; N ls o1 CH3: 4-(S)-2-(4-Ethylthiazol-2-yl)-2-(S)-2-[2-(methoxycar H bonyl)acetamide-3-phenylpropanamido)ethyl)phenyl 15 Sulfamic acid; 4-(S)-2-(S)-2-(tert-Butoxycarbonyl)-4-methylpentana mido)-2-[2-(thiophen-2-yl)thiazol-4-yl) ethylphenylsulfamic acid; 4-(S)-2-(S)-2-(Methoxycarbonyl)-4-methylpentana and pharmaceutically acceptable salts thereof. mido)-2-[2-(thiophen-2-yl)thiazol-4-yl) 48. The method according to claim 1, wherein the method ethylphenylsulfamic acid; and further comprises radiation therapy. (S)-4-2-[2-(tert-Butoxycarbonyl)acetamide-2-(4-eth 49. The method according to claim 1, wherein the com ylthiazol-2-yl)ethyl-phenylsulfamic acid. pound has the formula: 43. The method according to claim 1, wherein the com 25 pound has the formula:

S. S S S NY 30 VS / O O O NX-O. HO n N O \/ HN N l o1 CH:3 HO1 SN H 35

40 and pharmaceutically acceptable salts thereof. 50. The method according to claim 49, wherein the method and pharmaceutically acceptable salts thereof. further comprises radiation therapy. 44. The method according to claim 43, wherein the method 51. The method according to claim 1, wherein the cancer is 45 chosen from Acute Lymphoblastic; Acute Myeloid Leuke further comprises radiation therapy. mia; Adrenocortical Carcinoma; Adrenocortical Carcinoma, 45. The method according to claim 1, wherein the com Childhood; Appendix Cancer; Basal Cell Carcinoma; Bile pound has the formula: Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer; Osteosarcoma and Malignant Fibrous Histiocytoma; Brain 50 Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Central Ner vous System Atypical Teratoid/Rhabdoid Tumor, Childhood; O O Central Nervous System Embryonal Tumors; Cerebellar V/ Astrocytoma; Cerebral Astrocytoma/Malignant Glioma; S O 55 Craniopharyngioma, Ependymoblastoma; Ependymoma; HO1 n N O Medulloblastoma; Medulloepithelioma; Pineal Parenchymal Tumors of Intermediate Differentiation; Supratentorial N ls O1 CH Primitive Neuroectodermal Tumors and Pineoblastoma; H Visual Pathway and Hypothalamic Glioma; Brain and Spinal 60 Cord Tumors; Breast Cancer; Bronchial Tumors; Burkitt Lymphoma; Carcinoid Tumor; Carcinoid Tumor, Gas trointestinal; Central Nervous System Atypical Teratoid/ Rhabdoid Tumor; Central Nervous System Embryonal Tumors; Central Nervous System Lymphoma; Cerebellar and pharmaceutically acceptable salts thereof. 65 Astrocytoma; Cerebral Astrocytoma/Malignant Glioma, 46. The method according to claim 45, wherein the method Childhood; Cervical Cancer, Chordoma, Childhood; Chronic further comprises radiation therapy. Lymphocytic Leukemia; Chronic Myelogenous Leukemia; US 8,883,832 B2 161 162 Chronic Myeloproliferative Disorders; Colon Cancer; Col ity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, orectal Cancer, Craniopharyngioma; Cutaneous T-Cell Lym Neuroblastoma; Non-Small Cell Lung Cancer; Oral Cancer; phoma; Esophageal Cancer, Ewing Family of Tumors; Oral Cavity Cancer; Oropharyngeal Cancer; Osteosarcoma Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Can and Malignant Fibrous Histiocytoma of Bone; Ovarian Can cer: Eye Cancer, Intraocular Melanoma; Eye Cancer, Retino cer: Ovarian Epithelial Cancer: Ovarian Germ Cell Tumor; blastoma; Gallbladder Cancer; Gastric (Stomach) Cancer, Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Gastrointestinal Carcinoid Tumor; Gastrointestinal Stromal Pancreatic Cancer, Islet Cell Tumors: Papillomatosis; Par Tumor (GIST); Germ Cell Tumor, Extracranial; Germ Cell athyroid Cancer, Penile Cancer; Pharyngeal Cancer; Pheo Tumor, Extragonadal; Germ Cell Tumor, Ovarian: Gesta chromocytoma; Pineal Parenchymal Tumors of Intermediate tional Trophoblastic Tumor; Glioma; Glioma, Childhood 10 Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Differentiation; Pineoblastoma and Supratentorial Primitive Glioma, Childhood Visual Pathway and Hypothalamic: Hairy Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell Cell Leukemia; Head and Neck Cancer; Hepatocellular Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; (Liver) Cancer. Histiocytosis, Langerhans Cell; Hodgkin Primary Central Nervous System Lymphoma; Prostate Can Lymphoma; Hypopharyngeal Cancer, Hypothalamic and 15 cer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Pelvis Visual Pathway Glioma: Intraocular Melanoma; Islet Cell and Ureter, Transitional Cell Cancer; Respiratory Tract Car Tumors: Kidney (Renal Cell) Cancer; Langerhans Cell His cinoma Involving the NUT Gene on Chromosome 15: Ret tiocytosis: Laryngeal Cancer, Leukemia, Acute Lymphoblas inoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; tic: Leukemia, Acute Myeloid; Leukemia, Chronic Lympho Sarcoma, Ewing Family of Tumors; Sarcoma, Kaposi; Sar cytic, Leukemia, Chronic Myelogenous; Leukemia, Hairy coma, SoftTissue: Sarcoma, Uterine; S6zary Syndrome; Skin Cell: Lip and Oral Cavity Cancer; Liver Cancer; Lung Can Cancer (Nonmelanoma); Skin Cancer (Melanoma); Skin cer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, Carcinoma, Merkel Cell: Small Cell Lung Cancer; Small AIDS-Related; Lymphoma, Burkitt; Lymphoma, Cutaneous Intestine Cancer; Soft Tissue Sarcoma; Squamous Cell Car T-Cell; Lymphoma, Hodgkin, Lymphoma, Non-Hodgkin; cinoma, Squamous Neck Cancer with Occult Primary, Meta Lymphoma, Primary Central Nervous System; Macroglobu 25 static: Stomach (Gastric) Cancer; Supratentorial Primitive linemia, Waldenstrom, Malignant Fibrous Histiocytoma of Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous; Bone and Osteosarcoma; Medulloblastoma; Melanoma; Testicular Cancer; Throat Cancer; Thymoma and Thymic Melanoma, Intraocular (Eye); Merkel Cell Carcinoma; Carcinoma; Thyroid Cancer; Transitional Cell Cancer of the Mesothelioma; Metastatic Squamous Neck Cancer with Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Occult Primary; Mouth Cancer; Multiple Endocrine Neopla 30 Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sar sia Syndrome, (Childhood); Multiple Myeloma/Plasma Cell coma; Vaginal Cancer; Vulvar Cancer; Waldenstrom Macro Neoplasm: Mycosis Fungoides; Myelodysplastic Syn globulinemia; or Wilms Tumor. dromes; Myelodysplastic/Myeloproliferative Diseases: 52. The method according to claim 1, wherein the cancer is Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult chosen from renal cell carcinoma, lung cancer, malignant Acute; Myeloid Leukemia, Childhood Acute; Myeloma, 35 melanoma, or pancreatic cancer. Multiple: Myeloproliferative Disorders, Chronic; Nasal Cav k k k k k