AU2016203254B2 - Methods for treating vascular leak syndrome - Google Patents

Methods for treating vascular leak syndrome Download PDF

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AU2016203254B2
AU2016203254B2 AU2016203254A AU2016203254A AU2016203254B2 AU 2016203254 B2 AU2016203254 B2 AU 2016203254B2 AU 2016203254 A AU2016203254 A AU 2016203254A AU 2016203254 A AU2016203254 A AU 2016203254A AU 2016203254 B2 AU2016203254 B2 AU 2016203254B2
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Kevin Gene Peters
Robert Shalwitz
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Eyepoint Pharmaceuticals Inc
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Eyepoint Pharmaceuticals Inc
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Priority claimed from AU2014202211A external-priority patent/AU2014202211B2/en
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Abstract

Disclosed are methods for treating Vascular Leak Syndrome. Further disclosed are methods for treating vascular leakage due to inflammatory diseases, inter alia, sepsis, lupus, irritable bowel disease. Yet further disclosed are methods for treating renal cell carcinoma and melanoma. Still further disclosed are methods for reducing metastasis of malignant cells and/or preventing the proliferation of carcinoma cells via spreading due to vascular leakage.

Description

ABSTRACT
Disclosed are methods for treating Vascular Leak Syndrome. Further disclosed are methods for treating vascular leakage due to inflammatory diseases, inter alia, sepsis, lupus, irritable bowel disease. Yet further disclosed are methods for treating renal cell carcinoma and melanoma. Still further disclosed are methods for reducing metastasis of malignant cells and/or preventing the proliferation of carcinoma cells via spreading due to vascular leakage.
2016203254 18 May 2016
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
METHODS FOR TREATING VASCULAR LEAK SYNDROME
CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Provisional Application Serial Number
61/144,022 filed on January 12, 2009 and Provisional Application Serial Number
61/184,985 filed on June 8, 2009. The entire disclosure of both of these referenced applications is incorporated herein by reference.
The present application is a divisional application from Australian Patent Application No. 2010203352, the entire disclosure of which is incorporated into the present specification by this cross-reference,
FIELD
Disclosed are methods for treating Vascular Leak Syndrome. Further disclosed are methods for treating vascular leakage due to inflammatory diseases, inter alia, sepsis, lupus, irritable bowel disease. Also disclosed are methods for treating vascular leakage due to the presence of pathogens. Yet further disclosed are methods for treating metastatic renal cell carcinoma and metastatic melanoma.
BACKGROUND
Vascular leak is characterized by hypotension, peripheral edema, and hypoalbuminemia. Vascular leak can occur as a side effect of illness especially illnesses due to pathogens, inter alia, viruses and bacteria. Vascular leak complicates the healing process and can itself be a direct result of certain therapies. For example, patients suffering from malignant renal carcinoma are given Interleukin-2 to help boost their immune system; however, this treatment must be withdrawn in many patients due to the onset of severe vascular leak well before the full course of treatment can be administered. Therefore, the cancer treatment is withdrawn earlier than desired and usually before the therapy is maximally effective. VLS restricts the doses of IL-2 which can be administered to humans and, in some cases, necessitates the cessation of therapy.
VLS is characterized by an increase in vascular permeability accompanied by extravasation of fluids and proteins resulting in interstitial edema and organ failure.
Manifestations of VLS include fluid retention, increase in body weight, peripheral edema, pleural and pericardial effusions, ascites, anasarca and, in severe form, signs of pulmonary and cardiovascular failure. Symptoms are highly variable among patients and the causes are
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST poorly understood. Endothelial cell modifications or damage are thought to be important is vascular leak. The pathogenesis of endothelial cell (EC) damage is complex and can involve activation or
2016203254 18 May 2016
U
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 damage to ECs and leukocytes, release of cytokines and of inflammatory mediators, alteration in cell-cell and cell-matrix adhesion and in cytoskeleton function.
During the course of antiviral and antibacterial infections, patients can develop vascular leak that is induced as result of the initial infection. There is now a long felt need for a method of preventing vascular leak due to viral or bacterial infection, and therefore provide a method of increasing the survival of humans or other mammals infected with one or more pathogens. In addition, there is a long felt need for a method of preventing vascular leakage due to certain anticancer drugs or other anticancer therapies such that the administration of anticancer drugs or anticancer therapies can be given to humans or other mammals for a longer course of treatment or therapy.
SUMMARY
Disclosed herein are compounds that inhibit the intracellular catalytic site of protein tyrosine phosphatase beta (ΡΤΡ-β) molecule. ΡΤΡ-β is known only to be expressed in vascular endothelial cells. Inhibition of ΡΤΡ-β reduces the rate of dephosphorylaiion of the Tie-2 receptor tyrosine kinase. This inhibition results in amplification of the Angiopoietin 1 (Ang-1) signal through Tie-2, and effectively counters the inhibitory effects of Angiopoietin 2 (Ang-2) on Tie-2. Because Tie-2 is critical to maintaining vascular endothelial integrity, the disclosed ΡΤΡ-β inhibitors provide a method for providing vascular stabilization in humans and mammals. As such, the disclosed ΡΤΡ-β inhibitors provide Tie-2 signal amplification. One important manifestation of vascular de-stabilization is vascular leak syndrome (VLS) which has many causes, for example, infection of a human or mammal by a pathogen. Another common cause of vascular leak syndrome is the use of certain chemotherapeutic agents, inter alia, IL-2 which is used in treating certain forms of cancer.
Disclosed herein are methods for stabilizing human and mammalian vasculature. The stabilization of vasculature in patients compromised with an infection due to the presence of pathogens, inter alia, bacteria, vimses, yeasts, and fungi, provide a method for preventing complications due to infection such as sepsis, pulmonary edema, and the like, Subjects suffering from or diagnosed with certain cancers are given chemotherapeutic agents that result in vascular leak syndrome as a primary side effect causing cessation of treatment, before the desired full course has been achieved. For weakened humans and mammals, the onset of vascular leak syndrome due to one or more compromising events can be avoided by the disclosed methods for
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 monitoring the level of Ang-2 and administering the appropriate amount of ΡΤΡ-β inhibitor, either alone, or as part of a prophylactic combination therapy.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 depicts the effect of 4-{(5)-2-[(5)-2-(methoxycarbonyiamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yI]ethy{}phenylsulfamic acid ammonium salt (inhibitor) on murine blood pressure during IL-2 induced VLS at low and high IL-2 dosing. As depicted, High IL-2 dosing in the absence of a Tie-2 signal amplifier resulted in death, A depicts the control sample; B depicts mice treated with 180,000 1U of IL-2 for 5 days; C depicts mice treated with 180,000 IU of IL-2 for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days; D depicts mice treated with 400,000 IU of IL-2 for 5 days; E depicts mice treated with 400,000 IU of IL-2 for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days.
Figure 2 depicts the effect of 4-((5)-2-((5)-2-(methoxycarbonylamino)-3-phenyl· propanamido]-2-[2-(thiophen-2-yl)thiazoI-4-yl]ethyl}phenylsuifamic acid ammonium salt, a Tie2 signal amplifier, on IL-2 induced shock in mice. A depicts the control sample; B depicts mice treated with 180,000 IU of IL-2 for 5 days; C depicts mice treated with 180,000 IU of IL-2 for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days; D depicts mice treated with 400,000 IU of IL-2 for 5 days; E depicts mice treated with 400,000 IU of IL-2 for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days.
Figure 3 depicts the effect of 4-{(5)-2-[(5)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfam.ic acid ammonium salt, a Tie2 signal amplifier, on IL-2 induced murine mortality, A depicts the control sample; B depicts mice treated with 180,000 IU of IL-2 for 5 days; C depicts mice treated with 180,000 IU of IL-2 for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days; D depicts mice treated with 400,000 IU of IL-2 for 5 days; E depicts mice treated with 400,000 IU of IL-2 for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days.
Figure 4 depicts the status of the animals of each group after treatment with High 1L~2 dosing with and without the Tie-2 signal amplifier, 4-{(5)-2-[(5)~2~(methoxycarbonylamirto)-3phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenylsulfamic acid ammonium, salt, A depicts the control sample; B depicts the status of mice treated with 400,000 IU of IL-2
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 for 5 days; C depicts status of mice treated with 400,000 IU of IL-2 for 5 days and 40 mg/kg of
D91 for the first 2 days, then at 20 mg/kg for 3 days.
Figure 5 depicts the rescue of mice from IL-2 induced hypotension and death. A represents the systolic blood pressure of C3H/HeN female mice treated with vehicle control. B represents the systolic blood pressure of C3H/HeN female mice treated with 400.000 IU of IL-2. C represents the systolic blood pressure of C3H/HeN female mice treated with 400,000 IU of IL2 and 40 mg/kg of compound D9L Measurements were taken after 5 days of treatment.
Figure 6 depicts mice (4/group) that were treated with 400,000 IU of IL-2 in combination with various doses of D91 over 5 days. A represents 0 mg/kg D91, B represents 1 mg/kg D91, C represents 3 mg/kg D91, D represents 10 mg/kg D91, and E represents 30 mg/kg D91.
Figure 7 depicts the level of blood urine nitrogen (BUN) in male C57BL6 mice injected i.p. with 0.2 mg E. coli lipopolysaccharides per 25 g body weight at 0 hours. Line (o) represents mice receiving only LPS and line (®) represents mice receiving LPS and 50 mg/kg of D91 at 0,
8, and 16 hours.
Figure 8 depicts the level of LPS-induced renal neutrophil infiltration at 24 hours in male C57BL6 mice injected i.p. with 0,2 mg E. coli lipopolysaccharides per 25 g body weight at 0 hours. A depicts the neutrophil infiltration in sham (conrol), B depicts the neutrophil infiltration in male C57BL6 mice injected i.p. with 0.2 mg E. coli lipopolysaccharides per 25 g body weight and 50 mg/kg of D91, C depicts mice receiving only LPS.
Figure 9a depicts a Western blot analysis showing the increase in pAKT and pERKI/2 when EA.hy962 cells were cultured in the presence of varying amounts of D91 for 10 minutes.
Figure 9b depicts a Western blot analysis showing the levels of pAKT, pERKl/2 and βActin when BA.hy962 cells were cultured in the presence of 10 gg/mL D91 from start (T “ 0) to 120 minutes.
Figure IGa is a micrograph of a renal section from a mouse treated with vehicle control that is subsequently injected with 70 kDa fluorescent fixable dextran by intravenous catheter 2 minutes prior to sacrifice. G indicates glomerular capillaries where the dye should normally be contained.
Figure 10b is a micrograph showing the vascular leakage in cells of a renal section from a mouse treat with LPS that is subsequently injected with 70 kDa fluorescent fixable dextran by
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 intravenous catheter 2 minutes prior to sacrifice. The 70 kDa fluorescent dextran is now significantly located in the interstitial space between the capillaries and the cells.
Figure 10c is a micrograph showing that vascular integrity is preserved as compared to LPS treatment for cells in a renal section from a mouse treated with LPS and D91 that is subsequently injected with 70 kDa of fluorescent fixable dextran by intravenous catheter 2 minutes prior to sacrifice. The pattern of staining in this section is similar to 10a.
DETAILED DESCRIPTION
The materials, compounds, compositions, articles, and methods described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein.
Before the present materials, compounds, compositions, articles, devices, and methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.
Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.
General Definitions
In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings:
All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C) unless otherwise specified.
By ’’pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint,
A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.
By “effective amount” as used herein means “an amount of one or more of the disclosed Tie-2 signal amplifiers,: effective at dosages and for periods of time necessary to achieve the desired or therapeutic result.” An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated.
Although particular dosage regimes may be described in examples herein, a person skilled in. the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of this disclosure can be administered as frequently as necessary to achieve a therapeutic amount.
“Admixture” or “blend” is generally used herein means a physical combination of two or more different components “Excipient” is used herein to include any other compound that may be contained in or combined with one or more of the disclosed inhibitors that is not a therapeutically or biologically active compound. As such, an excipient should be pharmaceutically or biologically acceptable or relevant (for example, an excipient should generally be non-toxic to the subject). “Excipient” includes a single such compound and is also intended to include a plurality of excipients.
As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human.
By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., vascular leakage). It is understood that this is
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to he referred to.
By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.
By “treat” or other forms of the word, such as “treated” or “treatment,” is meant to administer a composition or to perform a method in order to reduce, prevent, inhibit, breakdown, or eliminate a particular characteristic or event (e.g., vascular leakge). The disclosed compounds affect vascular leakage by inhibiting ΡΤΡ-β (and the rodent equivalent, VE-PTP) which enhances or amplifies Tie-2 signaling.
By “chemotherapeutic agent” is meant any drug, pharmaceutical or otherwise, that can be given to a subject as part of a combination therapy. Non-limiting examples of chemotherapeutic agents include anticancer drugs, for example, IL-2, taxol, and the like, antimicrobials, anti-virais, anti-fungicides, and the like.
Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.
As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such composi tions, reference to “a phenylsulfamic acid” includes mixtures of two or more such phenylsuifamic acids, reference to “the compound” includes mixtures of two or more such compounds, and the like.
“Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed, then “less than or equal to” the value, “greater than or equal to the value,” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed, then “less than or equal to 10” as well as “greater than or equal to 10” is also disclosed. It is also understood that throughout the application data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.
The following chemical hierarchy is used throughout the specification to describe and enable the scope of the present disclosure and to particularly point out and distinctly claim the units which comprise the compounds of the present disclosure, however, unless otherwise specifically defined, the terms used herein are the same as those of the artisan of ordinary skill. The term “hydrocarbyl” stands for any carbon atom-based unit (organic molecule), said units optionally containing one or more organic functional group, including inorganic atom comprising salts, inter alia, carboxylate salts, quaternary ammonium salts. Within the broad meaning of the term “hydrocarbyl” are the classes “acyclic hydrocarbyl” and “cyclic hydrocarbyl” which terms are used to divide hydrocarbyl units into cyclic and non-cyclic classes.
As it relates to the following definitions, “cyclic hydrocarbyl” units can comprise only carbon atoms in the ring (i.e.. carbocyclic and aryl rings) or can comprise one or more
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 heteroatoms in the ring (i.e., heterocyclic and heteroaryl rings). For “carboeyciic” rings the lowest number of carbon atoms in a ring are 3 carbon atoms; cyclopropyl. For “aryl” rings the lowest number of carbon atoms in a ring are 6 carbon atoms; phenyl. For “heterocyclic” rings the lowest number of carbon atoms in a ring is 1 carbon atom; diazirinyl. Ethylene oxide comprises 2 carbon atoms and is a Cj heterocycle. For “heteroaryl” rings the lowest number of carbon atoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl. The following is a non-limiting description of the terms “acyclic hydrocarbyl” and “cyclic hydrocarbyl” as used herein,
A, Substituted and unsubstituted acyclic hydrocarbyl:
For the purposes of the present disclosure the term “substituted and unsubstituted acyclic hydrocarbyl” encompasses 3 categories of units:
1) linear or branched alkyl, non-limiting examples of which include, methyl (Ci), ethyl {CT}, n-propyl (€3), iso -propyl (C3), n-butyl (Ci), sec-butyl (Ci), rio-butyl (Ci), ic/7-butyl (C4), and the like; substituted linear or branched alkyl, non-limiting examples of which includes, hydroxymethyl (CO, chloromethyl (CQ, trifiuoromethyi (Ci), aminomethyl (Ci), 1-chloroethyl (Cj), 2-hydroxyethyl (C?), 1,2-di fluoroethyl (C2), 3-carboxypropyl (C3), and the like.
2) linear or branched alkenyl, non-limiting examples of which include, ethenyl (C2), 3propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen2-yl) (C3), buten-4-yl (Co), and the like; substituted linear or branched alkenyl, nonlimiting examples of which include, 2-chloroethenyl (also 2-chlorovinyl) (CF), 4hydroxybuten-l-yl (€4), 7-hydroxy-7-methyloct-4-en-2-yl (C9), 7-hydroxy-7-methyloct3,5-dlen-2-yl (Cs), and the like.
3) linear or branched alkynyl, non-limiting examples of which include, ethynyl (Cf), prop-2ynyl (also propargyl) (C3), propyn-l-yl (C3), and 2-methyl-hex-4-yn-l-yi (C?); substituted linear or branched alkynyl, non-limiting examples of which include, 5hydroxy-5-methylhex-3-ynyl (C?), 6-hydroxy-6-methylhept-3-yn-2-yl (C§), 5-hydroxy-5ethylhept-3-ynyi (C9), and the like.
B. Substituted and unsubstituted cyclic hydrocarbyl:
For the purposes of the present disclosure the term “substituted and unsubstituted cyclic hydrocarbyl” encompasses 5 categories of units:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
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1) The term “carbocyclic” is defined herein as “encompassing rings comprising from 3 to 20 carbon atoms, wherein the atoms which comprise said rings are limited to carbon atoms, and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms.” The following are non-limiting examples of “substituted and unsubstituted carbocyclic rings” which encompass the following categories of units:
i) carbocyclic rings having a single substituted or unsubstifuted hydrocarbon ring, non-limiting examples of which include, cyclopropyl (C3), 2-methyl-cyclopropyl (C3), cyclopropenyl (Cj), cyclobutyl (€4), 2,3-dihydroxycycIobutyl (C«), cyctobutenyl (C-0, cyclopentyl (C5), cvclopentenyl (C5), cyclopentadienyl (C5), cyclohexyl (€¢), cyclohexenyl (Cg), cycloheptyl (C?), cyclooctanyl (Cg), 2,5-dimethylcycIopentyl (C5), 3,5-dichlorocyclohexyl (€¢), 4-hydroxycyclohexyl (Ce), and 3,3,5-trimethylcyclohex-l-yl (C6).
ii) carbocyclic rings having two or more substituted or unsubstituted fused hydrocarbon rings, non-limiting examples of which include, octahydropentalenyl (Cg), octahydro-l//-indenyl (C9), 3a,4,5,6,7,7a-hexahydro-3//-inden-4-yl (C9), decahydroazulenyl (Cjo).
iii) carbocyclic rings which are substituted or unsubstituted bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2,1 jbepianyl, bicyclo[3.1.1 Jheptanyl, 1,3-dimethyl[2.2. l]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
2) The term “aryl” is defined herein as “units encompassing at least one phenyl or naphthyl ring and wherein there are no heteroaryl or heterocyclic rings fused to the phenyl or naphthyl ring and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms.” The following are nonlimiting examples of “substituted and unsubstituted aryl rings” which encompass the following categories of units:
i) Cg or Cjs- substituted or unsubstituted aryl rings; phenyl and naphthyl rings whether substituted or unsubstituted, non-limiting examples of which include, phenyl (C0), naphthylen-l-yl (Cio), naphthylen-2-yl (Cjo), 4-ftuorophenyl (Cg), 2-hydroxyphenyl (Cg), 3-methylpheny 1 (€¢), 2-atnino-4-fluorophenyl (€¢), 2-(M/V-diethylamino)phenyl
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 (Ci). 2-cyanophenyl (Cg), 2,6-di-ter/-butylphenyl (Cg), 3-raethoxyphenyl (Cg), 8hydroxynaphthylen-2-yl (C^), 4,5-dimethoxynaphthylen-l-yl (Cm), and 6-cyanonaphthylen-l-yl (Cio).
ii) Cg or Cio aryl rings fused with 1 or 2 saturated rings to afford Cg-Cjo ring systems, non-limiting examples of which include, bicycio[4.2.0]octa-l,3,5-trienyl (Cs), and indanyl (C?).
3) The terms “heterocyclic” and/or “heterocycle” are defined herein as “units comprising one or more rings having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein further the ring which contains the heteroatom is also not an aromatic ring.” The following are non-limiting examples of “substituted and unsubstituted heterocyclic rings” which encompass the· following categories of units;
i) heterocyclic units having a single ring containing one or more heteroatoms, nonlimiting examples of which include, diaztrinyl (Ci), aziridinyl (C2), urazolyl (C?), azetidinyl (Cj), pyrazolidinyl (Cj), imidazolidinyl (Cj), oxazolidinyl (Cs), isoxazolinyl (Cj), thiazolidinyl (Cj), isothiazolinyl (C3), oxathiazolidinonyl (Ca), oxazolidinonyl (C3), hydantoinyl (Ca), tetrahydrofuranyl (C4), pyrrolidinyl (C4), morpholtny! (C4), piperazinyl (€4), piperidinyl (C4), dihydropyranyl (C5), tetrahydropyranyl (Cs), piperidin-2-onyl (valerolactam) (Cs), 2,3,4,5-tetrahydro-IH-azepinyl (C&), 2,3-dihydro-l//-indole (Cs), and 1,2,3,4-letrahydroquinoline (C9).
ii) heterocyclic units having 2 or more rings one of which Is a heterocyclic ring, nonlimiting examples of which include hexahvdro-l/Z-pyrrolizinyl (C?), 3a,4,5,6,7,7ahexahydro-l//-benz,o[d]imidazolyl (C?), 3a,4,5,6,7t7a-hexahydro-l//-indolyl (Cs),
1.23,4-tetrahydroquinolinyl (C9), and decahydro- l//-cycloocta[b]pyrrolyl (Cio).
4) . The term “heteroaryl” is defined herein as “encompassing one or more rings comprising from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein further at least one of the rings which comprises a heteroatom is an aromatic ring.” The following are non-limiting examples of “substituted and unsubstituted heterocyclic rings” which encompass the following categories of units:
Π
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
i) heteroaryl rings containing a Mngle ring, non-limiting examples of which include,
1,2,3,4-tetrazolyl (CQ, [l,2,3]triazolyl (C2), [l,2,4]triazolyl (Cf), triazinyl (C3), thiazolyl (C3), 1/7-imidazolyl (Cs), oxazolyl (C3), isoxazolyl (C3), isothiazolvl (C3), furanyl (C4), thiophenvl (C4), pyrimidinyl (C4)} 2-phenyipyrimidinyl (C4), pyridinyl (C5), 3methyipyridinyl (C5), and 4-dimethylaminopyridinyl (Cj) ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non-limiting examples of which include: 7/7-purinyl (Cj), 9/7-purinyl (C5), 6amino-9/Apurinyl (Cs), 5/f~pyrrolo[3,2-ri]pyrimidinyl (Cs), 7/7-pyrroio[2i3ifjpyrimidinyl (C<:). pyrido[2,3-d]pyrimidmyl (C?), 2-phenylbenzo[d]thiazolyl (C7), 1/7indolyi (Cg), 4,5,6,7-tetrahydro-l-//-indoiyl (Cg), quinoxalinyl (Cg), 5methylquinoxaiinyl (Cg), quinazolinyl (Cg), quinolinyl (€?), 8-hydroxy-quinoItnyl (C9), and isoqninolinyl (Cg).
5} Cj-Cs tethered cyclic hydrocarbyl units (whether carbocyclic units, Cs or Cio aryl units, heterocyclic units, or heteroaryl units) which connected to another moiety, unit, or core of the molecule by way of a Ci-Ce alkylene unit. Non-limiting examples of tethered cyclic hydrocarbyl units include benzyl Cj-(Cs) having the formula:
Figure AU2016203254B2_D0001
wherein Rfi is optionally one or more independently chosen substitutions for hydrogen. Further examples include other aryl units, inter alia, (2-hydroxyphenyl)hexyl C/-(CT); naphthalen-2-ylmethyl Cr(C-.g), 4-fluorobenzyi Ci^Ci), 2-(3-hydroxyphenyl)ethyl C2·· (Cfi), as well as substituted and unsubstituted C3-Cio alkylenecarbocyclic units, for example, cyclopropylmethyl Ci-(C3), eyclopentylethyl C2-(C5), cyclohexylmethyl Ci(Ce);. Included within this category are substituted and unsubstituted Cs-Cio alkyleneheteroaryl units, for example a 2-picolyl C|-(C6) unit having the formula:
Figure AU2016203254B2_D0002
wherein Ra is the same as defined above. In addition, C1-C12 tethered cyclic hydrocarbyl units include Ci-Cw alkyleneheterocyclic units and alkylene-heteroaryl units, nonlimiting examples of which include, aziridinylmethyl Cj-(C2) and oxazol-2-ylmethyl Cj12
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
For the purposes of the present disclosure carbocyelie rings are from Ca to C20; aryl rings are Cg or Cfo; heterocyclic rings are from C5 to Co; and heteroaryl rings are fora C[ to C9.
2016203254 18 May 2016
For the purposes of the present disclosure, and to provide consistency in defining the present disclosure, fused ring units, as well as spirocyciic rings, bicyclic rings and the like, which comprise a single heteroafom will be characterized and referred to herein as being encompassed by the cyclic family corresponding to the heteroatom containing ring, although the artisan may have alternative characterizations. For example, 1,2,3,4-tetrahydroquinoline having the formula:
H is, for the purposes of the present disclosure, considered a heterocyclic unit. 6,7-Dihydro-5/fcyclopentapyrimidine having the formula:
is, for the purposes of the present disclosure, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated ring (heterocyclic ring) and an aryl ring (heteroaryl ring), the aryl ring will predominate and determine the type of category to which the ring is assigned herein, for the purposes of describing the invention. For example, 1,2,3,4-tetrahydro[l,8]naphthpyridine having the formula:
Figure AU2016203254B2_D0003
is, for the purposes of the present disclosure, considered a heteroaryl unit.
The term “substituted” is used throughout the specification. The term “substituted” is applied to the units described herein as “substituted unit or moiety is a hydrocarbyl unit or moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below.” The units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring (aryl ring)”, (N,Ndimethyi-5-amino)octanyl is a “ substituted Cg linear alkyl unit, 3~guanidinopropyl is a “substituted €3 linear alkyl unit,” and 2-carboxypyridinyi is a “substituted hcteroaryl unit.”
The following are non-limiting examples of units which can substitute for hydrogen atoms on a carbocyclic, aryl, heterocyclic, or heteroaryl unit:
i) Ci-Cis linear, branched, or cyclic alkyl, alkenyl, and alkynyl; methyl (Cj), ethyl (C2), ethenyl (C2), ethynyl (Cfo, n-propyl (€3), iso-propyl (C3), cyclopropyl (C3), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2methylethcn-2-yl) (C3), prop-2-ynyl (also propargyl) (C3), propyn-l-yl (C3), nbutvl (C4), s’ec-butyi (Q), /so-butyl (C4), iert-butyl (C4), cyclobutyl (C4), buten-4 yl (€4), cyclopentyl (Cs), cyclohexyl (C<s);
substituted or unsubsiituted Cg or Cjq aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Cie) or naphthylen-2-yl (Cw)); substituted or unsubstituted €<$ or Cw alkylenearyl; for example, benzyl, 2phenylethyl, naphthylen-2-yImethy 1;
substituted or unsubstituted Ci-C<s heterocyclic rings; as described herein below; substituted or unsubsiituted Ci-Cg heteroaryl rings; as described herein below; -<CR102aR!02\OR10!; for example, -OH, ~CH2GH, -OCH3, -CH2OCH3,
I2CH3, “CH2OCH2CH3, -GCH2CH2CH3, and CHjOCFLCHT ii) iv)
v) vi) vii) -CCRi02aRW2!,)aCiO)Ri0i; for example, -COCH3} -CH2COCH3, - COCH2CH3, viii) ix) 2COCH2CH3j -COCH2CH2CH3s and -CH2COCH2CH2CH3; ~(CR!02sRltKb)aC(O)ORi0!; for example, -CO2CH3j CH2CO2CH.:, CO2CH2CH3> -CH2CO2CH2CH3, ~CO2CH2CH2CH3s and -CH2CO2CH2CH2CH3;
-(CRI02sRW2b)#C(O)N(Rl0l)2;· for example, -CGNH>, ~€H2CONH2, CONHCHj, -CH2CONHCH3, -CON(CH3)2s and -CH2CON(CH3)2;
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
x) ~(CRlO2aRW2b)aN(Rl0l)2; for example, <-NH& ™CH2NHCH3,
-N(CH3)2s and ~CH2N(CH.,)2;
xi) halogen; -F, ~Cl, -Br, and -I;
xii) “(CRl02aRi03b)aCN; xifi) ~(CRi02aRwzb)aNO2;
xiv) -CHsXj-; wherein X is halogen, the index j is an integer from 0 to 2. j + k —3; for example, -CH2F, -CHFj, -CF3, -CC13, oro~CBr3;
xv) 4CR?®V32b)aSRl0s; · SH, CH2SH, -SCFl·., CH2SCH3, -SCt;Hs and CH2SC6H5;
xvi) -(CRiO2aRW2b)aSG2R!Oi; for example, -SO2H, ~CH2SO2H, -8O2CH3s CH2SO2CH3s -SO2C6H5, and -CH2SO2C6H5; and xvii) 4eR102#R?02b)aSQ3R!<H; for example, ~SO3H, -CH2SO3H, -SO3CH3, CH2SO3CH3, -SO3C6Hs, and -CHzSOjC^Hs;
wherein each RW1 is independently hydrogen, substituted or unsubstituted Cj-Q linear, branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two Rws units can be taken together to form a ring comprising 3-7 atoms; RW2k and R!02b are each independently hydrogen or Cj-C4 linear or branched alkyl; the index “a” is from 0 to 4.
For the purposes of the present disclosure the terms “compound, “analog,” and “composition of matter” stand equally well for each other and are used interchangeably throughout the specification. The disclosed compounds include all enantiomeric forms, diastereomerie forms, salts, and the like.
The compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids. The following are non-limiting examples of anions that can form salts with protonated basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, 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.
The disclosed compounds have Formula (I):
IS
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST wherein the carbon atom having the amino unit has the (S) stereochemistry as indicated in the following formula:
2016203254 18 May 2016
Figure AU2016203254B2_D0004
0, O ¥
HO N
Figure AU2016203254B2_D0005
The unite which comprise R and Z can comprise units having any configuration, and, as such, the disclosed compounds can be single enantiomers, diastereomeric pairs, or combinations thereof.
In addition, the compounds can be isolated as salts or hydrates. In the case of salts, the compounds can comprises more than one cation or anion. In the case of hydrates, any number of water molecules, or fractional part thereof (for example, less than 1 water molecule present for each molecule of analog) can be present.
R is a substituted or unsubstituted thiazolyl unit having the formula:
Figure AU2016203254B2_D0006
R2, R5, and R4 are substituent groups that can be independently chosen from a wide variety of non-carbon atom containing units (for example, hydrogen, hydroxyl, amino, halogen, nitro, and the like) or organic substituent units, such as substituted and unsubstituted acyclic hydrocarbyl and cyclic hydrocarbyl units as described herein. The carbon comprising units can comprise from 1 to 12 carbon atoms, or I to 10 carbon atoms, or I to 6 carbon atoms.
An example of compounds of Formula (I) include compounds wherein R units are thiazol-2-yl units having the formula:
Figure AU2016203254B2_D0007
A wherein R and R' are each independently chosen from:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
i) hydrogen;
ii) substituted or unsubstituted C;~C<. linear, branched, or cyclic alkyl;
iii) substituted or unsubstituted Cs-C* linear, branched, or cyclic alkenyl;
iv) substituted or unsubstituted C;~C<; linear or branched alkynyl;
v) substituted or unsubstituted C® or C w ary 1;
vi) substituted or unsubstituted C1-C9 heteroaryl, vh) substituted or unsubstituted C1-C9 heterocyclic; or vi») IC and R? can be taken together to form a saturated or unsaturaied ring having from 5 to 7 atoms; wherein from 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 R2 and F? units. The following substituents, as well as others not herein described, are each independently chosen:
i) CrCt2 linear, branched, or cyclic alkyl, alkenyl, and alkynyl; methyl (CO, ethyl (C2), ethenyl (C2), ethynyl (C2), n-propyl (C3), wo-propyl (C3), cyclopropyl (C3), 3-propenyI (CQ, 1-propenyl (also 2-methySethenyl) (C3), isopropenyl (also 2meihylethen-2-yl) (C3), prop-2 -ynyl (also propargyl) (C3), propyn-l-yl (C3), nbutyl (CQ, rec-butyl (CQ, Zso-butyl (CQ, iert-butyl (C4), cyclobuiyl (CQ, buten-4 yl (CQ, eyelopentyl (C5), cyclohexvl (CQ;
ii) substituted or unsubstituted C$ or Cm aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Cm) or naphthylen-2-yl (C30));
hi) substituted or unsubstituted Cg or Cw alkylenearyl; for example, benzyl, 2phenylethyl, naphthylen-2-ylmethyl;
iv) substituted or unsubstituted Cs-Cp heterocyclic rings; as described herein;
v) substituted or unsubstituted Cs-C<j heteroaryl rings; as described herein;
vi) -<CR2UR2'%ORW; for example, -OH, -CH2OH, ~OCH3,-CH2OCH3, OCH2CH-CH2OCHgCH3, »OCH2CH2CH3> and -CH2OCH2CH2CH3;
vii) -CCR2UR2?b)pC(O)RMj for example, -COCHj, -CH2COCH3i -€OCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3, and ~CH2COCH2CH2CH3;
viii) -(CR21aR25b)PC(O)OR20; for example, ~CO2CH3, ~CH2CO2CH3, ~CO2CH2CH3, < CH2CO2CH2CH3, -CO2CH2CH2CH3, and -CH2CO2CH2CH2CH3;
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
x) -iCR2iaR2ib)f,C(Q)N(R2<5)2; for example, -C0NH2s ~CH2C0NHj, -C0NHCH j, CH2CONHCH3s -CON(CH3)2, and -CH2CON(CH3>;
x) --(CR2iaR21b)pN(R20)2; for example, -NH2, -CH2NHS:, -NHCft, ™€HSNHCH^ N(CH3)2, and-CH2N(CH3)2;
xi) halogen; -F, -Ci, -Br, and -I;
xii) ~(CR2!aR2Eb)pCN;
xiii) -(CR2isR2Eb)pNO2;
xiv) ~(CHj’Xk')hCHjX]s; wherein X is halogen, the index j is an integer from 0 to 2, j T k - 3, the indexj’ is an integer from 0 to 2, j’ + k’ -2, the index h is from 0 to 6; for example, -CH2F, -CHF2, -CF3, -CH2CF3, -CHFCF3, ~CCb or -CBr3;
xv) -(CR2!aR2ib)pSR20; ASH, -CH2SH, -SCH3, -CH2SCH3, -SC(,H<, and CH2SC6H5;
xvi) ~<CR2EflR2!b)PSO2R20; for example, ~SG2H, ~CH28G2HS -SQ2CH3,
CH2SO2CH3, ~SO2C6HSj and:>CH2SO2C6H5; and xvii) ~(CR21aRSii’)pSO3R2ii; for example, SO3H, -CHiSOsH, -SO3CH3,
CH2SO3CH3, -SO3C6H5, and -OTSOsCA;
wherein each R is independently hydrogen, substituted or unsubstituted CrC4 linear, branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R20 units can be taken together to form a ring comprising 3-7 atoms; R2tS and R2ib are each independently hydrogen or C{~C4 linear or branched alkyl; the index p is from 0 to 4.
An example of compounds of Formula (Ϊ) includes R units having the formula;
Figure AU2016203254B2_D0008
wherein R3 is hydrogen and R2 is a unit chosen from methyl (Cs), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec -butyl (C4), Ao-hutyl (C4), tert-butyl (C4), n-pentyl (Cs), 1methylbutyl (Cs), 2~methyifautyl (Cs), 3-methylbutyl (Cj), cyclopropyl (C3), n-hexyl (Cg), 4methylpentyl (Cg), and cyclohexyi (Cg).
Another example of compounds of Formula (Ϊ) include R units having the formula;
Figure AU2016203254B2_D0009
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 wherein R2 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), ,«c~butyl (C4), wo-butyl (C4), and iert-butyl (Q); and R3 is a unit chosen from methyl (C3) or ethyl (C2). Non-limiting examples of this aspect of R includes 4,5-dimethylthiazol-2-yl, 4ethyi-5-methyiihiazoI-2-yl, 4-methyl-5-ethylthiazol-2-yl, and 4,5-diethylthiazol-2-yf.
A further example of compounds of Formula (I) includes R units wherein R3 is hydrogen and R; is a substituted alkyl unit, said substitutions chosen from:
I) halogen: ~F, -Cl, - Br, and -1;
ii) -N(RH)i;and iii) OR A, wherein each R!! is independently hydrogen or C1-C4 linear or branched alkyl. Non-limiting examples of units that can be a substitute for a R2 or R3 hydrogen atom on R units include · CH2F, -CHF2, -CF3s -CHiCFa, -€Η2€Η?εΡ3, -CH2C1, »CH2OH, ~CH2OCHJs -CHSCH2GH, CH2CH2OCH3, -CH2NHj, -CH2NHCH3i -CH2N(CH3)2, and ~-CH2NH(CH2CH3).
Further non-limiting examples of units that can be a substitute for a R2 or R3 hydrogen atom on R units include 2,2-difluorocyclopropyl, 2-meihoxycyclohexyl, and 4-chlorocyclohexyl.
A yet further example of compounds of Formula (I), R. units include units wherein P? is hydrogen and Rz is phenyl or substituted phenyl, wherein non-limiting examples of R2 units include phenyl, 3,4-dimethylphenyI, 4-rert-butylphcnyl, 4-cyclopropylphenyl, 4diethyiaminophenyi, 4-{trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 3-chloropheny, 4-ohlorophenyl, and 3,4-dichlorophenyl, which when incorporated info the definition of R affords the following R units 4-phenylthiazol-2-yI,
3,4-dimethylphenylthiazoi-2-yl, 4-rerf-butyiphenylthiazol-2-yl, 4-cyclopropylphenylthiazol~2-yh 4-die.ihylaminophenylthiazol-2-yl3 4-(trifluoromethyl)phenylthiazol-2-yl, 4methoxyphenylthiazol-2-yl, 4-(difluoromethoxy)phenylfhiazol-2-yl, 4(trifiuoromeihoxy)phenylthiazol-2-yl, 3-chiorophenylthiazo!-2~yl, 4-chlorophenylthiazol-2-yI, and 3,4-dichloropheny lthiazol-2 ~yI.
A still further example of compounds of Formula (I) includes R unite wherein R2 is chosen from hydrogen, methyl, ethyl, n-propyl, and isopropyl and R3 is phenyl or substituted phenyl, A non-limiting example of a R unit according to the fifth aspect of the first category of R units includes 4-methyl-5-phenylthiazol-2-yl and 4-ethyl-5-phenylthiazol-2-yl.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Another further example of compounds of Formula (I) includes R units wherein R3 is hydrogen and R2 is a substituted or unsubstituted heteroaryl unit chosen from l,2,3,4-tetrazol~I~ yl ,1,2,3,4-tetrazol-5-yi, [1,2,3]triazol-4-yi, [ 1,2,3]triazol~5~yl, [l,2.4]triazol“4-yl, [ 1,2,4] triazol5-yl, imidazol-2-yl, imidazol-4-yl, pyrroi-2-yl, pyrrol-3-yl, oxazoi~2~yl, oxazoi-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yS, isoxazol-5-yl, [l,294]oxadiazol-3-yi, [S,2,4]oxadiazol-5-yl, [1.3.4] oxadiazol-2-yl, furan-2-yl, foran-3-yi, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yJ, isothiazoM-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5~yl, [l,2,4]thiadiazol~3-yl, (1.2.4] thiadiazoi-5-yl, and [l,3,4]thiadiazol-2-yl.
Further non-limiting example of compounds of Formula (I) includes R units wherein R2 is substituted or unsubstituted thiophen-2-yl, for example thiophen-2-yl, 5-chlorothiophen-2-yl, and 5-methylthiophen-2-yl.
A still further example of compounds of Formula (I) includes R units wherein R2 is substituted or unsubstituted thiophen-3-yIs for example thiophen-3-yl, 5-chIorothiophen-3-yl, and 5-methylthiophen-3-yl.
Another example of compounds of Formula (I) includes R units wherein R2 and R3 are taken together to form a saturated or unsaturated ring having from 5 to 7 atoms. Non-limiting examples of the sixth aspect of the first category of R units include 5,6-dihydro-4/f~ cyclopenta[i/]thiazol~2~yl and 4,5,6,7-teirahydrobenzo[6Qthiazol-2-yL
Further examples of compounds of Formula (1) include R units that are thiazol~4~yl units having the formula:
Figure AU2016203254B2_D0010
wherein R2 is a unit chosen from:
i) hydrogen;
ϋ) substituted or unsubstituted Ci-Cg linear, branched, or cyclic alkyl;
iii) substituted or unsubstituted Cj-Ce linear, branched, or cyclic alkenyl;
iv) substituted or unsubstituted C$-C<s linear or branched alkynyl;
v) substituted or unsubstituted Cs or Cw aryl;
vi) substituted or unsubstituted Ci-Cs heteroaryl; or vii) substituted or unsubstituted Ci-Cj» heterocyclic.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
The following are non-limiting examples of units that can substitute for one or more hydrogen atoms on the R4 units. The following substituents, as well as others not herein described, are each independently chosen:
i) CpCn linear, branched, or cyclic alkyl, alkenyl, and alkynyl; methyl (Cj), ethyl (Ca), ethenyl (C2), ethynyl (Ci), n-propyl (C3), iso-propyl (C3), cyclopropyl (C3)> 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2methylethen-2-yl) (C3), prop-2-ynyl (η/,so propargyl) (C3), propyn-l-yl (C3), nbutyl (CQ, sec-butyl (C4), iso-butyl (C4), tert-butyl (C4), cyclobutyl (CQ, buten-4yl (C4), cyclopentyl (Cs), cyclohexyl (Cs);
it) substituted or unsubstituted Cg or Cio aryl; for example, phenyl, naphthyl (also referred fo herein as naphthylen-l-yl (Cho) or naphthylen-2-yl (Cto));
iii) substituted or unsubstituted Cfl or Cto alkylenearyl; for example, benzyl, 2phenylethyi, naphthylen-2-ylmethyl;
iv) substituted or unsubstituted C1-C9 heterocyclic rings; as described herein below;
v) substituted or unsubstituted CrC<> heteroaryl rings; as described herein below;
vi) -(CR2hlR2ib)pOR2G; for example, -OH, -CH2QH, OCH3, ~CH2OCH3s OCH2CH3, -CH2OCH2CH3> ™OCH2CH2CH3, and CH2OCH2CH2CH3;
vh) -(CR2iaR2Sb)pC(O)R20; for example, -COCH3, CHjCOCH.?, COCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3, and-CH2COCH2CH?CH3;
viii) -(CR2!i,R2ib)pC(O)OR20; for example, -CO2CH3, -CH2CO2CH3j ~CO2CH2CH3, CH2CO2CH2CH3, -CO2CH2CH2CH35 and -CH2CO2CH2CH2CH3;
xi) -(CR2;aR2ib),C(O)N(R2'))2; for example, -CONH2, -CH2CONH2, -CONHCHj, CH2CONHCH - CON(CH3)2, and -CH2CON(CH3)2;
x) -TCR2iaR2!b);3N(R2fl)2; for example, -NH2, ~CH2NH2, -NHCH3s -CH2NHCH3, ™ N(CH3)2, and -CH2N(CH3)2;
xi) halogen; -F, -Cl, -Br, and ~I;
xii) -(CR21aR2!b)pCN;
xiii) -fCR2iftR2ib)pNO2; xiv) -(CHj’Xk’)hCHjXk; wherein X is halogen, the index j is an integer from 0 fo 2, j + k -3, the index j’ is an integer from 0 to 2, j’t k’ 2, the Index h is from 0 to 6; for example, -CH2F, -€HF2, ~CF3, -~CH2CF3, CHFCF3, ~CC13, or -CBr3;
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 xv) -(CR^R^SR20; -SH, -CH2SH, -SCHj, -CH2SCH3, ~SC6%, and CHjSQHj;
xvi) -iCR2iBR2ib)pSO2R20; for example, -SO2H, -~CH2SO2H, -SOgCHj,
CH2SO2CH3, -SO2C6H5, and CH2SO2C0H5; and xvii) ~(CR21*R21b)pSO3R20; for example, -SO3H, --CH1SO3H, -SO3CH3,
CH2SO3CH3, -SOiQHj, and -CH2SO3C6H5;
wherein each Ri0 is independently hydrogen, substituted or unsubstituted C;-C4 linear, branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R20 units can be taken together to form a ring comprising 3-7 atoms; R2!a and R2lb are each independently hydrogen or C1-C4 linear or branched alkyl; the index p is from 0 to 4.
An example of compounds of Formula (I) includes R units wherein R4 is hydrogen.
A further example of compounds of Formula (I) includes R units wherein R4 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (Cj), n-butyl (Q), sec-butyl (C4), iso-butyl (Gj), and tert-butyl (C4). Non-limiting examples of this aspect of R includes 2methylthiazoI-4-yl, 2-eihyIthiazol-4-vlf 2-(n~propyl)thiazol-4-yl, and 2-(wo-propyl)thiazol-4-yl.
A still further example of compounds of Formula (1) includes R units wherein R4 is substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2fluorophenyl, 2-chlorophenyl, 2-methyiphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4methyiphenyl, and 4~methoxyphenyL
Yet further example of compounds of Formula (I) includes R units wherein R4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include ihiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazoi-5-yl, 2,5-dimethylthiazol-4-yl, 2,4dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and 3-methyl1,2s4-oxadiazoi~5-yl.
Another example of S-member ring R units includes substituted or unsubstituted imidazolyl units having the formula:
Figure AU2016203254B2_D0011
One example of imidazolyl R units includes imidazol-2-yl units having the formula:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0012
wherein Rx and R3 are each independently chosen from;
i) hydrogen;
ii) substituted or unsubstituted Cj-Cf, linear, branched, or cyclic alkyl;
ίϋ) substituted or unsubstituted Cz-Cg linear, branched, or cyclic alkenyl;
iv) substituted or unsubstituted C2-C<s linear or branched alkynyl;
v) substituted or unsubstituted Cg or Cjo aryl;
vi) substituted or unsubstituted C ί ~C§ heteroaryl;
vii) substituted or unsubstituted C1-C9 heterocyclic; or viii) R2 and RJ can he taken together to form a saturated or unsaturated ring having from 5 to 7 atoms; wherein from 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 R3 and R units. The following substituents, as well as others not herein described, are each independently chosen;
i) Ci-Cji linear, branched, or cyclic alkyl, alkenyl, and alkynyl; methyl (Ci), ethyl (Q), ethenyi (C2), ethynyl (G), n-propyl (C3), iso-propyl (C3), cyclopropyl (C3), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2mefhyiethen-2-yl) (C3)s prop-2-ynyl (οΖϊο propargyl) (C3), propyn-l-yl (C3), n~ butyl (C<j), sec-butyl (C4), «ο-butyl (G), ferz-butyl (C4), cyclobutyl (G), buten-4 yl (G), cyclopentyl (Cj), cyclohexyl (Ce);
ii) substituted or unsubstituted G, or Go aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Cjo) or naphthylen-2-yi (Go));
iii) substituted or unsubstiluted G or Go alkylenearyl; for example, benzyl, 2phenylethyl, naphthylen-2-ylmethyl;
iv) substituted or unsubstituted G-G heterocyclic rings; as described herein;
v) substituted or unsubstituted G-G heteroaryl rings; as described herein;
vi) for example, -OH, ~CH20H, -OCH3, -CH2OCH3, OCH2CH.s, -CH2OCH2CH3s OCH2CH2CH3s and -CH2OCH2CH2CH3;
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 vii) ~(CR2!liR2ib)2C(O)R20; for example, -COCH3, -CH2COCH3, -CGCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3) and -CH2COCH2CH2CH3;
viii) -(CR21aR2Sb)2C(O)OR20; for example, -CO2CH3, -CH2CO2CH3, -CO2CH2CH3, CH2CO2CH2CB3, -CO2CH2CH2CH3, and -CH2CO2CH2CH2CH3;
xii) ~(CR2!aR21b)zC(O)N(R20)2; for example, -CGNH2, -CH2CONH2, -CONHCH3, CH2CONHCH3,-CON(CH3)2, and ~CH2CON(CH3)2;
x) -(CR2l8R2ib)zN(R2is)2; for example, -NH2, -CH2NH2, -NHCH3, -CH2NHCH3, N(CH3)2, and CH2N(CH?,)2;
xi) halogen; ™F, '-Cl, -Br, and 1;
xii) (CR2iaR2!b}?CN;
xiii) -(CR2iaR2ib)zNO2;
xiv) · (CH;-Xk’)hCHjXk; wherein X is halogen, the index j is an integer from 0 to 2, j 4 k ® 3, the index j ’ Is an integer from 0 to 2, j’ + k’ ~ 2, the index h is from 0 to 6; for example, ~CH2F, -CHF2, ~CF3, -CH2CF3, ~€HFCF3, -CCl3> or -CBr3;
xv) ~(CR2UR2!b)zSRM; -SH,-CH2SHi-SCHJ,-CH2SCH3i-SC6H5, and
CH2SC6H5;
xvt) -(CR21aR2ib)zSO2R20; for example, -SO2H, -CH2SO2H, -SO2CH3,
CH2SO2CH3, -SOjCkHj, and —CH2SO2C.5H5; and xvii) -(CR2iaR2ib)zSO3R20; for example, -SO3H, -CH2SO3H, -SO3CH3,
CH2SO3CH3, -SChCsHj, and ~€H2SO3C6H5;
wherein each R20 is independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R20 units can be taken together to form a ring comprising 3-7 atoms: R2ia and R2ib are each independently hydrogen or C1-C4 linear or branched alkyl; the index p is from 0 to 4.
One example of R units includes compounds wherein R units have the formula:
Figure AU2016203254B2_D0013
wherein R3 is hydrogen and R2 is a unit chosen from methyl (CQ, ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (¢4), sec-butyl (CO, Bo-butyi (C4), and fert-butyl (C4).
Another example of R units includes compounds wherein R2 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), Bo-butyl (C4), and
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 tert-butyl (C4); and R3 is a unit chosen from methyl (CO or ethyl (C2). Non-limiting examples of this aspect of R includes 4,5-dimethySimidazol~2~yl, 4-ethyl-5-methylimidazol-2~yl, 4-methyi-5~ ethyhmidazol-2-yl, and 4,5-diethylimidazoi-2-yi.
An example of R units includes compounds wherein RJ is hydrogen and R2 is a substituted alkyl unit chosen, said substitutions chosen from:
i) halogen: -Fs -Cl, -Br, and -I;
ii) ~N(RU)2; and iii) -OR”;
wherein each Rl! is independently hydrogen or Ci~C7 linear or branched alkyl.
Non-limiting examples of units comprising this embodiment of R includes: -CHjF, -CHF2, -CF3j ~CH2CF3i CHjCk -CHjOH, -€H2OCH3i -CH2CH2OH, -CH2CH2OCH3, CH2NH2, -CH2NHCH3j ~CH2N(CH,)2s and -€H2NH(CH2CH3).
A yet further example of R units include units wherein R3 is hydrogen and R2 is phenyl,
A still further example of R units include units wherein R3 is hydrogen and R2 is a heteroaryl unit chosen from 1,2,3,4-tetrazoM ~yl ,1,2,3,4-(6ίΓ&ζο1-5-γ1, [l,2,3]triazol-4~yl, [152,3]triazol-5-yl, [l,2,4]triazoi”4-yl, [l,2,4]triazol-5-yl, smtdazol-2-yl, irnidazol-4-yL pyrrol-2-yl, pyrrol-3-yf oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, (l,2s4]oxadiazoI-3-yl, [1,2,4]oxadiazol-5-vl, [l,3,4]oxadiazol-2-yk furan-2-yl, furan-3-yS, thiophen-2-yl, thiophen-3-yl, isothiazoi-3-yi, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yh thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol~5~yl, and [1,3,4]thiadiazol-2yl.Z Units
Z is a unit having the formula:
(L)rRs
R? is chosen from:
i) hydrogen;
ii) hydroxyl;
di) amino;
iv) substituted or unsubstituted CrCs linear, branched or cyclic alkyl;
v) substituted or unsubstituted Cs-Cc linear, branched or cyclic alkoxy;
vi) substituted or unsubstituted Cg or Cso aryl;
vii) substituted or unsubstituted C1-C9 heterocyclic rings; or
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 viii) substituted or unsubstituted C;~Cy heteroaryl rings.
The following are non-limiting examples of units that can substitute for one or more hydrogen atoms on the R1 units. The following substituents, as well as others not herein described, are each independently chosen:
i) C1-C12 linear, branched, or cyclic alkyl, alkenyl, and alkynyl; methyl (C0, ethyl (C2), ethenyl (C2), ethynyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), 3-propenvl (C3), l-propenyl (also 2-methyiethenyl) (Cj), isopropenvl (also 2methy lethen-2-yl) (C3), prop-2-ynyl (a&o propargyl) (C3), propyn-l-yl (C3), nbutyl (C4), sec-butyl (C4), /so-buty 1 (Cb), tert-butyl (C4), cyclobutyl (C4), bnteo-4 yl (C4), cyclopentyl (Cj), cyclohexyl (Cg);
ii) substituted or unsubstituted Q or Cw aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Gw) or naphthylen-2-yl (Cw));
iii) substituted or unsubstituted Q. or Cm alkylenearyl; for example, benzyl, 2phenyieihyi, naphthylcn-2-ylmethyl;
iv) substituted or unsubstituted Ct-G? heterocyclic rings; as described herein;
v) substituted or unsubstituted Ct-Cs heteroaryl rings; as described herein;
vi) -(CR3 Si!R3 lb),OR30; for example, -OH, ~CH2QH, -OCH3, CH-OCik OCH2CH3, - ~CH2OCH2CH3, OCHzCH2CH3, and CH2OCH2CH2CH3;
vii) -(CR3iaR3!b)(iC(O)R30; for example, -COCH3j -CH2COCH3, ~€OCH2CH3i -CH2COCH2CH3, -COCH2CH2CH3, and'CH2COCH2CH2CH3;
νϋΐ) -(CR31aR3ib)qC(O)OR30; for example, -COjCHa, CHjCO2CH;, CO2CH2CH3, ~ CH2CO2CH2CH3, -CO2CH2CH2CH3, and -CH2CO2CH2CH2CH3;
xiii) -(CR3!aR31\C<O)N(RM)2; for example, ~C0NH& -€H2CONH2, ~CONHCH3, CH2CONHCH3s CONOR):;. and -CH2CON(CH3)2;
x) ~(CR3iBR31s\N(R3O)2; for example, -NH2, -CH2NH2, ~NHCH3, -CH2NHCH3, N(CH3)2, and -CH2N(CH3)2;
xi) halogen; -F, -Cl, -Br, and -J;
xii) -<CR3iaR3!b)qCN;
xiii) HCR33eR35b)qNO2;
to
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 xiv) -(CHj’Xk’XCHjXk; wherein X is halogen, the index j is an integer from 0 to 2, j A: k = 3, the index j’ is an integer from 0 to 2, j! + k’ - 2, the index h is from 0 to 6: for example, -CH2F, -CHF?., -CF5, ~CH2CF3, -CHFCF3, -CC13, or ™CBr3;
xv) --(CR''i3Ri;%SR30; -SH, -CH2SH, -SCH3, ~CH2SCH3, -SCgHj, and CH2SC6H5;
xvi) ~(CR3,aR3li>)qSO2R30; for example, -SO2H, -CH2SG2H, -SOjCHj,
CH2SO2CH3, -SOzGsHs, and ~-CH2SG2C0H5; and xvii) -(CR31aR31b)qSO3R30; for example, -SO3H, -CHgSO3H, --SO3CH3,
CH2SO3CH3, -SOjCsHs, and -CH2SO3C6Hs;
wherein each Ryi is independently hydrogen, substituted or unsubstituted C-rCg linear, branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R30 units can be taken together to form a ring comprising 3-7 atoms; R31a and R3!b are each independently hydrogen or C1-C4 linear or branched alkyl; the index q is from 0 to 4.
One example of R* units includes substituted or unsubstituted phenyl (Cg aryl) units, wherein each substitution is independently chosen from: halogen, C1-C4 linear, branched alkyl, or cyclic alkyl, -OR11, -CN, -N(R!i)2, -CO2Rn, -C(O)N(Ru)2s ANRuC(O)Rn, ~NO2, and SO2R1!; each R11 is independently hydrogen; substituted or unsubstituted C1-C4 linear, branched, cyclic alkyl, alkenyl, or alkynyi; substituted or unsubstituted phenyl or benzyl; or two Rn units can be taken together to form a ring comprising from 3-7 atoms.
Another example of R1 units includes substituted C<> aryl units chosen from phenyl, 2fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2.3-difluorophenyl, 3,4-difluorophenyl, 3,5difTuorophenyl, 2-ehlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichiorophenyl, 3,4dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4dimethoxyphenyl, and 3,5-dimethoxyphenyl.
A further example of R1 units includes substituted or unsubstituted Ce aryl units chosen from 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5trichlorophenyl, and 2,4,6-trichlorophenyk
This data, for appfication number 20f42022f f, is current as of 20f6-05-f6 2f :00 AEST
2016203254 18 May 2016
A yet further example of R! units includes substituted Ce aryl units chosen from 2methylphenyl, 3-methylphenyl, 4-methylphenyi, 2,3-dimethylphenyl, 2,4-dimethylphenvl, 2,5dimethylphenyl, 2,6-dimethyiphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5trimethylphenyl, 2,3,6-trimeihylphenyl, 2,4,5-trimethylphenyi, 2,4,6-trimefhylphenyl, 2ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyI, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 2-isopropylphenyl, 3isopropylphenyl, and 4-isopropylphenyl.
Another still further example of R! units includes substituted Cg aryl units chosen from 2 aminophenyl, 2-(77-methylamino)phenyl, 2-(77,jV~dimethylamino)phenvi, 2-(/7ethyiamino)phenyl, 2-(W,/7-diethyIamino)phenyl, 3-aminophenyi, 3-(/7-methylamino)phenyl, 3(77,Ar-dimethylamino)phenyl, 3-(;V-ethylamino)phenyI, 3-(77,77-diethylamino)phenyl, 4aminophenyl, 4-(/7-methylamino)phenyl, 4-(A]77-dimethylamino)phenyl, 4-(77ethylamino)phenyl, and 4-(/V,Ar-diethylamino)phenyl.
P? can comprise heteroaryl units. Non-limiting examples of heteroaryl units include:
Figure AU2016203254B2_D0014
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
Ν·
J
2016203254 18 May 2016 vi) vii) viii) ix)
x) xi) xii) xfii) xiv) “W
O'
N'
0.
Figure AU2016203254B2_D0015
Figure AU2016203254B2_D0016
Figure AU2016203254B2_D0017
,G
V-N· ,o
Figure AU2016203254B2_D0018
Figure AU2016203254B2_D0019
Figure AU2016203254B2_D0020
Ns SN . J , br ; and
-K
-N
R. heteroaryl units can be substituted or unsubstituted. Non-limiting examples of units that can substitute for hydrogen include units chosen from:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
i) C'rCs, linear, branched, and cyclic alkyl;
ii) substituted or unsubstituted phenyl and benzyl;
hi) substituted of unsubstituted C1-C9 heteroaryl;
iv) -C(O)R9; and
v) -NHCiOiR5, wherein R9 is Cj-Cg linear and branched alkyl; Cj-Cg linear and branched alkoxy; or NHCFbCiOjR10; Rlsi is chosen from hydrogen, methyl, ethyl, and Zert-butyL
An example of R* relates to units substituted by an alkyl unit chosen from methyl, ethyl, n-propyl, Ao-propyl, n-butyl, iso-butyl, sec-butyl, and tori-butyi.
Another example of R1 includes units that are substituted by substituted or unsubststuted phenyl and benzyl, wherein the phenyl and benzyl substitutions are chosen from one or more:
i) halogen;
ii) Ci-Ch alkyl;
iii) C1-C3 alkoxy;
iv) -CO2R1'; and
v) NHCOR16;
wherein Rn and R16 are each independently hydrogen, methyl, or ethyl.
Another example of R* relates to phenyl and benzyl units substituted by a carboxy unit having the formula -C(O)R9; R9 is chosen from methyl, methoxy, ethyl, and ethoxy.
A further example of R1 includes phenyl and benzyl units substituted by an amide unit having the formula -NHC(O)R9; R9 is chosen from methyl, methoxy, ethyl, ethoxy, ier/-buty!, and terf-butoxy.
A yet further example of R1 includes phenyl and benzyl 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 to 1, but is absent when the index n is equal to 0. L units have the formula:
-[Q]y[C(R5aR5b)]x[Q1]z[C(R6ilR^)]wwherein Q and Q‘ are each independently:
i) -C(O)-;
ii) -NH-;
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
iii)
iv) ™NHC(O>·;
v) ~NHC(0)NH;
Vl) -NHC(O)O~i
vii) CiO)O<
viii) ™C(O)NHC(O)-;
ix) ...o-
x) ~S~;
xi) -SOrS
xii)
xiii)
xiv) NHC(-NH)-, or
xv) -NHC(-;NH)NH -
When the index y is equal to 1, Q is present. When the index y is equal to 0, Q is absent. When the index z is equal to 1, Q! is present. When the index z is equal to 0, Qf is absent.
R5a and Ra are each independently:
i) hydrogen;
ii) hydroxy;
iii) halogen;
iv) Cj-Ce substituted or unsubstituted linear or branched alkyl; or
v) a unit having the formula:
™[C(R7aR7b)]tR8 wherein R.7a and R7b are each independently:
i) hydrogen; or ii) substituted or unsubstituted Ci-Cc linear, branched, or cyclic alkyl,
Rs Is:
i) hydrogen;
ii) substituted or unsubstituted Cj-Cg linear, branched, or cyclic alkyl;
iii) substituted or unsubstituted Cg or Cw· ary 1;
iv) substituted or unsubstituted CrCs heteroaryl; or
v) substituted or unsubstituted Ci-Cg heterocyclic.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Roa and R6b are each independently:
i) hydrogen; or ii) Ci-C4 linear or branched alkyl.
The indices t, w and x are each independently from 0 to 4.
The following are non-limiting examples of units that can substitute for one or more hydrogen atoms on RSa, R3b, R'\ R7b, and R8 units. The following substituents, as well as others not herein described, are each independently chosen:
i) CrCS2 linear, branched, or cyclic alkyl, alkenyl, and alkynyl; methyl (Ci), ethyl (C2), ethenyl (C2), ethynyl (C2), n-propyl (C3)} riro-propyl (C3)} cyclopropyi (C3), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2methylethen-2-yl) (C3), prop-2-ynyl (also propargyl) (C3), propyn-l-yl (C3), nbutyl (Q), scc-butvl (C4), iso-butyl (C4), tot-butyl (C4), cyclobutyl (C4), buten-4yl (C4), cyclopentyi (C5), cyclohexyl (Ce);
ii) substituted or unsubstituted C6 or C|0 aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen-i-yl (Cm) or naphthylen-2-yI (C10));
iii) substituted or unsubstituted Gs or C10 alkylenearyl; for example, benzyl, 2phmylethyl, naphthylen-2-ylmethyl;
Iv) substituted or unsubstituted C1-C9 heterocyclic rings; as described herein below;
v) substituted or unsubstituted Ci-Cg heteroaryl rings; as described herein below;
vi) -(CR4 ,aR4ib)rOR‘1°; for example, -OH, -CH2OH,>OCH3, -CHsOCH3s OCH2CH3, CH2OCH2CH3, -OCH2CH2CH3, and-CH2OCH2C%CH3;
vii) ~-(CR£iiaR’ib)rC(O)R40; for example, -COCH3, -CH2COCH3, ~COCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3} and -CH2COCH2CH2CH3;
viii) -(CR^R^XCCOjOR40; for example, -CG2CH3, ~CH2CO2CH3, -CO2CH2CH3s -CH2CO2CH2CH3, ~€O2CH2CH2CH3, and -GH2CO2CH2CH2CH3;
xiv) -(CR4kR4ib)rC(O)N(R40)2; for example, -CONH2, -CH2CONH2, “CONHCH3, CH2CONHCH3, -CON(CH3)j, and -CH2CON(CH3)2;
x) -(CR4 iaR4!b)rN(R40)2; for example, ~ΝΗ ·:-€Η2ΝΗ2, -NHCH3, -CH2NHCH3s -N(CH3)2, and -CH2N(CH3)2;
xi) halogen; F, -Cl, -Br, and -I;
xii) -(CR4iaR4Jfa)rCN;
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 xiii) ~<CR41aR4%NO2;
xiv) -(CHvXvXCHjXjc; wherein X is halogen, the index j is an integer from 0 to 2, j 4 k - 3, the index j’ is an integer from 0 to 2, j5 fr k’ - 2, the index h is from 0 to 6; for example, -CH2F,.-CHF2» -CF3,>CH2€F3s ~CHFCF3, -CCi3, or-CBr3;
xv) ™(CR4!sR4!&)r8R40; -SH, -CHjSH, -SCffe, ~CHsSCH3, -SC6Hs, and CH2SC6H5;
xvi) -(CR4laR4!b)rSO2R40; for example, -SG2H, -CH2302H, - SO2CH3,
CH2SO2CH3, --SOjCeHj, and -CH2SG2C6H5; and xvii) -(CR4 ^R^ySOsR40; for example, -SO3H, -~CH2S03H, -S03CB3,
CH2SO3CH3, -SO3C6H5, and :>CH2SO3CeHs;
wherein each R4'3 is independently hydrogen, substituted or unsubstituted Cj-Cs linear, branched, or cyclic· alkyl, phenyl, benzyl, heterocyclic, or heteroaryk or two R40 units can be taken together to form a ring comprising 3-7 atoms; R‘Sia and R43b are each independently hydrogen or C1-C4 linear or branched alkyl; the index r is from 0 to 4.
One aspect of L units relates to units having the formula:
C(O)[C(R5aRSb)']xNHG(O>· wherein R5a is hydrogen, substituted or unsubstituted Cj-iri alkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; and the index x is 1 or 2. One embodiment relates to linking units having the formula:
i) -C(0)[C(R'aH)]NHC(0)O-;
ίί) C(O)[C(RaH)][CH2]NHC(0)0·;
ii) C(O)[CHg][C(R5aH)]NHC(O)O-;
iv) •C(O}iC(R?,sH)]NHC(O) ;
v) -C(O)[C(R5aH)][CH2]NHC(O)» or vi) ~€(0)[CH2][C(R58H)]NHC(OK w'herein R5a is:
i) hydrogen;
ii) methyl;
iii) ethyl;
iv) isopropyl;
v) phenyl;
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 vi) benzyl:
vii) 4-hydroxybenzyl;
viii) hydroxymethyl; or ix) 1-hydroxyethyl.
When the index x is equal to 1, this embodiment provides the following non-limiting examples of L units:
Figure AU2016203254B2_D0021
H ; and 0 H
When the index x is equal to 2, this embodiment provides the following non-limiting examples of L units:
Figure AU2016203254B2_D0022
Another embodiment of L units includes units wherein Q is -0(0)-, the indices x and z are equal to 0, w is equal to 1 or 2, a first R6a unit chosen from phenyl, 2-fluorophenyl, 3fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenvl, 2chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichfoiOphenyl, 3,4-di chlorophenyl, 3,5dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3methoxyphenyl, 4-methoxyphenyI, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5dimethoxyphenyl; a second Rfe unit is hydrogen and R6b units are hydrogen. For example a linking unit having the formula:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0023
A further example of this embodiment of L includes a first R.&i unit as depicted herein above that is a substituted or unsubstituted heteroaryl unit as described herein above.
A yet further example of this embodiment of L includes units having the formula; -C(O)[C(R6aR6h)]w··;
wherein R6il and R61’ are hydrogen and the index w is equal to 1 or 2; said units chosen from:
i) Ct O)CH r-; and ii) ~C(G)CH2CH2 -,
Another embodiment of L units includes units having the formula:
™C(O)[C(R5aR5b)]xC(O)··;
wherein R5s and R>b are hydrogen and the index x is equal to I or 2; said units chosen from:
i) -C(O)CHjC(O>; and ii) ~C(O)CH2CH2C(Ob.
A still further embodiment of L units includes units having the formula:
C(O)NH[C(RSaRSb)]x-;
wherein RSa and R3i> are hydrogen and the index w is equal to 0, 1 or 2; said units chosen from:
ii) -C(O)NHCH2-; and iii) -C(O)NHCH2CH2-.
A yet still further example of L units includes units having the formula:
-SOztQR^R615)]^-;
wherein R8a and R8b are hydrogen or methyl and the index w is equal to 0, 1 or 2; said units chosen from:
i) -SO2-;
ii) -SO2CH.2-; and iii) -SO2CH2CHs··,
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
The disclosed compounds (analogs) are arranged into several Categories to assist the fbrmulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein,
A described herein above the disclosed compounds include all pharmaceutically acceptable salt forms, A compound having the formula:
2016203254 18 May 2016
Figure AU2016203254B2_D0024
can form salts, for example, a salt of the sulfamic acid:
Figure AU2016203254B2_D0025
Figure AU2016203254B2_D0026
Ca
The compounds can also exist in a zwitterionic form, for example:
Figure AU2016203254B2_D0027
: or
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 as a salt of a strong acid, for example:
Figure AU2016203254B2_D0028
The first aspect of Category I of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-2-yl unit having the formula:
Figure AU2016203254B2_D0029
one embodiment of which relates to inhibitors having the formula:
Figure AU2016203254B2_D0030
wherein R units are thiazoi-2~yl units, that when substituted, are substituted with R2 and R3 units. R and R5a units are further described in Table I.
No. R R5®.........
Al | thiazol-2-yi (S)-benzyl
A2 4-methyithiazol-2-yl (5)-benzyl
A3 | 4-ethylthiazol~2-yi (&)-benzyl (5)-benzyl
A4 i 4-propyIthiazol-2-yl
A5 | 4~is<?-propylthiazol-2-yl (5}-benzyl
A6 j 4»cyciopropyithiazol“2~yl (S)-benzyl
A7 i 4-butylthiazol~2~yl (S)~benzyl
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
I No, | R
A8 | 4-ier/-butylthiazoi-2-yl (S)-benzyl
A9 j 4-cyclohexylthiazol-2-yl (5)-benzyl
A10 4-(2,2,2~trifluoroethyl)thiazol-2-yl (S)~benzyl
All 4-(3,3,3-irifluoropropyl)thiazol-2-yl (S)-benzyl
A12 4-(2,2-difluorocyclopropyl)thiazol-2-yl (5)-benzyl
A13 4-(methoxymethyl)thiazol-2-yl (<S)-benzyl
A14 4-(carboxylic acid ethyl ester)thiazol-2-yl (S)-benzyl
A15 4,5-dimethylthiazoi»2-yl (S}-benzyl
A16 4-methyl-5-ethyhhiazol-2-yf (5)-benzyi
A17 4-phenyithiazol~2~yl (S')-bcnzyi
A18 4-(4-chlorophenyl)thiazol-2-yl (5)-benzyl
A19 4-(3s4-dimethylphenyS)thiazol~2-yl (5)-benzyi
A20 4-meihyl-5-phenyithiazol-2-yl (5)-benzyl
A21 4-(thiophen-2-yl)thiazoS-2-yl (5)~benzyl [
A22 4-(ihiophen-3 -y l)thiazo 1-2 -y 1 (S^-benzyl
A23 4-(5-chloroihiophen-2-yl)ihiazol-2~yl (j$)-benzyl
A24 5J6-dihydro-4/f-cyclopenta[d]thiazol-2-yl (S)~benzyl |
A25 4,5,6,7-tetrahydiObenzo[i/}thiazol-2-yl (5)-benzyl ?
The compounds encompassed within the first aspect of Category' I of the present disclosure can he prepared by the procedure outlined in Scheme Ϊ and described in Example I herein below.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0031
Figure AU2016203254B2_D0032
Figure AU2016203254B2_D0033
Reagents and conditions: (c) CH3CN; reflux, 3 hr.
Figure AU2016203254B2_D0034
Figure AU2016203254B2_D0035
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Reagents and conditions: (d) Boe-Phe, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
Figure AU2016203254B2_D0036
Figure AU2016203254B2_D0037
Reagents and conditions: (e) (i) FRcPd/C, MeOH; (ii) SGa-pyridine, NHLjOH; rt, 2 hr,
EXAMPLE 1
4-{(S)-2-[(S)-2“(teFr-Butoxycarbonylamino)-3-phenyIpropanamidoh2~(4~ethylthiazol-2yt)ethyl}phenylsulfamic add (S)
Preparation of [l-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid fert-butyl ester (1): To a 0 °C solution of 2-(1S)-/eri-butoxycarbonyIamino-3-(4-nitrophenyl)-propionic acid and Nmethylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwise iso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at 0 °C for 20 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 successively with 5% citric acid, water, 5% NaHCOj, water and brine, dried (NaiSOQ, filtered and concentrated in vacuo to a residue that is triturated with a mixture of EtOAe/petroIeum ether to provide 2.2 g (74%) of the desired product as a white solid.
Preparation of (2-(4-nitrophenyl)-l-(5)-thiocarbamoylethyl]carbamic acid ieri-butyl ester (2): To a solution of [l-(5)-carbamoyl-2-(4-nitrophenyi)ethyl-carbamic acid ieri-butyl ester, 1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson’s reagent (0.262 g. 0.65 mmol). The reaction mixture 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, CDCh) δ 8.29 (s, IH),
8.10 (d. J -8.4 Hz, 2H), 8.01 (s, IH), 7.42 (d, ../-8.4 Hz, 2H), 5.70 (d, J- 7.2 Hz, 1H),4.85 (d, J-7.2 Hz, IH), 3.11-3.30 (m, IH), 1.21 (s, 9H).
<
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Preparation of l-(S)-(4-ethylthia2ol-2-yl)-2-(4-m'trophenyi)ethyl amine (3): A mixture of [2-(4~nitrophenyl)-i-(5)-thiocarbamoylethyl]-carbamic acid tert-butyl ester, 2, (0.245 g, 0.753 mmol), 1 -bromo-2-butanone (0.125 g, 0.828 mmol) in CH3CN (5 mL) is refluxed 3 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration. The solid is dried under vacuum, to afford 0.242 g (90% yield) of the desired product. ESI+ MS 278 (M+l).
Preparation of {1 -[ 1 -(4-ethyIthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2phenylethyl) carbamic acid tert-butyl ester (4): To a solution of l-(S)-(4-ethylthiazol-2-yl)-2-(4nitrophenyl)ethyl amine hydrobromide, 3, (0,393 g, 1.1 mmol), (5)-(2-tertbutoxycarbonylamino)-3phenylpropionic acid (0.220 g, 0.828 mmol) and 1hydroxybenzotriazolc (HOBt) (0.127 g, 0.828 mmol) in DMF (10 mL) at 0 °C, is added 1-(3dimethylaminopropyl)~3-ethylcarbodiimide (EDCI) (0,159 g, 0.828 mmol) followed by diisopropylamine (0,204 g, 1.58 mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HC1, 5 % aqueous NaHCOj, water and brine, and dried over NasSCfo The solvent is removed in vacuo to afford 0.345 g of the desired product which is used without further purification. LC/MS ESI+ 525 (MM).
Preparation of 4- {(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-pheny{propanamido]-2-(4ethylthiazol-2-yl)ethyl}phenylsulfamic acid ammonium salt (5): {l-[l-(4-ethyith.iazol-2-yl)-2~ (4-nitrophenyl)ethylcarbamoyl]-2-phenylethy]} carbamic acid tert-butyl ester, 4, (0.345 g) is dissolved in MeOH (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 CELlTEiM and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SOj-pyridine (0.314 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH (50 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.222 g of the desired product as the ammonium salt. !H NMR (CDjOD): δ 7.50-6.72 (m, 10B), 5.44-5.42 (d, IH, .A 6.0 Hz), 4.34 (s, IH), 3.34-2,79 (m, 4H), 2.83-2.76 (q, 2H, .7-7.2 Hz), 1,40 (s, 9H), 1.31 (t, 3H, .7=7.5 Hz).
The disclosed inhibitors can also be isolated as the free acid, A non-limiting example of this procedure is described herein below in Example 4.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
The following is a non-limiting example of compounds encompassed within this embodiment of the first aspect of Category Ϊ of the present disclosure.
2016203254 18 May 2016
Figure AU2016203254B2_D0038
4-{(5)-2-[(/?)-2-(zeri-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2yl)ethyl} phenyl sulfamic acid: !H NMR (CD3OD ): δ 7.22-7,02 (m, 10H), 5,39 (s, IH), 4.34 (s, IH), 3.24-2.68 (m, 6H), 1.37 (s, 9H), 1.30 (t, 3H, ./-7,5 Hz),
Another embodiment of this aspect of Category I relates to inhibitors having the formula
Figure AU2016203254B2_D0039
wherein R units and Rja units further described in Table II.
TABLE II
No. R RSa
B26 thiazol-2-yi (S)-benzyl
B27 4-methyithiazol-2-yl (5)-benzyl
B28 4-ethylthiazol-2-yl (S)~benzyl
B29 4-propylthlazoI-2-yl (5)-benzyl
B30 4-iso -propy Ithi azol-2-yI (5)-benzyl
B31 4-cycIopropyithiazol-2-yi (5)-benzyl
B32 4-butylthiazol-2-yi (S)-benzyl
B33 4-iert-butylthiazol-2-yl (S)-benzyi
B34 4-cy clohexy Ithi azol-2-y I (5)-benzyi
B35 4-(2,2,2-trifluor0ethyl)thiazoi-2-yl (5)-benzyl
B36 4-(3,3,3-trifluoropropyt)thiazol“2-yi (5)-benzyl
B37 4-(2,2-difluorocyclopropyl)thiazoI-2-yl (Sj-benzyl
B38 4-(methoxymethyl)thiazoi-2-yl (Sj-benzyl
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0040
B39 ~B40
4-(carboxyltc acid ethyl esier)thiazol-2-yl 4.5dimethylthiazoi-2-yi
4-methyi-5-ethylthiazol-2-yl
Figure AU2016203254B2_D0041
(S)-benzyl (S)-benzyl (^-benzyl
Figure AU2016203254B2_D0042
Figure AU2016203254B2_D0043
4-phenylthi azo t-2-y 1 4-(4-chiorophenvl)thiazol-2-yl 4-(3,4-dimethy Ipheny l)thiazol-2-yl 4-methyl-5’phenylthiazol-2-yl 4-(thiophen-2-yljthiazol-2-yi 4-(thiophen-3-yi)thiazol-2-yl
....X B50 !
4-(5-chlorothiophen-2-yl)i hiazoI-2-y 1 5,6-dihydro-4//-cyclopenta[d]thiaz,ol-2~yl 43,6, 7-tetr ahydrobenzo[</]th iazoi-2 -yi («S)-benzyl (iS)”benzyl (S)-benzyl (5)-benzyl (S'j-benzyl (S)-benzyl )~benzyl I (S)-benzyl
The compounds of this embodiment can be prepared according to the procedure outlined above in Scheme I and described in Example 1 by substituting the appropriate Boc-p-amino acid for (5)-(2-ie/'i-butoxycarbonylamino)-3~phenylpropionic acid in step (d).
Figure AU2016203254B2_D0044
{l-[l-(4-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyIcarbamoyl]-(1S)-2phenylethyl} methyl carbamic acid tert-butyl ester: *H NMR (300 MHz, MeOH-dit) δ 8.36 (d, J = 8.1 Hz, IH), 7.04-7.22 (m, 9H), 5.45 (s, IH), 3.01-3.26 (m, 2H)> 2.60-2.88 (m, 4H), 2.33 (s,
I), 1.30 (s, 9H).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0045
(1-(1 -(4-Phenylihiazol-2-yl)-(5)-2-(4-suifoaminophenyl)ethylcarbamoyl]-(S)-2phenyiethyl}methyl carbamic acid tert-butyl ester: Τϊ NMR (300 MHz, MeOH-dQ S 8.20 (d, J
8.1 Hz, 1H), 7.96-7.99 (m, 2H), 7.48-7.52 (m, 3H), 7.0O~?.23(m, 7H), 6,89 (s, 1H), 5.28 (q, J 7.5 Hz, 1H), 4.33 (t, J- 6.6 Hz, 1H), 3.09-3.26 (m, 2H), 3.34 (dd, ,/-13.2 and 8.4 Hz, 1H), 2.8: (dd, J- 13.2 and 8.4 Hz, 1H), 1.38 (s, 9H).
The second aspect of Category I of the present disclosure relates to compounds wherein
Figure AU2016203254B2_D0046
Figure AU2016203254B2_D0047
wherein R units and Rja units further described in Table HI.
No. R --
C51 thiazol-4-yl (S)~benzyl
C52 2 -methy Ithiazo i-4-y I (S)-benzyl
C53 2-ethylthiazol-4-yl (&)-benzyl
C54 2-propylthiazoM-yl (S)-benzyl
C55 2-/so-propylthiazol-4-yl (S)-benzyl
€56 2-cyclopropylthiazol~4~yi (S)-benzyl
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No.'”TR .........................j
| !
I C57 2-butylihiazol-4-yl (5)-benzyl
C58 2~/ert-butylthiazol-4-yl (SRbenzyl
C59 2-cyclohexyithiazol-4-yl (S)-benzyl
C60 2-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl
C61 2-(3.3,3 -tri fluoropropy Dthiazo 1-4 -y 1 (Si-benzyl
C62 2-(252-dit1uorocyclopropyl)thiasol-4-yl (S)-benzyi
C63 2-ph eny lthiazo 1-4 -y 1 (S)-benzyl
C64 2-(4-chloraphenyl)thiazol-4~yl (S)-benzyl
C65 2-(3,4 -dim ethy Ipheny l)th iazo I -4-y 1 (S)-benzy|
C66 2-(thiopben-2-yI)thiazol-4-yi (S)-benzyl
C67 2-(thiophen-3 -yl)thiazoi-4-yl (5) -benzyl
C68 2-(3-chlorothiophen~2-yl)thiazol-4-yl (^-benzyl
C69 2-(3-methy Hhiop hen-2-yi)thi azol-4-y 1 (S)~benzyl i
C70 2 -(2-methy Ithi azol-4-yl)thi azo l-4~y 1 (S)-benzyl
C71 2-(fiiran-2-yl)thiazol-4-yl (S)-benzyl
C72 2-(pyrazin~2-yl)thiazol-4-y! (S)-benzyl
C73 2-[(2-methyl)pyridin-5 -v 1] thi azol -4-yl i (S)-benzyl
C74 2-(4-ch lorobenzenesulfony Imethy l)thi azol-4 -y 1 (S)-benzyi
C75 2-(tcrr-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl j
The compounds encompassed within the second aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme II and described in Example 2 herein below.
Figure AU2016203254B2_D0048
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Reagents and. conditions: (a)(i) (wo-butyl)OCOCl, Et3N. THF; 0 °C, 20 min. (ii) CH2N2; room temp for 3 hours.
Figure AU2016203254B2_D0049
Figure AU2016203254B2_D0050
Reagents and conditions: (b) 48% HBr, THF; 0 °C, 1.5 hr.
Figure AU2016203254B2_D0051
Figure AU2016203254B2_D0052
Reagents and conditions: (c)(i) thiobenzamide, CH3CN; reflux, 2 hr. (ii) Boc-Phe, HOBt, DIPEA, DMF; rt, 18 hr.
Figure AU2016203254B2_D0053
Figure AU2016203254B2_D0054
Reagents and conditions: (d) (i) H2:Pd/C, MeOH; (ii) SGr pyridine, NH4OH; rt, 12hr.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
EXAMPLE 2
4-{(5)-2-($)2-(ferABu toxyc&rbo ny lam in ©}-3-p foeny 1 propo amid o~2~(2~phen y HhmoMyi)}phenylsuifamic add (9)
Preparation of (S)-[3-diazo-l-(4-nitrobenzyl)-2-oxo-propyl3-carbamiC acid tert-butyl ester (6): To a 0 °C solution of 2-(5)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0 °C for 20 minutes and filtered. The filtrate is treated with an ether solution of diazomethane (-16 mmol) at 0 °C. The reaction mixture is stirred at room temperature for 3 hours then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed successively with water and brine, dried (NajSOi), filtered and concentrated. The residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. *H NMR (300 MHz, CDC13) 3 8.16 (d, J= 8.7 Hz, 2H), 7.39 (d, J- 8.7 Hz, 2H), 5.39 (s, IH), 5.16 (d, J-6,3 Hz, IH), 4.49 (s, IH), 3.25 (dd,,/- 13.8 and 6.6, IH), 3.06 (dd,./ - 13,5 and 6.9 Hz, IH), 1.41 (s, 9H).
Preparation of (iS)-?ert~butyl 4-bromo-l-(4-nitrophenyl)~3~oxohutan-2-ylcarbamaie (7):
To a 0 °C solution of ($~[3~diazo~l~(4~mlrobenzyl)-2-oxo-propyl]~carbamic acid tert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, J .25 mmol), The reaction mixture is stirred at 0 °C for 1,5 hours then the reaction is quenched at 0 °C with sat, Na2CO3. The mixture is extracted with EtOAc (3x 25 ml) and the combined organic extracts are washed with brine, dried (Na2SO,i), filtered and concentrated to obtain 0.400 g of the product which is used in the next step without further purification. !H NMR (300 MHz, CDClj) δ 8.20 (d,,/- 8.4 Hz, 2H), 7.39 ¢0,/= 8.4 Hz, 2H), 5.06 (d,./- 7.8 Hz, IH), 4.80 (q, J- 6.3 Hz, IH), 4.04 (s, 2H), 1.42 (s, 9H).
Preparation of tert-butyl (5)-l-(5)-2-(4-nitrophenyl)-l-(2-phenyithiazole-4yl)ethylamino-l -oxo-3-phenylpropan-2-ylcarbamate (8): A mixture of thiobenzamide (0.117 g, 0.85 mmol) and (S)-tert-butyl 4-bromo~L(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (0,300 g, 0.77 mmol) in CH3CN (4 mL) is refluxed 2 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to precipitate the intermediate 2-(nitrophenyl)-(S)-1-(4phenylthiasol“2-yl)ethylamine which is isolated by filtration as the hvdrobromide salt. The hydrobromide salt is dissolved in DMF (3 mL) together with diisoproylethylamine (0.42 mL,
This data, for appfication number 20f42022f f, is current as of 20f6-05-f6 2f :00 AEST
2016203254 18 May 2016
2.31 mmol), 1-hydroxy benzoin azole (0,118 g, 0.79 mmol) and (5)-(2-ierr-butoxycarbonylamino)-3-phenylpropionie acid (0.212 g, 0.80 mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCOs, water and brine, and dried over NajSO^. The solvent is removed in vacuo to afford 0.395 g (90 % yield) of the desired product which is used without further purification. LCMS ES1+ 573 (M-H).
Preparation of 4- {(5)-2-(S)-2-(te^butoxycarbonyl)-3-phenylpropaneamido-2-(2· phenylthiazoIe-4-yl)}phenylsulfamic acid (9): tert-butyl (5)-1-(5)-2-(4-nitrophenyI)-1-(2phenylthiazole-4-y!)ethy!amino-l-oxG-3-phenylprQpan-2-ytearbamate, 8, (0.360 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 12 hours. The reaction mixture is filtered through a bed of CELITEJM and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO3-pyridine (0.296 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH40H (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.050 g of the desired product as the ammonium salt. JH NMR (300 MHz, MeOH-cL0
Figure AU2016203254B2_D0055
5.28 (q, J- 7.5 Hz, IH), 4.33 (t, J- 6.6 Hz, IH), 3.09-3.26 (m, 2H), 3.34 (dd, 13.2 and 8.4
Hz, IH). 2.82 (dd, J™ 13.2 and 8.4 Hz, IH), 1.38 (s, 9H).
The first aspect of Category II of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-4-yl unit having the formula:
HO
Figure AU2016203254B2_D0056
H
O
O
CH,
H one embodiment of which relates to inhibitors havin g the formula:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST wherein R units are thiazol-4-yl units, that when substituted, are substituted with R4 units. R and
R5a units are further described in 'Table IV.
2016203254 18 May 2016
Figure AU2016203254B2_D0057
Figure AU2016203254B2_D0058
(5)~benzyl (S)-benzyl («S)-benzyl
2-f5(9-propylthiazol-4-yl
D81 2-cyclopropylthiazoi-4-yl (5)-benzyl
! D82 2-butylthiazol-4-yl (S)-benzyl
D83 2~fer/-huty ithi azo I-4-y 1 (6)-benzyl
D84 2-cyclohexyithiazol“4-yl (S)-benzyI
D85 2-(2,2,2 -trifluor oethy l)thiazol~4-y Ϊ (S)-benzyl
D86 2-(3,3,3-trifluorGpropyl)thiazoi~4~yI (S)-benzyl
D87 2-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl
D88 2~phenylthiazol-4-yS (5)~benzyl
D89 2-(4-chiorophenyl)thiazoI-4-yl (S)-benzyl
D90 2-(3,4-dimethylphenyl)thiazol-4-yl (6)-benzyi
D91 2 (thiophen-2-y I)t hi azo ί-4-y 1 (S)-benzyl
D92 2-(thiophen-3-yl)thiazol-4-yI (0)-benzyl
D93 2-(3-chioroihiophen~2~Yi)thiazol-4-yl (S)-benzyl
D94 2-(3 -methy Ithiophen-2-yl)thiazo 1-4-y 1 (S)-benzyl
D95 2-(2-methylthiazol-4-yr)thiazol-4-yl (5)~benzvl
D96 2-(fhran-2-yl)thiazol-4-yi (S)-benzyl
D97 2-{pyrazin-2-yl)thiazol-4-yi (S)-benzyl
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. R
D98 2-[(2-melhyl)pyridin-5-yi)thiazoI-4-yl (S)~benzyi
D99 2-(4-chIorohenzenesulfonylmethyl)thiazol~4-yi (5)-benzyl
D100 2-(feri-butylsulfonylmethyl)thiazol-4-yI (5)-benzy1
The compounds encompassed within the second aspect of Category II of the present disclosure can be prepared by the procedure outlined in Scheme ΙΠ and described in Example 3 herein below.
Scheme IH
Figure AU2016203254B2_D0059
Figure AU2016203254B2_D0060
Reagents and conditions: (a)(i) propaneth ioamide, CH3CN; reflux, 2 hr. (ii) Boc-Phe, HOBt, DIPEA, DMF; rt, 18 hr.
Figure AU2016203254B2_D0061
Figure AU2016203254B2_D0062
Reagents and conditions: (b) (i) KfcPd/C, MeOH; (ii) SOj-pyridine, NH4OH; rt, 18 hr.
EXAMPLE 3
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
4-{(5>2-[(5)-2-(Methosycarbonylamino>3-pheny]propananiido[-2-(2-ethyhhiazo]-4-yI) ethyl}phenylsulfamic add (13)
Preparation of methyl (5)-1 -[(5)-1 ~(2~ethylihiazo]e-4-yl)-2-(4-nitrophenyi)«ethyl]amino1-oxo-3-phenylpropane-2-ylcarbamate (12): A mixture of propanethioamide (69 mg, 0.78 mmol) and (5)-teri-butyl 4-bromo-l-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (0.300 g, 0.77 mmol) in CH3CN (4 mL) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to precipitate the intermediate 2-(nitropheny 1)-(5)-1-(4ethylthiazol-2-yl)ethyIamine which is isolated by filtration as the hydrobromide salt. The hydrobromide salt is dissolved in DMF (8 mL) together with diisoproylethylamine (0.38 mL,
2.13 mmol), 1-hydroxybenzotriazole (107 mg, 0.71 mmol) and(5)-(2-methoxycarbonyl-amino)3-pbenylpropionic acid (175 mg. 0.78 mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCOj, water and brine, and dried over Na2S0.3, The solvent is removed in vacuo to afford 0,300g (81% yield) of the desired product which is used without further purification. LC/MS ESI+MS 483 (M+l).
Preparation of 4-((S)-2-((5)-2-(methoxycarbonyiamino)~3-pheny!propanamido)-2-(2ethylthiazol-4-yl) ethyl)phenylsulfamic acid ammonium salt (13): forf-Butyl (5)-1-(5)-2-(4nitrophenyl)- l-(2-ethylthiazoIe-4-yl)ethylamino-1 -oxo-3-phenylpropan-2-ylcarbamate, 12, (0.300g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SOj-pyridine (223 mg, 1,40 mmol).
The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH (12 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 25 mg of the desired product as the ammonium salt, NMR (300 MHz, MeOH-ά,) 5 7.14-7.24 (m, 6H), 6.97-7.0 (m, 4H), 6,62 (s,
IH), 5.10 -5.30 (m, IH), 4.36 (t,J- 7.2 Hz, IH), 3.63 (s, 3H), 3,14 (dd, J- 13.5 and 6.3 Hz,
1H), 2.93-3.07 (m,5H), 2.81 (dd, J - 13.5 and 6,3 HZ, IH), 1.39 (t./- 7.8 Hz, 3H).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
In another iteration of the process of the present disclosure, compound 13, as well as the other analogs which comprise the present disclosure, can be isolated as the free acid by adapting the procedure described herein below.
2016203254 18 May 2016
Figure AU2016203254B2_D0063
Figure AU2016203254B2_D0064
Reagents and conditions: (a) H^Pd/C, MeOH; rt, 40 hr.
Figure AU2016203254B2_D0065
Figure AU2016203254B2_D0066
Reagents and conditions: (b) SOj-pyridine, CHjCN; heat, 45 min.
EXAMPLE 4
4-((5>-2*-((5)-2-(ΜβΑοχγε3Γϋοηγΐ3ΐη]ηο>-3-ρΗ6ηγ]ρΓοραηβιη1ύο)-2-(2-β{Η}ΊΐΗιαζο1-4-γ1) ethyl)phenylsulfamic add [Free Add Ferns] (13)
Preparation of {1 -(2-( J)~(4-(S)~aminophenyl)-1 -(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2phenylefhvlj-carbarmc acid methyl ester (12a): A Parr hydrogenation vessel is charged with tert- butyl (6)-l-(5)-2-(4-nitrophenyl)-l-(2-ethylthiazole-4-yl)ethylamino-l-oxo-3-phenylpropan2-ylcarbamate, 12, (18.05 g, 37.4 mmol, 1.0 eq) and Pd/C (10 % Pd on C, 50 % wet, Degussatype E101 NE/W, 2.68 g, 15 wt %) as solids. MeOH (270 mL, 15 mL/g) is added to provide a suspension. The vessel is put on a Parr hydrogenation apparatus. The vessel is submitted to a
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 fill/vacuum evacuate process with N2 (3 x 20 psi) to inert, followed by the same procedure with Ii2 (3 x 40 psi). The vessel is filled with and the vessel is shaken under 40 psi H2 for -40 hr. The vessel is evacuated and the atmosphere is purged with N2 (5 x 20 psi). An aliquot is filtered and analyzed by HPLC to insure complete conversion. The suspension is filtered through a pad of celite to remove the catalyst, and the homogeneous yellow filtrate is concentrated by rotary evaporation to afford 16.06 g (95% yield) of the desired product as a tan solid, which is used without further purification.
Preparation of4-((IS)-2-((5)-2-(methoxycarbonyl)-3-phenylpropanamido)-2-(2ethylthiazol-4-yl) ethyljphenylsulfamic acid (13): A 100 mL RBF is charged with {1-(2-(5)-(4(5)-aminophenyl)-l -(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamic acid methyl ester, 12a, (10.36 g, 22.9 mmol, 1.0 eq.) prepared in the step described 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 SO3· pyr (5.13 g, 32,2 mmol, 1.4 eq.) and acetonitrile (50 mL 5 mL/g) and the white suspension is stirred at room temperature. Both suspensions are gently heated until the reaction solution containing {1-(2-(5)-(4-(5)aminophenyl)-l~(2~ethylthiazol-4-yl)ethy!-earbamoyl]-2-phenylethyl)-carbamic acid methyl ester becomes red-orange in color (typically for this example about 44 °C), This substrate containing solution is poured in one portion into the stirring suspension of SOy pyr 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. H2O (200 mL, 20 mL/g) is added to the orange suspension to provide a yellow-orange homogeneous solution having a pH of approximately 2,4, Concentrated H3PO4 is added slowly over 12 minutes to lower the pH to approximately 1.4. During this pH adjustment, an off-white precipitate is formed and the solution is stirred at room temperature for 1 hr. The suspension is filtered and the filter cake is washed with the filtrate. The filter cake is air-dried on the filter overnight to afford 10.89 g (89 % yield) of the desired product as a fan solid.
The following are further non-limiting examples of the second aspect of Category Π of the present disclosure.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(S)-2-[(6')-2-(Meihoxycarbonylamino)~3~phenylpropanamido]-2-(2-methykhiazoi-4yl)ethyl}phenylsulfamic acid: Ή NMR (300 MHz, MeOH-cU) δ 8.15 (d, J8.4 Hz, 1H), 7.16
7.25 (m, 5H), 6.97-7.10 (m, 4H), 6.61 (s, 1H), 5.00-5.24 (m, 1H), 436 (t, 7.2 Hz, 1H), 3.64 (s,2H), 3.11-3,19 (s, 1H), 2.92-3.04 (s,2H),2.81 (dd, J- 13,5 and 8.1 Hz, 1H), 2,75 (s, 3H).
2016203254 18 May 2016
Figure AU2016203254B2_D0067
Figure AU2016203254B2_D0068
4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonyiammo)-3-phenylpropan(m, 5H), 7.02-7.12 (m, 4H), 6.83 (s, 1H), 5,10-5.35 (m, 1H), 3.52-3.67(m, 3H), 3.18-3,25 (m, 2H), 3.05 (q, J-··· 7.5 Hz, 2H), 2.82-2.95 (m, 2H), 2.65 (s, 3H), 1.39 (t,./- 7.5 Hz, 3H).
Figure AU2016203254B2_D0069
4“{(5')-2-(2-lsopi'opyithia7.ol-4~yl)~2-[(S)-2-(methoxycai'bonylamino)-3-phenylpropan~ amido]ethyl}phenylsulfamic acid: lH NMR (CD3OD) 8 8.16 (d, 1H, J = 8.7Hz), 7.22-7.13 (m, 3H), 7.07 (d, 1H, J - 8.4Hz), 6,96 (d, 1H, J - 8.1Hz), 6.62 (s, 1H), 5.19 (t, 1H, J = 7.2Hz), 4.36 (1,1H, J = 7.8Hz), 3.63 (s, 3H), 3.08 (SH, A of ABX, J 3.6,14.5Hz), 2.99 (1H, B of ABX, J 7.2, 13.8Hz), 2.85-2.78 (m, 1H), 1.41 (d, 6H, J - 6.9Hz).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(S)-2-(2-Cyclopropylthiazol-4-yi)-2-[(S)-2-(niethoxycarbonylamino)-3phenylpropanamidojethyl} phenyl sulfamic acid: NMR (CD3OD): δ 7.15-7.02 (m, 5H), 6.966.93 (d, 2H, >8.4 Hz), 6.86-6.83 (d, 2H, >8.3 Hz), 6.39 (s, IH), 5.01 (t, 1H,>5.O Hz), 4,22 (t,
IH, >7.4 Hz), 3.51 (s, 3H), 2.98-2.69 (m, 2H), 2.22-2.21 (m, IH), 1.06-1.02 (m, 2H), 0.92-0.88 (m, 2H).
2016203254 18 May 2016
Figure AU2016203254B2_D0070
Figure AU2016203254B2_D0071
4-{(S)-2-{2-[(4-ChlorophenylsulfonyS)meihyl]thiazol-4-yl}~2~[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid: SH NMR (CDjOD): δ 7.967.93 (d, 2H, >8.6 Hz), 7.83-7.80 (d, 2H, >8.6 Hz), 7.44-7.34 (m, 5H), 7.29-7.27 (d, 2H, >8.4 Hz), 7.14-7.11 (d, 2H, >8.4 Hz), 6.97 (s, IH), 5.31 (t, IH, >6.8 Hz), 5.22-5.15 (m, 2H), 4.55 (t, IH, >7,3 Hz), 3.84 (s, 3H), 3.20-2.96 (m, 4
Figure AU2016203254B2_D0072
4- {(S)-2-[2-(ierf-Buty 1 sul fony lmethyl)thi azol-4-y 1 ]-2-[(S)-2 -(methoxycarbony iamino)-3 phenylpropanamido]ethyl)phenylsulfamic acid: !H NMR (CD3OD): δ 7.40-7.30 (m, 5H), 7,21 7,10 (m, 4H), 7.02 (s, IH), 5,37 (t, 1H,>6.9 Hz), 5.01-4.98 (m,2H), 4.51 (1,
3.77 (s, 3H), 3.34-2.91 (m, 4H), 1.58 (s, 9H).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(S)-2-[(S)-2-(Methoxycarbouylamino)~3~phenylpropionamido]-2-(2-phenyhhiazole-4yl)ethyl}phenylsuifamic acid: 'H NMR (300 MHz, DMSO-d6) δ 7.96-7.99 (m, 2H), 7.51-7.56 (m, 3H), 7.13-7.38 (m, 6H), 6.92-6.95 (m, 4H), 5.11-5.16 (m, 1H), 4.32-4.35 (m, 1H), 3.51 (s,
3H), 3.39-3.40 (m, 2H), 3.09-3.19 (m, IH), 2.92-3,02 (m, 2H), 2.75 (dd,./ - 10.5 Hz and 9.9 Hz,
2016203254 18 May 2016
Figure AU2016203254B2_D0073
ο
Figure AU2016203254B2_D0074
4-{(5)-2-[(5)-2-(Methoxycarbonyiamino)-3-phenylpropanamido]-2-[2-(thiophen-2yi)thiazol-4-yl]ethyl}phenyisulfamic acid: ’H NMR (CD3OD): δ 7.61-7,56 (m, 2H), 7.25-7.01 (m, 10H), 6.75 (s, IH), 5.24-5.21 (q, iH, >7,2 Hz), 4.38 ft, 1H, /-7.2 Hz), 3.60 (s, 3H), 3.23-
Figure AU2016203254B2_D0075
4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yI]-2-[(,S)-2-(methoxycarbonylarnino)-3“ phenylpropanamido]ethyl}phenylsulfamic acid: *H NMR (CDjOD): δ 7.78-7.76 (d, IH, /-5.4 Hz), 7.36-7.14 (m, 10H), 7.03 (s, IH), 5.39 (t, IH, /-6.9 Hz), 4.54 (t, IH, /-7.3 Hz), 3.80 (s, 3H), 3.39-2.98 (m, 4H).
$6
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(S)-2-[(iSr>-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3methylthiophen-2-yi)thiazol-4-yl]ethyl}phcnylsnlfamic acid: lH NMR (CD3OD): S 7.38 (d, 1H, >5,1 Hz), 7.15-6.93 (m, 10H), 6.73 (s, 1H), 5.17 (t, 1H, >6.9 Hz), 4.31 (t, 1H,> 7.3 Hz), 3.57 (s, 3H), 3.18-3.11 (m, 1H), 3.02-2.94 (m, 2H), 2.80-2.73 (m, 1H), 2.46 (s, <-*'2
2016203254 18 May 2016
ο. .0
Figure AU2016203254B2_D0076
Figure AU2016203254B2_D0077
4-{[(i5)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(5)-2-(methoxycarbonylamino)-3phenylpropanamido]ethyl}phenylsulfamic acid: *H NMR (CD3OD): 8 7.54-7.46 (m,
6.79 (m, 10H), 6.55-6,51 (ra, 1H), 6.44-6.41 (m, 1H), 5.02-5.00 (q, 1H, >6.4 Hz), 4. 1H,/=7.1 Hz), 3.43 (s, 3H), 2.96-2,58 (m, 4H).
,7.( .141
Figure AU2016203254B2_D0078
4-{(^-2-[(5)-2-(Methoxyearbonyiamino)-3-phenyipropanamido3~2-[2-(2-methykhiazole4-yl)thiazole-4yl]ethyl}phenyisuifemic acid: NMR (300 MHz, MeOH-di) S 8.27(d, J~ 5.4 Hz, 1H), 7.97 (s, 1H), 6.99-7.21(m, 8H), 5.18-5.30 (tn, 1H), 4.30-4.39 (m, 1H), 3.64 (s, 3H),
3.20 (dd, J - 14,1 and 6.6 Hz, 1H), 2.98-3.08(m, 2H), 2.84 (dd, ,/ =-14.1. and 6.6 Hz, 1H), 2.78 (s,
5?
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(i5)-2-[(iS)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[(2-pyrazin-2yl)thiazole-4-yl]ethyl}phenylsuifamic acid: !H NMR (300 MHz, MeQH-d^) δ 9.34 (s, 1H), 8.65 (s, 2H), 8.34 (d, /- 8.1 Hz, IH), 7.00-5,16 (m. 9H), 5,30 (q, /- 7.2 Hz, 1H), 4.41 (t,,/- 7,2 Hz,
ΪΗ), 3.65 (s, 3H), 3.23 (dd, J- 13.8 and 6.9 Hz, 1H), 2.98-3.13 (m, 2H), 2.85 (dd, J- 13.8 and
6.9 Hz, 1H).
2016203254 18 May 2016
Figure AU2016203254B2_D0079
Figure AU2016203254B2_D0080
- {(6)-2-[(S)-2-(Methoxycarbony lamino)-3 -pheny Ipropanamido]-2-[2-(6-met hy Ipyri di n1H), 7.39-7.36 (d, IH, >8,2 Hz), 7,07-6,88 (m, 9H), 6.79 (s, IH), 5,17 (t, IH, >7.0 Hz), 4.29 (t, IH, >7,4 Hz), 3,54 (s, 3H), 3.10-2.73 (m, 4H), 2.53 (s, 3H).
Category IH of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-2-yl unit having the formula:
Figure AU2016203254B2_D0081
Figure AU2016203254B2_D0082
one embodiment of which relates to inhibitors having the formula:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST wherein R units are thiazol-2-yl units, that when substituted, are substituted with R2 and R3 units
2016203254 18 May 2016
Figure AU2016203254B2_D0083
5a units are further described in Table V.
Πνο7~” TART F V Jt rskJL? JUi JUr V
R R5*
Γεϊοι thiazoi-2-yi (J)-benzyi
ΕΪ02 4-methylthiazol-2-yl (S)-benzyl
ΓεϊοΓ 4-ethylthiazoi-2-yi (S)-benzyl
E104 4-propykhiazol-2-yl (S)-benzyl
El 05 4-Ao-propylthiazol-2-yl (5)-benzyi
j ΕΪ06 4-cyciopropyithiazol-2-yi (5)-benzyl
El 07 4-butylthiazol-2-yl (^-benzyl
El 08 s 4-ieri-butyithiazoi-2-yl (»S)~benzyl i
j El 09 4-cyclohexylthiazol~2-yl (S)-benzyl
f E110 442,2,2-trifluoroethyl)thiazol-2-yl (<S)-benzyl
Bill 4-(3,3,3-trifluoropropyl)thiazoi-2-yl (5)-benzyI
El 12 4-(2,2-difiuorocy elopropy l)thiazo 1 -2-y I (<S)-benzyl
El 13 4-(methoxymethyl)thiazoi-2-yl (Si-benzyl
El 14 4-(carboxyiic acid ethyl ester)thiazol-2-yI (S)-benzyl
Ell 5 4,5-dimethv Ithiazol-2-yl (S)-benzyl
E116 4-methyl-5-ethylthiazol-2-yl (S)~benzyl
E117 4-phenylthiazol-2-yl (5)-benzyl
ΕΠ8 4-(4-chlorophenyl)thiazol-2-yl ($)-benzyl
ΕΠ 9 4-(3,4-dimethyiphenyl)thiazol~2-yi (S)-benzyl
E120 4-methyi-5-phenyithiazol-2-yl (5)-benzyl
E121 4-(thiophen-2-yl)thiazoi-2-yl (5)-benzyl
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. R
E122 4-(thiophen~3-yl)thiazol-2-yl (SV-benzyl
EI23 4 -(5-chlorot hiophen-2 -yl)thiazo 1-2-y 1 (>5)~benzyl
El 24 5,6-dihydro-4ff-cydopentaii/]thiazol-2-yI (J)-benzvi
El 25 4,5!6,7-tetrahydroben2o[if]thIazol-2-yl (S’)-benzyl
The compounds encompassed within Category Hi of the present disclosure can be prepared by the procedure outlined in Scheme IV and described in Example 5 herein below
Scheme IV
Figure AU2016203254B2_D0084
Figure AU2016203254B2_D0085
Reagents and conditions: (a) Ac~Phe, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
Figure AU2016203254B2_D0086
Figure AU2016203254B2_D0087
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3~pyridine, NH^OH.
EXAMPLE 5
4-((S)~2~((»S)-2-Aceiamido-3-phenyIpropanamido)~2~(4~ethylthiazol-2yl)ethyl]phenylsulfaoilc add (15)
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Preparation of (S)-2-acetamido-Ar-[(S)-i-(4-ethylthiazol-2-yi)-2-(4-nitrophenyl)-ethyl]-3phenylpropanamide (14); To a solution of l-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyf)ethyl amine hydrobromide, 3, (0,343 g, 0.957 mmol), jV-acetyl-L-phenylalanine (0.218 g), 1hydroxybenzotriazole (HOBt) (0.16lg), diisopropyl-ethylamine (0,26 g), in DMF (10 mL) at 0°, is added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0,201 g), The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction, mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCCb, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.313 g (70 % yield) of the desired product which is used without further purification. LC/MS ES1+ 467 (M+l).
Preparation of4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-2-(4-ethylthiazoi-2yl)ethyl)phenylsulfamic acid (15): (S)-2-Acetamido-Af-[(iS)-l-(4-ethylthiazol-2-yl)-2-(4nitrophenyl)ethyl]-3-phenylpropanamide, 14, (0,313 g) is dissolved in MeOH (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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SOj-pyridine (0.320 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH^OH (30 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.215 g of the desired product as the ammonium salt. !H NMR (CD3OD): 6 7,23-6,98 (m, 10H), 5,37 (t, 1H), 4.64 (t, IH, ,7 6.3 Hz), 3.26-2.74 (m, 6H), 1.91 (s, 3H), 1.29 (t, 3H, 7-7.5 Hz),
The following are further non-limiting examples of compounds encompassed within Category IH of the present disclosure.
Figure AU2016203254B2_D0088
4-[(1S)-2-((jS)-2-Acetamido-3-phenylpropanamido)-2-(4“fert-butylthiazol-2yl)ethyl]phenylsulfamic acid: NMR (300 MHz, CDjOD): 8 7.22-7.17 (m, 5H), 7.06 (dd, 7=14,1, 8.4 Hz, 4H), 6.97 (d,>0.9 Hz, IH), 5.39 (dd,7=8.4, 6.0 Hz, IH), 4,65 Hzs
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
IH), 3.33-3.26 (m, IH), 3.13-3.00 (m, 3H), 2 (dd, >13.5, 8.7 Hz, IH),
1.91 (s,3H), 1.36 (s,
2016203254 18 May 2016
Figure AU2016203254B2_D0089
4-{(S!)-2-((,S')-2-Acetanndo-3-phenylpropanamido)-2-[4-(thiophen-3-yl)th!azol-2yl3ethyl)phenylsulfamic acid: !H NMR (300 MHz, CD3OD): δ 8.58 (d, >8.1 Hz, IH), 7.83-7.82 (m, IH), 7.57-7.46 (m, 3H), 7.28-6.93 (m, 11H), 5,54-5.43 (m, IH), 4.69-4.55 (m, 2H), 3,41-3.33 (tn, IH), 3.14-3.06 (3H), 2.86-2.79 (m, IH), 1.93 (s, 3H).
The first aspect of Category IV of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-2-yi unit having the formula;
Figure AU2016203254B2_D0090
one embodiment of which relates to inhibitors having the formula;
Figure AU2016203254B2_D0091
No. i R R5a
FI 26 thiazol-2-yi hydrogen
FI 27 4-methyl thiazoi-2-y 1 hydrogen
F128 4-ethylthiazoI-2-yl hydrogen
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. R T 5s
F129 4-propylthiazol~2-vI i hydrogen
FI 30 4 -Ao -propylthiazoi-2-y 1 i hydrogen
F131 4-eyciopropyhhiazol~2~yl [ hydrogen
FI 32 4-butylthiazoI-2-yl 1 hydrogen
F133 4-mrt~buiykhiazGl-2-yl hydrogen
FI 34 4-cyclohexy 1th i azo 1-2-y 1 | hydrogen
FI35 4,5-dimethylthiazol-2-yl j hydrogen
FI 36 4~methy l-S-ethylth iaszo 1-2-y 1 hydrogen
F137 4-phenylthiazol-2-yS j hydrogen
F138 thiazoI-2-y! (5)-Ao~propyl
F139 4 -methyl thiazol-2-yl | (jQ-rso-propyl
F140 4~ethylthiazol-2-yl I (S)-Ao-propyl
F141 4-propyithiazol-2-yl (S)-Ao~propyl
FI 42 4-Ao-propylthiazol~2~yi | (5)·· Ao·· propyl
F143 4-cyciopropykhiazol-2-yl | (5)-Ao-propyl
F144 4-butylthiazol-2-yi i (5)-/,ro-propyl
FI 45 4-iert-butylthiazol-2-yl | (S)-/50>propyl
FI 46 4-cyciohcxylthiazol~2~yl j (<S)-Ao-propyl
F147 4,5-dimethyithiazol-2-yl [ (<S)-Ao-propyl
F148 4-methyl~5~ethy!ihiazoS-2~yl j (5)~Ao-propyl
FI 49 4-phenylthiazol~2~yl (5) -Ao-propyl
FI 50 4-(thiophen-2-yl)thiazol-2-yl J (5)-Ao-propyi
The compounds encompassed within Category IV of the present disclosure can be prepared by the procedure outlined in Scheme V and described in Example 6 herein below
Scheme V
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0092
Figure AU2016203254B2_D0093
16
Reagents and conditions: (a) Boc-Val; EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
Figure AU2016203254B2_D0094
Figure AU2016203254B2_D0095
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SOa-pyridine, NH4OHS rt, 2 hr..
Preparation of tot-butyl 6Sj-1 -[(JS)-(4-ethylthiazol-2-yl)~2-(4-nitrophenyl)ethylamino]-3methyl-l-oxobutan-2-ylcarbamate (16): To a solution of l-(S)-(4-ethyItliiazol-2-yl)-2-(4nitrophenyl)ethyl amine hydrobromide, 3, (0.200 g, 0.558 mmol), (S)-(2-totbutoxycarbonylamino)-3-methylbutyric acid (0.133 g) and l-hydroxybenzo-triazole (HOBt) (0.094 g) in DMF (5 mL) at 0°, is added l-(3~dirnethytannnopropyl)-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 reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCO3, water and brine, and dried over Na2SQ4, The solvent is removed in vacuo to afford 0.219 g (82% yield) of the desired product which is used without further purification. LC/MS ESI+477 (M+l).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Preparation of 4- {(5)-2-[(5)-2-(ter/-butoxycarbonyiamino)-3-methylbutanamido]-2-(4ethylthiazol-2-yl)ethyi}phenylsulfamic acid (17): tert-Butyl (5)-1 -f(5)-(4-ethyithiazol-2-yl)-2(4-nitrophenyl)ethyIamino]-3-methyl-i-oxobutan-2-ylcafbamate, 16, (0.219 g) is dissolved in MeOH (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 CEL1TEiM and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (5 mL) and treated with SO3-pyridine (0.146 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NKjOH (30 mL) is added, The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.148 g of the desired product as the ammonium salt. NMR (CD3OD): 8 7.08 (s, 4H), 7.02 (s, IH), 5.43 (s, IH), 3.85 (s, IH). 3.28-2.77 (m, 4H), 1.94 (s, IH), 1.46 (s, 9H), 1.29 (s, 3H, >7.3 Hz), 0.83 (s, 6H).
The following are further non-limiting examples of the second aspect of Category IV of the present disclosure.
Figure AU2016203254B2_D0096
(5)-4- {2-[2-(tert-Butoxycarbony l)acetam ide]-2-(4-ethylthi azo 1-2 -yl )ethyl} ph enylsulfamie acid: !H NMR (CD3OD ): 8 7.09-6.91 (m, 5H), 5,30 (t, IH, >8.4 Hz), 3.60-2.64 (m,
Figure AU2016203254B2_D0097
yl)ethyi}phenylsulfamic acid: H NMR (CD3OD) δ 7.19-7.00 (m, 4H), 5.50-5.40 (m, IH), 4. E 4,06 (m, IH), 3.32 (IH, A of ABX, E 7.5, 18Hz), 3.12 (IH, B of ABX, j < - 8,1, 13.8Hz), 2.79 (q, 2H, J - 7,8,14.7Hz), 1.70-1.55 (m, IH), 1.46 (s, 9H), 1.33 (t, 3H, J - 2.7Hz), 0.92 (q, 6H, 3
6, lO.f
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(5)-2-[(S)-2-(te;if-Butoxycarbonylammo)”4”methylpentanamido]-2[2-(thiophen-2yl)thiazol-4-yl]ethy!}phenylsuIfamic acid: rH NMR (CD3OD) 8 8.06 (d, IH, J - 8.4Hz), 7.617.58 im. IH), 7.57 (s, IH), 7.15 (t, IH, J 0.6Hz), 7.09-6.98 (m, 6H), 5.30-5.20 (m, IH), 4,104.00 (m, IH), 3.19-3.13 (m, 2H), 1.63-1.55 (m, 2H), 1,48-1.33 (m, 10H), 0.95-0.89 (m, 6H).
2016203254 18 May 2016
Figure AU2016203254B2_D0098
Figure AU2016203254B2_D0099
(iS)-4-{2-[2-(tert-ButoxycarbonyI)acetamide]-2-(4-ethylthiazol-2-yl)ethy{}phenylsuifamic acid: SHNMR(CD3OD ): δ 7.09-6.91 (m, 5H), 5.30 (1, IH,>8 4 Hz), 3.60-2.64 (m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, >7.5 Hz).
A further embodiment of Category IV relates to inhibitors having the formula:
Figure AU2016203254B2_D0100
wherein R units and Ri:i units further described in Table VII.
TABLE VII
No. R
G151 thiazol-2-yl hydrogen
G152 4-methyithiazol-2-yl hydrogen
G153 4-ethylthiazol-2-yl hydrogen
G154 4-propy Ithiazo 1-2-yI hydrogen
G155 4-wo-propyIthiazol-2-yl hydrogen
G156 4-cyclopropylthiazoI-2-yl hydrogen
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No, j R Rs*
-----------......... 4-buty ithi azo 1-2-y 1 hydrogen
G158 4~fcrf-butylthiazol-2-yl hydrogen
G159 4-cyclohexylthiazol“2-yl hydrogen
GI60 4,5-dimethy Ithi azoi-2-y 1 hydrogen
G161 Ϊ..... 4-methyl-5-ethylthiazol-2-yl hydrogen
' G162 ! 4-phenylthiazol“2--yl hydrogen
G163 | thiazol-2-yI (5)-iw-propyi
' “θϊβΤΐ......... 4-methyiihiazoI-2-yl (S)-fro-propyl
G165 4-ethylthiazo]-2-yl (5Ι-β’ο-ρΓοργ1 Llri......
G166 4 -propy I thiazol-2-y 1 (5)-Ao~propyl
G167 4-fro-propyithiazol’2«yl (S)-iro-propyl
G168 4-cyclopropylthiazol~2-yI (5)-Ao»propyi
G169 4-butyithiazol-2-yl (,5)-fro-propyl i
G170 | 4-rc.fi-butylthiazol-2-yl (S)-&0-propyl
0271 | 4-cyclohexylthiazoi“2-yI ©Aw-propyl
G I72 | 4,5“dimethylthiazol-2~yl (S)»Ao-propyI
G173 | 4-methyI~5~ethylthiazoE2-yl (S)-ttO-propyl
G174 4-phenylihiazol-2-yl (5)-/,yo-propyl
Of 75 4-(thiophen-2-yl)thiazol-2-yl (S)-Ao-propyl
The compounds encompassed within this embodiment of Category IV can be made according to the procedure outlined in Scheme V and described in Example 6 by substituting the corresponding methylcarbamate for the Boc-protected reagent. The following are non-limiting examples of this embodiment.
S'
Figure AU2016203254B2_D0101
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(S)-2-(4~Ethyithiazol-2-yl)-2-[(<S)-2-(methoxycarbonyl)-4-methylpentanamido]ethyl}phenylsulfamic acid: *H NMR (CD3GD) δ 7.12-7.03 (m, 5H), 6.84 (d, IH, J 8.4Hz), 5.40 (t, IH, J - 5.7Hz), 4.16 (t, IH, J = 6.3Hz), 3.69 (s, 3H), 3.61-3,55 (m, IH), 3.293.27 (m, IH), 3.14-3,07 (m, IH), 2,81 (q, 2H, J = 3.9,11.2Hz), 1.66-1.59 (m, IH), 1.48-1,43 (m,
2H), 1,31 (t, 3H, J - 4.5Hz), 0.96-0.90 (m, 6H).
2016203254 18 May 2016
Figure AU2016203254B2_D0102
(S)-4- {2-(4-Ethyltblazol-2-yl)-2-[2-(methoxycarbon.yl)aceiamido]ethyl}-phenylsulfamic acid: !H NMR (CDjOD): δ 7.12-7,07 (m, 4H), 7.03 (s, IH), 5.42 (t, IH, >5.7 Hz), 3.83-3.68 (q, 2H, >11.4 Hz), 3,68 (s, 3H), 3.34-3,04 (m, 2H), 2.83-2.76 (q, 2H, >7.8 Hz), 1.31 (ί, 3H, >7.5 Hz).
Figure AU2016203254B2_D0103
4-{(Sr)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methy{butanamido]ethyljphenylsulfamic add: *H NMR (CDjOD) & 8.56 (d, IH, J - 7.8Hz), 7.09 (s, 4H), 7.03 (s, IH), 5,26-5.20 (m, IH), 3.90 (d, IH, J - 7.8Hz), 3.70 (s, 3H), 3.30 (IH, A of ABX, obscured by solvent), 3.08 (IH, B of ABX, J> 9.9, 9Hz), 2.79 (q, 2H, J - 11.1, 7.2Hz), 2.05-1.97 (m, IH), 1.31 (t, 3H, J - 7.5Hz), 0.88 (s, 3H), 0.85 (s, 3H), 0.79-0.75 (m, IH).
Figure AU2016203254B2_D0104
4-{(S)-2-[(S)-2-(Methoxycarbonyi)-4-methyipentanamido]-2-[2-(thiophen-2-yl)thiazol-4yl]ethyl}phenylsulfamic acid: !H NMR (CD3OD) δ 8.22 (d, IH, J - 9Hz), 7.62-7,57 (m, H), 7.15(1, IH, J = 0.6Hz), 7.10-6.97 (m,4H), 5.30-5.20 (m, IH), 4.16-4.11 (m, 1H),3.67 (s, 2H), 3.22 (IH, A of ABX, j - 6.9, 13.5Hz), 3.11 (IH, B of ABX, J = 7.8,13.6Hz), 1.65-1,58 (m, IH), 1.50-1.45 (m, 2H), 0.95-0.88 (m, 6H).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Category IV of the present disclosure relates to compounds having the formula:
,R
V
S-s,
HO N
Figure AU2016203254B2_D0105
wherein R is a substituted or unsubstituted thiophen.-2-yl or ihiophen-4-yl unit and non-limiting examples efR are further described in Table VIII.
No. ΗΪ76| R ihiazol-2-yl Rs poc(cm)^
ΗΪ77 | 4 -methy lthiazoI-2-y 1 rWcccmh
ΗΪ78| 4-ethy lthiazol-2 -y 1 poc(cm)7
H179j 4-cyclopropylthiazol-2-yl poc(cmh !
ΗΪ80Ί 4-ierf-buty 1th iazo 1-2-yi poeicmih
ΗΪ8Ϊ| 4-cyclohexylthiazoI-2-yl pocccmh
ΗΪ82| 4-(2,2,2-trifluoroethyl)thiazol-2-yl ~OC(CH3)3
Hm 4-(3,3 3 ”*ri fluoropropyl)thiazol-2-yf poc(cm)7
mWj 4-(2,2-difluorocyc lopropy l)t hiazol-2-y 1 pocxcmj?
Η185 4,5-dimethyIthiazoi-2-yl ~OC(CH3)3
ΗΪ86“I 4-methyl-5-ethylthiazol-2-yl ρδδ(αξ)Γ
ΗΪ87~] 4-phenylthiazoI-2-yl PoqchW
H189 mW
WT mW
Η19Ϊ “mW
ΗΪ95 hIW
4~(4-chlorophenyl)thiazol-2-yl I ~OC(CH3)3
-(3,4-dimethylphenyl)thiazol-2-yl i -OC(CH3)3
4-methyl-5-phenyIthiazol-2-yi i -OC(CH3)3
4-(thiophen-2-yl)thiazol-2-yl i -OC(CH3)3 thiazol-4-yl j ~0C(CH3)3
....................... {
4-methylthiazol-4-yi WOC(CH3)3
4~ethydthiazoM~y[ WoC(CHW
4-cyclopropylthiazol-4-yl |
4-ierf-butylthiazol-4-yl ] -OC(CH3)3
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. R Rs
H197 4-cyclohexylthiazoi-4-y{ -~OC(CH3b
H198 4-(2,2,2-trifluoroethyl)thiazol-4-yl ~OC(CH3)3
H199 4-(3,3,3 -tri fluoropropy l)thiazo 1-4 -y 1 -OC(CH3)3
H200 4-(2J2~difluorocyelopropyl)thiazol-4-yl ~OC(CH3)3
H201 4,5-dimethylthia2ol-4-yI ^oc(ch3)3
H202 4-methyl-5-ethyithiazoI-4-yI OC(CH3)3 ;
H2Q3 4pheuylthiazol-4-yl -OC(CH3)3
H204 4-(4-chiorophenyl)thiazol-4-yl ”-()C(CH3)3
H205 4-(3,4~dimethylpheuyl)thiazol-4-yl OC(CH3)3
ί H206 4-ffiethyl-5-phenylthiazo!-4~yl -OC(CH3)3
H207 4-(th iophen-2-y l)thiazo 1-4 -y 1 -OC(CH3)3
H208 thiazol-2-yl OCH.3
H209 4-methyIthiazol-2-yl OCHj
H210 4-ethylthiazol-2-yl -och3
H211 4-cyclopropy lthiazol-2-y I OCHj
H212 4-feri-butyithiazol-2-yl -0CH3 i
Η2Ϊ3 4-cydoh6xvlthiazol-2-yl -och3 i
! H214 4-(2,2,2-trifluoroethyl)thiazol-2-yI -0CH3 1
H215 4-(3,3,3-trifluoropropyl)thiazol-2-yl -OCH3
H216 I 4-(2,2-d;fii!orocyclopropyl)thiazol--2-y'! | -OCH3
H217 4,5-dimethylthiazol-2-y{ -gch3
H218 4-methyl-5-ethylthiazol-2-yl -och3
H219 4-phenyl thiazol-2-y 1 -OCH3
H220 4-(4-chlorophenyl)ihiazol~2~yl -OCHj
H221 4-(3,4-d imethy Ipheny l)thiazo 1-2-y 1 och3
H222 4-meihyl~5-phenylihiazot~2~yi —OCHj
H223 4-(thiophen-2-yl)thiazoI-2-yl ~gch3
H224 thiazol-4-yl -OCR,
H225 4-methy Ithiazo 1-4-y I OCH3
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
! No. R Rs
H226 4-ethylthiazol-4-yi ~gch3
H227 4-eyclopropylthiazol-4-yl -och3
H228 4-teri-butyl thiazol-4-y 1 --OCH3
H229 4-cyclohexylthiazol-4-yl -gch3
H230 4-(2,2,2-trifluoroethyl)thiazol-4-yl -och3
H231 4-(3,3,3 -tri fluoropropyl)thiazol-4-y{ -0CH3
H232 4-(2,2~difluorocyclopropyl)thiazol-4-yl -OCH3
H233 4,5-dimelhyIthiazol-4-yl och.
H234 4-methyI-5-ethylthiazoI-4-yl ~och3
H235 4-phenyhhiazol-4-yl -och3
H236 4-(4-chloropheny l)thiazo 1-4-y 1 -OCH,
H237 4-(354-άΪΜβΐΗχ1ρ1ιεηγ1)ίΗΪ3ζο1-4~γ1 -och3
H238 J 4~methyl~5-phenylthiazol-4-yl --OCH3
H239 4-(thiophen-2-yl)thiazol-4-yl ~gcb3
H240 thiazol-2-yI -CH,
H241 4-methylthiazo 1-2-y 1 ~ch3
H242 4-ethylthiazol-2-yl -ch3
H243 4-cyclopropylthiazol-2-yl -CH,
H244 4 -teri-buty Itfaiazo ϊ-2-y 1 ch3
H245 4-eyelohexylthiazol-2-yi -CH3
H246 4-(2,2,2 -trifluoroethy l)thiazo 1 -2-y 1 -ch3
H247 4-(3,3,3 -trifluoropropy 1) thiazo 1-2-y 1 -ch3
H248 4-(2,2-difluorocyclopropyi)thiazol-2-yl ~ch3
H249 4,5-dimethylthiazol-2-yl -ch3
H250 4-methyl-5-ethylthiazol-2~yi -ch3
H251 4-phenylthiazol-2-yi . . -ch3
H252 4 -(4-ehloropheny l)thiazol-2-yl -ch3
H253 4-(3,4-dimethyiphenyl)thiazol-2-yl CH,
H254 4-methy 1-5-pheny Ithi azol-2 ~y 1 -ch3
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0106
The compounds encompassed within Category IV of the present disclosure can prepared by the procedure outlined ίη VI and described in Example 7 herein below.
Figure AU2016203254B2_D0107
Figure AU2016203254B2_D0108
Reagents and conditions: (a)(i) CH3CN; reflux, 1,5 hr, (ii) Βοο20, pyridine, CH2CI2; rt, 2hr.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0109
Figure AU2016203254B2_D0110
Reagents and conditions: (b)(i) tfoPd/C, MeOH; reflux (ii) SOj-pyridine, ΝΗ-,ΟΗ; rt, 12 hr.
EXAMPLE 7 [ I -(S)-(P heny ] thiazoI-2-y I)~2~(4~su tins minopheny I)ethyl ] eartmmie acid tert-butyl ester (19)
Preparation of [2-(4-nitrophenyl)-l-(5)-(4-phenylthiazol-2-yl)ethyl]-carbamic acid tertbutyl ester (18): A mixture of [2-(4-nitrophenyl)-l-(5)-thiocarbamoyiethylj-carbamic acid tertbutyl ester, 2, (0.343 g, 1.05 mmol), 2-bromoacetophenone (0.231 g, 1.15 mmol), in CH3CN (5 mL) is refluxed 1.5 hour. The solvent is removed under reduced pressure and the residue redissolved in CHjCh then pyridine (0.24 mL, 3.0 mmol) and Boe?O (0.24 mL, 1.1 mmol) are added. The reaction is stirred for 2 hours and diethyl ether is added to the solution and the precipitate which forms is removed by filtration. The organic layer is dried (NazSO^), filtered, and concentrated to a residue which is purified over silica to afford 0.176 g (39%) of the desired product ESI+ MS 426 (M+l).
Preparation of [l-(S)-(phenylthiazol-2-yl)-2-(4-suIfoaminophenyl)ethyi]carbamic acid tert-butyl ester (19): [2-(4-nitrophenyl)-l-(S)-(4-phenyithiazol-2-yi)ethyi]carbamic acid tert-butyl ester, 18, (0.176 g, 0.41 mmol) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 12 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SOj-pyridine (0.195 g, 1.23 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.080 g of the desired product as the ammonium salt, 3H NMR (300 MHz, MeOH-iL) 8 7.93 (d,
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
J - 6.0 Hz, 2H), 7.68 (s, IH), 7.46-7.42 (m, 3H), 7,37-7.32 (m, IH), 7.14-7.18 (m, 3H), 5,135.18 (m, IH), 3.40 (dd, ,/-4.5 and 15.0 Hz, IH), 3.04 (dd,./- 9.6 and 14.1 Hz, IH), 1.43 (s,
2016203254 18 May 2016
The follo wing are further non-limiting examples of Category IV of the present disclosure.
no
Figure AU2016203254B2_D0111
NMR(CD3OD): δ 7.31 (s, 4H), 7.20 (s, IH), 5.61-5,56 (m, IH), 3.57-3.22 (m, 2H), 2.62 (s, 3H), 1.31 (s, 3H).
Figure AU2016203254B2_D0112
(S)-4-(2-(4-Ethylthiazol-2-yt)-2-pivalamidoethyl)phenylsulfamic acid: H NMR (300 MHz, MeOH-d4) δ 7.92 (d, J 8.1 Hz, IH), 7.12-7.14 (m, 4H), 7.03 (s, IH), 5,38-5.46 (m, IH),
3.3-3.4 (m, 1H),3.O8 (dd,J-10.2 and 13.8 Hz, IH), 2,79 (q, J—7.2 Hz, 2H), 1.30(1,./=7.2 Hz, 3H), 1.13 (s, 9H).
Figure AU2016203254B2_D0113
Ή NMR (300 MHz, MeOH-d4) δ 7.92 (d,./- 8.1 Hz, IH), 7.24 (s, IH), 7.08 (d, 7- 8.7 Hz, 2H), 7.00 (d, J- 8.7 Hz} 2H), 5.29-5.37 (m, IH), 4,55 (s, 2H), 3.30 (dd, J*4.8 and 13.5 Hz, IH), 2.99 (dd, J- 10.5 and 13.5 Hz, IH), 0.93 (s,
j.*—%
KO N H
Γ
Y~__ (S)-4-(2-(4-(Ethoxycarbonyl)thiazol-2-yl)-:
d4)S 8.30 (s, IH), 8.04 (d,/:* 8.1
1: Ή
IH), 7.13 (s, 4H), 5.41-5,49 (m,
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 ), 4.41 (q, ,/== 7.2 Hz, 2H), 3.43 (dd, ./ 5.1 and 13.8 IH), 1.42 (1,./ = 7.2 Hz, 3H), 1.14 (s, 9H).
Figure AU2016203254B2_D0114
J ~ 5,7 and 9.9 Hz, (5)-4-(2-(4-Phenyfthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid: ’HNMR (300 MHz, MeOH-dQ 5 7.94-8.01 (m, 3H), 7.70 (s, IH), 7.42-7.47 (m, 2H), 7.32-7.47 (m, IH), 7.137.20(m, 3H), 5.48-5.55 (m, IH), 3.50 (dd,./-5.1 and 14,1 Hz, IH), 3.18 (dd,./- 10.2 and 14.1 Hz, IH), 1.17(8,
4-((8)-2-(4-(3 (CD.OD): δ 7.96-7, ί, 1HS>8,O Hz), 7,14(s, .50-3.13 (m, 2H), 1.15 (s,
Figure AU2016203254B2_D0115
OCHt
-2-yi)-2-pivalamidoeihyl)phenylsulfamic acid; ’] 1, 1H,>8.1 Hz), 7.69 (s, IH), 7.51-7.49 (d, 21/,/-7.9 Hz), 7.33 6.92-6.90 (d, IH, >7.8 Hz), 5.50 (ί, IH, >5,1 Hz), 3.87 (s:
Figure AU2016203254B2_D0116
4-((3)-2-(4-(2,4-DimethGxyphenyl)thiaz0l-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:
8.11-8.09 (d, 1H,>7,8 Hz), 7,96-7.93 (d, IH, > 8.4 Hz), 7.74 (s, 7.18-7.16 (m, 4H), 6.67-6.64 (d, 2HS >9.0 Hz), 5,55-5.47 (m, IH), 3.95 (s3 3H), 3.87 (s, 3.52-3,13 (m, 2H), 1.17 (s,
Figure AU2016203254B2_D0117
-4-(2-(4-2-y l)-2-pivalanudoethy l)phenyls uIfamic acid:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST !H NMR (CD3OD) 8 7.85 (d, IH, J - 8.4Hz), 7.38-7.20 (m, 4H), 7.11-7.02 (m, IH), 7.00 (s,
5.42-5.37 (m, IH), 4,13 (s, 2H), 3.13-3,08 (m, 2H), 1,13 (s,
2016203254 18 May 2016 a, a
Figure AU2016203254B2_D0118
(S)-4-(2-Pivalamido-2-(4-(thiophen-2-ylmethyl)thiazol-2-yl)ethyl)phenylsulfamic acid: Ή NMR (CD3OD) δ 7.88-7.85 (d, IH), 7.38-7.35 (m, IH), 7,10-7.01 (m, 4H), 7.02 (s, IH), 5.45 5.38 (m, IH), 4.13 (s, 2H), 3,13-3.05 (m, 2H), 1.13 (2, 9H).
Figure AU2016203254B2_D0119
H,C (S)-4-(2-(4-(3-MethoxybenzyI)thiazol-2-yl)-2-pivalamidoethyi)phenylsulfamic acid: 1 NMR (CDjOD) S 7.85 (d, IH, J - 8.4Hz), 7.25-7.20 (m, IH), 7.11-7.02 (m, 4H), 7.01 (s, IH) 6.90-6.79 (m, 2H), 5.45-5.40 (m, IH), 4.09 (s, 2H), 3.79 (s, 3H), 3,.12-3,08 (m, 2H), 1.10 (a -o.
HQ N H
Figure AU2016203254B2_D0120
HNs-0
Figure AU2016203254B2_D0121
4-((S)-2-(4-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)thiazol-2-yl)-2-pivaIamidoethyl)phenyisulfamic acid: !H NMR (CDjOD): 8 7.53 (s, IH), 7.45 (s, IH), 7.42-7.40 (d, IH, >8.4 Hz), 7.19-7.15 (m, 4H), 6.91-6.88 (d, 2H,>8.4 Hz), 5,51-5.46 (m, IH), 4.30 (s, 4H), 3.51-3,12
Figure AU2016203254B2_D0122
(S)-4~(2-(5-Methyl-4-phenylthiazoi-2-yl)-2-pivalamidoethyl)phenylsidfamic acid: 3H NMR (CDjOD): S 7,63-7.60 (d, 2H, >7.1 Hz), 7.49-7.35 (m, 3H), 7.14 (s, 4H), 5.43-5.38 (m,
IH), 3,42-3.09 (ra, 2H), 2.49 (s, 3H), 1.14 (s, 9H).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (S)-4- (2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyI)phenylsulfamic acid:
NMR (CDjOD ): § 8.04-8.01 (m, 2H), 7.72-7.66 (m, 5H), 7.48-7.35 (m, 3H), 7.15 (s, >0 (t, IH, >5,0 Hz), 3.57-3,15 (d, 2H), 1.16 (s, 9H).
2016203254 18 May 2016
5.
Figure AU2016203254B2_D0123
a ,P
KO' “N (,5)-4-(2-icrtBuioxycarbonyl-2-(2-methylthaizol-4-y!)-phenylsulfamic acid !H NMR (300 MHz, fhQ) 8 6,99-7.002(m, 4H)S 6.82 (s, IH), 2.26 (dd,./- 13.8 and 7,2 Hz, IH),
Figure AU2016203254B2_D0124
(S)-4-(2-(fori-Butoxycarbonyl)-2-(4-propylihiazol-2-yl)dhyl)-phenyl sulfamic acid; ;300 MHz, CD3OD): δ 7,18-7.02 (m, 5H), 5.06-5.03 (m, IH), 3.26 (dd, >13.8,4,8 Hz,
IH), 2.95 (dd, >13.8,9.3 Hz, IH), 2.74 (dd,>15.0,7,2 Hz, 2H), 1,81-1.71 (m, 2H), 1.40 (s, 7H), 1.33 (bs, 2H), 0.988 (t, > 7,5 Hz 3H).
Figure AU2016203254B2_D0125
(S)-4-(2-(fer/-Butoxycarbonyl)~2~(4-terf-butylthiazol-2-yl)ethyi)-phenyi sulfamic acid: 5H NMR (300 MHz, CD3OD): δ 7.12 (s, 4H), 7.01 (s, IH), 5.11-5.06 (m, IH), 3.32-3.25 (m,
2.96 (in, IH), 1.42 (s, 8H), 1.38 (s, 9H), 1,32 (s, IH).
ί' ί
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (S)-4-(2-(ierr-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid: 'H NMR (300 MHz, CD3OD): 8 7.36 (s, 1H), 7.14-7.05 (m, 4H), 5.06 (dd, >9,0,
5.1 Hz, 1H), 4.55 (s, 2H), 3.42 (s, 3H), 3,31-3.24 (m, 1H), 2.97 (dd, >13.8, 9.9 Hz, 1H), 1.471.31 (m, 9H),
2016203254 18 May 2016
Figure AU2016203254B2_D0126
och3
Figure AU2016203254B2_D0127
(5)-4-(2 -ieri-ButoxycarbonyIamino)-2-(4-(2-hydroxymethyl)thiazoi~2~ yl)ethyl)phenylsulfamic acid: lH NMR (300 MHz, MeOH-d^) δ 7.22-7.25 (m, 1H), 7.09-7.15 (m,4H), 5.00-5.09 (m, 1H), 4.32-4.35 (m, 1H), 3.87 (t, J - 6.6 Hz, 2H), 3,23-3.29 (m, 1H), 3.09-
Figure AU2016203254B2_D0128
o
x.« (5)-4 -(2-/eri-Butoxycarbonylamino)-2-(4-(2 -etho xy-2 -oxoethyl)-thiazole-2-y 1)ethyl)phenylsulfamic acid: 5H NMR (300 MHz, MeOH-d4) δ 7.29 (s, 1H), 7.09-7.16 (m, 4H), 5.04-5.09 (m, 1H), 4.20 (q, > 6.9 Hz, 2H), 3.84 (s, 2H), 3.30 (dd, 4.8 and 14.1 HZ, 1H), (dd,7^9.6 Hz and 13.8 Hz, 1H), 1.41 (s, 9H), 1.29 (t,> 7.2 Hz, 3H).
Figure AU2016203254B2_D0129
OQL· (S)-4-(2-(fer/-Butoxycarbonylamino)-2-(4-(2-tnethoxy-2-oxoethyl)thiazol-2yl)ethyl)phenylsulfamic acid: !H NMR (300 MHz, MeOH-d^ δ 7,31 (s, 1H), 7.01-7.16 (tn, 5.04-5.09 (m, 1H), 4,01 (s, 2H), 3.78 (s, 2H), 3.74 (s, 3H), 3.29 (dd,- 5,1 and 13.8 Hz, IH) 2.99 (dd, > 9.3 and 13.8 Hz, 1H), 1.41 (s, 9H),
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (S)-4-(2-(tert-Butoxycarbonyiamino)-2-(2“(pivaioyloxy)thiazol-4-yl)ethyl)phenylsulfamic acid: 3H NMR (300 MHz, DjQ) 8 6.95 (s, 4H), 6.63 (s, IH), 2.94 (dd,./-13,5 and 4.8 Hz, IH), 2,75 (dd,/-13.5 and 4.8 Hz, IH), 1.16 (s, 9H), 1.13 (s, 9H).
2016203254 18 May 2016
Figure AU2016203254B2_D0130
Figure AU2016203254B2_D0131
(S)-4-(2-(teri~Butoxycarbon.ylamino)-2-(5-phenylthiazol-2-yl)ethyl)”phenyi sulfamic acid: Ή NMR (300 MHz, CD3OD): 8 7.98 (s, IH), 7.62 (d, /-7.2 Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs, IH), 3.07-2.99 (m, 2H), 1.43 (s,
Figure AU2016203254B2_D0132
4-((S)-2-(ieri-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiazoi-2yl)ethyl)phenyl sulfamic acid: SH NMR (300 MHz, CD3OD): 8 8.28 (s, IH), 8.22-8.19 (m, 1H),7.89 (s, IH), 7.65 (d,/-5.1 Hz, 2H), 7.45 (d,/-8.1 Hz, IH), 7.15 (s, 4H), 5.17-5.14 (m,
Figure AU2016203254B2_D0133
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (S)-4-(2-(terNButoxycarbonylamino)-2-(4-phenylthiazol-2-yl)ethyl)-phenyl sulfamic acid; 5H
2016203254 18 May 2016
NMR (300 MHz, CDjOD): δ 7,98 (s, IH), 7.94 (d, >7.2 Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s,
Figure AU2016203254B2_D0134
4H), 5.09 (bs, IH), 3.07-2.99 (ra,2H), 1.43 (s, 9H). 1 (S,S)-2-(2~{2-[2-tot-Butoxycarbonylamino-2-(4-suifoaniinophenyI)ethyl]thiazol-4yl)acetylamido)-3-phenylpropiomc acid methyl ester: 5H NMR (300 MHz, MeOH-dQ δ 6.856.94 (m, 9H), 6,64 (s, IH), 4.83 (s, IH), 4.54-4.58 (m, IH), 3.49 (s, 3H), 3.39 (s, 2H), 2.80-2.97 (m, IH), 2.64-2.78 (m, IH), 1.12 (s, 9H).
(S)-[l - (1 -Oxo-4-[2-( .1 -phenyl-1 H-tetrazol-5-sulfonyl)ethyl]-I H- lX4-thiazol-2-v 1} -2-(4sulfamino-phenyl)-ethy]]-carbamic acid tot-butyl ester: NMR (300 MHz, MeOH-d4) δ 7.227.75 (m, 2H), 7.62-7,69 (m, 2H), 7.55 (s, IH), 7.10-7.20 (m, 5H), 5.25 (m, IH), 4.27-4.36 (m, IH), 4.11-4.21 (m, IH), 3.33-3.44 (m, 4H), 2.84-2.90 (m, IH), 1.33 (s, 9H).
Figure AU2016203254B2_D0135
4-((8)- 2-(tot-Butoxyearbonylammo)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenyl sulfamic add: 'HNMR (300 MHz, CDjOD): δ 7.84 (dd,>3.0, 1,5 Hz, IH), 7,57-7.55 (m, 2H), 7.47 (dd, >4.8, 3.0 Hz, IH), 7.15(s, 4H), 5.15-5.10 (m, IH), 3.39-3.34 (m, IH), 3.01 (dd, >14.1, 9,6 Hz, IH), 1.42 (s, 8H), 1.32 (s, IH).
Figure AU2016203254B2_D0136
(S)-4-(2-(Benzo[d]thiazol-2-ylamino)-2-(teri-butoxycarbonyl)ethyl)phenylsulfamic acid: !H NMR (CD3OD) δ 7,86-7.82 (m, 2H), 7.42 (t, 2H, >7.1 Hz), 7,33 (t, IH, >8,2 Hz), 7.02 (s, 4H), 5,10-5.05 (m, IH), 2.99-2.91 (m, 2H), 1.29 (s, 9H).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)-4-(2-ieri-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)-phenylsuifamic acid 3H NMR (300 MHz, D2O) δ 6.99-7.002{m, 4H), 6.82 (s, IH), 2.26 (dd,./- 13.8 and 7.2 Hz, IH),
2.76 (dd,,/- 13.8 and 7.2 Hz, IH), 2.48 (s, 3H), 1.17 (s, 9H).
The first aspect of Category V of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
2016203254 18 May 2016
Figure AU2016203254B2_D0137
wherein R1, R2, R~\ and L are farther defined herein in Table IX herein below.
Figure AU2016203254B2_D0138
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. L 1 R* RJ
1286 -C(O)CH2- ί 3-hydroxyphenyl ch3 -H
1287 ~c(6)ch2-~ 4-hydroxyphenyl ~ch3 --H
1288 ~C(O)CH2- 2-methoxyphenyl -ch3 H
1 1289 -C(O)CH2- 3-methoxyphenyl ch3 ~~H
ί 1290 ! -C(O)CH2- 4-methoxyphenyl -ch3 -H
1291 -C(O)CH2- * 2,3-dimethoxyphenyl * ~ch3 -ΤΪ
1292 ™C(O)CH2- 3,4-dimethoxypheny 1 -ch3 -H
1293 -C(O)CH2 3,5 -dimethoxyphenyl ~ch3 H
1294 -C(O)CH2- phenyl CH2CHj -H
i 1295 ~c(6)ch2- 2-fluorophenyl ~ch2ch3
1 1296 } ~C(O)CH2-- 3-fluorophenyl -ch2ch3 H
j 1297 -C(O)CH2~ 4-fluorophenyl CH2CH3 -H
1298 -C(O)CHr- 2,3-difluorophenyl •~ch2ch3 -H
1299 '••C(O)CH2··· 3,4-difluoropheny 1 -ch2ch3 H
1300 ™C(O)CH2- 3,5 -difluoropheny 1 ~CH2CH3 h......]
1301 -~C(O)CH2-~ 2-ehlorophenyl -ch2ch3 “H j
1302 ~C(O)CH2- 3-chlorophenyl CH2CHj H
1303 -C(0)CH2- 4-chlorophenyl -CHjCHj -H
1304 -C(O)CH2- 2,3-dichlorophenyi -ch2ch3 -H
1305 -C(O)CH2- 3,4-dichiorophenyl ~ch2ch3 ......b.........
1306 C(O)CH;;- 3,5-dichlorophenyl -ch2ch3 -H ϊ
1307 -C(G)CHr~ 2-hydroxyphenyl ~ch2ch3 -H
1308 -C(O)CH2- 3-hydroxyphenyl -ch2ch3 -H
1309 ~C(O)CH;·- 4-hydroxyphenyl -ch2ch3 H |
BIO -C(O)CHr- 2-methoxyphenyl -ch2ch3 .........-H
1311 C(O)CH2- 3 -methoxyphenyl -ch2ch3
1312 -C(O)CH2- 4 -methoxyphenyl ~ch2ch3 H ! <
1313 -C(O)CH2~ 2,3-dimethoxyphenyl -ch2ch3
1314 -C(O)CH2- 3,4-dimethoxvphenyl -ch2ch3 -H
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
1315 | -C(0)CH2- 3,5-dimethoxyphenyl
| 13 Ϊ6 i-C(O)CH2CH2- phenyl
|Ϊ3Ϊ7~~ RocftchT7 2-fluorophenyl
|B18“ -C(O)CH2CH2- 3-fluorophenyl
Ϊ3Ϊ9 4-fluorophenyl
p320' ^•CiOlCiNCHr- 2,3-di fluorophenyl
ΠβζΓ” kC(O)CH^CH^ 3,4-difIuoropheny 1
ΠίζΓ” ••C(0)CH>CH2·· 3,5 -difluorophenyl
p323~ -C(O)CH2CH2-- 2-ehiorophenyl
p324~~ -C(O)CH2CH2- 3-chIorophenyl
p32T” 'a(wcIch7' 4-chlorophenyl
ΠΕ32ό~~ C(O)CH2CH2- 2,3-dichiorophenyl
|Ϊ32Τ” ~C(0)CH2CH2~ 3,4-dichlorophenyl
ί 1328 -C(O)CH2CH2- 3,5-dichlorophenyl
1329
-H
-C(O)CH2CH2 ΗΖαζ HbCtL
-CCOJCH^CH?^C’(0)CH2OL 'C(O)CH2CH2<X0)CWTi7
-C(0)CH2CH2~
C'Ki 2tn? i2€Hr
CffcCH? CEfcCH^
-c(O)ch^h7
; 2-hydroxyphenyl Γ -CH3 ___.........
| 3-hydroxyphenylΓ _____ η
| 4-hydroxyphenyl ~0Ϊ7 .........
i 2-methoxyphenyI ~ch3 ™H
j 3-methoxyphenyl J ~ch3 I H
J 4-methoxyphenyl i ...................
2,3-dimethoxyphenyl i .................... --H
jST-dimethoxyphenyl | —vrij ..........
3,5-dimethoxyphenyl '““''am Γ ~h
phenyl ~ch2ch3 1 -H
2-fluorophenyl ''''CH2CHrf
3-fluorophenyl ~~~4d..........
4-fluorophenyl '™S^chT| ~~~AH
2,3-difluorophenyl -.CHiCHTT ah
3,4-difluorophenyf 'T^tTcHTj ......~H......
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
ΓνοΤΊ l Ί R ......... R
'’l344j'-'c(O)CH2CHl | 3,5-difluorophenyl ”1<HXW
1345 AC(O)CH2CH2~ j 2-chlorophenyl _____
......1346 i ~C(0)CH2CH2-~ 3-chlorophenyl _____
Π347ψ·δ(δ}δΗ2θϊ;ν' |llWmOptenyl _____
ΓΒ4ί|ΐδ(σ)εΗχϊΗΪΐ 2,3-dichlorophenyl -CH2CH3
”134911δ(δ)δΗ2€Η21 I 3,4-dichlorophenyl ~CH2CH3
1350 -C(O)CH2CH2- 1 3,5 -d ichloropheny 1 ______
''l35i''''j-C(O)CHAW7 | 2-hydroxyphenyl -CH2CH3
1352 |-CtOlCHaCH;···· | 3-hydroxyphenyl -vnzLrh
1353 i~C(O)CH2CH2~ | 4-hydroxyphenyl _____
1354 i-C(O)CH2CH2- I 2-met boxy phenyl '''CH2CH5
1355 | -C(O)CH2CH2- 3-methoxyphenyl ______
'l356'''i~C(O)CH2CH2’’-' Ί 4-methoxyphenyl _____
'''''H57''''jl5(l)CHiCH;l' 2,3-dimethoxyphenyl -CH2CH3
1358 [110^hZch1™ J 3,4-dimethoxyphenyl --ch2ch3
n35TpC(O)CHiCHl” T 3,5-dimethoxyphenyl ! ______
The compounds encompassed within the first aspect of Category V of the present disclosure can be prepared by the procedure outlined in Scheme VII and described in Example 8 herein below.
Figure AU2016203254B2_D0139
NH,· HBr
Figure AU2016203254B2_D0140
Reagents and conditions: (a) C6H^CGjH, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0141
Figure AU2016203254B2_D0142
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) S Os-pyridine, NH4OH, rt, 18 hr.
EXAMPLE 8 {4-|2-(S)-(4-EthylthiazoS-2-yl)“2-(2-phenyiacetyIamido)ethyI]phenyl}sulfamlc acid (21)
Preparation of Ά7~[ 1 -(4-ethylthiazol-2-yl)-2-(4-nitrophenyi)ethyl]-2-phenyl-acetamide (20): To a solution of l-(S)-(4-ethy1thiazol-2-yI)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and 1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF ( 10 mL) at 0°, is added l-(3-dimethylaminopropyl)-3ethylcarbodiimide (EDCI) (0.268g, 1.4 mmol) followed by triethylamine (0.60 mL, 4.2mmol·). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCOj, water and brine, and dried over NajSCri. The solvent is removed in vacuo to afford 0.260 g (60 % yield) of the desired product which is used without further purification. ES1+ MS 396 (M+l).
Preparation of {4-[2-(5)-(4-ethyithiazol-2-yl)-2-(2-phenylacetylamido)ethyl]phenyljsulfamic acid (21): Ar~[l-(4-ethylthiazol-2-yi)-2-(4-nitrophenyl)ethyl]-2-phenylacetamide, 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 under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL.) and treated with SO3-pyridine (0.177 g, 1.23).
The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH (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. Ή NMR (CD3OD) δ 8.60 (d, IH, j- 8.1Hz), 7.33-7.23 (m, 3H), 7.16-7,00 (m, 6H), 5,44-5.41 (m,
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
IH), 3.28 (IH, A of ABX, obscured by solvent), 3.03 (IH, B of ABX, J - 14,1,9.6Hz), 2.80 (q,
2H, J - 10,5, 7.8Hz) 1.31 (t, 3H, J - 4.6Hz).
The following are non-limiting examples of the first aspect of Category V of the present disclosure.
2016203254 18 May 2016
Figure AU2016203254B2_D0143
(S)-4(2-(4-Ethyithiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenylsulfamie acid:
. (CDjOD) δ 8.65(d, IH, J- 8.4Hz), 7,29-7.15 (m, IH), 7,13-7.03 (m, 7H), 5.46-5.42 (m, IH), 3.64-3,51 (m, 2H), 3.29 (IH), 3.04 (IH, B of ABX, 3 - 13.8,9.6Hz), 2.81 (q, 2H, J™ 15.6, 3.5
Figure AU2016203254B2_D0144
(5)~4-(2~(4-Ethv (thiazol-2-y 1)-2-(2-(3-0 uorophenv l)a cetamido )e thy l)phenylsulfamic NMR (CD3OD) δ 8.74 (d, IH, J - 8.4Hz), 7.32 (q, IH, 3 - 6.6, 14.2Hz), 7.10-6.91 (m, 8H),
5.47-5.40 (m, IH), 3.53 (s, 2H), 3,30 (IH), 3.11 (IH, B of ABX, J - 9.6, 14.1Hz), 2.80 (q, 2H, J -6.6, 15.1Hz), 1.31 (t, 3H, J ~ 7.8Hz). 19F NMR 847.42.
Figure AU2016203254B2_D0145
(5)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-y!)ethyl)-phenylsuifamic acid: ‘H NMR (CD<OD) δ 7.16-7.05 (m, 5H), 6,85-6.80 (m, IH), 5.48-5.43 (m, IH), 3.63 (s, 2H), 3.38 (IH, A of ABX, obscured by solvent), 3,03 (IH), 2.80 (q, H, J = 15.1,7.8Hz), 1.31 (t, 3H,J-7.5Hz),
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)-4-(2-(2-(3,4-Difluorophenyl)acetarnido)-2-(4-ethylthiazol-2-yl)ethyl)-phenyIsulfamic δ 8.75 (d, 1H, J « 7.8Hz), 7,23-7.04 (ra, 6H), 6.88-6,84 (m, IH), 5.443.34 (IH), 3,02 (IH, B of ABX, J 14.1, 9.9Hz), 2.80 (q, 2H, J J - 7.5Hz). 19F NMR (CD3OD) δ 22.18, 19.45.
2016203254 18 May 2016 acid: ί 5.40 (m, IH), 3.49 (s, 15.1,7.8Hz), 1.31 (t,
Figure AU2016203254B2_D0146
Figure AU2016203254B2_D0147
HO N H
Figure AU2016203254B2_D0148
(5)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic acid: H NMR (CD3OD) δ 7,39-7.36 (m, IH), 7.27-7.21 (m, 2H), 7.15-6.98 (m, 5H), 5.49-5,44 (m, IH), 3.69 (d, 2H, X 1 i.7Hz), 3.32 (IH), 3,04 (IH, B of ABX, J 9.3, 13.9Hz), 2.80 (q j - 7.8. 15.3Hz), 1.31 (t, 3H, X 7.5Hz).
Figure AU2016203254B2_D0149
(5)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-elhylthiazoi-2-yl)ethyl)phenylsulfamic acid: SH NMR (CD3OD) 5 7.33-7,23 (m, 3H), 7.13-7.03 (m, 5H), 5.43 (q, IH, J « 5.1, 9.
3.51 (s, 2H), 3.29 (IH), 3.03 (IH, B of ABX, X 9.9, 14.1Hz), 2.80 (q, 2H, J ^7.5, 15Hz), 1.31 (t, 3H,X7.8Hz).
Figure AU2016203254B2_D0150
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)-phenylsulfamic acid: !HNMR (CD3OD) δ 7.16-7.08 (m, 3H), 7,03-7.00 (m, 3H), 6.70-6.63 (m, 2H), 5.42-5.40
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (m, IH), 3.44 (s, 2H), 3.28 (IH, A of ABX, obscured by solvent), 3.04 (B of ABX, J “ 14.1,
9.6Hz), 2.89 (q, 2H, J - 15, 7.5Hz), 1.31 (t, 3H, J - 7.5Hz).
ν γυίΛ ,» ΗΝ. J
HO W
H
2016203254 18 May 2016
Figure AU2016203254B2_D0151
(5)-4-(2-(4-EthyUhiazoi-2-yi)-2-(2-(2-methoxyphenyl)acetamido)ethyl)-phenylsuifamic acid: ‘HNMRiCDiODja 8.00(d, IH, J - 7.8Hz), 7.26(t, Hi, J- 13.2Hz), 7.09-7.05 (m, 4H), 7,01 (s, IH), 6.91-6.89 (m, 4H), 5.44-5.39 (m, IH), 3,71 (s, 3H), 3.52 (s, 2H), 3.26 (IH, A of ABX, J ~ 14.1, 5.1Hz), 3.06 (IH B of ABX, J - 13.8, 8.4Hz), 2.80 (q, 2H, J < 8.1, 15,6Hz), 1,31 (t, 3H, J :: 1,2Hz),
Figure AU2016203254B2_D0152
(5)-4-(2-(4-Ethylthiazoi-2-yl)-2-[2-(3-methoxyphenyl)acetamido]ethyl}-phenylsuifamic Ή NMR (CDjOD) δ 8.58 (d, IH, .1 - 8.1 Hz), 7.21 (t, IH, J - 7.8Hz), 7.12-7.02 (m,
6.81 (s, 2H), 6.72 (d, IH, J - 7,5Hz), 5.45-5.40 (m, IH), 3,79 (s, 3H), 3.50 (s, 2H), 3.29 (IH, A of ABX, obscured by solvent), 3.08 (IH, B of ABX, J - 11.8, 5.1Hz), 2.80 (q, 2H, J - 15,
HO
O. P
V ($)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanarnido)ethyi)phenyl8iilfanncacid: Ή
NMR (CD3OD) δ 8.56 (d, IH, J - 8.4Hz), 7.25-6.98 (m, 9H), 5.43-5,38 (m, IH), 3.26 (IH, A of ABX, J 14.1, 9.6Hz), 2.97 (IH, B of ABX, J - 10.9, 3Hz), 2,58-2.76 (m, 3H), 2.98 (q, 2H, J 13.8, 7.2Hz), Ϊ .29 (t, 3H, J - 8.7Hz).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)-4-(2 -(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic acid: !H NMR (CDjOD) 6 7.12-7.03 (m, 3H), 6.91 (d, IH, J > 8.4Hz), 6.82 (s,
IH), 6,66 (d, IH, J - 2.1Hz), 6.63 (d, IH, J - 2.1Hz), 5.43 (m, IH), 3.84 (s, 3H), 3.80 (s, 3H),
3.45 (s, 2H), 3,30 (IH), 3.03 (IH, B of ABX, J - 14.1, 9.6Hz), 2.79 (q, 2H, J-15.1, 7.2Hz),
1.30 (t, 3H,J»7.2Hz).
2016203254 18 May 2016
Figure AU2016203254B2_D0153
Figure AU2016203254B2_D0154
(5)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethyIthiazol-2-yl)ethyi)phenylsulfamic acid: !H NMR (CD3OD) δ 8.31 (d, IH, J 7.8Hz), 7.11-6,93 (m, 6H), 6,68 (d, IH, J - 7.5Hz), 5,49-5.40 (m, IH), 3.87 (s, 3H), 3.70 (s, 3H), 3.55 (s, 2H), 3.26 (IH, A of ABX, obscured by solvent), 3.06 (IH, B of ABX, J - 13.9, 9Hz), 2.80 (q, 2H, j - 14.8, 7.5Hz), 1.31 (t, 3H, J - 7,5Hz).
Figure AU2016203254B2_D0155
cxx 'Cl acid: !H NMR (CD3OD) δ 7.27-7.18 (m, 3H)S 7.13-7.08 (m, 5H), 7.01 (s, 5.1, 9.4Hz), 3.28 (IH, A of ABX, J - 5.1, 14.1Hz), 2.97 (IH, B of ABX, J (S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethyhhiazol-2-yl)ethyl)phenyl-sulfamic ),5.39 (q, IH, J 9.3, 13.9Hz), 2.88-
Figure AU2016203254B2_D0156
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)-4*(2-(4-Ethylthiazol-2-yI)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyJsulfamic acid: *H NMR (CDjOD) 5 7.18-7.08 (m, 6H), 6,92 (d, IH, J - 8.1Hz), 6.82 (t,
IH, J == 7.5Hz), 5.40-5.35 (m, IH), 3.25 (IH, A of ABX, J - 15, 5.4Hz), 3.00 (IH, B of ABX, J ™
10.5, 7.5Hz), 2,88-2,76 (m, 4H), 2.47 (q, 2H, J - 9.1,6Hz), 1.31 (t, 3H, J -7.8Hz).
2016203254 18 May 2016
Figure AU2016203254B2_D0157
phenylsulfamic acid: *HNMR (CD3OD) δ 7.1.9-7,00 (m, 5H), 6.75 (s, IH), 6,73 (s, IH), 5.425.37 (m, IH), 3.76 (s, 3H), 3.25 (IH, A of ABX, J - 13.9, 5.4Hz), 2.98 (IH, B of ABX, J - 14.1, 9.6Hz), 2.86-2,75 (m, 4H), 2.48 (q, 2H, J 11.7,1.2Hz), 1.31 (t, 3H, J - 7.5Hz).
Figure AU2016203254B2_D0158
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenylsulfamic acid: !H NMR (CDjOD) δ 7.13-6,99 (m, 7H), 6,82-6.78 (m, 2H), 5.42-5.37 (m, IH), 3.33 (s, 3H), 3.23 (IH), 2.97 (IH, B of ABX, J - 13.3, 11.4Hz), 2.83-2.75 (m, 4H), 2.49 (q, 2H. J - 6.4,3.3Hz), 1.31 (t, 3H, J - 7.5Hz).
Figure AU2016203254B2_D0159
(5)-4- {2-[2-(4-Ethyl~2,3-dioxopiperazin~ 1 -yl)acetamido]-2-(4-eihylthiazol-2yl)ethyl} phenylsulfamic acid: !H NMR (CD3OD) δ 7.14 (s, 4H), 7.08 (s, IH), 5.56-5.51 (m, IH), 4.34 (d, 2H, J - 16.2Hz), 3.88 (d, 2H, J = 17.6Hz), 3.59-3.40 (m, 3H), 3.26-3.14 (m, 3H), 2,98 (1H, B of ABX, J = 10,8,13.9Hz), 2.82 (q, 2H, 1 = 6.9, 15Hz), 132 (t, 3H, J = 7.5Hz), 1.21 (t, 3H, j - 7.2Hz).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0160
(5)-4-{2-(4-Ethylthiazoi-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidm-l(2E0yl)acetamido]ethyl}phenylsuifamic acid: !H NMR (CD3OD): δ 7.13 (s, IH), 7.06-7.02 (m,
6.95 (s, IH), 5.42-5.31 (m, IH), 4.43-4.18 (dd, 2H,>16.5 Hz), 3.24-2.93 (m, 2H), 2.74-2,69 (q,
Figure AU2016203254B2_D0161
(5)-4-[2-(benzo[^[i,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid: ]HNMR (CD3OD) δ 7.25 (d, IH, >6,5 Hz), 7.13 (s, IH), 7.06 (d, 2H, >8.5 Hz), 7.00 (d, 2H, >8,5 Hz), 6.91 (s, IH), 6.76 (d, IH, >8.1 Hz), 5,90 (s, 2H), 5.48 (q, IH,
Figure AU2016203254B2_D0162
(S)-4- {2-(2-(2,5 phenylsulfamic acid: ’l 2H), 3.33-3.01 (m, 2H), 2
4-yl)acetamido]-2-(4-ethyhhiazol-2-yl)ethyl}: δ 7.10-7.01 (m, 5H), 5.41 (t, 1H,.>6.9 Hz), 3,58
2.75 (q, 2H,>7.5 Hz), 2.59 (s, 3H)S 2.23 (s, 3H), 1.30 (i, 3H,
Figure AU2016203254B2_D0163
>1
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)~4-{2~[2-(2s4-Dimethyithiazol-5-yl)acetaniido]-2~(4-meihyHhiazol-’2-yl)ethyl}phenylsulfamic acid: !H NMR (CD3OD): δ 8.71-8.68 <d, IH, >8.4 Hz), 7,10-7.03 (m, 4H), 7.01 (s, IH), 5.41 (m, IH), 3.59 (s, IH), 3.34-2.96 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H),
2016203254 18 May 2016
Figure AU2016203254B2_D0164
(5)-4-{2-(4-Ethylthiazol-2-yl)-2~[3-(thiazol-2-yl)propanamido]ethyl)phenyIsulfamic acid: NMR (CD3OD): S 7.67-7.65 (m, IH), 7.49-7.47 (m, IH), 7.14-7.08 (m, 4H), 7.04 (s,
IH), 5.46-5.41 (q, 1 H,>5.1 Hz), 3.58 (s, 2H), 3.30-3.25 (m, 3H), 3.02-2.67 (m, 5H), 1.31 (t, 3H, >7.5 Hz).
Figure AU2016203254B2_D0165
(5)-4-{2-(4-Ethylihiazol~2-yl)~2~[2~(4-ethylthiazol-2-yl)acetamido]ethyl}-phenylsulfamic acid: Ή NMR (CD3OD): δ 7.04-6.91 (m, 6H), 5.32 (t, 1H,>5.4 Hz), 3.25-2.90 (m, 2H), 2,712.61 (m, 4H) 1.93 (s, 2H) 1.22-1.14 (m, 6H),
The second aspect of Category V of the present disclosure relates to 2-(thiazoi-4-yl)
Figure AU2016203254B2_D0166
wherein R1, R4, and L are further defined herein in Table X herein below.
No. L R1 R4
J360 -C(O)CH2- phenyl methyl
3361 -C(O)CH2~ phenyl ethyl
3362 phenyl phenyl
J363 -C(O)CH2- phenyl thiophen-2-yl
.1364 -C(O)CH>~ phenyl thiazol-2-yl
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0167
oxazo 1-2-y 1 isoxazol-3-yl
Figure AU2016203254B2_D0168
,5-dimethvlfhiazoI-4-yl
2,5 -dimethy lthiazoi-4 -y 1
3-fluorophenyl 3-fluorophenyi
2.5- dimethylthlazol-4
2.5- dimethylthiazol-4-yl
2s5-dimethylthiazol-4-yl
Figure AU2016203254B2_D0169
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No.
3394 -C(O)CHr
3395 j -0(0)0¾
3396 i ~^C(Q)CHr
3397 i ”^€(O)CH2·
3398
J399
3400
3403
3405 '3406'
3407
-C(O)CH2 ,5-dimethylthiazoM~yl
2,4 ~d imethy lthiazol-5 -yl 2,4 -dimethy Ithiazol-5 -y ί ,4-d imethy khi azol-5-y 1
2.4- dimethylthiazol-5-yl
2.4- dimethykhiazoi-5-yl
Figure AU2016203254B2_D0170
isoxazoi-3-yl
C(O)CH2~ •-C(O)CH2^0(0)01¾ ~-c(O)ch7 <(O)CHr €(0)032^C(O)CH^
A-dimethylthiazol-S-yl
2,4 -dimethy ll hiazol-5 -y 1 4-ethyhhiazol-2-’
4-ethyithiazoi-2-yi 4-ethylthiazol-24-ethylthiazol-24-eihylthiazoI~2-yl
Figure AU2016203254B2_D0171
Figure AU2016203254B2_D0172
thiophen-2-yI thiazoloxazol-2isoxazol-3-yl ethyl phenyl thiophen-2-yl thiazol-2-yl
4-ethykhiazol-2-yl
4-ethylthiazol-2-yi oxazoI-2-yl isoxazol-3-
3409 ! -C(O)CH2- 3-methyl-l s2,4-oxadiazol-5-yi methyl ethyl
3410 ~€(O)CH2~ 3-methyl-1 ,2,4-oxadiazol-5~yl
3411 | -€(O)CH2- “1412 j -0(0)0¾1 3-methyl-l ,2s4-oxadiazoi~5-yl phenyl
3-methyl-l ,2,4-oxadiazol-5-yl thiophen-2-yl thiaz.ol-2-yl
3413 -C(0)GH2™ - J- 3-methyl-l ,2,4-oxadiazol-5-yl
Γ3414 C(Q)CH2- 3-methyl-l ,2,4-oxadiazo 1-5-yl oxa.zol-2-yl
p4T5~” --0(0)03¾ 3 -methyl-1,2,4-oxadi azol-5-yl isoxazol-3-y!
Γ34Ϊ6....... -C(O)CH2CH2 phenyl methyl
| 3417 -C(O)CH2CH2- phenyl ethyl
Γΐ4ΪΓ“ -C(O)CH2CH2- phenyl phenyl
3419 -C(0)CH2CHr- phenyl thiophen-2-yI
Γ/420 1..................... -C(O)CH2CH2- phenyl thiazol-2-yl
Ϊ 3421 i ~C(0)CH2CH2- phenyl oxazol-2-yl
j 3422 O(O)CH2CH2- phenyl isoxazol-3-yl
<
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. L R* R*
J423 j ~C(O)CH2CH2 3-chlorophenyl methyl
J424 i ~C(G)CH2CH2~ 3-chlorophenyl ethyl
J425 ~C(O)CH>CHr·· 3-chlorophenyi phenyl
J426 -C(O)GH2CH2- 3-chlorophenyi thiophen-2-yl
J427 -C(O)CH2CH2- 3-chlorophenyi thiazol-2-yl
J428 1 -CiOjCHjCHz- 3-chlorophenyl oxazol-2-yl
~~J429 -C(O)CH2CH2- 3-chlorophenyl isoxazol-3-yl
.1430 ~C(O)CH2CH2- 3-methoxyphenyl methyl
1431 -C(G)CH2CH2~ 3-methoxyphenyl ethyl
1432 -C(O)CH2CH2- 3-methoxyphenyl phenyl
1433 -C(O)CH2CH2- 3-methoxyphenyl thiophen-2-yl
1434 -C(O)CH2CH2- 3-methoxyphenyl thiazol-2-yl
1435 -C(O)CH2CH2- 3-methoxyphenyl oxazol-2-yl
1436 -C(O}CH2CHj~ 3-methoxyphenyl isoxazol-3-yl
J437 -C(O)CH:2CH2- 3-fluorophenyl methyl
J438 ~-C(O)CH2CH2- 3-fluorophenyl ethyl
1439 -C(G)CH2CH2- 3-fluorophenyl phenyl
J440 -C(O)CH2CHr- 3-fluorophenyl thiophen-2-yl
3441 -C(G)CH2CH2··· 3-fluorophenyl thiazol-2-yl
1442 ~C(O)CH2CH2- 3-fluorophenyl oxazol-2-yl
1443 -C(O)CH2CH2~ 3-fluorophenyl isoxazoi-3-yl
1444 ~C(O)CH2CH2··· 2,5-dimethylthiazol-4-yi methyl
1445 -C(G)CH2CH2~ 2,5-dimethylfhiazol-4-yl ethyl
1446 -C(O)CH2CH2~ 2,5-dimethylthiazol~4-yl phenyl
1447 -C(O)CH2CH2- 2s5-dimefhyhhiazol~4-yl thiophen-2-yl
J448 -C(O)CH2CH2- 2,5-dimethylthiazol-4-yl thiazol-2-yi
J449 -C(O)CH2CH2-- 2,5-dimelhylthiazol-4-y 1 oxazol-2-yl
1450 -€(O)CH2CH2~ 2,5 -dimethy It hi azo 1 -4-y 1 isoxazol-3-yl
J451 ~C(O)CH2CH2~ 2,4-dimethy lthiazol-5 -yl methyl j
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0173
-C(O)CH2CH:
--c(0)ch1ch2
-C(O)CH2CH2
J455 s -C(O)CH2CH2-
Figure AU2016203254B2_D0174
2,4~dimethylthiazol-5-yi
2.4- dimethylthiazol-5-yl
2.4- dimethyithiazol-5-yi l,4-dimelhylthiazol-5-yl ethyl phenyl thiophen-2-yj
Figure AU2016203254B2_D0175
C(O)CH2CH2C(O)CH2CH?
C(O)CH?CHi
COCHiCH^'
-C(O)CH2CH2~ ^C(0)CHbCH2~’ •C(O)CTLCfE^ C(0)CR>€H.? CY0)CH^CR
C(O)CH2CH2- I 2,4-dimethylthiazol~5-yl COCHiCH^’l.......^4-dimefoj^zol-5-yl'
4-sthylthiazol-2-yl
4~eihylthiazol~2~yl
4-ethyithiazoi-2-yi
4-ethylthiazol-2-yI
4-ethylthiazol-2-yl
4~ethyIthiazol-2-yl
Figure AU2016203254B2_D0176
J470
4-ethylthiazo3-2~yl 3-meihyl-l ,2,4-oxadiazol-5-yl 3-methyl-3,2,4-oxadiazoi-5-yl
C(0)CH2CH2~ 3-methyi-1,2,4-oxadiazol-S-yl
-C(0)CH2CHrC(0)'CRCH^ <χδ)αζαΐΓ· • c(6)ch2ch^“
3-methyl-l,2,4-oxadiazol-53-methyl- ί ,2,4-oxadiazol-S-yl 3 -methyl-1,2,4-oxadiazol-5-yl 3-methyi-l ,2,4-oxadiazol-5-yl thiazol-2-yl _________L.
oxazol-2-yi isoxazol-3-yl methyl ethyl phenyl thiophen-2-yl thiazol-2-yl oxazol-2-yl isoxazol-3-yl methyl ethyl thiophen-2-yl thiazol-2-yl ί-2-νϊ
Figure AU2016203254B2_D0177
tsoxazol-j
The compounds encompassed within the second aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme II and described in Example ! herein below.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0178
Figure AU2016203254B2_D0179
Reagents and conditions: (b) (3-Cl)C6H4CO2H, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
Figure AU2016203254B2_D0180
Figure AU2016203254B2_D0181
Reagents and conditions: (c) (i) H2;Pd/C, MeOH; (ii) SOj-pyridine, NH4OH, rt, 18 hr.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Preparation of (S)-2-(4-nitropheny 1)-1 ~[(thiophen-2-yl)thiazol-4-yl]ethanamine hydrobromide salt (22): A mixture of (S)-tert-butyl 4-bromo-l-(4-nitrophenyl)-3-oxobutan-2ylcarbamate, 7, (7.74g, 20mmol), and thiophen-2-carbothioic acid amide (3.14g, 22mmol) in CH3CN (200 mL) is refluxed for 5 hours. The reaction mixture is cooied to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford 7.14 g (87 % yield) of the desired product. ESI+ MS 332 (M+l).
Preparation of 2-(3-chlQrophenyl)-A~{(50-2-(4-mtrophenyl)-l-[2-(thiophcn-2-yi)ihi.azoI4-yl]ethyl}acetamide (23): To a solution of 2-(4-nitrophenyl)-l-(2-thiophene2-ylthiazol~4~ yl)ethylamine, 22, (0,41 g, lmmol) 3-chlorophenylacetie acid (0.170g, lmmol) and 1hydroxybenzotriazole (HOBt) (0.070g, O.SOmmol) in DMF ( 5 mL) at 0 °C, is added 1-(3dimethy!aminopropyl)-3-ethyicarbodnmide (EDC'I) (0.190g, lmmol) followed by triethylamine (0.42mL, 3mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCO,, water and brine, and dried over Na^SCU The solvent is removed in vacuo to afford 0.290 g (60 % yield) of the desired product which is used without further purification. ESI- MS 482 (M-l),
Preparation of (4-[2-(3-chIorophenyl)acetylammo]-2-(2-thiophen-2-ylthiazol-4yl)ethyl]phenyl} sulfamic acid (24): 2-(3-chlorophenyl)-Ar-{(.S)-2-(4-nitrophenyl)-l-[2(thiophene2-yl)thiazol-4-yl]ethyl}acetamide, 23, (0,290 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO3~pyridine (0.157 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.078 g of the desired product as the ammonium salt. !H NMR (CD3OD) δ 7,61 (d, IH, J ~ 3.6Hz), 7.58 (d, IH, J —
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
5.1Hz), 7.41-7.35 (m, IH), 7.28-7.22 (m, 2H), 7.18-6.98 (m, 6H), 5.33 (t, IH, J - 6.6Hz), 3.70 (d, 2H, J - 3.9Hz), 3.23 (IH, A of ABX, J - 6.6,13.8Hz), 3.07 (IH, B of ABX, J - 8.1, 13.5Hz).
The following are non-limiting examples of compounds encompassed within the second aspect of Category V of the present disclosure.
2016203254 18 May 2016
Figure AU2016203254B2_D0182
4-((15)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid; Ή NMR (CD3OD) δ 8.35 (d, IH, J - 8.7Hz), 7.61-7.57 (m, 2H), 7.257,20 (m, 2H), 7.25-7.20 (m, 2H), 7.09 (s, IH), 7.05 (d, 2H, J - 4.2Hz), 6.99 (d, IH, J 8.7Hz), 6.81 (d, IH, J 7.8Hz), 6,77 (s, IH), 5.30-5,28 (m, IH), 3.76 (s, 3H), 3.51 (s, 2H), 3.20 (IH, A of ABX, J - 6.3, 13.6Hz), 3.06 (IH, B of ABX, J -8.1,13.8Hz).
Figure AU2016203254B2_D0183
4-{(S)-2-(3-Phenylpropanmido)-2-[2-(thiophene2-yi)thiaz0l-4-yl]ethyI}“phenylsulfamic acid: !H NMR (CD30D) δ 8,30 (d, IH, J-9Hz), 7.61-7.56 (m, 2H), 7,26-7.14 (m, 7H), 7.12 (d, IH, J — 1.5Hz), 7.09 (d, IH, J - 2.1Hz), 6.89 (s, IH), 5.28-5,26 (m, IH), 3.18 (IH, A of ABX, J -6.2,13.8Hz), 2,96 (IH, B of ABX, J - 8.4, 13.6Hz),
Figure AU2016203254B2_D0184
4-{(5)-2-(3-(3-ChloiOphenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4yl)ethyl}phenylsulfamic acid: ’H NMR (CD3OD) δ 7.61-7.56 (m, 3H), 7.22-7.14 (m, 6H), 7.08 (d, IH), 7.00 (d, IH, T- 77.5Hz), 6.870 (s, IH), 5.25 (t IH, J = 7.8Hz), 3.18 (IH, A of ABX, J ™ 6.6,13,8Hz), 2,97 (IH, B of ABX, J - 7.8, 13.8Hz), 2.87 (t, 2H, J - 7.5Hz), 2.51 (t, 2H, J — 7,2Hz).
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-{(5)-2-[2-(3-’Fluorophenyl)acetamido]-2-[2-(thiophen-2-yl)thiazoi-4yijethyljphenylsulfanuc acid: !H NMR (CD3OD) 8 7.61-7.57 (ra, 2H), 7.32-7.28 (m, IH), 7.197.16 (m, 2H), 7.08 (t, IH, J - 4.5Hz), 7.02-6.95 (m, 6H), 5.29 (t, IH, J - 8.1Hz), 3.53 (s, 2H),
3.22 (1H, A of ABX, J --6.6, 13.9Hz), 3.06 (IH, B of ABX, J - 8.4, 13.6Hz),
2016203254 18 May 2016
Figure AU2016203254B2_D0185
Figure AU2016203254B2_D0186
(5)-4- {2-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)acetamido]-2-(2-phenylthiazol-4yl)ethyl)phenyisulfamic acid: 3H NMR (CDjOD): 8 7.98-7,95 (m, 2H), 7.48-7.46 (ra,
7.23
Figure AU2016203254B2_D0187
4-{(S)-2-[2-(4-ethyl-2,3-dioxopiperazin~l-yl)acetamido]-2-[2-(thiophen-2-yl)lhiazol-4yl]ethyl}phenylsulfamic acid; !H NMR (CD3OD) δ 7.62 (d, IH, J - 3Hz), 7.58 (d, IH, J 15.6Hz), 7.27 (s, IH), 7.16 (t, IH, 3-1.5Hz), 5.42-5.32 (m, IH), 4.31 (d, IH, 3 - 15,6Hz), 3.91 (d, 1.H, 3 = 15.9Hz), 3.60-3.50 (m, 4H), 3.30-3.23 (m, 2H), 2.98 (IH, B of ABX, J-9.9, 13.8Hz), 1.21 (t, 3H, 3 - 6.9Hz).
The third aspect of Category V of the present disclosure relates to compounds flavin; formula:
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST wherein the linking unit L comprises a phenyl unit, said linking group having the formula:
-C(O)[(CR5aH)][(CR6aH)]~
K? is hydrogen, Ria is phenyl, RSa is phenyl or substituted phenyl and non-limiting examples of the units R2, R3, and R5a are further exemplified herein below in Table XI.
2016203254 18 May 2016
Figure AU2016203254B2_D0188
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0189
chlorophenyl chlorophenyl
3,4-dichloropheny 1
2- methoxy phenyl
3- methoxyphenyl
4- methoxyphenyi
The compounds e disclosure can be prepared by herein below.
within the third aspect of Category V of the present the procedure outlined in Scheme IX and described In Example
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0190
Figure AU2016203254B2_D0191
Reagents and conditions: (a) diphenylpropionic acid, EDCI, HOBt, TEA, DMF; 0 °C to rt, 18 hr.
Figure AU2016203254B2_D0192
Figure AU2016203254B2_D0193
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH^OH; rt, 18 hr.
(5)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazo]-2-yl)ethyl>
Preparation of (iS)-Ar-[l-(4-ethyithiazol“2-yi)-2-(4-nitrophenyl)ethyl]-2,3-dipheny{propanamide (25): To a solution of l-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyi)ethyi amine hydrobromide, 3, (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60 g, 2.65 mmol) and 1hydroxybenzotriazole (HOBt) (0.180 g, 1.33 mmol) in DMF ( 10 mL) at 0°, is added 1-(3dimethylaminopropyl)-3-ethyIcarbodiimide (EDCI) (0,502 gs 2.62 mmol) followed fay triethylamine (1,1 mL, 7.95 mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCOs, water and brine, and dried over MajSO^. The solvent is removed in vacuo to afford 0.903 g (70% yield) of the desired product which is used without further purification.
103
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Preparation of (5)-4-(2-(2,3-diphenylpropanamido)-2-(4-ethylthiazol-2yl)ethyl)phenylsulfamic acid (26) (S)-N-[l -(4-ethylthiazol-2-yl)-2-(4-nitrophenyi)efhyl]-2,3diphenyl-propanamide, 25, (0.903 g) is dissolved in MeOH (10 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is fdtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (30 mL) and treated with SO.?, · pyridine (0.621 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.415 g of the desired product as the ammonium salt. 3H NMR (CD3OD) δ 8.59-8.52 (m, 1H), 7.37-7.04 (m, 9H), 6,97-6.93 (m, 1H), 6.89-6,85 (m, 2H), 5.36-5.32 (m, 1H), 3.91-3.83 (m, IB), 3.29 (1H, A of ABX, obscured by solvent), 3.15 (IH, B of ABX. J * 5.4, 33.8Hz)s 2.99-2.88 (m, 2H)S 2.81-2.69 (m, 2H), 1.32-1.25 (m, 3H).
The precursors of many of the Z units which comprise the third aspect of Category V are not readily available. The following procedure illustrates an example of the procedure which can be used to provide different R5a units according to the present disclosure. Using the procedure outlined In Scheme X and described in Example 11 the artisan can make modifications without undue experimentation to achieve the RSa units encompassed by the present disclosure.
Figure AU2016203254B2_D0194
Reagents and conditions: (a) benzyl bromide, LDA, THF; 0 °C to rt 18 hr.
104
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST 'OH
2016203254 18 May 2016 h3c<
Figure AU2016203254B2_D0195
Reagents and conditions: (b) NaOH, THF/MeGH; rt, 18 hr.
EXAMPLE 11
2-(2-Methoxyphenyl)-3-phenylpropanoic acid (28)
Preparation of methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (27): A 500mL roundbottom flask is charged with methyl 2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, leq) and THF (200mL). The homogeneous mixture is cooled to 0 °C in an ice bath. Lithium diisopropyl amide (23.5mL of a 2.0M solution in heptane/THF) is added, maintaining a temperature less than 3°C. The reaction is stirred 45 minutes at this reduced temperature. Benzyl bromide (5.6mL, 47mmol, leq) is added dropwise. The reaction is allowed to gradually warm to room temperature and is stirred for 18 hours. The reaction is quenched with IN HCI and extracted 3 times with equal portions of EtOAc. The combined extracts are washed with H2O and brine, dried over Na2SOs, filtered, and concentrated. The residue is purified over silica to afford 4.433g (35%) of the desired compound. ESIi MS 293 (M+Na).
Preparation of 2-(2-methoxyphenyl)-3-phenylpropanoic acid (28): Methyl 2-(2methoxyphenyI)-3-phenylpropanoate(4.433g, 16mmol, leq) is dissolved in lOOmLofa 1:1 (v:v) mixture of THF and methanol. Sodium hydroxide (3.28g, 82mmol, Seq) is added and the reaction mixture is stirred 18 hours at room temperature. The reaction is then poured info H2O and the pH is adjusted to 2 via addition of IN HCI. A white precipitate forms which is removed by filtration. The resulting solution is extracted with 3 portion of diethyl ether. The extracts are pooled, washed with H2O and brine, dried over Na2SOd, filtered, and concentrated in vacuo, The resulting residue is purified over silica to afford 2.107g (51%) of the desired compound. ESIMS 255 (M-l), 211 (M-C02H).
HH
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST intermediate 28 can be carried forward according to the procedure and described in Example 10 to produce the following compound gory V.
2016203254 18 May 2016 in Scheme IX the third aspect of
Figure AU2016203254B2_D0196
(5)-4- {2-(4-Ethylthiazol-2-yI)~2-[2-(2-methoxyphenyl)-3-phenyIpropanamido]~ ethyljphenylsulfamic acid: 3H NMR (CD3OD) δ 7,32-7.12 (m, 7H), 7,05-7.02 (m, IH), 6,996,83 (m, 4H), 6.80-6.75 (m, 2H), 5.35-5,31 (m, IH), 4.31-4.26 (m, IH), 3.75 (s, 3H), 3,20-2.90 (m, 4H), 2.79-2.74 (m, 2H), 1,32-1.25 (m, 3H).
The following are further non-limiting examples of compounds according to the third aspect of Category I of the present disclosure.
Figure AU2016203254B2_D0197
(5)-4-{2-(4-Etl ethyl}phenyisulfemic acid: SH NMR (CD3OD) δ 7.33-6,87 (m, 14H), 5.39-5.25 (m, IH), 3.953,83 (m, IH), 3.31-3.10 (ra, IH), 3.05-2.88 (m, 2H), 2,80-2.70 (m, 2H), 1.32-1.23 (m, 3H). !'T NMR δ 47.59,
Figure AU2016203254B2_D0198
(S)-4-{2-(4-Ethylthiazoi~2-yl)-2-[2-(3-methoxyphenyI)-3*phenyIpropananiid0]ethyl}phenylsulfamic acid: !H NMR (CD3OD) δ 7.85 (d, IH, J - 8.4Hz), 7.25-7.20 (m, IH)
7.11- 7.02 (m, 4H), 7.01 (s, IH), 6.90-6.79 (m, 2H), 5.45-5.40 (m, IH), 4,09 (s, 2H), 3.79 (s,
3.12- 3.08 (m, 2H), 1.10 (s,
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
The fourth aspect of Category V of the present disclosure relates to compounds having the formula:
2016203254 18 May 2016
Figure AU2016203254B2_D0199
wherein the linking unit L comprises a phenyl unit, said linking group having the formula:
C(O)[(CRiaH)][(CR®sH}-R; is hydrogen, R“! is phenyl, R5a is substituted or unsubstituted heteroaryl and the units R2, R3 and R5a are further exemplified herein below in Table ΧΠ.
.496
j L497 methyl hydrogen
| L498..... methyl hydrogen
L499 methyl hydrogen
| L500 methyl hydrogen
| L501 ethyl hydrogen
L502 ethyl hydrogen
L503 ethyl hydrogen
t.....L504*“ 9 ethyl hydrogen
ethyl hydrogen
! L506 ethyl methyl
j L507 ethyl methyl
| L508 ethyl methyl
Figure AU2016203254B2_D0200
L511 | thiophen-2-yl
L512 I thiophen-2-yl hydrogen ~T~ -, hydrogen • 1,2,4-oxadiazol~5-yl thiophen-2-yl thiazol~2~yl oxazoi-2-yl isoxazol-3-vl
3-methyM ,2,,4~oxadiaz©t~5~yl thiophen-2-yi fhiazoi-2-yl oxazol-2-yl isoxazol-3-yl
3-methyl-l ,2,4-oxadiazol~5-yl thiophen-2-yl I thiazol-2-yl ( oxazol-2-yl isoxazol-33 -methyl-1,2,4-oxadiazo 1-5 -yl •yl
107
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
....................
thiophen-2-yl : hydrogen L515 thiophen-2-yl I hydrogen isoxazol-3-yl isoxazol-3isoxazol-3-yl isoxazol-3L520 oxazol-2-yi isoxazoT-3-yl hydrogen j 3~methyl~l,2,4-oxadiazol-5-Yi hydrogen f thiophen-2-yl ______________________________________s........................................................... hydrogen i thiazoi-2-yl
......—————.....
hydrogen
-3-yl hydrogen oxazol-2isoxazol-3-y!
The compounds encompassed within the fourth aspect of Category V of the present disclosure can be prepared by the procedure outlined in Scheme V and described in Example herein below.
Figure AU2016203254B2_D0201
Figure AU2016203254B2_D0202
Figure AU2016203254B2_D0203
Reagents and conditions: (b) CHjCGNOI-^NHs, K.2CO3, toluene; reflux, 18 hr
108
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0204
Figure AU2016203254B2_D0205
31
Reagents and conditions: (c) (i) tin. (Ii) chloride, EtOH; (ii) SGa-pyridine, NH4OH; rt, 18 hr,
EXAMPLE 12
4-{(5>2-<4~ΕΛγΙ{Ιιί8Ζ(^2^Ι)··2-[2-(3-Γη6<:Ιιγ1-1,2,4-0Χ8(1ί&ζοΙ-5-γ1)-3phenylpr©p8MmId0(ethyl}pheny!sulfarak acid (31)
Preparation of ethyl-2-benzyl-3-((5)-1 -(4-ethylihiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-3-0xopropanoate (29): To a solution of l-(«S)-(4-elhylthiazoi-2-yl)-2-(4~ nitrophenyi)ethyi amine hydrobromide, 3, (0.406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3oxopropanoic acid (0.277 g) and 1 -hydroxybenzotriazole (HOBt) (0.191 g, 1,41 mmol) in DMF ( 10 mL) at 0°, is added l-(3-dimethylaminopropyl)-3-ethyIcarbodiimide (EDCI) (0,240 g, 1.25 mmol) Followed by diisopropylethylamine (DIPEA) (0.306 g). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCOj, water and brine, and dried over NajSGU. The solvent is removed in vacuo to afford 0.169 g (31 % yield) of the desired product which is used without further purification.
Preparation ofAT-[(S)-l-(4-ethylthiazoi-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-l,2,4oxadiazol-5-yl)-3~phenyIpropanamide (30): Ethyl 2-benzyl~3-((S)-l-(4-ethylihiazol-2-yl)-2-(4nitrophenyl)ethylamino)-3-oxopropanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added, and treated with 80 mg potassium carbonate and 43 mg acetamide oxime at reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is chromatographed over silica to afford 0.22 Ig (94%) of the desired product as a yellow oil.
Preparation of4-{(5)-2-(4-ethylthiazol-2-yl)-2-[2-(3-methyH,2,4-oxadiazoI-5-yi)-3phenylpropanamidojethyl) phenylsulfamic acid (31): ;¥-[(£)-l-(4-ethylthiazol-2-y 1)-2-(4109
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 nitrophenyl)ethyi]-2-(3-methyl“li2i4-oxadiazoi-5-yl)-3-phenylpropanamide;, 30, (0. 221 g) and tin (II) chloride (507 mg, 2.2 mmol) are dissolved in EtOH (25 mL) 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 NaHCOa (50 mL) is added and the solution is stirred I hour.
The organic layer is separated and the aqueous layer extracted twice with EtOAc. The combined organic layers are dried (NajSO^), filtered and concentrated to a residue which Is dissolved in pyridine (0.143 g) and treated with SOs-pyridine (0.143 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0,07! g of the desired product as the ammonium salt. NMR (CDjOD): δ 7.29-6.87 (m, 10H), 5.38-5.30 (m, IH), 4.37-4.30 (m, IH), 3.42-2.74 (m, 6H), 2.38-2.33 (m, 3H), 1.34-1.28 (m, 3H).
Category VI of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
Figure AU2016203254B2_D0206
wherein R!, R2, R.L and L are further defined herein in Table X1H herein below.
No. R2 | ΪΡ.....................
M521 ethyl | hydrogen thiophen-2-y!
M522 ethyl 1 hydrogen thiazol-2-yl
M523 ethyl | hydrogen oxazol-2-yl
M524 ethyl | hydrogen isoxazol-3-yl
M525 ethyl | hydrogen imidazol-2-yl
M526 ethyl hydrogen isoxazol-3-y!
M527 ethyl | hydrogen oxazol-4-yI
M528 ethyl hydrogen isoxazol-4-y!
M529 ethyl hydrogen thiophen-4-y!
M530 ethyl [ hydrogen thiazoi-4-yl
110
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0207
M559 L__
111
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. IL R3| RJ
M560 thiophen~2-yl hydrogen 4-fluorophenyl
The compounds encompassed within Category VI of the present disclosure can be prepared by the procedure outlined in Scheme XII and described in Example 13 herein below.
Figure AU2016203254B2_D0208
Figure AU2016203254B2_D0209
Reagents and conditions: (a) 3-benzoylpropionic acid, SOCI2, 7V-methyl imidazole, CHjCb; rt, 18 hr.
Figure AU2016203254B2_D0210
Reagents and conditions: (b) (i) H?,:Pd/C, MeOH; (ii) SO3~pyridme, NH4OH.
EXAMPLE 13 (j)4-[2-(4-£thylthiaz0l-2-yl>>2-(4~oxo~4-phenylhutanamido)ethyI]phenylsuffamic acid (33)
Preparation of (5)-N-[l (4-ethylthiazol-2-yl)~2-(4~mtrophenyl)ethyl]-4~oxo-4phenylbutanamide (32): 3-Benzoylpropionic acid (0.250 g) is dissolved in CH2C12 (5 mL), ν'methyl imidazole (0.333 mL) is added and the resulting solution is cooled to 0 °C after which a solution of thionyl chloride (0.320 g) in CH2CI2 (2 mL) is added dropwise. After 0,5 hours (5)1-(4-ethyIthiazol-2-yl)-2~(4-nitrophenyl)ethasamine, 3, (0.388 g) is added. The reaction is stirred fori 8 hours at room temperature and then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed with IN HCI and brine. The solution is dried over Na2SO4,
112
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 filtered, and concentrated and the crude material purified over silica to afford 0.415 g of the desired product.
Preparation of (5)-4-[2-(4-ethylthiazol-2-yl)~2-(4-oxo-4-phenylbutanamido)ethyl]phenylsulfamic acid (33): (5)-JV-(l-(4-ethylthiazoI-2-yl)-2-(4-nitropbenyl)ethyl]-2,3diphenyl-propanamide, 32, (0.2 g) is dissolved in MeOH (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 reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (5 mL) and treated with SO3pyridine (0.153 g). The reaction is stirred at room temperature for 5 minutes after which a 7% soiution of NH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.090 g of the desired product as the ammonium salt, 'H NMR (CD30D) 8 8.68 (d, IH, >8.2 Hz), 8.00 (d, 2H, J=7.2 Hz), 7.80-7,50 (m, 3H), 7.12 (s, 4H), 7.03 (s, IH), 5,46-5,38 (m, IH), 3,29-3.14 (m, 2H), 3.06-2.99 (m, 2H),
2.83 (q, 2H, >7.5 Hz), 2.69-2.54 (m, 2H), 133 (t, 3H, >7,5 Hz).
The following are non-limiting examples of compounds encompassed within Category II of the present disclosure. The intermediate nitro compounds of the following can be prepared by coupling the appropriate 4-oxo-carboxcyIie acid with intermediate 3 under the conditions described herein above for the formation of intermediate 4 of scheme I.
Figure AU2016203254B2_D0211
(5j,4..(2-(4-Ethyithiazoi-2~yl)-2-(5-roethyl-4-oxohexanamido)ethyl)plien.ylsuitamic acid: SH NMR (CD3OD) 8 8.59 (d, IH, >8.1 Hz), 7.14 (s, 4H), 7,08 (t, IH, >13.0 Hz), 5.40-5.35 (m,
IH), 3.37-3.27 (m, 2H), 3.04-2.97 (m, IH), 2.83-2.61 (m,4H), 2.54-2,36 (m, 3H), 1.33 (t, 2H,
Figure AU2016203254B2_D0212
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (S)-4-{2-(4-(3,4-Dihydro-2H-benzoEb][l34]dioxepin-7-yl)-4-oxobutanamido]-2-(4ethylthiazoI-2-yl)ethyl}pheny!sulfamic acid: ‘HNMR(CDjOD) δ 8.64 (d, IH, >8 4
Hz), 7.60 (d, 2H, >10.6 Hz), 7,11 (s, 3H), 7.04 (d, 2H, >5,5 Hz), 5.42-5.40 (m, IH), 4.30-4.22 (m, 4H), 3.20-2,98 (m, 4H), 2.82 (q, 2H, >7.3 Hz), 2.67-2.48 (m, 2H), 2.23 (t, 2H, >5.5 Hz),
1,32(1,3H,J=7.3Hz).
2016203254 18 May 2016
Figure AU2016203254B2_D0213
(5)-4- {2-(4-(2,3 -Dimethoxypheny 1)-4 -oxobutanami do] -2-(4-ethy It hiazol-2 yl)ethyl}phenylsuifamic acid: ‘H NMR (CDjGD), 8 8.64 (?d, IH, >8.1 Hz), 7.21-7.11 (m, 7H), 7,02 (s, IH), 5.42 (q, IH, >5.9 Hz), 3.90 (d, 3H, >3.3 Hz), 3.88 (d, 3H, >2.9 Hz), 3.22-3.18
Figure AU2016203254B2_D0214
phenyIsnlfamic acid: SH NMR (CD3OD) δ 8.60 (d, IH, >12.8 Hz), 7.91-7.81 (m, 2H), 7.487.44 (m, IH), 7,22-7.21 (m, IH), 6,99 (s, 3H), 6.91 (s, IH), 5.30 (q, IH, >5.4 Hz), 3.36 (q, 2H, >7.0 Hz), 3.21-3.15 (m, IH), 2.91-2.85 (m, IH), 2.74 (q, 2H, >10.4 Hz), 2.57-2.50 (m, 2H),
1.20 (t, 3H, >7.5 Hz).
Figure AU2016203254B2_D0215
(S)-4- (2-(4-(2,3-dihydrobenzo[b][ 1,4]dioxin-6-yl)-4-oxobutananiido]-2-(4-ethylthiazol2-yl)ethyl}phenylsulfamic acid: 'H NMR (CD3OD) δ 7.52-7.47 (m,2 H), 7,1 l(s,4H), 7.03 (s,lH), 6.95 (d, IH, >8.4 Hz), 5.41 (q, IH, >3.7 Hz), 4.31 (d, 4H, >5.5 Hz), 3.24-3.12 (m, 2H), 3.06-2.98 (m, 2H), 2.83 (q, 2H, >7.3 Hz), 2.62-2.53 (m, 2H), 1.33 (t, 3H, >7.3 Hz).
114
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)-4-[2-(4-teri-butoxy-4-oxobutanamido)-2-(4-ethyhhiazol-2-yl)ethyi]phenylsuifamic acid: 3H NMR (CD3OD), 8 7.10 (s 4H), 7.02 (s, IH), 5.41 (q, IH, >3.7 Hz), 3.30-3,25 (m, IH),
3.06-2.99 (m, IH), 2.83 (q, 2H, >7.3 Hz), 2.52-2.40 (m, 4H), 1,42 (s, 9H), 1.33 (t, 3H, >7,3
2016203254 18 Ma
We
Figure AU2016203254B2_D0216
(5)-4-[2-(4-ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid: eH NMR (CDjGD) S 8.62 (d, IH, >8.4 Hz), 7.10 (s, 4H), 7.02 (s, IH), 5.40 (q,lH, 3.7 Hz), 4.15 (q, 2H, >7.3 Hz), 3.28-3.25 (m, IH), 3.05-3.02 (m, IH), 2.82 (q, 2HS >4.4 Hz), 2.54-2.48 (m, 2H), 1,33 (t, 3H, >7.3 Hz), 1.24 (t, 3H, >7.0 Hz).
The first aspect of Categoiy VH of the present disclosure relates to 2-(thiazol-2-yl) compounds having the foimula:
Figure AU2016203254B2_D0217
wherein non-limiting examples of Rs, R”, and R3 are farther described herein below in Table XIV.
TABLE XIV
No, R2 R3 R*
N561 methyl hydrogen phenyl
N562 methyl hydrogen benzyl
N563 methyl hydrogen 2-fluorophenyl
N564 methyl hydrogen 3-fluorophenyl
N565 methyl hydrogen 4-fluorophenvl
115
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. | R2 R3 | R*
; N566 methyl hydrogen 2-chioiophenyl
N567 methyl N568 methyl hydrogen | 3-chlorophenyl hydrogen | 4-chlorophenyl
N569 ethyl hydrogen | phenyl
| N570 N571 ethyl hydrogen | benzyl
ethyl hydrogen j 2-fluorophenyl
| N572 | ethyl J hydrogen j 3-fluorophenyl
i N573 | ethyl hydrogen 4-fluorophenyl
N574 ethyl | hydrogen J 2-chSorophenyl
N575 N576..... N577 ethyl ethyl thiene-2-yl hydrogen 1 3-chlorophenyl i hydrogen 4-chlorophenyl hydrogen | phenyl
N578 thiene-2-yl hydrogen j benzyl j
N579 thiene-2-yl hydrogen I 2-fluorophenyl j
N58O thiene-2-yl hydrogen j 3-fluorophenyl i
N581 thiene-2-yl hydrogen 4-fluorophenyl
N582 thiene-2-yl hydrogen J 2-ehlorophenyl 1
N583 thiene-2-yl hydrogen | 3-chlorophenyl
N584 thiene-2-yl hydrogen 1 4-chlorophenyl
The compounds encompassed within Category VH of the present disclosure can be prepared by the procedure outlined in Scheme XIII and described in Example 14 herein below.
Figure AU2016203254B2_D0218
Reagents and conditions: (a) benzyl isocyanate, TEA, CHjCb; rt, 18 hr.
116
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0219
Figure AU2016203254B2_D0220
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SOs-pyridine, NH4OH.
EXAMPLE 14 (S)~4-(2-(3-Benzylureido)-2”(4-elhyIthtazol-2yi)eihyI)phenyisnIfamic acid (35)
Preparation of (l5)-l-benzyl-3-[i-(4-ethylthiazol-2-yl)-2-(4-niirophenyl)ethyl]urea (34): To a solution of l-(5)-(4-ethylthiazol-2-yl)-2-(4-iiitrophenyl)ethyl amine hydrobromide, 3, (0.360 g, 1 mmol) and Et3N (0,42 mL, 3mmol) in 10 mL CH2CI2 is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.425 g (96% yield) of the desired product which is used without further purification.
Preparation of (S)-4-(2-(3-benzylureido)-2-(4-ethylthiazol-2-yl)ethyi)phenylsuifamic acid (35): (jS)'l-benzyl-3-(l-(4-ethylthiazol-2-yl)-2~(4-mtrophenyl)ethyl]urea, 34, (0,425 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SOrpyridine (0.220 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH is added. The mixture is then, concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.143 g of the desired product as the ammonium salt. !H NMR (CDjOD) δ 7.32-7,30 (m, 2H), 7.29-7.22 (m, 3H), 7.12-7.00 (m, 4H), 6.84 (d, IH, J - 8.1Hz), 5.35-5.30 (m, IH), 4.29 (s, 2H), 3.27-3.22 (m, 3H), 3.11-3.04 (m, 3H), 2.81 (q, 2H, J - 10.2, 13.0Hz), 1.31 (t, 3H, J = 4.5Hz).
The following is a non-limiting examples of compounds encompassed within the first aspect of Category VII of the present disclosure.
4- {[(<S)-2-(2-EthylthiazoI-4-yl)-2-(3-(/?)-methoxy-1 -oxo-3~phenyipropan-2yl)ureido]ethyl}phenylsuifamie acid: NMR (CD3OD) δ 7.36-7,26 (m, 3H), 7.19-7.17 (m,
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2H), 7.10-7.06 (m, 2H), 6.90-6.86 (m, 3H), 5.12-5,06 (m, IH), 4.60-4.55 (m, IH), 3.69 (s, 3H)
3.12-2.98 (m, 6H), 1.44-1.38 (m, 3H).
The second aspect of Category VII of the present disclosure relates to 2-{ihiazol-4-yl) compounds having the formula:
2016203254 18 May 2016
Figure AU2016203254B2_D0221
wherein non-limiting examples of R? and R'! are further described herein below in Table XV,
Figure AU2016203254B2_D0222
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
i No. kT 1 R4
j 0604 2-chlorophenyl § ethyl
j 0605 thiophen-2»yl --4— ethyl
1 0606 thiazol-2-yl ethyl
I 0607 1 „ .. oxazol-2-yl —j— ethyl
0608 1 0609 1 isoxazol-3-yi ethyl
methyl 1 tiiiophen~2~yl
j 0610 ethyl I thiophen-2-yi
1 0611 n-propyl thiophen-2-yl
j 0612 iso -propyl ί thiophen-2-yl
i 0613 1 .. phenyl ! thiophen-2-yl
{ 0614 benzyl } thiophen-2-yl
0615 Z-fluorophenyl thiophen-2-yi
0616 2-chlorophenyS thiophen-2-yl
thiophen-2-yl thiazol-2-yi thiophen-2-yl thiophen-2-yl thiophen-2-yl
Figure AU2016203254B2_D0223
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
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Figure AU2016203254B2_D0224
The compounds encompassed within the second aspect of Category VII of the present disclosure can be prepared by the procedure outlined in Scheme XIV and described in Example 14 herein below.
Figure AU2016203254B2_D0225
Reagents and conditions (a) benzyl isocyanate, TEA, CH2CI2; rt, 18 hr.
Figure AU2016203254B2_D0226
Figure AU2016203254B2_D0227
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
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Reagents and conditions: (b) (i) H^Pd/C, MeOH; (ii) SOa-pyridine, NH4OH.
EXAMPLE 15
4-{(S)-2-(3-Ben2ylureido)-2-{2-(thiophen-2~yl)thiazo]-4-yl]ethyi}phenylsutfnmlc add (37)
Preparation of I-benzyl-3-{(5)-2-(4-nitrophenyl)-l-[2-(thiophen-2-yl)thiazol-4y!]ethyl}urea (36): To a solution of (5)-2-(4-niirophenyl)-l-[(2-thiophen-2~yt)ihiazol~4-yl)eihaiiaminc hydrobromide salt, 8, and EtjN (G.42mL, 3mmol) in 10 mL DCM is added benzyl isocyanate (0.12mL, Innnol), The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.445 g (96% yield) of the desired product which is used without further purification.
Preparation of 4- {(.S)-2-(3-benzylureido)-2-[2-(thiophen-2-yl)thiazol-4yljeihyljphenyisulfamic acid (37): I-Benzyl-3-{(<S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4· yi]ethyl}urea, 36, (0.445g) Is dissolved in MeOH (10 mL) and CH2CI2 (5 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO.?-pyridine (0.110 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0,080 g of the desired product as the ammonium salt.
*HNMR (CD3OD) δ 7.61 (d, IH, J2.1Hz), 7,58 (d, IH, J** 6Hz), 7.33-7.22 (m, 4H), 7.17-7.14 (m, 1H), 7.09-6.94 (m,6H), 5.16 (t, IH, J - 6.6Hz), 4,13 (s, 2H), 3.14-3.11 (m, 2H).
Category VIII of the present disclosure relates to 2-(thiazol-4-yl) compounds having the formula:
Figure AU2016203254B2_D0228
wherein R.\ R.\ and L are further defined herein in Table XVI herein below.
TABLE XVI
No. R5 L R5
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No. R4 L R*
P645 methyl -S02~ methyl
P646 ethyl | —SO?— methyl
Figure AU2016203254B2_D0229
methyl ,2,2-trifluoroethyl
P658 ethyl -SO?··· 2,2,2 -tri fl uoroethy 1
' P659 phenyl -SO2- 2,2,2-trifluoroethyl
P660 fhiophen-2-yl -SO?- 2,2,2-trifluoroethyl
P661 methyl | -SO?-- phenyl
P662 | ethyl j -SO?- phenyl
P663 | phenyl -SO?·· phenyl
P664 thiophen-2-yl -so2~ phenyl
P665 methyl -so?- 4-fluorophenyl
P666 ethyl -so?- 4-fluorophenvl
P667 phenyl -SO?- 4-fluorophenyl
P668 thiophen-2-yl -so?- 4~fluorophenyl
P669 methyl -so?- 3s4-dihydro-2H-benzo[b][l,4]oxazm-7yl
P670 ethyl -SO?- 1 3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl
P67I ’ P672 phenyl -SO?™ 3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl
thiophen-2~yi -so?- 3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-y1
P673 methyl i -SO?- .. -.-....................................... ..... 1 -methyl-1 JT-imidazol-4-yl
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No. R'j L R?
P674 ethyl ~SO2~ 1-methyl-1//“imidazo 1-4-yl
P675 phenyl ~S02- 1-methyl-1 if-imidazol-4-yl
P676 thiophen-2-yi ~SO2- 1 -methyl-1 A-imidazo 1-4 -yl
P678 methyl -S02~ 4-acetamidophenyl
P679 ethyl --S02--· 4-acetamidophenyl
P680 phenyl -so2~ 4-acetamidophenyl
Ρ68Ϊ thiophen-2-yl -so2~ 4-acetamidophenyl
P682 methyl -SO2CH2- phenyl
P683 ethyl -so2ch2- phenyl
P684 phenyl SO2CH2- phenyl
P685 thiophen-2-yl ~S02CH2 - phenyl
P686 methyl -SOjCHj- (4-methyicarboxyphenyl)methyl
P687 ethyl -SOjCBr (4-methylcarboxyphenyl)methyl
P688 phenyl —S02CH2 (4-methylcarboxyphenyl)methyl
P689 thiophen-2-yl ~S02CH2~ (4-met hv Icarboxy pheny f)mei by 1
P690 methyl ~S02CH2~ (2-methylthiazoi-4-y!)methyl
Ρ69Ϊ ethyl -S02CH2- (2-methylthiazoi-4-yi)methyi
P692 phenyl -so2ch2- (2-methylthiazol-4-yl)methyl
P693 thiophen-2-yl ™SO2CH2- (2-methylthiazol-4-yl)methyl
P694 methyl -SO2CH2CH2~ phenyl
P695 ethyl ~so2ch2ch2~ phenyl
P696 phenyl ~S02CH2CH2~ phenyl
P697 thiophen-2-yl ~so2ch2ch2~ phenyl
The compounds encompassed within Category VIII of the present disclosure can be prepared by the procedure outlined in Scheme XV and described in Example 16 herein below.
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Figure AU2016203254B2_D0230
Figure AU2016203254B2_D0231
Reagents and conditions: (a) C6H4CH2SO2CI, DIPEA, CH2CI?.; 0 °C to rt, 14 hr.
Figure AU2016203254B2_D0232
Figure AU2016203254B2_D0233
Reagents and conditions: (b) (1) H2:Pd/C, MeOH; (ii) SOj-pyridine, NH4OH.
EXAMPLE 16 {4”(!y)”[2~Phenylmethanesnifonykmino-2-(2~tbfophen~2-yHh!azol~4yl)ethyl]phenyl}sulfamic add (39)
Preparation of (5)- tV“{2-(4-nitrophenyl)~l“[2-(thiophen-2yl)ihiazol-4yl]ethyl}-lphenylmethanesulfonamide (38): To a suspension of 2-(4-nitrophenyl)-l-(2-thiophene2ylthiazol~4~yl)ethylamine, 8, (330 mg, 0.80 mmol) in CH2CI2 (6 mL) at 0 °C is added diisopropylethylamine (0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg, 0.88 mmol). The reaction mixture is stirred at room temperature for 14 hours. The mixture is diluted with CH2CI2 and washed with sat, NaHCOj followed by brine, dried (N3.2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica to afford 210 mg of the desired product as a white solid,
Preparation of {4-(5)-[2-phenylmethanesulfonylamino~2-(2~thiophen-2-ylthiazol-4yl)ethyl]phenyl} sulfamic acid (3 9): (S)~ N- (2-(4-nitrophenyi)-1 - [2-(lhiophen-2-yl)thiazol-4yl]ethyl)-l-phenylmethanesulfonamide, 38, (210 mg, 0.41 mmol) is dissolved in MeOH (4 mL).
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A catalytic amount of Pd/C (10¾ w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture b filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SOpyridrae (197 mg, 1,23 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.060 g of the desired product as the ammonium salt. 3H NMR (300 MHz, MeOH-df) δ 7.52-7.63 (m, 6,707,28 (m, 1 IH), 4.75 (t, 7.2 Hz, IH), 3.95-4,09 (m, 2H), 3.20 (dd, J - 13.5 and 7,8 Hz, IH),
3.05 (dd,/ -13.5 and 7.8 Hz, IH), 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.
Scheme XVI
Figure AU2016203254B2_D0234
Reagents and conditions: (a) NagSOs, H2O; microwave @ 20OC, 20 min.
NaO ¥
Figure AU2016203254B2_D0235
-OR
Ci
Figure AU2016203254B2_D0236
Figure AU2016203254B2_D0237
N
Reagents and conditions: (b) PCI5, POCb; 50 8C, 3 hrs.
EXAMPLE 17 (2-MethylthiazoM-yl)methanesnIfonyI chloride (41)
Preparation of sodium (2-methylthiazol-4-yl)methanesulfonate (40): 4-Chloromethyl-2methylthiazole (250 mg, 1.69 mmol) is dissolved in H?O (2 mL) and treated with sodium sulfite (224 mg, L78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at 2QtriC. The reaction mixture is diluted with H2O (30 mL) and washed with EtOAc (2 x 25 mL), The aqueous layer is concentrated to afford 0,368g of the desired product as a yellow solid. LC/MS ESI+ 194 (M+l, free acid).
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-methylthiazol-4-y{)methanesulfonyl chloride (41): Sodium ¢2methylthiazol-4yl)methanesulfonate, 40, (357 mg, 1.66 mmol) is dissolved in phosphorous oxychloride (6 mL) and is treated with phosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture is stirred at 50 5C for 3 hours, then allowed to cool to room temperature. The solvent is removed under reduced pressure and the residue is re-dissolved in CH2CI2 (40 mL) is washed with sat, NaHCOj and brine. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo to afford 0.095 g of the desired product as a brown oil. LC/MS ESl-f 211 (M+l), Intermediates are obtained in sufficient purity to be carried forward according to
Figure AU2016203254B2_D0238
4- {(S)-2~[(2~meihy Sthiazo 1-4-y l)methy lsulfonamido]-2- [2-(?hiophen~2-y l)thi azo 1-4yljethyQphenylsulfamic acid: !H NMR. (CD.jOD): δ 7.71-7.66 (nt, 2H), 7.27-7.10 (m, 7H), 4.87 (t, IH, ./-7.3 Hz), 4.30-4.16 (q, 2H,>43.2 Hz), 3.34-3.13 (m, 2H), 2.70 (s, 3H).
The following are non-limiting examples of compounds encompassed within Category
Figure AU2016203254B2_D0239
acid: Ή NMR (300 MHz, MeOH-d4) δ 7.27-7.32 (m, 3H), 7.16-7.20 (in, 3H), 7.05-7.6 (m, 2H), 6.96 (d, J= 8.4 Hz, 2H), 4.70 (t, J= 9.0 Hz, IH), 3.91-4.02 (in, 2H), 2,95-3.18 (m, 4H), 1.41 (t, J
Figure AU2016203254B2_D0240
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST {4-(5)-(2-(3-Methoxyphenyl)methanesulfonyiamino-2-(2-ethylthiazol-4yl)ethyl}phenyl} sulfamic acid; !H NMR (300 MHz, MeOH-dq) δ 7.20 (t,J= 8.1 Hz. 1H), 6.947.08 (m,4H), 6.88-6.94 (rn, 3H), 6.75-6.80 (m, 1H), 4.67 (t, J- 7.2 Hz, ϊ H), 3.90-4.0 (m, 2H),
2016203254 18 May 2016
Figure AU2016203254B2_D0241
(5)-4-((1 -(2-Ethylthiazol-4-yl)-2-(4-sulfoammophenyl)ethylsulfamoyljmethyl} -benzoic add methyl ester: NMR (300 MHz, MeOH-dL·,) 5 7.90-7.94 (m, 2H), 7.27-7,30 (m, 2H), 7.06-7.11 (m, 3H), 6.97-7.00 (m, 2H), 4,71 (h J- 7.2 Hz, 1H), 3.95-4.08 (4, 2H), 3.92 (s, 3H), 2.80-3.50 (m, 4H), 1.38-1.44 (m, 3H).
Figure AU2016203254B2_D0242
phenylsulfamic add; 'H NMR (300 MHz, MeQH-do) δ 7,54 (s, 1H, 7.20 (s, 1H), 7.09 (s, 1H), 6.92-7.00 (m, 4H), 4.62 (f,./- 5.4 Hz, 1H), 3.70 (s, 3H), 2.98-3.14 (m,3H), 2.79 (dd, J*»9.3 and
Figure AU2016203254B2_D0243
ethyl}phenylsulfamic acid: *H NMR (CD3OD): δ 7.62-7.56 (m, 2H), 7.22 (s, 1H), 7.16-7.06 (m, 5H), 4.84 (t, 1H, 7=7.6 Hz), 3.71-3.62 (m, 2H), 3.32-3.03 (m, 2H).
ί -“W
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST phenyl)sulfamic acid: SH NMR (300 MHz, MeOH-d4) δ 7.56-7.62 (m, 2H),
2016203254 18 May 2016
Figure AU2016203254B2_D0244
7.04-7J9(m, 9H), 6,94-6.97 (m, 2H), 4.78 (t,./-7.8 Hz, IH), 3.22-3,30 (m, 2H)), 3.11 (dd, J«
Figure AU2016203254B2_D0245
{4-(S)-[3-(Phenyipropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyi}phenyi)sulfamic acid: NMR (300 MHz, MeOH-d4) δ 7.56-7.62 (m, 2H), 6.99-7.17 (m, 10H), 4.72 (t, /-7.8 Hz, IH), 3.21 (dd, /- 13.5 and 7.2 Hz, IH), 3.02 (dd,/- 13.5 and 7.2 Hz, IH),
Figure AU2016203254B2_D0246
(S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[l,4]oxazine-7-sulfonyiamino)-2-(2-thiophen~ 2“yhhiazol-4-yl)eihyl]phenyl}sulfamic acid: *H NMR (300 MHz, MeOH-dj) δ 7.53 (d, J - 5,1 Hz, IH) 7,48 (d, >5.1 Hz, IH), 7.13-7.10 (m, IH), 7.04 (d, J - 8.4 Hz, 2H), 6.93-6.88 (m, 3H),
6.75 (d, J - 8.1 Hz, IH), 6.54 (d, > 8.1 Hz, IH), 4.61 (t, J - 7.5 Hz, IH), 4.20-4,08 (m, 2H),
3.14-3.00 (m, 4H), 2.69 (s, 3H),
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0247
yl]ethyl}phenylsulfamic acid: H NMR (CD3OD): δ 7.67-7.52 (m, 6H), 7.24-7.23 (m, 1H), 7.127.09 (m, 3H), 7.02-6,99 (m, 2H), 4.70 (t, 1H, 7=7.3 Hz), 3.25-3.00 (m, 2H), 2.24 (s, 3H).
Th e first aspect of Category IX of the present disclosure relates to compounds having the formula:
Figure AU2016203254B2_D0248
wherein R1 is a substituted or unsubstituted heteroaryl and R4 is Cj-Cs linear, branched, or cyclic alkyl as further described herein below in Table XVII.
No. R4 r!
Q698 -ch3 4-(methoxycarbonyl)thiazol-5-yl
Q699 CHj 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl
Q700 -CH3 5-[l-2V-(2-methoxy-2-oxoethyl)-l-//-indol-3-yl]oxazol-2-yl
Q701 -ch3 5-(2-methoxyphenyl)oxazol-2-yl
Q702 ~ch3 5-[(S)-l-(tert-butoxycarbonyi)-2-phenylethyl]oxazol~2-yl
Q703 ~ch3 S-H-fmethylcarboxylphenylJloxazoi^-yl
Q704 -ch3 5-(3-methoxybenzvl)oxazol~2-yl
Q705 -CHj 5-(4-phenvl)oxazoi-2-yl
Q706 ch3 5-(2-methoxyphenyl)thiazol-2-yl
Q707 -CHj 5 -(3 -methox.yphenyl)thiazol~2-yl
Q708 ~ch3 5-(4-fluorophenyl)thiazo 1-2-yi
Q709 -ch3 5-(2,4-difluorophenyl)thiazoi-2-vl
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No. [ R4 R3 s
.....Q710T -cb3 5-(3 -methoxybenzyl)thiazo l-2-y 1
Q7J1 4-(3-mcthoxyphenyi)thiazol-2-yI
Q712 CHj 4 ~(4 -fluoropheny l)thiazol -2-y 1
Q713 -CH2CH3 4-(methoxycarbonyl)thiazol-5-yl
Q714 -ch2ch3 4- [(2-methoxy-2-oxoethy l)carbamoy l]thiazol-5 -y 1
1 Q‘^5 ί -ch2ch3 5-(l’Ar-(2-methoxy-2-oxoethyl)-l-//-indol-3-yi]oxazol-2-yl
Q716 -Ci-ECiE 5-(2-methoxyphenyl)oxazol-2-yl
Q717 -CH2CH3 5-[(£)-l-(tot-butoxycarbonyl)-2-phenylethyl]oxazol-2-yI
Q718 j -CH2CH3 5- [4-(mef hy Icarbo xy)ph eny 1] ox azo 1 -2~y 1
Q719 -CHvCH; 5-(3-methoxybenzyl)oxazol~2~yl
Q720 CfECiE 5-(4-phenyl)oxazol-2-yl
Q721 -ch2ch3 5-(2-methoxyphcnyl)thiazol-2-yl
Q722 “| “CH2CH3 5-(3~melhoxypheny!)thiazol~2~yl
Q723 ~CH2CH3 5-(4 -fluo ropheny l)thiazo 1-2-y 1
Q724 -ch2ch3 5-(2,4-difluorophenyl)thiazoI-2-yi
Q725 ~ch2ch3 5“(3“methoxybeitzyl)thiazoi-2-yl
Q726 -CiECFb 4-(3-methoxyphenyl)thiazol“2-yl
Q727 -CH2CH3 4-(4-fluorophenyl)thiazol-2-yi
Q728 cyclopropyi 4-(methoxycar bony l)thiazol-5-y 1
Q729 cyclopropyi 4-((2-methoxy-2-oxoefhyi)carbamoyl]thiazol-5-yl
Q730 cyclopropyi 5-[l-77-(2~methoxy~2~oxoethyi)-l-//~indol-3-yi]oxazol-2-yl
Q731 cyclopropyi 5-(2-methoxyphenyl)oxazol-2-yl
Q732 cyclopropyi 5-((5)-1 -(icrr-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
Q733 cyclopropyi 5-[4-(methylcarboxy)phenyl]oxazol-2-yl
Q734 cyclopropyi
Q735 cyclopropyi
Q736 cyclopropyi
Q737 { cyclopropyi cyclopropyi j
5-(3-methoxybenzyi)oxazoi-2-yl 5~(4-phenyl)oxazol~2-yl 5-(2-methoxyphenyl)thiazoi-2-yI
-(4-fiuoropheny l)tfaiazo ί-2-y1
Figure AU2016203254B2_D0249
130
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Figure AU2016203254B2_D0250
unsubstituted thiazol-4-yt unit for R1 can be prepared by the procedure outlined in Scheme XVII and described herein below in Example 18.
Figure AU2016203254B2_D0251
Reagents and conditions: (b) thiophosgene, CaCO··, CCI4, H2O; rt, 18 hr.
Figure AU2016203254B2_D0252
131
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
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Figure AU2016203254B2_D0253
45
Reagents and conditions: (d) (i) SnCh-SHjO, EtOH; reflux, 4 hours (ii) SOj-pyridine, NH4OH.
EXAMPLE 18 (5)-4-(2-(2-PhenylthiazQl-4-yl)2-(4-(meth0xycarhonyI)thiazole-5ylamino)ethyl)pheny)sulfamic acid (45)
Preparation of (5)-2-(4-nitrophenyl)-l-(2-phenylthiazo{-4-yi)ethanamine hydrobromide salt (42); A mixture of (S)-to?Abutyl 4-bromo-l-(4-nitrophenyi)-3-oxobutan-2-ylcarbamate, 7, (1.62 g, 4,17 mmol) and thiobenzamide (0,63 g, 4.60 mmol) in CH3CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid, is dried under vacuum to afford 3.2 g (67 % yield) of the desired product. LC/MS ES1+ 326 (Mt 1),
Preparation of (5)-4-(l-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylth:iazole (43): To a solution of (5')~2~(4~r;iirophenjzl)-l“(2-phcnyhh;azol'4yl)ethanarniiie hydrobromide salt, 42, (726 mg, 1.79 mmol) and CaCOj (716 mg, 7.16 mmol) in H2O (2 mL) is added CCL (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2CI2 and water. The layers are separated and the aqueous layer extracted with CH2CI2. The combined organic layers are washed with brine, dried (Na^Si» and concentrated in vacuo to a residue which is purified over silica (CH2CI2) to afford 480 mg (73 %) of the desired product as a yellow solid, : :iH NMR (300 MHz, CDCh) δ 8.15 (d, J 8.7 Hz, 2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, 8.7 Hz, 2H), 7.15 (d, J- 0.9 Hz, IH), 5.405.95 (m, IH), 3.60 (dd, J- 13.8 and 6.0 Hz, 1H), 3.46 (dd, J™ 13.8 and 6.0 Hz).
Preparation of (S’)-meihyl 5-[l-(2-phenylthiazoI-4-yl)-2-(4-nitrophenyl)ethylamino]thiazole-4-carboxylate (44): To a suspension of potassium ferf-butoxide (89 mg, 0,75 mmol) in THF (3 mL) is added methyl isocyanoacetate (65 uL, 0.68 mmol) followed by (5)-2phenyl-4-(l-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole, 43, (250 mg, 0.68 mmol). The
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2016203254 18 May 2016 reaction mixture is stirred at room temperature for 2 hours then poured into sat. NaHCOj, The mixture is extracted with EtOAc (3x 25 mL) and the combined organic layers are washed with brine and dried (NajSO.)) and concentrated in vacuo. The crude residue is purified over silica to afford 323 mg (~ 100% yield) of the desired product as a slightly yellow solid. !H NMR (300 MHz, CDCh) δ 8.09-8.13 (m, 2H), 7.95-7 98 (m, 3H), 7.84 (d,7“ 1.2 Hz, IH), 7.44-7.50 (m, 3H), 7.28-7.31(m, 2H)} 7.96 (d, 7= 0.6 Hz, IH), 4.71-4.78(m, IH), 3.92 (s, 3H), 3.60 (dd, 713.8 and 6.0 Hz, IH), 3.45 (dd, 7= 13.8 and 6.0 Hz, IH).
Preparation of (5)-4-(2 ~(2~p heny 1 thiazo 1-4-y I)2-(4-(methoxycarbonyi)thiazole-5 ylamino)ethyl)phenylsulfamic acid (45): (5)-methyl 5-[l-(2-phenylthiazol-4-yl)-2-(4nitrophenyl)-ethylamino]thiazole-4-carboxylate, 44, (323 mg, 0.68 mmol) and tin (II) chloride (612 mg, 2.72 mmol) are dissolved in EtOH and the solution is brought to reflux. The solvent is removed in vacuo and the resulting residue is dissolved in EtOAc. A saturated solution of NaHCOj is added and the solution is stirred 1 hour. The organic layer is separated and the aqueous layer extracted twice with EtOAc. The combined organic layers are dried (NajSO^), filtered and concentrated to a residue which is dissolved in pyridine (10 mL) and treated with SO3-pyridine (130 mg, 0.82 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NKUOH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.07 lg of the desired product as the ammonium salt 3H NMR (300 MHz, MeOH~d<fl δ 7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, IH), 7.03-7.13 (m, 4H), 4.74 0,7-6.6 Hz, IH), 3.88 (s, 3H), 3.28-3.42 (m,
2H).
Compounds according to the first aspect of Category IX which comprise a substituted or unsubstituted thiazol-2-yl unit for R1 can be prepared by the procedure outlined in Scheme XV1H and described herein below in Example 19. Intermediate 46 can be prepared according to Scheme II and Example 2 by substituting cyclopropane-carbothioic acid amide for thiophen-2carbothioic acid amide.
Figure AU2016203254B2_D0254
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Reagents and conditions: (a) thiophosgene .CaCCh, CCU/H2O; rt, 18 hr.
2016203254 18 May 2016
Figure AU2016203254B2_D0255
Figure AU2016203254B2_D0256
Reagents and conditions: (b) CH3CN, reflux, 24 hr.
Figure AU2016203254B2_D0257
Figure AU2016203254B2_D0258
Reagents and conditions: (c) (i) H2:Pd/C, MeOH; (ii) SOj-pyridine, NH40H.
EXAMPLE 19
4~ {(S)-2-(2-Cycl0propylthiazol-4-yl)-2- [4-(3- meth oxy p h enyl)thiazol-2ylatnino) ethyl) phenylsulfamic acid (50)
Preparation of (S)-1 -(1 -(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea (47): To a solution of {S)-l-(2-cydopiOpyithiaz»l-4-yI)-2-(4-nitrophenyl)ethan-amine hydrobrornide hydrobromide salt, 32, (4.04 g, 10.9 mmol) and CaCCL (2.18 g, 21.8 mmol) in CCWwater (25 mL/20 mL) is added thiophosgene (1.5 g, 13.1 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2CI2 and water. The layers are separated and the
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2016203254 18 May 2016 aqueous layer extracted with CH2CI2. The combined organic layers are washed with brine, dried (Na2S04) and concentrated in vacuo to a residue which is subsequently treated with ammonia (0.5M in 1,4-dioxane, 320 mL) which is purified over silica to afford 2.90 g of the desired product as a red-brown solid. LC/MS ESI- 347 (M-l).
Preparation of (5)-4-(3-methoxybenzyi)-/V-(l-(2-cyclopropylthiazoi-4-yl)-2-(4nitrophenyl)ethyl)thiazoi-2-amine (48): (5)-l-(l-(2-Cyclopropylthiazol-4-yi)-2-(4nitrophenyl)ethyl)-thiourea, 47, (350 mg, 1.00 mmol) and 2-bromo-3 ’-methoxy-acetophenone (253 mg, 1.10 mmol) are combined in 3 mL CH3CN and heated to reflux for 24 hours. The mixture is concentrated and chromatographed to afford 0.172 g of the product as a yellow solid. LC/MS ESI+ 479 (M+l).
Preparation of 4-{(S)-2-(2-cyciopropylthiazoi-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2yiaminojethyl)phenylsulfamic acid (49): (0)-4-(3-methoxybenzyl)-/V-(l-(2-cyclopropylthiazol4-yl>2-(4-nitK>phenyl)ethyl)thiazol-2-amine,.48, (0.172 g) is dissolved in 10 mL MeOH. A catalytic amount of Pd/C (30% w/w) is added and the mixture is stirred under a hydrogen atmosphere for 18 hours. The reaction mixture is filtered through a bed of CELITE ™ and the solvent is removed under reduced pressure. The crude product is dissolved in 5 mL pyridine and treated with SOs-pyridine (114 mg). The reaction is stirred at room temperature for 5 minutes after which 10 mL of a 7% solution of NH40H is added. The mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.033 g of the desired product as the ammonium salt. SH NMR (C'D3OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.846.80 (m, 2H), 5.02 (t, IH, >6,9 Hz), 3.82 (s, IH), 3.18 (q, 2H, >7.1 Hz), 2.36 (q, IH, >4.6 Hz), 1,20-1.13 (m, 2H), 1.04-0.99 (m, 2H).
The following are non-limiting examples of compounds encompassed within the first aspect of Category IX.
Figure AU2016203254B2_D0259
(S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-yiamino)2-(2-ethylthiazole-4yl)ethyl)phenylsulfamic acid: rH NMR (300 MHz, MeOH-d4) δ 7.91 (s, IH), 7,08-7.10 (m, 3H),
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6,99 (d, ,/- 8,7 Hz, 2H), 4.58 (t, J- 6.9 Hz, IH), 4.11 (d, J~ 2.7 Hz, 2H), 3.78 (s, 3H), 3.142016203254 18 May 2016
Figure AU2016203254B2_D0260
(5)-4-(2- (5-[ 1 -Ar-(2-Methoxy-2-oxoethylcarbamoyl)-.l -if-ntdol-3-yl ]oxazol-2-yiamino} 2-(2-methylthiazol-4-yl)ethy!)phenylsuifamic acid: fH NMR (300 MHz, MeOH~d4) δ 7.63 (d, J
7.8 Hz, IH), 7.37 (s, IH), 7.18-7.29 (m, 4H), 7.02-7.16 (m, 4H), 6.85 (s, IH), 5.04-5.09 (m, 1H),4.85 (s, 3H), 3.27 (dd, J- 13.5 and 8.1 Hz, IH), 3,10 (m,./- 13.5 and 8.1 Hz, IH), 2.69 (s, 3H).
HO’
Figure AU2016203254B2_D0261
4-((S)-2-(5-(2-McthoxyphenyI)oxazol-2-ylamino)-2-(2-methylthiazol-4yl)ethyl)phcnylsulfamic acid: SH NMR (300 MHz, MeOH-d4) δ 7.52 (dd,./ ::: 7.5 and 1.2 Hz, IH), 6.95-7.24 (m, 10H), 5.04-5.09 (m, IH), 3.92 (s, 3H), 3.26(dd,,/-13,8 and8.4 Hz,
3.10 (dd,,/- 13,8 and 8,4 Hz, IH), 2.72 (s, 3H),
Figure AU2016203254B2_D0262
4-((5)-2-(5-((5)-l-(ier/-Butoxycarbonyl)-2-phenyleihyI)oxazole-2-yiamino)-2-(2methylthiazoIe-4-yI)ethyl)phen.ylsulfamic acid: *H NMR (300 MHz, MeOH-d4) δ 7.03-7.27 (m, 10 H), 6.50 (s, IH), 4.95-5.00 (ra, IH), 4.76 (t,./- 6.9 Hz, IH), 3.22 (dd, J~ 14.1 and 6.9 Hz,
Figure AU2016203254B2_D0263
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)- {4- (2-[5-(4-Methoxycarbonyl)phenyl]oxazol-2-ylamino}-2-(2-methylthiazol-4yl)ethyl}phenylsuifamic acid: 'H NMR (300 MHz, MeOH-A,) δ 7.99 (d, J = 7.5 Hz,
2H), 7.56 7.59 (tn, 2H), 7,23-7.24 (m, IH), 7.08-7.14 (m, 4H), 6,83 (d,/ = 10.2 Hz, IH), 5.
2016203254 18 May 2016
Figure AU2016203254B2_D0264
yl)ethy!)phenylsulfamic acid: ‘H NMR (300 MHz, MeOH-d-s) δ 7.03--7.28 (m, 8H), 6.79-6,83 (m, IH), 5.70 (s, IH), 4.99-5.06 (m, 2H), 4.41 (d,/= 2.1 Hz, 2H), 3,80 (s, 3H), 3.27-3.37 (m, IH), 3.03-3.15 (m, IH), 2.71 (s, 3H).
Figure AU2016203254B2_D0265
(5)-4-(2-(2-Methylthiazole-4-yl)2-(5-phenyioxazole‘2-ylamino)ethyl)phenyl-sulfamic acid: -Ή NMR (300 MHz, MeOH-tL) δ 7.45 (d, J - 8.7 Hz, 2H), 7.33 (t, >= 7.8 Hz, 2H), 7.187.22 (m, IH), 7.10-7.14 (m, 6H), 7.04 (s, IH), 5.04-5,09 (m, IH), 3,26 (dd,>* 13.8 and 6.3 H: IH), 3.10 (dd, /- 13.8 and 6.3 Hz, IH), 2.70 (s, 3H).
Figure AU2016203254B2_D0266
OCH3
4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylamino)ethyl)phenylsuifamic acid: NMR (CDjOD): S 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.846.80 (m, 2H), 5.02 (t, IH, >6.9 Hz), 3.82 (s, IH), 3.18 (q, 2H, >7.1 Hz), 2.36 (q, IH, >4.6
Figure AU2016203254B2_D0267
(5)-4-(2~(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2-ylamino)etliyl)phenylsulfamic acid: SH NMR (CD3OD): δ 7.79-7.74 (m, 2H), 7.14-7.03 (m, 7H), 7.21 (s, IH),
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This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST .79 (s, IH), 5.08 (t IH, 7=6.6 Hz), 3.29-3.12 (m, 2H), 2.40 (q, 2.40,7=5.1 Hz), 1.23-1.18 (m,
1.08-1.02 (m, 2H).
2016203254 18 May 2016
Figure AU2016203254B2_D0268
4-((fS)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylaniino)ethyl)phenylsulfamic acid: SH NMR (CDjOD): δ 7.89-7.87 (d, IH, 7=7.6 Hz), 7.28 (t, IH, 7=7.0 Hz), 7.10-6.96 (m, 8H), 5.03 (t, IH, 7=6.9 Hz), 3.90 (s, IH), 3.19 (q, 2H, 7-6.6 Hz), 2.38 (q, IH,
Figure AU2016203254B2_D0269
4-((5)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazoi-2-ylamino)ethyl)phenyisulfamic acid: JH NMR (CD3OD): δ 8.06-8.02 (q, 2H, >6.9 Hz), 7.12-6.95 (m, 7H), 6.88 (s, IH), 5.11 (t, IH,7=6.9 Hz), 3.22-3.15 (m, 2H), 2.38 (q, 11:1,7-4.8 Hz), 1.22-1.15 (m, 2H), 1.06-1.02 (m, 2H).
Figure AU2016203254B2_D0270
(5)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropyIthiazol-4~ yl)ethyl)phenylsulfamic acid: *H NMR (CDjOD): δ 7.22-7.17 (m, 3H), 7.09-6.97 (m, 5H), 6.786.66 (m, 3H), 3.77 (s, 2H), 3.75 (s, 3H), 3.20-3.07 (m, 2H), 2.35 (q, 1H,>4.8 Hz), 1.19-1.13 (m, 2H), 1.03-1.00 (m,:
Figure AU2016203254B2_D0271
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This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)~{5~[l-(2-EthylthiazoM-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methyl-2H[l^s4]triaaole-3-yi}carbamic acid methyl ester: *H NMR (300 MHz, MeOH-df) δ 6.97-7.08 (m,
5H), 3.71 (s, 3H), 3,51 (s, 3H), 3.15 (dd, 13.5 and6.3 Hz, IH), 3.02-3.07 (m, 3H), 1.40 (t, J*
6.6 Hz, 3H).
The second aspect of Category V of the present disclosure relates fo compounds having the formula:
2016203254 18 May 2016
Figure AU2016203254B2_D0272
wherein Rs is a substituted or unsubstituted heteroaryi and R4 is substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl as further described herein below in Table XVIII.
No, | R4 “ R5 ..............................
R743 phenyl 4-(methoxycarhonyl)thiazol~5~yl
R744 phenyl 4-[(2-methoxy-2-oxoeihyl)earbamoyl]thiazol-5-yl
R745 phenyl | 5~[ 1 -iV~(2-methoxy-2-oxoethyl)” 1 -//-indol~3-yl]oxazol-2-yl L
R746 phenyl 5»(2-methoxyphenyl)oxazol-2-yl
R747 phenyl 5-[(5)-l-(ten-hutoxycarhonyl)-2-phenylethyl]oxazol-2-yl
R748 phenyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl
R749 phenyl 5-(3-methoxybenzyl)oxazol-2-yl
R750 phenyl 5-(4-phenyl)oxazol-2-yl
R751 ί phenyl 5-(2-methoxyphenyl)thiazol~2~yl
R752 | phenyl 5-(3-methoxyphenyI)thiazoi~2-yl
R753 phenyl 5-(4-fluorophenyl)thiazol-2-yl
R754 phenyl 5-(2s4-difluorophenyl)thiazol-2-yl
R755 phenyl 5-(3-methoxyheuzyl)thiazol-2-yl
R756 phenyl 4-(3 -methoxypheny l)ihiazol~2~y 1
R757 phenyl ----, 4-(4-fluorophenyl)thiazo 1-2-y 1 1................... .................. ...................
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2016203254 18 May 2016
I N©. Rs
R758 thiophen-2-yl 4-(melhoxycarbonyl)thiazol-5-yl
R759 tbiophen.-2-yl 4-[(2~mcthoxy-2-oxoethyl)carbamoyi]thiazol-5-yl
R760 thiophen-2-yI 5-[ 1 -Ar-(2-methoxy-2-oxoeib.yl)- l-7/-indol-3-yl]oxazol~2-yi
R.761 thiophen-2-yl 5-(2-methoxyphenyl)oxazol-2-yl
R762 thiophen-2-yl 5-((5)-l-(reri-butoxycarbonyl)*2“phenylethyl]oxazol-2-yl
R763 thiopfaen-2-yl 5-[4“(meihyicarboxy)phenyi]oxazol-2-yi
R764 thiophen-2-y! 5-(3-meihoxybenzyl)oxazol-2-yl
R.765 thiophen-2-yl 5-(4-phenyl)oxazol-2~yl
R766 thiophen-2-yl 5-(2-roethoxyphenyl)lhiaz.ol~2~yl
R767 thiophen-2-yl 5~(3~meihoxyphenyl)thiazol~2-yl
R.768 thiophen-2-yI 5“(4“f!uorophenyl)thiazol~2~yl
R769 thiophen-2-y] 5-(2,4-difluoropheny i)thi azo 1 -2-y 1
R770 thiophen-2-yl 5-(3~methoxybenzyl)thiazoS-2-yl
R771 fhiophen-2-yS 4-(3-methoxyphenyl)thiazol-2-yl
R.772 thiophen-2-yl 4-(4-fluorophenyl)thiazol-2-yl
R773 cyciopropyl 4-(methoxycarbonyl)thiazol-5~yi
R774 cyciopropyl 4-[(2-methoxy-2-oxoethy l)carbamoy 1] hi azo 1-5-y 1
R775 cyclopropyl 5-[ 1 -jV-(2-methoxy-2-oxoethy 1)-1 -if-indol-3-y l]oxaz.ol~2~yl
R776 cyciopropyl 5 -(2 -methoxy pheny l)oxazo 1-2 -y 1
R777 cyciopropyl 5 -((5)-1 -(/ert-butoxycarbony 1)-2 -phenylethyl]oxazol-2-yl
R.778 cyciopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl
R779 cyciopropyl 5-(3 -methoxybenzyl)ox azol-2 -y 1
R7S0 cyciopropyl 5-(4-phenyl)oxazoi-2-yl
R781 cyciopropyl 5-(2 -methoxypheny l)thiazo 1-2-y 1
R782 cyciopropyl 5-(3 -methoxypheny Ijthiazo 1-2 -yl
R783 cyciopropyl 5~(4~fluorophenyl)thiazol-2-yl
R.784 cyciopropyl 5-(2,4 -di fluorophenyl)thi azol-2-y 1
R785 cyciopropyl 5-(3-methoxybeozyl)thiazol-2-yl
R786 cyciopropyl 4-(3 -methoxy phenyl)thi az.ol~2~yl
MO
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. R4 R1
R787 cyclopropyl 4-(4-fluorophenyl)thiazol-2-yl
Compounds according to the second aspect of Category IX which comprise a substituted or unsubstituted thiazol-4-yl unit for R! can be prepared by the procedure outlined in Schemes XIX, XX, and XXI and described herein below in Examples 20, 21, and 22.
Figure AU2016203254B2_D0273
Reagents and conditions: (a)(i) (jso-butyl)OCOCi, Et3N, THF; 0 °C, 20 min. (ii) CH2N2; 0 ’'€ to room temp for 3 hours.
Figure AU2016203254B2_D0274
Figure AU2016203254B2_D0275
Reagents and conditions: (b) 48% HBr, THF; 0 °C, 1.5 hr.
Figure AU2016203254B2_D0276
Figure AU2016203254B2_D0277
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2016203254 18 May 2016
Reagents and conditions: (c) CHjCN; reflux 2hr.
Figure AU2016203254B2_D0278
Figure AU2016203254B2_D0279
Reagents and conditions: (d) thiophosgene, CaCO3, CCI4, H2O; rt, 18 hr.
Figure AU2016203254B2_D0280
Figure AU2016203254B2_D0281
Reagents and conditions: (e)(i) CH3C(O)NHNH2, EtOH; reflux, 2 hr. (ii) P0Ct?, rt 18 hr; 50 °C 2 hr.
Figure AU2016203254B2_D0282
Reagents and conditions: (f) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH,
EXAMPLE 20 (5)-4-(2-(5-Methyi-13Athiadiazol-2-yEamin0)-2-(2-plienyIthiazol-4yl)ethyl)phenylsulfamic add (55)
Preparation of [3-diazo-l-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester (50): To a 0 °C solution of 2-(5I)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4,4 mmol) followed by Bo-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0 °C
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This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 for 20 minutes then filtered. The filtrate is treated with an ether solution of diazomethane (-16 mmol) at 0 °C. The reaction mixture is stirred at room temperature for 3 hours and concentrated. The residue is dissolved in EtOAc and washed successively with water and brine, dried (NajSOzi), 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 slightly yellow solid. ’H NMR (300 MHz, CDC13) δ 8.16 (d, 7-8.7 Hz, 2H), 7.39 (d, 7-8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d,7- 6.3 Hz, 1H), 4.49 (s, IH), 3.25 (dd, 7- 13.8 and 6.6, IH), 3,06 (dd, 7- 13.5 and 6.9 Hz, IH), 1.41 (s, 9H).
Preparation of [3-bromo-l-(4-nitro-benzyl)-2-oxo-piopyl]-carbamic acid terf-butyl ester (51): To a 0 °C solution of [3-diazo-l-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester, 50, (0,350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0 °C for 1.5 hours and quenched at 0 °C with saturated aqueous Na2CO3. The mixture is extracted with EtOAc (3 x 25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), fdtered and concentrated in vacuo to afford 0.400 g of the desired product that is used in the next step without further purification. !H NMR (300 MHz, CDCI3) δ 8.20 (d, 7- 8.4 Hz, 2H), 7.39 (d,7 8.4 Hz, 2H), 5.06 (d,7- 7.8 Hz, 1H),
4.80 (q,7= 6.3 Hz, IH), 4.04 (s, 2H), 1.42 (s, 9H).
Preparation of (<S)-2-(4-nitrophenyl)-l-(2-phenylthiazoi-4-yl)ethanamine hydrobromide salt (52): A mixture of [3-bromo~l-(4~nitro-benzyl)~2-oxo-propyl]-carbamie acid teri-butyl ester, 51, (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol), in CH3CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooled to room temperature 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+l).
Preparation of (5)-4-(1 -isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole (53):
To a solution of (lS)-2-(4-nitrophenyi)-l-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt,
52, (2.03g, 5 mmol) and CaCO3 (1 g, 10 mmol) in CCU/water (10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CB.2CI2 and water. The layers are separated and the aqueous layer extracted with CH3CI2. The combined organic layers are washed with brine, dried (Na2SOq) and concentrated in vacuo to a residue that is purified over silica (CH2C12) to afford 1.7 lg (93% yield) of the desired product. ESI+MS 368 (M+l).
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This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Preparation of (5)-5-methyl-/V-[2-(4’nitrophenyl)-1 -(2-phenylthiazoi-4-yI)ethyl]~ 1,3.4thiadiazol-2-amine (54): A solution of (iS)-4-[l-isothiocyanato-2-(4-nitrophenyi)-ethyl]-2phenylthiazole, 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 PGCh (3 mL) and the resulting solution is stirred at room temperature for 18 hours after which the solution is heated to 50 for 2 hours. The solvent is removed in vacuo and the residue is dissolved in EtOAc (40 mL) and the resulting solution is treated with IN NaOH until the pH remains approximately 8, The solution is extracted with EtOAc, The combined aqueous layers are washed with EtOAc, the organic layers combined, washed with brine, dried over MgSOd, filtered, and concentrated in vacuo to afford 0,345 g (93% yield) of the desired product a yellow solid. 'H NMR (CDCh) 8,09 (d, J - 8.4 Hz, 2H), 7,91 (m, 2H), 7.46 (m, 4H), 7.44 (s, IH), 5.23 (m, IH), 3.59 (m, 2H), 2.49 (s, 3H). ESI+ MS 424 (M+l).
Preparation of (5)-4-[2-(5-methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4yl)ethyi]phenyisulfamic acid (55): (5)-5-Methyl-N-[2-(4-nitrophenyl)-I-(2-phenyithiazol-4yi)ethyl]-l,3,4-ihiadiazol-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 hydrogen atmosphere until the reaction is judged to be complete. The reaction mixture is filtered through a bed of CELITE1 M and the solvent removed under reduced pressure. The crude product is dissolved in pyridine (4 mL) and treated with SO3-pvridine (0.304 g, 1.91 mmol). The reaction is stirred at. room temperature for 5 minutes after which a 7% solution of NH^OH (50 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase preparative HPLC to afford 0,052 g (11% yield) of the desired product as the ammonium salt. NMR (CD3OD): S 8.00-7,97 (m, 2H), 7.51-7.47 (m, 3H), 7.23 (s, IH), 7.11-7.04 (q, 4H, /=9.0 Hz),
5.18 (t, IH, >7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 3H). ESI- MS 472 (M-I).
Figure AU2016203254B2_D0283
Reagents and conditions: (a) thiophosgene ,CaCO3s CCI4/H2O; rt, 18 hr,
144
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Figure AU2016203254B2_D0284
Reagents and conditions: (c) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; rt, 18 hr.
EXAMPLE 21
4-{(S>2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiopheR-2-yE)thiazol-4yl]ethy)}phenylsnlfamic add (58)
Preparation of (S)~ .1 -[ 1 -(thiophen-2-ylthiazo!-4-yl)-2-(4-nitrophenyl)ethyi]»thiourea (56): To a solution of (S)-2-(4-nitrophenyl)-l-(thiophen-2-yithiazol-4-yl)ethanamine hydrobromide salt, 8, (1.23 g, 2.98 mmol) and CaCCb (0.597 g, 5.96 mmol) in CCl4/water (10 mL. 5 mL) is added thiophosgene (0.412g, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CHjCh and water. The layers are separated and the aqueous layer extracted with CH2CI2. The combined organic layers are washed with brine, dried (Na^SCh) and concentrated in vacuo to a residue which is subsequently treated with ammonia (0.5M in 1,4145
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 dioxane, 29.4 mL, 14.7 mmol) which is purified over silica to afford 0.490 g of the desired product as a red-brown solid. ESI+ MS 399 (M+l).
Preparation of 4-(2-methoxyphenyl)-/V- {(S)~2-(4-nitrophenyl)-1 -[2-(thiophen-2yl)thiaz.ol-4-yl]ethyl}thiazol-2-amine (57): (S)~ 1 ~[ 1 -(thiophen-2-ylthiazol-4-yl)-2-(4u!tropheny])ethyl]~thiourea, 56, (265 mg, 0.679 mmol) is treated with bromo-2’methoxyacetophenone (171 mg, 0,746 mmol) to afford 0,221 g of the product as a yellow solid. ESIMS 521 (M+l).
Preparation on 4- {(S)-2-[4-(2-methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2yl)thiazol-4-yl]ethyl}phenylsuifamic acid (58): 4-(2-methoxyphenyl)-/V-{(S)-2-(4-nitrophenyi)l-(2-(thiophen-2-yl)thiazoi-4-yl]ethyi}thiazol-2-amine, 57, (0.229 g) is dissolved in 12 mL MeOH. A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere for 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in 6 mL pyridine and treated with SOj-pyridine (140 mg). The reaction is stirred at room temperature for 5 minutes after which 10 mL of a 7% solution of NH<tOH is added. The mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.033g of the desired product as the ammonium salt. *H NMR (CD3OD): δ 7.96-7.93 (m, IH), 7.60-7.55 (m, 2H), 7.29-7.23 (m, IH), 7.18-6.95 (m, 9H), 5.15 (t, 1H,>6.9 Hz), 3.90 (s, 3H), 3.35-3.24 (m, 2H),
Compounds according to the second aspect of Category IX which comprise a substituted or unsubstituted oxazol-2-yl unit for R1 can be prepared by the procedure outlined in Scheme XXI and described herein below in Example 22. Intermediate 39 can be prepared according to Scheme XVII and Example 18.
M6
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
Scheme XXI
Figure AU2016203254B2_D0285
HjCO
Reagents and conditions: (a) 1-azido-l-(3-methoxyphenyi)ethanone, PPh3, dioxane, 90 SC 20 minutes.
Figure AU2016203254B2_D0286
n3co h3co
Reagents and conditions: (b) (i) IfePd/C, MeOH; (ii) SO3-pyridme, NH^OH; rt, 18 hr.
EXAMPLE 22
4-{(5>2-[5-(3-MethoxyphenyI)oxazo]e-2-yIainino]-2-(2-phenylthjazole-4yl)ethy)}phenylsulfamic acid (61)
Preparation of [5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4’nitrophenyl)-l-(2-phenyithiazoie 4-yl) ethyljamine (60): A mixture of (5>4-(isothiocyanato-2-(4-nitophenyl)ethyl)-2phenylthiazole, 53, (300 mg, 0.81 mmol), l-azido-l-(3-methoxyphenyl)ethanone (382 mg, 2,0 mmol) and PPh3 (0.8 g, polymer bound, -3 mmol/g) in dioxane (6 mL) is heated at 90 °C for 20 minutes. The reaction solution is cooled to room temperature and the solvent removed in vacuo and the resulting residue is purified over silica to afford 300 mg (74% yield) of the desired product as a yellow solid. 3H NMR (300 MHz, MeOH-d4) δ 8.02 (d, J - 7.2 Hz, 2H), 7.92-7.99
147
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 (m, 2H), 7.42-7.47 (m, 3H), 7.22-7.27 (m, 3H), 6.69-7.03 (m, 4H), 6.75-6.78 (m, IH), 5.26 (t, J 6.3 Hz, IH), 3.83 (s, 4H), 3,42-3.45 (m, 2H).
Preparation of 4- {(S)~2-[5-(3-methoxyphenyl)oxazole-2-ylaraino]-2-(2-phenylthiazole-4 yl)ethyl}phenylsuifamic acid (61): [5-(3-methoxyphenyl)oxazol-2~yi]-[2-(4-nitrophenyl)-1-(2phenylthiazole-4-yl) ethyljamine, 60, (300 mg, 0.60 mmol) is dissolved in MeOH (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 reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (10 mL) and treated with SOrpyridine (190 mg, 1,2 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NTLOH is added. The mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.042 g of the desired product as the ammonium salt. NMR (300 MHz, MeOH-dZj δ 7.99 (d, A™ 7.5 Hz,
2H), 7.46-7,50 (m, 3H),7.23-7.29 (m, 3H), 7.04-7.12 (m, 6H), 6.78 (dd, J- 8.4 and 2.4 Hz, IH), 5,16 (t,J= 6.6 Hz, IH), 3.81 (s, 3H), 3.29-3.39 (m, IH), 3.17 (dd, J® 13.8 and 8.1 Hz, IH).
The following are non-limiting examples of the second aspect of Category IX of the present disclosure.
Q, ,i>
Figure AU2016203254B2_D0287
(5)-4-(2-(5-Phenyl-l,3,4-thiadiazol-2-ylamino)-2-(2-phenyithiazol-4-yI)ethyl)phenylsulfamic acid: 'HNMR (CDjOD): δ 7.97-7.94 (m, 2H), 7.73-7.70 (m, 2H), 7.44-7.39 (m,
7.25 (s, IH), 7.12 (s, 4H), 5,29 (t, 1H,>6.9 Hz), 3.35-3.26 (m,
Figure AU2016203254B2_D0288
4-((S)-2-(5-Propyi-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazoI-4yl)ethyl)phenylsulfamic acid: !Ή NMR (CDjOD): δ 7.59-7.54 (m, 2H), 7,17-7,03 (m,
5.13
148
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (t, 1H,>7.2 Hz), 332-3.13 (m, 2H), 2.81 (t, 2H,7=7.4 Hz), 1.76-1,63 (h, 6H,7=7.4 Hz),0.97 (t
311,./-7.3 Hz).
2016203254 18 May 2016
Figure AU2016203254B2_D0289
Figure AU2016203254B2_D0290
4-((S)-2-(5-Benzyl-l,3,4'thiadiazol-2-ylaniino)-2-(2-(thiophen-2-yl)thiazol-4yl)cthyl)phenytsulfamic acid: 3H NMR (CD3OD): δ (m, 2H), 7.49-7.45 (hi, 2H), 7.26-7.16 (m, 5H), 7.05-6.94 (m, 6H), 5.04 (t, IH, 7=7.1 Hz), 4.07 (s, 2H), 3.22-3.04 (m, 2H).
ο, £
V
HO g
4-((5)-2-(5-(Naphthalen-l-ylmethyl)-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen~2yi)thiazol-4-yi)ethyi)phenylsulfamic acid: !H NMR (CDjOD): δ 8.08-8.05 (m, IH), 7.89-7.80 (m, 2H), 7.55-7,43 (m, 6H), 7,11-7.00 (m, 6H), 5.08 (t, IH,7=7.1 Hz), 4.63 (s, 2H), 3.26-3.08
Figure AU2016203254B2_D0291
4-((«S)-2-(5-((Methoxycarbonyl)methyl)-],3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2yl)thiazol-4-yl)ethyl)phenylsulfamic acid: 3H NMR (CD3OD): δ 7.48-7.44 (m, 2H), 7.03-6.92 (m, 6H), 5,02 (t, IH, 7=7.2 Hz), 4.30 (s, 2H), 3.55 (s, 3H), 3.22-3.02 (m, 2H).
Figure AU2016203254B2_D0292
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
4-((5)-2-(5-((2-Methy{thiazol-4-yl)methyl)-l>3>4-thiadiazol-2-ylamino)-2-(2-(thiophen-2yi)thiazol-4-y5)ethyl)phenylsulfamic acid: 3H NMR (CDjOD): δ 7.60-7.56 (m, 2H), 7.19 (s,
IH), 7.15-7.12 (m, 2H), 7.09-7.03 (q,4H,>8.7 Hz), 5.14(1, 1HS>7.2 Hz), 4.28 (s, 2H), 3,333,)4 (m, 2H), 2.67 (s, 3H),
2016203254 18 May 2016
Figure AU2016203254B2_D0293
F
4-{(5)-2-[4-(2,4’Djfluoropheny{)thiazoi-2-ylamino]-2-[2-(ihiophen-2-yl)ihiazol-4yljethyl) phenylsulfamic acid: SH NMR (CD30D): δ 8.06-8.02 (q, IH, >6,8 Hz), 7.59-7.54 (m, 2H), 7.16-7.08 (m, 6H), 7.01-6.88 (m, 4H)S 5.20 (t, IH, >7.0 Hz), 3.36-3,17 (m, 2H).
a
Figure AU2016203254B2_D0294
(6)-4- {2-[4-(Ethoxycarbonyl)thiazol-2-ySamino]-2-(2-phenylthiazol-4yl)ethyl} phenylsulfamic acid: !H NMR (CDjOD): 8 8.02-7.99 (m, 2H), 7.54-7.45 (m, 4H), 7.26 (s, IH), 7.08 (s, 4H), 5.26 ¢1, IH, >6.9 Hz), 4.35-4.28 (q, 2H, >6.9 Hz), 3.38-3.18 (m, 2H), 1.36 (t, 3H, >7.2 Hz),
Figure AU2016203254B2_D0295
(5)-4-{2-i4-(2-Eihoxy-2-oxoethyl)ihiazoi~2-ylamino]-2-(2-phenyhhiazoi-4yl)ethyl)phenylsulfamic acid; Ή NMR (CD3OD): 8 7.96 (m, 2H)S 7.50-7.46 (m, 3H), 7.21 (s, IH), 7,10-7.04 (m, 4H), 6.37 (s, IH), 5.09 (t, 1HS>6.9 Hz), 4.17-4.10 (q, 2H, >7.1 Hz), 3.54 (s,
3.35-3.14 (m, 2H), 1,22 (t, 3H, >7.1 Hz).
Figure AU2016203254B2_D0296
S,
N N
S
NH
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (5)-4-{2-[4-(4-acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4yl)ethyl)phenylsuifamic acid: !H NMR (CD3OD): δ 8.11 (m, 2H), 7.82-7.80 (m, 2H), 7.71-7.61 (m, 6H), 7.40 (s, 1H), 7,23 (s, 4H), 5.32 (t, 1H, J-7.0 Hz), 3,51-3.35 (m, 2B), 2.28 (s,
X)
2016203254 18 May 2016
Figure AU2016203254B2_D0297
(S)-4-[2-(4phenyIthiazol-2-ybm.ino)-2-(2-phenyhhiazol~4~yl)eihyl]phenylsulfamic acid
NMR (CD3OD): δ 8.03-7.99 (m, 2H), 7.75-7.72 (d, 2H, 7-8.4 Hz), 7,53-7.48 (m, 3H), 7.42 (m, 4H), 7.12 (s, 4H), 6,86 (s, 1H), 5.23 (t, 1H, 7=7.2 Hz), 3.40-3.27 (m, 2H).
-s.
Q, ,0
Figure AU2016203254B2_D0298
COjCH-, (5)-4- {2-[4-(4-(methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4yl)ethyl}phenyisulfanuc acid: *H NMR (CDjOD): δ 8.04-8.00 (m, 4H), 7.92-7.89 (d, 2H, 7-9,0 Hz), 7.53-7.49 (m, 3H), 7.30 (s, 1H), 7.15 (s, 4H), 7.05 (s, 1H), 5.28 (t, IB,7-6,9 Hz), 3.93 (s, 3H), 3.35-3.24 (m, 2H).
Q .0
Figure AU2016203254B2_D0299
COjC3Hs
4-{(S)-2-[4-(Ethoxycarbonyl)thiazol.-2-ylaTnino]-2-[2-(thiophen-2-yl)thiazol-4yl]ethyl}phenylsulfamic acid: !H NMR (CD3OD): § 7,43-7.38 (m, 2H), 7.26 (s, 1H), 7.00-6.94 (m, 3H), 6.89 (s, 4H), 5.02 (t, 1H, 7=7.0 Hz), 4.16-4.09 (q, 2H, 7-7,1 Hz), 3.14-2.94 (m,
1.17 (t, 3H, 7-7.1 Hz),
Figure AU2016203254B2_D0300
(5)-4- [2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenyl ih iazo le-4yl)ethyl]phenylsulfamic acid: !H NMR (300 •d4) δ 7,97-8.00 (m, 3H), 7.48-7,52
151.
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST (m, 3H), 7.22 (ss 1H), 7,03-7.13 (m5 4H), 4,74 (t? J~ 6,6 Hz, IH), 3.88 (s5 3H)? 3,28-3.42 (ms
2016203254 18 May 2016
Figure AU2016203254B2_D0301
s._
N-^X~~V / (1S)~4~[2~(5~Phenyloxazol-2-ylamino)-2-(2-phenyHhiazoi~4~yl)ethyl3-phenylsulfamic acid: lH NMR (300 MHz, MeOH-d4) δ 7.94-7.96 (ra, 2H), 7.45-7.49 (m, 5H), 7.32 (t, ,/-7.8 Hz,:
7.12 (s, IH), 7,19 (t,/- 7.2 Hz, IH), 7.12 (s, 4H), 7.05 (s, IH), 5.15 (t, J- 6.4 Hz, IH), 3,34 ,J~ 14,1 and 8.4 Hz, IH), 3.18 (dd./ 14.1 and 8.4 Hz, rs'N
HN^ „0
NHO N
H
Figure AU2016203254B2_D0302
Figure AU2016203254B2_D0303
(5)-4 - {2- [ 5 -(4-Acetamidopheny l)oxazol-2-y lami no]~2~(2~p heny Ithiazol-4yl)ethyl}phenylsulfamic acid: *H NMR (300 MHz, MeOH-d4) 8 7.92-7.94 (m, 2H), 7.55-7.58 (m, 2H), 7,39-7.50 (ra, 5H), 7.26 (s, IH), 7.12 (s, 4H), 7.02 (s, 1H0), 5.14 (t, ./-7.8 Hz
Figure AU2016203254B2_D0304
4-((5)-2-(5-(2,4-Difluorophenyl)oxazoIe-2-ylamino)-2-(2-phenylthiazole-4yl)ethyl)phenylsulfamic acid: !H NMR (300 MHz, MeOH-dj) δ 7.97-7.99 (tn,
2H), 7.54 7.62 (m, IH), 7,45-7.50 (m, 3H), 7.28 (s, IH), 7.12 (s, 4H), 6.97-7,06 (ra, 3H), 5.155,20 (m, IH), 3.28-3,40 (m, IH), 3.20 (dd,/- 13.8 and 8.4 Hz, IH).
O„ .0
Figure AU2016203254B2_D0305
QCK,
4-{(5)-2-[5-(3-Methoxyphenyl)oxazol-2-yIamino]-2-[(2-thiophen-2-yl)thiazoie-4yl]ethyl)phenyisulfamic acid: lH NMR (300 MHz, MeOH-d4) δ 7,55-7.60 (ra, 2H), 7.26 (t, >
152
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
8.1 Hz, IH), 7.21 (s, IH), 7.04-7.15 (m, 8H), 6.77-6.81 (m, IH), 5.10 (1,3-6.3 Hz, IH), 3.81 (s,
3H), 3.29-3.36(m, IH), 3.15 (dd, 7= 14.1 and 8.4 Hz, IH).
2016203254 18 May 2016
Figure AU2016203254B2_D0306
(S)~4-[2“(4,6“Dimethylpyrimidin~2~yla.mino)-2-(2-methylihiazole-4yl)ethyl]phenylsulfamic acid: JH NMR (300 MHz, MeOH-d«) δ 7.00-7.10 (m,
5H), 6.44 (s, IH), 5.50 (1,3= 7.2 Hz, IH), 3.04-3.22 (m, 2H), 2.73 (s, 3H), 2.27 (s, 6H).
Figure AU2016203254B2_D0307
(5)-4-[2-(4-Hydroxy-6-mefhylpyrimidine-2-ylaminG)-2-(2-methyithiazole~4yl)ethyl]phenylsulfamic acid: NMR (300 MHz, MeOH-d4) δ 7.44 (d, 78.4Hz,2H), 6.97-7.10 (m, 4H), 5.61 (s, IH), 5.40-5.49 (m, IH), 3,10-3.22 (m, 2H), 2.73 (s, 3H), 2.13 (s, 3H).
The first aspect of Category X of the present disclosure relates to compounds having the formula:
Figure AU2016203254B2_D0308
wherein R? is heteroaryl and R4 is further described herein below in Table XIX.
No. 1? R1
S788 phenyl 4-(methoxycarbonyl)thi azo 1-5 -yi
S789 phenyl 4-[(2-methoxy-2~oxoethy l)carb arnoy Ijthi azol-5 -y 1
S790 phenyl 5-[l-77-(2-ntethoxy-2-oxoethyl)-l~/f-indol-3-y{]oxazoi-2-yi
S791 phenyl 5-(2-methoxyphenyl)oxazol-2-yl
153
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
5792
5793 phenyl phenyl
5-[(5)-l-(/eri-butoxycarbonyi)-2-phenylethyl]oxazol-2-yl
5-[4-(methylcarboxy)phenyl]oxazol-2-yl 5-(3 -methoxy benzy t)ox azo 1-2-y 1
S795 i phenyl i 5-(4-phenyl)oxazol-2-yl
! S796 j phenyl [ 5-(2-methoxyphenyl)thiazol-2-y 1
S797 phenyl 1 5-(3-methoxyphenyl)thiazol-2-yl
S798 phenyl 5 -(4-fluoropheny l)th iazo 1-2-y 1
S799 phenyl | 5 -(2,4-difluoropheny l)t hiazo 1 -2-y 1
S800 phenyl 1 i 5 -(3-methoxybenzy i)thi azo 1 -2-yl
S801 phenyl 4-(3-methoxyphenyl)thiazo 1-2-y 1
S802 phenyl [ 4-(4-fluorophenyl)thiazol-2-yl
S803 thiophen-2-yl 4-(methoxycarbonyl)thiazol~5~yl
SS04 thiophen-2-yl 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl
S805 thiophen~2~yl j5-[l-Al-(2-methoxy-2-oxoethyl)-l-Jfir-indol-3-yl]oxazoi-2-yl
S806 ihiophcn-2-yl 5-(2-methoxyphenyl)oxazol~2-yl
S807 thiophen-2-yl 5 -((5)-1 -(/er/-butoxycarbonyl)-2-phenylethyl]oxazol-2-y{
S808 thiophen-2-yl 5- [4-(methy icarboxy)phenyl joxazo 1-2 -yl
S809 thiophen-2-yl 5-(3-methoxybenzyl)oxazol-2-yl
S810 thiophen-2-yl 5-(4-phenv l)ox azol-2-y 1
S811 lhiophen-2-yl 5-(2~melhoxyphenyI)ihiazol-2-yl
S812 thiophen-2-yl 5-(3-methoxyphenyl)thiazol-2-yl
.....§813..... thiophen-2~yi 5-(4-fluorophenyl)thiazol~2~yl
S814 thiophen-2-yl 5-(2,4-difluorophenyl)thiazol-2-yl
8815 thiophen-2-yl 5-(3-methoxybenzyl)thiazol-2-yl
S816 thiophen-2-yi 4-{3-methoxyphenyl)thiazol~2~yI
S817 thiophen-2-yl 4-(4-fiuorophenyI)thiazoI-2-yl
8818 cyclopropyl 4-(methoxycarbonyi)thiazol-5-yl
S819 cydopropyl 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl
S820 cyclopropyl 5-[ 1 -JV-(2-methoxy-2-oxoethy 1)-1 -Z/-indol-3-yl]oxazol-2 -yl
154
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016
No. I R*
S821 j cyclopropyl
~S822j' cyclopropyl
S823 J cyclopropyl
S824 cyclopropyl
S825| cyclopropyl
S827
S828' | §829 cycle cyclopropyl cyclopropyl cyclopropyl
5-(2-methoxyphenyl)oxazol-2-yl
-(terf-butoxycarbonyl)-2-phenylethyl]oxazoi-2-yl
5-(4-(methylcarboxy)phenyl]oxazol-2-yl
5-(3-methoxybenzyl)oxazol-2-yl
5-(4-phenyl)oxazoi-2-yl
5-(2-methoxyphenyl)thiazol-2-yl
5-(3-methoxyphenyl)thiazol-2-yi
5“(4~fluorophenyfjthiazoi~2~yi S-^A-difluorophenyOthiazoi-i-yl 5-(3-methoxybenzyl)thiazol-2-yl
S83O 1 cyclopropyl cvciopropyl ~~j 4-(3-methoxyphenyl)thiazol-2-yl
4-(4-fluorophenyI)thiazol-2-yl
S832
Figure AU2016203254B2_D0309
Figure AU2016203254B2_D0310
Compounds according to the first aspect of Category X can be prepared by the procedure outlined in Scheme XXII and described herein below in Example 23.
Figure AU2016203254B2_D0311
Figure AU2016203254B2_D0312
Figure AU2016203254B2_D0313
155
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
Reagents and conditions: (b) (3~Cl)QHdCO2Hs EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
2016203254 18 May 2016
6:2
Figure AU2016203254B2_D0314
Figure AU2016203254B2_D0315
Reagents and conditions: (c) (1) H2:Pd/C, MeOH; (ii) SOa-pyridine, NH4GH, rt, 18 hr.
Preparation of (S)~2~(4~nilropheny!)-1 -[(thiophen-2-yl)oxazol-4-yl]ethanamme hydrobromide salt (62): A mixture of (.S'l-tert-buty; 4-bromo-l-(4-nitrophenyl)-3-oxobutan-2ylcarbamate, 7, (38,7 g, 100 mmol), and thiophen-2-carboxamide (14 g, 110 mmol) (available from Alfa Aesar) in CH3CN (500 mL) is refluxed for 5 hours. The reaction mixture is cooled to room temperature and diethyl ether (200 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford the desired product which can be used for the next step without purification.
Preparation of 2-(3 -chlorophenyl)-#- {(5)-2-(4-nitrophenyl)-1 -[2~(thiophen-2-yl)oxazoI4-yl]ethyi}acetamide (63): To a solution of (S)-2-(4-nitrophenyl)~l-[(thiophen~2-yi)oxazol-4yljethanamine HBr, 47, (3.15 g, 10 mmol) 3-chlorophen.yl-acetic acid (1.70 g, 10 mmol) and Ihydroxybenzotriazole (HOBt) (0.70g, 5.0 mmol) in DMF ( 50 mL) at 0 °C, is added 1-(3dimethylaminopropyl)-3-ethyIcarbodiimide (EDCI) (1.90 g, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCO,, water and brine, and dried over NajSOi. The solvent is removed /« vacuo to afford the desired product which is used without further purification.
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Preparation of-((5)-2-(2-(3-chlorophenyS)acetamido)~2-(2-(thiophen-2-yl)oxazol-4yl)ethyl)phenylsulfamic acid (64): 2-(3-chlorophenyl)-tV- {(5)-2~(4-niirophenyl)-1 ~[2-(thiophen 2-yl)oxazol-4-yl]ethy3(acetamide, 63, (3 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO3pyridine (0,157 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NfLGH is added. The mixture is then concentrated and the resulting residue can be purified by reverse phase chromatography to afford the desired product as the ammonium salt.
The second aspect of Category X of the present disclosure relates to compounds having the formula:
Figure AU2016203254B2_D0316
wherein R1 is aryl and R2 and R3 are further described herein below in Table XX.
Nu. R2 1 ET
T833 methyl | hydrogen phenyl
T834 methyl ί hydrogen benzyl
T835 methyl hydrogen 2-fluorophenyl
T836 methyl | hydrogen 3-fluorophenyl
ί T837 | ί methyl j hydrogen 4-fluorophenyl
ί T8.38 methyl | hydrogen 2-chIorophenyI
T839 j methyl hydrogen 3-chlorophenyl
T840 methyl hydrogen 4-chlorophenyI
T841 ethyl j hydrogen phenyl
T842 | ethyl hydrogen benzyl
1 T843 | ethyl j hydrogen 2-fluorophenyl
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1 No. R2 .............. R1
T844 ethyl hydrogen 3-fluorophenyl
T845 ethyl hydrogen 4-fluorophenyl
T846 ethyl hydrogen 2-chlorophenyl
T847 ethyl hydrogen 3-chlorophenyl
T848 ethyl hydrogen 4-ehlorophenyl
T849 thien-2-yl hydrogen phenyl
T850 thien-2-yl hydrogen benzyl
T851 thien-2-yl hydrogen 2-fluorophenyl
T852 thien-2-yl hydrogen 3-iluorophenyl
T853 fhien-2-yl hydrogen 4-fluorophenyl
T854 thien-2-yi hydrogen 2-chlorophenyl
T855 thien-2-yl hydrogen 3-chlorophenyl
T856 thiene-2-yl hydrogen 4~ehiorophenyl
Compounds according to the second aspect of Category X can be prepared by the procedure outlined in Scheme XXIH and described herein below in Example 24.
Figure AU2016203254B2_D0317
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Reagents and conditions: (h) CsH^CO^H, EDCI, HOBt, DIPEA. DMF; rt, 18 hr.
Figure AU2016203254B2_D0318
Figure AU2016203254B2_D0319
Reagents and conditions: (c) (i) FfoPd/C, MeOH; (h) SO3-pyridine, ΝΗ4ΟΗ, rt, 18 hr.
EXAMPLE 24 {4-I2-(5>(4-EthyIoxazol-2-yI)-2-phenykcety]aminoethyI)
-phenyl}sulfemie acid (67)
Preparation of (,S)-l-(4-ethyIoxazol-2-y{)-2-(4-nitrophenyl)ethanamine (65): A mixture of [l-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbaniic acid w-butyl ester, 1, (10 g, 32.3mmol) and l~bromo-2-butanone (90%, 4.1 mL, 36 mmol) in CH3CN (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 is removed by filtration and is used without further purification.
Preparation of j¥-[ 1 -(4-eihyloxazol-2-yl)-2-(4-nifrophenyl)ethyl]-2-phenyl-acetamide (66): To a solution of (5)-l-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamme, 65, (2.9 g, 11 mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hydroxyhenzotriazole (HOBt) (0,94 g, 7.0 mmol) in DMF ( 100 mL) at 0 °C, is added l-(3-dimethylamino-propyi)-3-ethylcarbodiimide (EDCI) (2.68g, 14 mmol) followed by triethylamine (6.0 mL. 42mmol), The mixture is stirred at 0 aC for 30 minutes then at room temperature overnight. The reaction mixture is diluted with wafer and extracted with EtOAc, The combined organic phase is washed with 1 N aqueous HCI, 5 % aqueous NaHCO3, water and brine, and dried over Na2SO4, The solvent is removed in vacuo to afford the desired product which is used without further purification.
Preparation of {4-[2-(5)-(4-ethyloxazol-2-yl)-2-phenylacefylaminoethyl3pheny!) sulfamic acid (67): 7V-[l-(4-ethyloxazol-2-yl)-2-(4-riitrophenyl)ethyl]-2-phenyIacetamide, 66, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w)
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2016203254 18 May 2016 is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is fdtered through a bed of CELITE1 M and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SGs-pyridine (0.177 g, 1,23).
The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH (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,
METHODS
The vascular endothelium lines the inside of all blood vessels, forming a nonthrombogenic surface that controls the entry and exit of plasma and white blood cells to and from the bloodstream. The quiescent endothelium has turnover rates of months to years, and proliferates only following angiogenic activation. The loss of endothelial quiescence is a common feature of conditions such as inflammation, atherosclerosis, restenosis, angiogenesis and various types of vasculopathies,
Vasculogenesis and angiogenesis are down-regulated in the healthy adult and are, except for the organs of the female reproductive system, almost exclusively associated with pathology when angiogenesis is induced by microenvironmental factors such as hypoxia or inflammation. These pathological processes associated with, or induced by, angiogenesis include diseases as diverse as cancer, psoriasis, macular degeneration, diabetic retinopathy, thrombosis, and inflammatory disorders including arthritis and athrerosclerosis. However, in certain instances insufficient angiogenesis can lead to diseaeses such as ischemic heart disease and pre-eclampsia.
The quiescent vascular endothelium forms a tight barrier that controls the passage of plasma and cells from the bloodstream to the underlying tissues, Endothellial cells adhere to each other through junctional transmembrane proteins that are linked to specific intracelllar structural and signaling complexes. The endothelial layer can undergo a transition from the resting state to the active state wherein activation of the endothelium results in the expression of adhesion molecules. This endothelium activation is a prerequisite for initiating angtogensesis, inflammation and inflammation associated diseases,
Tie-2, a receptor-like tyrosine kinase exclusively expressed in endothelial cells that controls endothelial differentiation. Tie-2 binds and is activated by the stimulatory ligand angiopoeitin-1 (Ang-1) which promotes autophosphorylation of the Tie-2 receptor leading to a cascade of events that results in stabilization of vascular structures by promoting endothelial cell
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2016203254 18 May 2016 viability and preventing basement membrane dissolution. As such, Tie-2 activation is a method for attenuating leaking vasculature by maintaining a quiescent, intact vascular endothelium.
Tie-2 activation is inhibited by Ang-2, which exhibits Ang-1 antagonism by competitively binding fo Tie-2 and thus blocking phosphorylation of Tie-2. Elevated levels of Ang-2 have been found to be associated with infiammatoiy diseases, inter alia, sepsis, lupus, irritable bowel disease and metastatic diseases such as cancer,
During periods of high Ang-2 levels, fissures or breaks in the endothelium form which results in vascular leak syndrome. Vascular leak syndrome results in life-threatening effects such as tissue and pulmonary edema. For many disease states elevated Ang-2 levels are clear markers that a disease state or condition exists. Once a disease state has been resolved, the Angl/Ang-2 balance returns and the vascular endothelium is stabilized.
Amplification of Tie-2 Signaling
In conditions wherein the normal balance between Ang-1 and Ang-2 has been disrupted, the disclosed compounds have been found to amplify Tie-2 signaling by inhibiting dephosphorylation of phosphorylated Tie-2 via inhibition of Human Protein Tyrosine Phosphatase-β (ΗΡΤΡ-β). In addition, the disclosed compounds can be used in varying amounts to increase the Tie-2 signaling in a very controlled manner, and to therefore titrate the level of Tie-2 amplification,
IL-2 Induced Vascular Leak: Treatment of Metastatic Cancers
Immunotherapy is one method of treating cancer. Up-regulation of the body’s own immune system is one aspect of immunotherapy. Among the many immune system signaling molecules is interleukin-2 (IL-2) which is instrumental in the body’s natural response fo microbial infection and in discriminating between foreign (non-self) and self. High-dose interleukin-2 (HDIL-2) is an FDA approved treatment for patients with metastatic renal cell carcinoma (RCC) and metastatic melanoma. Although it has been reported that only 23% of those subjects given this therapy show a tumor response, the duration of this response can exceed 10 years (Elias L. et al., “ A literature analysis of prognostic factors for response and quality of response of patients with renal cell carcinoma to interleukin-2-based therapy.” Oncology (2001); 61: pp. 91-101). As such, IL-2 therapy is the only available treatment that offers the potential for cure.
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Gallagher (Gallagher, D.C. et al.f “Angiopoietin 2 Is a Potential Mediator of High-Dose Interleukin 2-Induced Vascular Leak” Clin Cancer Res (2007):13(7) 2115-2120) reports that elevated levels of angiopoietin-2 are found in patients treated with high doses of IL-2 and suggests that overcoming Ang-2 blockade of Tie-2 signaling might be curative for vascular leak syndrome which is a side effect of this therapy. As many as 65% of patients receiving this IL-2 therapy will necessarily interrupt or discontinue treatment due to VLS. VLS is typicallycharacterized by 2 or more of the following 3 symptoms (hypotension, edema, hypoalfaummemia), although other manifestations include prerenal azotemia, metabolic acidosis, pleural effusions, and non-cardiogenic pulmonary edema.
IL-2 is known to cause endothelial cell activation, however, with loss of proper barrier function. Amplification of Tic-2 signaling during High Dose IL-2 immunotherapy would lead to attenuation of vascular leakage since Tie-2 stimulation promotes endothelial cell stability. As such, by administering an agent that can amplify Tie-2 signaling, vascular stability can be increased and, hence, the side effects of high IL-2 dosing mitigated. The disclosed compounds can amplify Tie-2 signaling under the conditions of low angiopoietin-1 concentrations or when high concentrations of angiopoietin-2 are present as in IL-2 treated patients.
By amplifying Tie-2 signaling without affecting Ang-2 levels, the use of elevated levels of Ang-2 as a potential pathology marker is retained. For example, a patient suffering from an inflammatory disease such as sepsis will normally have an elevated Ang-2 level that acts to suppress Ang~l stimulation of Tie-2. This elevated Ang-2 results in edema which is a symptom of vascular leakage. The present methods, by amplifying Tie-2 signaling without affecting the Ang-2 level, provide a method for alleviating the symptoms that are associated with vascular leak while retaining the ability to use Ang-2 levels as a measure of disease progress and resolution.
Reduction of Vascular Leak Caused by an Anticancer Therapy
The following demonstrates the effectiveness of the disclosed compounds on Tie-2 signal amplification, and thus, the alleviation of vascular leakage due to administration of high doses of an anticancer treatment that induces vascular leak syndrome, i.e., IL-2.
Twenty-five mice were used for the following experiment. Five are selected as the control and received no treatment. The remaining twenty mice were divided into four groups of five mice each and dosed as follows over a period of 5 days:
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Low dose of IL-2 was at 180,000 units per day
High dose of IL-2 was at 400,000 units per day
Tie-2 signal amplifier at 40 mg/kg for the first 2 days, then at 20 mg/kg for 3 days.
The animals were monitored for symptoms related to vascular leak syndrome seen in patients treated with high doses of IL-2, inter alia, blood pressure (hyportension/shock), viability (death), lung histology (VSL pathology) and serum cytokine etc, (VSL mechanistic analysis.
The disclosed compound, 4-{(5)-2-[(5)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsuifamic acid, D91, having the formula:
Figure AU2016203254B2_D0320
was used as the Tie-2 signal amplifier. As depicted in Figure 1 the blood pressure of the animals treated with a high dose of IL-2 went to 0 mm Hg (death), whereas the animals treated with4-{(S)-2-[(5)-2-(methoxycarbonylamino)-3-phenyl-propanamido)-2-(2-(thiophen.-2yl)thiazoi-4-yl]ethyI}phenylsuifamic acid ammonium salt showed little effect on blood pressure even in the case of those animals treated with the high dose of IL-2.
As depicted in Figure 2, of the animals receiving high doses of IL-2, 60% showed clinical symptoms of shock, whereas the animals receiving high doses of IL-2 and the Tie-2 signal amplifier 4-{(S)-2-[(iS)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2~ (thiophen-2-yl)thiazol-4-yl]ethyl)phenylsulfamic acid ammonium salt showed no signs of shock.
As depicted in Figure 3, of the animals receiving high doses of IL-2, 40% died, whereas the animals receiving high doses of IL-2 and the Tie-2 signal amplifier 4-((5)-2-((5)-2(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4yl]ethyl}phenylsulfamic acid ammonium salt survived.
Figure 4 depicts a summary of the status of the animals treated with high doses of IL-2, those treated with high doses of IL-2 and the Tie-2 signal amplifier 4-{(5)-2-((5)-2-(methoxycarbonylamino)~3-phenyl-propanamido3-2-[2-(thiophen-2-yl)thiazol~4~yl]ethyi}phenylsulfamic acid ammonium salt versus control.
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The disclosed compounds can act as Tie-2 signaling amplifiers and, therefore can be used as an effective therapy to reduce vascular leak. The disclosed compounds can be coadministered with IL-2 or administered separately. As such, the IL-2 and Tie-2 signal amplifier can be administered in any order and by any method, for example, intravenously, orally, by patch, subcutaneous injection, and the like.
Disclosed herein is a method for treating renal cell carcinoma by administering to a patient in need of treatment a therapy that comprises:
a) an effective amount of interleukin-2 such that an immune response is provided; and
b) an effective amount of one or more of the disclosed compounds;
wherein the interleukin-2 and the disclosed compounds can. be administered together or in any order.
As such, disclosed herein is a method for treating renal cell carcinoma by contacting a patient with a composition comprising:
a) a high dose of interleukin-2; and
b) an effective amount of one or more of the compounds disclosed herein.
Disclosed herein is a method for treating metastatic melanoma by contacting a patient with a composition comprising:
a) a high dose of interleukin-2; and
b) an effective amount of one or more of the compounds disclosed herein.
Further disclosed is a method for treating metastatic melanoma by contacting a patient with a series of compositions, wherein the compositions can be administered in any order and at any effective amount, a first composition comprising, a high dose of interleukin-2 and the second composition comprising an effective amount of one or more of the disclosed compounds.
Still further disclosed is a method for treating renal cell carcinoma by contacting a patient with a series of compositions, wherein the compositions can be administered in any order and at any effective amount, a first composition comprising a high dose of interleukin-2 and the second composition comprising an effective amount of one or more of the disclosed compounds.
Disclosed herein is a method for treating metastatic melanoma by administering to a patient in need of treatment a therapy that comprises:
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a) an effective amount of interleukin-2 such that an immune response is provided; and
b) an effective amount of one or more of the disclosed compounds;
wherein the interleukin-2 and the one or more disclosed compounds can be administered together or in any order.
Also disclosed herein is a method for treating metastatic melanoma by administering to a patient in need of treatment a therapy that comprises:
a) an effective amount of interieukin-2 such that an immune response is provided; and
b) an effective amount of one or more of the disclosed compounds;
wherein the inter leukin-2 and the one or more disclosed compounds can be administered together or in any order.
Tumor growth is often a multi-step process that starts with the loss of control of cell proliferation. The cancerous cell then begins to divide rapidly, resulting in a microscopically small, spheroid tumor: an in situ carcinoma. As the tumor mass grows, the cells will find themselves further and further away from the nearest capillary. Finally the tumor stops growing and reaches a steady state, in which the number of proliferating cells counterbalances the number of dying cells. The restriction in size is caused by the lack of nutrients and oxygen. In tissues, the oxygen diffusion limit corresponds to a distance of 100 pm between the capillary and the cells, which is in the range of 3-5 lines of cells around a single vessel. In situ carcinomas may remain dormant and undetected for many years and metastases are rarely associated with these small (2 to 3 mm2), avascular tumors.
When a tumor’s growth is stopped due to a lack of nutrients and/or oxygen, this reduction In tumor vasculature also limits the ability of anti-tumor drugs to be delivered to the malignant cells. Moreover, if there is a slight increase in tumor vasculature, this will allow delivery of antitumor therapies to the malignant cells without initiating metastasis. As such, the disclosed compounds when used to slightly amplify Tie-2 signaling can be used to increase blood flow to the tumor cells without setting off metastasis or uncontrolled tumor cell proliferation while providing a method for delivering anti-cancer drugs to malignant cells.
Disclosed herein is a method for treating cancer comprising, administering to a patient in need an amount of one or more of the disclosed compounds that amplify' Tie-2 signaling in
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2016203254 18 May 2016 conjunction with a chemotherapeutic compound or immunotherapeutic compound. By “chemotherapeutic compound” is meant any composition which comprises one or more compounds that can be administered to a patient for the purposes of attenuating or eliminating the presence of tumor cells. By “slightly amplify Tie-2 signaling” is meant that a sufficient amount of a disclosed compound is administered to a patient such that the amount of tumor cell vasculature is increased such that the increased circulation allows for delivery of the anti-tumor compound or therapy without instigating tumor growth wherein the rate of tumor cell growth is less than the rate of tumor cell death.
Disclosed herein is a method for treating a cancer wherein the cancer is medulloblastoma, ependymoma, ogliodendroglioma, pilocytic asrocytoma, diffuse astrocytoma, anaplasic astrocytoma, or glioblastoma. Further disclosed is a method for treating a tumor or invasive cancer chosen from medulloblastoma, ependymoma, ogliodendroglioma, pilocytic asrocytoma, diffuse astrocytoma, anaplasic astrocytoma, or glioblastoma wherein an effective amount of one or more disclosed Tie-2 signal amplifiers is administered to a subject. In addition, the method can comprise monitoring the Ang-2 level of the subject while the subject is undergoing treatment,
Angiopoietin-2 is significantly correlated to Gleason Score, metastases, and to cancer specific survival (Lind AJ. et a!., “Angiopoietin-2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer” Prostate (2005) 62:394-299), Angiopoietin-2 was found to be expressed in prostate cancer bone, liver and lymph node metastases, but with little to no angiopoietin-1 expression in prostate cancer tumor cells in bone, liver, and lymph nodes (Morrissey C. et al. “Differential expression, of angiogenesis associated genes in prostate cancer bone, live and lymph node metastases” Clin. Exp Metastasis (2008) 25:377-388). As such, monitoring the level of Ang-2 provides a method for evaluating the presence of prostate cancer and the spread of prostate cancer cells throughout the body due to vascular leakage.
Vasculature Stabilization in Diseases Caused by Pathogens
Disclosed herein is a method for treating vascular leak syndrome caused by one or more pathogens, comprising administering to a human or other mammal in need of treatment an effective amount of one or more of the disclosed compounds.
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Also disclosed herein is a method for treating vascular leak syndrome caused by one or more pathogens, comprising administering to a human or other mammal in need of treatment a composition comprising:
a) an effective amount of one or more compounds effective against a pathogen present in the human or mammal; and
b) an effective amount of one or more of the disclosed compounds;
wherein the of one or more compounds effective against a pathogen and the one or more of the disclosed compounds can be administered together or in any order.
Further disclosed herein is a method for preventing vascular leak syndrome in a human, or other mammal diagnosed with an pathogen that can produce vascular leak syndrome in a human or mammal, comprising administering to a human or mammal a composition comprising:
a) an effective amount of one or more compounds effective against a pathogen present in the human or mammal; and
b) an effective amount of one or more of the disclosed compounds;
wherein the of one or more compounds effective against a pathogen and the one or more of the disclosed compounds can be administered together or in any order.
Increased amplification of Tie-2 signaling using the disclosed compounds provides a method for stabilizing vasculature without the need to affect Ang-1 and/or Ang-2 levels. Disclosed herein are methods for stabilizing vasculature, comprising administering to a patient in need an effective amount of one or more of the disclosed Tie-2 amplifiers.
Because the disclosed compounds can amplify Tie-2 signaling without increasing the amount of Ang-2, monitoring the amount of Ang-2 in blood serum of a subject while administering to a subject one or more of the disclosed compounds, serves as a method for determining the course of various illnesses or disease states associated with vascular leak syndrome, for example, sepsis as a result of infection. As such, disclosed is a method for stabilizing vasculature in a patient suffering from an inflammatory disease wherein the level of angiopoietin-2 is elevated, comprising:
a) administering to a subject an effective amount of one or more of the disclosed compounds as a treatment;
b) monitoring the level of angiopoietin-2 present in the subject; and
c) discontinuing treatment when the angiopoietin-2 level returns to a normal range.
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What is meant herein by “normal angiopoietin-2 level” is an amount of Ang-2 in blood serum of from about I ng/mL io about 2 ng/mL. Alternatively, the level of Ang-2 can be determined for an individual suffering from a disease state, for example, severe sepsis and the level of Ang-2 can be monitored until the amount of Ang~2 in the subject’s serum drop to a level that is nearer the normal range. In this case, the co-administration of a drug can be continued or discontinued. Therefore, disclosed herein, is a method for stabilizing the vasculature of a subject during a course of treatment, comprising:
a) co-administering to a subject an effective amount of one or more of the disclosed compounds and one or more drugs as a treatment;
b) monitoring the level of angiopoietin-2 present in the subject; and
c) discontinuing the administration of the one or more drugs and selecting one or more other drags for use as a treatment if the level of serum angiopoetin-2 does not decrease.
The disclosed compounds, while stabilizing the vasculature of a patient such that a course of treatment against a pathogen can be sustained, can also be used to stabilize a subject during a period wherein an effective treatment against a pathogen is being determined. That is, the disclosed compounds by themselves can have a beneficial effect on the outcome of diseases caused by pathogens by reducing vascular leak and its complications,
Liposacehnride Induced Vascular Leak Model
The following liposaccharide induced vascular leakage model can be used to confirm the ability of the disclosed compounds to decrease the effects of vascular leak syndrome caused by pathogens. In the following example acute kidney injury (AKI) was studied to show the effect of D91 as a successful strategy that can preserve renal endothelial Tie2 phosphorylation in septic AKI.
Acute kidney injury is a frequent and serious problem in hospitalized patients, and is frequently a consequence of sepsis. The renal endothelium plays a key role in sepsis induced AKI. Activated Tie2, expressed mainly in endothelial cell surfaces, has many effects which are expected to be protective in sepsis-induced AKI, such as downregulation of adhesion molecule expression, inhibition of apoptosis, preservation of barrier function, and angiogenesis.
Male C57BL6 mice, 9 to 10 weeks old, were injected i.p. with 0.2 mg E, Coii lipopolysaccharide per 25 g body weight at time 0. Mice were injected with D91 at 50 mg/kg, 50
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2016203254 18 May 2016 μΕ versus vehicle (50 μΕ) at the time 0, 8, and 16 hours.. Mice were sacrificed at 24 hours after
LPS injection. Vehicle control (saline) injected mice were studied in parallel as controls. Serum samples were analyzed for blood urea nitrogen (BUN) as a marker of kidney function.
As shown in Figure 7, the level of blood urine nitrogen (BUN) in the animals receiving only LPS (ri) was approximately 150 mg/dL at 24 hours, whereas animals treated with 50 mg/kg of D91(«) had a blood urine nitrogen level of less than 80 mg/dL. These data show that D91is capable of protecting mice against AKI in this model.
Tissue samples from the animals were analyzed by high powered field microscopy to determine the number of polymorphonuclear leukocytes present. As shown in Figure 8, the number of PMN cells present in the LPS/vehicle animals was on average 26 whereas the number of PMN cells present in animals receiving D91 was on average 12. As such, this model demonstrates the effectiveness of D91 in preventing acute kidney injury due to pathogens, i.e., E. coli.
Phosphatase inhibition by the disclosed ΡΤΡ-β inhibitors reduces LPS-induced renal vascular leak. Mice were injected with LPS at time 0 and D91 or vehicle at 1,6, and 16h. Two minutes prior to sacrifice at 24 hours 70kDa. fluorescent fixable dextrans were administered by intravenous catheter. Frozen sections showed extrusion of dye beyond the small peritubular capillaries was induced by LPS, but is reduced by D91. Figure 10a is a micrograph of the control sample for the 70 kDa sample wherein the Letter “G” represents glomerular capillaries where the dye should normally be contained. Figure 10b represents a renal section taken from an LPS treated animal and Figure 10c represents a renal section taken from an animal treated with LPS and D91.
The following are non-limiting examples of virsus, bacteria, and other pathogens where virulence can be controlled by mitigating the degree of vascular leak that is induced by the organism. The following describe tests and assays that can be used to determine the effectiveness of the disclosed compounds, either alone, or a combination therapy,
ANTHRAX
Anthrax, the disease caused by Bacillus anthracis, was once a disease commonly spread among animals, but there is now a concern that this disease will be used as a part of bioterrorism. Inhalation anthrax is a deadly disease for which there is currently no effective treatment.
Anthrax toxin, a major virulence factor of this organism, consists of three polypeptides:
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2016203254 18 May 2016 protective antigen (PA), lethal factor (LF), and edema factor (EF). PA is required for binding and translocation of EF and LF into target cells (Collier R, J, el al., (2003) Anthrax toxin, Arant. Rev. Cell Dev. Biol. 19:45-70). As such, lethal factor metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. The injection of lethal toxin (LT is LF plus PA) into animals is sufficient to induce some symptoms of anthrax infection, including pleural effusions indicative of vascular leak and lethality (Beall F. A. el al. (1966) The pathogenesis of the lethal effect of anthrax toxin in the rat. J. Infect. Dis.
116:377-389; Beall F. A. etal., (1962) Rapid lethal effect in rats of a third component found upon fractionating the toxin of Bacillus anthracis. J. Bact&riol. 83:1274-1280; Cui X. et al., (2004) Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am. J, Physiol, Regul. Integr. Comp. Physiol. 286:R699-R709; Fish D. C, etal., (1968) Pathophysiological changes in the rat associated with anthrax toxin, J. Infect, Dis. 118:114-124; Klein F. et al., (1962) Anthrax toxin: causative agent in the death of rhesus monkeys. Science 138:1331-1333; Klein, F. el al., (1966) Pathophysiology of anthrax.,/. Infect. Dis. 116:123-138; and Moayeri M. et al,, (2003) Bacillus anthracis lethal toxin induces TNF-α-independent hypoxia-mediated toxicity in mice. J. Clin. Investig. 02:670-682), Early studies of anthrax suggested that lethal toxin kills animals by inducing nonspecific shock-like manifestations, and recent studies with mice and rats have confirmed an LT-mediated cytokine-independent vascular collapse. It has been reported that humans and primates exposed to spores via aerosol, present pleural effusions as the most common symptom of disease. Histopathological analyses of human subjects with inhalational anthrax infections display hemorrhaging in various organs resulting from destruction of both large and small vessels. Clearly, LT is an important virulence factor and contributes to some but not all the pathology observed with spore infection.
Recently, LT-mediated endothelial cell killing has been proposed to contribute to the vascular pathology observed during the course of anthrax (Kirby, J. E, (2004) Anthrax lethal toxin induces human endothelial ceil apoptosis, Infect, hnmim. 72:430-439). Since this LTinduced endothelial cytotoxicity occurs gradually (over 72 hours) and death from LT-mediated vascular collapse can occur in as little as 45 min (Ezzell J. W, et al., (1984)
Immunoelectrophoretlc analysis, toxicity, and kinetics of in vitro production of the protective
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2016203254 18 May 2016 antigen and lethal factor components of Bacillus anthracis toxin. Infect. Immun. 45:761-767), there is a need for a method for preventing increased vascular leakage due to anthrax lethal toxin.
In Vivo Vascular Leak
The Miles assay (Mites, A. A., and E. M, Mites (1952) Vascular reactions to histamine, histamine-liberator and leukotaxine in the skin of guinea-pigs. J. Physiol. 118:228-257 incorporated herein by reference in its entirety) can be used to directly investigate and quantify lethal toxin, as well as edema toxin (ET [PA plus EF])-mediated vascular leakage in the mouse model. The following is a modified Miles assay as described by Gozes Y, et al., Anthrax Lethal Toxin Induces Ketotifen-Sensitive Intradermal Vascular Leakage in Certain Inbred Mice Infect Immun. 2006 February; 74(2): 1266-1272 incorporated herein by reference in its entirety, that can be used to evaluate the disclosed compounds for their ability to prevent vascular leakage in humans and animals exposed to anthrax.
Highly pure PA, LF, and mutant LF E687C are purified as previously described (Varughese M, et aL, (1998) Internalization of a Bacillus anthracis protective antigen-c~Myc fusion protein mediated by cell surface anti-c-Myc antibodies. Mol. Med. 4:87-95 Included herein by reference in its entirety). Doses of ET or LT refer to the amount of each component (i.e,, 100 pg LT is 100 pg PA plus 100 pg of LF). All drugs except for azelastine can be purchased from Sigma Aldrich (St. Louis, MO); azelastine can be purchased from LKT Laboratories (St. Paul, MN),
Animals.
BALB/cJ, DBA/2J, C3H/HeJ, C3H/HeOuJ, WBB6Fl/J-Kit%Kh?</;'; and colony-matched wild-type homozygous control mice can be purchased from The Jackson Laboratory (Bar Harbor, ME). BALB/c nude, C57BL/6J nude, and C3H hairless (Ci .Qg/TifBomTac~hf) mice can be purchased from Laconic Farms (Germantown, NY). C3H nude mice can be purchased from The National Cancer Institute Animal Production Area (Frederick, MD). Mice are used when they are 8 to 12 weeks old. Except for C3H hairless and nude animals, all mice are shaved 24 hours prior to intradermal (i.d.) injections. In order to assess the susceptibility to systemic LT. mice are injected intraperitoneally (i.p.) with 100 pg LT and observed over 5 days for signs of malaise or death. Fischer 344 rats can be purchased from Taconic Farms (Germantown, NY) and used at weights of 150 to 180 g. Rats are injected intravenously (i.v.) in the tail vein with 12
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2016203254 18 May 2016 pg LT, with or without 250 gg of the mast cell stabilizer drug ketotifen and monitored for the exact time fo death.
Miles Assay.
'The Miles assay uses i.v. injection of Evans blue dye (which binds to endogenous serum albumin) as a tracer to assay macromolecular leakage from peripheral vessels after i.d. injection of test substances. Nude mice and normal shaved mice are injected i.v, with 200 μΐ of 0.1% Evans blue dye (Sigma Chemical Co., St. Louis, MO). After 10 min, 30 μΐ of test toxin or control samples (PA only, LF only, EF only, or phosphate-buffered saline) are injected i.d. in both left and right flanks, as well as at single or dual dorsal sites. To quantify the extents of leakage, equally sized (1.0- to 1.5-cm diameter) skin regions surrounding i.d. injection sites are removed 60 min after injection and placed in formamide (1 ml) at 4FC for 48 h, allowing for dye extraction. The of samples is read, and the extent of leakage is calculated by comparison with phosphate-buffered saline-, PA-, or LF-treated controls.
In experiments wherein the effectiveness of the disclosed compounds are tested for LTmediated leakage, mice are injected i.v. with Evans blue as described above, and the test compound introduced systemically through i.p. injection 10 min after dye injection, LT was introduced by i.d. injection 30 min after the injection of Evans blue. In another embodiment, the compound to be tested can be introduced locally by i.d. injection and LT injected in the same site after 10 min.
Cytotoxicity eExperiments.
MC/9 mast cells can be obtained from ATCC (Manassas, VA) and grown In Dulbecco’s modified Eagle's medium supplemented with 1-glutamine (2 mM), 2-mercaptoethanol (0.05 mM), Rat T-STIM (BD Biosciences-Discovery Labware, Bedford, MA) (10%), and fetal bovine serum (FBS, 10% final concentration; Invitrogen-GIBCO BRL, Gaithersburg, MD). Cells are then seeded at a density of lQ4/weil in 96-weIl plates prior fo treatment with various LT concentrations or PA-only controls. After 6, 12, and 24 hours, viability is assessed using Promega's CellTiter 96 AQueous One Solution cell proliferation assay (Promega, Madison, Wl) per the manufacturer's protocol. Alternatively, toxicity assays can be performed in medium provided with all supplements except FBS (serum-free medium). In other embodiments, pooled human umbilical vein endothelial cells (HUVECs) at third to fifth passage can be obtained from Cambrex Corp, (Cambrex, Walkersville, MD) and grown in an EGM-MV Bulletkit (Cambrex,
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Walkersville, MD) in flasks pretreated with endothelial cell attachment factor (Sigma, St. Louis, MO). For cytotoxicity experiments, cells are typically seeded in 96-well plates in an EGM-MV Bulletkit. On the day of assays, this medium is then replaced with Ml 99 medium (Sigma, St. Louis, MO) supplemented with 10% FBS or human serum (Sigma, St. Louis, MO), and cells are reseeded in 96-well plates at a density of 2 χ 1,070.1 ml/well and treated with various concentrations of LT in triplicate. Cell viability is typically assessed as for MG9 cells at 24, 48, and 72 hour time points.
HUVEC Permeability Assay
HUVEC monolayers can be effectively cultured on Transwell-Clear cell culture inserts (6.5-mm diameter, 0.4~pm pore size; Corning-Costar, Acton, MA) in 24-weli plates, creating a two-chamber culturing system consisting of a luminal compartment (inside the insert) and a subluminal compartment (the tissue culture plate well). Prior to seeding cells, the inserts are coated with endothelial cell attachment factor (Sigma, St. Louis, MO). Prewarmed CS-C medium (Sigma, St. Louis, MO) containing 10% iron-supplemented calf serum and 1% endothelial cell growth factor (Sigma, St. Louis, MO) is added to wells prior to insert placement. A HUVEC cell suspension (200 pL of 5 A·. 10s cells/ml) is then added to each insert. Ceils are cultured at 37 *C in 5% CO;, for up to 21 days to ensure proper formation of a monolayer. For testing barrier function, medium can be changed to RPMI supplemented with 10% FBS or to RPMI without serum. To assess barrier function, horseradish peroxidase enzyme (Sigma, St. Louis, MO) is added to the inserts (10 pg/well). LT (1 gg/mL) or control treatments of PA alone (1 pg/mL) or LF alone (1 pg/mL) are added to duplicate wells, and every hour (for 12 hours), a sample of 10 pL was taken from the subtuminal compartment and tested for the enzymatic activity of horseradish peroxidase by adding 100 pL substrate [2',2'-azino-bis(3-ethylbenzthizoHn 6sulfonic acid)] (A-3219; Sigma, St. Louis, MO) and reading at 405 nm.
Anthrax Combination Therapy
Increased stabilization of vascular tissue c an increase the effectiveness of known antimicrobials against anthrax infection. As such, the disclosed compounds can be evaluated as a combination therapy for the treatment of anthrax. The following describes a series of assays that can be used to determine the effectiveness of the disclosed compounds as one part of a combination therapy useful for treating anthrax infections.
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LF has been found to cleave mitogen-activated protein kinase kinases (MAPKK), disrupts signal transduction, and leads to macrophage lysis. As such, in addition to the Miles
Assay, the following cell-based and peptide cleavage assay can be used to confirm the potency of the disclosed compounds to inhibit the effect of LT activity. For the following assay,
MAPKKide can be purchased from List Biological Laboratories (Campbell, CA. Fluorinated peptide substrate is available from Anaspec (San Jose, CA).
In Vivo Assays
One week before beginning an evaluation of a combination course of treatment for anthrax, test compounds (200 mg each) are dissolved in 800 pL of DMSO and stored at -20 °C. Immediately before injection, each compound is diluted in PBS, resulting in a final concentration of 0.5 rtig/mL in 2% DMSO. Test animal are challenged on day 0 with 2x10' spores per mouse in PBS through i.p. injection. Treatment was started 24 hours after challenge. One example of a suitable treatment regiment is the combination of ciprofloxacin (50 mg/kg) and one or more of the disclosed compounds (5 mg/kg), A control sample of untreated animals, ciprofloxacin alone, a disclosed compound alone, and ciprofloxacin in combination with a disclosed compound are given to the animals and they are monitored twice per day until day 14 after injection.
Ciprofloxacin and the compound to be tested can be conveniently administered through parenteral injection with a volume of 200 gL for each once per day for 10 days. All surviving animals are sacrificed on day 14. Sick animals that appear moribund (i.e., exhibiting a severely reduced or absent activity or locomotion level, an unresponsiveness to external stimuli, or an inability to obtain readily available food or water, along with any of the following accompanying signs: ruffled haircoat, hunched posture, inability to maintain normal body temperature, signs of hypothermia, respiratory distress, or other severely debilitating condition) should be sacrifice on the same day these symptoms are manifested.
Modulation of Bacterium-Induced Vascular Leak
Pathogenic bacteria are known to cause vascular leak. This induced vascular leakage inhibits the ability of antimicrobials and other pharmaceuticals from targeting the invading microorganism. As such, the disclosed compounds can be used alone or in combination with other pharmaceutical ingredients to boost the host immune system by preventing excess vascular leakage that occurs as a result of a bacterial infection.
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Staphylococcus aureus is a major pathogen of gram-positive septic shock and is associated with consumption of plasma kininogen. The effect of the disclosed compounds on S'.
aureus induced vascular leakage activity can be determined by measuring the activity of these compounds with respect to two cysteine proteinases that are secreted by S. aureus.
Proteolytically active staphopain A (ScpA) induces vascular leakage in a bradykinin (BK) B2receptor-dependent manner in guinea pig skin. This effect is augmented by staphopain B (SspB), which, by itself, had no vascular leakage activity. ScpA also produces vascular leakage activity from human plasma.
An important pathophysiologic mechanism of septic shock is hypovolemic hypotension that is caused by plasma leakage into the extravascular space. It has been found that ScpA induced vascular leakage at a concentration as low as 20 nM within 5 minute after in jection, into the guinea pig skin—-with the reaction being augmented by coexisting SspB indicating that vascular leakage induction by these proteinases occurs efficiently in vivo (Imamura T. et al., Induction of vascular leakage through release of bradykinin and a novel kinin by cysteine proteinases from Staphylococcus aureus (2005) J. Experimental Medicine 201:10, 1669-1676).
Staphopains also can act on LK--whose plasma molar concentration has been found to be threefold greater than HK—they also have more opportunity to interactwith substrate than proteinases that generate BK only from HK. Taken together, these results indicate that vascular leakage induction by staphopains is a mechanism of septic shock induction in severe S. aureus infection that provides an assay for determining the effectiveness of compounds to modulate vascular leakage.
Vascular Leakage Assay,
Animals can be evaluated for vascular leakage using the following procedure, 100 pL of a 1% solution of Evans blue dye (Sigma Aldrich) in saline is injected into the tail vein. Thirty minutes later, mice are sacrificed and perfused with saline via the right ventricle to remove intravascular Evans blue. Lungs are excised and extracted in 1 mL of formamide at 55 °C overnight. Evans blue content is determined as ODea minus ODjoo of the fonnamide extract. INFLUENZA
During the years following World War I, it is estimated that more that 50 million people were killed by a world-wide influenza pandemic. Recently, the spread of highly pathogenic avian influenza A (H5N1) viruses from Asia also poses a threat of becoming another influenza
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2016203254 18 May 2016 pandemic. If is thought that highly pathogenic (HP) influenza strains stimulate a stronger immune response than seasonal strains, causing severe vascular leakage and lung edema, and eventual death, A study of mouse immune cell responses following exposure to mouse-adapted influenza viruses that mimic either a seasonal flu or a HP flu strain (Aldridge J.R. et al., ( 2009). TNF/tNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection, Proc Nail Acad Sci USA 106: 5306- 5311),
The compounds disclosed herein can be used as a single pharmaceutical therapy to prevent the severity of influenza by mediating the effects of vascular leak caused by viruses, and hence, allowing the body’s own immune system to affect greater resistance to these pathogens. The following assays can be used to determine the effect of the disclosed compounds to inhibit viral severity because of improved vascular integrity.
The disclosed assays can utilize inhibition of viral plaques, viral cytopathic effect (CPE), and viral hemagglutitin.
Proteolytic Sensitivity Assay
The disclosed compounds can be determined to bind to hemagglutinin and thereby destabilize the protein assembly. The following procedure can be used to determine the increase in destabilization and therefore the increased sensitivity of hemagglutinin to proteolytic attack caused by the disclosed compounds, At the fusion conformation, HA becomes more sensitive to protease digestion. This property can be used to verify if a fusion inhibitor interacts with HA (Luo G. et al. “Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus.” J Virol (1997); 71(5):4062-70). Thus, the disclosed compounds, due to the control of vascular leakage, can be evaluated for their ability to indirectly effect HA digestion by enhancing the body’s immune response.
The purified trimer of hemagglutinin ectodomain is incubated with the compound to be tested at a concentration of 5 μΜ. The irimers are subjected to trypsin digestion at pH 7,0 and pH 5.0 with controls of untreated HA and HA treated with DMSO which is the solvent used to dissolve the test compound. For the pH 5.0 sample, the HA trimers are treated with a pH 5.0 buffer for 15 minutes and neutralized to pH 7.0. Trypsin (20 ng) is added to the sample in 10 gland the digestion allowed to proceed for 1 hour at 37 °C, The amount of HA present is assessed by a western blot gel electrophoresis using anti-HA (H3) antisera. Samples containing effective inhibitors will provide an increase in digestion of HA by trypsin.
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In addition, combination therapies can provide a method for treating influenza by providing an antiviral medication together with a compound that prevents the severity of vascular leakage due to influenza viruses.
An antiviral compound, for example, oseltamivir, can be used for an in vivo evaluation of the disclosed combination therapy and to evaluate the effectiveness of the disclosed compounds. The drag combination is administered in a single dose to mice infected with the influenza A/NWS/ (HIN1) virus, In some instances, infection of the animals will include multiple passage of the virus through their lungs. One convenient protocol involves administering 20 mg/kg per day twice daily for 5 days beginning 4 hours prior to virus exposure. The animals are then challenged with different concentrations of virus, ranging 10-fold from 10'2 ¢105,75 cell culture 50 % infectious doses (CCID50) per mL). Four mice in each group are sacrificed on day 6 and their lungs removed, assigned a consolidation score ranging from 0 (normal) to 4 (maximal plum coloration), weighted, homogenized, the homogenates centrifuged at 2000 x g for 10 minutes, and varying 10-fold dilutions of the supemata assayed for vims titer in MDCK cells using CPE produced after a 96-bour incubation at 37 ”C as endpoint.
The serum taken from mice on day 6 is assayed for a·.-AG using single radial immunodiffusion kites. Eight additional mice in each group are continually observed daily for death for 21 days, and their arterial oxygen saturation (SaOj) values determined by pulse oximetery (Sidwell R. et al., (1992) Utilization of pulse oximetry for the study of the inhibitory effects of antiviral agents on influenza virus in mice. Antimicrob. Agents Chemother. 36,473476) on day 3, when SaO:, decline usually begins to occur, through day 11, when the values are seen to decline to the maximum degree of the animals otherwise die.
Vasogenic Edema adult male Sprague-Dawley rats purchased from Charles River, Germany and weighing 250-330 g were used for the experiment. Animals were housed at a standard temperature (22 ± PC) and in a light-controlled environment (lights on from 7 am to 8 pm) with ad libitum access to food and water.
Animals were grouped as follows:
Group A: 15 rats treated with Vehicle (2 mL/kg, t.i.d., s.c.) starting 1 hour after stroke onset Group B: 15 rats treated with AKB-9778-AS (15 mg/kg, t.i.d., s.c.) stalling 1 hour after stroke onset
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2016203254 18 May 2016 tMCAO
Transient focal cerebral ischemia was produced by MCA occlusion in male SpragueDawley rats according to Koizumi with modifications (Koizumi et al, Jprt. J. Stroke 8:1-8,
1986), The rats were anesthetized with isoflurane in 70% N?O and 30% Cb; flow 300 mL/min. 2-3 min anesthesia induction with 5% isoflurane after which 1-2% isoflurane. The rectal temperature was maintained above 36.0 “C with a homeothermic blanket system. After a midlinc skin incision, the right common carotid artery (CCA) was exposed, and the external carotid artery (EGA) was ligated distal from the carotid bifurcation, A 0.25-mm diameter monofilament nylon thread, with tip blunted, was inserted 22-23 mm into the internal carotid artery (ICA) up to the origin of MCA. The wound was temporarily closed and the rats were allowed to recover. After 60 min of ischemia, the rats were re-anesthetized and MCA blood flow was restored by removal of the thread. The wounds were dosed, disinfected, and the animals were allowed to recover from anesthesia. The rats were carefully monitored for possible post-surgical complications after the tMCAO. The rats were fed with standard laboratory diet suspended in tap water.
D91 or vehicle was administered s.c. three times a day. Treatment was given 1,8, 16, 23, 32, 40 and 47 h after the onset of occlusion. Administration volume was 2 ml/kg and the vehicle is sterile saline. The body weight of each animal is measured daily.
MRJ at 24 and 48 hours: Absolute T2 and Spin Density for Vasogenic Edema and Infarct Volume
T2-MRI was performed at 24 and 48 hours post-ischemia in a horizontal 7T magnet with bore size 160 mm (Magnex Scientific Ltd., Oxford, UK) equipped with Magnex gradient set (max. gradient strength 400 mT/m, bore 100 mm) interfaced to a Varian DirectDrive console (Varian, Inc.. Palo Alio, CA) using a volume coil for transmission and surface phased array coil for receiving (Rapid Biomedical GmbH, Rimpar, Germany). Isoflurane -anesthetized (1% in 30/70 O2/N2) rats were fixed to a head holder and positioned in the magnet bore in a standard orientation relative to gradient coils. All MRI data were analyzed using ίη-house written Matlab software. Region of interest analysis was performed for ipsilateral hemisphere, lesion core and perifocal area. Values from contralateral hemisphere were used as a reference.
Tissue viability and vasogenic edema was determined using absolute T2 MRI, Multi-echo multi-slice sequence was used with following parameters; TR - 3 s, 6 different echo times (12,
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24, 36, 48, 60, 72 ms) and 4 averages. Seventeen (17) coronal slices of thickness 1 mm were acquired using field-of-view 30x30 mm2 and 256x128 imaging matrix (zero-filled to 256x256).
In addition to absolute T2, spin density (amount of MR! visible protons, indicator of vasogenic edema) ratio of ipsi and contralateral ROFs was determined by extrapolating signal intensity at
TE~0 from multiple TE data (intercept of T2 fitting).
For the determination of infarct volume, the same acquired T2-weighted images were analyzed using in-house written Matlab based software for morphometric measurement. The infarct volume analysis was done by an observer blinded to the treatment groups.
Dav for Cytotoxic Edema
Cytotoxic edema (and its time course) was evaluated also at 24 and 48 hours as a control measure using diffusion MRI; the data for calculation of 1/3 of the trace of the diffusion tensor (which is an orientation independent measure of apparent water difftision) were acquired using a diffusion weighted Fast Spin-Echo sequence. Following parameters were used: TR *=* 1.5 s, ETL/TEeff:::4/26 ms, b-values 0, 1000 xl0-3 s/mm2, NT® 4, Imaging resolution, slice thickness and slice positioning were kept identical to absolute T2 MR! acquisition above. 5 slices were acquired and these were selected from absolute T2 images to best correspond to the center of lesion in antero-posterior direction.
Contrast Enhanced Tl-weighted MRI for BBB Leakage
At 48 hours post-operation, Gadolinium based contrast enhanced Tl-weighted MRI was applied to detect blood-brain barrier leakage. Femoral vein was cannuialed before the rat was placed into the MRI. Contrast agent was injected as an i.v. bolus (0.5 M Gd-DTPA 0,4 ml/kg i.v. bolus). Pre- and post-contrast agent Tl-weighted images were acquired with 15 min delay to allow proper uptake of the contrast agent, MRI was performed with conventional Tl-weighted gradient echo sequence with identical imaging resolution and slice positioning and with following parameters; TR ;; 0,16 s, TE = 5 ms, 70 degree flip and NT::: 32. Subtraction images (deltaR, post-Gd minus pre-Gd) were produced to highlight and quantify BBB leakage. Gd-based contrast agents affect the T2 relaxation, thus this MRI component was performed at the very end of the MRI session.
Endpoint - Edema Evaluation
After the 48 hour MRI, the rats were decapitated, The brains were quickly removed, cut into ipsi- and contralateral hemispheres that were weighed for tissue wet weight (edema
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2016203254 18 May 2016 analysis). Edema % was calculated: [wet weight of ipsilateral hemisphere in mg /wet weight of contralateral hemisphere in mg] x 100, Thereafter the brains were fresh-frozen on dry ice for possible PK or biochemical purposes. Bbrain tissue wet weight was found significantly lower in ischemic hemisphere in D91 treated rats, suggesting that D91 reduces the brain edema after
1MCAO.
Inhibition of Protein Tyrosine Phosphatase beta in a Ceil
Disclosed herein are methods for inhibiting protein tyrosine phosphatase beta (ΡΤΡ-β) activity in a cell, comprising contacting a cell with an effective amount of one or more of the disclosed compounds. The cell can be contacted in vivo, ex vivo, or in vitro.
COMPOSITONS
Disclosed herein are compositions which can be used to treat patients with cancer, wherein the patient having cancer is treated with one or more anticancer agents that induce vascular leak syndrome in the patient. As such, disclosed herein are compositions effective in reducing vascular leak resulting from an anticancer treatment, the compositions comprising an effective amount of one or more of the disclosed compounds.
In another aspect, disclosed herein are compositions effective for treating humans or other mammals having a medical condition or disease state wherein the treatment for the medical condition or disease state induces vascular leak syndrome, the composition comprising:
a) an effective amount of one or more of the compounds disclosed herein; and
b) one or more pharmaceutical drugs;
wherein at least one of the pharmaceutical drugs induces vascular leak syndrome.
In a further aspect, disclosed herein are compositions comprising;
a) an effective amount of one or more of the compounds disclosed herein: and
b) one or more chemotherapeutic agents.
Also disclosed herein are compositions which can be used to control vascular leakage, the compositions comprising an effective amount of one or more of the compounds disclosed herein. Still further disclosed herein are compositions which can be used to treat patients with an inflammatory disease, non-limiting examples of which include sepsis, lupus, and irritable bowel disease, the compositions comprising an effective amount of one or more of the Tie-2 signaling amplifiers disclosed herein.
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Disclosed herein are compositions which can be used to treat humans or other mammals having vascular leakage due to bacterial or viral infections, the compositions comprising an effective amount of one or more of the compounds disclosed herein.
Disclosed herein are compositions comprising one or more of the disclosed compounds wherein the compositions are useful for treatment of the disclosed conditions, illness, injuries, courses of treatment, cellular treatments, and the like.
One aspect relates to a composition comprising:
a) an effective amount of one or more compounds disclosed herein; and
b) one or more pharmaceutically acceptable ingredients.
Another aspect relates a composition comprising:
a) an effective amount of one or more compounds disclosed herein; and
b) an effective amount of one or more antiviral or antibacterial agents; wherein the disclosed compounds and the antiviral or antibacterial ingredients can be administered together or in any order.
A further aspect relates to a composition comprising:
a) an effective amount of one or more compounds disclosed herein; and
b) an effective amount of one or more antibacterial agents effective against anthrax; wherein the disclosed compounds and the antibacterial ingredients effective against anthrax can be administered together or in any order.
A yet further aspect relates to a composition comprising:
a) an effective amount of one or more compounds disclosed herein; and
b) an effective amount of one or more antiviral agents;
wherein the disclosed compounds and the antiviral agents can be administered together or in any order.
For the purposes of the present disclosure the term “excipient” and “carrier” are used interchangeably throughout the description of the present disclosure and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”
The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active
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2016203254 18 May 2016 ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present disclosure have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
The term “effective amount” as used herein means “an amount of one or more ΡΤΡ-β inhibitors, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result.” An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although particular dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may he proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of the present disclosure can be administered as frequently as necessary to achieve a therapeutic amount.
The disclosed ΡΤΡ-β inhibitors can also be present in liquids, emulsions, or suspensions for delivery of active therapeutic agents in aerosol form to cavities of the body such as the nose, throat, or bronchial passages. The ratio of ΡΤΡ-β inhibitors to the other compounding agents in these preparations will vary as the dosage form requires.
Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include, as noted above, an effective amount of the ΡΤΡ-β inhibitor in combination with a pharmaceutically acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose* starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such
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2016203254 18 May 2016 as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example see Remington‘s Pharmaceutical Sciences, referenced above.
Parental administration, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions, A more recently revised approach for parental administration involves use of a slow release or sustained release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795, which is incorporated by reference herein.
KITS
Also disclosed are kits comprising the compounds be delivered into a human, mammal, or cell. The kits can comprise one or more packaged unit doses of a composition comprising one or more compounds to be delivered into a human, mammal, or cell. The unit dosage ampoules or multi-dose containers, in which the compounds to be delivered are packaged prior to use, can comprise an hermetically sealed container enclosing an amount of polynucleotide or solution containing a substance suitable for a pharmaceutically effective dose thereof, or multiples of an effective dose. The compounds can be packaged as a sterile formulation, and the hermetically sealed container is designed to preserve sterility of the formulation until use.
The disclosed compounds can also be present in liquids, emulsions, or suspensions for delivery' of active therapeutic agents in aerosol form to cavities of the body such as the nose, throat, or bronchial passages. The ratio of compounds to the other compounding agents in these preparations will vary as the dosage form requires.
Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include, as noted above, an effective amount of the compounds in combination
183
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
2016203254 18 May 2016 with a pharmaceutically acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monoiaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example see Remington’$ Pharmaceutical Sciences, referenced above.
Parental administration, If used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parental administration involves use of a slow release or sustained release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,730,795, which is incorporated by reference herein.
When the compounds are to be delivered into a mammal other than a human, the mammal can be a non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The terms human and mammal do not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to he covered, A patient, subject, human or mammal refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.
While particular embodiments of the present disclosure have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to cover in the appended claims ah such changes and modifications that are within the scope of this disclosure.
184
This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
R
2016203254 21 Aug 2018

Claims (23)

  1. WHAT IS CLAIMED IS:
    1. A use of a compound having the formula:
    HO'
    H wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
    or
    R2, R3, and R4 are each independently:
    i) hydrogen;
    ii) substituted or unsubstituted C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl;
    iii) substituted or unsubstituted C2-C6 linear, C3-C6 branched, or C3-C6 cyclic alkenyl;
    iv) substituted or unsubstituted C2-C6 linear or C3-C6 branched alkynyl;
    v) substituted or unsubstituted C6 or C10 aryl;
    vi) substituted or unsubstituted C1-C9 heteroaryl;
    vii) substituted or unsubstituted C1-C9 heterocyclic; or viii) R2 and R3 taken together form a saturated or unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3 atoms are optionally oxygen, nitrogen, or sulfur;
    Z is a unit having the formula:
    —(L)n—R1
    R1 is:
    i) hydrogen;
    ii) hydroxyl;
    iii) amino;
    iv) substituted or unsubstituted Ci-Ce linear, C3-C6 branched, or C3-C6 cyclic alkyl;
    v) substituted or unsubstituted C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkoxy;
    vi) substituted or unsubstituted C6 or C10 aryl;
    185
    2016203254 21 Aug 2018 vii) substituted or unsubstituted C1-C9 heterocyclic rings; or viii) substituted or unsubstituted C1-C9 heteroaryl rings;
    L is a linking unit having the formula:
    -[Q]y[C(R5aR5b)]x[Q1]z[C(R6aR6b)]wQ and Q1 are each independently:
    i) -C(O)-;
    ii) -NH-;
    iii) -C(O)NH-;
    iv) -NHC(O)-;
    v) -NHC(O)NH-;
    vi) -NHC(O)O-;
    vii) -C(O)O-;
    viii) -C(O)NHC(O)-;
    ix) -O-;
    x) -S-;
    xi) -SO2-;
    xii) -C(=NH)-;
    xiii) -C(=NH)NH-;
    xiv) -NHC(=NH)-; or xv) -NHC(=NH)NH-;
    R5a and R5b are each independently:
    i) hydrogen;
    ii) hydroxy;
    iii) halogen;
    iv) substituted or unsubstituted Ci-Ce linear or C3-C6 branched alkyl; or
    v) a unit having the formula:
    -[C(R7aR7b)]tR8
    R7a and R7b are each independently:
    i) hydrogen; or ii) substituted or unsubstituted Ci-Ce linear, C3-C6 branched, or C3-C6 cyclic alkyl; R8 is:
    -1862016203254 21 Aug 2018
    i) hydrogen;
    ii) substituted or unsubstituted C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl;
    iii) substituted or unsubstituted C6 or C10 aryl;
    iv) substituted or unsubstituted C1-C9 heteroaryl; or
    v) substituted or unsubstituted C1-C9 heterocyclic;
    R6a and R6b are each independently:
    i) hydrogen; or ii) C1-C4 linear or C3-C4 branched alkyl;
    the index n is 0 or 1; the indices t, w, and x are each independently from 0 to 4; and the indices y and z are each independently 0 or 1;
    or a pharmaceutically-acceptable salt thereof, in the preparation of a medicament for treating brain edema in a subject.
  2. 2. The use according to Claim 1, wherein the subject has an inflammatory disease.
  3. 3. The use according to Claim 1, wherein the subject is undergoing a treatment for a cancer.
  4. 4. The use according to Claim 1, wherein the subject is infected with a pathogen.
  5. 5. The use according to any one of Claims 1 to 4, wherein R has the formula:
  6. 6. The use according to any one of Claims 1 to 5, wherein R2 is methyl or ethyl.
  7. 7. The use according to any one of Claims 1 to 4, wherein R has the formula:
    -1872016203254 21 Aug 2018
  8. 8. The use according to any one of Claims 1 to 4 and Claim 7, wherein R4 is methyl or ethyl.
  9. 9. The use according to any one of Claims 1 to 4 and Claim 7, wherein R4 is substituted or unsubstituted heteroaryl.
  10. 10. The use according to any one of Claims 1 to 4 and Claim 7, wherein R4 is thiophen-2-yl or thiophen-3-yl.
  11. 11. The use according to any one of Claims 1 to 10, wherein R1 is hydrogen, methyl, ethyl, tert-butyl, or methyl substituted with phenyl.
  12. 12. The use according to any one of Claims 1 to 11, wherein L has the formula:
    -C(O)[C(R5aR5b)]xNHC(O)R5a is hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; and the index x is 1 or 2.
  13. 13. The use according to any one of Claims 1 to 12, wherein R5a has the formula:
    -[C(R7aR7b)]tR8 wherein each R7a is independently hydrogen, methyl, or ethyl; each R7b is hydrogen; R8 is hydrogen, substituted or unsubstituted C1-C4 linear, C3-C4 branched, or C3-C6 cyclic alkyl, or substituted or unsubstituted phenyl, wherein the substitutions are one or more hydroxy, halogen, or C1-C4 alkyl; R5b is hydrogen; and the index t is 1 or 2.
  14. 14. The use according to any one of Claims 1 to 11, wherein L has the formula:
    i) -C(O)[C(R5aH)]NHC(O)O-;
    ii) -C(O)[C(R5aH)][CH2]NHC(O)O-;
    ii) -C(O)[CH2][C(R5aH)]NHC(O)O-;
    iv) -C(O)[C(R5aH)]NHC(O)-;
    v) -C(O)[C(R5aH)][CH2]NHC(O)-; or vi) -C(O)[CH2][C(R5aH)]NHC(O)-;
    -1882016203254 21 Aug 2018 and R5a is:
    i) hydrogen;
    ii) methyl;
    iii) ethyl;
    iv) isopropyl;
    v) phenyl;
    vi) benzyl;
    vii) 4-hydroxybenzyl;
    viii) hydroxymethyl; or ix) 1 -hydroxy ethyl.
  15. 15. The use according to any one of Claims 1 to 4 and Claim 7, wherein R4 is methyl, ethyl, phenyl, thiophen-2-yl, thiazol-2-yl, oxazol-2-yl, or isoxazol-3-yl; and L has the formula C(O)CH2- or -C(O)CH2CH2-.
  16. 16. The use according to any one of Claims 1 to 10 and Claims 12 to 15, wherein R1 is substituted or unsubstituted with:
    i) Ci-Ce linear, C3-C6 branched, or C3-C6 alkyl;
    ii) substituted or unsubstituted phenyl and benzyl;
    iii) substituted or unsubstituted heteroaryl;
    iv) -C(O)R9; or
    v) -NHC(O)R9;
    R9 is Ci-Ce linear or branched alkyl; Ci-Ce linear or C3-C4 branched alkoxy; or -NHCH2C(O)R10; and R10 is hydrogen, methyl, ethyl, or tert-butyl.
  17. 17. The use according to any one of Claims 1 to 10 and Claims 12 to 15, wherein R1 is substituted by methyl, ethyl, n-propyl, Ao-propyl, n-butyl, iso-butyl, .see-butyl, or tertbutyl.
    -1892016203254 21 Aug 2018
  18. 18. The use according to any one of Claims 1 to 10 and Claims 12 to 15, wherein R1 is a heteroaryl unit substituted by -NHC(0)R9 and R9 is methyl, methoxy, ethyl, ethoxy, tert butyl, or tert-butoxy.
  19. 19. The use according to any one of Claims 1 to 4, wherein the compound has the formula:
    wherein R2 is methyl or ethyl; and R3 is hydrogen.
  20. 20. The use according to any one of Claims 1 to 4, wherein the compound has the formula:
    wherein R4 is methyl, ethyl, phenyl, or thiophen-2-yl.
  21. 21. The use according to any one of Claims 1 to 4, wherein the compound has the formula:
    or a sodium salt thereof.
    -19022. The use according to any one of Claims 1 to 4, wherein the compound has the formula:
    2016203254 21 Aug 2018 or a pharmaceutically-acceptable salt thereof.
  22. 23. The use according to any one of Claims 1 to 4, wherein the compound has the formula:
    or a pharmaceutically-acceptable salt thereof.
  23. 24. The use according to any one of Claims 1 to 16, 18, and 19, wherein the compound is a pharmaceutically-acceptable having a cation that is ammonium, sodium, lithium, potassium, calcium, magnesium, bismuth, or lysine.
    -191b?
    2016203254 18 May 2016
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    FI
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    2016203254 18 May 2016
    ABC
    Ixm
    F
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    2016203254 18 May 2016
    This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST w
    2016203254 18 May 2016
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    2016203254 18 May 2016
    DPS s> s * 5 si '« i»,<· KiJ ϋ» $8» W p'<M h Vί Γ ; ?: X 4 X μν :¾ * t; . ft , , ,JS
    W ’Ά *4 i*M 2
    Maa
    This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST ο
    2016203254 18 May 2016 . 10c3
    This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
    2016203254 18 May 2016
    This data, for application number 2014202211, is current as of 2016-05-16 21:00 AEST
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AU2014202211A AU2014202211B2 (en) 2009-01-12 2014-04-23 Methods for treating vascular leak syndrome
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000057901A1 (en) * 1999-03-26 2000-10-05 Regeneron Pharmaceuticals, Inc. Modulation of vascular permeability by means of tie2 receptor activators
US20070299116A1 (en) * 2006-06-27 2007-12-27 The Procter & Gamble Company Human protein tyrosine phosphatase inhibitors and methods of use
US20080004267A1 (en) * 2006-06-27 2008-01-03 The Procter & Gamble Company Human protein tyrosine phosphatase inhibitors and methods of use
WO2008002569A2 (en) * 2006-06-27 2008-01-03 The Procter & Gamble Company Human protein tyrosine phosphatase inhibitors and methods of use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000057901A1 (en) * 1999-03-26 2000-10-05 Regeneron Pharmaceuticals, Inc. Modulation of vascular permeability by means of tie2 receptor activators
US20070299116A1 (en) * 2006-06-27 2007-12-27 The Procter & Gamble Company Human protein tyrosine phosphatase inhibitors and methods of use
US20080004267A1 (en) * 2006-06-27 2008-01-03 The Procter & Gamble Company Human protein tyrosine phosphatase inhibitors and methods of use
WO2008002569A2 (en) * 2006-06-27 2008-01-03 The Procter & Gamble Company Human protein tyrosine phosphatase inhibitors and methods of use

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