Hydroxylamine-based EGFR inhibitors for the treatment of cancer with brain metastases

Abstract

In accordance with the purposes of this disclosure, as embodied and broadly described herein, the disclosure relates in one aspect to scaffold molecules that inhibit epidermal growth factor receptor (EGFR), methods of making same, pharmaceutical compositions comprising same, and methods of treating cancers associated with aberrant EGFR activity.

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R21GM144753 awarded by the NIH. The U.S. Government has certain rights in this invention. (37 CFR 401.14f(4))

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63 / 375,622, filed September 14, 2022, and U.S. Provisional Patent Application No. 63 / 507,876, filed June 13, 2023, the contents of which are incorporated herein by reference in their entireties. [Background technology]

[0003] Lung cancer remains the leading cause of cancer-related death worldwide, with an estimated 2.2 million new cases and 1.79 million deaths annually. 1 The epidermal growth factor receptor (EGFR, erbB1, HER-1) is an attractive molecular target for lung cancer drug discovery. Activating mutations, such as the exon 21 point mutation L858R and the in-frame exon 19 deletion delE746_A750, detected in 10–30% of non-small cell lung cancer (NSCLC) patients, confer sensitivity to first-generation reversible EGFR-targeted tyrosine kinase inhibitors (TKIs), such as gefitinib (1) (Figures 1–2). 2~5 Unfortunately, in NSCLC, up to 40% of patients will develop brain metastases (BM), and this number is expected to increase as treatment options continue to improve life expectancy for patients with advanced disease. 6 Therefore, BM is a significant risk and a cause of poor prognosis for NSCLC patients treated with TKIs that have poor central nervous system (CNS) penetration. 6~10Numerous studies have revealed that the majority of commercially available EGFR-TKIs have poor CNS penetration due to active efflux by transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). These transporters are highly enriched at the blood-brain barrier (BBB), and in combination with tight junctions, ultimately exclude up to 98% of all drugs from the CNS (Figure 1). 7~10 Therefore, future treatment options for NSCLC have the advantage of improving CNS pharmacokinetics, allowing treatment of local disease and subsequent BM. Summary of the Invention

[0004] In accordance with the purposes of this disclosure, as embodied and broadly described herein, the disclosure relates in one aspect to scaffold molecules that inhibit epidermal growth factor receptor (EGFR), methods of making same, pharmaceutical compositions comprising same, and methods of treating cancers associated with aberrant EGFR activity.

[0005] Other systems, methods, features, and advantages of the present disclosure will become apparent to those skilled in the art upon examination of the following drawings and detailed description. All such additional systems, methods, features, and advantages are intended to be included within this specification, be within the scope of this disclosure, and be protected by the accompanying claims. Furthermore, all optional preferred features and modifications of the described embodiments can be used in all aspects of the present disclosure taught herein. Furthermore, all optional preferred features and modifications of the described embodiments, as well as individual features of the dependent claims, are combinable and interchangeable with each other.

[0006] Many aspects of the present disclosure can be better understood by reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals indicate corresponding parts throughout the several views. [Brief explanation of the drawings]

[0007] [Figure 1] Figure 1 shows the chemical structures of selected approved EGFR tyrosine kinase inhibitors (TKIs) and their efflux status for efflux transporters. [Figure 2] FIG. 2 shows the novel bioisosteric modifications. [Figure 3] Figure 3 shows an alternative synthetic route towards the hydroxylamine precursor (17). [Figure 4] FIG. 4 shows the synthesis of a hydroxylamine EGFR inhibitor (6). [Figure 5] FIG. 5 shows an exemplary procedure for making the compounds described herein. [Figure 6] FIG. 6 shows an exemplary procedure for making the compounds described herein. [Figure 7] FIG. 7 shows the hydroxylamine EGFR inhibitors described herein. [Figure 8-1] FIG. 8 shows the synthesis of a hydroxylamine EGFR inhibitor (15). [Figure 8-2] Table 1 shows the in vitro ADMET properties of gefitinib and hydroxylamine-based EGFR inhibitors. Unless otherwise noted, each value represents the mean of two independent replicates. Negative Ames test results in 15 were effective up to 50 μM, above which bacterial toxicity was observed. "Aq.Sol." is aqueous solubility; "LMClint" is intrinsic clearance in liver microsomes; "HEPClint" is intrinsic clearance in hepatocytes; "t1 / 2" is half-life; "Papp" is apparent permeability; "MDCK" is Madin-Darby canine kidney; "MDR1" is multidrug resistance 1 (or P-glycoprotein). Abbreviations: "H" is human; "R" is rat; and "nd" is untested. [Figure 9-1]Figure 9 shows the in vitro antiproliferative activity of gefitinib and hydroxylamine-based EGFR inhibitors. The hydroxylamine-based EGFR inhibitor (15) exhibited potent antiproliferative activity in the patient-derived non-small cell lung cancer cell lines HCC827 (EGFR mutation = exon 19del), NCI-H3255 (EGFR mutation = L858R), and osimertinib-resistant modified cell lines (Ba / F3-L858R / C797S; Ba / F3 del E746_A750 / C797S), but not in NCI-H1975 (EGFR mutation = L858R / T790M) and only minimal activity in the A431 cell line (EGFRwt overexpression) (72-hour treatment period). In all antiproliferative assays, points represent the mean and error bars represent SD; n = 3 independent replicates; IC50 values ​​(nM) are reported alongside the dose-response curves and show the mean ± SEM. [Figure 9-2] Table 2 shows 15 additional in vitro ADMET profiles. Values ​​represent the mean of independent replicates with n = 2 or more. Negative test results in the in vitro micronucleus assay were valid up to 31 μM (with rat liver S9) and 8 μM (without rat liver S9), above which cytotoxicity was observed. "Aq.Sol." is aqueous solubility; "fu, plasma%" is the unbound fraction in plasma; "fu, brain%" is the unbound fraction in brain; and "HEPClint" is the intrinsic clearance in hepatocytes. Abbreviations: "H" is human; "R" is rat; "C" is cynomolgus monkey; and "D" is dog. [Figure 10] Figure 10 shows the results of a KINOMEScan screen of 15 native or lipid kinases at a screening concentration of 1 μM. Circle size, mapped onto the kinase phylogenetic tree using DiscoverX TREEspot, corresponds to the strength of binding affinity. [Figure 11] Figure 11 shows the binding (Kd) and biochemical inhibition (IC50) of 15 follow-up kinases that showed less than 10% activity on KINOMEScan. Results are the mean of n=2 independent replicates. [Figure 12]Figure 12 shows the in vitro antiproliferative activity of 15 in breast cancer cell lines with different HER2 status. 15 exhibits moderate antiproliferative activity in the patient-derived HER2-positive breast cancer cell lines AU565, SK-BR-3, BT474, and ZR-75-30. In all antiproliferative assays, points represent the mean and error bars represent SD; n = 3 independent replicates; IC50 values ​​(nM) are reported alongside the dose-response curves and represent the mean ± SEM. [Figure 13] Figure 13 shows the total plasma versus time profiles (0–24 h) of 15 after administration of single doses of 2 mg / kg IV and 20 mg / kg PO to SD rats and 3 mg / kg IV and 30 mg / kg PO to BALB / c nude mice. "AUC0-inf (nM·hr)" is the area under the concentration-time curve from 0 to ∞; "t1 / 2 (hr)" is the mean elimination half-life obtained from either intravenous infusion (IV) or oral gavage (PO); F (%), bioavailability (%); Tmax (hr), time to peak plasma concentration; "Cmax (nM)" is the peak plasma concentration; and "CL (mL·min·kg)" is the clearance obtained from intravenous infusion. For pharmacokinetic profiles, points represent the mean, and error bars represent SD; n = 3 animals / route (total n = 6). Values ​​are expressed as mean ± SD. [Figure 14] Figure 14 shows the pharmacokinetic profile of the hydroxylamine EGFR inhibitor (15) in the central nervous system. The total plasma and brain concentration versus time profiles (0–24 h) of 15 after administration by oral gavage (PO) to SD rats at a single dose of 20 mg / kg and to CD1 mice at 40 mg / kg demonstrate excellent brain penetration. KpBrain(AUCinf) refers to the brain-plasma partition coefficient. Kp,uuBrain(AUCinf) refers to the unbound brain-unbound plasma partition coefficient. In the pharmacokinetic profiles, points represent the mean, and error bars represent SD; n = 3 animals per time point (total n = 21). [Figure 15]FIG. 15 shows bioluminescence images of the vehicle control and 15 (10 mg / kg, PO, bid) treatment groups showing the change in tumor volume over 21 days of treatment. [Figure 16] Figure 16 shows the intracranial bioluminescence plots of 15 over time and the mean body weight plots of the mice during the study. In the bioluminescence plots, points represent the mean, and error bars represent SEM; P = 0.0059; n = 10 mice per group. "PDX" refers to patient-derived xenografts. p values ​​were obtained from an unpaired, two-tailed t-test comparing the mean values ​​of the vehicle-control test group with the mean values ​​of the 15 (10 mg / kg PO bid) test group after 21 days of treatment. *P < 0.05; **P < 0.01. In the mean body weight plots, points represent the mean, and error bars represent SEM; P = 0.2275; n = 10 mice per group. p values ​​were obtained from an unpaired, two-tailed t-test comparing the mean values ​​of the vehicle-control test group with the mean values ​​of the 15 (10 mg / kg PO bid) test group after 21 days of treatment. "ns" refers to "not significant." [Figure 17] 17-18 show exemplary routes to hydroxylamine-based nitrogen heterocycles. [Figure 18] Same as above DETAILED DESCRIPTION OF THE INVENTION

[0008] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to be limiting of the invention, as claimed.

[0009] Many modifications and other embodiments of the compositions and methods disclosed herein will occur to those skilled in the art to which the disclosed compositions and methods pertain who have the benefit of the teachings provided in the foregoing description and the accompanying drawings. It is to be understood that the disclosure is not limited to the particular embodiments disclosed, and that modifications and other embodiments are intended to be encompassed within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the aspects described herein. These variations and adaptations are also encompassed by the teachings of the present disclosure and are intended to be encompassed within the scope of the claims of this application.

[0010] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0011] As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that may be readily separated from or combined with the features of any of the other embodiments without departing from the spirit of the present disclosure.

[0012] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless expressly stated otherwise, it is not intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Thus, unless a method claim specifically recites in the claim or specification that the steps are limited to a particular order, no order is intended to be implied in any way. This applies to all possible, unexpressed criteria of interpretation, including logical issues regarding the placement of steps or operational flow, the general meaning derived from grammatical structure and punctuation, and the number and type of aspects described herein.

[0013] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications mentioned herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication mentioned herein may be different from the actual publication dates, which may require independent confirmation.

[0014] Although aspects of the present disclosure may be described and claimed in particular statutory classifications, such as systems statutory classifications, this is for convenience only, and those skilled in the art will understand that each aspect of the present disclosure may be described and claimed in any statutory classification.

[0015] It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. Furthermore, it should be understood that terms defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the context of the present specification and the relevant technical field, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0016] Prior to describing various aspects of this disclosure, the following definitions are provided, and these definitions should be used unless otherwise indicated. Additional terms may be defined elsewhere in this disclosure.

[0017] definition As used herein, "comprising" is interpreted as specifying the presence of the stated features, integers, steps, or components as stated, but does not exclude the presence or addition of one or more other features, integers, steps, or components, or groups thereof. Furthermore, the terms "by," "comprising," "comprises," "comprised of," "including," "includes," "included," "involving," "involves," "involved," and "such as" are each used in an open, non-limiting sense and can be used interchangeably. Furthermore, the term "comprising" is intended to encompass examples and aspects encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to encompass examples encompassed by the term "consisting of."

[0018] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to an "excipient" includes, but is not limited to, mixtures or combinations of two or more such excipients.

[0019] Ratios, concentrations, amounts, and other numerical data may be expressed herein in range format. It is further understood that the endpoints of each range are significant in relation to the other endpoint, and independently of the other endpoint. It is also understood that, where there are numerical values ​​herein, each value is herein disclosed as "about" that particular value in addition to its own value. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value constitutes a further aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

[0020] When a range is expressed, a further embodiment includes ranges greater than or equal to the one particular value and / or the other particular value. For example, when the stated range includes one or both endpoints, ranges excluding either or both of those included endpoints are also encompassed within the disclosure; for example, a phrase "from x to y" includes ranges from "x" to "y," as well as ranges greater than "x" and less than "y." Ranges may also be expressed as upper limits (e.g., "up to about x, up to about y, up to about z") and should be interpreted to include the specific ranges "about x," "about y," and "about z," as well as the ranges "less than x," "less than y," and "less than z." Similarly, the phrase "greater than or equal to about x, greater than or equal to about y, greater than or equal to about z" should be interpreted to include the specific ranges "about x," "about y," and "about z," as well as the ranges "greater than x," "greater than y," and "greater than z." Furthermore, the expression "about 'x' to 'y'" (where 'x' and 'y' are numerical values) encompasses "about 'x' to about 'y'".

[0021] It should be understood that such range formats are used for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​stated as the range endpoints, but also all individual numerical values ​​and subranges subsumed within such ranges, as if each numerical value and subrange were expressly stated. For example, a numerical range of "about 0.1% to about 5%" should be interpreted not only to include the specified value of about 0.1% to about 5%, but also to include individual numerical values ​​(e.g., about 1%, about 2%, about 3%, and about 4%) and subranges within the stated range (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, and about 0.5% to about 4.4%, as well as other possible subranges). Thus, for example, if an ingredient is present at about 1%, about 2%, about 3%, about 4%, or about 5%, where any value can be the lower or upper limit of a range, any range between 1% and 5% (e.g., 1%-3%, 2%-4%, etc.) is contemplated.

[0022] As used herein, the terms "about," "approximate," "at or about," and "substantially" mean that the amount or value in question may be the exact value or a value that will produce an equivalent result or effect to that recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as appropriate, to produce an equivalent result or effect, reflecting tolerances, conversion factors, rounding, measurement error, and the like, as well as other factors known to those skilled in the art. In some cases, a value that will produce an equivalent result or effect may not be reasonably determined. In such cases, "about" and "at or about," as used herein, are generally understood to mean a variation of ±10% of the nominal value stated, unless otherwise indicated or estimated. Typically, an amount, size, formulation, parameter, or other quantity or characteristic is accompanied by "about," "approximately," or "just or near." When "about," "approximately," or "just or near" is used before a quantitative value, unless otherwise specified, the parameter is understood to encompass the specific quantitative value itself.

[0023] As used herein, "IC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process or component of a process. For example, IC 50 refers to the concentration (IC) that inhibits half (50%) of a substance as determined by an appropriate assay.

[0024] As used herein and in the final claims, a residue of a chemical species refers to a moiety that is the result of that chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether that moiety was actually derived from that chemical species. That is, an ethylene glycol residue of a polyester refers to one or more -OCH2CHO- units of the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue of a polyester refers to one or more -CO(CH2)8CO- moieties of the polyester, regardless of whether that residue was derived by reacting sebacic acid or a sebacic acid ester to obtain the polyester.

[0025] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, the following: The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible organic substituents described herein that satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. It is also contemplated that in certain embodiments, unless expressly indicated to the contrary, individual substituents may be optionally further substituted (i.e., further substituted or unsubstituted).

[0026] The position of a substituent can be defined relative to the position of other substituents in the aromatic ring. For example, as shown below in connection with an "R" group, a second substituent can be "ortho," "para," or "meta" relative to the R group, meaning that the second substituent is attached to the carbon labeled ortho, para, or meta as shown below. Combinations of ortho, para, and meta substituents for a given group or substituent are also contemplated and should be considered disclosed.

[0027] [ka]

[0028] In defining various terms, this specification uses the term "A 1 ","A 2 ","A 3 " and "A 4 " is used as a generic symbol to represent various specific substituents. These symbols can represent any substituent and are not limited to those disclosed herein, and what is defined as a particular substituent in one instance may be defined as any other substituent in another instance.

[0029] The terms "aliphatic" or "aliphatic group," as used herein, refer to a hydrocarbon moiety that may be straight-chained (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclic) and may be fully saturated or contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, aliphatic groups contain 1 to 20 carbon atoms. Aliphatic groups include, but are not limited to, straight-chain or branched-chain alkyl, alkenyl, and alkynyl groups, and hybrid forms thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0030] The term "alkyl," as used herein, refers to a branched or unbranched, saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Alkyl groups can be cyclic or acyclic. Alkyl groups can be branched or unbranched. Alkyl groups can also be substituted or unsubstituted. For example, alkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A "lower alkyl" group is an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl group may also refer to C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, etc. up to C1-C24 alkyl.

[0031] Throughout the specification, the term "alkyl" is generally used to refer to both substituted and unsubstituted alkyl groups, although substituted alkyl groups are also specifically referred to by specifying the particular substituents on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halogens, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halogen, such as fluorine, chlorine, bromine, or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group substituted with two or more halogens, independently of one another. That is, each halogen substituent need not be the same halogen as another halogen substituent, and the halogen substituents need not be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxy groups. Where "alkyl" is used in some instances and a specific term such as "hydroxyalkyl" is used in other instances, it is not intended to imply that the term "alkyl" does not refer to the specific term such as "hydroxyalkyl."

[0032] This convention is also used for other groups described herein. That is, a term such as "cycloalkyl" refers to both unsubstituted and substituted cycloalkyl moieties, although the substituted moieties may also be specifically identified herein; for example, a particular substituted cycloalkyl may be referred to specifically as, for example, an "alkylcycloalkyl." Similarly, a substituted alkoxy may be specifically referred to specifically as, for example, a "halogenated alkoxy," and a particular substituted alkenyl may be, for example, an "alkenylalcohol." Again, the convention of using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" is not intended to imply that the general term does not encompass the specific term.

[0033] The term "cycloalkyl," as used herein, refers to a non-aromatic, carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term "heterocycloalkyl" refers to a type of cycloalkyl group, as defined above, encompassed within the meaning of the term "cycloalkyl," in which at least one of the carbon atoms of the cycloalkyl ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0034] The term "alkanediyl," as used herein, refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as points of attachment, a straight or branched chain, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. -CH- (methylene), -CHCH-, -CHC(CH)CH-, and -CHCHCH- are non-limiting examples of alkanediyl groups.

[0035] The terms "alkoxy" and "alkoxyl," as used herein, refer to an alkyl or cycloalkyl group bonded through an ether linkage; i.e., an "alkoxy" group is -OA 1 And A 1 is alkyl or cycloalkyl as defined above. "Alkoxy" also includes polymeric alkoxy groups as defined above; i.e., alkoxy includes -OA, ... 1 -OA 2 or -OA 1 -(OA 2 ) a -OA 3 and the like, wherein "a" is an integer from 1 to 200, and A 1 , A 2 , and A 3 can be an alkyl group and / or a cycloalkyl group.

[0036] The term "alkenyl," as used herein, refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon double bond. 1 A 2 )C=C(A 3 A 4), are intended to encompass both the E and Z isomers. This can be assumed in structural formulas herein where an asymmetric alkene is present, or can be designated by the bond symbol C═C. Alkenyl groups can be optionally substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0037] The term "cycloalkenyl," as used herein, refers to a non-aromatic, carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term "heterocycloalkenyl" is a species of cycloalkenyl group, as defined above, and is encompassed within the meaning of the term "cycloalkenyl," in which at least one of the carbon atoms of the cycloalkyl ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups can be substituted or unsubstituted. The cycloalkenyl and heterocycloalkenyl groups may be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0038] The term "alkynyl," as used herein, refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups can be unsubstituted or substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0039] The term "cycloalkynyl," as used herein, refers to a non-aromatic, carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cyclooctynyl, cyclononynyl, and the like. The term "heterocycloalkynyl" is a type of cycloalkenyl group, as defined above, and is encompassed within the meaning of the term "cycloalkynyl," in which at least one of the carbon atoms of the cycloalkyl ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkynyl and heterocycloalkynyl groups can be substituted or unsubstituted. The cycloalkynyl and heterocycloalkynyl groups may be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0040] The term "aromatic group," as used herein, refers to a ring structure having a cyclic, delocalized π-electron cloud above and below the plane of the molecule, the π-electron cloud containing (4n+2) π-electrons. Further discussion of aromaticity can be found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled "Aromaticity," pp. 477-497, which is incorporated herein by reference. The term "aromatic group" is inclusive of both aryl and heteroaryl groups.

[0041] The term "aryl," as used herein, refers to a group containing any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. Aryl groups can be substituted or unsubstituted. Aryl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. The term "biaryl" is a specific type of aryl group and is included within the definition of "aryl." Furthermore, aryl groups can be single ring structures, fused ring structures, or contain multiple ring structures joined through one or more bridging groups, such as carbon-carbon bonds. For example, biaryl is two aryl groups bonded together through a fused ring structure, such as naphthalene, or through one or more carbon-carbon bonds, such as biphenyl. Fused aryl groups are also contemplated, including, but not limited to, indene and naphthalene groups.

[0042] The term "aldehyde" as used herein is represented by the formula -C(O)H, where "C(O)" is an abbreviation for a carbonyl group, i.e., C=O.

[0043] The term "amine" or "amino" as used herein refers to a group of the formula -NA 1 A 2 and A 1 and A 2 are each independently hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is —NH.

[0044] The term "alkylamino," as used herein, is represented by the formula -NH(-alkyl) and -N(-alkyl), where alkyl is as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl)amino, (tert-butyl)amino, pentylamino, isopentylamino, (tert-pentyl)amino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, dipentylamino, diisopentylamino, di(tert-pentyl)amino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, and N-ethyl-N-propylamino.

[0045] The term "carboxylic acid" as used herein is represented by the formula --C(O)OH.

[0046] The term "ester" as used herein refers to an ester of the formula -OC(O)A 1 or formula -C(O)OA 1 and A 1can be an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a cycloalkynyl group, an aryl group, or a heteroaryl group, as described herein.

[0047] The term "ether" as used herein refers to a compound of formula A 1 Office Automation 2 and A 1 and A 2 may each independently be an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a cycloalkynyl group, an aryl group, or a heteroaryl group, as described herein.

[0048] The terms "halo," "halogen," or "halide," as used herein, may be used interchangeably and refer to F, Cl, Br, or I.

[0049] The terms "pseudohalide," "pseudohalogen," or "pseudohalo," as used herein, may be used interchangeably and refer to functional groups that behave substantially similarly to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0050] The term "heteroalkyl," as used herein, refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, where nitrogen, phosphorous, and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroalkyls may be substituted with alkyl groups as defined above.

[0051] The term "heteroaryl," as used herein, refers to an aromatic group having at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, with N-oxides, sulfur oxides, and dioxides being permissible heteroatom substituents. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. Heteroaryl groups can be monocyclic or fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further non-exclusive examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0052] The terms "heterocycle" and "heterocyclyl," as used herein, may be used interchangeably and refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is other than carbon. Thus, the terms encompass, but are not limited to, "heterocycloalkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle." Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole (including 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole), triazole (including 1,2, 3-triazole, including 1,3,4-triazole), tetrazole (including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole), pyridazine, pyrazine, triazine (including 1,2,4-triazine and 1,3,5-triazine), tetrazine (including 1,2,4,5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can refer to C2-C18 heterocyclyl, such as C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, etc. For example, C2 heterocyclyl includes groups having two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.Alternatively, for example, C5 heterocyclyl includes groups having 5 carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, etc. It is understood that heterocyclyl groups may be bonded through a heteroatom in the ring, if chemically possible, or through one of the carbons that constitute the heterocyclyl ring.

[0053] The terms "bicyclic heterocycle" or "bicyclic heterocyclyl," as used herein, refer to a ring system in which at least one ring member is other than carbon. Bicyclic heterocyclyl includes ring systems in which an aromatic ring is fused to another aromatic ring or an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclyl includes ring systems in which a benzene ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, or a pyridine ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0054] The term "heterocycloalkyl," as used herein, refers to an aliphatic, partially unsaturated, or fully saturated, 3- to 14-membered ring system, including monocyclic rings of 3 to 8 atoms, as well as bicyclic and tricyclic ring systems. Heterocycloalkyl ring systems contain 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen heteroatom is optionally substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0055] The terms "hydroxyl" or "hydroxy" as used herein are represented by the formula --OH.

[0056] The term "ketone" as used herein refers to a compound of formula A 1 C(O)A 2 and A 1 and A 2 may each independently be an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a cycloalkynyl group, an aryl group, or a heteroaryl group, as described herein.

[0057] The terms "azide" or "azide" as used herein are represented by the formula -N3.

[0058] The term "nitro" as used herein is represented by the formula -NO2.

[0059] The term "nitrile" or "cyano" as used herein is represented by the formula --CN.

[0060] The term "silyl" as used herein is a group of the formula -SiA 1 A 2 A3 and A 1 , A 2 , and A 3 may be, independently of each other, hydrogen or an alkyl group, a cycloalkyl group, an alkoxy group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a cycloalkynyl group, an aryl group, or a heteroaryl group, as described herein.

[0061] The term "sulfo-oxo" as used herein refers to a group of the formula -S(O)A 1 , -S(O)2A 1 , -OS(O)2A 1 , or -OS(O)2OA 1 and A 1 can be hydrogen or an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, cycloalkynyl group, aryl group, or heteroaryl group, as described herein. As used herein, "S(O)" is an abbreviation for S=O. The term "sulfonyl" is used herein to refer to a group of the formula -S(O)A 1 is used to refer to a sulfo-oxo group represented by A 1 can be hydrogen, or an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, cycloalkynyl group, aryl group, or heteroaryl group, as described herein. The term "sulfone," as used herein, refers to a group of formula A 1 S(O)2A 2 and A 1 and A 2 may each independently be an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a cycloalkynyl group, an aryl group, or a heteroaryl group, as described herein. The term "sulfoxide" as used herein refers to a group of formula A 1 S(O)A 2 and A 1 and A 2may each independently be an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a cycloalkynyl group, an aryl group, or a heteroaryl group, as described herein.

[0062] The term "thiol" as used herein is represented by the formula --SH.

[0063] "R 1 "," "R 2 "," "R 3 ",..."R n " (n is an integer), as used herein, may independently have one or more of the above groups. For example, R 1 When is a straight-chain alkyl group, one of the hydrogen atoms of the alkyl group may be optionally substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, etc. Depending on the group selected, the first group may be embedded within the second group, or the first group may be pendant (i.e., attached) to the second group. For example, in the phrase "an alkyl group comprising an amino group," the amino group may be embedded within the backbone of the alkyl group. Alternatively, the amino group may be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is embedded or attached to the second group.

[0064] As described herein, the compounds of the invention may contain "optionally substituted" moieties. Generally, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens on the specified moiety have been replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each of the group's substitutable positions, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, those substituents may be the same or different at each position. Combinations of substituents contemplated by the invention are preferably those that result in the formation of stable or chemically feasible compounds. It is also contemplated that, in certain embodiments, individual substituents may be optionally further substituted (i.e., further substituted or unsubstituted) unless expressly indicated to the contrary.

[0065] The term "stable," as used herein, refers to a compound that remains substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0066] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently of one another, halogen; -(CH) 0-4 R ○ ;-(CH2) 0-4 OR ○ ;-O(CH2) 0-4 R ○ , -O-(CH2) 0-4 C(O)OR ○ ;-(CH2) 0-4 CH(OR ○ )2;-(CH2) 0-4 SR ○ ;R ○ may be substituted with -(CH2) 0-4 Ph;R ○ may be substituted with -(CH2) 0-4 O(CH2) 0-1 Ph;R○ -CH=CHPh; R ○ may be substituted with -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R ○ )2;-(CH2) 0-4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0-4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0-4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0-4 C(O)R ○ ;-C(S)R ○ ;-(CH2) 0-4 C(O)OR ○ ;-(CH2) 0-4 C(O)SR ○ ;-(CH2) 0-4 C(O)OSiR ○ 3;-(CH2) 0-4 OC(O)R ○ ;-OC(O)(CH2) 0-4 SR-, SC(S)SR ○ ;-(CH2) 0-4 SC(O)R ○ ;-(CH2) 0-4 C(O)NR ○ 2;-C(S)NR ○ 2;-C(S)SR ○ ;-(CH2) 0-4 OC(O)NR ○ 2;-C(O)N(OR○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH2) 0-4 SSR ○ ;-(CH2) 0-4 S(O)2R ○ ;-(CH2) 0-4 S(O)2OR ○ ;-(CH2) 0-4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0-4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;SiR ○ 3;-(C 1-4 Linear or branched alkylene)ON(R ○ )2; or -(C 1-4 Linear or branched alkylene)C(O)ON(R ○ )2, where each R ○ are optionally substituted as defined below and independently represent hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R ○together with the intervening atoms form a monocyclic or bicyclic, 3-12 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted as defined below.

[0067] R ○ (Two independent R ○ and the atoms between them together form a ring), are independently halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● are unsubstituted or, if preceded by "halo", are substituted only with one or more halogens, and, independently of each other, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0068] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, where each independent R * occurrences of C are hydrogen, which may be substituted as defined below 1-6 The "optionally substituted" group is preferably selected from the group consisting of an aliphatic group, an unsubstituted 5-6 membered saturated ring, a partially unsaturated ring, or an aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of the "optionally substituted" group include -O(CR * 2) 2-3 O-, wherein each independent R * occurrences of C are hydrogen, which may be substituted as defined below 1-6 It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0069] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● are unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and independently of each other, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- or 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0070] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † are, independently of each other, hydrogen, optionally substituted as defined below, C 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R † together with the intervening atoms form a monocyclic or bicyclic unsubstituted 3-12 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0071] R † Suitable substituents on the aliphatic groups are, independently of each other, halogen, -R ● ,-(Halo R● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● are unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and independently of each other, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- or 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0072] The term "leaving group" refers to an atom (or group of atoms) that has electron-withdrawing ability and can be displaced as a stable chemical species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonates, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0073] The compounds described herein may contain one or more double bonds and may therefore occur as cis / trans (E / Z) isomers and other conformational isomers. Unless specifically stated to the contrary, the present invention includes all such possible isomers, as well as mixtures of such isomers.

[0074] Unless specifically stated to the contrary, formulas having chemical bonds shown only as solid lines, and not as wedges or dashed lines, contemplate each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, such as racemic or scalemic mixtures. The compounds described herein may contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. Unless specifically stated to the contrary, the present invention encompasses all such possible diastereomers and racemic mixtures thereof, their substantially pure separated enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also encompassed. During the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0075] Many organic compounds exist as optically active forms, possessing the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around the chiral center. The prefixes d and l, or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning the compound is levorotatory. Compounds with a (+) or d prefix are dextrorotatory. For a given chemical structure, these compounds are called stereoisomers and are identical except that they are non-superimposable mirror images of each other. Specific stereoisomers are also called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture. Many of the compounds described herein may have one or more chiral centers and therefore may exist in different enantiomeric forms. Where appropriate, asymmetric carbons can be designated with an asterisk (*). When a bond to an asymmetric carbon is depicted as a straight line in the formulae of this disclosure, it is understood that both the (R) and (S) configurations of the asymmetric carbon, and therefore both enantiomers and mixtures thereof, are encompassed within the formula. As used in the art, when it is desired to designate the absolute configuration around an asymmetric carbon, one bond to the asymmetric carbon can be depicted as a wedge (a bond to an atom above a plane) and the other bond can be depicted as a series of short parallel lines or as a wedge (a bond to an atom below a plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to an asymmetric carbon.

[0076] The compounds described herein include atoms at both natural isotopic abundance and non-natural abundance.The compounds of the present disclosure may be isotopically labeled or isotopically substituted compounds identical to those described, except that one or more atoms are replaced with atoms having atomic masses or mass numbers different from the atomic masses or mass numbers typically found in nature.Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, for example, 2 H,3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 The compounds further include prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are also within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, 3 H and 14 Those in which radioactive isotopes such as 3C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 The C isotope is particularly preferred for its ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent by carrying out the following procedure.

[0077] The compounds described in the present invention can exist as solvates. In some cases, the solvent used to prepare solvates is an aqueous solution, and this solvate is often called a hydrate. The compounds can exist as hydrates, and hydrates can be obtained, for example, by crystallization from a solvent or aqueous solution. In this regard, one, two, three, or any number of solvent or water molecules can be combined with the compounds of the present invention to form solvates and hydrates. Unless otherwise specified, the present invention encompasses all such possible solvates.

[0078] It is also understood that certain compounds described herein may exist in tautomeric equilibrium, for example, a ketone having an α-hydrogen may exist in equilibrium between the keto and enol forms.

[0079] [ka]

[0080] Similarly, amides with an N-hydrogen may exist in equilibrium between the amide form and the imidic acid form, and unless specifically stated to the contrary, the present invention encompasses all such possible tautomers.

[0081] Chemical substances are known to form solids in various ordered states called polymorphs or polymorphic forms or modifications. The various polymorphs of a polymorphic substance can have significantly different physical properties. The compounds of the present invention can exist in various polymorphic forms and, in the case of certain polymorphs, may be metastable. Unless otherwise specified, the present invention encompasses all such possible polymorphs.

[0082] In some embodiments, the structure of the compound can be represented by the following formula:

[0083] [ka]

[0084] is understood to be equivalent to the following expression:

[0085] [ka]

[0086] where n is typically an integer, i.e., R n is five independent substituents, R n(a) , R n(b) , Rn(c) , R n(d) , and R n(e) By "independent substituents" it is meant that each R substituent can be defined independently of the others. For example, in some cases R n(a) Even if R is a halogen, n(b) In that case, it is not necessarily a halogen.

[0087] As used herein, "administering" can refer to oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intraarticular, parenteral, intraarteriolar, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravitreal, intracerebral, and intraventricular, intratympanic, intracochlear, intrarectal, intravaginal, by inhalation, by catheter, by stent, or via a device such as an implanted reservoir that actively or passively (e.g., by diffusion) administers the composition to the perivascular space and adventitia. For example, a medical device such as a stent can include a composition or formulation disposed on its surface, which can dissolve or otherwise distribute to surrounding tissues and cells. The term "parenteral" can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Administration can be continuous or intermittent. In various embodiments, the formulations can be administered therapeutically; i.e., to treat an existing disease or condition. In further various embodiments, the formulations can be administered prophylactically; i.e., to prevent a disease or condition.

[0088] As used interchangeably herein, a "subject," "individual," or "patient" can refer to a vertebrate organism, such as a mammal (e.g., a human). A "subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, and preferably refers to humans and components thereof.

[0089] As used herein, the terms "treating" and "treatment" may generally refer to obtaining a desired pharmacological and / or physiological effect. This effect may be, but is not necessarily, prophylactic, in that it prevents or partially prevents a disease, symptom, or condition, such as a hematological tumor, breast cancer, and / or another solid malignancy. This effect may be therapeutic, in that it partially or completely cures the disease, condition, symptoms, or adverse effects caused by the disease, disorder, or condition. The term "treatment," as used herein, may include any treatment of a hematological tumor, breast cancer, and / or another solid tumor in a subject, particularly a human. This term may include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease; (b) inhibiting, i.e., halting, the development of the disease; and (c) palliating the disease, i.e., alleviating or ameliorating the disease and / or its symptoms or condition. The term "treatment," as used herein, can refer to therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need of treatment) can include those already with the disorder and / or those in whom the disorder is to be prevented. As used herein, the term "treating" can include inhibiting a disease, disorder, or condition, e.g., preventing its progression; as well as alleviating a disease, disorder, or condition, e.g., reversing the disease, disorder, and / or condition. Treating a disease, disorder, or condition can include ameliorating at least one symptom of a particular disease, disorder, or condition even if the underlying pathophysiology has not been affected, such as treating a subject's pain with an analgesic (even if such an analgesic does not treat the cause of the pain).

[0090] As used herein, "therapeutic" can refer to treating, curing, and / or ameliorating a disease, disorder, condition, or side effect, or reducing the rate of progression of a disease, disorder, condition, or side effect.

[0091] As used herein, "effective amount" may refer to an amount of a compound or pharmaceutical composition of the present disclosure provided herein sufficient to effect a beneficial or desired biological, emotional, medical, or clinical response in a cell, tissue, system, animal, or human. An effective amount may be administered in one or more administrations, applications, or dosages. The term may also include within its scope an amount effective to enhance or restore substantially normal physiological function.

[0092] For example, it is well within the skill of one of ordinary skill in the art to begin administering an antibody at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If necessary, the effective daily dose can be divided into multiple doses for administration. Consequently, a single-dose composition may contain such amounts or subunits thereof to make up the daily dose. Dosages can be adjusted by the individual physician if contraindications exist. Generally, it is preferred to use the maximum dose of the pharmacological agent of the present invention (alone or in combination with other therapeutic agents), i.e., the highest safe dose according to sound medical judgment. However, those skilled in the art will understand that a patient may insist on a lower dose or tolerated dose for medical, psychological, or virtually any other reason.

[0093] Response to a therapeutically effective amount of a compound and / or pharmaceutical composition of the present disclosure can be measured by determining the physiological effect of the treatment or agent, such as, for example, a reduction or absence of disease symptoms after administration of the treatment or pharmacological agent. Other assays are known to those skilled in the art and can be employed to measure the level of response. The amount of treatment can be varied, for example, by increasing or decreasing the amount of a compound and / or pharmaceutical composition of the present disclosure, changing the compound and / or pharmaceutical composition of the present disclosure administered, changing the route of administration, changing the timing of administration, etc. Dosages can vary and may be administered once or multiple times daily for one or several days. Guidance can be found in the literature regarding appropriate dosages for a given class of pharmaceuticals.

[0094] As used herein, the term "prophylactically effective amount" refers to an amount effective to prevent the development or onset of a disease or condition.

[0095] As used herein, the term "prevent" or "preventing" refers to making it impossible, avoiding, making unnecessary, forestalling, deterring, or impeding something from happening, especially by prior action. Where reduce, inhibit, or prevent are used herein, it is understood that the use of the other two words is also expressly disclosed unless otherwise indicated.

[0096] The term "pharmaceutically acceptable" refers to a substance that is biologically or otherwise undesirable, i.e., does not cause unacceptable levels of undesired biological effects or interact adversely.

[0097] The term "pharmaceutically acceptable salt" as used herein refers to a salt of an active ingredient that is tolerated by a biological system or tolerated by a subject when administered in a therapeutically effective amount, or that is prepared using an acid or base that is tolerated by a biological system and tolerated by a subject. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a desired base in a suitable inert solvent or without a solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, magnesium salts, lithium salts, strontium salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a desired acid in a suitable inert solvent or without a solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid.

[0098] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to a prodrug of a compound of the present disclosure that is within the scope of reasonable medical judgment, suitable for use in contact with the tissues of humans and lower animals, lacks undue toxicity, irritation, allergic response, etc., commensurate with a reasonable risk / benefit ratio, and is effective for its intended use. The prodrugs of the present disclosure may be rapidly transformed in vivo, for example by hydrolysis in blood, to the parent compound having the structure of the disclosed compound. A detailed discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0099] As used herein, "dose," "unit dose," or "dosage" may refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or pharmaceutical composition thereof calculated to produce one or more desired responses associated with its administration.

[0100] Certain materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Acros Organics, Inc. (Morris Plains, New Jersey), Fisher Scientific (Pittsburgh, Pennsylvania), or Sigma (St. Louis, Missouri), or may be obtained from sources such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers). They can be prepared in a manner known to those skilled in the art according to procedures described in the literature, such as (Inc., 1989).

[0101] Unless expressly stated otherwise, it is not intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Thus, if a method claim does not actually specify the order in which the steps must be followed, or if the claim or specification does not specifically state that the steps are limited to a particular order, no order is intended to be implied in any way. This applies to all possible, unexpressed criteria of interpretation, including logical issues regarding the placement and operational flow of steps, general meanings derived from grammatical construction and punctuation, and the number and type of embodiments described herein.

[0102] Disclosed are the components used to prepare the compositions of the invention, as well as the compositions themselves used within the methods disclosed herein. While these and other materials are disclosed herein, when combinations, subsets, interactions, groups, etc., of these materials are disclosed, it is understood that each is specifically contemplated and described herein, even though specific reference to the various individual and collective combinations and variations of these compounds may not be explicitly disclosed. For example, when a particular compound is disclosed and discussed, and numerous variations that can be made to numerous molecules that comprise this compound are discussed, each and every combination and permutation of the compound and possible variations is specifically contemplated unless specifically indicated otherwise. Thus, if a class of molecules A, B, and C is disclosed, as well as classes of molecules D, E, and F, and an example of a combined molecule, AD, each is individually and collectively contemplated, even if each is not individually listed, meaning that the combinations AE, AF, BD, BE, BF, CD, CE, and CF are considered to be disclosed. Similarly, any subset or combination of these is also disclosed. Thus, for example, the sub-groups AE, BF, and CE would be considered disclosed. This concept applies to all aspects of this application, including, but not limited to, each step in the methods of making and using the compositions of the invention. Thus, where there are various additional steps that may be performed, it is understood that each of these additional steps may be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0103] It is understood that the compositions disclosed herein have specific functions. Disclosed herein are specific structural requirements for performing the disclosed functions, and it is understood that there are various structures that can perform the same function related to the disclosed structures, and that these structures will typically achieve the same result.

[0104] As used herein, the term "optionally present" or "optionally" means that the subsequently described phenomenon or circumstance may or may not occur, and that the description encompasses instances where the phenomenon or circumstance occurs and instances where the phenomenon or circumstance does not occur.

[0105] Unless otherwise specified, temperatures stated herein are at atmospheric pressure (ie, 1 atmosphere).

[0106] Compounds and methods of making and using the compounds In one aspect, disclosed herein are compounds having the structure of Structure I, or a pharmaceutically acceptable salt thereof.

[0107] [ka]

[0108] During the ceremony, R 1 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; n is an integer from 1 to 5, and each R 2 are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, a halide, or an alkoxy group; m is an integer from 1 to 3, and each R 3 are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, a halide, or an alkoxy group; o is an integer from 1 to 10; X is O or NR 4 where R 4is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR 5 , or CR 6a R 6b where R 5 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 6a and R 6b are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

[0109] In one embodiment, X in Structure I is O. In another embodiment, Y in Structure I is O. In another embodiment, Y in Structure I is NR 5 and R 5 is a C1-C5 alkyl group. In another embodiment, Y in structure I is CR 6a R 6b and R 6a is hydrogen and R 6b is a substituted or unsubstituted amino group. In another embodiment, R in structure I 1 is hydrogen. In another embodiment, R in structure I 3 is an alkoxy group. In another embodiment, R in structure I 3is an alkoxy group and m is 1. In another embodiment, o in Structure I is an integer from 1 to 5. In another embodiment, R in Structure I 2 is a halide and n is 2. In another embodiment, R in structure I 2 is a fluoride in the ortho position. In another embodiment, R in structure I 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h In another embodiment, R in structure I is 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are deuterium atoms.

[0110] In another embodiment, the compound has structure II or a pharmaceutically acceptable salt thereof.

[0111] [ka]

[0112] During the ceremony, R 1 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 2a and R 2b is a halide; R 3 is an alkoxy group; o is an integer from 1 to 5; X is O or NR 4 where R 4is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR 5 , or CR 6a R 6b where R 5 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 6a and R 6b are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

[0113] In one embodiment, X in Structure II is O. In another embodiment, Y in Structure II is O. In another embodiment, Y in Structure II is NR 5 and R 5 is a C1-C5 alkyl group. In another embodiment, Y in structure II is CR 6a R 6b and R 6a is hydrogen and R 6b is a substituted or unsubstituted amino group. In another embodiment, R in structure II 1 is hydrogen. In another embodiment, R in structure II 3is a C1-C10 substituted or unsubstituted straight or branched chain alkoxy group. 3 is a methoxy group. In another embodiment, o in Structure II is an integer from 1 to 5. In another embodiment, R in Structure II is 2 is a halide. In another embodiment, R in structure II 2a is chloride, and R 2b is fluoride. In another embodiment, R in structure II 2a is fluoride, and R 2b is chloride. In another embodiment, R in structure II 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h Each R in structure II is hydrogen. 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are deuterium atoms.

[0114] In another embodiment, the compound has structure III or a pharmaceutically acceptable salt thereof.

[0115] [ka]

[0116] During the ceremony, R 1 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 2a and R 2b is a halide; R 3 is an alkoxy group; o is an integer from 1 to 5; X is O or NR 4 where R 4 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR 5 , or CR 6a R 6b where R 5 is hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 6a and R 6b are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

[0117] In one embodiment, X in structure III is O. In another embodiment, Y in structure III is O. In another embodiment, Y in structure III is NR 5 and R 5 is a C1-C5 alkyl group. In another embodiment, Y in structure III is CR 6a R 6b and R 6a is hydrogen and R 6bis a substituted or unsubstituted amino group. In another embodiment, R in structure III 1 is hydrogen. In another embodiment, R in structure III 3 is a C1 to C10 substituted or unsubstituted straight or branched chain alkoxy group. 3 is a methoxy group. In another embodiment, o in Structure III is an integer from 1 to 5. In another embodiment, R in Structure III 2 is a halide. In another embodiment, R in structure III 2a is chloride, and R 2b is fluoride. In another embodiment, R in structure III 2a is fluoride, and R 2b is chloride. In another embodiment, R in structure II 2a is fluoride, and R 2b is chloride. In another embodiment, R in structure III 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h In another embodiment, R in structure III is 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are deuterium atoms.

[0118] In another embodiment, the compound has the structure:

[0119] [ka]

[0120] (General synthesis method) In one embodiment, the compounds described herein can be produced by reacting a compound having structure IV with a compound having structure V in the presence of a base.

[0121] [ka]

[0122] wherein the variables in Structures IV and V are as defined above, and LG is a leaving group.

[0123] The reaction between a compound having structure IV and a compound having structure V is typically carried out in an organic solvent, and a suitable amount of base is provided to deprotonate the XH hydrogen ion of structure IV. In one embodiment, the base comprises a hydride, an alkoxide, a Grignard reagent, or an alkyllithium compound. In one embodiment, the leaving group LG of structure V is a halide or sulfonate group. In one embodiment, the compounds described herein can be produced using the procedures depicted in Figures 4-6 and 8. Compounds having structure IV and compounds having structure V can be synthesized using organic techniques or can be purchased commercially. In one embodiment, the compound having structure IV has CAS Registry Number 184475-71-6.

[0124] Also described herein are synthetic methods for producing piperazinyl hydroxylamines and morpholino hydroxylamines on a large scale and in high yield. This synthetic approach requires a minimal number of steps and can produce piperazinyl hydroxylamines and morpholino hydroxylamines on a multigram scale. Piperazinyl hydroxylamines and morpholino hydroxylamines are useful intermediates for producing the compounds described herein.

[0125] FIG. 3 and FIGS. 17-18 show exemplary general synthetic procedures for producing piperazinyl hydroxylamines and morpholino hydroxylamines.

[0126] Referring to FIG. 17, four steps AD are used to generate piperazinyl hydroxylamines having structure X.

[0127] [ka]

[0128] During the ceremony, R 5 is a substituted or unsubstituted straight or branched chain alkyl group, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

[0129] In one embodiment, a method for making a piperazinyl hydroxylamine having structure X includes: (A) reacting a compound having structure XI with a compound having structure XII in the presence of a base to form a compound having structure XIII;

[0130] [ka]

[0131] In the formula, R 10 is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, LG is a leaving group; (B) reacting a compound having structure XIII with a first oxidizing agent with heating to form a compound having structure XIV;

[0132] [ka]

[0133] (C) reacting a compound having structure XIV with (i) a second oxidizing agent and then (ii) a first reducing agent to produce a first intermediate; and (D) reacting the first intermediate with a second reducing agent to produce a compound having structure X.

[0134] Step A comprises reacting a compound having structure XI with a compound having structure XII in the presence of a base to form a compound having structure XIII;

[0135] [ka]

[0136] During the ceremony, R 5 is a substituted or unsubstituted straight or branched chain alkyl group, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; each Z is, independently of the other, hydrogen or deuterium; R 10 is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, LG is a leaving group.

[0137] In one embodiment, R of Structure XI and Structure XIII 10 is a C1-C5 straight or branched chain alkyl group. In another embodiment, R in Structure XI and Structure XIII 10 is a C1-C5 straight or branched chain alkoxy group. In another embodiment, R in Structure XI and Structure XIII 10 is a C1-C5 straight or branched chain alkoxy group substituted with an aryl group. In another embodiment, R in Structure XI and Structure XIII 10 is a benzyloxy group.

[0138] Step A involves allylation of a compound having structure XI with an allylic compound having structure XII in the presence of a base. In one embodiment, the leaving group LG of allylic compound XII is a halide, sulfonate, carbonate, or phosphate. In another embodiment, the leaving group is bromide. In one embodiment, allylic compound XII can be partially or fully deuterated. In another embodiment, each Z in allylic compound XII is hydrogen. The molar ratio of the compound having structure XI to the compound having allylic structure XII can be 0.5:1 to 1:3, or 0.5:1, 1:1, 1:1.5, 1:2, 1:2.3, or 1:3, where either value can be the lower or upper limit of a range (e.g., 1:1.5 to 1:2).

[0139] Step A is carried out in an organic solvent. In one embodiment, the organic solvent is an aprotic organic solvent, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methylTHF), diethyl ether, methyl tert-butyl ether (MTBE), 1,4-dioxane, 1,2-dimethoxyethane, pentane, hexane, heptane, cyclohexane, N,N'-dimethylpropylene urea (DMPU), or a combination thereof.

[0140] The base is a compound capable of deprotonating the hydrogen ion of the amino on the piperazine ring of compound XI. In one embodiment, it includes carbonates, hydroxides, phosphates, hydrides, dialkylamides, or hexamethyldisilazide. The molar ratio of the compound having structure XI to the base can be 0.5:1 to 1:3, or 0.5:1, 1:1, 1:1.5, 1:2, 1:2.3, or 1:3, where either value can be the lower or upper limit of a range (e.g., 1:1.5 to 1:2).

[0141] In one embodiment, Step A is carried out at elevated temperatures. In one embodiment, the reaction of Step A is carried out at a temperature of about 25°C to about 100°C, or at 25°C, 35°C, 45°C, 55°C, 65°C, 75°C, 85°C, 95°C, or 100°C, where any value can be the lower or upper limit of a range (e.g., 55°C to 75°C). After Step A, a compound having structure XIV is produced. A compound having structure XIII can then be purified using techniques known in the art.

[0142] Step B involves oxidation of a compound having structure XIII followed by a Meisenheimer rearrangement to produce a compound having structure XIV.

[0143] In one embodiment, step B comprises the following steps: (i) reacting a compound having structure XIII with a first oxidizing agent in a first organic solvent to form a first composition; (ii) adding an aqueous base to the first composition to form a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to obtain a residue; (v) dissolving the residue in a second organic solvent to form a second composition; and (vi) heating the second composition to about 50° C. to about 100° C. to form a compound having structure XIV.

[0144] In one embodiment, the first oxidizing agent in Step B comprises peroxyacid, oxone, or hydrogen peroxide / acetic acid. In another embodiment, the first oxidizing agent in Step B comprises metachloroperbenzoic acid. In another embodiment, the molar ratio of the first oxidizing agent to the compound having structure XIII is from 0.95:1 to 1:1.05.

[0145] Step B is carried out in an organic solvent that does not react with the first oxidizing agent. In one embodiment, the first organic solvent is dichloromethane. The first solvent can then be removed using techniques known in the art, and the remaining residue can be dissolved in a second organic solvent to produce a second composition. In one embodiment, the second organic solvent is a higher boiling point solvent, such as toluene. In one embodiment, the second composition of Step B is carried out at a temperature of about 50°C to about 100°C, or at 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C, where any value can be the lower or upper limit of a range (e.g., 70°C to 90°C). During the heating step, a Meisenheimer rearrangement occurs to produce a compound having structure XIV. The compound having structure XIIV can then be purified using techniques known in the art.

[0146] Step C involves oxidation of an alkenyl group in a compound having structure XIIV, followed by reduction to form a first intermediate.

[0147] In one embodiment, step C comprises the following steps: (i) reacting a compound having structure XIV with a second oxidizing agent in a third organic solvent to form a third composition; and (ii) combining the first reducing agent with the third composition to form a first intermediate.

[0148] In one embodiment, the second oxidizing agent used in Step C comprises ozone or osmium tetroxide together with sodium metaperiodate. Step C is carried out in an organic solvent. In one embodiment, the third organic solvent comprises an alcohol (e.g., methanol, ethanol, butanol, or any combination thereof) and an aprotic solvent (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methylTHF), diethyl ether, methyl tert-butyl ether (MTBE), 1,4-dioxane, 1,2-dimethoxyethane, pentane, hexane, heptane, cyclohexane, N,N'-dimethylpropylene urea (DMPU), or any combination thereof).

[0149] In one embodiment, the compound having structure XIV is reacted with the second oxidizing agent at a temperature of about −50° C. to about −100° C., or at 50° C., −60° C., −70° C., −80° C., −90° C., or −100° C., where any value can be the lower or upper limit of a range (e.g., −70° C. to −90° C.).

[0150] After oxidation of the alkenyl group in a compound having structure XIIV, a first reducing agent is then added to the reaction to produce a first intermediate, which is a terminal alcohol as shown below.

[0151] [ka]

[0152] In one embodiment, the first reducing agent comprises a hydride, which is any compound capable of delivering a hydrogen anion. In one embodiment, the first reducing agent comprises a borohydride. In one embodiment, the hydride is sodium borohydride, lithium aluminum hydride, or diisobutylaluminum hydride. The molar ratio of the first reducing agent to the compound having structure XIV is 1.5:1 to 2.5:1, or 1.5:1, 1.75:1, 2:1, 2.25:1, or 2.5:1, where any value can be the lower or upper limit of a range (e.g., 1.75:1 to 2:1). The first intermediate produced in Step C can then be purified using techniques known in the art prior to Step D.

[0153] Step D involves reducing the carbonyl group in the first intermediate to generate piperazinyl hydroxylamine compound X.

[0154] In one embodiment, step D comprises the following steps: (i) dissolving the first intermediate in an aprotic solvent to form a fourth composition; (ii) combining a second reducing agent with the fourth composition to produce a compound having structure X; and (iii) isolating and purifying the compound having structure X.

[0155] The first intermediate is dissolved in an aprotic solvent (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methylTHF), diethyl ether, methyl tert-butyl ether (MTBE), 1,4-dioxane, 1,2-dimethoxyethane, pentane, hexane, heptane, cyclohexane, N,N'-dimethylpropylene urea (DMPU), or any combination thereof), followed by the addition of a second reducing agent. In one embodiment, the hydride is sodium borohydride, lithium aluminum hydride, or diisobutylaluminum hydride. The molar ratio of the first reducing agent to the compound having structure XIV is 2:1 to 4:1, or 2:1, 2.5:1, 3:1, 3.5:1, or 4:1, where any value can be the lower or upper limit of a range (e.g., 2.5:1 to 3.5:1).

[0156] In one embodiment, the first intermediate is reacted with the second reducing agent at a temperature of about 10° C. to about −50° C., or at 10° C., 0° C., −10° C., −20° C., −30° C., −40° C., or −50° C., where any value can be the lower or upper limit of a range (e.g., 10° C. to −30° C.). The piperazinyl hydroxylamine compound X produced in Step D can then be purified using techniques known in the art prior to Step D.

[0157] Referring to Figure 18, three steps A-C are used to generate morpholinohydroxylamines having the structure XX:

[0158] [ka]

[0159] During the ceremony, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7hare, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

[0160] In one embodiment, a method for making a morpholinohydroxylamine having structure XX includes: (A) reacting a compound having structure XXI with a compound having structure XXII in the presence of a base to form a compound having structure XXIII;

[0161] [ka]

[0162] (wherein LG is a leaving group); (B) reacting a compound having structure XXIII with a first oxidizing agent to form a compound having structure XXIV;

[0163] [ka]

[0164] and (C) reacting a compound having structure XXIV with (i) a second oxidizing agent and then (ii) a first reducing agent to produce a compound having structure XX.

[0165] The same reaction conditions and reagents used in Steps A-C to generate piperazinyl hydroxylamines can be used to generate morpholino hydroxylamines having structure XX, where Step D is not required to generate the morpholino hydroxylamines.

[0166] Exemplary methods for producing the compounds described herein, as well as characterization information, are provided in the Examples. Solvents, temperatures, the presence or absence of protecting groups, and other reaction conditions may vary depending on the particular substituents in the compound being synthesized.

[0167] Exemplary methods for producing the compounds described herein, as well as characterization information, are provided in the Examples. Solvents, temperatures, the presence or absence of protecting groups, and other reaction conditions may vary depending on the particular substituents in the compound being synthesized.

[0168] (Pharmaceutical composition) In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the present disclosure, at least one product of a method of the present disclosure, or a pharmaceutically acceptable salt thereof. As used herein, "pharmaceutically acceptable carriers" refers to one or more of pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizing agents, emulsifiers, coloring agents, releasing agents, coating agents, sweeteners, flavoring and perfuming agents, and adjuvants. The pharmaceutical compositions of the present disclosure can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy and pharmacy.

[0169] In a further aspect, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of at least one compound of the present disclosure, at least one product of the method of the present disclosure, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agents, and optionally one or more adjuvants. The pharmaceutical compositions of the present disclosure include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. In a further aspect, the pharmaceutical compositions of the present disclosure can be formulated to allow for oral, nasal, inhalation, parenteral, paracancer, transmucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intraventricular, intracranial, and intratumoral administration.

[0170] As used herein, "parenteral administration" includes administration by bolus injection or infusion, as well as intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0171] In various aspects, the present disclosure also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of the present disclosure, a product of the process of the present disclosure, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemical isomer thereof, as an active ingredient. In a further aspect, the compound of the present disclosure, a product of the process of the present disclosure, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemical isomer thereof, or any subgroup or combination thereof, can be formulated into various pharmaceutical forms for administration purposes.

[0172] In practice, the compounds of the present disclosure or pharmaceutically acceptable salts thereof can be formulated as active ingredients in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) administration. Thus, pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the composition can be presented as a powder, granules, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compounds of the present disclosure and / or pharmaceutically acceptable salts thereof can also be administered by controlled-release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, after which the product can be conveniently shaped into the desired presentation.

[0173] It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage forms for ease of administration and uniformity of dosage. The term "unit dosage form," as used herein, refers to physically discrete units suitable as unit doses, each containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in association with the necessary pharmaceutical carrier. That is, a "unit dosage form" refers to a single dose in which all active and inactive ingredients are combined in a suitable system, such that a patient or a person administering the drug to a patient can open a single container or package to contain the entire dose, eliminating the need to mix ingredients from two or more containers or packages. Typical examples of unit dosage forms include tablets (including scored or coated tablets), capsules, or pills for oral administration; single-dose vials for injection or suspension; suppositories for rectal administration; powder packets; cachets; and segregated multiples thereof. This recitation of unit dosage forms is not intended to be limiting in any way, but merely to illustrate typical examples of unit dosage forms.

[0174] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, one or more additional therapeutic agents. In various embodiments, the pharmaceutical compositions of the present disclosure may comprise a pharmaceutically acceptable carrier and a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In further embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The compositions include those suitable for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous administration), although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0175] Techniques and compositions for making dosage forms useful in the materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; JG Hardy, SS Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). .

[0176] The compounds described herein will typically be administered in admixture with a suitable pharmaceutical diluent, excipient, filler, or carrier (herein referred to as a pharmaceutically acceptable carrier, or carrier) appropriately selected for the intended mode of administration and consistent with conventional pharmaceutical practice. Deliverable compounds will be in a form suitable for oral, rectal, topical, intravenous, or parenteral administration. Carriers include solids or liquids, and the type of carrier is selected based on the type of administration being used. Compounds may be administered as a dose having a known amount of the compound.

[0177] Oral administration may be the preferred dosage form due to ease of administration, with tablets and capsules being the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are clearly employed. However, other dosage forms may be appropriate depending on the clinical population (e.g., age and severity of clinical condition), the solubility characteristics of the particular compound of the present disclosure used, and the like. Thus, the compounds of the present disclosure may be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Any convenient pharmaceutical medium may be employed when preparing compositions for oral dosage forms. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid dosage forms such as suspensions, elixirs, and solutions; while carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid dosage forms such as powders, capsules, and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0178] The pharmaceutical compositions of the present disclosure in oral dosage form may include one or more pharmaceutical excipients and / or additives. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starch (e.g., corn starch or amylose), dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talc, lysosmodium, silica gel (e.g., colloidal), cellulose, cellulose derivatives (e.g., cellulose derivatives in which the hydroxy groups of cellulose are substituted with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols, e.g., methyloxypropyl cellulose, methyl hydroxy ... cellulose, hydroxypropyl methylcellulose, cellulose ethers partially etherified with hydroxypropyl methylcellulose phthalate), fatty acids, and magnesium salts, calcium salts, or aluminum salts of fatty acids having 12 to 22 carbon atoms, especially saturated fatty acids (e.g., stearic acid), emulsifiers, fats and oils, especially vegetable fats (e.g., peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case optionally hydrated); saturated fatty acids C 12 H 24 O2~C 18 H 36Glycerol and polyglycerol esters of O2 and mixtures thereof, in which the hydroxy groups of glycerol can be completely or only partially esterified (e.g., monotriglycerides, ditriglycerides, and triglycerides); pharmaceutically acceptable mono- or polyhydric alcohols and polyglycols, such as polyethylene glycol and its derivatives, aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols, such as glycol, glycerol, diethylene glycol, Examples of the ester include esters of glycerol, pentaerythritol, sorbitol, mannitol, etc., which may be etherified if desired, esters of citric acid and primary alcohols, acetic acid, urea, benzyl benzoate, dioxolane, glycerol formal, tetrahydrofurfuryl alcohol, polyglycol ethers with C1 to C12 alcohols, dimethylacetamide, lactamide, lactate, ethyl carbonate, silicones (especially medium viscosity polydimethylsiloxane), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, and the like.

[0179] Other adjuvants useful in preparing oral dosage forms are those that cause disintegration (so-called disintegrants), such as cross-linked polyvinylpyrrolidone, sodium starch glycolate, sodium carboxymethylcellulose, or microcrystalline cellulose. Conventional coating materials may also be used to prepare oral dosage forms. Examples include polymers and copolymers of acrylic acid and / or methacrylic acid and / or their esters; copolymers of acrylic acid and methacrylic acid esters with a low ammonium group content (e.g., Eudragit® RS); copolymers of acrylic acid esters and methacrylic acid esters with trimethylammonium methacrylate (e.g., Eudragit® RS). RL); polyvinyl acetate; oils, waxes, fatty alcohols; hydroxypropyl methylcellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate, and polyvinyl acetate phthalate, carboxymethylcellulose; methylcellulose phthalate, methylcellulose succinate, methylcellulose phthalate succinate, and methylcellulose phthalic acid half ester; zein; ethylcellulose and ethylcellulose succinate; shellac, gluten; ethylcarboxyethylcellulose; methacrylic acid (ethacrylate)-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

[0180] Plasticizers that may be considered as coating materials in oral dosage forms of the present disclosure are as follows: citric acid and tartaric acid esters (acetyltriethyl citrate, acetyltributyl citrate, tributyl citrate, triethyl citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate. butyl glycolate; alcohols (propylene glycol, polyethylene glycols of various chain lengths), adipates (diethyl adipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate; benzophenone; diethyl and dibutyl sebacate, dibutyl succinate, dibutyl tartrate; diethylene glycol dipropionate; ethylene glycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbar 50); sorbitan monooleate.

[0181] Furthermore, suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, fluidizing agents, and melting agents may be included as carriers. The pharmaceutical carriers employed may be, for example, solid, liquid, or gaseous. Examples of solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include liquid sugar, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0182] In various embodiments, binders may include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn syrup, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. In further embodiments, disintegrants may include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0183] In various embodiments, oral dosage forms, such as solid dosage forms, can include a compound of the present disclosure conjugated to a polymer as a targetable drug carrier or as a prodrug. Suitable biodegradable polymers useful in achieving controlled release of drugs include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0184] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0185] Tablets containing the compounds of the present disclosure can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersing agent. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0186] In various embodiments, solid oral dosage forms such as tablets can be coated with an enteric coating to prevent rapid disintegration in the stomach. In various embodiments, enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate, and cellulose acetate phthalate. Akihiko Hasegawa, "Application of solid dispersions of nifedipine with enteric coating agent to prepare a sustained-release dosage form," Chem. Pharm. Bull. 33:1615-1619 (1985). Various enteric coating materials can be experimentally selected to achieve an enteric-coated dosage form originally designed to have a desirable combination of dissolution time, coating thickness, and diametral crushing strength (see, e.g., S. Porter et al., "The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose Acetate Phthalate," J. Pharm. Pharmacol. 22:42p (1970)). In further embodiments, the enteric coating may include hydroxypropyl-methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate, and cellulose acetate phthalate.

[0187] In various embodiments, the oral dosage form may be a solid dispersion with a water-soluble or water-insoluble carrier, including, but not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose, or hydroxypropyl methylcellulose, ethylcellulose, or stearic acid.

[0188] In various embodiments, oral dosage forms may be liquid dosage forms, including those that are taken orally or administered as mouthwash or gargle.For example, liquid dosage forms may include aqueous suspensions, which contain the active substance in a mixture with an excipient suitable for the preparation of an aqueous suspension.In addition, oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin.Oily suspensions may also contain various excipients.The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may contain excipients such as sweeteners and flavoring agents.

[0189] For the preparation of solutions or suspensions, it is possible to use, for example, water, in particular sterile water, or physiologically acceptable organic solvents such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and derivatives thereof, fatty alcohols, partial esters of glycerol), oils (for example, peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil, castor oil, ox foot oil), paraffin, dimethyl sulfoxide, triglycerides, etc.

[0190] In the case of liquid dosage forms such as drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic monohydric and polyhydric alcohols having 2 to 4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols having a molecular weight of 200 to 600 (for example, 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, such as amides of aliphatic C1 to C6 carboxylic acids with ammonia, or primary, secondary, or tertiary C1 to C4 amines or C1 to C4 hydroxyamines, such as urea, urethane, acetamide, N-methylacetamide, N,N-diethylacetamide, N,N-dimethylacetamide, lower aliphatic amines and diamines having 2 to 6 carbon atoms, such as ethylenediamine, hydroxyethyltheophylline, tromethamine (for example, 0.1 to 20% aqueous solution), and aliphatic amino acids.

[0191] In preparing the liquid dosage forms of the present disclosure, solubilizers and emulsifiers may be used, including, but not limited to, polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated sorbitan fatty acid esters, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolized oleotriglycerides, polyethylene oxide condensates of fatty alcohols, alkylphenols, or fatty acids, or 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context, polyoxyethylated means that the substance contains polyoxyethylene chains, the degree of polymerization of which is usually 2 to 40, particularly 10 to 20. Polyoxyethylated substances of this type can be obtained, for example, by reacting compounds containing hydroxyl groups (e.g., mono- or diglycerides or unsaturated compounds such as those containing an oleic acid radical) with ethylene oxide (e.g., 40 moles of ethylene oxide per mole of glyceride). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, and corn oil. See also Dr. HP Fiedler, "Lexikon der Hillsstoffe fur Pharmazie, Kostnetik und angrenzende Gebiete," 1971, pp. 191-195.

[0192] In various embodiments, the liquid dosage form may further comprise preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, coloring agents, antioxidants, complex formers, etc. Complex formers that may be considered include, for example, chelating agents such as ethylenediamine retrascetic acid, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, and salts thereof.

[0193] If desired, it may be necessary to stabilize the liquid dosage form with a physiologically acceptable base or buffer in the pH range of approximately 6 to 9. Wherever possible, neutral or weakly basic pH values ​​(maximum pH 8) may be preferred.

[0194] To enhance the solubility and / or stability of the compounds of the present disclosure in the liquid dosage forms, parenteral injection forms, or intravenous injection forms of the present disclosure, it may be advantageous to use α-, β-, or γ-cyclodextrin or derivatives thereof, particularly hydroxyalkyl-substituted cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Cosolvents such as alcohols may also improve the solubility and / or stability of the compounds of the present disclosure in pharmaceutical compositions.

[0195] In various embodiments, the liquid dosage forms, parenteral injection forms, or intravenous injection forms of the present disclosure may further comprise liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0196] Pharmaceutical compositions of the present disclosure are suitable for parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection can be prepared as a solution or suspension of the active compound in water. A suitable surfactant may be included, such as hydroxypropylcellulose. Dispersions can also be prepared in oils, glycerol, liquid polyethylene glycols, and mixtures thereof. In addition, preservatives may be included to prevent the growth of harmful microorganisms.

[0197] Pharmaceutical compositions of the present disclosure suitable for parenteral administration may include sterile aqueous or oily solutions, suspensions, or dispersions. Furthermore, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some embodiments, the final injectable dosage form must be sterile and effectively fluid for use in syringes. The pharmaceutical composition should be stable under the conditions of manufacture and storage, and thus preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0198] Injectable solutions can be prepared, for example, by using a carrier containing saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc. can be used. In some embodiments, the parenteral formulations of the present disclosure can contain about 0.01 to 0.1 M, e.g., about 0.05 M, phosphate buffer. In further embodiments, the parenteral formulations of the present disclosure can contain about 0.9% saline.

[0199] In various embodiments, parenteral pharmaceutical compositions of the present disclosure may contain pharmaceutically acceptable carriers, such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include, but are not limited to, water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Parenteral vehicles may include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as antimicrobials, antioxidants, collating agents, and inert gases. In further embodiments, parenteral pharmaceutical compositions of the present disclosure may contain small amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. Solid formulations that are intended to be converted to liquid formulations immediately prior to use are also contemplated as injectable pharmaceutical compositions. Furthermore, other adjuvants may be included to render the formulation isotonic with the blood of the subject or patient.

[0200] In addition to the pharmaceutical compositions described herein, the compounds of the present disclosure can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0201] The pharmaceutical compositions of the present disclosure may be in a form suitable for topical administration. As used herein, the phrase "topical application" refers to administration to a biological surface, including, for example, skin areas (e.g., hands, forearms, elbows, legs, face, nails, anal and genital areas) or mucous membranes. As described in more detail herein below, by selecting an appropriate carrier and, if desired, other ingredients that may be included in the composition, the compositions of the present disclosure may be formulated into any form commonly used for topical administration. Topical pharmaceutical compositions may be in the form of creams, ointments, pastes, gels, lotions, milks, suspensions, aerosols, sprays, foams, dusting powders, pads, and patches. Furthermore, the compositions may be in a form suitable for use in transdermal devices. These formulations may be prepared using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, via conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic substance and water with about 5 wt% to about 10 wt% of the compound to obtain a cream or ointment having the desired consistency.

[0202] In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable wetting agent, optionally combined with minor proportions of suitable additives of any nature, which do not cause significant adverse effects on the skin. The additives may facilitate application to the skin and / or may be useful in formulating the desired composition. These compositions may be administered in various ways, for example, as a transdermal patch, a spot-on, or an ointment.

[0203] Ointments are semi-solid formulations, typically based on petrolatum or petroleum derivatives. The particular ointment base used is one that provides optimal delivery of the active agent selected for a given formulation and preferably also provides other desirable characteristics (e.g., emollient properties). Like other carriers or solvents, ointment bases should be inert, stable, non-irritating, and non-sensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may be divided into four classes: oleaginous bases; emulsifiable bases; emulsifiable bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semi-solid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of different molecular weights.

[0204] Lotions are preparations that are applied to the skin surface without rubbing. Lotions are typically liquid or semi-liquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, as more fluid compositions are easier to apply. Lotions are typically suspensions of solids, often containing a liquid oil-in-water emulsion. Insoluble materials in lotions usually need to be finely divided. Lotions typically contain suspending agents to create better dispersion and compounds, such as methylcellulose and sodium carboxymethylcellulose, that are useful for localizing and retaining the active agent in contact with the skin.

[0205] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal phase," is usually composed of petrolatum and / or a fatty alcohol such as cetyl alcohol or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume and usually contains a humectant. The emulsifier in a cream formulation is usually a nonionic surfactant, an anionic surfactant, a cationic surfactant, or an amphoteric surfactant. For further information, reference may be made to Remington: The Science and Practice of Pharmacy, supra.

[0206] Pastes are semi-solid dosage forms in which a bioactive agent is suspended in a suitable base. Based on the nature of the base, pastes are divided into fatty pastes and pastes made from single-phase aqueous gels. The base in fatty pastes is usually petrolatum, hydrophilic petrolatum, etc. Pastes made from single-phase aqueous gels usually incorporate carboxymethylcellulose, etc., as a base. For further information, additional reference may be made to Remington: The Science and Practice of Pharmacy.

[0207] Gel formulations are semisolid suspension-type systems. Single-phase gels contain an organic polymer substantially uniformly dispersed throughout a carrier liquid, typically aqueous, but preferably also containing alcohol and, optionally, oil. Preferred organic polymers, i.e., gelling agents, are crosslinked acrylic acid polymers, such as the carbomer polymer family, such as carboxypolyalkylenes, available commercially under the Carbopol™ trademark. Other preferred polymers in this context are hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; modified celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersing agent such as alcohol or glycerin may be added, or the gelling agent may be dispersed by trituration, mechanical mixing or stirring, or a combination thereof.

[0208] Sprays typically provide an active agent in an aqueous and / or alcoholic solution, which can be delivered by spraying onto the skin. Such sprays include those formulated to concentrate the active agent solution at the administration site after delivery; for example, the spray solution may be primarily composed of a volatile liquid, such as alcohol, that can dissolve the active agent. Once delivered to the skin, the carrier evaporates, leaving the concentrated active agent at the administration site.

[0209] Foam compositions are typically formulated in a single- or multi-phase liquid form and packaged in a suitable container, optionally with a propellant to facilitate release of the composition from the container, resulting in conversion to a foam upon application. Other foam-forming techniques include, for example, the "bag-in-a-can" formulation technique. Compositions formulated in this manner typically contain a low-boiling hydrocarbon, such as isopropane. When such compositions are applied and stirred at body temperature, the isopropane vaporizes to produce a foam, in a manner similar to pressurized aerosol foaming systems. Foams can be aqueous or aqueous / alcoholic, but are typically formulated with a high alcohol content. Upon application to the user's skin, they rapidly evaporate, driving the active ingredient through the upper layers of the skin to the treatment site.

[0210] Skin patches typically comprise a backing material to which a reservoir containing an active agent is attached. The reservoir can be, for example, a pad dispersed or impregnated with the active agent or composition, or a liquid reservoir. The patch typically also comprises a water-permeable adhesive on the front surface, which adheres and secures the device to the treatment area. Self-adhesive silicone rubber can alternatively be used. In either case, a protective permeable layer can be used to protect the adhesive surface of the patch before use. Skin patches may also comprise a removable cover, which aids in protection during storage.

[0211] Examples of patch configurations that can be used with the present invention include single-layer or multi-layer drug-in-adhesive systems, characterized by the drug being directly incorporated into the adhesive that contacts the skin. In such transdermal patch designs, the adhesive not only serves to attach the patch to the skin but also serves as the formulation substrate, containing the drug and all excipients under a single backing film. In multi-layer drug-in-adhesive patches, a membrane is placed between two different drug-in-adhesive layers, or multiple drug-in-adhesive layers are incorporated under a single backing film.

[0212] Examples of pharmaceutically acceptable carriers suitable for topical pharmaceutical compositions include carrier substances well known in the cosmetic and pharmaceutical fields for use as bases for, for example, emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols, etc., depending on the form of the final composition. Representative examples of suitable carriers of the present invention therefore include, but are not limited to, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and similar substances commonly used in cosmetic and medicinal compositions. Other suitable carriers of the present invention include, but are not limited to, monohydric and polyhydric alcohols, such as alcohols such as ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexylene glycol, mannitol, and propylene glycol; ethers such as diethyl ether or dipropyl ether; polyethylene glycol and methoxypolyoxyethylene (carbowaxes having a molecular weight ranging from 200 to 20,000); polyoxyethylene glycerol, polyoxyethylene sorbitol, stearoyl diacetin, and the like.

[0213] The topical compositions of the present disclosure can be provided in a pack or dispenser device, such as an FDA-approved kit, which can contain one or more unit dosage forms containing the active ingredient, if desired. The dispenser device can include, for example, a tube. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser device can also be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting the agency's approval of the composition form for human or veterinary administration. Such notice can include, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or the notice of an approved product insert. Compositions comprising the topical compositions of the present invention formulated in a pharmaceutically acceptable carrier can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0214] Another patch system configuration that can be used with the present invention is a reservoir transdermal system design, characterized by a liquid compartment containing a drug solution or suspension separated from a release liner by a semipermeable membrane and an adhesive. The adhesive component of this patch system can be incorporated as a continuous layer between the membrane and the release liner or in a concentric arrangement around the membrane. Yet another patch system configuration that can be used with the present invention is a matrix system design, characterized by a semisolid matrix containing the drug solution or suspension in direct contact with the release liner. The component responsible for skin adhesion is incorporated into an overlay, forming a concentric arrangement around the semisolid matrix.

[0215] The pharmaceutical composition of the present disclosure can be in a form suitable for rectal administration, where the carrier is solid.Preferably, the mixture forms unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be easily formed by first mixing the composition with softened or melted carrier, then cooling and shaping in molds.

[0216] Pharmaceutical compositions containing the compounds of the present disclosure and / or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.

[0217] Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Generally, an article for distribution includes a container containing the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper-evident assemblage to prevent indiscreet access to the contents of the package. Additionally, the container is typically affixed with a label describing the contents of the container and any appropriate warnings or instructions.

[0218] The pharmaceutical compositions of the present disclosure may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may have attached thereto a notice, in a form prescribed by a governmental authority regulating the manufacture, use, or sale of pharmaceuticals, associated with the container, which notice reflects the agency's approval of the drug form for human or veterinary administration. Such notice may, for example, be labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Pharmaceutical compositions comprising a compound of the present disclosure formulated in a compatible pharmaceutical carrier may be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0219] As is well known to those skilled in the art, the exact dosage and frequency of administration depend on the specific compound of the present disclosure, the product of the manufacturing method of the present disclosure, its pharmaceutically acceptable salt, solvate, or polymorph, its hydrate, solvate, polymorph, or its stereochemical isomer; the specific condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered, such as the age, weight, sex, degree of disability, and general health of the specific subject, as well as other medications that the individual may be taking. Furthermore, it is clear that the aforementioned effective daily amount may be reduced or increased depending on the response of the treated subject and / or the evaluation of the physician prescribing the compound of the present disclosure.

[0220] Depending on the mode of administration, the pharmaceutical composition will contain 0.05 to 99% by weight, preferably 0.1 to 70% by weight, more preferably 0.1 to 50% by weight, of the active ingredient and 1 to 99.95% by weight, preferably 30 to 99.9% by weight, more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0221] In one embodiment, suitable dosage levels typically range from about 0.01 to 1000 mg of a compound described herein per kg of patient body weight per day, and can be administered in single or multiple doses. In various embodiments, dosage levels range from about 0.1 to about 500 mg / kg / day, about 0.1 to 250 mg / kg / day, or about 0.5 to 100 mg / kg / day. Suitable dosage levels can be about 0.01 to 1000 mg / kg / day, about 0.01 to 500 mg / kg / day, about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, dosages can be 0.05 to 0.5 mg / kg / day, 0.5 to 5.0 mg / kg / day, or 5.0 to 50 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, particularly 1.0 mg, 5.0 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 750 mg, 800 mg, 900 mg, and 1000 mg of active ingredient, for symptomatic adjustment of the dosage for the patient being treated. The compounds may be administered according to a dosage regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimum therapeutic response.

[0222] Unit doses such as those described above and below herein can be administered more than once daily, for example, two, three, four, five, or six times daily. In various embodiments, such unit doses can be administered once or twice daily, such that the total dosage for a 70 kg adult is within the range of 0.001 to about 15 mg / kg of subject body weight per administration. In further embodiments, the dosage is 0.01 to about 1.5 mg / kg of subject body weight per administration, and such treatment can extend for weeks or months, or even years. However, as will be appreciated by those skilled in the art, it will be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the particular compound used; the age, weight, general health, sex, and diet of the individual being treated; the time and route of administration; the rate of excretion; other previously administered medications; and the severity of the particular disease being treated.

[0223] Typical dosages include tablets of 1 mg to about 100 mg or tablets of 1 mg to about 300 mg taken once or multiple times daily, or sustained-release capsules or tablets containing a high percentage of the active ingredient taken once daily. The sustained-release effect can be achieved by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known controlled-release means.

[0224] It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art. Furthermore, it should be noted that the clinician or treating physician will know how or when to initiate, interrupt, adjust, or terminate treatment depending on the response of an individual patient.

[0225] The pharmaceutical compositions of the present disclosure may further comprise other therapeutically active compounds normally applied in the treatment of the above mentioned pathological or clinical conditions.

[0226] It is understood that the compositions of the present disclosure can be prepared from the compounds of the present disclosure, and that the compositions of the present disclosure can be used in the methods of use of the present disclosure.

[0227] As previously mentioned, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present disclosure, a product of a manufacturing method of the present disclosure, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof, and a pharmaceutically acceptable carrier. Additionally, the present disclosure relates to processes for preparing such pharmaceutical compositions, wherein the pharmaceutically acceptable carrier is intimately admixed with a therapeutically effective amount of a compound of the present disclosure.

[0228] Methods for Treating Cancer in a Subject In one embodiment, disclosed herein is a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the subject is human. In another embodiment, the subject has been diagnosed as needing cancer treatment prior to the administering step. In some embodiments, the method further comprises identifying a subject in need of cancer treatment. In one embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), neuroblastoma, glioblastoma multiforme, metastatic brain cancer, brain cancer, prostate cancer, or breast cancer.

[0229] In one embodiment, the compounds described herein can treat brain metastases (BM). Brain metastasis remains a major problem in lung cancer. 6 Treatment with most small molecule targeted therapeutics is severely restricted by efflux transporters at the blood-brain barrier (BBB). 6~10 Unfortunately, in NSCLC, up to 40% of patients will develop brain metastases (BM), and this number is expected to increase as treatment options continue to improve life expectancy for patients with advanced disease. 6 Therefore, BM is a significant risk and a cause of poor prognosis for NSCLC patients treated with tyrosine kinase inhibitors (TKIs) that have poor central nervous system (CNS) penetration. 7~10As demonstrated herein, the compounds described herein exhibit high brain penetration and potent activity in osimertinib-resistant cell lines.

[0230] In another aspect, disclosed herein is a method for inhibiting epidermal growth factor receptor (EGFR) in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In one aspect, the subject is a human.

[0231] In one embodiment, the compound is orally administered to a subject. In another embodiment, the compound is administered at a dose of about 50 mg / day to about 1,000 mg / day, or at a dose of about 50 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, or 1,000 mg / day, where any value can be the lower or upper limit of a range (e.g., 100 mg / day to 300 mg / day).

[0232] As shown in the examples, the compounds described herein are non-mutagenic and exhibit metabolic stability comparable to that of gefitinib. Furthermore, the compounds exhibit improved permeability and reduced efflux as measured in cellular assays. The compounds described herein can be used alone or in combination with other chemotherapeutic agents and / or radiation.

[0233] Aspects Aspect 1. A compound having structure I, or a pharmaceutically acceptable salt thereof: [ka]

[0234] During the ceremony, R 1is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; n is an integer from 1 to 5, and each R 2 are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, a halide, or an alkoxy group; m is an integer from 1 to 3, and each R 3 are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, a halide, or an alkoxy group; o is an integer from 1 to 10; X is O or NR 4 where R 4 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR 5 , or CR 6a R 6b where R 5 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 6a and R 6b are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium. Embodiment 2 The compound of embodiment 1, wherein X is O. Aspect 3 The compound of aspect 1 or aspect 2, wherein Y is O. Aspect 4 Y is NR 5 and R 5 The compound according to embodiment 1 or embodiment 2, wherein is a C1 to C5 alkyl group. Aspect 5 Y is CR 6a R 6b and R 6a is hydrogen and R 6b The compound of embodiment 1 or embodiment 2, wherein is a substituted or unsubstituted amino group. Aspect 6 R 1 The compound of any one of aspects 1-5, wherein is hydrogen. Aspect 7 R 3 The compound of any one of aspects 1 to 6, wherein is an alkoxy group. Aspect 8 R 3 The compound according to any one of aspects 1 to 6, wherein is an alkoxy group and m is 1. Aspect 9 The compound of any one of aspects 1 to 8, wherein o is an integer from 1 to 5. Aspect 10 R 2 The compound according to any one of embodiments 1 to 9, wherein is halide and n is 2. Aspect 11 R 2 The compound of any one of embodiments 1 to 10, wherein is a fluoride in the ortho position.

[0235] Embodiment 12: A compound of embodiment 1 having structure II, or a pharmaceutically acceptable salt thereof:

[0236] [ka]

[0237] During the ceremony, R1 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 2a and R 2b is a halide; R 3 is an alkoxy group; o is an integer from 1 to 5; X is O or NR 4 where R 4 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR 5 , or CR 6a R 6b where R 5 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 6a and R 6b are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium. Embodiment 13 The compound of embodiment 12, wherein X is O. Aspect 14. A compound according to aspect 12 or aspect 13, wherein Y is O. Aspect 15: Y is NR5 and R 5 The compound according to embodiment 12 or embodiment 13, wherein is a C1-C5 alkyl group. Aspect 16 Y is CR 6a R 6b and R 6a is hydrogen and R 6b

[0037] The compound according to embodiment 12 or embodiment 13, wherein is a substituted or unsubstituted amino group. Aspect 17 R 1 17. The compound of any one of embodiments 12-16, wherein is hydrogen. Aspect 18 R 3 18. The compound according to any one of aspects 12 to 17, wherein is a C1 to C10 substituted or unsubstituted straight or branched chain alkoxy group. Aspect 19 R 3 18. The compound of any one of aspects 12 to 17, wherein is a methoxy group. Aspect 20 The compound of any one of aspects 12 to 19, wherein o is an integer from 1 to 5. Aspect 21 R 2 21. The compound of any one of embodiments 12 to 20, wherein is halide. Aspect 22 R 2a is chlorine, and R 2b 22. The compound of any one of embodiments 12-21, wherein is fluoride.

[0238] Aspect 23 R 2a is fluoride, and R 2b 22. The compound of any one of embodiments 12-21, wherein is chloride. Embodiment 24: A compound of embodiment 1 having structure III, or a pharmaceutically acceptable salt thereof:

[0239] [ka]

[0240] During the ceremony, R 1is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 2a and R 2b is a halide; R 3 is an alkoxy group; o is an integer from 1 to 5; X is O or NR 4 where R 4 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR 5 , or CR 6a R 6b where R 5 is hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 6a and R 6b are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium. Embodiment 25. The compound of embodiment 24, wherein X is O. Aspect 26. A compound according to aspect 24 or aspect 25, wherein Y is O. Aspect 27 Y is NR 5and R 5 26. The compound according to embodiment 24 or embodiment 25, wherein is a C1-C5 alkyl group. Aspect 28 Y is CR 6a R 6b and R 6a is hydrogen and R 6b 26. The compound according to embodiment 24 or embodiment 25, wherein is a substituted or unsubstituted amino group. Aspect 29 R 1 The compound of any one of aspects 24-18, wherein is hydrogen. Aspect 30 R 3 Aspect 30. The compound according to any one of aspects 24 to 29, wherein is a C1 to C10 substituted or unsubstituted straight or branched chain alkoxy group. Aspect 31 R 3 30. The compound of any one of aspects 24 to 29, wherein is a methoxy group. Aspect 32 The compound of any one of aspects 24 to 31, wherein o is an integer from 1 to 5. Aspect 33 R 2 The compound of any one of aspects 24 to 32, wherein is a halide. Aspect 34 R 2a is chlorine, and R 2b The compound of any one of aspects 24 to 32, wherein is fluoride. Aspect 35 R 2a is fluoride, and R 2b The compound of any one of aspects 24 to 32, wherein is chloride. Aspect 36

[0241] [ka]

[0242] The compound of embodiment 1, wherein Aspect 37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 and a pharmaceutically acceptable carrier. Aspect 38. A method for treating a subject having non-small cell lung cancer, neuroblastoma, glioblastoma multiforme, metastatic brain cancer, brain cancer, breast cancer, or prostate cancer, comprising administering to the subject an effective amount of a compound of any one of aspects 1-36. Embodiment 39 A method for inhibiting epidermal growth factor receptor (EGFR) in a subject, comprising administering to said subject an effective amount of a compound of any one of embodiments 1-36. Aspect 40. A method for treating a subject having an osimertinib-resistant cancer, comprising administering to said subject an effective amount of a compound of any one of claims 1-36. Aspect 41. A method for treating a subject having brain metastases, comprising administering to said subject an effective amount of a compound of any one of claims 1-36. Aspect 42 The method of any one of Aspects 38 to 41, wherein the compound is administered orally to the subject. Aspect 43 The method of any one of Aspects 38 to 42, wherein the compound is administered at a dose of about 50 mg / day to about 1,000 mg / day. Embodiment 44 comprises reacting a compound having structure IV with a compound having structure V in the presence of a base;

[0243] [ka]

[0244] During the ceremony, R 1 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 2a and R 2b is a halide; R 3 is an alkoxy group; o is an integer from 1 to 5; X is O or NR 4 where R4 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR 5 , or CR 6a R 6b where R 5 is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R 6a and R 6b are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; each Z is, independently of the other, hydrogen or deuterium; LG is a leaving group, A method for making a compound according to any one of embodiments 1 to 16. Embodiment 45 The method of embodiment 44, wherein LG is a halide or sulfonate group.

[0046] A method according to any one of

[0047] Aspect 46 or Aspect 45, wherein the base comprises a hydride, an alkoxide, a Grignard reagent, or an alkyllithium compound. Embodiment 47 A method for making a compound having structure X, comprising:

[0245] [ka]

[0246] (In the formula, R 5 is a substituted or unsubstituted straight or branched chain alkyl group, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium. (a) reacting a compound having structure XI with a compound having structure XII in the presence of a base to form a compound having structure XIII;

[0247] [ka]

[0248] (In the formula, R 10 is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, LG is a leaving group) (b) reacting a compound having structure XIII with a first oxidizing agent with heating to form a compound having structure XIV;

[0249] [ka]

[0250] (c) reacting a compound having structure XIV with (i) a second oxidizing agent and then (ii) a first reducing agent to produce a first intermediate; and (d) reacting the first intermediate with a second reducing agent to produce a compound having structure X. A method comprising: Aspect 48 R 1048. The method of embodiment 47, wherein is a C1 to C5 linear or branched alkyl group. Aspect 49 R 10 48. The method of embodiment 47, wherein is a C1 to C5 straight or branched chain alkoxy group. Aspect 50 R 10 48. The method of embodiment 47, wherein is a C1 to C5 linear or branched alkoxy group substituted with an aryl group. Aspect 51 R 10 is a benzyloxy group. Embodiment 52 The method of any one of embodiments 46 to 51, wherein LG is a halide, sulfonate, carbonate, or phosphate. Aspect 53 The process of any one of aspects 47 to 52, wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide. Embodiment 54 The method of any one of embodiments 47 to 53, wherein step (a) is carried out in an aprotic organic solvent. Embodiment 55 The method of any one of embodiments 47 to 54, wherein step (a) is carried out at a temperature of from about 25°C to about 100°C. Aspect 56: Step (b) (i) reacting a compound having structure XIII with a first oxidizing agent in a first organic solvent to form a first composition; (ii) adding an aqueous base to the first composition to form a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to obtain a residue; (v) dissolving the residue in a second organic solvent to form a second composition; and (vi) heating the second composition to about 50° C. to about 100° C. to form a compound having structure XIV. 56. The method of any one of aspects 47 to 55, comprising: Aspect 57 The method of aspect 56, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene. Embodiment 58 The method of any one of embodiments 47 to 57, wherein the first oxidizing agent in step (b) comprises peroxyacid, oxone, or hydrogen peroxide / acetic acid. Embodiment 59 The method of any one of embodiments 47 to 57, wherein the first oxidizing agent in step (b) comprises metachloroperbenzoic acid. Embodiment 60. The method of any one of embodiments 47 to 57, wherein the molar ratio of the first oxidizing agent to the compound having the structure XIII is from 0.95:1 to 1:1.05. Aspect 61: Step (c) (i) reacting a compound having structure XIV with a second oxidizing agent in a third organic solvent to form a third composition; and (ii) combining the first reducing agent with the third composition to form a first intermediate. 61. The method of any one of aspects 47 to 60, comprising: Aspect 62. The method of aspect 61, wherein the second oxidizing agent comprises ozone or osmium tetroxide together with sodium metaperiodate. Aspect 63. The method of aspect 61 or 62, wherein the third organic solvent comprises an alcohol and an aprotic solvent. Aspect 64 The method of any one of aspects 61 to 63, wherein the compound having structure XIV is reacted with the second oxidizing agent at a temperature of from about -50°C to about -100°C. Embodiment 65 The method of any one of embodiments 47 to 64, wherein the first reducing agent comprises a hydride. Embodiment 66 The method of any one of embodiments 47 to 64, wherein the first reducing agent comprises a borohydride. Embodiment 67 The method of any one of embodiments 47 to 66, wherein the molar ratio of the first reducing agent to the compound having the structure XIV is from 1.5:1 to 2.5:1. Embodiment 68 The method of any one of embodiments 47 to 67, wherein the first intermediate is isolated prior to step (d). Aspect 69: Step (d) (i) dissolving the first intermediate in an aprotic solvent to form a fourth composition; (ii) combining the second reducing agent with the fourth composition to form a compound having structure X; and (iii) isolating and purifying the compound having the structure X. 69. The method of any one of embodiments 47 to 68, comprising: Embodiment 70 The method of embodiment 69, wherein the second reducing agent is combined with the fourth composition at a temperature of from about 10°C to about -50°C. Embodiment 71 The method of any one of embodiments 47 to 70, wherein the second reducing agent comprises a hydride. Embodiment 72 The method of any one of embodiments 47 to 70, wherein the second reducing agent comprises aluminum hydride. Aspect 73 The method of any one of aspects 47 to 70, wherein the molar ratio of the second reducing agent to the first intermediate is from 4:1 to 2:1. Aspect 74 R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h 74. The method of any one of embodiments 47 to 73, wherein each is hydrogen. Aspect 75 R 5 is a methyl group, and R7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h 74. The method of any one of embodiments 47 to 73, wherein each is hydrogen. Embodiment 76 A method for making a compound having structure XX, comprising:

[0251] [ka]

[0252] (In the formula, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium. (a) reacting a compound having structure XXI with a compound having structure XXII in the presence of a base to produce a compound having structure XXIII;

[0253] [ka]

[0254] (wherein LG is a leaving group). (b) reacting a compound having structure XXIII with a first oxidizing agent to produce a compound having structure XXIV;

[0255] [ka]

[0256] and (c) reacting said compound having structure XXIV with (i) a second oxidizing agent and then (ii) a first reducing agent to produce a compound having structure XX. A method comprising: Embodiment 77 The method of embodiment 76, wherein LG is a halide, sulfonate, carbonate, or phosphate. Aspect 78. The process of aspect 76 or aspect 77, wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide. Embodiment 79 The method of any one of embodiments 76 to 78, wherein step (a) is carried out in an aprotic organic solvent. Embodiment 80 The method of any one of embodiments 76 to 79, wherein step (a) is carried out at a temperature of from about 25°C to about 100°C. Aspect 81: Step (b) (i) reacting a compound having structure XXIII with a first oxidizing agent in a first organic solvent to form a first composition; (ii) adding an aqueous base to the first composition to form a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to obtain a residue; (v) dissolving the residue in a second organic solvent to form a second composition; and (vi) heating the second composition to about 50° C. to about 100° C. to form a compound having structure XXIV. 81. The method of any one of embodiments 76 to 80, comprising: Aspect 82 The method of aspect 81, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene. Embodiment 83 The method of any one of embodiments 76 to 82, wherein the first oxidizing agent in step (b) comprises peroxyacid, oxone, or hydrogen peroxide / acetic acid. Embodiment 84 The method of any one of embodiments 76 to 83, wherein the first oxidizing agent in step (b) comprises metachloroperbenzoic acid. Embodiment 85. The method of any one of embodiments 76 to 83, wherein the molar ratio of the first oxidizing agent to the compound having the structure XIII is from 0.95:1 to 1:1.05. Aspect 86: Step (c) (i) reacting a compound having structure XXIV with a second oxidizing agent in a third organic solvent to form a third composition; and (ii) combining the first reducing agent with the third composition to form a compound having structure XX; and (iii) isolating and purifying the compound having the structure XX. 85. The method of any one of embodiments 76 to 84, comprising: Aspect 87. The method of aspect 86, wherein the second oxidizing agent comprises ozone or osmium tetroxide together with sodium metaperiodate.

[0072] Aspect 88. The method of aspect 86 or aspect 87, wherein the third organic solvent comprises an alcohol and an aprotic solvent. Aspect 89 The method of any one of aspects 86 to 88, wherein the compound having structure XXIV is reacted with the second oxidizing agent at a temperature of from about -50°C to about -100°C. Embodiment 90 The method of any one of embodiments 76 to 89, wherein the first reducing agent comprises a hydride. Embodiment 91 The method of any one of embodiments 76 to 89, wherein the first reducing agent comprises a borohydride. Embodiment 92 The method of any one of embodiments 76 to 91, wherein the molar ratio of the first reducing agent to the compound having the structure XXIV is from 1.5:1 to 2.5:1. Aspect 93 R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h 93. The method of any one of embodiments 76-92, wherein each is hydrogen. Aspect 94 R 5 is a methyl group, and R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h 74. The method of any one of embodiments 47 to 73, wherein each is hydrogen. Embodiment 95. A compound having the structure XXX:

[0257] [ka]

[0258] (In the formula, Y is O or NR 5 and R 5 is a substituted or unsubstituted straight or branched chain alkyl group, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

[0259] Having provided a general description of aspects of the present disclosure above, the following examples illustrate some additional aspects of the present disclosure. While aspects of the present disclosure will be described in connection with the following examples and corresponding text and drawings, it is not intended to limit the aspects of the present disclosure to this description. On the contrary, all alternatives, modifications, and equivalents are intended to be encompassed within the scope of the present disclosure. [Example]

[0260] The following examples are set forth to provide those of ordinary skill in the art with a complete disclosure and description of how to make and evaluate the compounds, compositions, articles, devices, and / or methods claimed herein, and are intended to be merely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperatures are in °C, or are at ambient temperature and pressure.

[0261] Example 1 General Experiments All reactions were carried out in oven-dried glassware capped with rubber septa under an argon atmosphere unless otherwise noted. All organic solutions were concentrated under reduced pressure using a rotary evaporator and a water bath. Flash column chromatography was performed using silica gel (Fisher Silica Gel Sorbent (230-400 Mesh, Grade 60)). Thin-layer chromatography (TLC) was performed using 250 μM glass-backed silica (XHL) plates with a fluorescent indicator (254 nm). TLC plates were visualized by ultraviolet (UV) exposure and / or immersion in cerium ammonium molybdate (CAM) in ethanol followed by heating on a hotplate (120 °C, 10–15 s).

[0262] material The starting material 2-(tert-butyldimethylsilyloxy)-ethan-1-ol was purchased from AK Scientific. 2-Hydroperoxy-2-methyltetrahydro-2H-pyran (MTHPOOH) was prepared according to literature procedures. 11-13 The compound was prepared according to the method described in [1], and the spectral data were consistent with those previously reported in the literature. Morpholine and N-methylpiperazine were purchased from Sigma-Aldrich. Isopropylmagnesium chloride-lithium chloride complex solution (1.3 M in THF) was purchased from Sigma-Aldrich. Ethylmagnesium bromide (3 M in THF) was purchased from Sigma-Aldrich. Tetrabutylammonium fluoride (1 M in THF) was purchased from TCI. Thionyl chloride was purchased from Alfa Aesar. Sodium hydride (60% mineral oil dispersion) was purchased from Sigma-Aldrich. 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol was purchased from AK Scientific. 4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol was purchased from Ambido. Gefitinib (1) (≥98% (HPLC), SML1657-50MG) was purchased from Sigma-Aldrich. Materials for in vitro assays are described in the "In Vitro Assay Methods" section of the Examples section. The purity of assayed compounds (6, 13-15) was determined to be >95% by UHPLC and NMR.

[0263] Device Nuclear magnetic resonance (NMR) spectra of all compounds were obtained in CDCl3 (δ 7.26 and 77.16 ppm, respectively) or DMSO-D6 (δ 2.50 and 39.52 ppm, respectively) on a 500 MHz EZC500 JEOL instrument at 25 °C. Chemical shifts (δ) were calculated relative to the residual solvent peak and are reported in ppm. Multiplicities are abbreviated as follows: s (singlet), m (multiplet), b (broad), d (doublet), t (triplet), q (quartet), and hept (quintet). High-resolution mass spectra were obtained on a Thermo Fisher Orbitrap Q-Exactive using electrospray ionization (ESI). Melting points were measured on a Barstead Electrothermal 9100. UHPLC traces of 8, 13, and 15 were obtained using a PDA detector and an Acclaim 120 18 Acquisition was performed using a Thermo Fisher Vanquish UHPLC equipped with a C 4.6 x 50 mm column and % purity was determined using the Avalon peak area algorithm. The equipment used for the in vitro assay is described in the In Vitro Assay Method section of the Examples section.

[0264] Literature procedures 14 Synthesis of tert-butyldimethyl(2-((2-methyltetrahydro-2H-pyran-2-yl)peroxy)ethoxy)silane (8) by

[0265] [ka]

[0266] To a stirred solution of 7 (13.33 g, 75.71 mmol, 1.0 equiv) in anhydrous DCM (250 mL) at 0 °C, pyridine (9.66 mL, 113.57 mmol, 1.5 equiv) was added, followed by dropwise addition of TfO (15.26 mL, 90.85 mmol, 1.2 equiv), and the solution was stirred at 0 °C for 45 min. After that time, the mixture was diluted with DCM (100 mL) and washed sequentially with 1 N HCl (1 x 150 mL), aqueous NaHCO (1 x 150 mL), and aqueous brine (1 x 150 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. This crude triflate was used directly in the next step without further purification.

[0267] MTHPOOH in anhydrous THF (260 mL) at 0°C 11~13 To a stirred solution of (12 g, 90.85 mmol, 1.2 equiv.) KO t Bu (10.19 g, 90.85 mmol, 1.2 equiv) was added, and the solution was stirred for 30 min. After that, the crude triflate from the previous step was added dropwise in anhydrous THF (40 mL). The solution was warmed to room temperature and stirred for 90 min. After that time, the mixture was diluted with EtOAc (100 mL) and quenched by the addition of NaHCO (1 x 200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (eluent: 10:90 EtOAc:hexanes) to afford the title compound 8 (11.19 g, 38.56 mmol, 51%) as an off-yellow oil. Spectroscopic data are consistent with those previously reported in the literature. 14

[0268] R f = 0.50 (20:80 EtOAc:hexane; CAM). 1H NMR (500 MHz, CDCl3): δ 4.13-4.07 (m, 2H), 3.92 (td, J = 11.4, 2.8 Hz, 1H), 3.85 (t, J = 5.4 Hz, 2H), 3.71-3.68 (m, 1H), 1.79-1.50 (m, 6H), 1.43 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H). 13 C NMR (126 MHz, CDCl3): δ 102.5, 76.7, 61.8, 60.8, 33.3, 26.0, 24.9, 24.6, 19.2, 18.5, -5.2.

[0269] Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)morpholine (10)

[0270] [ka]

[0271] To a stirred solution of morpholine (7.64 mL, 87.33 mmol, 3.0 equiv) in anhydrous THF (73 mL) at 0° C. i PrMgCl LiCl (1.3 M in THF) (56 mL, 72.78 mmol, 2.5 equiv) was added, and the solution was allowed to warm to room temperature and stirred for 45 min. After that time, 8 (8.45 g, 29.11 mmol, 1.0 equiv) was added dropwise in anhydrous THF (73 mL), and the solution was stirred for 3 h. After that time, the solution was quenched with NaHCO (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (eluent: 15:85 EtOAc:hexanes) to afford the title compound 10 (4.95 g, 18.95 mmol, 65%) as a pale yellow oil.

[0272] R f = 0.20 (10:90 EtOAc:hexane; CAM). 1 H NMR (500 MHz, CDCl3): δ 3.88 (d, J = 11.8 Hz, 2H), 3.79-3.72 (m, 4H), 3.62-3.54 (m, 2H), 3.15 (d, J =10.6 Hz, 2H), 2.66 (td, J = 10.9, 3.3 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H). 13 C NMR (126 MHz, CDCl3): δ 73.1, 66.4, 61.6, 56.4, 26.0, 18.5, -5.1. HRMS-ESI(m / z):[C 12 H 28 O3N 28 Si] + [M+H] + Calculated value: 262.1833, Measured value: 262.1835.

[0273] 1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methylpiperazine (16)

[0274] [ka]

[0275] To a stirred solution of N-methylpiperazine (12.62 mL, 113.73 mmol, 3.0 equiv) in anhydrous THF (95 mL) at 0° C. iPrMgCl LiCl (1.3 M in THF) (72.9 mL, 94.78 mmol, 2.5 equiv) was added, and the solution was allowed to warm to room temperature and stirred for 45 min. After that time, 8 (11 g, 37.91 mmol, 1.0 equiv) was added dropwise in anhydrous THF (95 mL), and the solution was stirred for 3 h. After that time, the solution was quenched with NaHCO (75 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (eluent: 40:55:5 hexanes:EtOAc:triethylamine) to afford the title compound 16 (6.99 g, 25.5 mmol, 67%) as a yellow oil.

[0276] R f = 0.30 (40:55:5 hexane: EtOAc: triethylamine; CAM). 1 H NMR (500 MHz, C6D6) δ 3.83 (t, J = 5.2 Hz, 2H), 3.75 (t, J = 5.5 Hz, 2H), 3.15-3.13 (m, 2H), 2.84 (brs, 2H), 2.49-2.46 (m, 2H), 2.10-2.06 (m, 2H), 2.02 (s, 3H), 0.99 (s, 9H), 0.09 (s, 6H). 13 C NMR (126 MHz, C6D6) δ 73.2, 62.0, 55.9, 54.4, 45.6, 26.2, 18.6, -5.1. HRMS-ESI(m / z):[C 13 H 31 O2N2Si] + [M+H] + Calculated value: 275.2149, Measured value: 275.2146.

[0277] Synthesis of 2-(morpholinoxy)ethan-1-ol (11)

[0278] [ka]

[0279] To a stirred solution of 10 (4.90 g, 18.80 mmol, 1.0 equiv) in anhydrous THF (150 mL) at 0° C., TBAF (1 M in THF) (37.60 mL, 37.60 mmol, 2.0 equiv) was added dropwise, and the solution was allowed to warm to room temperature and stirred for 1 h, after which time the mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (eluent: 95:5 EtOAc:triethylamine) to afford the title compound 11 (2.17 g, 14.75 mmol, 79%) as a yellow oil.

[0280] R f = 0.50 (95:5 EtOAc:triethylamine; CAM) 1 H NMR (500 MHz, CDCl3): δ 3.91 (d, J = 12.3 Hz, 2H), 3.86-3.79 (m, 4H), 3.56 (t, J = 12.6 Hz, 2H), 3.34 (br s, 1H), 3.21 (d, J = 11.9 Hz, 2H), 2.67 (td, J = 10.9, 3.3 Hz, 2H). 13 C NMR (126 MHz, CDCl3): δ 71.6, 66.3, 63.6, 56.2. HRMS-ESI(m / z):[CH 14 O3N] + [M+H] + Calculated value: 148.0968, Measured value: 148.0964.

[0281] 2-((4-methylpiperazin-1-yl)oxy)ethan-1-ol (17)

[0282] [ka]

[0283] To a stirred solution of 16 (6.35 g, 23.16 mmol, 1.0 equiv) in anhydrous THF (300 mL) at 0° C., TBAF (1 M in THF) (46.32 mL, 46.32 mmol, 2.0 equiv) was added dropwise, and the solution was allowed to warm to room temperature and stirred for 90 min, after which time the mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (eluent: 90:10 EtOAc:triethylamine) to afford the title compound 17 (2.18 g, 13.61 mmol, 71%) as a yellow oil.

[0284] R f = 0.10 (90:10 EtOAc:triethylamine; CAM). 1 H NMR (500 MHz,Toluene-D8) δ 3.69-3.66 (m, 2H), 3.65-3.60 (m, 2H), 3.01 (br d, J = 10.3 Hz, 2H), 2.73-2.59 (m, 2H), 2.41 (br d, J = 11.3 Hz, 2H), 1.96 (s, 3H), 1.94-1.90 (m, 2H). 13 C NMR (126 MHz, toluene-D8) δ 72.2, 63.2, 55.4, 54.2, 45.3. HRMS-ESI(m / z):[CH 17 O2N2] + [M+H] + Calculated value: 161.1285, Measured value: 161.1282.

[0285] Synthesis of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(2-(morpholinoxy)ethoxy)quinazolin-4-amine (6)

[0286] [ka]

[0287] To a stirred solution of 11 (1 g, 6.80 mmol, 1.0 equiv) in anhydrous toluene (20 mL) at 0 °C was added SOCl (1.23 mL, 17.00 mmol, 2.5 equiv) dropwise and stirred until the exotherm ceased, then brought to 60 °C and stirred for 3 h, after which time the mixture was concentrated in vacuo and the resulting residue was used directly in the next step without further purification.

[0288] To a stirred solution of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol (3.26 g, 10.20 mmol, 1.5 equiv) in anhydrous DMF (35 mL) at 0 °C, NaH (60% mineral oil dispersion) (406 mg, 10.20 mmol, 1.5 equiv) was slowly added, and the solution was allowed to warm to room temperature and stir for 45 min. After this time, the crude chloride from the previous step was added dropwise in DMF (5 mL), and the solution was brought to 80 °C and stirred for 16 h. After this time, the mixture was concentrated in vacuo and co-concentrated with toluene (3 x 50 mL). The resulting residue was then redissolved in EtOAc (200 mL) and washed sequentially with 1 M NaOH (2 x 100 mL) and brine (2 x 100 mL), after which the combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (eluent: 10:90 triethylamine: EtOAc) to give the title compound 6 (1.08 g, 2.41 mmol, 35% over two steps) as a pale yellow powder.

[0289] R f = 0.50 (10:90 triethylamine: EtOAc; UV, CAM) 1H NMR (500 MHz, DMSO-D6): δ 9.51 (s, 1H), 8.50 (s, 1H), 8.12 (dd, J = 6.8, 2.7 Hz, 1H), 7.83-7.78 (m, 2H), 7.44 (t, J = 9.1 Hz, 1H), 7.20 (s, 1H), 4.29 (t, J = 4.5 Hz, 2H), 4.08 (t, J = 4.5 Hz, 2H), 3.94 (s, 3H), 3.81 (d, J = 11.6 Hz, 2H), 3.44 (t, J = 11.4 Hz, 2H) 3.18 (d, J = 10.4 Hz, 2H), 2.54 (d, J = 11.8 Hz, 2H)。 13 C NMR (126 MHz, DMSO-D6): δ 156.0, 154.5, 153.1 (d, 1 J C-F = 243.2 Hz), 152.7, 148.2, 147.0, 136.8 (d, 3 J C-F = 3.8 Hz), 123.4, 122.2 (d, 3 J C-F = 6.3 Hz), 118.8 (d, 2 J C-F = 18.9f Hz), 116.5 (d, 2 J C-F =21.4 Hz), 108.7, 107.4, 102.7, 69.0, 67.4, 65.5, 56.2, 55.8。 13 C NMR { 19 F} (126 MHz, DMSO-D6): δ 156.0, 154.5, 153.1, 152.7, 148.2, 147.0, 136.8, 123.4, 122.2, 118.8, 116.5, 108.7, 107.4, 102.7, 69.0, 67.4, 65.5, 56.2, 55.8。 19 F { 1 H} (470 MHz, DMSO-D6): -123.2 HRMS-ESI(m / z):[C 21 H 23 O4N4 35 ClF] + [M+H] + Calculated value: 449.1386, Measured value: 449.1378. mp: 186.4~187.5℃ (average value of n=3 measurements)

[0290] Synthesis of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(2-(morpholinoxy)ethoxy)quinazolin-4-amine (13)

[0291] [ka]

[0292] To a stirred solution of 11 (1.90 g, 12.9 mmol, 1.0 equiv) in anhydrous toluene (40 mL) at 0 °C was added SOCl (3.84 mL, 32.25 mmol, 2.5 equiv) dropwise and stirred until the exotherm ceased, then brought to 60 °C and stirred for 3 h, after which time the mixture was concentrated in vacuo and the resulting residue was used directly in the next step without further purification.

[0293] To a stirred solution of 4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (6.19 g, 19.35 mmol, 1.5 equiv) in anhydrous DMF (70 mL) at 0 °C, NaH (60% mineral oil dispersion) (770 mg, 19.35 mmol, 1.5 equiv) was slowly added, and the solution was allowed to warm to room temperature and stir for 45 min. After this time, the crude chloride from the previous step was added dropwise in DMF (10 mL), and the solution was brought to 80 °C and stirred for 16 h. After this time, the mixture was concentrated in vacuo and co-concentrated with toluene (3 x 75 mL). The resulting residue was then redissolved in EtOAc (150 mL) and washed sequentially with 1 M NaOH (2 x 75 mL) and brine (2 x 75 mL), after which the combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (eluent: 10:90 triethylamine: EtOAc) to afford the title compound 13 (1.67 g, 3.73 mmol, 29% over two steps) as an off-white powder.

[0294] R f = 0.50 (10:90 triethylamine: EtOAc; UV, CAM) 1 H NMR (500 MHz, DMSO-D6): δ 9.61 (s, 1H), 8.38 (s, 1H), 7.82 (s, 1H), 7.54-7.52 (m, 1H), 7.49-7.46 (m, 1H), 7.28 (t, J = 8.3 Hz, 1H), 7.21 (s, 1H), 4.28 (t, J = 4.6 Hz, 2H), 4.07 (t, J = 4.6 Hz, 2H), 3.94 (s, 3H), 3.81 (d, J = 12.0 Hz, 2H), 3.44 (t, J = 11.3 Hz, 2H), 3.17 (d, J = 10.4 Hz, 2H), 2.55-2.52 (m, 2H). 13 C NMR (126 MHz, DMSO-D6): δ 156.9, 154.6, 153.0, 152.4 (d, 1 J C-F= 249.5 Hz), 148.2, 147.0, 128.4 (d, 2 J C-F = 12.6 Hz), 127.1, 126.9, 124.9 (d, 3 J C-F = 5.0 Hz), 120.2 (d, 2 J C-F = 16.4 Hz), 108.6, 107.2, 102.8, 69.0, 67.3, 65.5, 56.2, 55.9. 13 C NMR { 19 F} (126 MHz, DMSO-D6): δ 156.9, 154.6, 153.0, 152.4, 148.2, 147.0, 128.4, 127.1, 126.9, 124.9, 120.2, 108.6, 107.2, 102.8, 69.0, 67.3, 65.5, 56.2, 55.9. 19 F { 1 H} (470 MHz, DMSO-D6): --120.4. HRMS-ESI(m / z):[C 21 H 23 O4N4 35 ClF] + [M+H] + Calculated value: 449.1386, Measured value: 449.1376.

[0295] Synthesis of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(2-((4-methylpiperazin-1-yl)oxy)ethoxy)quinazolin-4-amine (14)

[0296] [ka]

[0297] To a stirred solution of 17 (300 mg, 1.87 mmol, 1.0 equiv) in anhydrous toluene (7 mL) at 0 °C, SOCl (340 μL, 4.68 mmol, 2.5 equiv) was added dropwise and stirred until the exotherm ceased, then brought to 60 °C and stirred for 3 h. After that time, the mixture was concentrated in vacuo, and the resulting residue was dissolved in EtOAc (20 mL) and washed with aqueous KCO (2 x 15 mL). The combined organic layers were then dried over NaSO, filtered, and concentrated. The resulting residue was used without further purification.

[0298] To a stirred solution of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol (898 mg, 2.81 mmol, 1.5 equiv) in anhydrous DMF (10 mL) at 0 °C, NaH (60% mineral oil dispersion) (112 mg, 2.81 mmol, 1.5 equiv) was slowly added, and the solution was warmed to room temperature and stirred for 45 min. After this time, the crude chloride from the previous step was added dropwise in DMF (5 mL), and the solution was brought to 80 °C and stirred for 16 h. After this time, the mixture was concentrated in vacuo and co-concentrated with toluene (3 x 20 mL). The resulting residue was then redissolved in EtOAc (30 mL) and washed sequentially with 1 M NaOH (2 x 20 mL) and brine (2 x 20 mL), after which the combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (eluent: 85:10:5 EtOAc:MeOH:triethylamine) to afford the title compound 14 (286 mg, 0.687 mmol, 33% over two steps) as a pale orange powder.

[0299] R f = 0.40 (85:10:5 EtOAc:MeOH:triethylamine; UV, CAM). 1H NMR (500 MHz, DMSO-D6): δ 9.53 (s, 1H), 8.50 (s, 1H), 8.12 (dd, J = 6.8, 2.6 Hz, 1H), 7.84-7.78 (m, 2H), 7.44 (t, J = 9.1 Hz, 1H), 7.21 (s, 1H), 4.28 (t, J = 5.0 Hz, 2H), 4.04 (t, J = 5.0 Hz, 2H), 3.94 (s, 3H), 3.15-3.13 (m, 2H), 2.70-2.67 (m, 2H), 2.57 (br s, 2H), 2.13-2.09 (m, 5H)。 13 C NMR (126 MHz, DMSO-D6): δ 156.0, 154.5, 153.1 (d, 1 J C-F = 243.2 Hz), 152.7, 148.2, 147.0, 136.8, 126, 123.4, 122.2 (d, 3 J C-F = 6.3 Hz), 118.8 (d, 2 J C-F = 18.9 Hz), 116.5 (d, 2 J C-F =21.4 Hz), 108.7, 107.4, 102.7, 69.1, 67.4, 55.9, 55.0, 53.5, 45.0。 13 C NMR { 19 F} (126 MHz, DMSO-D6): δ 156.0, 154.5, 153.1, 152.7, 148.2, 147.0, 136.8, 123.4, 122.2, 118.8, 116.5, 108.7, 107.4, 102.7, 69.0, 67.4, 55.9, 55.0, 53.5, 45.0。 19 F { 1 H} (470 MHz、 DMSO-D6): -123.2。 HRMS-ESI(m / z):[C 22 H 26 O3N5 35 ClF]+ [M+H] + Calculated value: 462.1703, Measured value: 462.1691. mp: 64.0-66.5℃ (average value of n=3 measurements)

[0300] Synthesis of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(2-((4-methylpiperazin-1-yl)oxy)ethoxy)quinazolin-4-amine (15)

[0301] [ka]

[0302] To a stirred solution of 17 (2.10 g, 13.12 mmol, 1.0 equiv) in anhydrous toluene (50 mL) at 0 °C, SOCl (2.38 mL, 32.80 mmol, 2.5 equiv) was added dropwise and stirred until the exotherm ceased, then brought to 60 °C and stirred for 3 h. After that time, the mixture was concentrated in vacuo, and the resulting residue was dissolved in EtOAc (100 mL) and washed with aqueous KCO (2 x 75 mL). The combined organic layers were then dried over NaSO, filtered, and concentrated. The resulting residue was used without further purification.

[0303] To a stirred solution of 4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (6.29 g, 19.68 mmol, 1.5 equiv) in anhydrous DMF (90 mL) at 0 °C, NaH (60% mineral oil dispersion) (783 mg, 19.68 mmol, 1.5 equiv) was slowly added, and the solution was allowed to warm to room temperature and stir for 45 min. After this time, the crude chloride from the previous step was added dropwise in DMF (10 mL), and the solution was brought to 80 °C and stirred for 16 h. After this time, the mixture was concentrated in vacuo and co-concentrated with toluene (3 x 25 mL). The resulting residue was then redissolved in EtOAc (150 mL) and washed sequentially with 1 M NaOH (2 x 100 mL), aqueous brine (2 x 100 mL), and the combined organic layers were then dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (eluent: 85:10:5 EtOAc:triethylamine:MeOH) to give the title compound 15 (1.19 g, 2.58 mmol, 20% over two steps) as a pale yellow powder.

[0304] R f = 0.30 (85:10:5 EtOAc:MeOH:triethylamine; UV, CAM). 1 H NMR (500 MHz, DMSO-D6): δ 9.61 (s, 1H), 8.39 (s, 1H), 7.83 (s, 1H), 7.57-7.51 (m, 1H), 7.48-7.46 (m, 1H), 7.29-7.26 (m, 1H), 7.21 (s, 1H), 4.27 (t, J = 4.6 Hz, 2H), 4.03 (t, J = 4.6 Hz, 2H), 3.94 (s, 3H), 3.15-3.12 (m, 2H), 2.69-2.67 (m, 2H), 2.57 (br s, 2H), 2.13-2.06 (m, 5H). 13 C NMR (126 MHz, DMSO-D6): δ 156.9, 154.6, 153.0, 152.4 (d, 1 J C-F= 249.5 Hz), 148.2, 147.0, 128.4 (d, 2 J C-F = 11.3 Hz), 127.1, 126.8, 124.9 (d, 3 J C-F = 5.0 Hz), 120.2 (d, 2 J C-F = 16.4 Hz), 108.6, 107.2, 102.8, 69.0, 67.2, 55.9, 55.0, 53.6, 45.0. 13 C NMR { 19 F} (126 MHz, DMSO-D6): δ 156.9, 154.6, 153.0, 152.4, 148.2, 147.0, 128.4, 127.1, 126.8, 124.9, 120.1, 108.6, 107.2, 102.8, 69.0, 67.2, 55.9, 55.0, 53.6, 45.0. 19 F { 1 H} (470 MHz, DMSO-D6): -120.4. HRMS-ESI(m / z):[C 22 H 26 O3N5 35 ClF] + [M+H] + Calculated value: 462.1703, Measured value: 462.1695. mp: 143.5-144.9℃ (average value of n=3 measurements)

[0305] Alternative piperazinylhydroxylamine synthesis An exemplary synthetic scheme for making the piperazinyl analogs described herein is shown in Figure 3. The [2,3]-Meisenheimer rearrangement is utilized to introduce the hydroxylamine unit. 15~17Starting from commercially available 18, allylation with allyl bromide under basic conditions gave the N-allylic derivative (19) in 72% yield. 19 was N-oxidized with metachloroperbenzoic acid (MCPBA) and then subjected to a [2,3]-Meisenheimer rearrangement to give 20 in 47% yield in two steps. The alkene present in 20 was then subjected to ozonolysis, followed by reduction with sodium borohydride (NaBH), after which the carboxybenzyl group was removed with lithium aluminum hydride. 18 Further reduction with (LiAlH4) afforded the desired hydroxylamine precursor 17 in 50% yield in two steps.

[0306] (experiment) (Synthesis of benzyl 4-allylpiperazine-1-carboxylate (19))

[0307] [ka]

[0308] To a stirred solution of benzylpiperazine-1-carboxylate (15 g, 68.14 mmol, 1.0 equiv) in anhydrous THF (250 mL) at room temperature was added KCO (18.8 g, 136.28 mmol, 2.0 equiv), followed by the slow addition of allyl bromide (11.8 mL, 136.28 mmol, 2.0 equiv). The solution was brought to 65 °C and stirred for 16 h, after which time the mixture was cooled to room temperature and quenched by the addition of 1 M NaOH (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (eluent: 50:45:5 hexanes:EtOAc:triethylamine) to give the title compound 19 (12.81 g, 49.2 mmol, 72%) as a yellow oil. f = 0.60 (50:45:5 hexane: EtOAc: triethylamine; CAM, UV). 1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.89-5.78 (m, 1H), 5.23-5.14 (m, 2H), 5.13 (br s, 2H), 3.56 (m, 4H), 3.00 (d, J = 6.6 Hz, 2H), 2.40 (br s, 4H). 13 C NMR (126 MHz, CDCl3) δ 155.4, 136.9, 134.7, 128.6, 128.1, 128.0, 118.5, 67.2, 61.8, 52.8, 43.9. HRMS-ESI(m / z) [C 15 H 21 N2O2] + [M+H] + Calculated value: 261.1598, Measured value: 261.1594.

[0309] (Synthesis of benzyl 4-(aryloxy)piperazine-1-carboxylate (20))

[0310] [ka]

[0311] To a stirred solution of 19 (12.2 g, 46.9 mmol, 1.0 equiv) in anhydrous DCM at −30° C., MCPBA (70% mixture of 3-chlorobenzoic acid and water) (11.56 g, 46.9 mmol, 1.0 equiv) was added portionwise over 5 min. After the entire addition, the reaction mixture was stirred at −30° C. for 1 h, then quenched with aqueous NaHCO (150 mL) and the layers separated. After washing the organic layer with NaHCO (3×150 mL), the organic layer was dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was dissolved in toluene heated to 80° C. and stirred for 14 h. After that time, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (eluent: 80:15:5 hexanes:EtOAc:triethylamine) to give the title compound 20 (6.13 g, 22.2 mmol, 47%) as a clear oil. f= 0.50 (30:70 EtOAc:hexane; CAM, UV). 1 H NMR (500 MHz, CDCl3) δ 7.39-7.30 (m, 5H) 5.99-5.88 (m, 1H), 5.27 (d, J = 17.3 Hz, 1H), 5.18 (d, J = 10.3 Hz, 1H), 5.13 (s, 2H), 4.21 (d, J = 6.1 Hz, 2H), 4.03 (s, 2H), 3.19-3.11 (m, 4H), 2.57 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 155.3, 136.8, 134.6, 128.7, 128.2, 128.1, 118.0, 73.2, 67.4, 55.3, 42.7. HRMS-ESI(m / z):[C 15 H 21 N2O3] + [M+H] + Calculated value: 277.1547, Measured value: 277.1540.

[0312] (Synthesis of 2-((4-methylpiperazin-1-yl)oxy)ethan-1-ol (17))

[0313] [ka]

[0314] Compound 20 (5.6 g, 20.27 mmol, 1.0 equiv) was dissolved in a mixture of DCM (200 mL) and methanol (50 mL) and cooled to −78 °C. Ozone was bubbled through the reaction mixture for 30 minutes to completely consume the starting material. When ESIMS showed completion, argon was bubbled through the reaction mixture to remove any remaining ozone. NaBH (1.53 g, 40.54 mmol, 2.0 equiv) was then added in portions at −78 °C, and the solution was allowed to gradually warm to room temperature and stirred for 1 hour. After that time, the mixture was quenched with aqueous NaHCO (200 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 150 mL) and the combined organic layers were washed with aqueous brine (2 x 150 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the alcohol directly as a clear oil (5.26 g, 18.8 mmol, 93% crude yield). TLC R f = 0.10 (70:30 EtOAc:hexane; CAM, UV). 1 H NMR (500 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.13 (s, 2H), 4.07 (s, 2H), 3.84-3.81 (m, 4H), 3.24-3.10 (m, 5H), 2.60-2.56 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 155.2, 136.6, 128.7, 128.3, 128.1, 71.9, 67.5, 65.3, 55.0, 42.7. HRMS-ESI(m / z) [C 14 H 21 O4N2] + [M+H] + Calculated value: 281.1496, Measured value: 281.1489.

[0315] The crude alcohol thus obtained (5.26 g, 18.8 mmol, 1.0 equiv.) from the previous step was dissolved in anhydrous THF (68 mL) and cooled to 0 °C. LiAlH (2.31 g, 60.81 mmol, 3.2 equiv.) was then added portionwise over 5 min. After the entire addition, the solution was warmed to room temperature and stirred for 2 h. After that time, the reaction mixture was cooled back to 0 °C and quenched by the slow addition of HO. After the effervescence had ceased, the solution was acidified to approximately pH 2 with concentrated HCl. The aqueous layer was then extracted with EtOAc (4 x 150 mL), after which the aqueous layer was cooled to 0 °C and basified to approximately pH 10 by the portionwise addition of solid NaOH. The basified aqueous layer was extracted with EtOAc (4 x 100 mL), and the resulting organic layer was dried over NaSO, filtered, and concentrated in vacuo to give the title compound 17 (1.63 g, 10.2 mmol, 50% yield over two steps from 20) as a yellow oil. Spectroscopic data were identical to those of an authentic sample.

[0316] In vitro assays Kinase activity In vitro kinase activity (inhibitor binding constant (K d ) and biochemical inhibition (IC 50 )) was installed on Eurofins DiscoverX (K d Measurement) and Cerep (biochemical IC 50 The evaluation was carried out by K d For measurements, compounds were run in duplicate (n=2) and assayed using an 11-point, 3-fold dilution series with a highest compound test concentration of 10 μM on a Eurofins KINOMEScan KdELECT assay. Biochemical IC 50 Compounds were run in duplicate (n=2) and tested in an enzyme radiometric assay using a 9-point, half-log dilution series with a highest test compound concentration of 10 μM and an ATP concentration of 10 μM using Eurofins KinaseProfiler technology.

[0317] LogD by the shake flask method7.4 (Pharmalon Co., Ltd., Ningbo, China) The lipophilicity of the compounds was determined by Pharmaron using the shake-flask method in 1-octanol and PBS (pH 7.4). Each compound was assayed in duplicate (n=2) at 1 μM in a 96-well plate at 25°C with shaking at 2,000 rpm for 2 hours. Samples were analyzed by LC-MS / MS.

[0318] Solubility determination in PBS at pH 7.4 (Pharmalon Co., Ltd., Ningbo, China) Solubility was measured by Pharmaron, and each compound was assayed in duplicate (n=2) by adding 15 μL of compound stock solution (10 mM in DMSO) to a 96-well plate along with 485 μL of buffer, followed by shaking at 1,100 rpm at 25°C for 2 hours. The wells were filtered to collect 5 μL samples, which were then diluted with an equal volume of 5 μL DMSO and 490 μL of aqueous solution. The samples were analyzed by LC-MS / MS.

[0319] metabolic stability assay (Pharmalon Co., Ltd., Ningbo, China); Pharmaron conducted an evaluation of the metabolic stability of the compound when incubated with human and rat liver microsomes and hepatocytes using a compound depletion approach. Compound 15 underwent additional stability evaluation in monkey and dog hepatocytes. Microsomal stability was assayed in duplicate (n=2) using human (BD Gentest) and SD rat (BD Gentest) liver microsomes (0.5 mg / mL) in the presence and absence of NADPH. 1 μM of compound was incubated in liver microsomes, and samples (30 μL) were withdrawn at 0.5, 15, 30, 45, and 60 minutes for analysis by LC-MS / MS. Hepatocyte stability was assessed in duplicate (n=2) using 0.5×10 6Assays were performed using human (BioIVT), SD rat (BioIVT), cynomolgus monkey (RILD), or beagle dog (BioIVT) hepatocytes at a working cell density of 1000 cells / mL. 1 μM of compound was incubated in the hepatocytes, and samples (25 μL) were taken at 0.5, 15, 30, 60, 90, and 120 minutes and analyzed by LC-MS / MS. In vitro half-lives and intrinsic clearance were previously reported. 19 was measured as it was.

[0320] In vitro half-life (in vitro t 1 / 2 ) is an in vitro 1 / 2 This was calculated from the slope value of =-(0.693 / k).

[0321] where k was determined by linear regression of the curve of the natural logarithm of the parent drug residual rate against incubation time.

[0322] Plasma protein binding by equilibrium dialysis (Pharmalon Co., Ltd., Ningbo, China). Plasma protein binding and brain tissue binding were measured by Pharmaron using equilibrium dialysis. Each compound was assayed in duplicate (n=2) at 5 μM with a final volume percentage of 0.5% organic solvent. Compounds were incubated at 37°C, 5% CO2, and 100 rpm for 6 hours, with samples (50 μL) withdrawn at the beginning and end of the incubation. After incubation, samples were analyzed by LC-MS / MS, and compound concentrations were measured in the buffer and plasma chambers.

[0323] Plasma stability (Pharmalon Co., Ltd., Ningbo, China) Each compound was evaluated by Pharmaron to determine its stability upon incubation with human plasma (Pharmaron) and SD rat plasma (IPHASE) using a compound deletion approach. Compounds were assayed in duplicate (n = 2) and incubated at 5 μM in plasma. Samples (50 μL) were collected at 0, 15, 30, 60, and 120 min and analyzed by LC-MS / MS. Peak area ratios were determined from extracted ion chromatograms, and the percentage of compound remaining at each time point was calculated using the following formula: Survival rate t分 (%) = Peak area ratio t分 / peak area ratio 0分 ×100 where, peak area ratio t分 is the peak area ratio of the control and test compound at t minutes, and the peak area ratio 0分 is the peak area ratio of the control and test compound at time zero.

[0324] Permeability test (Pharmalon Co., Ltd., Ningbo, China) Each compound was evaluated at Pharmaron for its ability to penetrate Caco-2 and MDCKII-MDR1 cells. Caco-2 and MDCKII-MDR1 cells were seeded in 96-well HTS Transwell plates (Corning). Caco-2 cells were seeded at 6.86 × 10 5 MDCKII-MDR1 cells were seeded at a density of 1.56 × 10 cells / mL and cultured for 14–18 days before assay. 6Cells were seeded at a density of 1000 cells / mL and cultured for 4-8 days before assay. To determine drug transport rates in both the absorptive (apical to basolateral (AB)) and secretory (basolateral to apical (BA)) directions, each compound (5 μM in DMSO for Caco-2 cells and 1 μM in DMSO for MDCKII-MDR1 cells) was added to the donor wells. The plate was incubated at 37°C for 2 hours. Samples (50 μL) were withdrawn from both the donor and acceptor wells at the beginning and end of the incubation period. The assay was performed in duplicate (n=2). Samples were analyzed by LC-MS / MS. (cm / s×10 -6 ) apparent permeability coefficient (P app ) was calculated using the following formula: P app =V A ×[Drug] アクセプター / area x time x [drug] 初期、ドナー In the formula, V A represents the volume (mL) in the acceptor well. The area is the membrane surface (0.143 cm for Transwell-96 well plates). 2 ) and time is the total transport time in seconds. The discharge ratio was calculated using the following formula: Discharge ratio = P app (BA) / P app (AB) In the formula, P app (BA) indicates apparent permeability in the basolateral to apical direction, and P app (AB) shows apparent permeability in the apical to basolateral direction.

[0325] hERG channel inhibition assay The potential inhibitory effect of each compound on the hERG channel was previously reported by Pharmaron. 20The evaluation was performed using a manual patch clamp system as described in [1]. HEK293 cells stably transfected with the hERG gene (Invitrogen) were used. Each compound was tested at five concentrations (0.37 μM, 1.11 μM, 3.33 μM, 10 μM, and 30 μM) and measured in triplicate (n=3). IC 50 IC values ​​were determined by plotting % inhibition versus compound concentration from a nonlinear regression equation fitted to a sigmoidal dose-response curve using GraphPad Prism. 50 Values ​​are expressed as mean ± SEM.

[0326] Measurement of human CYP450 inhibition by 15 The potential of compound 15 to inhibit cytochrome P450 (CYP) isoforms was evaluated at Pharmaron using human liver microsomes. The activities tested were O-demethylation of phenacetin via CYP1A2, 4'-hydroxylation of (S)-mephenytoin via CYP2C19, 4'-hydroxylation of diclofenac via CYP2C9, O-demethylation of dextromethorphan via CYP2D6, and 1'-hydroxylation of midazolam via CYP3A4. The substrate concentrations were phenacetin (40 μM), mephenytoin (50 μM), diclofenac (6 μM), dextromethorphan (2 μM), and midazolam (1 μM). The probe substrates phenacetin, mephenytoin, and dextromethorphan were incubated at 37°C for 20 min. The probe substrates diclofenac and midazolam were incubated at 37°C for 5 min. Compound 15 was tested in an eight-point, three-fold dilution series (0.01 μM to 30 μM) in DMSO and incubated with pooled human liver microsomes (0.5 mg / mL) (BD Gentest) and a probe substrate cocktail for selective CYP isoforms. The reaction was initiated by the addition of NADPH (1 mM final concentration) after a 5-min preincubation, and assays were performed in duplicate (n = 2). Samples were analyzed by UPLC-MS / MS. Inhibition of each P450 enzyme was measured as the percent reduction in marker metabolite formation activity compared to the uninhibited control. IC 50 Values ​​were determined in GraphPad Prism by fitting the residual activity (%) and the logarithm of the inhibitor concentration with a nonlinear fit [inhibitor] versus normalized response (variable slope).

[0327] Measurement of time-dependent CYP2D6 inhibition by 15 Compound 15 was evaluated at Pharmaron for potential time-dependent CYP2D6 inhibition using human liver microsomes (BD Gentest) and primary human hepatocytes (BioIVT). Bufuralol (2 μM) was used as the substrate for liver microsomes, and dextromethorphan (40 μM) was used for hepatocytes. The activities tested were CYP2D6-mediated 1'-hydroxylation of bufuralol and CYP2D6-mediated O-demethylation of dextromethorphan. Compound 15 was assayed in duplicate (n=2) at six points, a three-fold dilution series in DMSO (0.03 μM to 10 μM), and was then tested in pooled human liver microsomes (0.5 mg / mL) or primary human hepatocytes (0.3 × 10 6 The CYP2D6 inhibitors were incubated with 1000kJ / mL (1000kcal / mL cells). Incubations with pooled human liver microsomes were performed with or without preincubation with NADPH (1 mM final concentration) at 37°C, 5% CO2 for 30 minutes. Incubations with human hepatocytes were performed without preincubation or with preincubation at 37°C, 5% CO2 for 30 minutes. Experiments were performed at 37°C, 5% CO2 for 5 minutes. Inhibition of CYP2D6 was measured as the percentage reduction in marker metabolite formation activity compared to the uninhibited control. IC 50 Values ​​were determined in GraphPad Prism by fitting the residual activity (%) and the logarithm of the inhibitor concentration with a nonlinear fit [inhibitor] versus normalized response (variable slope).

[0328] AMES Fluctuation Test (Eurofins PanLabs, St. Charles, Missouri, USA) Each compound was previously reported 21Mutagenicity was evaluated at Eurofins PanLab in 384-well plates using four Salmonella strains: TA98 (quercetin used as a control) to probe frameshift mutations, TA100 and TA1535 (streptozotocin used as controls) to probe base pair insertion / deletion, and TA1537 (aminoacridine used as a control) to probe frameshift mutations, as described previously. Each compound was incubated at 37°C for 96 hours at four different concentrations (5 μM, 10 μM, 50 μM, and 100 μM) (each concentration tested with 48 replicates) in both the presence and absence of rat liver S9 metabolic activation. To exclude false negatives, parallel bacterial toxicity assays were performed at 0.6 μM, 1.2 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 100 μM. Bacterial virulence was measured as a percentage of control growth (OD 650 Compounds that showed less than 60% growth of the control were marked and considered to be bacterially toxic. Wells that showed bacterial growth due to reversion of the histidine mutation (OD 430 / OD 570 The number of positive cases (determined by a ratio of >1.0) was counted and recorded as the number of positive cases. The significance of the number of positive cases between the treatment and control groups was determined using a one-tailed Fisher's exact test.

[0329] In vitro micronucleus assay Compound 15 was evaluated for genotoxicity by Eurofins PanLab using an in vitro micronucleus assay in Chinese hamster ovary (CHO-K1) cells as previously reported. 22Compound 15 was incubated in a 96-well plate format at various concentrations (8 μM, 16 μM, 31 μM, 62 μM, 125 μM, 250 μM, 500 μM, and 1000 μM) for 4 h at 37°C in the presence of metabolic activation with rat liver S9 and for 24 h at 37°C in the absence of metabolic activation with rat liver S9. Micronuclei were detected using high-content analysis and fluorescence imaging and compared to positive controls (cyclophosphamide (run at 7.2 μM) and mitomycin C (run at 0.3 μM)). The significance of the number of positives between treatment and control groups was determined by a two-sample, equal-variance, one-tailed t-test.

[0330] 15 kinase selectivity determination Profiling of a panel of 468 human kinases was performed at Eurofins DiscoverX using the KINOMEScan platform. The panel of 468 kinases was assayed against 15 kinases at a single concentration of 1 μM. Percentages relative to control were mapped onto a kinome tree using TREEspot™. S scores were calculated as previously reported. 23 The S score reflects the number of kinases bound by 15 divided by the total number of wild-type kinases.

[0331] In vitro CTG assay (Crown Biosciences) cell line The A431, HCC827, SK-BR-3, ZR-75-30, AU565, and Caco-2 cell lines were obtained from ATCC. The NCI-H1975 cell line was obtained from SIBS. The NCI-H3255 cell line was obtained from CoBioer. The modified Ba / F3 cell line was obtained from Crown Biosciences. MCKII-MDR1 cells were obtained from the Netherlands Cancer Institute. HEK293 cells were obtained from Invitrogen. A431 cells were cultured in DMEM (Life Technologies) containing 10% FBS. HCC827, NCI-H1975, and AU565 cells were cultured in RPMI 1640 (Invitrogen) containing 10% FBS. NCI-H3255 cells were cultured in BEGM (Lonza) containing 10% FBS. Ba / F3 EGFR-del E746_A750 / C797S cells and Ba / F3 EGFR-L858R / C797S cells were cultured in RPMI (Invitrogen) containing 10% FBS. SK-BR-3 cells were cultured in McCoy's 5a (Invitrogen) containing 10% FBS. ZR-75-30 cells were cultured in RPMI 1640 (Invitrogen) containing 20% ​​FBS. BT474 cells were cultured in DMEM (Gibco) containing 10% FBS and 10 μg / mL insulin. Culture information for Caco-2 and MCKII-MDR1 cells is provided in the permeability study section. HEK293 cells were cultured in DMEM (Gibco) containing 10% FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, μg / mL blasticidin, and 400 μg / mL geneticin. All cells were maintained in a 5% CO atmosphere. 2、 The cells were cultured in a humidified incubator at 37°C.

[0332] Viability assays using A431 cells, HCC827 cells, NCI-H1975 cells, NCI-H3255 cells, Ba / F3 EGFR-del E746_A750 / C797S cells, Ba / F3 EGFR-L858R / C797S cells, AU565 cells, SK-BR-3 cells, and ZR-75-30 cells were performed at Crown Biosciences. Cells were seeded at 1,500–7,000 cells / well in 96-well plates and treated with compounds (0.15 nM–10 μM) in DMSO in triplicate (n=3) at nine 4-fold dilutions. After 72 hours, cell viability was assessed using the CellTiter-Glo Luminescent Viability Assay (Promega). Dose-response curves were generated and IC values ​​were calculated. 50 was used to calculate the IC 50 Values ​​were calculated using a nonlinear regression equation fitted to a sigmoidal dose-response in GraphPad Prism and are presented as mean ± SEM.

[0333] Animal testing Animal studies were performed at Pharmaron, Inc., and animal use was approved by the Pharmaron Institutional Animal Care and Use Committee (IACUC) at Pharmaron, Inc. (Pharmaron IACUC, Protocol No. PK-M-07182022, No. PK-R-06012022, and No. ON-CELL-XEN-06012022) in accordance with AAALAC guidelines. Six- to eight-week-old male SD rats (approximately 200–300 g) obtained from Sea Bay Fu Laboratory Animal Technology, Inc., 6- to eight-week-old male CD1 mice (approximately 20–30 g) obtained from Sea Bay Fu Laboratory Animal Technology, Inc., and 6- to eight-week-old female BALB / c nude mice (approximately 20–30 g) obtained from Sea Bay Fu Laboratory Animal Technology, Inc. were used in the pharmacokinetic studies. Six- to eight-week-old female BALB / c nude mice (approximately 18–22 g) obtained from Beijing Anikeeper Biotech Co., Ltd. were used in the intracranial PDX study. The animals were housed at 20–25°C and a relative humidity range of 40–70%, and were exposed to a 12-hour light / dark cycle with free access to food and water.

[0334] In vivo testing 15 pharmacokinetic studies Standard pharmacokinetic evaluation of 15 was performed using intravenous (IV) tail vein injection (1:99 DMSO:10% captisol / saline) and oral (PO) gavage (1% methylcellulose) administration. Blood samples were collected at eight time points (0.0833, 0.25, 0.5, 1, 2, 4, 7, and 24 h) for IV administration and seven time points (0.25, 0.5, 1, 2, 4, 8, and 24 h) for PO administration, with n = 3 animals per administration route (total n = 6). Approximately 0.03 mL of blood was collected from the dorsal metatarsal vein (CD1 mice), 0.03 mL from the orbital vein (BALB / c nude mice), or 0.2 mL from the jugular vein (SD rats) at each time point. Blood samples from each sampling point were transferred to plastic microcentrifuge tubes containing K2-EDTA. The collection tubes containing the blood sample and anticoagulant were inverted several times to properly mix the contents of the tube and placed on ice until centrifugation to obtain plasma. Plasma was obtained by centrifugation of the blood samples at 4,000 g for 5 minutes at 4°C. Samples were stored in a -75°C freezer before analysis. The concentrations of the test substance in the plasma samples were measured using LC-MS / MS, and pharmacokinetic calculations were performed using WinNonlin 8.3 (Phoenix™). The obtained values ​​were plotted using GraphPad Prism software and are expressed as mean ± SD.

[0335] Oral CNS pharmacokinetic evaluation of 15 was performed by oral gavage (formulation: 1% methylcellulose) followed by blood and brain sampling at seven time points (0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose), with n = 3 animals per time point (total n = 21). For plasma collection, approximately 0.03 mL of blood was collected from the dorsal metatarsal vein (CD1 mice) or 0.2 mL of blood was collected from the jugular vein (SD rats) at each time point. Blood at each sampling point was transferred to a plastic microcentrifuge tube containing K2-EDTA. The collection tube containing the blood sample and anticoagulant was inverted several times to properly mix the contents of the tube and placed on ice before centrifugation for plasma. The blood sample was then centrifuged at 4,000 g for 5 minutes at 4°C to obtain plasma. The sample was then stored in a -75°C freezer before analysis. For brain sampling, rodents were completely exsanguinated before collection, the chest cavity was opened to expose the heart, and a catheter was inserted through the left ventricle. A small incision was then made in the right atrial appendage, and saline was gently administered via a syringe. Brain samples were collected at each time point and quickly frozen in an icebox. Samples were stored at -75°C before analysis. All brain samples were prepared with water to achieve a brain weight (g):water volume (mL) ratio of 1:4 prior to analysis. The concentration of 15 in plasma and brain samples was measured using LC-MS / MS, and WinNonlin 8.3 (Phoenix™) was used for pharmacokinetic calculations. The values ​​obtained were plotted using GraphPad Prism software and are expressed as mean ± SD.

[0336] 15 intracranial PDX models Intracranial injection of HCC827 cells stably expressing luciferase (HCC827-luc) was performed. Briefly, 3 × 10 cells suspended in 2 μL of RPMI 1640 medium were used. 5HCC827-luc tumor cells were injected into the right forebrain of anesthetized mice (anesthesia: intramuscular injection of Zoletl™ 50 (Virbac)). Mice were imaged biweekly using an IVIS Lumina III (PerkinElmer). Images were acquired 10 minutes after intraperitoneal (IP) injection of 15 mg / mL (5 μL / g body weight) D-luciferin into anesthetized mice (anesthesia: 1-2% isoflurane inhalation). On day 20 after cell inoculation, mice were randomly assigned to two treatment groups (n = 10 mice / group): 1) 1% methylcellulose as a vehicle control, and 2) 15 mg / kg (10 mg / kg) (formulation: 1% methylcellulose), administered PO twice daily (12 hours apart) for 7 days, 21 days. Mice were euthanized in the following circumstances: 1) if the animal showed obvious signs of severe distress and / or pain, 2) if the body weight (BW) loss exceeded 20%, or 3) if the animal was unable to obtain sufficient food or water. All mice were weighed every other week during the study, and the percentage change in BW (expressed as %) was calculated using the following formula: BW change rate (%) = (BW X日目 / BW 0日目 ) x 100 During the ceremony, BW X日目 is the BW on a given day, and BW 0日目 is the BW on day 0 (start of treatment).

[0337] statistical analysis Statistical analysis was performed using GraphPad Prism 9.0. Data are presented as mean ± SD or SEM, as indicated, when n is 3 or greater, or as mean when n = 2. For in vitro ADME and kinase activity studies, data are presented as mean values ​​of n = 2 independent replicates. For in vivo PK studies, data are presented as mean ± SD (n ≥ 3 animals / study group). For in vitro short-term growth retardation studies, IC 50Values ​​were determined from a nonlinear regression equation fitted to a sigmoidal dose-response curve and are expressed as mean ± SEM (n = 3 independent replicates). Intracranial PDX study data (mean bioluminescence and body weight at 21 days after treatment initiation, n = 10 animals per study group) were compared using an unpaired, two-tailed t-test. A p value of < 0.05 was considered statistically significant.

[0338] Results and Discussion As shown in Figure 4, the hydroxalog (6) was prepared using a direct NO bond-forming reaction. 11 For this purpose, 2-methyltetrahydropyranyl (MTHP) monoperoxyacetal 11~13 (8) was derived from commercially available 2-((tert-butyldimethylsilyl)oxy)ethanol (7) in 51% yield, and exposure to morpholine-derived magnesium amide afforded hydroxylamine (10) in 65% yield on an 8 gram scale. Notably, Knochel 24 Turbo Grignard (developed by i The use of PrMgCl·LiCl proved optimal for larger-scale NO bond formation. Formation of the morpholine-derived magnesium amide from EtMgBr afforded the product in reproducible yields on a small scale, but on a larger scale (>5 grams), this magnesium amide exhibited solubility issues, leading to the investigation of alternatives (see the Examples section for details). Nevertheless, desilylation of 10 in 79% yield afforded the alcohol 11, which was converted to the chloride by reaction with thionyl chloride and subsequently displaced with commercially available 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol under basic conditions to afford the desired hydroxyl analog 6 in 35% yield in two steps. Overall, the hydroxyl analog 6 was prepared in just four linear steps (LLS) from readily available starting materials, highlighting the direct NO bond formation achieved by all synthetic transformations performed on a gram scale.

[0339] With 6 in hand, we first evaluated the inhibitor binding constants and biochemical inhibition of related EGFR kinase forms (direct hydroxylamine analogs) of 1 and 6. Both 1 and 6 demonstrated single-digit nanomolar activity against EGFR harboring activating mutations, demonstrating that the N-(noralkoxy)morpholine unit is an effective bioisostere of the N-alkylmorpholine unit. We then evaluated their in vitro ADME properties, first using a colon carcinoma (Caco-2) cell permeability assay, which expresses both P-gp and BCRP. 6 exhibited a 14-fold increase in permeability and a significant decrease in efflux compared to 1 (Table 1). This effect was further substantiated by a Madin-Darby canine kidney (MDCK) MDCKII-MDR1 cell permeability assay, which also demonstrated an approximately 4-fold increase in permeability and a significant decrease in efflux compared to 1. This assay is commonly used to mimic the BBB through overexpression of the active efflux transporters P-gp or MDR1. These results are consistent with the known results observed in 1 by replacing the N-alkylmorpholine units with N-(noralkoxy)morpholine units. 25 It is noteworthy that the current third-generation EGFR TKI, osimertinib (5), is a substrate of both P-gp and BCRP, yet it inhibits EGFR. + It is the only approved EGFR TKI that shows promise in treating BM in NSCLC 8 Next, we performed AMES fluctuation assays on four Salmonella strains (TA98, TA100, TA1537, and TA1535) both in the presence and absence of metabolic activation with rat liver S9 (+ / -S9), and found that neither 1 nor 6 was mutagenic. 26 Combined with the similar stability profile in liver microsomes and plasma across multiple species compared to 1, these findings alleviate earlier concerns regarding mutagenicity and instability that were perceived with respect to the oxidative metabolism of the trisubstituted hydroxalamine unit of 6.

[0340] By synthesizing inhibitors bearing additional trisubstituted hydroxylamines (see below) (Figures 7-8), we aimed to further minimize efflux and improve the drug-like properties, particularly the aqueous solubility of 6. Considering the importance of hydrogen bond donors (HBDs) in substrate recognition by efflux transporters, and noting that the EGFR inhibitors AZD3759 and JCN037 have improved CNS permeability, 13 was designed to minimize the ability of the HBD of the adjacent aniline by substituting a fluorine from the para position to the ortho position (Figure 7). 27~30 Furthermore, 14 and 15 were prepared by substituting the morpholine unit with an N-methylpiperazine group, while retaining the key trisubstituted hydroxylamine moiety throughout, with the intention of improving aqueous solubility and potential in vivo exposure. All newly prepared analogs maintained single-digit nanomolar to subnanomolar binding and biochemical inhibition of activating mutant EGFR. In Caco-2 cell assays, 13 and 15, which contain ortho-fluorines, exhibited significantly enhanced permeability and reduced efflux ratios compared with 1, further demonstrating improvements over those observed with 6 (Table 1). Notably, 14, which contains a more basic nitrogen-containing heterocycle and para-fluorine substitution on the aniline ring than 1, 6, and 13, exhibited a higher efflux rate and reduced permeability. This highlights the synergistic improvement in substrate recognition by efflux transporters through HBD modification and reduced pKa. In MDCKII-MDR1 cell assays, 13 and 15 exhibited superior permeability and low excretion rates compared to 1 and 14, and even compared to 6. Importantly, 15 also exhibited good stability in human and rat microsomes and hepatocytes, while demonstrating significantly improved aqueous solubility compared to both 1 and 6.

[0341] The anticancer activity of hydroxylamine-containing inhibitors was evaluated against four patient-derived cell lines with different EGFR status, with cisplatin used as a positive control throughout (Figure 9). Notably, 15 inhibited the common EGFR L858R demonstrated excellent activity against the NCI-H3255 NSCLC cell line harboring the mutation, and IC 50The EGFR activity of 15 was 7.2 nM, representing approximately a 12-fold improvement over 6. del E746_A750 It also showed strong activity against HCC827 NSCLC cells carrying IC 50 The C797S point mutation blocks the binding of covalent inhibitors to EGFR L858R / C797S Osimertinib-resistant artificial Ba / F3 cell line with EGFR del E746_A750 / C797S In the same cell line containing 15, 15 showed potent activity, with IC 50 were 4.6 nM and 2.5 nM, respectively. 31 Overexpressed EGFR wt In the skin-derived A431 cell line, which has 50 15 demonstrated potent activity against activating mutant EGFR over wild-type EGFR, demonstrating 12- to 42-fold selectivity for activating mutant EGFR over wild-type EGFR. Overall, 15 is a potent inhibitor in osimertinib-resistant engineered and patient-derived NSCLC cell lines NCI-H3255 and HCC827, which harbor EGFR mutations that account for approximately 85% of all newly diagnosed mutant EGFR+ NSCLC cases.

[0342] The unbound fraction in plasma and brain tissue was determined using 15 (Table 2). 10 Both 15 and 1 showed similar plasma protein binding, but 15 exhibited significantly higher plasma protein binding than 1 (f u,脳 % = 0.6), the unbound fraction in rat brain tissue (f u,脳 Regarding potential toxicity, only moderate inhibition of the human ether-a-go-go-related gene (hERG) potassium ion channel by 15 was confirmed, and the IC 50 The IC value was 6.48 μM, with a maximum inhibition of approximately 60% at 10 μM (Table 2). Furthermore, when CYP inhibition against all major isoforms (3A4, 1A2, 2C9, 2D6, and 2C19) was evaluated, moderate inhibition of CYP2D6 (IC value) was observed. 50 No inhibition was observed (IC = 1.1 μM) except for 50=>30 μM) (Table 2). Follow-up CYP2D6 time-dependent inhibition (TDI) IC in human liver microsomes and primary human hepatocytes. 50 Time-course experiments showed that the latter activity was not time-dependent, thus eliminating concerns about potential drug-drug interactions (DDIs). 32 In an AMES fluctuation assay in four Salmonella strains (TA98, TA100, TA1537, and TA1535) and in an in vitro micronucleus test in Chinese hamster ovary (CHO-K1) cells with and without metabolic activation by rat liver S9 (+ / - S9), 15 was neither mutagenic nor genotoxic, contradicting the commonly held belief that hydroxylamines are inherently mutagenic and genotoxic (Table 2). 33~34、26、35 Overall, these experiments demonstrate that 15 is a potent inhibitor of EGFR harboring activating mutations and does not exhibit the efflux tendency characteristic of currently approved EGFR-targeted therapies.

[0343] Using KINOMEScan technology, the selectivity of 15 kinases against a panel of over 400 human kinases was measured at 1 μM, demonstrating exquisite kinase selectivity with an S(10) score of 0.015 (6 / 403 unmutated kinases exhibiting ≤10% activity at 1 μM) (Figure 10). 23 EGFR wt With the exception of 15 (0.30%), 15 only showed high affinity for ERBB2 (HER2) (0.45%). Moderate affinities for ABL1 (7.7%), DRAK1 (8.3%), LYN (7.4%), and PIKFYVE (1.6%) were also observed, but follow-up binding experiments confirmed that this was of minor importance given the strong binding to EGFR (Kd = <0.2 nM) (Figure 11). The moderate affinity for HER2 (Kd) was confirmed in follow-up binding experiments. d = 21 nM) and considering the lack of efficient treatments for metastatic HER2+ breast cancer. 36Further profiling of 15 against HER2 was performed using additional biochemical and cellular assays (Figure 12). 15 showed reduced antiproliferative activity in HER2+ breast cancer cell lines compared to EGFR+ cells harboring activating mutations, demonstrating IC 50 was found to be in the range of 0.99-1.6 μM.

[0344] To qualify 15 as a candidate for further study, its pharmacokinetic properties were evaluated after administration to Sprague-Dawley (SD) rats (Figure 13). Contrary to the commonly held belief that hydroxylamines are inherently toxic, 33~34 No adverse events or signs of toxicity were observed at the doses tested. Furthermore, 15 demonstrated high oral bioavailability (F = 64%), low exposure (AUC ) and a significant improvement in serotonin activity (SSC) in SD rats at 2 mg / kg intravenous (IV) and 20 mg / kg oral (PO) doses. inf = 3907 h ng / mL), and an acceptable half-life (t 1 / 2 = 2.37 hours) and a high volume of distribution (V ss After a single oral dose of 20 mg / kg was administered to SD rats, 15 showed a K of 0.33. p,uu (unbound brain / unbound plasma partition coefficient) (AUC inf ) and a K of 0.95 p (brain / plasma partition coefficient) (AUC inf ) and demonstrated excellent brain penetration (Figure 14). 10,37 In support of this effect, CD1 mice received a single oral dose of 40 mg / kg, showing a K p,uu (AUC inf ) and a K of 0.77 p (AUC inf ) was obtained (Figure 14).

[0345] To evaluate the viability of 15 as a promising treatment for BM in EGFR+ NSCLC, we performed an intracranial patient-derived xenograft (PDX) model in which luciferase-labeled HCC827 cells were implanted into the brains of BALB / c nude mice (Figure 15). At 10 mg / kg PO bid (twice daily), significant tumor shrinkage (P = 0.0059) was observed compared with the vehicle control (1% methylcellulose), confirming the intracranial antitumor activity of 15 (Figure 16). Furthermore, over the 21-day treatment window, mean body weight loss did not exceed 10%, and no adverse clinical events were observed at any of the doses tested, demonstrating the potential of 15 as a candidate for CNS metastatic EGFR+ NSCLC (Figure 16).

[0346] conclusion We report 15, a highly selective, orally bioavailable, brain-penetrant EGFR inhibitor containing a novel amine bioisostere, a trisubstituted hydroxylamine. Contrary to common expectations for hydroxylamines in medicinal chemistry, 15 exhibits good stability in vitro and in vivo, without mutagenicity or genotoxicity. Oral administration of 15 induced significant tumor regression in an intracranial PDX mouse model, suggesting that this novel compound is a promising lead for the treatment of localized NSCLC and CNS metastatic NSCLC caused by activating EGFR mutations, as well as for osimertinib-resistant EGFR+ NSCLC. Overall, these results demonstrate that incorporating a trisubstituted hydroxylamine moiety, a "structural alert" in medicinal chemistry, into a drug scaffold can improve drug properties while maintaining potent biological activity and avoiding molecular weight creep. These findings support the widespread application of trisubstituted hydroxylamines as bioisosteres in drug discovery programs for lead optimization and patent lifecycle management.

[0347] It should be emphasized that the above-described embodiments of the present disclosure are merely examples of possible implementations set forth for a clear understanding of the principles of the present disclosure. Many variations and modifications can be made to the above-described embodiments without significantly departing from the spirit and principles of the present disclosure. All such modifications and modifications are intended to be included within the scope of the present disclosure and protected by the following claims.

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Claims

1. A compound having structure I: or a pharmaceutically acceptable salt thereof: 【Chemical 1】 During the ceremony, R １ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; n is an integer from 1 to 5, and each R ２ are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, a halide, or an alkoxy group; m is an integer from 1 to 3, and each R ３ are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, a halide, or an alkoxy group; o is an integer from 1 to 10; X is O or NR ４ wherein R ４ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR ５ , or CR ６ａ R ６ｂ wherein R ５ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R ６ａ and R ６ｂ are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

2. The compound of claim 1 wherein X is O.

3. The compound of claim 1 , wherein Y is O.

4. Y is NR ５ and R ５ The compound of claim 1, wherein is a C1 to C5 alkyl group.

5. Y is CR ６ａ R ６ｂ and R ６ａ is hydrogen, and R ６ｂ The compound of claim 1 , wherein is a substituted or unsubstituted amino group.

6. R １ The compound of claim 1 , wherein is hydrogen.

7. R ３ The compound of claim 1 , wherein is an alkoxy group.

8. R ３ The compound of claim 1 , wherein is an alkoxy group and m is 1.

9. The compound of claim 1, wherein o is an integer from 1 to 5.

10. R ２ 2. The compound of claim 1, wherein is a halide and n is 2.

11. R ２ The compound of claim 1 , wherein is a fluoride in the ortho position.

12. 10. The compound of claim 1 having the structure II: or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 During the ceremony, R １ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R ２ａ and R ２ｂ is a halide; R ３ is an alkoxy group; o is an integer from 1 to 5; X is O or NR ４ wherein R ４ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR ５ , or CR ６ａ R ６ｂ wherein R ５ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R ６ａ and R ６ｂ are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

13. 13. The compound of claim 12, wherein X is O.

14. 13. The compound of claim 12, wherein Y is O.

15. Y is NR ５ and R ５ The compound of claim 12, wherein is a C1 to C5 alkyl group.

16. Y is CR ６ａ R ６ｂ and R ６ａ is hydrogen, and R ６ｂ The compound of claim 12, wherein is a substituted or unsubstituted amino group.

17. R １ The compound of claim 12, wherein is hydrogen.

18. R ３ The compound according to claim 12, wherein is a C1 to C10 substituted or unsubstituted straight or branched chain alkoxy group.

19. R ３ The compound of claim 12, wherein is a methoxy group.

20. 13. The compound of claim 12, wherein o is an integer from 1 to 5.

21. R ２ 13. The compound of claim 12, wherein is a halide.

22. R ２ａ is chloride, and R ２ｂ The compound of claim 12, wherein is fluoride.

23. R ２ａ is fluoride, and R ２ｂ 13. The compound of claim 12, wherein is chloride.

24. 10. The compound of claim 1 having the structure III: 【Chemistry 3】 During the ceremony, R １ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R ２ａ and R ２ｂ is a halide; R ３ is an alkoxy group; o is an integer from 1 to 5; X is O or NR ４ wherein R ４ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR ５ , or CR ６ａ R ６ｂ wherein R ５ is hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R ６ａ and R ６ｂ are, independently of each other, hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

25. 25. The compound of claim 24, wherein X is O.

26. 25. The compound of claim 24, wherein Y is O.

27. Y is NR ５ and R ５ is a C1 to C5 alkyl group.

28. Y is CR ６ａ R ６ｂ and R ６ａ is hydrogen, and R ６ｂ 25. The compound of claim 24, wherein is a substituted or unsubstituted amino group.

29. R １ 25. The compound of claim 24, wherein is hydrogen.

30. R ３ The compound according to claim 24, wherein is a C1 to C10 substituted or unsubstituted straight or branched chain alkoxy group.

31. R ３ 25. The compound of claim 24, wherein is a methoxy group.

32. 25. The compound of claim 24, wherein o is an integer from 1 to 5.

33. R ２ 25. The compound of claim 24, wherein is a halide.

34. R ２ａ is chloride, and R ２ｂ 25. The compound of claim 24, wherein is fluoride.

35. R ２ａ is fluoride, and R ２ｂ 25. The compound of claim 24, wherein is chloride.

36. [Catalog 4] 2. The compound of claim 1, wherein:

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 and a pharmaceutically acceptable carrier.

38. 37. A method for treating a subject having non-small cell lung cancer, neuroblastoma, glioblastoma multiforme, metastatic brain cancer, brain cancer, prostate cancer, or breast cancer, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 36.

39. 37. A method for treating a subject having an osimertinib-resistant cancer, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 36.

40. 37. A method for treating a subject with brain metastases, comprising administering to said subject an effective amount of a compound of any one of claims 1 to 36.

41. 37. A method for inhibiting epidermal growth factor receptor (EGFR) in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 36.

42. 39. The method of claim 38, wherein the compound is administered orally to the subject.

43. 40. The method of claim 39, wherein the compound is administered orally to the subject.

44. 41. The method of claim 40, wherein the compound is administered orally to the subject.

45. 39. The method of claim 38, wherein the compound is administered at a dose of about 50 mg / day to about 1,000 mg / day.

46. 40. The method of claim 39, wherein the compound is administered at a dose of about 50 mg / day to about 1,000 mg / day.

47. 41. The method of claim 40, wherein the compound is administered at a dose of about 50 mg / day to about 1,000 mg / day.

48. A method for making a compound of any one of claims 1 to 16, comprising reacting a compound having structure IV with a compound having structure V in the presence of a base: 【Chemistry 5】 During the ceremony, R １ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R ２ａ and R ２ｂ is a halide; R ３ is an alkoxy group; o is an integer from 1 to 5; X is O or NR ４ wherein R ４ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; Y is O, NR ５ , or CR ６ａ R ６ｂ wherein R ５ is hydrogen, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, or a substituted or unsubstituted aryl group; R ６ａ and R ６ｂ are, independently of each other, hydrogen, deuterium, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted amino group; R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium; LG is a leaving group.

49. 49. The method of claim 48, wherein LG is a halide or sulfonate group.

50. 49. The method of claim 48, wherein the base comprises a hydride, an alkoxide, a Grignard reagent, or an alkyllithium compound.

51. 1. A method for making a compound having structure X, comprising: 【Chemistry 6】 (In the formula, R ５ is a substituted or unsubstituted straight or branched chain alkyl group; R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium. (a) reacting a compound having structure XI with a compound having structure XII in the presence of a base to form a compound having structure XIII; 【Chemistry 7】 (In the formula, R １０ is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, LG is a leaving group. (b) reacting a compound having structure XIII with a first oxidizing agent with heating to form a compound having structure XIV; 【Chemistry 8】 (c) reacting a compound having structure XIV with (i) a second oxidizing agent and then (ii) a first reducing agent to produce a first intermediate; and (d) reacting the first intermediate with a second reducing agent to produce a compound having structure X. A method comprising:

52. R １０ 52. The method of claim 51, wherein is a C1 to C5 straight or branched chain alkyl group.

53. R １０ 52. The method of claim 51, wherein is a C1 to C5 straight or branched chain alkoxy group.

54. R １０ 52. The method of claim 51, wherein is a C1 to C5 straight or branched chain alkoxy group substituted with an aryl group.

55. R １０ is a benzyloxy group.

56. 52. The method of claim 51, wherein LG is a halide, sulfonate, carbonate, or phosphate.

57. 52. The method of claim 51 , wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide.

58. 52. The method of claim 51 , wherein step (a) is carried out in an aprotic organic solvent.

59. 52. The method of claim 51, wherein step (a) is carried out at a temperature of from about 25°C to about 100°C.

60. Step (b) (i) reacting a compound having structure XIII with a first oxidizing agent in a first organic solvent to form a first composition; (ii) adding an aqueous base to the first composition to form a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to obtain a residue; (v) dissolving the residue in a second organic solvent to form a second composition; and (vi) heating the second composition to about 50° C. to about 100° C. to produce a compound having structure XIV.

52. The method of claim 51, comprising:

61. 61. The method of claim 60, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene.

62. 52. The method of claim 51 , wherein the first oxidizing agent in step (b) comprises peroxyacid, oxone, or hydrogen peroxide / acetic acid.

63. 52. The method of claim 51 , wherein the first oxidizing agent in step (b) comprises metachloroperbenzoic acid.

64. 52. The method of claim 51, wherein the molar ratio of said first oxidizing agent to said compound having structure XIII is from 0.95:1 to 1:1.

05.

65. Step (c) (i) reacting a compound having structure XIV with a second oxidizing agent in a third organic solvent to form a third composition; and (ii) combining the first reducing agent with the third composition to form the first intermediate.

52. The method of claim 51, comprising:

66. 66. The method of claim 65, wherein the second oxidizing agent comprises ozone or osmium tetroxide in combination with sodium metaperiodate.

67. 66. The method of claim 65, wherein the third organic solvent comprises an alcohol and an aprotic solvent.

68. 66. The method of claim 65, wherein the compound having structure XIV is reacted with the second oxidizing agent at a temperature of about -50°C to about -100°C.

69. 52. The method of claim 51 , wherein the first reducing agent comprises a hydride.

70. 52. The method of claim 51 , wherein the first reducing agent comprises a borohydride.

71. 52. The method of claim 51, wherein the molar ratio of said first reducing agent to said compound having structure XIV is from 1.5:1 to 2.5:

1.

72. 52. The method of claim 51 , wherein the first intermediate is isolated prior to step (d).

73. Step (d) (i) dissolving the first intermediate in an aprotic solvent to form a fourth composition; (ii) combining the second reducing agent with the fourth composition to form a compound having structure X; and (iii) isolating and purifying the compound having the structure X.

52. The method of claim 51, comprising:

74. 74. The method of claim 73, wherein the second reducing agent is combined with the fourth composition at a temperature of from about 10°C to about -50°C.

75. 52. The method of claim 51 , wherein the second reducing agent comprises a hydride.

76. 52. The method of claim 51 , wherein the second reducing agent comprises aluminum hydride.

77. 52. The method of claim 51, wherein the molar ratio of the second reducing agent to the first intermediate is from 4:1 to 2:

1.

78. R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ 52. The method of claim 51 , wherein each is hydrogen.

79. R ５ is a methyl group, and R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ 52. The method of claim 51 , wherein each is hydrogen.

80. A method for making a compound having structure XX, comprising: 【Chemistry 9】 (In the formula, R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium. (d) reacting a compound having structure XXI with a compound having structure XXII in the presence of a base to produce a compound having structure XXIII; 【Chemistry 10】 wherein LG is a leaving group. (a) reacting a compound having structure XXIII with a first oxidizing agent to form a compound having structure XXIV; 【Chemistry 11】 and (b) reacting said compound having structure XXIV with (i) a second oxidizing agent and then (ii) a first reducing agent to produce a compound having structure XX. A method comprising:

81. 81. The method of claim 80, wherein LG is a halide, sulfonate, carbonate, or phosphate.

82. 81. The method of claim 80, wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide.

83. 81. The method of claim 80, wherein step (a) is carried out in an aprotic organic solvent.

84. 81. The method of claim 80, wherein step (a) is carried out at a temperature of from about 25°C to about 100°C.

85. Step (b) (i) reacting a compound having structure XXIII with a first oxidizing agent in a first organic solvent to form a first composition; (ii) adding an aqueous base to the first composition to form a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to obtain a residue; (v) dissolving the residue in a second organic solvent to form a second composition; and (vi) heating the second composition to about 50° C. to about 100° C. to produce a compound having structure XXIV.

81. The method of claim 80, comprising:

86. 86. The method of claim 85, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene.

87. 81. The method of claim 80, wherein the first oxidizing agent in step (b) comprises peroxyacid, oxone, or hydrogen peroxide / acetic acid.

88. 81. The method of claim 80, wherein the first oxidizing agent in step (b) comprises metachloroperbenzoic acid.

89. 81. The method of claim 80, wherein the molar ratio of the first oxidizing agent to the compound having structure XIII is from 0.95:1 to 1:1.

05.

90. Step (c) (i) reacting a compound having structure XXIV with a second oxidizing agent in a third organic solvent to form a third composition; and (ii) combining the first reducing agent with the third composition to produce a compound having structure XX; and (iii) isolating and purifying the compound having structure XX.

81. The method of claim 80, comprising:

91. 91. The method of claim 90, wherein the second oxidizing agent comprises ozone or osmium tetroxide in combination with sodium metaperiodate.

92. 91. The method of claim 90, wherein the third organic solvent comprises an alcohol and an aprotic solvent.

93. 91. The method of claim 90, wherein the compound having structure XXIV is reacted with the second oxidizing agent at a temperature of from about -50°C to about -100°C.

94. 81. The method of claim 80, wherein the first reducing agent comprises a hydride.

95. 81. The method of claim 80, wherein the first reducing agent comprises a borohydride.

96. 81. The method of claim 80, wherein the molar ratio of said first reducing agent to said compound having structure XXIV is from 1.5:1 to 2.5:

1.

97. R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ 81. The method of claim 80, wherein each is hydrogen.

98. R ５ is a methyl group, and R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ 52. The method of claim 51 , wherein each is hydrogen.

99. R ５ is a methyl group, and R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ 81. The method of claim 80, wherein each is hydrogen.

100. Compounds having the structure XXX: 【Chemistry 12】 During the ceremony, Y is O or NR ５ and R ５ is a substituted or unsubstituted straight or branched chain alkyl group, R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, independently of each other, hydrogen, deuterium, or a substituted or unsubstituted alkyl group; Each Z is independently hydrogen or deuterium.

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