S6K1 PROTEIN KINASE INHIBITORS AS CANCER THERAPEUTICS

Abstract

The present disclosure relates to compounds that act as protein kinase inhibitors, especially RPS6K1 and the synthesis of the same. Further, the present disclosure teaches the utilization of such compounds in a treatment for proliferative diseases, including cancer, particularly breast cancer, and especially ER+ and/or HER2+ breast cancer, prostate cancer, lung cancer, and metastatic cancer.

Claims

1. A compound according to formula (IIa) or formula (IIb), and/or a stereoisomer and/or pharmaceutically acceptable salt and/or solvate thereof: ##STR00041## wherein R is H, alkyl, aryl, substituted aryl, hetereocyclyl, or substituted heterocyclyl; X is —NHR.sup.4, —NR.sup.5COR.sup.5, OH, or SH; R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, —NHR.sup.4, OR.sup.4, Br, Cl, I, —NH—CR.sup.4═CR.sup.4—, —NR.sup.5—, —NR.sup.5CH.sub.2—, —CH.sub.2NR.sup.5—,—NR.sup.5CO—, —NR.sup.5COR.sup.5, —CONR.sup.5—, —N═N—, —NH—CO—NH—, —NH—CS—NH—, —CO—O—, CO—O—CH.sub.2—, —SO.sub.2NH—, —NH—SO.sub.2—, —C≡C—, —O—CH.sub.2—CO—, —OCH.sub.2CH.sub.2O—, —CH(OH)—, and —NO.sub.2 bridging groups; R.sup.4 is selected from the group consisting of H, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, haloC.sub.1-6 alkoxy, —COOH, —CONH.sub.2, —COC.sub.1-6 alkyl, O—C.sub.1-6 alkyl, NH— C.sub.1-6 alkyl, —S C.sub.1-6 alkyl groups, —CN, —NH.sub.2, and —NO.sub.2; and R.sup.5 is selected from the group consisting of H, aryl, C.sub.3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heteroaryl, wherein the aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more R.sup.4 groups.

2. The compound of formula (IIa) or (IIb) according to claim 1, wherein X is —NH.sub.2, —NR.sup.5COR.sup.5, OH, or SH.

3. The compound of formula (IIa) according to claim 1, wherein: R is H or alkyl; X is NH.sub.2; R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, —NHR.sup.4, and —NR.sup.5COR.sup.5; R.sup.4 is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, O—C.sub.1-6 alkyl, —CN, —NH.sub.2, and —NO.sub.2; and R.sup.5 independently represents hydrogen, heteroaryl, or aryl, wherein the heteroaryl or aryl group may be optionally substituted by one or more R.sup.4 groups.

4. The compound of formula (IIa) according to claim 1, wherein R is H; R.sup.1 and R.sup.3 are H; R.sup.2 is —NR.sup.5COR.sup.5; R.sup.4 is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, O—C.sub.1-6 alkyl, —CN, —NH.sub.2, and —NO.sub.2; and R.sup.5 independently represents hydrogen or thiophene or phenyl, wherein the thiophene or phenyl group may be optionally substituted by one or more R.sup.4 groups.

5. The compound of formula (IIa) according to claim 1, wherein R is H; R.sub.1 and R.sub.3 are H; R.sub.2 is —NR.sup.5COR.sup.5; R.sup.4 is selected from the group consisting of hydrogen, halogen, and —NO.sub.2; and R.sup.5 represents hydrogen or phenyl, wherein the phenyl group may be optionally substituted by one or more R.sup.4 groups.

6. The compound of formula (IIb) according to claim 1, wherein: R is H or alkyl; X is NH.sub.2 or —NR.sup.5COR.sup.5, R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, —NHR.sup.4, and —NR.sup.5COR.sup.5; R.sup.4 is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, O—C.sub.1-6 alkyl, —CN, —NH.sub.2, and —NO.sub.2; and R.sup.5 independently represents hydrogen, C.sub.1-6 alkyl, heteroaryl, or aryl, wherein the heteroaryl or aryl group may be optionally substituted by one or more R.sup.4 groups.

7. The compound of formula (IIb) according to claim 1, wherein R is H or methyl; R.sup.2 and R.sup.3 are H; R.sup.1 is NH.sub.2 or —NR.sup.5COR.sup.5; R.sup.4 is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, O—C.sub.1-6 alkyl, —CN, —NH.sub.2, and —NO.sub.2. In a further embodiment, R.sup.4 is selected from the group consisting of hydrogen, halogen, —OCH.sub.3, —CN, —NH.sub.2, and —NO.sub.2; and R.sup.5 independently represents hydrogen, methyl, thiophene, or phenyl, wherein the thiophene or phenyl group may be optionally substituted by one or more R.sup.4 groups. In a further embodiment, R.sup.5 represents hydrogen or phenyl, wherein the phenyl group may be optionally substituted by one or more R.sup.4 groups.

8. The compound of formula (IIa) and (IIb) according to claim 1, wherein the compound is selected from the group consisting of: ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##

9. The compound of formula (IIa) according to claim 1, wherein the compound is selected from the group consisting of ##STR00051## ##STR00052## ##STR00053##

10. The compound of formula (IIa)according to claim 1, wherein the compound is ##STR00054##

11. The compound of formula (IIa) according to claim 1, wherein the compound is ##STR00055##

12. The compound of formula (IIa) according to claim 1, wherein the compound is ##STR00056##

13. The compound of formula (IIa) according to claim 1, wherein the compound is: ##STR00057##

14. A pharmaceutical composition comprising the compound of claim 1, and/or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or a solvate thereof, and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 16, wherein said pharmaceutical composition is suitable for enteral administration, oral administration, or parenteral administration.

16. A method of inhibiting protein kinase to treat a protein kinase dependent disease comprising administering to a subject the compound of claim 1.

17. The method according to claim 16, wherein the protein kinase is RPS6K1 protein.

18. A method of treating a cancer comprising administering to a subject in need of such treatment the compound of claim 1.

19. The method according to claim 18, wherein the cancer is breast cancer selected from the group consisting of ER-positive breast cancer and HER2-positive breast cancer.

20. The method according to claim 18, wherein the cancer is selected from the group consisting of prostate cancer, lung cancer (NSCLC), and metastatic cancer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0066] For a further understanding of the nature, objects, and advantages of the present disclosure, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements.

[0067] FIG. 1 shows growth inhibition of (A) HER2 positive (SKBR3), (B)ER-positive (MCF7) breast cancer cell lines and (C) prostate cancer cell line (DU-145) by the three compounds RJ19, RJ22 and RJ28. (D), (E) and (F) show the dose response curves of growth inhibition of SKBR3 breast cancer cell line.

[0068] FIG. 2 shows synthetic scheme for the synthesis of 4-amino-6-amidoisoindoline-1,3-dione derivatives.

[0069] FIG. 3 shows docking of RJ22 in the ATP-binding pocket of S6K1 protein. (A) shows 3D-depiction of the binding mode of RJ22 is shown and the hydrogen bonds with Glu150 and Leu152 are depicted with borken cyan lines; (B) shows 2D-depiction of the interaction of RJ22 with S6K1 binding pocket residues; and (C) the surface mapping of the binding pocket aournd the inhibitor showing the coverage of RJ22 in the pocket.

DETAILED DESCRIPTION

[0070] Before the subject disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments of the disclosure described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present disclosure will be established by the appended claims.

[0071] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

[0072] As used herein, the term “minimize” or “reduce”, or derivatives thereof, include a complete or partial inhibition of a specified biological effect (which is apparent from the context in which the terms “minimize” or “reduce” are used).

[0073] The compounds according to the disclosure are isolated and purified in a manner known per se, e.g., by distilling off any solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to a customary purification method, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC of compounds of the present disclosure, which possess a sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present disclosure which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present disclosure which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into their free base or free acid form, respectively, by various methods known to the person skilled in the art, or can be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of compounds of the present disclosure may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognize which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g., salt, free base, solvate, inclusion complex) of a compound of the present disclosure as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

[0074] One aspect of the disclosure is salts of the compounds according to the disclosure including all inorganic and organic salts, especially all pharmaceutically acceptable inorganic and organic salts, particularly all pharmaceutically acceptable inorganic and organic salts customarily used in pharmacy.

[0075] Examples of salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine, ammonium, salts optionally derived from NH.sub.3 or organic amines having from 1 to 16 C-atoms such as, e.g., ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperindine and guanidinium salts.

[0076] The salts include water-insoluble and, particularly, water-soluble salts.

[0077] As used herein, “pharmaceutically acceptable salts” refers to derivatives of the compounds disclosed herein wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0078] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0079] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0080] Salts of the compounds of formulas (IIa) and (IIb) according to the disclosure can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.

[0081] According to the person skilled in the art the compounds of formulas (IIa) through (IIb) according to this disclosure as well as their salts may contain, e.g., when isolated in crystalline form, varying amounts of solvents. Included within the scope of the disclosure are therefore all solvates and in particular all hydrates of the compounds of formulas (IIa) through (IIb) according to this disclosure as well as all solvates and in particular all hydrates of the salts of the compounds of formulas (IIa) through (IIb) according to this disclosure.

[0082] “Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H.sub.2O.

[0083] The compounds according to the disclosure and their salts can exist in the form of tautomers which are included in the embodiments of the disclosure.

[0084] “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.

[0085] Where the present specification depicts a compound prone to tautomerization, but only depicts one of the tautomers, it is understood that all tautomers are included as part of the meaning of the chemical depicted. It is to be understood that the compounds disclosed herein may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included, and the naming of the compounds does not exclude any tautomer form.

[0086] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (—CHO) in a sugar chain molecule reacting with one of the hydroxy groups (—OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0087] Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine.

[0088] The compounds of the disclosure may, depending on their structure, exist in different stereoisomeric forms. These forms include configurational isomers or optically conformational isomers (enantiomers and/or diastereoisomers including those of atropisomers). The present disclosure therefore includes enantiomers, diastereoisomers as well as mixtures thereof. From those mixtures of enantiomers and/or disastereoisomers pure stereoisomeric forms can be isolated with methods known in the art, preferably methods of chromatography, especially high performance liquid chromatography (HPLC) using achiral or chiral phase. The disclosure further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.

[0089] The compounds of the disclosure may, depending on their structure, exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms have been replaced with deuterium atoms, those in which one or more nitrogen atoms have been replaced with .sup.15N atoms, or those in which one or more atoms of carbon, fluorine, chlorine, bromine, sulfur, or oxygen have been replaced by the stable isotope of the respective, original atoms.

[0090] Some of the compounds and salts according to the disclosure may exist in different crystalline forms (polymorphs) which are within the scope of the disclosure.

[0091] It is a further object of the disclosure to provide protein kinase RPS6K1 inhibitor compounds disclosed herein, methods of synthesizing the protein kinase inhibitor compounds, methods of manufacturing the protein kinase inhibitor compounds, and methods of using the protein kinase inhibitor compounds. The compounds can also be made by synthetic schemes well established in the art.

[0092] Another object of the disclosure is to provide a composition, for example a pharmaceutical composition, comprising at least one protein kinase inhibitor compound disclosed herein in an amount effective for the indication of proliferative diseases such as cancer, including but not limited to breast cancer, prostate cancer, lung cancer, metastatic cancer, or solid tumors, etc. In an embodiment, the cancer is an ER-positive tumor and/or a HER2-positive tumor, such as a tumor of the breast, endometrium, uterus, or ovary. In an embodiment, the tumor is an ER-positive and/or HER2-positive tumor of the breast. In an embodiment, the tumor is a tumor of the prostate.

[0093] In an embodiment, the object of such treatment is to inhibit protein kinases, especially RPS6K1.

[0094] As used herein, “treating” means administering to a subject a pharmaceutical composition to ameliorate, reduce or lessen the symptoms of a disease. As used herein, “treating” or “treat” describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” may also include treatment of a cell in vitro or an animal model. As used herein, “subject” or “subjects” refers to any animal, such as mammals including rodents (e.g., mice or rats), dogs, primates, lemurs or humans.

[0095] Treating cancer may result in a reduction in size of a tumor. A reduction in size of a tumor may also be referred to as “tumor regression.” Preferably, after treatment, tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.

[0096] Treating cancer may result in a reduction in tumor volume. Preferably, after treatment, tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Tumor volume may be measured by any reproducible means of measurement.

[0097] Treating cancer may result in a decrease in number of tumors. Preferably, after treatment, tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

[0098] Treating cancer may result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. The number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

[0099] Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0100] Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0101] Treating cancer may result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0102] Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound disclosed herein, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof. Preferably, the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%. A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. A decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.

[0103] Treating cancer may result in a decrease in tumor growth rate. Preferably, after treatment, tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate may be measured according to a change in tumor diameter per unit time.

[0104] Treating cancer may result in a decrease in tumor regrowth, for example, following attempts to remove it surgically. Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.

[0105] Treating or preventing a cell proliferative disorder may result in a reduction in the rate of cellular proliferation. Preferably, after treatment, the rate of cellular proliferation is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The rate of cellular proliferation may be measured by any reproducible means of measurement. The rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0106] Treating or preventing a cell proliferative disorder may result in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The proportion of proliferating cells may be measured by any reproducible means of measurement. Preferably, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample. The proportion of proliferating cells may be equivalent to the mitotic index.

[0107] Treating or preventing a cell proliferative disorder may result in a decrease in size of an area or zone of cellular proliferation. Preferably, after treatment, size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. The size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.

[0108] Treating or preventing a cell proliferative disorder may result in a decrease in the number or proportion of cells having an abnormal appearance or morphology. Preferably, after treatment, the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement. An abnormal cellular morphology may be measured by microscopy, e.g., using an inverted tissue culture microscope. An abnormal cellular morphology may take the form of nuclear pleiomorphism.

[0109] As used herein, “subject” or “subjects” refers to any animal, such as a warm-blooded animal, i.e., mammals including rodents (e.g., mice or rats), dogs, primates, lemurs or humans.

EXAMPLES

[0110] Hereby are provided non-limiting examples of embodiments of compounds disclosed herein.

[0111] Derivative compounds having the core structure isoindoline-1,3-dione (formula (Ia)) were synthesized.

[0112] We identified 4,6-diaminoisoindoline-1,3-dione (RJ1) (RPS6KB1 (p70S6K), formula (Ib)) as a RPS6K1-selective inhibitor when tested against a panel of 120 disease relevant kinases (Table 1) using the SelectScreen™ Biochemical Kinase Profiling Service. The complete list of the kinases given in Table 1 and their details can be found on the ThermoFisher website for Biochemical Kinase assays (thermofisher.com/us/en/home/industrial/pharma-biopharma/drug-discovery-development/target-and-lead-identification-and-validation/kinasebiology.html).

TABLE-US-00001 TABLE 1 High-throughput screening of 4,6-diaminoisoindoline-1,3- dione against a panel of disease relevant human kinases Kinase % Inhibition CDK7/cyclin H/MNAT1 −1 * CDK9/cyclin T1 16 * GSG2 (Haspin) 65 ** PIK3CA/PIK3R1 (p110 alpha/p85 23 * alpha) PIK3CG (p110 gamma) 12 * SPHK1 23 * CDK7/cyclin H/MNAT1 1 * CDK9/cyclin T1 10 * GSG2 (Haspin) 34 * PIK3CA/PIK3R1 (p110 alpha/p85 3 * alpha) PIK3CG (p110 gamma) 11 * SPHK1 53 ** ABL1 59 ** ABL2 (Arg) 54 ** AKT1 (PKB alpha) 11 * AKT2 (PKB beta) 9 * ALK 32 * AURKA (Aurora A) 43 ** AURKB (Aurora B) 63 ** AURKC (Aurora C) 40 * AXL 10 * BRAF V599E 22 * BRAF 19 * BTK 43 ** CDC42 BPA (MRCKA) 0 * CDC42 BPB (MRCKB) 0 * CDK1/cyclin B 8 * CDK2/cyclin A 9 * CDK5/p25 27 * CHEK1 (CHK1) 72 ** CHEK2 (CHK2) 38 * CSF1R (FMS) 26 * CSNK1E (CK1 epsilon) 33 * CSNK2A1 (CK2 alpha 1) 5 * EGFR (ErbB1) 12 * EPHA1 15 * EPHA2 16 * EPHB2 10 * EPHB4 9 * ERBB2 (HER2) 6 * ERBB4 (HER4) 25 * FER 23 * FES (FPS) 36 * FGFR1 51 ** FGFR4 20 * FGR 51 ** FLT1 (VEGFR1) 18 * FLT3 29 * FLT4 (VEGFR3) 55 ** FRAP1 (mTOR) 6 * FYN 17 * HCK 21 * IGF1R 10 * IKBKB (IKK beta) 16 * IKBKE (IKK epsilon) 16 * JAK1 9 * JAK2 JH1 JH2 V617F 6 * JAK2 JH1 JH2 15 * JAK2 22 * JAK3 28 * KDR (VEGFR2) 56 ** KIT 7 * LCK 31 * LYN A 12 * MAP2K1 (MEK1) 13 * MAP3K8 (COT) 29 * MAP4K4 (HGK) 66 ** MAPK14 (p38 alpha) 2 * Direct MATK (HYL) −5 * MET (cMet) −4 * MST1R (RON) 27 * MST4 52 ** NEK2 −20 * NTRK1 (TRKA) 5 * PAK4 29 * PDGFRA (PDGFR alpha) 13 * PDGFRB (PDGFR beta) 5 * PDK1 Direct 33 * PIM1 35 * PLK1 9 * PLK3 77 ** PRKCB2 (PKC beta II) 23 * PTK2 (FAK) 26 * PTK2B (FAK2) 18 * PTK6 (Brk) 4 * RAF1 (cRAF) Y340D 6 * Y341D RET 79 ** ROCK1 21 * ROS1 3 * RPS6KB1 (p70S6K) 80 *** SGK (SGK1) 50 ** SRC 9 * SYK 39 * TBK1 18 * TEK (Tie2) 20 * TYRO3 (RSE) 25 * YES1 24 * Legend <40% Inhibition * 40%-80% Inhibition ** ≥80% Inhibition ***

[0113] The compound (RPS6KB1 (p70S6K), denoted RJ1) showed 80% inhibition of the kinase at a concentration of 10 μM. RJ1 was taken as the lead structure for the synthesis of several diamide and monoamide derivatives of 4,6-diaminoisoindolin-1,3-dione.

A. Synthesis of various 4,6-diaminoisoindolin-1,3-dione/4-amino-6-amidoisoindoline-1,3-dione derivatives

[0114] FIG. 2 shows steps of synthesis for various 4-amino-6-amidoisoindoline-1,3-dione derivatives.

[0115] Experimental Methods:

[0116] All reagents were used as received from the manufacturer, with the exception of (N-Bromosuccinimide), which was recrystallized from water and allowed to dry before use. All NMR spectra were recorded with an Agilent 400 MHz NMR magnet using tetramethylsilane as an internal solvent reference. Aluminum backed 60F254 silica plates were used for thin-layer chromatography. Flash chromatography was performed using a Teledyne Isco CombiFlash automated column machine with ethyl acetate and hexane as the mobile solvents.

[0117] Synthesis of 3,5-dinitrophthalic acid (2): To a stirring solution of 4,6-dinitrotoluic acid (1) (25 g, 0.111 mol) in 200 mL of sulfuric acid at 80° C. was added potassium dichromate (65.014, 0.222 mol) in portions keeping the reaction temperature below 90° C. After completion of the addition, stirring of the resulting reaction mixture continued at 80° C. for 2 days. Upon completion, the reaction mixture was cooled down to room temperature and the reaction mixture was poured into an ice+water mixture. Extraction was performed with diethyl ether and concentrate under reduced pressure to get a slightly yellowish solid, which contains both product and starting material. To purify, the mixture was heated to 80° C. with 100 mL of benzene for 15 min. and decanted while hot. The benzene wash was performed multiple times (at least twice), and purity was verified by NMR. (31).

[0118] Synthesis of 4,6-dinitroisoindoline-1,3-dione (3): To a stirring solution of 3,5-dinitrophthalic acid (2) (2.56 g, 10.0 mmol) in 20 mL of acetic acid was added urea (1.20 g, 20 mmol) and refluxed for 4 h. After completion of 4 h, the reaction mixture was cooled to room temperature, poured onto ice, and stirred. The obtained precipitate was filtered, washed with water and dried under vacuum to get the product 4,6-dinitroisoindoline-1,3-dione (3) in 76% yield. (32).

[0119] Synthesis of 4,6-diaminoisoindoline-1,3-dione (4): Pd/C (10mg) was added to 4,6-dinitroisoindoline-1,3-dione (0.024 g, 0.1 mmol) in methanol and subjected to hydrogenation in a Parr Shaker at a H.sub.2 pressure of 40 psi for 70 minutes. Upon completion, the reaction was filtered through celite and concentrated to obtain the product as a dirty green solid with over 90% yield. H.sup.1 NMR: 10.3 (s, 1H), 6.19 (S, 1H), 6.01 (s, 2H), 5.96 (s, 2H), 5.90 (s, 1H)

[0120] General method to synthesis of monoamido pthalimide derivatives (5—RJ Series of compounds): A solution of acyl chloride (0.173 mmol) in 3 ml of acetonitrile was added, dropwise, to a stirring solution of 4,6-diaminoisoindoline-1,3-dione (4) (0.0231 g, 0.173 mmol) in 2 ml of N-methyl-2- pyrrolidone at 0° C. The resulting solution was stirred at 0° about corresponding time (refer to table), after completion reaction mixture was poured into ice+water. Resulted precipitate was filtered off and washed with water for several time and dried under vacuum to get the corresponding product.

TABLE-US-00002 TABLE 2 Compound Reaction Isolated ID Acyl Chloride Product Structure time Yield RJ-19 [00018] [00019] 5 min 81.6% RJ-20 [00020] [00021] 3 min 86.4% RJ-21 [00022] [00023] 1 h 91.7% RJ-22 [00024] [00025] 4 h 80.6% RJ-23 [00026] [00027] 8 min 87.5% RJ-24 [00028] [00029] 8 min 83.4% RJ-25 [00030] [00031] 1 h at 0° C. + 4 h at RT 68.9% RJ-26 [00032] [00033] 3 min 98.3% RJ-27 [00034] [00035] 6 min 97.5% RJ-28 [00036] [00037] 1 min 63.5%

NMR Data:

[0121] RJ-19: .sup.1HNMR: δ 10.79 (s, 1H), 10.45 (s, 1H), 7.92 (d, 2H, J=4 Hz), 7.59-7.50 (m, 4H), 7.34 (s, 1H), 6.40 (b, 2H) ppm; .sup.13C NMR: δ 170.9, 169.7, 166.5, 147.6, 145.7, 134.9, 132.3, 128.9, 128.3, 110.2, 106.2, 106.4, 104.23 ppm.

[0122] RJ-20: .sup.1H NMR: δ 10.82(s, 1H), 10.66 (s, 1H), 8.07 (d, 2H, J=12 Hz), 8.01 (d, 2H, J=8 Hz), 7.52 (s, 1H), 7.32 (s, 1H), 6.44 (b, 2H) ppm; .sup.13C NMR: 6170.85, 169.61, 165.14, 147.56, 145.27, 138.99, 134.91, 132.94, 129.12, 118.71, 114.53, 110.41, 106.70, 104.10 ppm.

[0123] RJ-21: .sup.1HNMR: δ 10.81(s, 1H), 10.45 (s, 1H), 7.93 (d, 1H, J=4 Hz), 7.40 (d, 1H, J=4 Hz), 7.27 (d, 2H, J=8 Hz), 6.43 (b, 2H) ppm; .sup.13C NMR: δ 170.84, 169.59,159.55, 147.51, 144.97, 138.96, 135.07, 134.95, 130.23, 128.79, 110.22, 106.64, 103.96 ppm.

[0124] RJ-22: .sup.1H NMR: 10.81 (s, 1H), 10.75 (s, 1H), 7.71 (d, 1H, J=4 Hz), 7.42-7.54 (m, 4H), 7.19 (s, 1H), 6.43 (b, 2H); .sup.13C NMR: 170.87, 169.58, 166.71, 147.67, 145.28, 139.11, 135.04, 133.18, 131.87, 129.29, 128.22, 119.35, 104.73, 106.59, 103.46 ppm.

[0125] RJ-23: .sup.1HNMR: δ 10.82 (s, 1H), 10.53 (s, 1H), 8.09 (s, 1H), 7.91 (d, 1H, J=8 Hz), 7.79 (d, 1H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.30 (s, 1H), 6.40 (b, 2H); .sup.13C NMR: δ 170.88, 169.64, 164,89, 147.54, 145.42, 137.08, 135.02, 134.86, 131.10, 130.79, 127.46, 122.12, 110.37, 106.59, 104.21 ppm.

[0126] RJ-24: .sup.1HNMR: δ 10.80 (s, 1H), 10.50 (s, 1H), 7.87 (d, 2 H, J=12 Hz), 7.73 (d, 2H, J=8 Hz), 7.51 (s, 1H), 7.31 (s, 1H), 6.41 (b, 2H) ppm; .sup.13C NMR: δ 170.88, 169.65, 165.49, 147.55, 145.52, 134.87, 133.99, 131.88, 130.38, 126.16, 110.30, 106.52, 104.18 ppm.

[0127] RJ-25: .sup.1H NMR: δ 11.04 (s, 1H), 10.84 (s, 1H), 7.41 (s, 1H), 7.25(t, 3H, J=8 Hz), 7.16 (s, 1H), 6.46 (b, 2H) ppm; .sup.13CNMR: δ 170.81, 169.48, 160.43, 159.0, 157.96, 147.71, 144.70, 135.2, 132.88, 115.67, 115.23, 112.73, 109.66, 106.96, 103.03 ppm.

[0128] RJ-26: .sup.1HNMR: δ 10.82(s, 1H), 10.53 (s, 1H), 8.09 (s, 1H), 7.91(d, 1 H, J=8 Hz), 7.79 (d, 1H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.30 (s, 1H), 6.60 (b, 2H) ppm; .sup.13CNMR: 170.86, 169.61, 164.25, 148.13, 147.54, 145.22, 136.28, 134.90, 134.77, 130.66, 126.87, 123.00, 110.54, 106.74, 104.20 ppm.

[0129] RJ-27: .sup.1HNMR: δ 10.83(s, 1H), 10.74(s, 1H), 8.35(d, 2H, J=8 Hz), 8.15 (d, 2H, J=8 Hz), 7.52 (s, 1H), 7.32 (s, 1H), 6.45 (b, 2H) ppm; .sup.13C NMR: δ 170.85, 169.59, 164.84, 149.70, 147.54, 145.21, 140.57, 134.91, 129.80, 123.99, 110.46, 106.76, 104.11

[0130] RJ-28: .sup.1HNMR: δ 10.98 (s, 1H), 10.86 (s, 1H), 9.13 (s, 2H), 9.00 (s, 1H), 7.51 (s, 1H), 7.34 (s, 1H), 6.49 (b, 2H) ppm; .sup.13C NMR: δ 170.78, 169.50, 162.09, 148.45, 147.48, 144.76, 137.38, 134.87, 128.57, 121.72, 110.69, 106.95, 104.13 ppm.

[0131] General Procedure for the synthesis of RJ-29, RJ-30 and RJ-31:

##STR00038##

[0132] Pd/C (10 mg) was added to N-(7-amino-1,3-dioxoisoindolin-5-yl)-3-nitrobenzamide (RJ-26) (0.033 g, 0.1 mmol) in methanol and subjected to hydrogenation in a Parr Shaker at a H.sub.2 pressure of 40 psi for 1 h. Upon completion, the reaction was filtered through celite and concentrated to obtain the product 3-amino-N-(7-amino-1,3-dioxoisoindolin-5-yl)benzamide (6a) with an isolated yield 93.2%. A similar procedure was followed for the conversion of RJ-27 and RJ-28 to RJ-30 and RJ-31, respectively.

TABLE-US-00003 TABLE 3 Compound ID Product Structure Isolated Yield RJ-29 93.2% RJ-30 [00039] 91.7% RJ-31 [00040] 94.5%

NMR Data:

[0133] General Procedure for the synthesis of RJ-29, RJ-30 and RJ-31:

[0134] RJ-29: .sup.1HNMR: δ 10.76 (b, 1H), 10.30 (s, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 7.13 (t, 2H, J=8 Hz), 7.02 (d, 1H, J=12 Hz), 6.73 (d, 2H, J=4 Hz), 6.37 (s, 1H), 5.33 (b, 2H) ppm; .sup.13CNMR: 170.91, 169.72, 167.32, 149.25, 147.56, 145.95, 135.93, 134.81, 129.27, 117.53, 115.27, 113.40, 110.05, 106.18, 104.20 ppm.

[0135] RJ-30: .sup.1HNMR: δ 10.72 (b, 1H), 9.97 (s, 1H), 7.69 (d, 2H, J=8 Hz), 7.52 (s, 1H), 7.32 (s, 1H), 6.57 (d, 2H, J=8 Hz), 6.33 (s, 2H), 5.83 (s, 2H) ppm; .sup.13C NMR: δ 170.92, 169.79, 166.06, 152.97, 147.55, 146.45, 134.75, 130.08, 120.83, 112.94, 104.70, 105.74, 104.20

[0136] RJ-31: .sup.1HNMR: δ 10.74 (b, 1H), 10.20 (s, 1H), 7.52 (s, 1H), 7.26 (s, 1H), 6.34 (s, 2H), 6.24 (s, 2H), 5.98 (s, 1H), 4.96 (s, 4H) ppm; .sup.13CNMR: 6170.91, 169.74, 168.23, 149.63, 147.56, 146.18, 144.50, 136.80, 134.78, 109.81, 105.96, 104.13, 102.87, 102.73 ppm.

[0137] Cell viability assays used the methods outlined in an earlier publication: Identification of New Mono/Dihydroxynaphthoquinone as Lead Agents that Inhibit the Growth of Refractive and Triple-negative Breast Cancer Cell lines. Schroeder, R.; Sfondouris, M.; Goyal, N.; Komati, R.; Weerathunga, A.; Gettridge, C.; Stevens, C. L. K.; Jones, F. E.; Sridhar, J. ACS Omega, 2019 Jun 19. 4(6):10610-10619.

B. Inhibitory Activity of the various 4,6-diaminoisoindolin-1,3-dione/4-amino-6-amidoisoindoline-1,3-dione derivatives

[0138] The 4-amino-6-amidoisoindolin-1,3-diones were found to inhibit RPS6K1 with a range of 27% to 86% at a 10 μM concentration (Table 4).

TABLE-US-00004 TABLE 4 High-throughput screening of the 4-amino-6-amidoisoindoline- 1,3-dione compounds for the for the inhibition of RPS6K1. RPS6K1% inhibition at 10 mM Compound compound concentration RJ-7 50 RJ-19 71 RJ-20 27 RJ-21 37 RJ-22 86 RJ-23 40 RJ-24 40 RJ-25 38 RJ-26 50 RJ-27 65 RJ-28 79 RJ-29 65 RJ-30 64 RJ-31 58

[0139] As seen from Table 4, three of the compounds RJ19, RJ22 and RJ28 were found to exhibit >70% inhibition of the kinase in the high-throughput screening. These three compounds were then subjected to IC.sub.50 value determination (dose response curve) using the same FRET based assay by ThermoFisher (Table 5). RJ-2 was determined to be selective for two other kinases (WEE1 and PLK3) (not shown in Table). It also selectively inhibited CK1epsilon (70%) over CK1delta (30%).

TABLE-US-00005 TABLE 5 IC.sub.50 values of inhibition of RPS6K1 for the compounds RJ-19, RJ-22 and RJ-28. IC.sub.50 value of inhibition Compound of RPS6K1 in μM RJ-28 2.56 RJ-22 >2.78 RJ-19 3.48

[0140] As shown by Table 5, the IC.sub.50 values of inhibition for RJ19, RJ22 and RJ28 were 3.48 μM, >2.78 μM and 2.56 μM, respectively.

[0141] RPS6K1 is known to play a critical role in several cancers including HER2 positive breast cancer, ER positive breast cancer, prostate cancer and small cell lung cancer. To verify whether RPS6K1 inhibitors of the instant disclosure could inhibit growth of these types of cancers, MTT assays were performed using the HER2 positive breast cancer cell line SKBR3, ER positive breast cancer cell line MCF7, and the prostate cancer cell line DU-145. The MTT assay is a colorimetric assay for assessing cell metabolic activity. NAD(P)H-dependent cellular oxidoreductase enzymes may, under defined conditions, reflect the number of viable cells present. These enzymes are capable of reducing the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to its insoluble formazan, which has a purple color. RJ22 and RJ28 showed excellent growth inhibition of all three cell lines in the low micromolar range (FIGS. 1A, 1B and 1C). RJ19 showed inhibition of the HER2 positive breast cancer cell line SKBR3, but was not as effective for the ER positive breast cancer cell line MCF7 (FIGS. 1A and 1B). The IC.sub.50 values of growth inhibition of the SKR3 breast cancer cell line for all three compounds RJ19, RJ22 and RJ28 was determined to be 3.3 μM, 1.9 μM and 4.7 μM, respectively.

[0142] To understand the nature of binding of these compounds to the ATP-binding pocket of the RPS6K1 protein (4L3J.pdb), docking studies were performed using the molecular modeling software MOE (CHEMCOMP Group). We found that a carbonyl and the NH of the phthalimide core structure formed hydrogen bonds with the hinge region residues Glu150 and Leu152 (FIG. 3). An aromatic π-methyl interaction was found to occur between the phenyl ring of phthalimide and the binding cavity residue Va182. The 6-amido carbonyl group was within hydrogen bonding distance of the side chain hydroxyl group of residue Thr212.

[0143] Thus, this demonstrates that a new class of compounds has been identified, and that these compounds are selective inhibitors of RPS6K1 protein. These compounds show growth inhibition of several cancer cell lines including HER2 positive breast cancer, ER positive breast cancer and prostate cancer cell lines. These compounds can serve as therapeutics for any type of cancer where the AKT/mTOR signaling pathway is upregulated.

[0144] All references cited in this specification are herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior invention.

[0145] It will be understood that each of the elements described above, or two or more together may also find a useful application in other types of methods differing from the type described above. Without further analysis, the foregoing will so fully reveal the gist of the present disclosure that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this disclosure set forth in the appended claims. The foregoing embodiments are presented by way of example only; the scope of the present disclosure is to be limited only by the following claims.

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