INHIBITORS OF KRAS(G12D)

Provided are small molecule inhibitors of the KRAS(G12D) mutant oncoprotein having the structural formula:   and pharmaceutically acceptable salts and compositions thereof, which are useful for treating cancers and related conditions.

BACKGROUND

Discovered as a human oncogene in the early 1980s, the Kirsten rat sarcoma virus homolog (KRAS) gene encodes a monomeric small 21 kDa GTPase that has long been an elusive cancer drug target (Chang et al., PNAS, 1982, 79:4848-52; McCoy et al., Nature, 1983, 302:79-8). KRAS functions as a molecular switch for promoting cell growth by cycling between GTP- and GDP-bound states. In the GTP-bound state, KRAS signals for growth through the RAF-MAPK and PI3K-AKT-MTOR pathways. KRAS subsequently hydrolyzes GTP to GDP with the aid of GTPase activating proteins (GAPs). This GDP-bound state switches “off” KRAS pro-growth signaling. KRAS can then be switched back “on” by GDP to GTP exchange through the aid of guanine nucleotide exchange factors, such as SOS1 (Cox and Der, Small GTPases, 2010, 1:2-27; Kerk et al., Nat Rev Cancer, 2021, 21:510-525). Preventing this exchange by locking KRAS in the GDP-bound state is a practical method for inhibiting its growth promoting activity.

The human KRAS gene is encoded on Chromosome 12p12.1 and is among the most frequently mutated genes in human cancers (Pylayeva-Gupta et al., Nat Rev Cancer, 2011, 11:761-774). Mutations that prevent GTP-hydrolysis lock KRAS in the active GTP-bound state and reprogram cells for perpetual proliferation. KRAS mutated from glycine (G) at the 12th codon to aspartate (D) creates a chronically active KRAS(G12D) oncoprotein, the gene for which is observed in 6.8% of cancers cases as analyzed by next-generation sequencing (Zhou et al., Pathol Oncol Res, 2020, 26:2835-2837). In tumor type-specific studies, KRAS(G12D) is associated with poor clinical outcomes and observed in 17% of lung, 14.3% of colorectal, and 48% of pancreatic tumors (Aredo et al., Lung Cancer, 2019, 133:144-150; Olmedillas-López et al., World J Gastroenterol, 2017, 23(39): 7087-709; Miglio et al., Pathol Res Pract, 2014, 210:307-11; Gou et al., Br J Cancer, 2020, 22:857-867), among other cancers. Historically, oncogenic KRAS mutants have been considered undruggable (McCormick F, Biochem J, 2019, 476:356-74), however the discovery of an allosteric pocket in GDP-bound KRAS has allowed the search for small molecule inhibitors (Ostrem et al., Nature, 2013, 503: 548-51). The G12D mutation moreover provides a unique chemical moiety-binding space due to the encoding of an acidic amino acid residue (D) in place of a small flexible amino acid residue possessing only a hydrogen side chain (G). This alteration of the KRAS protein structure provides a unique space that may be targeted with small molecules drugs that specifically inhibit KRAS(G12D) oncogenic activity. It is therefore desirable to design and develop small molecule drugs that target KRAS(G12D) with sufficient bioavailability to treat diseases such as cancer.

SUMMARY

Provided herein are small molecule inhibitors of the KRAS(G12D) mutant oncoprotein. Inhibitors of KRAS(G12D) include those having the structural formula I:

and pharmaceutically acceptable salts and compositions comprising such, wherein Y, X, R1, R2, R3, R4, R5, R6, R7, R8, and R9are as defined herein. The use of these compounds, salts, and compositions for treating diseases responsive to the inhibition of KRAS(G12D), such as cancer, is also disclosed. In one aspect, disclosed compounds show improved bioavailability. See e.g., Table 3.

DETAILED DESCRIPTION

1. General Description of Compounds

As part of a first embodiment, provided is a compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein

Y is hydrogen or —C(O)OCHRaOC(O)Rb;

X is CH or N;

R2is a 4- to 6-membered monocyclic heterocyclyl substituted with 1 to 3 groups selected from Rcor a 6- to 10-membered bicyclic heterocyclyl optionally substituted with 1 to 3 groups selected from Rd;

R8and R9are taken together to form ═CH or cyclopropyl;

Raand Rbare each independently selected from hydrogen and (C1-C4)alkyl; and

As used herein, the articles “a” and “an” refer to one or more than one, e.g., to at least one, of the grammatical object of the article. The use of the words “a” or “an” when used in conjunction with the term “comprising” herein may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

As used herein the term “comprising” or “comprises” are used in reference to compositions, methods, and respective component(s) thereof, that are present in a given embodiment, yet open to the inclusion of unspecified elements.

As used herein, the term “alkynyl” means a saturated straight chain or branched non-cyclic hydrocarbon having, unless specified otherwise, from 2 to 10 carbon atoms (e.g., (C2-C6)alkynyl or (C2-C4)alkynyl) and having at least one carbon-carbon triple bond.

The term “oxo” refers to the group ═O.

As used herein, the term “haloalkyl” means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from —F, —Cl, —Br, and —I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by —O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

“deuterated alkoxy” refers to an alkoxy group in which one or more hydrogens (e.g., one or two hydrogens) has been replaced by deuterium.

“Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., —OCHF2or —OCF3.

As used herein, the term “halogen” or “halo” means F, Cl, Br or I.

The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

The term “fused” refers to two rings that share two adjacent ring atoms with one another.

The term “bridged” refers to two rings that share three ring atoms with one another.

When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, —(C1-C4)alkylaryl and means that the point of attachment for these groups occurs on the alkyl group.

A hash bond as in “” represents the point at which the depicted group is attached to the defined variable.

The term “KRAS” refers to the protein product of the KRAS proto-oncogene, GTPase gene.

The term “KRAS(G12D)” refers to the protein product of the KRAS gene carrying a mutation that results in the glycine amino acid at position 12 of KRAS being replaced by an aspartate.

A “chemical entity which binds KRASG12D” refers to a small molecule or a distinct portion of a larger molecule which binds to a portion of KRASG12D. In some aspects, the chemical entity which binds KRASG12Dis a small molecule. In some aspects, the chemical entity which binds KRASG12Dis a small molecule having a molecular weight of less than 2,000 g/mol. In some aspects, the chemical entity which binds KRASG12Dinduces a confirmation change in KRASG12D.

The term “SOS1” refers to the protein product of the SOS1 gene that functions as a guanine nucleotide exchange factor for RAS proteins.

The compounds described herein may have chiral centers and/or geometric centers (E- and Z-isomers). It will be understood that the present disclosure encompasses all stereoisomers and geometric isomers. Tautomeric forms of the compounds described herein are also part of the present disclosure.

When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the depicted stereoisomer plus the weight of the other stereoisomers.

For use in medicines, the pharmaceutically acceptable salts of the disclosed compounds refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

As used herein, the term “subject” refers to human and non-human animals, including veterinary subjects. The term “non-human animal” includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dog, cat, horse, cow, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human and may be referred to as a patient.

As used herein, the terms “treat,” “treating” or “treatment” refer, preferably, to an action to obtain a beneficial or desired clinical result including, but not limited to, alleviation or amelioration of one or more signs or symptoms of a disease or condition, diminishing the extent of disease, stability (i.e., not worsening) of the state of disease, amelioration or palliation of the disease state, diminishing rate of or time to progression, and remission (whether partial or total). “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment does not need to be curative.

A “therapeutically effective amount” is that amount sufficient to treat a disease in a subject. A therapeutically effective amount can be administered in one or more administrations. In one aspect, a therapeutically effective amount refers to a dosage of from about 0.01 to about 100 mg/kg body weight/day.

The terms “administer,” “administering” or “administration” include any method of delivery of a pharmaceutical composition or agent into a subject's system or to a particular region in or on a subject. In certain embodiments, an agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transcutaneously, or mucosally. In certain embodiments, an agent is administered intravenously. In In certain embodiments, an agent is administered orally. Administering an agent can be performed by a number of people working in concert. Administering an agent includes, for example, prescribing an agent to be administered to a subject and/or providing instructions, directly or through another, to take a specific agent, either by self-delivery, e.g., as by oral delivery, subcutaneous delivery, intravenous delivery through a central line, etc.; or for delivery by a trained professional, e.g., intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

As part of a second embodiment, the compound of Formula I is of the Formula II:

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

As part of a third embodiment, the compound of Formula I is of the Formula III:

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

As part of a fourth embodiment, the compound of Formula I is of the Formula IV:

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

As part of a fifth embodiment, the compound of Formula I is of the Formula V:

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

As part of a sixth embodiment, R1in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the variables are as described above for Formula I.

As part of a seventh embodiment, X in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is N, wherein the variables are as described above for Formula I or the sixth embodiment.

As part of an eighth embodiment, R3in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is halo, wherein the variables are as described above for Formula I or the sixth or seventh embodiment. Alternatively, as part of an eighth embodiment, R3in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the variables are as described above for Formula I or the sixth or seventh embodiment.

As part of a ninth embodiment, R5in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is (C2)alkynyl, wherein the variables are as described above for Formula I or any one of the sixth to eighth embodiments.

As part of a tenth embodiment, R6in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is halo, wherein the variables are as described above for Formula I or any one of the sixth to ninth embodiments. Alternatively, as part of a tenth embodiment, R6in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the variables are as described above for Formula I or any one of the sixth to ninth embodiments.

As part of an eleventh embodiment, R7in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is OH, wherein the variables are as described above for Formula I or any one of the sixth to tenth embodiments.

As part of a twelfth embodiment, R4in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, (C1-C4)alkoxy, deuterated(C1-C4)alkoxy, —N[(C1-C4)alkyl]2, halo, (C3-C6)cycloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkyl, and NH2, wherein the variables are as described above for Formula I or any one of the sixth to eleventh embodiments. Alternatively, as part of a twelfth embodiment, R4in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, methyl, methoxy, isopropoxy, OCDF2, —OCHF2, —N(CH3)2, NH2, chloro, and cyclopropyl, wherein the variables are as described above for Formula I or any one of the sixth to eleventh embodiments.

As part of a thirteenth embodiment, R2in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is a 4- to 6-membered nitrogen containing monocyclic heterocyclyl substituted with 1 to 3 groups selected from Rcor a 7- to 10-membered nitrogen containing fused or spiro bicyclic heterocyclyl optionally substituted with 1 to 3 groups selected from Rd, wherein the variables are as described above for

Formula I or any one of the sixth to twelfth embodiments. Alternatively, as part of a thirteenth embodiment, R2in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is azetidinyl, piperidinyl, morpholinyl, or pyrrolidinyl, each of which being substituted with 1 to 3 groups selected from Rcor R2in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, or 1,2,3,6-tetrahydropyridinyl, each of which being optionally substituted with 1 to 3 groups selected from Rd, wherein the variables are as described above for Formula I or any one of the sixth to twelfth embodiments.

As part of a fourteenth embodiment, Rcand Rdin the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, are each independently selected from halo, cyano, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkoxy, —S(O)Ra, and —SO2NRaRb, wherein the variables are as described above for Formula I or any one of the sixth to thirteenth embodiments. Alternatively, as part of a fourteenth embodiment, Rcand Rdin the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, are each independently selected from fluoro, cyano, CF3, methoxy, isopropyl, OCF3, —S(O)CH3, and —SO2N(CH3)2, wherein the variables are as described above for Formula I or any one of the sixth to thirteenth embodiments.

As part of a fifteenth embodiment, R8and R9in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, are taken together to form cyclopropyl, wherein the variables are as described above for Formula I or any one of the sixth to fourteenth embodiments.

As part of a sixteenth embodiment, Y in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is hydrogen or —C(O)OCH(CH3)OC(O)CH3, wherein the variables are as described above for Formula I or any one of the sixth to fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, Y in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the variables are as described above for Formula I or any one of the sixth to fifteenth embodiments.

Additional compounds are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included.

4. Uses, Formulation and Administration

Compounds and compositions described herein are generally useful as anticancer therapies. In one aspect, the disclosed compounds and compositions behave as inhibitors of KRAS(G12D). Their mechanisms of action include, but are not limited to, inhibiting KRAS(G12D) and thereby impeding down-stream signals that may result in inhibition of cancer cell growth and/or induction of cancer cell death or other KRAS or KRAS(G12D) functions. In one aspect, the disclosed compounds effectuate the inhibition of KRAS(G12D).

Thus, provided herein are methods of treating conditions which are responsive to the inhibition of KRAS(G12D) comprising administering to a subject in need thereof, a therapeutically effective amount of one or more compounds or compositions described herein. Also provided is the use of one or more compounds or compositions described herein in the manufacture of a medicament for treating conditions which are responsive to the inhibition of KRAS(G12D). Further provided is the use of a compound or composition described herein for treating conditions which are responsive to the inhibition of KRAS(G12D).

“Solid tumor,” as used herein, is understood as any pathogenic tumor that can be palpated or detected using imaging methods as an abnormal growth having three dimensions. A solid tumor is differentiated from a blood tumor such as leukemia. However, cells of a blood tumor are derived from bone marrow; therefore, the tissue producing the cancer cells is a solid tissue that can be hypoxic.

“Tumor tissue” or “tumorous tissue” are understood as cells, extracellular matrix, and other naturally occurring components associated with the solid tumor.

Chemical Synthesis

The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention. General starting materials used were obtained from commercial sources or prepared in other examples, unless otherwise noted.

The compounds claimed herein were prepared following the procedures outlined in the Scheme 1.

Preparation of Example 1

Step 3: tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. To a stirred mixture of [1-(hydroxymethyl)cyclopropyl]methanol (14.31 g, 140 mmol, 3 eq) and t-BuONa (13.46 g, 140 mmol, 3 eq) in THF was added tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 g, 46.697 mmol, 1 eq) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 1 h under nitrogen atmosphere. The reaction was quenched with Water at 0° C. The resulting mixture was extracted with CH2Cl2(3×10mL). The combined organic layers were washed with sat. NaCl aq. (2×5 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford intermediate 1-4 (14.5 g, 62.86%) as a white solid. LCMS (ES, m/z): 494 [M+H]+

Step 5: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of intermediate 5 (200 mg, 0.323 mmol, 1 eq) in DCM was added Dess-Martin (410.38 mg, 0.969 mmol, 3 eq) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. NaHCO3(aq.) at 0° C. The resulting mixture was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with sat. NaCl (aq.) (3×5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ES, m/z): 618 [M+H]+

Step 6: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-fluoropiperidin-1- yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of intermediate 1-6 (100 mg, 0.162 mmol, 1 eq) and 4-fluoropiperidine hydrochloride (45.17 mg, 0.324 mmol, 2 eq) in DMF were added STAB (102.87 mg, 0.486 mmol, 3 eq) in portions at room temperature. The resulting mixture was stirred for 16 h at room temper ature. The reaction was quenched with Water at room temperature. The resulting mixture w as extracted with EtOAc (3×10 mL). The combined organic layers were washed with sat. N aCl aq. (2×5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ES, m/z): 605 [M+H]+

The following compounds in Table 1 were prepared according to the methods described above using the appropriate starting materials.

A compound described herein may also selected from any one of the following

or a pharmaceutically acceptable salt of any one of the foregoing.

Cell Lines

Binding of test compounds to KRAS(G12D) target protein, which in turn blocks KRAS(G12D) interaction with the SOS1 protein, was measured in the absences of GTP by homogeneous time-resolved fluorescence using the KRAS-G12D/SOS1 Binding Assay Kit (Cisbio, 63ADK000CB17PEH), following the manufacturer's instructions, except as noted. 3-fold serial dilutions of each test compound were prepared ranging from 20 μM to 1.02 nM. The test compound was mixed and incubated with reaction components, incubated in a sealed plate at 4° C. for 3 hr and fluorescence was measured using a PerkinElmer Envision plate reader. The KRAS(G12D)-SOS1 IC50values (the concentration of 50% of the maximal inhibition) were calculated using GraphPad Prism 7 software. Results are listed inCancer cell line proliferation(CellTiter-Glo® assays)

Oral Bioavailability

CD-1 mice were randomly assigned to 6 groups with 3 male mice in each compound group. Control groups included reference compound 1 (50 mg/kg), reference compound 2 (25 mg/kg) and example 1 (25 mg/kg). Inventive compound groups included prodrug compound of Example 52 (50 mg/kg), compound of example 2 (50 mg/kg), compound of example 3 (50 mg/kg) and compound of example 4 (25 mg/kg). Compounds were orally administered (PO) in a single dose to each mouse in its group. Blood samples were taken within 72 hours. Bioavailability (F %) was determined and by liquid chromatography-mass spectrometry (LC-MS/MS). The mean oral % F is provided in Table 3.

Compound 3 was evaluated in the human lung carcinoma A427 xenograft model using female NOD SCID mice (6-8 weeks old). Each mouse was inoculated subcutaneously in the right flank with A427 tumor cells (1×107) in 0.1 ml of Medium and Matrigel mixture (1:1 ratio) to initiate tumor development. Once tumors reached an average size of ˜170 mm3, mice were randomized among treatment groups followed by administration of test articles or vehicle. Compound 3 was administrated by oral gavage (PO) once daily at 200 mg/kg for 5 weeks. And vehicle was administrated by oral gavage twice daily. Body weight and tumor volume was measured twice weekly until the study finished. The results are illustrated inFIG.1andFIG.2.

Compound 34 was evaluated in the human colon adenocarcinoma GP2D xenograft model using female BALB/c nude mice (6-8 weeks old). Each mouse was inoculated subcutaneously on the right flank with GP2D tumor cells (1×107) in 0.1 ml of Medium and Matrigel mixture (1:1 ratio) to initiate tumor development. Once tumors reached an average size of ˜230 mm3, mice were randomized among treatment groups followed by administration of test articles or vehicle. Compound 34 was administrated by oral gavage (PO) once daily at 200 mg/kg for 4 weeks and vehicle was administrated by oral gavage once daily for 4 weeks. Body weight and tumor volume was measured twice weekly until the study finished. The results are illustrated inFIG.3andFIG.4.

Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure are intended and understood by those skilled in the relevant field in which this disclosure resides to be within the scope of the disclosure as represented by the following claims.