6-(pyrimidin-5-YL)-3,4-dihydropyrazino[l,2-a]imdol-l(2H)-one MCL-1 inhibitors

Abstract

Substituted 6-(pyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-ones inhibit binding of Mcl-1 to Bcl-2 family members, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.

Description

SUBSTITUTED 6-(PYRIMIDIN-5-YL)-3,4-DIHYDROPYRAZINO[1,2-A]INDOL-1(2H)-ONE MCL-1 INHIBITORS RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 664,043, filed June 25, 2024, which is hereby incorporated by reference in its entirety. STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under Contract No. HHSN261200800001E and Grant No. P50CA098131, awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD

[0003] The present invention pertains to compounds that inhibit the activity of an anti- apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) protein, compositions containing the compounds, and methods of treating cancer involving over-expressed or dysregulated Mcl-1 protein. BACKGROUND

[0004] Abnormal regulation of apoptosis is now recognized to play an important role in the development of cancer. The apoptosis pathway can be initiated by various extracellular and intracellular stresses, including growth factor deprivation, DNA damage, oncogene induction, and cytotoxic drugs (Danial, N. N. and Korsmeyer, SJ. Cell (2004) 116, 205-219). The death signal leads to the oligomerization of the pro-apoptotic proteins Bax and Bak. Upon activation, they permeabilize the mitochondrial outer membrane and release apoptogenic factors into the cytoplasm. This process is tightly regulated by both pro-apoptotic (Bax, Bak, Bad, Bid, Bim, Bmf, NOXA, PUMA) and anti-apoptotic (Bcl-2, Bcl-xL, Bcl-w, Bcl2-A1, Mcl-1) members of the Bcl-2 family of proteins. Recent data suggests that the anti-apoptotic Bcl-2 proteins function to protect the cell from apoptotic insults, primarily by preventing disruption of mitochondrial outer membrane integrity by binding to the pro-apoptotic proteins as described in Adams, J. M. and Cory S. Oncogene (2007) 26, 1324-1337; Willis, S. N. et al. Science (2007)315,856-859. Because tumor cells are under stress, alterations in their apoptotic signaling pathways are believed to be crucial for survival. Recent data implicates down-regulated apoptosis in the onset of cancer. Research has shown, for example, that anti-apoptotic proteins, are over-expressed in many cancer cell types as described in Beroukhim, R. et al. Nature (2010) 463, 899-905; Zhang J. Y., Nature Reviews Drug Discovery, (2002) 1, 101; Kirkin, V. et al. Biochimica et Biophysica Acta (2004) 1644, 229-249; and Amundson, S.A. et al. Cancer Research (2000) 60, 6101-6110. This dysregulation results in the survival of cells that would otherwise have undergone apoptosis such as cancer cells. This suggests that neutralizing the function of anti-apoptotic Bcl-2 proteins may offer an effective strategy for the elimination of cancer cells. In addition, resistance to chemotherapy which is a major cause of treatment failure and poor prognosis in many cancers can be caused by the upregulation of anti-apoptotic Bcl-2 family proteins.

[0005] An important anti-apoptotic member of the Bcl-2 family is Myeloid cell leukemia-1 (Mcl-1). Mcl-1 is one of the most frequently amplified anti-apoptotic genes in human cancers including prostate, lung, pancreatic, breast, ovarian, and cervical cancers, as well as melanoma, B-cell chronic lymphocytic leukemia (B-CLL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (Beroukhim et al. Nature (2010) 463, 899-905). Moreover, its overexpression is implicated as a resistance factor for multiple therapies including widely prescribed microtubule-targeted agents for breast cancers, such as paclitaxel and vincristine as well as Gemcitabine, a first-line treatment option for pancreatic cancer (Wei et al. Cancer Chemother Pharmacol (2008) 62, 1055-1064 and Wertz et al. Nature (2011) 471, 110-114). These data suggest that Mcl-1 is an important target for a wide variety of cancers.

[0006] In many cancer cell types, the cancer cell’s survival is attributed to the dysregulation of the apoptotic pathway caused by the over-expression of one or more anti-apoptotic Bcl-2 protein family members. Because of the important role for Bcl-2 family of proteins in regulating apoptosis in both cancerous and non-cancerous cells, and the inter-cell variability of Bcl-2 family protein expression, it could be advantageous to have a small molecule inhibitor that selectively targets and preferably binds to one type or a subset of anti-apoptotic Bcl-2 protein(s). A selective compound also may confer certain advantages in the clinical setting, by providing flexibility to select a dosing regimen to reduce on-target toxic effects in normal cells.

[0007] Because Mcl-1 protein is an important Bcl-2 family member associated with a number of diseases, there is a need for compounds which bind to and inhibit the activity of Mcl-1 protein. SUMMARY

[0008] In some embodiments, the present invention provides compounds, and pharmaceutically acceptable compositions thereof, that are effective as inhibitors of Mcl-1.

[0009] In one aspect, the invention provides compounds of formula (I),R2a, at each occurrence, is independently C1-4alkyl; R2bis C1-4alkyl or H; R3is C1-2alkyl; R4is OH, –OC1-6alkyl, or –OPG; PG is a carboxylic acid protecting group;R5is H, C1-4alkyl, or C3-4cycloalkyl; R6is C1-4alkyl or C3-4cycloalkyl; R7is G or –CH2–G; G is a 4- to 7-membered heterocyclyl containing 1-2 oxygen atoms and optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro and methyl; R8a, at each occurrence, is independently C1-4alkyl; R8bis halogen; and R9is C1-4alkyl, C3-4cycloalkyl, or H.

[0010] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In another aspect, the invention provides a method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0012] In another aspect, the invention provides a method for inhibiting the binding of Mcl- 1 to Bcl-2 family members, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0013] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of cancer.

[0014] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the inhibition of binding of Mcl-1 to Bcl-2 family members.

[0015] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0016] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the inhibition of binding of Mcl-1 to Bcl-2 family members.

[0017] In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use. BRIEF DESCRIPTION OF THE FIGURES

[0018] FIG.1A shows anti-tumor efficacy of a single IV dose of compound 26 at 60 mg / kg and 80 mg / kg in a NCI-H929 cell line-derived multiple myeloma (MM) mouse xenograft model, compared to control.

[0019] FIG.1B shows body weights for mice in the NCI-H929 cell line-derived MM mouse xenograft study.

[0020] FIG.2A shows anti-tumor efficacy of compound 26 in an A427 cell line-derived NSCLC mouse xenograft model. Compound 26 (60 mg / kg) is dosed as a single agent or together with docetaxel (10 mg / kg) and effects compared to control and docetaxel alone (10 mg / kg).

[0021] FIG.2B shows body weights for mice in the NCI-H929 cell line-derived MM mouse xenograft study.

[0022] FIG.3A shows relative tumor volumes at day 21 for individual mice dosed compound 26 in the A427 cell line-derived NSCLC mouse xenograft study.

[0023] FIG.3B shows relative tumor volumes at day 21 for individual mice dosed docetaxel in the A427 cell line-derived NSCLC mouse xenograft study.

[0024] FIG.3C shows relative tumor volumes at day 21 for individual mice dosed docetaxel and compound 26 in the A427 cell line-derived NSCLC mouse xenograft study. DETAILED DESCRIPTION 1. Definitions

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0026] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0027] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9- 1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0028] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0029] The term “alkoxy,” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy.

[0030] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “C1-6alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-4alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0031] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.

[0032] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon, for example, of 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CD2-, -CH2CH2-, -C(CH3)(H)-, -C(CH3)(D)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0033] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][1,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6- membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0034] The term “cycloalkyl” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0035] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl in which two non- adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0036] The term “carbocyclyl” means a “cycloalkyl” or a “cycloalkenyl.” The term “carbocycle” means a “cycloalkane” or a “cycloalkene.” The term “carbocyclyl” refers to a “carbocycle” when present as a substituent.

[0037] The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a fluoro group. Representative examples of fluoroalkyl include CH2F, CHF2, CF3, and CH2CHF2.

[0038] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0039] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0040] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatom- containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl” is used herein to refer to a heteroarene when present as a substituent. The monocyclic heteroaryl are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g.1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8- to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 10π electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4- yl). A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclicheteroaromatic ring system having four double bonds and at least one heteroatom contributing a lone electron pair to a fully aromatic 10π electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ring system composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2- yl.

[0041] The term “heterocycle” or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term “heterocyclyl” is used herein to refer to a heterocycle when present as a substituent. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to,azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2- thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3- dihydrobenzothien-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa- 6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indol-1- yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1- azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). Themonocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety at a non-aromatic ring atom.

[0042] The term “imino” refers to the group “=NH.”

[0043] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance ( e.g., "C1-4alkyl," "C3-6cycloalkyl," "C1-4alkylene"). These designations are used as generally understood by those skilled in the art. For example, the representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "C3alkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "C1-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "C1-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0044] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups may include, for example, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0045] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0046] ABBREVIATIONS AcOH = acetic acid aq. = aqueous atm. = atmosphere Bn = benzyl BnBr = benzylbromide Boc = tert-butyl carbamate / carboxylate(Bpin)2= bis(pinacolato)diboron Cbz = benzyl carbamate Cbz-Cl = benzyl chloroformate CDCl3= chloroform, deuterated Celite® = diatomaceous earth conc. = concentrated = chemical shift d = doublet DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane DCE = dichloroethane dd = doublet of doublets ddd = doublet of doublet of doublets dt = doublet of triplets DIPEA = N,N-diisopropylethylamine DMAP = N,N-dimethyl-4-aminopyridine DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide DMSO-d6= DMSO, deuterated Dt-BAD = Di-tert-butyl azodicarboxylate EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide eq = equivalents ESI = electron spray ionization EtOAc = ethyl acetate EtOH = ethanol g = gram(s) h or hr = hour(s)1H NMR = proton nuclear magnetic resonance HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxidhexafluorophosphate hex = hexanesHPLC = high pressure liquid chromatography Hz = hertz iPrOH = isopropanol J = coupling constant (Hz) KOAc = potassium acetate LAH = lithium aluminum hydride LiBHEt3= lithium triethylborohydride LCMS = liquid chromatography / mass spectrometry LiOH = lithium hydroxide M = molar, molarity m = multiplet [M+H]+= the protonated mass of the free base of the compound MeCN = acetonitrile MeI = iodomethane MeOD = methanol, deuterated MeOH = methanol mg = milligram(s) MHz = megahertz min = minute(s) mL = milliliter(s) mmol = mmol MS = mass spectrometry Ms = methanesulfonyl MsCl = methanesulfonyl chloride mol = moles m / z = mass / charge ratio N = normal NaOEt = sodium ethoxide NaOMe = sodium methoxide NBS = N-bromosuccinamide n-BuLi = n-butyllithiumNIS = N-iodosuccinamidePdCl2(dppf)•CH2Cl2 = [1,1 -Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane Pd2dba3= tris(dibenzylideneacetone)dipalladium(0) Pd(OH)2 / C = palladium (II) hydroxide on carbon Pd(PPh3)4= tetrakis(triphenylphosphine)palladium (0) PPh3= triphenylphosphine PPTS = pyridinium p-toluenesulfonic acid quant. = quantitative RT= retention time (min) rt / RT = room temperature s = singlet sat. = saturated SEM-Cl = (2-Chloromethoxyethyl)trimethylsilane sm = starting materialS-Phos = dicyclohexyl(2 ,6 -dimethoxy[1,1 -biphenyl]-2-yl)phosphanet = triplettBuBrettPhos = 2-(Di-tert-butylphosphino)-2 ,4 ,6 - triisopropyl-3,6-dimethoxy-1,1 -biphenylTEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran Tosic acid = para-toluene sulfonic acid Tosyl = para-toluene sulfonyl μmol = micromole wt. = weight Xantphos = (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) 2. Compounds

[0047] In one aspect, disclosed are compounds of formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8a, R8b, and R9are as defined herein.

[0048] Optionally substituted cyclic groups (i.e., unsubstituted or substituted cyclic groups), such as optionally substituted aryl, heteroaryl, etc., are composed of a ring system and the ring system's optional substitution. Accordingly, a “ring system” refers to the base molecular structure formed by the constituent ring atoms, including any hydrogens required to satisfy the valency of the ring atoms. A ring system may be defined independently of its substituents. Thus, where only the ring system of an optionally substituted cyclic group is redefined with a more specific definition, any optional substitution of the original optionally substituted cyclic group remains for the new more specifically defined ring system. For example, an optionally substituted 5- to 12-membered heteroaryl may be further defined by specifying the ring system of the optionally substituted 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., 5- to 6-membered heteroaryl ring system), in which case the optional substitution of the original optionally substituted 5- to 12-membered heteroaryl continues to apply to the 5- to 6- membered heteroaryl ring system, unless otherwise expressly indicated.

[0049] In the following, numbered embodiments of the invention are disclosed, E1, E2, E3, etc. In the numbered embodiments, the reference to a range of preceding embodiments in multiple dependent format is a reference, in the alternative, to each embodiment sequentially listed herein in the recited range.

[0050] E1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, (I)wherein: R1is halogen;R2a, at each occurrence, is independently C1-4alkyl; R2bis C1-4alkyl or H; R3is C1-2alkyl; R4is OH, –OC1-6alkyl, or –OPG; PG is a carboxylic acid protecting group; R5is H, C1-4alkyl, or C3-4cycloalkyl; R6is C1-4alkyl or C3-4cycloalkyl; R7is G or –CH2–G; G is a 4- to 7-membered heterocyclyl containing 1-2 oxygen atoms and optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro and methyl; R8a, at each occurrence, is independently C1-4alkyl; R8bis halogen; and R9is C1-4alkyl, C3-4cycloalkyl, or H.

[0051] E2. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein R1is chloro.

[0052] E3. The compound of E1 or E2, or a pharmaceutically acceptable salt thereof, wherein R2a, at each occurrence, is methyl.

[0053] E4. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R2bis methyl.

[0054] E5. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R2bis H.

[0055] E6. The compound of any of E1-E5, or a pharmaceutically acceptable salt thereof, wherein R3is methyl.

[0056] E7. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein R4is OH or –OC1-6alkyl.

[0057] E7.1. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R4is OH.

[0058] E7.2. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R4is –OC1-6alkyl.

[0059] E7.3. The compound of E7.2, or a pharmaceutically acceptable salt thereof, wherein R4is –OCH2CH3.

[0060] E8. The compound of any of E1-E7.3, or a pharmaceutically acceptable salt thereof, wherein R5is H.

[0061] E9. The compound of any of E1-E8, or a pharmaceutically acceptable salt thereof, wherein R6is C1-4alkyl.

[0062] E9.1. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R6is methyl.

[0063] E9.2. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R6is ethyl.

[0064] E10. The compound of any of E1-E9.2, or a pharmaceutically acceptable salt thereof, wherein R7is –CH2–G.

[0065] E11. The compound of any of E1-E9.2, or a pharmaceutically acceptable salt thereof, wherein R7is G.

[0066] E12. The compound of any of E1-E11, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted heterocyclyl of G is tetrahydropyranyl or tetrahydrofuranyl.

[0067] E12.1. The compound of E12, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted heterocyclyl of G is tetrahydropyran-4-yl, tetrahydrofuran-2-yl, or tetrahydrofuran-3-yl.

[0068] E13. The compound of any of E1-E11, or a pharmaceutically acceptable salt thereof, wherein G is or .

[0069] E13.1. The compound of E12.1 or E13, or a pharmaceutically acceptable salt

[0075] E13.7. The compound of E13.5, or a pharmaceutically acceptable salt thereof, wherein.

[0076] E14. The compound of any of E1-E13.7, or a pharmaceutically acceptable salt thereof, wherein R8ais methyl.

[0077] E15. The compound of any of E1-E14, or a pharmaceutically acceptable salt thereof, wherein R8bis chloro.

[0078] E16. The compound of any of E1-E15, or a pharmaceutically acceptable salt thereof, wherein R9is C1-4alkyl.

[0079] E16.1. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R9is methyl.

[0080] E17. The compound of E1 selected from the group consisting of:7-((R)-7-chloro-10-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-6-(2,4,6- trimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4- dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-(((R)-tetrahydrofuran-2- yl)methoxy)-1H-indole-2-carboxylic acid 7-((R)-7-chloro-10-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-4-methyl-1-oxo-6- (2,4,6-trimethylpyrimidin-5-yl)-3,4- dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-(((S)-tetrahydrofuran-3- yl)oxy)-1H-indole-2-carboxylic acid 7-((R)-7-chloro-10-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-4-methyl-1-oxo-6- (2,4,6-trimethylpyrimidin-5-yl)-3,4- dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-(((R)-tetrahydrofuran-3- yl)oxy)-1H-indole-2-carboxylic acidor a pharmaceutically acceptable salt thereof.

[0081] E18. A pharmaceutical composition comprising the compound of any of E1- E17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0082] E19. The compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E18, for use in the treatment of cancer.

[0083] E20. The compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E18, for use in the inhibition of cancer cell proliferation.

[0084] E21. A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E18.

[0085] E22. A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of any of E1-E17, or a pharmaceutically acceptablesalt thereof, or the pharmaceutical composition of E18, in an amount effective to inhibit the cancer cell proliferation.

[0086] E23. Use of the compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E18, in the manufacture of a medicament for the treatment of cancer.

[0087] E24. Use of the compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E18, in the manufacture of a medicament for the inhibition of cancer cell proliferation.

[0088] Compound names can be assigned / determined by using Struct=Name naming algorithm as part of CHEMDRAW® ULTRA.

[0089] Compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In the compounds of formula (I), when no specific configuration is indicated at a stereogenic center (e.g., carbon), the compounds include all possible stereoisomers.

[0090] Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

[0091] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the invention.

[0092] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium) and2H (deuterium). Accordingly, any group comprising one or more hydrogen atoms encompasses corresponding deuterium-labeled versions of the group. For example,encompasses

[0093] The present disclosure also includes an isotopically-labeled compound (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively.

[0094] Isotopically-enriched forms of compounds of formula (I), or any subformulas, may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent of isotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label).

[0095] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, thrichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0096] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. A. Binding to Mcl-1

[0097] In some embodiments, a provided compound has a Kivalue less than about 0.011 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.1 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.2 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.3 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.4 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.5 M for inhibition of Mcl- 1. In some embodiments, a provided compound has a Kivalue less than about 0.6 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.7 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.8 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 0.9 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 1 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 2 M for inhibition of Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 3 M for inhibition of Mcl- 1. In some embodiments, a provided compound has a Kivalue less than about 4 M for inhibitionof Mcl-1. In some embodiments, a provided compound has a Kivalue less than about 5 M for inhibition of Mcl-1. Exemplary assays for measuring Kivalue for inhibition of Mcl-1 are widely known in the art, including but not limited to those described in the examples herein. B. General Synthesis

[0098] Compounds of formula (I) may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[0099] The compounds of the present disclosure can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference as to the subject matter referenced herein. Compounds of formula (I) may be also prepared by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[0100] The compounds of the disclosure may be prepared using the exemplary reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effective. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. One having ordinary skill in the art may adjust one or more of the conditions described herein. One skilled in the art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of the disclosure falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods can be used.

[0101] The Mcl-1 inhibitors described herein may be prepared following the representative synthetic routes in Schemes 1-2. R1in Schemes 1 and 2 corresponds to R7in the embodiments and claims for formula (I).

[0102] Scheme 1: Synthetic Route for 4,6-Dimethyl Pyrimidines

[0103] Synthesis of the 4,6-dimethylpyrimidine series proceeds through a route illustrated in Scheme 1. Suzuki coupling of indole 39 with 4,6-dimethylpyrimidyl boronic acid 40 affords compound 41, followed by indole N-alkylation with the sulfinate 42. Boc deprotection with TFA and cyclization to the tricyclic piperazinone under basic conditions affords intermediate 44. Compound 44 is then cross coupled using Buchwald conditions with indole 45 to afford 46. Compound 46 may then be alkylated with MeI to afford 47, which could in turn may be hydrogenated to afford phenol 48. Alkylation of the 5-OH position with the appropriate tosylate or alkyl halide furnishes ester 49, which may then be saponified using LiOH to furnish final analogs of structure 50.

[0104] Scheme 2: Synthetic Route for 2,4,6-Trimethyl PyrimidinesConditions: a) [Pd(cinnamyl)Cl]2,tBu-BrettPhos, Cs2CO3, toluene. b) MeI, Cs2CO3, DMF. c) Pd / C, Pd(OH)2 / C, THF, isopropanol. d) R1-X, Cs2CO3, DMF. e) LiOH, THF / MeOH / H2O.

[0105] Synthesis of the trimethyl pyrimidine series (Scheme 2) begins with conversion of 5- bromo-4,6-dimethylpyrimidine 51 to methyl alcohol 52 by treatment with ammonium persulfate in methanol. Alcohol 52 is protected with benzyl bromide to afford 53, followed by boronylation under Miyaura conditions to give pinacol boronic ester 54. Suzuki coupling to indole 39 affords compound 55. Sulfinate alkylation with 42, Boc deprotection, and lactam cyclization affords compound 57. The resultant benzyloxy pyrimidine is deprotected with Pd / C under an atmosphere of H2, followed by mesylation of the resultant alcohol to afford compound 58. Treatment of mesylate 58 with lithium triethylborohydride furnishes trimethyl pyrimidine tricyclic core 59, which may then be functionalized to final compounds 62 using the same synthetic sequence described for the 4,6-dimethylpyrimidine series.

[0106] The compounds and intermediates may be isolated and purified by methods well- known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England.

[0107] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[0108] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0109] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0110] Carboxylic protecting groups PG are well known in the art, as described in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Suitable carboxylic acid protecting groups include, for example, alkyl esters (e.g., methyl, ethyl, tert-butyl) and benzyl esters (e.g., benzyl (Bn)).

[0111] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0112] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material,or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0113] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims. C. Examples

[0114] Chemistry. General. All NMR spectra were recorded at room temperature on a 400 MHz AMX Bruker spectrometer.1H chemical shifts are reported in values in ppm downfield with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), integration, coupling constant (Hz). Low-resolution mass spectra were obtained on an Agilent 1200 series 6140 mass spectrometer with electrospray ionization. All samples were of 95% purity as analyzed by HPLC. Analytical HPLC was performed on an Agilent 1200 series with UV detection at 214 and 254 nm along with ELSD detection. LC / MS parameters were as follows: Method 1: Phenomenex-C18 Kinetex column, 50 x 2.1 mm, 2 min gradient, 5% (0.1% TFA / MeCN) / 95% (0.1% TFA / H2O) to 95% (0.1% TFA / MeCN) / 95% (0.1% TFA / H2O), Method 2: Phenomenex-C18 Kinetex column, 50 x 2.1 mm, 2 min gradient, 50% (0.1% TFA / MeCN) / 50% (0.1% TFA / H2O) to 95% (0.1% TFA / MeCN) / 5% (0.1% TFA / H2O). Preparative reverse phase purification was performed on a Gilson HPLC (Phenomenex-C18, 100 x 30 mm, 10 min gradient, 5 to 95% MeCN / H2O with 0.1% TFA). Normal phase purification was performed with Combi-flash Rf (plus-UV) Automated Flash Chromatography System. Solvents for reactions, extraction, and washing were ACS reagent grade, and solvents for chromatography were HPLC grade. All reagents were purchased from chemical suppliers and used without purification. Compound 39 was synthesized as previously reported (Burke, J. P. et al., J. Med. Chem.2015, 58, 3794-3805).

[0115] The following Examples are offered as illustrative as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical symbols have their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared,isolated and characterized using the Schemes and other methods disclosed herein or may be prepared using same. Chemistry General Procedures

[0116] General Procedure A: Ullmann Cross Coupling. In a reaction vessel, the (R)- methyl-dihydropyrazinoindolone core (e.g., 44 or 59) (1.0 eq), 7-bromoindole or 7-iodoindole (1.5 eq), CuI (0.5 eq), (trans)-1,2-N,N’-dimethylaminocyclohexane (0.5 eq), and K2CO3(2.0 eq) are combined. The reaction vessel is charged with toluene (0.4 M) and sparged with argon for 5 min. The vessel is then sealed and heated to 100 °C for 48 h. The reaction is cooled to room temperature and diluted with 1:1 EtOAc / H2O. The aqueous layer is separated and extracted with EtOAc (2x). The combined organic layers are washed with sat. NH4Cl, sat. NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The crude residue is purified by flash column chromatography eluting with EtOAc / hexanes to afford the desired compound.

[0117] General Procedure B: Buchwald Cross Coupling Procedure 1. In a reaction vessel, the (R)-methyl-dihydropyrazinoindolone core (e.g., 44 or 59) (1.0 eq), 7-bromoindole or 7-iodoindole (1.5 eq), Pd2(dba)3(0.1 eq), Xantphos (0.2 eq), and Cs2CO3(2.5 eq) are combined. The reaction vessel is charged with toluene (0.4 M) and sparged with argon for 5 min. The reaction is sealed and heated to 100 °C for 18 h. The reaction is cooled to room temperature and diluted with 1:1 EtOAc / H2O. The aqueous layer is separated and extracted with EtOAc (2x). The combined organic layers are washed with sat. NH4Cl, sat. NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude residue is purified by flash column chromatography eluting with EtOAc / hexanes to afford the desired compound.

[0118] General Procedure C: Buchwald Cross Coupling Procedure 2. In a reaction vessel, the (R)-methyl-dihydropyrazinoindolone core (e.g., 44 or 59) (1.0 eq), 7-bromoindole or 7-iodoindole (1.2 eq), [Pd(cinnamyl)Cl]2(0.05 eq),tBu-BrettPhos (0.1 eq), and Cs2CO3(4.0 eq) are combined. The reaction vessel is charged with toluene (0.2 M) and sparged with argon for 5 min. The reaction is sealed and heated to 100 °C for 2-24 h. The reaction is cooled to room temperature and diluted with 1:1 EtOAc / H2O. The aqueous layer is separated and extracted with EtOAc (2x). The combined organic layers are washed with sat. NH4Cl, sat. NaHCO3,water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The crude residue is purified by flash column chromatography eluting with EtOAc / hexanes to afford the desired compound.

[0119] General Procedure D: Indole N-Methylation. In a reaction vessel, the N-H indole core (e.g., 46) (1.0 eq) is dissolved in DMF (0.2 M) followed by addition of Cs2CO3(2.0 eq). MeI was added and the reaction is heated to 60 °C for 3 h. The reaction is cooled to room temperature and diluted with 1:1 EtOAc / H2O. The aqueous layer is separated and extracted with EtOAc (2x). The combined organic layers are washed with sat. NH4Cl, sat. NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The crude residue is purified by flash column chromatography eluting with EtOAc / hexanes to afford the desired compound.

[0120] General Procedure E: Hydrogenolysis of Benzyl Ether. In a reaction vessel, the benzylic ether (e.g., 47) (1.0 eq) is dissolved in THF / iPrOH (3:1) and the resultant mixture is sparged with argon for 5 min. Pd / C (10% wt., 0.1 eq) and Pd(OH)2 / C (20% wt., 0.1 eq) are added to the reaction vessel, and the reaction is flushed with argon. The reaction mixture is allowed to stir under an atmosphere of H2at 40 °C until complete by LCMS. The reaction mixture is filtered through a pad of Celite®, rinsed with DCM, and concentrated. The crude residue is used without further purification.

[0121] General Procedure F: Alkylation of Indole 5-OH. In a reaction vessel, the 5- hydroxy indole core (e.g., 48) (1.0 eq) is dissolved in DMF (0.2 M). Cs2CO3(3.0 eq) is added, followed by addition of the appropriate alkylating agent (2.0 eq). The reaction is heated to 90 °C and allowed to stir for 3 h, after which time the reaction is determined to be complete by LCMS. The reaction is cooled to room temperature and diluted with 1:1 EtOAc / H2O. The aqueous layer is separated and extracted with EtOAc (2x). The combined organic layers are washed with sat. NH4Cl, sat. NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The crude residue is purified by flash column chromatography eluting with EtOAc / hexanes or MeOH / DCM to afford the desired compound.

[0122] General Procedure G: Saponification of Indole Ester. In a reaction vessel, the ester (e.g., 49, 61) is dissolved in THF / MeOH / H2O (5:1:1, 0.2 M). LiOH (10 eq.) is added, and the reaction is heated at 50 °C for 3-24 h until the LCMS shows complete conversion. The reaction is extracted with DCM, acidified with 1M HCl, washed with H2O, washed with brine,dried over MgSO4, filtered, and concentrated. The crude residue is purified by reverse phase HPLC eluting with MeCN / H2O with 0.1% TFA additive. The resultant compound is concentrated, dissolved in DCM, washed with aq. NaHCO3, dried with MgSO4, filtered, and concentrated to afford the desired product. Syntheses of Intermediates

[0123] (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6- dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (44). In a heavy-walled flask equipped with a stir bar compound 39 (8.2 g, 16.5 mmol), (4,6- dimethylpyrimidin-5-yl)boronic acid (40) (8.5 g, 35.6 mmol), 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (1.0 g, 2.5 mmol), Pd2(dba)3(1.20 g, 1.3 mmol), and K3PO4(17.4 g, 82 mmol) were combined. Toluene (80 mL) and THF (80 mL) were added, and the reaction was sparged with argon for 5 min. The flask was sealed and heated to 110 °C overnight. The reaction was poured into brine and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford compound 41 (7.19 g, 83% yield). To a round-bottomed flask compound 41 (8.0 g, 15 mmol), tert-butyl (S)-5-methyl- 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (42, 9.0 g, 38 mmol), and Cs2CO3(9.9 g, 30.4 mmol) were added. Anhydrous MeCN (100 mL) was added and the solution was stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc, and washed with brine, dried over MgSO4, filtered, and then concentrated. The residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford 43 (8.0 g in 77% yield). Compound 43 was dissolved in DCM (80 mL) and cooled to 0 °C. TFA (20 mL) was added dropwise and the reaction mixture was allowed to stir at room temperature for 4 h. The solvent was removed in vacuo. Anhydrous EtOH (80 mL) was added followed by K2CO3(6.8 g, 49 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated to 1 / 3 volume and diluted with ethyl acetate (100 mL) and washed with brine (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM to afford 44 (5.2 g, 84% yield). LCMS Method 2: RT= 1.313 min, MS (ESI): m / z 537.2 (M+H)+.1H NMR (CDCl3): 9.09 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H),6.63 (s, 1H), 3.98 (t, J = 4.8 Hz, 2H), 3.72 (dd, J = 12.4, 3.6 Hz, 1H),3.60 (t, J = 4.8 Hz, 1H), 3.32-3.40 (m, 2H), 3.15 (dd, J = 12.4, 3.6 Hz, 1H), 2.39 (s, 3H), 2.33 (s, 6H), 2.20 (s, 6H), 1.02 (d, J = 6.8 Hz, 3H).

[0124] Ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6- dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5- hydroxy-4-methoxy-1-methyl-1H-indole-2-carboxylate (48). Compound 44 (1.0 g, 1.86 mmol, 1.0 eq) and compound 45 (978 mg, 2.42 mmol, 1.3 eq) were coupled following General Procedure C (1.51 g, 94% yield), LCMS Method 2: RT= 1.972 min, MS (ESI): m / z 860.2 (M+H)+. The resultant compound (46) was alkylated with MeI following General Procedure D (1.22 g, 80% yield), LCMS Method 2: RT= 2.303, 2.372 min, MS (ESI): m / z 874.1 (M+H)+. The resultant compound (47) was hydrogenated following General Procedure E to afford compound 48 (970 mg, 88% yield), LCMS Method 2: RT= 1.743, 1.819 min, MS (ESI): m / z 784.2 (M+H)+.1H NMR (CDCl3): (s, 1H), 7.855 (d, J = 8.8 Hz, 0.3H), 7.850 (d, J = 8.4 Hz, 0.7H), 7.40-7.34 (m, 2H), 6.81 (s, 0.7H), 6.80 (s, 0.3H), 6.62 (s, 1.4H), 6.60 (s, 0.6H), 4.39- 4.33 (m, 2H), 4.20 (dd, J = 13.6, 4.0 Hz, 1H), 4.17-4.08 (m, 4H), 4.00-3.97 (m, 4H), 3.57-3.53 (m, 1H), 3.39-3.33 (m, 2H), 2.59 (s, 1H), 2.57 (s, 2H), 2.41 (s, 1H), 2.40 (s, 2H), 2.32 (s, 6H), 2.19-2.15 (m, 2H), 1.40 (t, J = 6.8 Hz, 3H), 1.28 (d, J = 7.2 Hz, 2H), 1.20 (d, J = 6.8 Hz, 1H).

[0125] (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(2,4,6- trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (59). In a reaction vessel, compound 39 (6.75 g, 13.5 mmol), compound 54 (14.0 g, 39.5 mmol), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos, 2.44 g, 5.94 mmol), Pd2(dba)3(1.81 g, 1.98 mmol), and K2CO3(8.2 g, 59.4 mmol) were combined. Toluene (80 mL) and THF (80 mL) were added and the reaction mixture was sparged with argon for 5 min. The reaction was then sealed and heated to 110 °C for 4 h. The reaction mixture was cooled to room temperature and diluted into EtOAc / H2O. The mixture was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 40% EtOAc in hexanes to afford compound 55 (8.08 g, 63% yield). To a round-bottomed flask were added compound 55 (4.47 g, 6.9 mmol, 1.0 eq), tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (42, 2.46 g, 10.4 mmol), and Cs2CO3(3.38 g, 10.4 mmol). Anhydrous MeCN (80 mL) was added and the solution was stirred at 80 °C overnight. The reaction mixture was diluted withEtOAc, and washed with brine, dried over MgSO4, filtered, and then concentrated (56). Compound 56 was then dissolved in DCM (80 mL) and cooled to 0 °C. TFA (8 mL) was added dropwise and the reaction mixture was allowed to stir at room temperature for 4 h. The solvent was removed in vacuo. Anhydrous EtOH (80 mL) was added followed by K2CO3(23 g, 167 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated to 1 / 3 volume and diluted with ethyl acetate (100 mL) and washed with brine (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM to afford 57 (2.6 g, 84% yield). Compound 57 (2.6 g, 3.95 mmol, 1.0 eq) was dissolved in MeOH (40 mL) and Pd / C (10 wt.%, 420 mg, 0.39 mmol, 0.1 eq) was added. The reaction was stirred at room temperature for 24 h under an atmosphere of hydrogen. The reaction was filtered through a pad of Celite®, rinsed with DCM, and concentrated (2.20 g, 97% yield). LCMS Method 1: RT= 1.969 min, MS (ESI): m / z 567.0 (M+H)+. The resultant material (2.2 g, 3.88 mmol, 1.0 eq) was dissolved in DCM (40 mL) at 0 °C, followed by addition of MsCl (666 mg, 5.81 mmol, 1.5 eq) and TEA (785 mg, 7.75 mmol, 2.0 eq). The reaction was allowed to stir for 1 h at room temperature, followed by extraction with DCM, washed with H2O, dried over MgSO4, filtered, and concentrated to afford the crude product 58 (2.5 g, quant. yield), LCMS Method 1: RT= 2.131 min, MS (ESI): m / z 644.8 (M+H)+. The resultant product was taken up in THF (40 mL) and cooled to -40 °C. LiBHEt3(1.0 M, 11.6 mL, 11.6 mmol, 3.0 eq) was added and the reaction was allowed to stir at 0 °C for 5 h. The reaction was quenched with H2O, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM to afford 59 (1.6 g, 75% yield), LCMS Method 1: RT= 2.090 min, MS (ESI): m / z 550.9 (M+H)+.1H NMR (CDCl3) 7.718.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.63 (s, 2H), 5.74 (d, J = 5.2 Hz, 1H), 4.00 (td, J = 6.4, 1.6 Hz, 2H), 3.75-3.69 (m, 2H), 3.42-3.30 (m, 2H), 3.15 (dd, J = 11.2, 5.6 Hz, 1H), 2.79 (s, 3H), 2.33 (s, 9H), 2.19 (quint, J = 7.2 Hz, 2H), 2.14 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H).

[0126] Ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1- oxo-6-(2,4,6-trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5- hydroxy-4-methoxy-1-methyl-1H-indole-2-carboxylate (60). Compound 59 (1.1 g, 2.05 mmol, 1.0 eq) and compound 45 (1.08 g, 2.66 mmol, 1.3 eq) were coupled following GeneralProcedure C (1.61 g, 91% yield), LCMS Method 2: RT= 1.870 min, MS (ESI): m / z 874.3 (M+H)+. The resultant compound was alkylated with MeI following General Procedure D (1.43 g, 85% yield), LCMS Method 2: RT= 1.979, 2.025 min, MS (ESI): m / z 888.2 (M+H)+. The resultant compound was hydrogenated following General Procedure E to afford compound 60 (1.07 g, 83% yield), LCMS Method 2: RT= 1.639, 1.703 min, MS (ESI): m / z 798.2 (M+H)+.1H NMR (CDCl3): (d, J = 8.8 Hz, 0.3H), 7.845 (d, J = 8.8 Hz, 0.7H), 7.375 (d, J = 8.8 Hz, 0.3H), 7.365 (d, J = 8.8 Hz, 0.7H), 7.30 (s, 0.3H), 7.26 (s, 0.7H), 6.79 (s, 0.7H), 6.77 (s, 0.3H), 6.62 (s, 1.4H), 6.60 (s, 0.6H), 4.38-4.32 (m, 2H), 4.19-4.05 (m, 5H), 3.99-3.95 (m, 4H), 3.50-3.47 (m, 1H), 3.39-3.31 (m, 2H), 2.97 (s, 1H), 2.96 (s, 2H), 2.61 (s, 1H), 2.58 (s, 2H), 2.41 (s, 3H), 2.32 (s, 6H), 2.21-2.15 (m, 2H), 1.41-1.37 (m, 3H), 1.27 (d, J = 6.4 Hz, 2H), 1.19 (d, J = 6.4 Hz, 1H). Synthesis of Examples:

[0127] (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6- dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-indole-2-carboxylic acid (22). The title compound (30 mg, 39% yield) was prepared following General Procedure F using compound 48 (70 mg, 0.089 mmol, 1.0 eq) and (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (75 mg, 0.27 mmol, 3.0 eq) followed by saponification using General Procedure G. LCMS Method 2: RT= 1.378 min, MS (ESI): mass calcd for C46H49Cl2N5O7, 853.3, m / z found 853.8 (M+H)+.1H NMR (400 MHz, CDCl3) 9.14 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.49 (s, 0.75H), 7.48 (s, 0.25H), 7.35 (d, J = 10.4 Hz, 1H), 6.83 (s, 0.25H), 6.82 (s, 0.75H), 6.61 (s, 1.5H), 6.59 (s, 0.5H), 4.48 (dd, J = 13.2, 3.6 Hz, 0.3H), 4.18 (dd, J = 13.2, 3.6 Hz, 0.9H), 4.13 (s, 0.8H), 4.03-3.97 (m, 9H), 3.87-3.74 (m, 2.3H), 3.73-3.68 (m, 0.7H), 3.49- 3.32 (m, 5H), 2.46 (s, 2.3H), 2.44 (s, 0.7H), 2.30 (s, 6H), 2.29 (s, 0.7H), 2.28 (s, 2.3H), 2.23- 2.16 (m, 1H), 2.09-2.04 (m, 1H), 1.76 (d, J = 8.0 Hz, 2H), 1.46 (dq, J = 12.0, 4.4 Hz, 2H), 1.28 (d, J = 6.4 Hz, 2.3H), 1.18 (d, J = 6.4 Hz, 0.7H), mixture of rotamers.

[0128] 7-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6- dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-(((S)-tetrahydrofuran-2-yl)methoxy)-1H-indole-2-carboxylic acid (23). The title compound (34 mg, 45% yield) was prepared following General Procedure F using compound 48 (70 mg, 0.089 mmol, 1.0 eq) and (S)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (75 mg, 0.29 mmol, 3.2 eq) followed by saponification using General Procedure G. LCMS Method 2: RT= 1.353 min, MS (ESI): mass calcd for C45H47Cl2N5O7, 839.3, m / z found 839.8 (M+H)+.1H NMR (400 MHz, CDCl3) 9.18 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.49 (s, 0.3H), 7.48 (s, 0.7H), 7.34 (d, J = 8.8 Hz, 1H), 6.93-6.92 (M, 1H), 6.61 (s, 1.3H), 6.60 (s, 0.7H), 4.39 (d, J = 8.4 Hz, 0.3H), 4.30-4.23 (m, 1H), 4.17 (dd, J = 13.2, 3.6 Hz, 0.7H), 4.11 (s, 1H), 4.06 (s, 2H), 4.04 (s, 1H), 4.03-3.95 (m, 6H), 3.93-3.88 (m, 1H), 3.86-3.78 (m, 1H), 3.72-3.70 (m, 1H), 3.49 (d, J = 12.0 Hz, 1H), 3.42-3.31 (m, 2H), 2.49 (s, 1H), 2.47 (s, 2H), 2.32-2.30 (m, 9H), 2.22-2.14 (m, 2H), 2.09-2.01 (m, 1H), 1.98-1.89 (m, 2H), 1.82-1.71 (m, 1H), 1.28 (d, J = 6.4 Hz, 2H), 1.18 (d, J = 6.4 Hz, 1H), mixture of rotamers.

[0129] 7-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6- dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-(((R)-tetrahydrofuran-2-yl)methoxy)-1H-indole-2-carboxylic acid (24). The title compound (32 mg, 43% yield) was prepared following General Procedure F using compound 48 (70 mg, 0.089 mmol, 1.0 eq) and (R)-(tetrahydrofuran-2-yl)methyl 4- methylbenzenesulfonate (75 mg, 0.29 mmol, 3.2 eq) followed by saponification using General Procedure G. LCMS Method 2: RT= 1.376 min, MS (ESI): mass calcd for C45H47Cl2N5O7, 839.3, m / z found 839.8 (M+H)+.1H NMR (400 MHz, CDCl3) 9.15 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.49 (s, 0.3H), 7.47 (s, 0.7H), 7.35 (d, J = 8.8 Hz, 1H), 6.93 (s, 0.7H), 6.92 (s, 0.3H), 6.61 (s, 0.7H), 6.60 (s, 0.3H), 4.38 (dd, J = 12.8, 4.4 Hz, 0.3H), 4.29-4.22 (m, 1H), 4.16 (dd, J = 13.6, 4.0 Hz, 0.7H), 4.11 (s, 1H), 4.04 (s, 2H), 4.03 (s, 1H), 4.01-3.95 (m, 6H), 3.91-3.87 (m, 1H), 3.84 (m, 1H), 3.73-3.70 (m, 1H), 3.48 (d, J = 12.8 Hz, 1H), 3.41-3.31 (m, 2H), 2.47 (s, 1H), 2.45 (s, 2H), 2.30 (s, 8H), 2.28 (s, 1H), 2.22-2.14 (m, 2H), 2.08-2.02 (m, 1H), 1.97-1.89 (m, 2H), 1.78-1.70 (m, 1H), 1.29 (d, J = 7.6 Hz, 2H), 1.17 (d, J = 6.8 Hz, 1H), mixture of rotamers.

[0130] (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6- (2,4,6-trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1- methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-indole-2-carboxylic acid (26). The title compound (3.10 g, 61% yield) was prepared following General Procedure F using compound 60 (4.10 g, 5.10 mmol, 1.0 eq) and (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (4.20 g, 15 mmol, 3.0 eq) followed by saponification using General Procedure G. The crude residue was purified by flash column chromatography eluting with 0to 100% EtOAc in hexanes to afford the title compound. LCMS Method 1: RT= 2.289 min, MS (ESI): mass calcd for C47H51Cl2N5O7, 867.3, m / z found 867.9 (M+H)+.1H NMR (400 MHz, CDCl3) 7.76 (d, J = 8.8 Hz, 1H), 7.48 (s, 0.3H), 7.47 (s, 0.7H), 7.34 (d, J = 8.4 Hz, 1H), 6.82 (s, 0.3H), 6.81 (s, 0.7H), 6.60 (s, 1.4H), 6.58 (s, 0.6H), 4.37 (dd, J = 12.0, 4.0 Hz, 0.3H), 4.19 (dd, J = 13.2, 3.6 Hz, 0.7H), 4.11 (s, 1H), 4.02-3.94 (m, 9H), 3.87-3.78 (m, 3H), 3.51-3.35 (m, 3H), 3.34-3.28 (m, 2H), 2.82 (s, 1H), 2.81 (s, 2H), 2.42 (s, 1H), 2.41 (s, 2H), 2.30 (s, 6H), 2.25 (s, 1H), 2.23 (s, 2H), 2.20-2.17 (m, 2H), 2.09-2.02 (m, 1H), 1.76 (d, J = 12.4 Hz, 2H), 1.46 (dq, J = 12.4, 4.4 Hz, 2H), 1.29 (d, J = 6.4 Hz, 2H), 1.18 (d, J = 6.8 Hz, 1H), mixture of rotamers.

[0131] 7-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2,4,6- trimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-(((S)-tetrahydrofuran-2-yl)methoxy)-1H-indole-2-carboxylic acid (27). The title compound (40 mg, 58% yield) was prepared following General Procedure F using compound 60 (65 mg, 0.081 mmol, 1.0 eq) and (S)-(tetrahydrofuran-2-yl)methyl 4- methylbenzenesulfonate (63 mg, 0.24 mmol, 3.0 eq) followed by saponification using General Procedure G. LCMS Method 1: RT= 2.295 min, MS (ESI): mass calcd for C46H49Cl2N5O7, 853.3, m / z found 853.9 (M+H)+.1H NMR (400 MHz, CDCl3) 7.72 (d, J = 8.4 Hz, 0.3H), 7.71 (d, J = 8.4 Hz, 0.7H), 7.32-7.28 (m, 2H), 6.83 (s, 0.3H), 6.81 (s, 0.7H), 6.57 (s, 2H), 4.34 (dd, J = 12.4, 4.0 Hz, 0.3H), 4.22-4.18 (m, 1H), 4.12 (dd, J = 12.4, 4.0 Hz, 0.7H), 4.06 (s, 1H), 3.96-3.89 (m, 8H), 3.85 (q, J = 6.8 Hz, 2H), 3.81-3.74 (m, 2H), 3.44 (t, J = 11.2 Hz, 1H), 3.36- 3.26 (m, 2H), 2.78 (s, 1H), 2.77 (s, 2H), 2.37 (s, 3H), 2.26 (s, 6H), 2.20 (s, 1H), 2.19 (s, 2H), 2.14 (t, J = 6.8 Hz, 2H), 2.05-1.99 (m, 1H), 1.93-1.87 (m, 2H), 1.74-1.67 (m, 1H), 1.27 (d, J = 6.4 Hz, 2H), 1.14 (d, J = 6.4 Hz, 1H), mixture of rotamers.

[0132] 7-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2,4,6- trimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4- methoxy-1-methyl-5-(((R)-tetrahydrofuran-2-yl)methoxy)-1H-indole-2-carboxylic acid (28). The title compound (29 mg, 42% yield) was prepared following General Procedure F using compound 60 (65 mg, 0.081 mmol, 1.0 eq) and (R)-(tetrahydrofuran-2-yl)methyl 4- methylbenzenesulfonate (63 mg, 0.24 mmol, 3.0 eq) followed by saponification using General Procedure G. LCMS Method 1: RT= 2.301 min, MS (ESI): mass calcd for C46H49Cl2N5O7, 853.3, m / z found 853.9 (M+H)+.1H NMR (400 MHz, CDCl3) 7.69 (d, J = 8.8 Hz, 0.3H),7.68 (d, J = 8.8 Hz, 0.7H), 7.30-7.27 (m, 1H), 7.23 (s, 0.7H), 7.18 (s, 0.3H), 6.78 (s, 0.3H), 6.76 (s, 0.7H), 6.54 (s, 1.3H), 6.52 (s, 0.7H), 4.35 (dd, J = 9.2, 4.0 Hz, 0.3H), 4.22-4.15 (m, 1H), 4.08 (d, J = 10.4 Hz, 0.7H), 4.01 (s, 1H), 3.94-3.83 (m, 10H), 3.80-3.73 (m, 2H), 3.41 (t, J = 13.2 Hz, 1H), 3.32-3.26 (m, 2H), 2.77 (s, 1H), 2.76 (s, 2H), 2.35 (s, 3H), 2.23 (s, 4H), 2.22 (s, 2H), 2.20 (s, 1H), 2.17 (s, 3H), 2.14-2.10 (m, 2H), 2.04-1.96 (m, 1H), 1.68-1.62 (m, 1H), 1.24 (d, J = 6.4 Hz, 2H), 1.10 (d, J = 6.4 Hz, 1H), mixture of rotamers.

[0133] 7-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6- (2,4,6-trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1- methyl-5-(((S)-tetrahydrofuran-3-yl)oxy)-1H-indole-2-carboxylic acid (29). The title compound (108 mg, 69% yield) was prepared following General Procedure F using compound 60 (150 mg, 0.19 mmol, 1.0 eq) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (135 mg, 0.56 mmol, 3.0 eq) followed by saponification using General Procedure G. LCMS Method 1: RT= 2.203 min, MS (ESI): mass calcd for C45H47Cl2N5O7, 839.3, m / z found 839.8 (M+H)+.1H NMR (400 MHz, DMSO-d6) 7.95 (d, J = 8.8 Hz, 0.3H), 7.94 (d, J = 8.8 Hz, 0.7H), 7.47- 7.43 (m, 1H), 7.11 (s, 0.3H), 7.06 (s, 1H), 6.78 (s, 1.4H), 6.76 (s, 1.3H), 5.02-4.97 (m, 1H), 4.71 (dd, J = 12.8, 4.4 Hz, 0.3H), 4.35 (dd, J = 13.6, 3.2 Hz, 0.7H), 4.12 (s, 1H), 4.06-4.01 (m, 4H), 3.96-3.91 (m, 5H), 3.86-3.78 (m, 3H), 3.72-3.66 (m, 1H), 3.38-3.24 (m, 2H), 2.71 (s, 3H), 2.32 (s, 1H), 2.30 (s, 4H), 2.29 (s, 2H), 2.27 (s, 2H), 2.20 (s, 2H), 2.19 (s, 1H), 2.13-2.07 (m, 4H), 1.27 (d, J = 6.8 Hz, 2H), 1.16 (d, J = 6.8 Hz, 1H), mixture of rotamers.

[0134] 7-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6- (2,4,6-trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1- methyl-5-(((R)-tetrahydrofuran-3-yl)oxy)-1H-indole-2-carboxylic acid (30). The title compound (59 mg, 86% yield) was prepared following General Procedure F using compound 60 (65 mg, 0.081 mmol, 1.0 eq) and (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (59 mg, 0.24 mmol, 3.0 eq) followed by saponification using General Procedure G. LCMS Method 1: RT= 2.211 min, MS (ESI): mass calcd for C45H47Cl2N5O7, 839.3, m / z found 839.8 (M+H)+.1H NMR (400 MHz, CDCl3) 7.75 (d, J = 8.8 Hz, 1H), 7.48 (s, 0.3H), 7.47 (s, 0.7H), 7.34 (d, J = 8.8 Hz, 0.3H), 7.33 (d, J = 8.4 Hz, 0.7H), 6.81 (s, 0.3H), 6.79 (s, 0.7H), 6.60 (s, 1.4H), 6.58 (s, 0.6H), 4.91-4.88 (m, 1H), 4.35 (dd, J = 13.2, 3.6 Hz), 0.3H), 4.16 (dd, J = 13.2, 3.6 Hz, 0.7H), 4.11 (s, 1H), 4.06-3.97 (m, 9H), 3.91-3.79 (m, 3H), 3.50-3.29 (m, 3H), 2.81 (s, 0.7H),2.80 (s, 2.3H), 2.41 (s, 0.7H), 2.40 (s, 2.3H), 2.25-2.07 (m, 7H), 1.27 (d, J = 6.4 Hz, 2.3 H), 1.18 (d, J = 6.4 Hz, 0.7H); mixture of rotamers.

[0135] 7-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6- (2,4,6-trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-ethoxy-1- methyl-5-(((S)-tetrahydrofuran-3-yl)oxy)-1H-indole-2-carboxylic acid (31): Compound 59 (500 mg, 0.91, 1.0 eq) and ethyl 5-(benzyloxy)-4-ethoxy-7-iodo-1H-indole-2-carboxylate (720 mg, 1.54 mmol, 1.7 eq) were coupled following General Procedure A (580 mg, 72% yield), LCMS Method 2: RT= 1.676 min, MS (ES) 888.10 (M+H). The resultant product was alkylated with MeI following General Procedure D (550 mg, 93% yield), LCMS Method 2: RT= 1.963, 2.020 min, MS (ES) 902.10 (M+H). The benzyl ether of the resultant product was cleaved following General Procedure E (quantitative yield), LCMS Method 2: RT= 1.576, 1.648 min, MS (ES) 812.10 (M+H). The resultant 5-OH indole (70 mg, 0.86 mmol, 1.0 eq) was alkylated with (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (63 mg, 0.26 mmol, 3.0 eq) followed by saponification using General Procedure G (35 mg, 48% yield). LCMS Method 2: RT= 1.446 min, MS (ESI): mass calcd for C46H49Cl2N5O7, 853.3, m / z found 853.8 (M+H).1H NMR (400 MHz, CDCl3) 7.83 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.37 (d, J = 8.8 Hz, 0.3H), 7.36 (d, J = 8.8 Hz, 0.7H), 6.84 (s, 0.3H), 6.80 (s, 0.7H), 6.61 (s, 1.4H), 6.59 (s, 0.6H), 4.95- 4.92 (m, 1H), 4.42 (dd, J = 12.8, 4.0 Hz, 0.3H), 4.30-4.23 (m, 2H), 4.19 (dd, J = 13.6, 4.0 Hz, 0.7H), 4.12 (s, 1H), 4.08-3.97 (m, 6H), 3.95-3.89 (m, 1H), 3.87-3.79 (m, 2H), 3.55-3.50 (m, 1H), 3.43-3.30 (m, 2H), 2.94 (s, 1H), 2.92 (s, 2H), 2.55 (s, 1H), 2.52 (s, 2H), 2.35 (s, 3H), 3.21 (s, 6H), 2.20-2.15 (m, 3H), 2.10-2.03 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 1.30 (d, J = 6.4 Hz, 2H), 1.19 (d, J = 6.4 Hz, 1H).

[0136] (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6- (2,4,6-trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-ethoxy-1- methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-indole-2-carboxylic acid (32): The title compound (190 mg, 36% yield) was prepared following General Procedure F using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(2,4,6- trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-ethoxy-5-hydroxy-1- methyl-1H-indole-2-carboxylate (495 mg, 0.61 mmol, 1.0 eq) and (tetrahydro-2H-pyran-4- yl)methyl 4-methylbenzenesulfonate (494 mg, 1.83 mmol, 3.0 eq) followed by saponification using General Procedure G. LCMS Method 2: RT= 1.535 min, MS (ESI): mass calcd forC48H53Cl2N5O7, 881.3, m / z found 882.3 (M+H).1H NMR (400 MHz, CDCl3) 7.84 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.8 Hz, 0.3H), 7.37 (d, J = 8.8 Hz, 0.7H), 6.84 (s, 0.3H), 6.80 (s, 0.7H), 6.61 (s, 1.3H), 6.59 (s, 0.7H), 4.42 (dd, J = 12.4, 4.0 Hz, 0.3H), 4.28-4.21 (m, 2H), 4.18 (dd, J = 13.2, 3.2 Hz, 0.7H), 4.09 (s, 1H), 4.05 (dd, J = 11.2, 3.2 Hz, 2H), 4.00-3.97 (m, 2H), 3.94 (s, 2H), 3.87-3.79 (m, 3H), 3.52-3.29 (m, 5H), 2.94 (s, 1H), 2.93 (s, 2H), 2.58 (s, 1H), 2.55 (s, 2H), 2.38 (s, 3H), 2.31 (s, 6H), 2.20-2.15 (m, 2H), 2.09-2.05 (m, 1H), 1.79-1.75 (m, 2H), 1.53-1.45 (m, 2H), 1.43-1.38 (m, 3H), 1.31 (d, J = 6.4 Hz, 2H), 1.18 (d, J = 6.4 Hz, 1H). 3. Pharmaceutical compositions

[0137] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human).

[0138] The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention [e.g., a compound of formula (I)] are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0139] For example, a therapeutically effective amount of a compound of formula (I), may be about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg toabout 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0140] The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0141] Thus, the compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in "Remington's Pharmaceutical Sciences", (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0142] The routes by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0143] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0144] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0145] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0146] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0147] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0148] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0149] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0150] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[0151] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[0152] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0153] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0154] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0155] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0156] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[0157] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of active [e.g., compound of formula (I)] and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0158] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0159] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate,sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0160] Capsules (including implants, time release and sustained release formulations) typically include an active compound [e.g., a compound of formula (I)], and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0161] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[0162] Solid compositions may be coated by conventional methods, typically with pH or time- dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac.

[0163] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0164] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; andbinders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0165] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound [e.g., a compound of formula (I)], and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0166] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the medicament. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0167] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0168] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0169] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropylmyristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[0170] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0171] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0172] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0173] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0174] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified Montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0175] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[0176] Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.4. Methods of Treatment

[0177] In another aspect the present disclosure provides a method of treating a disease or disorder associated with the expression or over-expression of anti-apoptotic Bcl-2 family protein members, and in certain embodiments those diseases characterized by the expression or the over-expression of Mcl-1 proteins, comprising administering to a mammalian patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate or a pharmaceutically acceptable carrier thereof.

[0178] Further, in accordance with the present invention, a method is provided for preventing, modulating, or treating the progression or onset of diseases or disorders associated with the upregulated activity of the Bcl-2 family of proteins, specifically Mcl-1 protein, such as defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula (I) is administered to a mammalian, i.e., human, patient in need of treatment.

[0179] Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.

[0180] According to another embodiment, the invention relates to a method of inhibiting Mcl-1, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by Mcl-1, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0181] Compounds of the present invention modulate the activity of the Bcl-2 family of proteins. Preferably, compounds of the present invention inhibit the activity of one type or a subset of anti-apoptotic Bcl-2 family of proteins, for examples of Mcl-1, Bcl-2, Bcl-xL, and Bcl-w proteins. Consequently, the compounds of the present invention may be used in the treatment of multiple diseases or conditions of abnormal cell growth and / or dysregulated apoptosis, such as cancer, autoimmune disease and pro-thrombotic conditions. Examples of diseases or disorders associated with down-regulated apoptosis can be prevented, modulated, or treated according to the present invention include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, adrenocortical cancer, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer, brain cancer, brain stem glioma, breast cancer, bronchogenic carcinoma, cervical cancer, cholangiocarcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, duodenal cancer, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fallopian tube carcinoma, fibrosarcoma, follicular lymphoma, gastric carcinoma, germ cell testicular cancer, gestational trophobalstic disease, glioblastoma, gall bladder cancer, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer both small cell lung cancer and non-small cell lung cancer, lymphagioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, including Diffuse Large B- celllymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma (cutaneous or intraocular), meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, parathyroid cancer, peripheral T -cell lymphoma, pinealoma, pituitary adenoma, polycythemia vera, prostate cancer including hormone-insensitive (refractory) prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small intestine cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, spinal axis tumors, spleen cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, urethra cancer, uterine cancer, Waldenstram's macroglobulinemia, testicular tumors, vaginal cancer, vulva cancer, Wilms' tumor and others.

[0182] The compounds of the present invention possess activity as inhibitors of the Bcl-2 family proteins, particularly Mcl-1 protein, and, therefore, may be used in the treatment of diseases associated with anti-apoptotic Bcl-2 family of proteins. Via the inhibitition of the activity of anti-apoptotic Bcl-2 family proteins, the compounds of the present invention may preferably be employed to release pro-apoptotic and promote apoptosis.

[0183] Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating, preventing, or slowing the progression of various hematologic and solid tumor types and related conditions, resistance development associated with chemotherapy. Consequently, it is believed that the compounds of the present invention may be used in preventing, inhibiting, or treating acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, adrenocortical cancer, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer, brain cancer, brain stem glioma, breast cancer, bronchogenic carcinoma, cervical cancer, cholangiocarcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, duodenal cancer, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fallopian tube carcinoma, fibrosarcoma, follicular lymphoma, gastric carcinoma, germ cell testicular cancer, gestational trophobalstic disease, glioblastoma, gall bladder cancer, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer both small cell lung cancer and non-small cell lung cancer, lymphagioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, including Diffuse Large B-celllymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma,melanoma (cutaneous or intraocular), meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, parathyroid cancer, peripheral T -cell lymphoma, pinealoma, pituitary adenoma, polycythemia vera, prostate cancer including hormone-insensitive (refractory) prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small intestine cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, spinal axis tumors, spleen cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, urethra cancer, uterine cancer, Waldenstram's macroglobulinemia, testicular tumors, vaginal cancer, vulva cancer, Wilms' tumor and others.

[0184] It is also expected that the compounds of the present invention may be used in preventing, inhibiting, or treating pediatric cancers or neoplasms including embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoidlrhabdoid tumor of the central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer and the like. Cancer Res., 2000, 60, 6101-10); and autoimmune disorders include, acquired immunodeficiency disease syndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, thrombocytopenia and the like (Current Allergy and Asthma Reports 2003,3:378-384; Bf.1. Haematol.2000 Sep; 110(3): 584-90; Blood 2000 Feb 15;95(4):1283-92; and New England Journal of Medicine 2004 Sep; 351(14): 1409-1418).

[0185] Involvement of Mcl-l in acute lymphoblastic leukemia is reported in Blood (1998) 91, 991-1000.

[0186] Involvement of Mcl-1 in pancreatic carcinoma is reported in Cancer Chemotherapeutic Pharmacology (2008) 62,1055-1064.

[0187] Involvement of Mcl-1 in breast cancer is reported in Anticancer Research (2004) 24,473-482.

[0188] Involvement of Mcl-1 in breast and non small-cell lung cancer is also reported in Nature (2010) 463, 899-905

[0189] Involvement of Mcl-1 in non small-cell lung cancer is also reported in Oncogene (2011) 30,1963-1968

[0190] Involvement of Mcl-1 in acute myelogenous leukemia is reported in Blood (1998) 91, 991-1000.

[0191] Involvement of Mcl-1 in cervical cancer is reported in Cancer Letters (Shannon, Ireland) (2002) 180, 63-68.

[0192] Involvement of Mcl-1 in cervical cancer is also reported in Medical Oncology (2011) 3, 673-677.

[0193] Involvement of Mcl-1 in chronic lymphocytic leukemia is reported in Journal of the National Cancer Institute (2004) 96, 673-682 and Immunology (2005) 114, 441-449.

[0194] Involvement of Mcl-1 in colorectal cancer, is reported in Annals of oncology: Official Journal of the European Society for Medical Oncology / ESMO (2001) 12, 779-785.

[0195] Involvement of Mcl-1 in gastric carcinoma, is reported in Gastric Cancer (2004) 7, 78-84.

[0196] Involvement of Mcl-1 in gestational trophobalstic disease is reported in Cancer (2005) 103, 268-276.

[0197] Involvement of Mcl-1 in glioblastoma is reported in Journal of Neurology, Neurosurgery, and Psychiatry (1999) 67, 763-768.

[0198] Involvement of Mcl-1 in head and neck cancer is reported in Archives of Otolaryngology-Head and Neck Surgery (1999) 125, 417-422.

[0199] Involvement of Mcl-1 in lung cancer is reported in Pathology Oncology Research: POR (1999) 5, 179-186.

[0200] Involvement of Mcl-1 in lung cancer is also reported in Cancer Biology and Therapy (2005) 4, 267-276.

[0201] Involvement of Mcl-1 in mesothioloma, is reported in Clinical Cancer Research (1999) 5, 3508-3515.

[0202] Involvement of Mcl-1 in mesothioloma, is also reported in Carcinogenesis (2010) 6, 984-993.

[0203] Involvement of Mcl-1 in multiple myeloma is reported in European Journal of Immunology (2004) 34, 3156-3164.

[0204] Involvement of Mcl-l in non-Hodgkin's lymphoma is reported in British Journal of Haematology (2002) 116, 158-161.

[0205] Involvement of Mcl-l in oligodenroglioma is reported in Cancer (1999) 86, 1832- 1839.

[0206] Involvement of Mcl-l in ovarian cancer is reported in Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology (2000) 18, 3775-3781.

[0207] Involvement of Mcl-l in ovarian cancer is also reported in Molecular Genetics, Gastrointestinal Carcinoma and Ovarian Carcinoma (2005) 4, 479-486.

[0208] Involvement of Mcl-l in pancreatic cancer is reported in Oncology (2002) 62, 354- 362.

[0209] Involvement of Mcl-l in peripheral T-cell lymphoma is reported in Journal of Pathology (2003) 200, 240-248.

[0210] Over-expression of Bcl-2 family protein members is associated with resistance to chemotherapy and is correlated with clinical outcome, disease progression, overall prognosis or a combination thereof in various hematologic and solid tumor types Examples of diseases or disorders associated with the hyperactivity of the Bcl-2 family of proteins, particularly Mcl-1, that can be prevented, modulated, or treated according to the present invention include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, adrenocortical cancer, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer, brain cancer, brain stem glioma, breast cancer, bronchogenic carcinoma, cervical cancer, cholangiocarcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-celllymphoma, duodenal cancer, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fallopian tube carcinoma, fibrosarcoma, follicular lymphoma, gastric carcinoma, germ cell testicular cancer, gestational trophobalstic disease, glioblastoma, gall bladder cancer, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer both small cell lung cancer and non-small cell lung cancer, lymphagioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, including Diffuse Large B-celllymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma (cutaneous or intraocular), meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, parathyroid cancer, peripheral T -cell lymphoma, pinealoma, pituitary adenoma, polycythemia vera, prostate cancer including hormone-insensitive (refractory) prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small intestine cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, spinal axis tumors, spleen cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, urethra cancer, uterine cancer, Waldenstram's macroglobulinemia, testicular tumors, vaginal cancer, vulva cancer, Wilms' tumor and others.

[0211] It is also expected that compounds having formula (I) would inhibit growth of cells derived from a pediatric cancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoidlrhabdoid tumor of the central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer and the like.

[0212] In some embodiments, the administered composition can increase tumor free survival, reduce tumor mass, slow tumor growth, increase tumor survival, or a combination thereof in the subject. The administered composition can reduce tumor volume in the subject in need thereof. The administered composition can increase tumor free survival in the subject after administration of the composition.

[0213] In some embodiments, the composition can be administered to clear or eliminate the cancer or tumor expressing the one or more oncogenes without damaging or causing illness or death in the subject administered the composition. A. Modes of Administration

[0214] Methods of treatment may include any number of modes of administering a disclosed composition. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non- aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire.TM.). In the pharmaceutical composition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.

[0215] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, oliveoil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano- suspensions.

[0216] The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. B. Combination Therapies

[0217] Additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I). The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. For example, the compound of Formula (I) can be combined with a variety of different anti-cancer drugs such as chemotherapeutics, anti-tumor agents, and anti-proliferative agents.

[0218] Further, the compound of formula (I) can be combined with the following, but not limited to, actinomycins, alkylating agents, anthracyclines, antifolates, antiestrogen agents, anti- metabolites, anti-androgens, antimicrotubule agents, aromatase inhibitors, bleomycins, bromodomain inhibitors, Ca2+adenosine triphosphate (ATP)ase inhibitors, cytosine analogs, deltoids / retinoids, dihydrofolate reductase inhibitors, deoxyribonucleic acid (DNA) topoisomerase inhibitors, dopaminergic neurotoxins, glucocorticoids, histone deacetylase inhibitors, hormonal therapies, immunotherapeutic agents, inosine monophosphate (IMP)dehydrogenase inhibitors, isoprenylation inhibitors, luteinizing hormone-releasing hormone agonists, mammalian target of rapamycin (mtor) inhibitors, multi-drug resistance (MDR) inhibitors, mitomycins, photodyamic therapies, proteasome inhibitors, platinum containing compounds, radiation, receptor tyrosine kinase inhibitors, ribonucleotide reductase inhibitors, thrombospondin mimetics, uracil analogs, vinca alkaloids, vitamin D3 analogs, ^-radiation, DOT1L inhibitors, agents targeting epigenetic mechanisms, or an additional chemotherapeutic agent such as N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-NHCH2CH3 or a salt thereof, actinomycin D, AG13736, 17-allylamino-17-demethoxygeldanamycin, 9-aminocamptothecin, N-(4-(3-amino-1H-indazol-4-yl)phenyl}-N'-(2-fluoro-5-methylphenyl)urea or a salt thereof, N- (4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl}-N'-(2-fluoro-5-(trifluoromethyl)phenyl)urea or a salt thereof, temozolomide, nedaplatin, satraplatin, triplatin tetranitrate, procarbazine, altretamine, mitozolomide, anastozole, AP-23573, asparaginase, azacitidine, bevacizurnab, bicalutamide, bleomycin a2, bleomycin b2, bortezemib, busulfan, campathecins, carboplatin, carmustine (BCNU), CB1093, cetuximab, CHOP (C: Cytoxan® (cyclophosphamide); H: Adriamycin® (hydroxydoxorubicin); O: Vincristine (Oncovin®); P: prednisone), chlorambucil, CHIR258, cisplatin, CNF-101, CNF-1001, CNF-2024, CP547632, crisnatol, cytarabine, cyclophosphamide, cytosine arabinoside, daunorubicin, dacarbazine, dactinomycin, dasatinib, daunorubicin, deferoxamine, demethoxyhypocrellin A, depsipeptide, dexamethasone, 17- dimethylaminoethylamino-17-demethoxygeldanamycin, docetaxel, doxifluridine, doxorubicin, EB 1089, epothilone D, epirubicin, 5-ethynyl-1-13-D-ribofuranosylimidazole-4-carboxamide (EICAR), erlotinib, etoposide, everolimus, 5-fluorouracil (5-FU), floxuridine, fludarabine, flutamide, gefitinib, geldanamycin, gemcitabine, goserelin, N-(2-(4-hydroxyanilino}-3- pyridinyl}-4-methoxybenzenesulfonamide or a salt thereof, hydroxyurea, idarubicin, ifosfamide, imatinab, interferon-a, interferon-y, IPI-504, irinotecan, KH 1060, lapatanib, leucovorin calcium, LAQ824, leuprolide acetate, letrozole, lomustine (CCNU), lovastatin, megestrol, melphalan, mercaptopurine, methotrexate, 1-methyl-4-phyenylpyridinium, MG132, mitomycin, mitoxantrone, MLN518, MLN4924, MS-275, mycophenolic acid, mitomycin C, nitrosoureas, oprelvekin, oxaliplatin, paclitaxel, PARP inhibitors (e.g., rucaparib, niraparib, olaparib, iniparib, talazoparib, and veliparib), PD98059, peplomycin, photosensitizer Pc4, phtalocyanine, pirarubicin, plicamycin, prednisone, procarbizine, PTK787, PU24FC1, PU3, radicicol, raloxifene, rapamycin, ratitrexed, retinoids such as pheuretinide, ribavirin, rituximab (Rituxin®),sorafenib, staurosporine, steroids such as dexamethasone and prednisone, suberoylanilide hydroxamic acid, tamoxifen, taxol, temozolamide, teniposide, thapsigargin, thioguanine, thrombospondin-1, tiazofurin, topotecan, trapoxin, trastuzumab, treosulfan, trichostatin A, trimetrexate, trofosfamide, tumor necrosis factor, valproic acid, VER49009, verapamil, vertoporfin, vinblastine, vincristine, vindesine, vinorelbine vitamin D3, VX-680, zactima, ZK- EPO, zorubicin, bevacizumab, enzastaurin, temsirolimus, cilengitide, lapatinib, sunitinib, axitinib, pazopanib, vemurafenib, dabrafenib, JQ1 or combinations thereof.

[0219] The disclosed compounds may be included in kits comprising the compound [e.g., one or more compounds of formula (I)], a systemic or topical composition described above, or both; and information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may include the medicament, a composition, or both; and information, instructions, or both, regarding methods of application of medicament, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans). 5. Biological Activity Assays for Bcl-2 Family Proteins Activity

[0220] The in vitro modulation of Bcl-2 family proteins was determined as follows: TR-FRET binding assay

[0221] Measurements were carried out in OptiPlate-384 White Opaque 384-well plates (Perkin Elmer, Shelton, CT). A TR-FRET based competitive binding assay was carried out using Mcl-1 protein and a fluorescein isothiocyanate (FITC)-labeled BH3 tracer peptide derived from Bak (FITC-AHx-GQVGRQLAIIGDDINR-NH2) that was purchased from GenScript (Piscataway, NJ) at >95% purity and used without further purification. 300 nM FITC-Bak peptide, 1 nM recombinant 6xHIS tagged Mcl-1 and 1 nM terbium conjugated anti- 6HIS antibody were added to assay buffer (4.5 mM Monobasic potassium phosphate, 15.5 mM Dibasic potassium phosphate, 1 mM Sodium EDTA, 50 mM NaCl, 1 mM DTT, 0.05% Pluronic F-68, 1% Fetal Bovine Serum, pH 7.5). Compounds are diluted in DMSO in a 16- point, semilog serial dilution scheme.50 nL of compound is added to 20 μL of assay buffer containing Bak- FITC, 6xHIS tagged Mcl-1 protein and terbium conjugated anti 6xHISantibody, for a final DMSO concentration of 0.25% and a top concentration of 10 . A FITC-Bak peptide alone (100 % inhibition) and peptide plus protein (0 % inhibition) control is included on each assay plate. The plate was mixed and incubated for 3 hours at room temperature. TR-FRET signal (Delta F) is measured on a Biotek Cytation 3 multimode plate reader equipped with a filter cube containing an Ex 340 / 30 Em 620 / 10 nm filter and an Ex 340 / 30 Em 520 filter. TR-FRET signal is plotted against compound concentration to generate an IC50(inhibitor concentration at which 50% of bound peptide is displaced) by fitting the data to a 4-parameter logistic model using XLFit software (Guildford, Surrey, UK). IC50is converted to a binding dissociation constant (Ki value) according to the formula of Wang Z. FEBS Lett. (1996) 3, 245: Ki= [I]50 / ([L]50 / Kd+ [P]0 / Kd+1) where [I]50is the concentration of the free inhibitor at 50% inhibition, [L]50is the concentration of the free labeled ligand at 50% inhibition, [P]0is the concentration of the free protein at 0% inhibition, Kirepresents the dissociation constant of the FITC peptide probe. The results for representative compounds are shown in Table 2. 1 nM terbium conjugated anti-6HIS antibody were added to assay buffer. Cellular Viability of Human Tumor Cell Lines

[0222] Human cancer cell lines H929 and A427 were cultured in media supplemented with 10% fetal bovine serum (FBS). To evaluate compound effect on cellular proliferation, cells were plated at 3,000 cells / well in 96-well tissue culture plates in a total volume of 90 medium supplemented with 10% FBS (Sigma, Saint Louis, MO).24 hours later, 10 L. of compound (in a 2.5-fold serial dilution) is added to the cells for a top concentration of 50 and a final DMSO concentration < 1%. After 72 hours, 50 of Cell TiterGlo (Promega, Madison, Wisconsin, USA) reagent is added to each well and plates are incubated at room temperature, in the dark, for 30 minutes. Luminescence is measured on a BioTek Cytation 3. Luminescence values are imported into a template in XLFit (Guildford, Surrey, UK) that uses a four- parameter fit to generate an IC50value for each compound dilution series on the plate.a). Mcl-1 Ki in the presence of 1% fetal bovine serum. All data points are an average of at least n = 2, run in triplicate. b). All data points are an average of at least n = 2, run in triplicate.

[0223] These data demonstrate the utility of representative compounds as inhibitors of cellular proliferation of human cancer cell lines and initiators of apoptosis in a Mcl-1 sensitive human cancer cell lines. In Vivo Xenograph Effects

[0224] Female BomTac:NMRI-Foxn1nu mice and CB17 / Icr-Prkdc(scid) / IcrCrl and were obtained from Taconic Denmark at an age of 6-8 weeks. After arrival, mice were allowed to adjust to housing conditions at least for 5 days before the start of the experiment. Mice were group-housed under pathogen-free and controlled environmental conditions and handled according to the institutional, governmental and European Union guidelines (Austrian Animal Protection Laws, GV-SOLAS and FELASA guidelines). To establish subcutaneous tumors mice were injected with 5*106A427cells in Matrigel (CB17 / Icr-Prkdc(scid) / IcrCrl), 1*106NCI-H1048 cells in Matrigel (BomTac:NMRI-Foxn1nu and 5*106NCI-H929 cells in Matrigel (CB17 / Icr-Prkdc(scid) / IcrCrl ). Tumor diameters were measured with a caliper three times a week. The volume of each tumor [in mm3] was calculated according to the formula “tumor volume = length * diameter2* π / 6.” To monitor side effects of treatment, mice were inspected daily for abnormalities and body weight was determined three times per week. Animals were sacrificed when the tumors reached a size of 1,500 mm3. Mice were dispatched randomly into treatment groups when the tumor size was 290mm3(NCI-H929) and 153mm3(A-427). Tumorswere reported as regressing when the tumor volume at a given day was below the tumor volume at treatment start.

[0225] Compound 26 was dosed IV as a single dose at either 60 or 80 mg / kg NCI-H929 subcutaneous multiple myeloma xenograft model. The two doses exhibited a dose-linear exposure profile and were both able to demonstrate initial tumor regression (FIG.1A). The tumor regression at 60 mg / kg persisted until day 7 after dosing start; whereas the 80 mg / kg dose achieved a more durable effect with regression persisting until day 15. For both doses, no significant change was observed in the median weight of the mice (FIG. 1B).

[0226] The following table displays the average AUC (0-24 hours), average percent tumor growth inhibition (TGI) at day 12 (d12), and the number of mice having tumor regressions at day 21 (d21) out of eight total mice, following IV administration of 60 or 80 mg / kg of compound 26.

[0227] When compound 26 was dosed IV as a single agent at 60 mg / kg q7d in a subcutaneous non-small cell lung cancer cell line A427 xenograft model, tumor regression was observed with outgrowth occurring around day 7 after treatment start (FIG.2A). On study day 21, best tumor control was in a single animal receiving 26 at 60 mg / kg exhibiting tumor stasis. A 10 mg / kg q7d dose of docetaxel alone resulted in tumor regression, with all study animals still exhibiting regressions at day 21; however, tumor outgrowth began around day 15 after treatment start. The combination of 26 and docetaxel (60 mg / kg + 10 mg / kg, q7d) resulted in a deepened response relative to either single agent treatment, with no sign of outgrowth after 21 days. Treatment effects on body weight are shown in FIG.2B.

[0228] The following table displays the average AUC (0-24 hours after a single dose), average percent tumor growth inhibition (TGI) at day 21 (d21), and the number of mice having tumor regressions at day 21 (d21) out of eight total mice, following IV administration once every seven days (q7d) of 60 mg / kg of compound 26, 10 mg / kg of docetaxel, or compound 26 (60 mg / kg) + docetaxel (10 mg / kg).Pharmacokinetic (PK) analyses

[0229] For PK analysis, dogs were administered intravenously with compound formulated either in 10% ethanol and 10% Cremophor EL for mice or in 50% ethanol and 50% PEG500 for dogs. Plasma samples were obtained at predefined timepoints and compound concentrations in plasma were measured by quantitative HPLC-MS / MS using an internal standard. Calibration and quality control samples were prepared using blank plasma from untreated animals. Samples were precipitated with acetonitrile and injected into a HPLC system (Agilent 1200). Separationwas performed by gradients of 5 mmol / L ammonium acetate pH 5.0 and acetonitrile with 0.1%formic acid on a Luna C8 reversed-phase column with 2.5 μm particles (Phenomenex). TheHPLC was interfaced by ESI operated in positive ionisation mode to a triple quadrupole mass spectrometer (6500+ Triple Quad System, SCIEX) operated in multiple reaction monitoring mode. Chromatograms were analyzed with Analyst (SCIEX) and pharmacokinetic parameters were calculated by non-compartmental analysis using proprietary software. Dog PK Results of Pyrimidine Mcl-1 Inhibitorsa) dosed at 0.25 mg / kg. b) dosed at 0.5 mg / kg. c) dosed at 0.9 mg / kg

[0230] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,R2a, at each occurrence, is independently C1-4alkyl; R2bis C1-4alkyl or H; R3is C1-2alkyl; R4is OH, –OC1-6alkyl, or –OPG; PG is a carboxylic acid protecting group;R5is H, C1-4alkyl, or C3-4cycloalkyl; R6is C1-4alkyl or C3-4cycloalkyl; R7is G or –CH2–G; G is a 4- to 7-membered heterocyclyl containing 1-2 oxygen atoms and optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro and methyl; R8a, at each occurrence, is independently C1-4alkyl; R8bis halogen; and R9is C1-4alkyl, C3-4cycloalkyl, or H.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is chloro.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2a, at each occurrence, is methyl.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R2bis methyl.

5. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R2bis H.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R3is methyl.

7. The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R4is OH or –OC1-6alkyl.

8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R5is H.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R6is C1-4alkyl.

10. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R7is –CH2–G.

11. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R7is G.

12. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted heterocyclyl of G is tetrahydropyranyl or tetrahydrofuranyl.

13. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein.

14. The compound of any of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R8ais methyl.

15. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R8bis chloro.

16. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R9is C1-4alkyl.

17. The compound of claim 1 selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, for use in the treatment of cancer.

20. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, for use in the inhibition of cancer cell proliferation.

21. A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18.

22. A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, in an amount effective to inhibit the cancer cell proliferation.

23. Use of the compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, in the manufacture of a medicament for the treatment of cancer.

24. Use of the compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, in the manufacture of a medicament for the inhibition of cancer cell proliferation.

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