US20100075947A1 - Methods of Using PI3K and MEK Modulators - Google Patents

Methods of Using PI3K and MEK Modulators Download PDF

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US20100075947A1
US20100075947A1 US12/373,257 US37325707A US2010075947A1 US 20100075947 A1 US20100075947 A1 US 20100075947A1 US 37325707 A US37325707 A US 37325707A US 2010075947 A1 US2010075947 A1 US 2010075947A1
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amino
phenyl
quinoxalin
methyloxy
sulfonyl
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Dana T. Aftab
A. Douglas Laird
Peter Lamb
Jean-Francois A. Martini
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Exelixis Inc
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to methods of treating cancer with a combination of compounds that modulate protein kinase enzymatic activities and the resultant modulation of cellular activities (such as proliferation, differentiation, programmed cell death, migration, chemoinvasion and metabolism).
  • this invention relates to a compound that inhibits mitogen activated protein kinase (MEK) used in combination with a compound that inhibits phosphatidylinositol 3-kinase (PI3K) signaling pathways.
  • MEK mitogen activated protein kinase
  • PI3K phosphatidylinositol 3-kinase
  • Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i.e., virtually all aspects of cell life in one-way or another depend on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
  • Protein kinases can be categorized as receptor type or non-receptor type.
  • Receptor-type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular. They are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified.
  • One tyrosine kinase subfamily, designated the HER subfamily is comprised of EGFR (HER1), HER2, HER3, and HER4.
  • Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.
  • Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R.
  • the PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II.
  • FLK kinase insert domain receptor
  • FLK-1 fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • flt-1 fms-like tyrosine kinase-1
  • the non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors.
  • the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk.
  • the Src subfamily of enzymes has been linked to oncogenesis.
  • MEK One particularly attractive target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is MEK.
  • the MEK-ERK signal transduction cascade is a conserved pathway which regulates cell growth, proliferation, differentiation, and apoptosis in response to growth factors, cytokines, and hormones. This pathway operates downstream of Ras which is often upregulated or mutated in human tumors. It has been demonstrated that MEK is a critical effector of Ras function.
  • MEK-ERK signal transduction pathway is an appropriate pathway to target for therapeutic intervention.
  • the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, particularly MEK, is desirable as a means to treat or prevent disease states associated with cancer and is an object of this invention.
  • Phosphatidylinositol 3-kinase a dual specificity protein kinase, is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit.
  • the protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2.
  • PI3K ⁇ has been implicated in the control of cytoskeletal reorganization, apoptosis, vesicular trafficking, proliferation and differentiation processes.
  • Increased copy number and expression of PIK3CA is associated with a number of malignancies such as ovarian cancer, cervical cancer, breast cancer, colorectal cancer, and glioblastomas, among others.
  • the tumor suppressor PTEN inhibits cell growth through multiple mechanisms. PTEN can dephosphorylate PIP3, the major product of PIK3CA. PIP3, in turn, is required for translocation of protein kinase B (AKT1, PKB) to the cell membrane, where it is phosphorylated and activated by upstream kinases. The effect of PTEN on cell death is mediated through the PIK3CA/AKT1 pathway.
  • an object of this invention is the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, particularly phosphatidylinositol 3-kinase, in order to treat, prevent, and/or inhibit diseases and conditions associated with cancers.
  • This invention provides a method of using an MEK inhibitor of Formula I, Ia, Ic, Id, II, III, IV, or V in combination with a PI3K inhibitor of Formula VI, VIa, VIb, or VII, or in combination with a PI3K inhibitor of Formula VIII, VIIIa, VIIIb, IX, X, XI or XI for the treatment of hyperproliferative disorders, such as cancers.
  • an MEK inhibitor of Formula I is as follows:
  • a ring, X, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as defined below in Section I.
  • a PI3K inhibitor of Formula VI is as follows:
  • a PI3K inhibitor of Formula VIII is as follows:
  • the invention encompasses using the MEK inhibitor disclosed in Section I in combination with the PI3K inhibitor of section II or section III to treat a hyperproliferative diseases and disorders and in particular cancers comprising administering to a patient a compound of Formula I, Ia, Ic, Id, II, III, IV, or V, with a compound of the Formula VI, VIa, VIb, or VII, or a compound of the Formula VIII, VIIIa, VIIIb, IX, X, or XI, or a pharmaceutical composition thereof.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • Some of the compounds of the invention may have imino, amino, oxo or hydroxy substituents off aromatic heterocyclyl systems.
  • imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
  • the compounds of the invention may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.
  • the compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • a particular group with its bonding structure is denoted as being bonded to two partners; that is, a divalent group, for example, —OCH 2 —
  • a divalent group for example, —OCH 2 —
  • either of the two partners may be bound to the particular group at one end, and the other partner is necessarily bound to the other end of the particular group, unless stated explicitly otherwise.
  • divalent groups are not to be construed as limited to the depicted orientation, for example “—OCH 2 —” is meant to mean not only “—OCH 2 —” as drawn, but also “—CH 2 O—.
  • optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomers may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and urunodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step may be required to liberate the desired enantiomeric form.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.
  • Kinase-dependent diseases or conditions refer to pathologic conditions that depend on the activity of one or more protein kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).
  • ocular diseases diabetic retinopathy, age-related macular degeneration, and the like
  • inflammation psoriasis, rheumatoid arthritis, and the like.
  • phosphatases can also play a role in “kinase-dependent diseases or conditions” as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth.
  • abnormal levels of cell proliferation i.e. tumor growth
  • apoptosis programmed cell death
  • angiogenesis associated with tumor growth.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.
  • the therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • “Cancer” refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (
  • “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, trifluoro
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylarnine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
  • salts of primary, secondary, and tertiary amines substituted amines including naturally occurring substituted amines, cyclic
  • organic bases are isopropylamine, diethylamine, ethanolamine, trimethylanine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.).
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
  • Treating” or “treatment” as used herein covers the treatment of a disease-state in a human, which disease-state is characterized by abnormal cellular proliferation, and invasion and includes at least one of: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i.e., arresting its development; and (iii) relieving the disease-state, i.e., causing regression of the disease-state.
  • Such suitable x-ray quality crystals can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of kinases.
  • Such methods may be characterized by the following embodiments: a) introducing into a suitable computer program, information defining a ligand binding domain of a kinase in a conformation (e.g.
  • Such methods may further entail: employing a candidate agent, so-determined to fit spatially into the ligand binding domain, in a biological activity assay for kinase modulation, and determining whether said candidate agent modulates kinase activity in the assay. Such methods may also include administering the candidate agent, determined to modulate kinase activity, to a mammal suffering from a condition treatable by kinase modulation, such as those described above.
  • compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a kinase.
  • a method may be characterized by the following embodiments: a) creating a computer model of a kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transderrnally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
  • Compositions of the invention may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic Formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • the compounds of the invention may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure.
  • the compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomers may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomer enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
  • this invention relates to compounds of Formula I and which inhibit MEK.
  • the invention provides a compound of Formula I or Ia where R 7 is halo and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • R 7 is iodo or bromo.
  • R 7 is iodo.
  • the compound is that where R 7 is iodo or bromo; the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • the invention provides a compound of Formula I or Ia where X is halo and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • X is fluoro or chloro.
  • X is fluoro.
  • the compound is that where X is fluoro or chloro; the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • the invention provides a compound of Formula I or Ia where R 1 , R 2 , R 5 , and R 6 are hydrogen and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • R 1 , R 2 , R 5 , and R 6 are hydrogen; the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • the invention provides a compound of Formula I or Ia where the A ring is a phenylene ring optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 where R 10 , R 12 , R 14 , R 16 , and all groups are as defined for a Compound of Formula I or Ia, respectively.
  • the invention provides a compound of Formula I or Ia where R 7 and X are halo and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • R 7 is iodo and X is fluoro.
  • the compound of Formula I or Ia is that where R 7 and X are halo; the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • R 7 is iodo and X is fluoro; the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • the invention provides a Compound of Formula I or Ia where the A ring is phenylene; R 14 and R 16 are hydrogen; R 10 and R 12 are independently hydrogen or halo; and all other groups are as defined for a Compound of Formula I or Ia, respectively
  • R 10 and R 12 are independently hydrogen or fluoro.
  • R 10 is 3-fluoro and R 12 is hydrogen.
  • R 10 and R 12 are fluoro.
  • R 10 and R 12 are 3-fluoro and 4-fluoro, 4-fluoro and 5-fluoro, or 4-fluoro and 6-fluoro.
  • the compound of Formula I or Ia is that where R 1 , R 2 , R 5 and R 6 are hydrogen; the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • the invention provides a Compound of Formula Ia where the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; X, R 7 , R 10 , R 12 , R 14 , and R 16 are as defined for a Compound of Formula Ia; and
  • the invention provides a Compound of Formula Ia where the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; X, R 7 , R 10 , R 12 , R 14 , and R 16 are as defined for a Compound of Formula Ia; and
  • Another embodiment of embodiment A5 is that where R 1 , R 2 , R 5 and R 6 are hydrogen.
  • the Compound id of Formula Ia where the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; X, R 7 , R 10 , R 12 , R 14 , and R 16 are as defined for a Compound of Formula Ia; and
  • embodiment A6 Another embodiment of embodiment A6 is that where R 1 , R 2 , R 5 and R 6 are hydrogen.
  • the invention provides a Compound of Formula Ia where the A ring is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 where R 14 and R 16 are hydrogen and where R 10 and R 12 are independently hydrogen or halo; X and R 7 are halo; R 1 , R 2 , R 5 and R 6 are hydrogen; and
  • the invention provides a Compound of Formula I or Ia where the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; R 3 is hydrogen, halo, hydroxy, alkoxy, or amino; and all other groups are as defined in Formula I or Ia, respectively.
  • R 3 is hydrogen, fluoro, hydroxy, methoxy, or amino.
  • R 3 is hydrogen or hydroxy.
  • R 3 is hydroxy.
  • X and R 7 are halo;
  • A is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 where R 14 and R 16 are hydrogen and where R 10 and R 12 are independently hydrogen or halo; R 1 , R 2 , R 5 and R 6 are hydrogen; and R 4 is as defined in Formula I or Ia, respectively.
  • the invention provides a Compound of Formula Ia where the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ; R 1 , R 2 , R 5 and R 6 are hydrogen; R 3 is hydrogen, halo, hydroxy, alkoxy, or amino; and R 4 is heterocycloalkyl, heteroaryl, or alkyl substituted with —NR 8 R 8′ where R 8 and R 8′ and all other groups are as defined in Formula Ia.
  • R 4 is alkyl substituted with —NR 8 R 8′ where R 8 and R 8′ and all other groups are as defined in Formula Ia.
  • the compound is of Formula I(c) or I(d):
  • R 3 is as defined in A9; X, R 7 , R 8 , R 8′ , R 10 , R 12 , R 14 , and R 16 are as defined in Formula Ia.
  • Another embodiment of embodiment A9 is that where R 4 is heterocycloalkyl.
  • the compound is that where X and R 7 are halo;
  • A is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 where R 14 and R 16 are hydrogen and where R 10 and R 12 are independently hydrogen or halo;
  • R 3 is hydroxy;
  • R 4 is alkyl substituted with —NR 8 R 8′ or R 4 is heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halo, lower alkanyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR 8 , —NR 8 R 8′ , —NHS(O) 2 R 9 , —CN, —S(O) m R 9 , —C(O)R 8 , —C(O)OR 8 , —C
  • the invention provides a Compound of Formula Ia where the A ring is phenylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , and R 16 ;
  • A10 is that wherein X and R 7 are halo;
  • A is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 where R 14 and R 16 are hydrogen and where R 10 and R 12 are independently hydrogen or halo;
  • R 1 , R 2 , R 5 and R 6 are hydrogen; and
  • R 3 is hydrogen, halo, hydroxy, alkoxy, or amino.
  • Another embodiment of embodiment A10 is that where R 3 is hydrogen and R 4 is
  • embodiment A10 Another embodiment of embodiment A10 is that where R 3 is alkoxy and R 4 is lower alkanyl substituted with —NR 8 R 8′ (where R 8 and R 8′ are independently hydrogen, lower alkanyl, or lower alkenyl). In another embodiment, R 3 is methoxy and R 4 is lower alkanyl substituted with —NR 8 R 8′ (where R 8 and R 8′ are independently hydrogen, lower alkanyl, or lower alkenyl).
  • embodiment A10 Another embodiment of embodiment A10 is that where R 3 is halo and R 4 is lower alkanyl substituted with —NR 8 R 8′ (where R 8 and R 8′ are independently hydrogen, lower alkanyl, or lower alkenyl). In another embodiment, R 3 is fluoro and R 4 is lower alkanyl substituted with —NR 8 R 8′ (where R 8 and R 8′ are independently hydrogen, lower alkanyl, or lower alkenyl).
  • embodiment A10 is that where R 3 is amino and R 4 is lower alkanyl substituted with —NR 8 R 8′ (where R 8 and R 8′ are independently hydrogen, lower alkanyl, or lower alkenyl).
  • A11 provides a compound of Formula I or Ia where the A ring is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 ; R 3 and R 4 together with the carbon to which they are attached form C(O) or C( ⁇ NOH); and all other groups are as defined for a Compound of Formula I or Ia, respectively.
  • X and R 7 are halo;
  • A is phenylene optionally substituted with with R 10 , R 12 , R 14 , and R 16 where R 14 and R 16 are hydrogen and where R 10 and R 12 are independently hydrogen or halo;
  • R 1 , R 2 , R 5 and R 6 are hydrogen; and
  • R 3 and R 4 together with the carbon to which they are attached form C(O) or C( ⁇ NOH).
  • A12 provides a Compound of Formula I or Ia where the A ring is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 where R 14 and R 16 are hydrogen and where R 10 and R 12 are independently hydrogen or halo; X and R 7 are halo; and R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen; and all other groups are as defined in Formula I or Ia, respectively.
  • A14 provides a Compound of Formula I or Ia where the A ring is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 ; R 1 is hydrogen; and R 2 is alkyl substituted with —NR 8 R 8′ ; where R 8 and R 8′ and all other groups are as defined in Formula I or Ia, respectively.
  • A15 provides a Compound Formula I or Ia where the A ring is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 ; R 7 is iodo or bromo; X is fluoro or chloro; R 1 , R 2 , R 5 , and R 6 are hydrogen; and R 10 , R 12 , R 14 , and R 16 are independently hydrogen or fluoro; and all other groups are as defined in Formula I or Ia, respectively.
  • R 10 is 3-fluoro and R 12 , R 14 , and R 16 are hydrogen or halo;
  • R 10 is 3-fluoro, R 12 is 4-fluoro, and R 14 and R 16 are hydrogen;
  • R 10 is 4-fluoro, R 12 is 5-fluoro, and R 14 and R 16 are hydrogen;
  • R 10 is 4-fluoro, R 12 is 6-fluoro, and R 14 and R 16 are hydrogen; or
  • R 12 is 4-fluoro and R 10 , R 14 , and R 16 are hydrogen.
  • the invention is a compound of Formula I or Ia where the A ring is phenylene optionally substituted with R 10 , R 12 , R 14 , and R 16 ; R 3 is hydroxy and R 4 is heterocycloalkyl, lower alkanyl, or heteroaryl, where the lower alkanyl is optionally substituted with —NR 8 R 8′ (where R 8 is hydrogen or lower alkanyl and R 8′ is hydrogen, lower alkanyl, or cycloalkyl where the cycloalkyl is optionally substituted with groups independently selected from hydroxy and lower alkanyl) and the heteroaryl is optionally substituted with lower alkanyl; and all other groups are as defined in Formula I or Ia, respectively.
  • R 3 is hydroxy and R 4 is heterocycloalkyl or lower alkanyl, where the lower alkanyl is optionally substituted with —NR 8 R 8′ (where R 8 is hydrogen or lower alkanyl and R 8′ is hydrogen, lower alkanyl, or cycloalkyl where the cycloalkyl is optionally substituted with groups independently selected from hydroxy and lower alkanyl).
  • R 10 , R 12 , R 14 and R 16 are independently selected from hydrogen, lower alkanyl, lower alkenyl, lower alkynyl, halo, haloalkoxy, hydroxy, lower alkoxy, amino, alkylamino, dialkylamino, haloalkyl, —NHS(O) 2 R 8 , —CN, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 8′ and —NR 8 C(O)R 8′ .
  • R 7 and X are halo and R 10 , R 12 , R 14 and R 16 are independently selected from hydrogen and halo.
  • X and R 7 are halo.
  • X is fluoro or chloro and R 7 is iodo or bromo.
  • R 3 is halo, nitro, —NR 8 R 8′ , —OR 8 , —NHS(O) 2 R 8 , —CN, —S(O) m R 8 , —S(O) 2 NR 8 R 8′ , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 8′ , —NR 8 C(O)OR 8′ , —NR 8 C(O)NR 8′ R 8′′ , —NR 8 C(O)OR 8′ , —NR 8 C(O)R 8′ , lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four,
  • R 3 and R 4 are independently halo, nitro, —NR 8 R 8′ , —OR 8 , —NHS(O) 2 R 8 , —CN, —S(O) m R 8 , —S(O) 2 NR 8 R 8′ , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 8′ , —NR 8 C(O)OR 8′ , —NR 8 C(O)NR 8′ R 8′′ , —NR 8 C(O)OR 8′ , —NR 8 C(O)R 8′ , lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two,
  • the invention provides a Compound of Formula I where the A ring is thien-diyl and X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , and R 12 are as defined in Formula I.
  • the A ring is thien-3,4-diyl; R 10 and R 12 are hydrogen; X and R 7 are halo; and R 1 , R 2 , R 5 , and R 6 are hydrogen.
  • X is fluoro or chloro; R 7 is iodo or bromo; R 3 is hydrogen or hydroxy; and R 4 is —NR 8 R 8′ (where R 8 and R 8′ are independently hydrogen or lower alkanyl), heterocycloalkyl, heteroaryl (optionally substituted with lower alkanyl), or lower alkanyl where the lower alkanyl is optionally substituted with —NR 8 R 8′ (where R 8 is hydrogen or lower alkanyl and R 8′ is hydrogen, lower alkanyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and lower alkanyl).
  • R 8 and R 8′ are independently selected from hydrogen, hydroxy, lower alkanyl, lower alkenyl, lower alkynyl, aryl, heterocycloalkyl, heteroaryl, and cycloalkyl;
  • Embodiment (E) is directed to a Compound of Formula Ia where
  • Another embodiment (F) of the Invention is a Compound of Formula Ia where
  • Another embodiment (G) of the Invention is directed to a Compound of Formula Ia where
  • Another embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any of Formulas I, Ia, Ic, Id, II, III, IV, and V or a compound as depicted in Table 1, and a pharmaceutically acceptable carrier.
  • the Compound is according to Formula Ia, according to Formula V, or according to Embodiment G.
  • Alkyl or “lower alkyl” means a (C 1 -C 20 ) linear, branched, or cyclic hydrocarbon group and combinations thereof, inclusively.
  • C 8 alkyl refers to an n-octyl, iso-octyl, cyclohexylethyl, isobutenyl, and but-2-ynyl groups and the like.
  • Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.
  • Exemplary alkyl groups are those of C 20 or below.
  • alkyl includes alkanyl, alkenyl, alkynyl, and cycloalkyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like.
  • alkyl residue having a specific number of carbons all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either “butyl” or “C 4 alkyl” is meant to include n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-ynyl groups; and for example, “propyl” or “C 3 alkyl” each include n-propyl, propenyl, and isopropyl.
  • Alkanyl means a linear saturated monovalent hydrocarbon radical of one to twenty carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 20 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.
  • “Lower alkanyl” means alkanyl having one to six carbons atoms.
  • cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having three to thirteen carbon atoms.
  • the cycloalkyl can be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • Cycloalkyl includes fused, bridged, and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Optionally substituted cycloalkyl means a cycloalkyl radical, as defined herein, that is optionally substituted with one, two, three, or four groups independently selected from C 1 -C 6 alkanyl, C 1 -C 6 alkoxy, halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, carb
  • Alkenyl means a straight or branched hydrocarbon radical having from 2 to 20 carbon atoms and at least one double bond and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. “Lower alkenyl” is alkenyl having 2-6 carbon atoms.
  • Alkynyl means a straight or branched hydrocarbon radical having from 2 to 20 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like. “Lower alkynyl” is alkynyl having 2-6 carbon atoms.
  • Alkylene means a straight or branched divalent group consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, n-butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH2CH 2 —), dimethylpropylene (—CH 2 C(CH 3 ) 2 CH 2 —), and cyclohexylpropylene (—CH 2 CH 2 CH(C 6 H 13 )).
  • Alkylidene means a straight or branched, divalent group consisting solely of carbon and hydrogen atoms, having from two to ten carbon atoms, and containing at least one double bond. Representative examples include ethylidene, propylidene, n-butylidene, and the like.
  • Alkylidyne means a straight or branched chain divalent group consisting solely of carbon and hydrogen atoms having from two to ten carbon atoms, and containing at least one triple bond, for example, propylid-2-ynyl, n-butylid-1-ynyl, and the like.
  • Alkoxy or “alkoxyl” means —O-alkyl, where the alkyl group includes from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
  • “Substituted alkoxy” means an —OR radical where R is substituted alkyl as defined herein.
  • Representative examples include groups such as —OCH 2 CH 2 OCH 3 , and glycol ethers such as polyethyleneglycol and —O(CH 2 CH 2 O) x CH 3 , (where x is an integer of between two and twenty, preferable, between two and ten, and more preferably, between two and five).
  • Another exemplary substituted alkoxy group is hydroxyalkoxy or —OCH 2 (CH 2 ) y OH (where y is an integer of between one and ten, in another example y is an integer of between one and four).
  • Alkoxyalkyl means a lower alkyl group, as defined herein, substituted with at least one, preferably one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like.
  • Alkoxycarbonylamino means a —NR′C(O)OR′′ group where R′ is hydrogen, alkyl, hydroxy, or alkoxy and R′′ is alkyl.
  • Alkylcarbonyloxy means an —OC(O)R group where R is alkyl, as defined herein.
  • “Acyl” means a —C(O)R radical where R is alkyl (i.e., one to ten carbon atoms of a straight, branched, or cyclic configuration, and is saturated or unsaturated) or R is optionally substituted aryl or optionally substituted heteroaryl. One or more carbons in the R residue may be replaced by nitrogen, oxygen or sulfur. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, and pyridinylcarbonyl, and the like. Lower-acyl refers to groups containing one to six carbons.
  • “Acylamino” means a —NRR′ group where R is acyl, as defined herein, and R′ is hydrogen or alkyl.
  • Alkylamino means a —NHR radical where R is alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, and the like.
  • Alkylaminoalkyl means an alkyl group substituted with one or two alkylamino groups, as defined herein.
  • Alkylaminocarbonyl means a —C(O)NHR radical where R is Ikyl, as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenyl, naphthyl, and indanyl, and the like.
  • Optionally substituted aryl means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or heterocyclyl), and —NHS(O) 2 R′ (where R′ is alkyl, aryl, or heteroaryl).
  • Arylalkyl means a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. “Lower arylalkyl” refers to an arylalkyl where the “alkyl” portion of the group has one to six carbons; this can also be referred to as C 1-6 arylalkyl.
  • Optionally substituted arylalkyl means an alkyl group substituted with one or two optionally substituted aryl group(s) as defined herein.
  • the alkyl group may itself be substituted as described under “substituted alkyl”.
  • Arylalkyloxy means an —OR group where R is arylalkyl, as defined herein.
  • Carboxy ester means a —C(O)OR group where R is lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which is defined herein. Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like.
  • Dialkylamino means a —NRR′ radical where R and R′ are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino, and the like.
  • Dialkylaminoalkyl means an alkyl group substituted with one or two dialkylamino groups, as defined herein.
  • Dialkylaminocarbonyl means a —C(O)NRR′ group where R and R′ are alkyl.
  • Exo-alkenyl refers to a double bond that emanates from an annular carbon, and is not within the ring system.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups.
  • saturated carbons of such fused groups i.e. saturated ring structures
  • fused-polycyclic or “fused ring system” means a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • Haloaloxy means an —OR′ group where R′ is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
  • Halogen or “halo” means fluoro, chloro, bromo or iodo.
  • Haloalkyl and haloaryl mean an alkyl and an aryl group, respectively, that are substituted with one or more halogens, preferably one to five halo atoms.
  • haloaryl dihaloaryl
  • dihaloalkyl dihaloalkyl
  • trihaloaryl etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • Heteroatom refers to O, S, N, or P.
  • Heterocyclyl means a stable three- to fifteen-membered ring substituent that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclyl substituent may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems.
  • the terms “heterocycloalkyl” and “heteroaryl” are groups that are encompassed by the broader term “heterocyclyl.”
  • the nitrogen, phosphorus, carbon and sulfur atoms in the heterocyclyl group may be optionally oxidized to various oxidation states.
  • the group —S(O) 0-2 — refers to —S— (sulfide), —S(O)— (sulfoxide), and —SO 2 — (sulfone).
  • nitrogens particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding N-oxide form, although not explicitly defined as such in a particular example.
  • annular nitrogen atoms may be optionally quaternized; and the ring substituent may be partially or fully saturated or aromatic.
  • heterocyclyl groups include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl
  • Optionally substituted heterocyclyl means a heterocyclyl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo (valency rules permitting), lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or heterocyclyl), amino, alkylamino, dialkylamino, and
  • Heteroalicyclic and “heterocycloalkyl” mean a non-aromatic heterocyclyl group, as defined herein.
  • a “heteroalicyclic” or “heterocycloalkyl” may be fully saturated or may contain unsaturation, but is not aromatic.
  • Heteroalicyclic” or “heterocycloalkyl” may be monocyclic or bicyclic (including fused, bridged, and spiro ring systems).
  • Optionally substituted heteroalicyclic and “optionally substituted heterocycloalkyl” mean, respectively, a heteroalicyclic and heterocycloalkyl ring, each as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or heterocyclyl),
  • Heteroaryl means a 5- to 12-membered, monocyclic aromatic heterocyclyl (where heterocyclyl is defined herein) or bicyclic heterocyclyl ring system (where at least one of the rings in the bicyclic system is aromatic) where the monocyclic ring and at least one of the rings in the bicyclic ring system contains one, two, three, four, or five heteroatom(s) selected from nitrogen, oxygen, phosphorous, and sulfur.
  • Representative examples include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, firyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quin
  • Optionally substituted heteroaryl means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or heterocyclyl), and —NHS(O) 2 R′ (where R′ is alkyl, aryl, or hetero
  • Optionally substituted heterocyclylalkyl means an alkyl group substituted with an optionally substituted heterocyclyl group, as defined herein. Examples include (4-methylpiperazin-1-yl) methyl, (morpholin-4-yl) methyl, (pyridin-4-yl) methyl, 2-(oxazolin-2-yl)ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. In addition, the alkyl portion of a heterocyclylalkyl group may be substituted as described in the definition for “substituted”.
  • “Lower heterocyclylalkyl” means a heterocyclylalkyl where the “alkyl” portion of the group has one to six carbons.
  • “Heteroalicyclylalkyl” or “lower heterocycloalkylalkyl” means a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and “heteroarylalkyl” means a heterocyclylalkyl where the heterocyclyl portion of the group contains an aromatic ring.
  • Such terms may be described in more than one way, for example, “lower heterocyclylalkyl” and “heterocyclyl C 1-6 alkyl” are equivalent terms.
  • C x -C y the number of annular atoms (including heteroatoms) in a heterocycle
  • x and y are integers.
  • C 5 -C 14 -heterocyclyl refers to a 5 to 14 membered ring system having at least one heteroatom and not a ring system containing 5 to 14 annular carbon atoms.
  • Preferred heterocyclyls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizin
  • Hydroalkyl means an alkanyl, alkenyl, or alkynyl radical, as defined herein, substituted with at least one, preferably one, two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl, and the like.
  • “Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class “saturated bridged ring system.
  • “Spiro”, “Spirocyclyl” or “spiro ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B′), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • “Substituted” alkyl, alkylene, alkylidene, and alkylidyne refer respectively to alkyl, alkylene, alkylidene, and alkylidyne where one or more (for example up to about five, in another example, up to about three) hydrogen atoms are replaced by a substituent independently selected from halo, optionally substituted aryl, hydroxy, alkoxy, optionally substituted heterocyclyl, alkylenedioxy, amino, alkylamino, dialkylamino), amidino, aryloxy, arylalkyloxy, carboxy, carboxy ester, alkylcarbonyloxy, carbamyl, alkylaminocarbonyl, dialkylaminocarbonyl, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, nitro, S(O) n1 R′ (where n1 is 0, 1, or 2 and R′ is alkyl, substituted alkyl
  • Table 1 depicts a representative example of the compounds of Section I.
  • the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 4 ⁇ M or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 3 ⁇ M or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 2 ⁇ M or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 1.6 ⁇ M or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 1 ⁇ M or less.
  • the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 0.7 ⁇ M or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 0.3 ⁇ M or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 0.2 ⁇ M or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table I having a MEK-binding affinity of about 0.1 ⁇ M or less.
  • LC-MS Liquid chromatography-mass spectral analyses were performed using at least one of: a Hewlett-Packard Series 1100 MSD, an Agilent 1100 Series LC/MSD (available from Agilent Technologies GmbH of Waldbronn Germany), or a Waters 8-Channel MUX System (available from Waters Corporation of Milford, Mass.). Compounds were identified according to either their observed mass [M+1] or [M+Na] ion (positive mode) or [M ⁇ 1] ion (negative mode). 1 H-NMR data for compounds was taken with a Varian AS400 Spectrometer (400 MHz, available from Varian GmbH, Darmstadt, Germany).
  • Methyl 4-(2-Fluoro-4-iodo-phenylamino)-thiophene-3-carboxylate (270 mg, 0.72 mmol) was dissolved in a mixture of tetrahydrofuran:methanol (6:1, 3 mL) and a solution of lithium hydroxide (0.1 g, 4.2 mmol) in 1 mL of water was added. The solution was stirred at room temperature for 18 hours and the solvent was concentrated. The residue was dissolved in 5 mL of water and the solution was acidified to pH 1 with 1N HCl.
  • compounds of the invention were screened in a triple coupled cRaf-MEK-ERK2 assay using ALPHASCREEN (Registered Trademark of Perkin Elmer) technology (Perkin Elmer).
  • substrate mixture composed of unactive MEK1 (3 nM), ATP (50 ⁇ M), unactive ERK2 (4 nM), biotinylated MBP peptide (b-FFKNIVTPRTPPPSQGK, 1 ⁇ M) and antiphospho MBP peptide (0.5 nM).
  • substrate mixture is then gently shaken for 30 minutes at room temperature followed by addition of active cRaf (5 ⁇ L at 0.5 nM) to initiate reaction.
  • the invention provides compounds that are useful as inhibitors of PI3K that have the Formula VI:
  • the invention provides a PI3K inhibitor of formula VIa:
  • the invention provides a PI3K inhibitor of formula VIb:
  • the invention provides a compound of Formula VIa where R 1 is hydrogen, C 1 -C 6 optionally substituted alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroalicyclicalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and all other groups are as defined in Formula VIa.
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalicyclicalkyl.
  • R 1 is hydrogen, alkyl, alkyl substituted with one or two hydroxy, alkyl substituted with alkoxy, alkyl substituted with aryl, C 3 -C 7 cycloalkyl, or heteroalicyclicalkyl.
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-isopropoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-piperidin-1-ylethyl.
  • R 1 is ethyl, isopropyl, cyclopentyl, or cyclohexyl.
  • R 1 is ethyl.
  • the invention provides a compound of Formula VIa where R 2 is hydrogen or optionally substituted C 1 -C 6 alkyl; and all other groups are as defined in Formula VIa.
  • R 2 is hydrogen or alkyl where the alkyl is optionally substitued with one, two, or three amino, alkylamino, dialkylamino, or halo.
  • R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl, 3-(N-methylamino)-propyl, or 3-(N,N-dimethylamino)-propyl.
  • R 2 is hydrogen or ethyl.
  • R 2 is hydrogen.
  • the invention provides a compound of Formula VIa or VIb where R 2 is hydrogen and all other groups are as defined for Formula VIa or VIb, respectively.
  • the invention provides a compound of Formula VIa or VIb where R 2 is optionally substituted C 1 -C 6 alkyl; and all other groups are as defined in Formula VIa or VIb, respectively.
  • R 2 is alkyl where the alkyl is optionally substitued with one, two, or three arnino, alkylamino, dialkylamino, or halo.
  • R 2 is methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl, 3-(N-methylamino)-propyl, or 3-(N,N-dimethylamino)-propyl.
  • R 2 is ethyl.
  • the invention is directed to a Compound of Formula VIa where R 4 is optionally substituted C 1 -C 6 alkyl; and all other groups are as defined in Formula VIa.
  • R 4 is methyl or ethyl. In another embodiment, R 4 is methyl.
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or optionally substituted C 1 -C 6 alkyl and R 6 is acyl; and all other groups are as defined in Formula VIa or VIb, respectively.
  • R 6 is alkylcarbonyl.
  • R 6 is acetyl.
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or optionally substituted C 1 -C 6 alkyl and R 6 is phenyl optionally substituted with 1, 2, 3, or 4 R 9 groups; and all other groups are as defined in Formula VIa or VIb, respectively.
  • R 6 is phenyl optionally substituted with one or two R 9 groups; and R 9 at each instance is independently selected from aryl, halo, alkoxy, aryloxy, alkoxycarbonyl, alkyl, and haloalkyl.
  • R 6 is phenyl optionally substituted with one or two R 9 groups; and each R 9 at each instance is independently selected from phenyl, fluoro, chloro, methoxy, phenyloxy, methyl, methoxycarbonyl, and trifluoromethyl.
  • R 6 is phenyl, phenyl substituted with phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, phenyl substituted with chloro and fluoro, methoxyphenyl, dimethoxyphenyl, phenyloxyphenyl, or trifluoromethylphenyl.
  • R 6 is phenyl, 2-phenyl-phenyl, 3-phenyl-phenyl, 4-phenyl-phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-
  • the invention is directed to a Compound of Formula VIa or VIb where R 6 is phenyl subtituted with 1, 2, 3, or 4 R 9 groups; and all other groups are as defined in Formula VIa or VIb, respectively.
  • the invention is directed to a Compound of Formula VIa or VIb where R 6 is heteroaryl optionally substituted with 1, 2, 3, 4, or 5 R 9 groups; and all other groups are as defined in Formula VIa or VIb, respectively.
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or optionally substituted C 1 -C 6 alkyl and R 6 is heteroaryl optionally substituted with 1, 2, 3, 4, or 5 R 9 groups; and all other groups are as defined in Formula VIa or VIb, respectively.
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or ethyl and R 6 is a 6-membered heteroaryl optionally substituted with one or two R 9 ; and all other groups are as defined in Formula VIa or VIb, respectively.
  • R 6 is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with one R 9 where R 9 at each instance is halo.
  • R 6 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3-fluoropyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl, each of which is optionally substituted with one or two R 9 .
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or ethyl and R 6 is pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with one R 9 where R 9 at each instance is halo; and all other groups are as defined in Formula VIa or VIb, respectively.
  • R 6 is pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl.
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or ethyl and R 6 is 5-membered heteroaryl optionally substituted with one or two R 9 ; and all other groups are as defined in Formula VIa or VIb, respectively.
  • R 6 is pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with one R 9 where R 9 at each instance is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
  • R 6 is pyrazolyl, thienyl, thiazolyl, oxazolyl, furanyl, or pyrrolyl, each of which is optionally substituted with one R 9 where R 9 at each instance is alkyl, alkoxycarbonyl, or halo.
  • R 6 is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl; each of which is optionally substituted with one R 9 where R 9 at each instance, is methyl, N-tert-butoxycarbonyl, or chloro.
  • R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, or pyrrol-3-yl; each of which is optionally substituted with one R 9 where R 9 , when present, is methyl, N-tert-butoxycarbonyl, or chloro.
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or ethyl and R 6 is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazo]-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, or tetrazol-5-yl, each of which is optionally substituted with one R 9 where R 9 , when present, is methyl, N-tert-butoxycarbonyl, or chloro; and all other groups are as defined in Formula VIa or VIb, respectively.
  • the invention is directed to a Compound of Formula VIa or VIb where R 2 is hydrogen or ethyl and R 6 is indolyl optionally substituted with 1, 2, 3, or 4 R 9 groups; and all other groups are as defined in Formula VIa or VIb, respectively.
  • R 6 is indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, or indol-7-yl; each of which is optionally substituted with 1, 2, 3, or 4 R 9 groups.
  • R 6 is indol-6-yl.
  • the invention is directed to a Compound of Formula VIa where R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, or optionally substituted heteroalicyclicalkyl; R 2 is hydrogen or C 1 -C 6 alkyl optionally substituted with amino, alkylamino, dialkylamino, or halo; R 4 is alkyl; R 6 is phenyl or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with one, two, or three R 9 groups; and each R 9 , when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
  • the invention is directed to a Compound of Formula VIa where R 2 is hydrogen or ethyl, R 4 is methyl, and R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-y], thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, or pyrrol-3-yl; each of which is optionally substituted with 1, 2, 3, 4, or 5 R 9 groups; and all other groups are as defined in Formula VIa.
  • the invention is directed to a Compound of Formula VIa where R 1 is alkyl or cycloalkyl; R 4 is methyl; and R 6 is heteroaryl optionally substituted with one or two R 9 groups; and all other groups are as defined in Formula VIa.
  • each R 9 when present, is independently alkyl, alkoxycarbonyl, or halo.
  • R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,furan-2-yl, furan-3-yl, pyrrol-2-yl, or pyrrol-3-yl; each of which is optionally substituted with one R 9 where R 9 , when present, is methyl or N-tert-butoxycarbonyl.
  • the invention is directed to a Compound of Formula VIa where R 2 is hydrogen; and all other groups are as defined in Embodiment K.
  • the invention is directed to a Compound of Formula VIa where R 2 is methyl or ethyl; and all other groups are as defined in Embodiment K.
  • the invention is directed to a Compound of Formula VIa where R 1 is alkyl or cycloalkyl; R 4 is methyl; and R 6 is phenyl optionally substituted with one or two R 9 groups; and all other groups are as defined in Formula VIa.
  • each R 9 when present, is independently halo, alkoxy, or haloalkyl.
  • the invention is directed to a Compound of Formula VIa where R 1 is alkyl or cycloalkyl; R 4 is methyl; and R 2 is hydrogen; and all other groups are as defined in Formula VIa.
  • the invention is directed to a Compound of Formula VIa where R 1 is alkyl or cycloalkyl; R 4 is methyl; and R 2 is optionally subtituted alkyl; and all other groups are as defined in Formula VIa.
  • the invention is directed to a Compound of Formula VII:
  • R 2 where the phenyl and heterocyclyl-aryl- groups in R 2 are optionally substituted with 1, 2, 3, or 4 R 8 groups; or
  • the invention is directed to a Compound of Formula VII where R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroalicyclicalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and all other groups are as defined in Formula VII.
  • R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 7 cycloalkyl.
  • R 1 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.
  • R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, R 1 is ethyl, isopropyl, or cyclopentyl.
  • the invention is directed to a Compound of Formula VII where R 4 is optionally substituted C 1 -C 6 alkyl; and all other groups are as defined in Formula VII.
  • R 4 is methyl or ethyl. In another embodiment, R 4 is methyl.
  • the invention is directed to a Compound of Formula VII where R 6 is acyl and R 2 is heterocyclyl-aryl- optionally substituted with 1, 2, 3, or 4 R 8 groups; and all other groups are as defined in Formula VII.
  • R 6 is alkylcarbonyl.
  • R 6 is acetyl.
  • the invention is directed to a Compound of Formula VII where R 6 is acyl and R 2 is heteroalicyclic-phenyl- optionally substituted with 1, 2, 3, or 4 R 8 groups; and all other groups are as defined in Formula VII.
  • R 8 when R 8 is present, is C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, or aryl C 1 -C 6 alkyl.
  • R 2 is piperazinyl-phenyl- where the piperazinyl is optionally substituted with one R 8 where R 8 , when present, is methyl, ethyl, isopropyl, tert-butoxycarbonyl, or benzyl.
  • R 2 is piperazinyl-phenyl- where the piperazinyl is optionally substituted with C 1 -C 6 alkyl.
  • the invention is directed to a Compound of Formula VII where R 6 is phenyl optionally substituted with 1, 2, 3, or 4 R 9 groups; and R 2 is phenyl or heterocyclyl-aryl-; where the phenyl and heterocyclyl-aryl- groups in R 2 are optionally substituted with 1, 2, 3, or 4 R 8 groups; and all other groups are as defined in Formula VII.
  • R 6 is phenyl, phenyl substituted with one or two halo.
  • R 6 is phenyl, fluorophenyl, difluorophenyl, chlorophenyl, or dichlorophenyl.
  • R 6 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, or 3,5-difluorophenyl.
  • the invention is directed to a Compound of Formula VII where R 2 is phenyl or heteroalicyclic-phenyl-; where the phenyl and heteroalicyclic-phenyl- groups in R 2 are optionally substituted with 1, 2, 3, or 4 R 8 groups; and all other groups are as defined in Embodiment E.
  • the invention is directed to a Compound of Formula VII where R 2 is phenyl or heteroalicyclic-phenyl-; where the phenyl and heteroalicyclic-phenyl- groups in R 2 are optionally substituted with one or two R 8 where each R 8 , when present, is independently hydroxy, C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, alkoxycarbonyl, or —O—C 1 -C 6 alkylheteroalicyclic; and all other groups are as defined in Embodiment E1.
  • R 2 is phenyl or phenyl substituted with one or two R 8 where each R 8 , when R 8 is present, is independently hydroxy, —O—C 1 -C 6 alkylheteroalicyclic, or C 1 -C 6 alkoxy where the C 1 -C 6 alkoxy is optionally substituted with amino, alkylamino or dialkylamino; and all other groups are as defined in Embodiment E1.
  • R 2 is phenyl, hydroxyphenyl, [(2-aminoethyl)-oxy]-phenyl, [(2-alkylamino-ethyl)-oxy]-phenyl, [(2-dialkylamino-ethyl)-oxy]-phenyl, (morpholinylalkyloxy)-phenyl, (piperidinylalkyloxy)-phenyl, (piperazinylalkyloxy)-phenyl, (N-alkyl-piperazinylalkyloxy)-phenyl, or (N-benzylpiperazinylalkyloxy)-phenyl.
  • R 2 is hydroxyphenyl, [(2-aminoethyl)-oxy]-phenyl, [(2-alkylamino-ethyl)-oxy]-phenyl, [(2-dialkylamino-ethyl)-oxy]-phenyl, (morpholinylalkyloxy)-phenyl, (piperidinylalkyloxy)-phenyl, (piperazinylalkyloxy)-phenyl, (N-alkyl-piperazinylalkyloxy)-phenyl, or (N-benzylpiperazinylalkyloxy)-phenyl.
  • R 2 is piperazinyl-phenyl- where the piperazinyl is optionally substituted with one R 8 where R 8 , when present, is alkyl; and all other groups are as defined in Embodiment E1.
  • R 2 is morpholinylphenyl, piperazinylphenyl, or (N-alkyl-piperazinyl)-phenyl.
  • R 2 is 4-morpholin-4-ylphenyl, 4-piperazin-4-ylphenyl, 4-(N-methyl-piperazin-4-yl)-phenyl, or 4-(N-ethyl-piperazin-4-yl)-phenyl.
  • the invention is directed to a Compound of Formula VII where R 6 is heteroaryl optionally substituted with 1, 2, or 3 halo; and R 2 is heterocyclyl-aryl- optionally substituted with 1, 2, 3, 4, or 5 R 8 groups.
  • the invention is directed to a Compound of Formula VII where R 6 is a 5-membered heteroaryl optionally substituted with one or two halo; R 2 is heteroalicyclic-phenyl- where the heteroalicyclic and phenyl portions of R 2 are independently optionally substituted with one R 8 where R 8 , when R 8 is present is C 1 -C 6 alkyl or aryl C 1 -C 6 alkyl; and all other groups are as defined in embodiment F.
  • the invention is directed to a Compound of Formula VII where R 6 is pyrazolyl, thienyl, thiazolyl, oxazolyl, furanyl, or pyrrolyl, each of which is optionally substituted with one or two halo.
  • R 6 is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, or furan-3-yl; each of which is optionally substituted with one chloro.
  • R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, or furan-3-yl.
  • the invention is directed to a Compound of Formula VII where R 6 is halo and R 2 is optionally substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, aryl-C 1-6 alkyl, heteroalicyclicalkyl, or heterocyclyl-aryl-; where the C 3 -C 7 cycloalkyl, phenyl, phenyl, aryl-C 1-6 alkyl, heteroalicyclicalkyl, and heterocyclyl-aryl- groups in R 2 are optionally substituted with 1, 2, 3, or 4 R 8 groups.
  • R 6 is bromo and R 2 is C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl optionally substituted with heteroalicyclic, dialkylamino, phenyl substituted with one or two halo, or heteroalicyclic-phenyl-; where the heteroalicyclic-phenyl- is optionally substituted with one or two R 8 selected from C 1 -C 6 alkyl and phenyl-C 1-6 alkyl.
  • R 2 is cyclopentyl, cyclohexyl, 2-(morpholinyl)-ethyl, 3-(morpholinyl)-propyl, 3-(dimethylamino)-propyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-[4-methyl-piperazinyl]-phenyl, 4-[4-ethyl-piperazinyl]-phenyl, 4-[4-benzyl-piperazinyl]-phenyl, or 4-(morpholinyl)-phenyl.
  • the invention is directed to a Compound of Formula VII where R 1 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; R 4 is methyl; and R 6 is heteroaryl.
  • R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, or furan-3-yl.
  • the invention is directed to a Compound of Formula VII where R 1 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; R 4 is methyl; R 5 is hydrogenand R 6 is phenyl optionally substituted with 1, 2, or 3 halo.
  • the invention is directed to a Compound of Formula VII where R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, or furan-3-yl.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula VI, VIa, VIb or VII, or a pharmaceutically acceptable salt or solvate thereof, in combination with a compound of formula I, Ia, Ic, Id, II, III, IV, or V and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method of inhibiting the in vivo activity of PI3K ⁇ , and MEK the method comprising administering to a subject an effective PI3K ⁇ -inhibiting amount of a compound of formula VI, VIa, VIb or VII, or a pharmaceutically acceptable salt or solvate thereof, in combination with a compound of formula I, Ia, Ic, Id, II, III, IV, or V or a pharmaceutical composition thereof.
  • Another aspect of the invention is a method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities effected directly or indirectly by PI3K ⁇ and MEK, the method comprising administering to a mammal (preferably human) in need thereof a therapeutically effective amount of a compound of any of formula VI, VIa, VIb or VII, or a pharmaceutically acceptable salt or solvate thereof, in combination with a compound of formula I, Ia, Ic, Id, II, III, IV, or V or a pharmaceutical composition thereof.
  • the MEK Compound is of Formula Ia and the PI3K Compound is of Formula VIa.
  • the MEK Compound is of Formula Ia and the PI3K Compound is of Formula VIb.
  • the MEK Compound is of Formula V and the PI3K Compound is of Formula VIa or VIb.
  • the MEK Compound is of Section I, Embodiment G and the PI3K Compound is of a compound from Section II, Formula VIa or VIb, Embodiment E.
  • the MEK Compound is of Section I, Embodiment G and the PI3K Compound is of a compound of Section II, Formula VIa or VIb, Embodiment G or G3.
  • the MEK Compound is of Formula Ia and the PI3K Compound is of Formula VII.
  • the MEK Compound is of Formula V and the PI3K Compound is of Formula VII.
  • the MEK Compound is of Section I, Embodiment G and the PI3K Compound is of a compound from Section II, Formula VII, Embodiment E.
  • the MEK Compound is of Section I, Embodiment G and the PI3K Compound is of a compound of Section II, Formula VI, Embodiment F1 or F2.
  • the MEK Compound is of Section I, Table 1 and the PI3K Compound is of Formula VI, VIa, VIb or VII.
  • Another aspect of the invention is a method of inhibiting proliferative activity in a cell, the method comprising administering to a cell or a plurality of cells an effective amount of a compound of formula VI, VIa, VIb or VII, or a pharmaceutically acceptable salt or solvate thereof, in combination with a compound of formula I, Ia, Ic, Id, II, III, IV, or V or pharmaceutical composition thereof.
  • a further aspect of the invention is a method of treating malignancies such as melanoma, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, and glioblastomas, among others, in a patient in need of such treatment, by administering a compound or salt of formula VI, VIa, VIb or VII, or a pharmaceutically acceptable salt or solvate thereof, in combination with a compound of formula I, Ia, Ic, Id, II, III, IV, or V or a pharmaceutical composition thereof.
  • the symbol “—” means a single bond
  • “ ⁇ ” means a double bond
  • “ ⁇ ” means a triple bond
  • the symbol to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous. When a group is depicted removed from its parent formula, the symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
  • a substituent “R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • a substituent “R” may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the —NH— in the formula above), implied hydrogen (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, “X” equals ⁇ CH—) from one of the ring atoms, so long as a stable structure is formed.
  • the “R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • the two “R's” may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
  • Alkyl is intended to include linear or branched hydrocarbon structures and combinations thereof, inclusively.
  • C 8 alkyl may refer to an n-octyl, iso-ctyl, and the like.
  • Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-utyl, isobutyl, pentyl, and the like.
  • Higher alkyl refers to alkyl groups containing more that eight carbon atoms.
  • a “C 0 ” alkyl (as in “C 0 -C 6 -alkyl”) is a covalent bond.
  • exemplary alkyl groups are those of C 20 or below.
  • alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include vinyl, allyl, isoprenyl, and the like.
  • alkyl residue having a specific number of carbons all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either “butyl” or “C 4 alkyl” is meant to include n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-ynyl groups; and for example, “propyl” or “C 3 alkyl” each include n-propyl, propenyl, and isopropyl.
  • Cycloalkyl means a cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • Alkoxy refers to the group —O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
  • Optionally substituted alkoxy refers to the group —OR where R is optionally substituted alkyl, as defined herein.
  • One exemplary substituted alkoxy group is “polyalkoxy” or —O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as —OCH 2 CH 2 OCH 3 , and glycol ethers such as polyethyleneglycol and —O(CH 2 CH 2 O) x CH 3 , where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five.
  • Another exemplary substituted alkoxy group is hydroxyalkoxy or —OCH 2 (CH 2 ) y OH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
  • “Acyl” refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.
  • “Acylamino” means an —NHR group where R is acyl as defined herein.
  • “Amino” refers to the group —NH 2 . “Substituted amino,” refers to the group —N(H)R or —(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino.
  • Aryl refers to aromatic six- to fourteen-membered carbocyclic ring, for example, benzene, naphthalene, indane, tetralin, fluorene and the like, univalent substituents. As univalent substituents, the aforementioned ring examples are named, phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl.
  • Arylalkyl refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Both the aryl and the corresponding alkylene, alkylidene, or alkylidyne group portion of an arylalkyl group may be optionally substituted. “Lower arylalkyl” refers to an arylalkyl where the “alkyl” portion of the group has one to six carbons; this can also be referred to as C 1-6 arylalkyl.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups.
  • saturated carbons of such fused groups i.e. saturated ring structures
  • Halogen or “halo” refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl and haloaryl refer generically to alkyl and aryl groups that are substituted with one or more halogens, respectively.
  • dihaloaryl dihaloalkyl
  • trihaloaryl etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • Haloalkyl includes, for instance, mono- to per-haloC 1 -C 6 alkyl.
  • Heteroatom refers to O, S, N, or P.
  • Heterocyclyl refers to a stable three- to fifteen-membered ring substituent that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclyl substituent may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl group may be optionally oxidized to various oxidation states.
  • the group —S(O) 0-2 — refers to —S— (sulfide), —S(O)— (sulfoxide), and —SO 2 — (sulfone).
  • nitrogens particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding N-oxide form, although not explicitly defined as such in a particular example.
  • annular nitrogen atoms may be optionally quaternized; and the ring substituent may be partially or fully saturated or aromatic.
  • heterocyclyl groups include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl
  • Heteroalicyclic refers specifically to a non-aromatic heterocyclyl group.
  • a heteroalicyclic may contain unsaturation, but is not aromatic.
  • Heteroalicyclicalkyl refers specifically to an alkyl group substituted with one or two non-aromatic heterocyclyl group.
  • the heteroalicyclic ring portion of this group may contain unsaturation, but is not aromatic.
  • Heteroaryl refers specifically to an aromatic heterocyclyl group.
  • Heterocyclylalkyl refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include (4-methylpiperazin-1-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. Both the heterocyclyl and the corresponding alkylene, alkylidene, or alkylidyne portion of a heterocyclylalkyl group may be optionally substituted.
  • “Lower heterocyclylalkyl” refers to a heterocyclylalkyl where the “alkyl” portion of the group has one to six carbons. “Heteroalicyclylalkyl” refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and “heteroarylalkyl” refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is aromatic Such terms may be described in more than one way, for example, “lower heterocyclylalkyl” and “heterocyclyl C 1-6 alkyl” are equivalent terms.
  • C x -C y the number of annular atoms (including heteroatoms) in a heterocycle
  • x and y are integers.
  • C 5 -C 14 -heterocyclyl refers to a 5 to 14 membered ring system having at least one heteroatom and not a ring system containing 5 to 14 annular carbon atoms.
  • Preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl
  • Heterocyclyl-aryl- means an aryl group substituted with at least one, specifically 1 or 2 heterocyclyl, as defined herein. “Optionally substituted heterocyclyl-aryl-” means that either or both the aryl and the heterocyclyl can be substituted as defined in “substituted.”
  • “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “Optionally substituted” refers to all subsequent modifiers in a term. So, for example, in the term “optionally substituted arylC 1-8 alkyl,” optional substitution may occur on both the “C 1-8 alkyl” portion and the “aryl” portion of the molecule may or may not be substituted. A list of exemplary optional substitutions is presented below in the definition of “substituted.”
  • “Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class “saturated bridged ring system.
  • “Spirocyclyl” or “spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B′), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • Substituted alkyl, cycloalkyl, aryl, and heterocyclyl refer respectively to alkyl, aryl, and heterocyclyl, where one or more (for example up to about five, in another example, up to about three) hydrogen atoms are replaced by a substituent.
  • the substituent(s) on alkyl, aryl, heteroaryl, and heterocyclyl include, for instance, one or more groups selected from alkylenedioxy (for example methylenedioxy), aryloxy (for example, phenoxy), carboxy, acyloxy, acylamino, benzyloxycarbonylamino, acyl, carbamyl, oxo, hydroxy, halo, nitro, cyano, 'O—C 1 -C 6 alkyl, haloalkyl, C 1 -C 6 alkyl, cycloalkyl, —C(O)O—C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl-aryl, —C 1 -C 6 alkyl-aryl, —O—C 1 -C 6 alkyl-O
  • heterocyclyl groups formed by R a and R b include morpholinyl and piperazinyl.
  • Each substituent of a substituted group is optionally substituted, but these optional substituents themselves are not further substituted.
  • an optionally substituted moiety is one that may or may not have one or more substituents, and each of the substituents may or may not have one or more substituents. But, the substituents of the substituents may not be substituted.
  • “Sulfanyl” refers to the groups: —S-(optionally substituted alkyl), —S-(optionally substituted aryl), and —S-(optionally substituted heterocyclyl).
  • “Sulfinyl” refers to the groups: —S(O)—H, —S(O)-(optionally substituted alkyl), —S(O)-optionally substituted aryl), and —S(O)-(optionally substituted heterocyclyl).
  • “Sulfonyl” refers to the groups: —S(O 2 )—H, —S(O 2 )-(optionally substituted alkyl), —S(O 2 )-optionally substituted aryl), —S(O 2 )-(optionally substituted heterocyclyl), —S(O 2 )-(optionally substituted alkoxy), —S(O 2 )-optionally substituted aryloxy), and —S(O 2 )-(optionally substituted heterocyclyloxy).
  • the compounds of the invention can be prepared by one skilled in the art based only on knowledge of the compound's chemical structure.
  • the chemistry for the preparation of the compounds of this invention is known to those skilled in the art. In fact, there is more than one process to prepare the compounds of the invention. Specific examples of methods of preparation can be found in the art. For examples, see M. Barvian et al. J. Med. Chem. 2000, 43, 4606-4616; S. N. VanderWei et al. J. Med. Chem. 2005, 48, 2371-2387; P. L. Toogood et al. J. Med. Chem. 2005, 48, 2388-2406; J. Kasparec et al.
  • the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 9 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 5 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 3 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 1.5 ⁇ M or less.
  • the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 1 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.6 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.3 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.2 ⁇ M or less.
  • the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.1 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.04 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.020 ⁇ M or less.
  • PI3Kalpha activity is measured as the percent of ATP consumed following the kinase reaction using luciferase-luciferin-coupled chemiluminescence. Reactions were conducted in 384-well white, medium binding microtiter plates (Greiner). Kinase reactions were initiated by combining test compounds, ATP, substrate (PIP2), and kinase in a 20 ⁇ L volume. The standard assay concentrations for enzyme, ATP, and substrate are 1.1 nm, 1 ⁇ M, and 7.5 ⁇ M, respectively. The reaction mixture was incubated at ambient temperature for 2 h.
  • luciferase-luciferin mix Promega Kinase-Glo
  • chemiluminescence signal measured using a Victor2 plate reader (Perkin Elmer).
  • Total ATP consumption was limited to 40-60% and IC50 values of control compounds correlate well with literature references.
  • preferred compounds of the invention exhibit an IC 50 of less than 50 micromolar. More preferred compounds of the invention exhibit an IC 50 of less than I micromolar. Even more preferred compounds of the invention exhibit an IC 50 of less than 500 nanomolar. Still more preferred compounds of the invention exhibit an IC50 of less than 250 nanomolar.
  • PC3 cells were seeded on 6-well plates at 150,000 cells/well. Cells were cultured for 3 days, then treated with compounds in serum-free medium for 3 hr. EGF (100 ng/ml) was added for the last 10 min. Cells were lysed in TENN buffer. Phospho T308 Akt and total Akt were quantified by ELISA performed according to the Biosource assay protocol. The readings of phospho Akt were normalized to total Akt readings.
  • PC3 cells were seeded on 96-well plates at 8,000 cells/well. For each experiment, cells were seeded and treated in duplicated plates: one plate for phospho S6 CellELISA, and one plate for total S6 CellELISA. Cells were cultured on the plates for 3 days, then treated with compounds in serum-free medium for 3 hr in triplicate. Cells were fixed with 4% formaldehyde, quenched with 0.6% H 2 O 2 , blocked with 5% BSA, incubated with either phospho S6 antibody or total S6 antibody overnight, incubated with goat-anti-rabbit-IgG-HRP for 1 hr, and developed in chemiluminescent substrate.
  • MCF-7 cells grown in 10-cm dishes were starved for 3 hours in DMEM, and then treated with compounds for 20 minutes. In the last 2 minutes of the incubation with the compounds, EGF (100 ng/ml) was added to stimulate the production of PIP3. The medium was aspirated and the cells were scraped with 10% trichloroacetic acid. The lipids were extracted from the pellet after the cell lysates were centrifuged. PIP3 in the cellular lipid extraction was quantified with the AlpbaScreen assay in which Grp1-PH is used as the PIP3 specific probe. The amount of cellular PIP3 was calculated from the standard curve of diC 8 PI (3,4,5) P3.
  • the invention provides a compound of Formula VIIIa where X is —N(R 5 )—, R 5 is hydrogen, and all other groups are as defined above for a compound of Formula VIIIa.
  • the invention provides a compound of Formula VIIIa where A is aryl or heteroaryl where the aryl and the heteroaryl are optionally substituted with (R 2 ) n1 where n1 is 1, 2, 3, 4, or 5; B is aryl or heteroaryl where the aryl and the heteroaryl are optionally substituted with (R 3 ) n2 where n2 is 1, 2, 3, 4, or 5; and all other groups are as defined above for a compound of Formula VIIIa.
  • the invention provides a compound of Formula VIIIa where W 1 , W 2 , W 3 , and W 4 are —C(R 1 )‘ where each R 1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or nitro; and all other groups are as defined in the Summary of the Invention.
  • W 1 and W 4 are —CH— and W 2 and W 3 are —C(R 1 )— where each R 1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or nitro.
  • W 1 and W 4 are —CH— and W 2 and W 3 are —C(R 1 )— where each R 1 is independently hydrogen, methyl, methoxy, or nitro. In another embodiment, W 1 , W 2 , W 3 , and W 4 are —CH—.
  • the invention provides a compound of Formula VIIIb:
  • the invention provides a compound according to Embodiment B, wherein R 1 is hydrogen, —NO 2 , C 1 -C 4 alkoxy, or C 1 -C 3 alkyl.
  • R 1 is hydrogen, —NO 2 , C 1 -C 4 alkoxy, or C 1 -C 3 alkyl.
  • one or two R 1 are hydrogen, methoxy, or methyl and the remaining R 1 are hydrogen.
  • each R 1 is hydrogen.
  • the invention provides a compound according to Embodiment B wherein n1 is 1 or 2 and each R 2 is independently halo, —OR 6 (where R 6 is hydrogen or alkyl), —N(R 7 )—C(O)—C 0 -C 6 alkyl-N(R 7b )R 7a (where R 7 , R 7a , and R 7b are independently hydrogen or C 1 -C 6 -alkanyl), or —C 0 -C 6 alkyl-C(O)R 6 (where R 6 is C 1 -C 6 -alkanyl).
  • each R 2 is independently chloro, bromo, fluoro, hydroxy, methoxy, —N(H)C(O)—CH 2 —N(CH 3 ) 2 , —C(O)CH 3 , or methyl.
  • each R 2 is independently hydrogen, methoxy, or chloro.
  • the invention provides a compound according to Embodiment B wherein n2 is 1 or 2 and each R 3 is independently C 1 -C 6 -alkanyl, C 1 -C 6 -alkenyl, halo, —C 0 -C 6 -alkyl-N(R 7 )C(O)—C 0 -C 6 -alkyl-N(R 7b )R 7a , —C 0 -C 6 -alkyl-N(R 7 )C(O)—C 0 -C 6 -alkyl-N(R 7b )—C 0 -C 6 -alkyl-N(R 7c )(R 7a ), —C 0 -C 6 -alkyl-N(R 7 )C(O)—C 0 -C 6 -alkyl-(R 7a ), —C 0 -C 6 -alkyl-N(R 7 )C(O)—C
  • n2 is 1 and R 3 is C 1 -C 6 -alkanyl, halo, —N(R 7 )C(O)—C 1 -C 6 -alkyl-N(R 7b )R 7a , —N(R 7 )C(O)—C 0 -C 6 -alkyl-N(R 7b )—C 1 -C 6 -alkyl-N(R 7c )(R 7a ), —N(R 7 )C(O)—C 0 -C 6 -alkyl-(R 7a ), —N(R 7 )C(O)—C 0 -C 6 -alkyl-heterocycloalkyl, —N(R 7 )R 7a , or —N(R 7 )C(O)—C 1 -C 6 -alkyl-heteroaryl; where R 7 , R 7a , R 7b
  • n2 is 1 and R 3 is methyl, chloro, —NHC(O)CH 2 NH(CH 3 ), —NHC(O)CH 2 NH(CH 2 CH 3 ), —NHC(O)CH(CH 3 )NH 2 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 N(CH 3 ) 2 , —NHC(O)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , —NHC(O)CH(NH 2 )CH 2 CH 3 , —NHC(O)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH(CH 3 ), —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 NH(CH 3 ), —NHC(O)CH 2 N(CH 3 ) 2 , —NHC(O)CH 2
  • n2 is 1 and R 3 is methyl, —NHC(O)CH 2 NH(CH 3 ), —NHC(O)CH(CH 3 )NH 2 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 N(CH 3 ) 2 , —NHC(O)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , —NHC(O)CH(NH 2 )CH 2 CH 3 , —NHC(O)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , or —NHC(O)CH(CH 3 )NH(CH 3 ).
  • the invention provides a compound of Formula VIIIb where n1 is two; R 2 is selected from —OR 6 (where R 6 is C 1 -C 6 -alkyl) and halo; n2 is 1; R 3 is —C 0 -C 6 alkyl-N(R 7 )C(O)—C 0 -C 6 -alkyl-N(R 7b )R 7a (where R 7 , R 7a , and R 7b are independently hydrogen or —C 1 -C 6 -alkanyl); and n3 is 0.
  • the invention comprises a pharmaceutical composition comprising a PI3K inhibitor of Formula Formula VIII, VIIIa, VIIIb, or IX in combination with a compound of Formula I, Ia, Ic, Id, II, III, IV, or V and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the compound is of Formula VIIIa or VIIIb.
  • the invention provides a method of treating a disease or condition mediated by PI3K and MEK comprising administering to a patient a PI3K compound of Formula VIII, VIIIa, VIIIb, or IX in combination with a MEK compound of Formula I, Ia, Ic, Id, II, III, IV, or V.
  • the PI3K compound is of Formula VIIIa or VIIIb.
  • the MEK Compound is of Formula Ia and the PI3K Compound is of Formula VIIIa.
  • the MEK Compound is of Formula Ia and the PI3K Compound is of Formula VIIIb.
  • the MEK Compound is of Formula V and the PI3K Compound is of Formula VIIIb.
  • the MEK Compound is of Section I, Embodiment G and the PI3K Compound is of VIIIb.
  • the MEK Compound if of Section I, Table 1 and the PI3K compound is of Formula VIII, VIIIa, or VIIIb.
  • Another embodiment of the invention is directed to suitable x-ray quality crystals, and one of ordinary skill in the art would appreciate that they can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of kinases.
  • Such methods may be characterized by the following embodiments: a) introducing into a suitable computer program, information defining a ligand binding domain of a kinase in a conformation (e.g.
  • Such methods may further entail: employing a candidate agent, so-determined to fit spatially into the ligand binding domain, in a biological activity assay for kinase modulation, and determining whether said candidate agent modulates kinase activity in the assay. Such methods may also include administering the candidate agent, determined to modulate kinase activity, to a mammal suffering from a condition treatable by kinase modulation, such as those described above.
  • compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a kinase.
  • a method may be characterized by the following embodiments: a) creating a computer model of a kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket.
  • a substituent “R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • a substituent “R” may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the —NH— in the Formula above), implied hydrogen (for example as in the Formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the Formula above, “X” equals ⁇ CH—) from one of the ring atoms, so long as a stable structure is formed.
  • the “R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • the two “R's” may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
  • “Acyl” means a —C(O)R radical where R is alkyl (i.e., one to ten carbon atoms of a straight, branched, or cyclic configuration, and is saturated or unsaturated) or R is optionally substituted aryl or optionally substituted heteroaryl. One or more carbons in the R residue may be replaced by nitrogen, oxygen or sulfur. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, and pyridinylcarbonyl, and the like. Lower-acyl refers to groups containing one to six carbons.
  • “Acylarnino” means a —NRR′ group where R is acyl, as defined herein, and R′ is hydrogen or alkyl.
  • Alkyl means a (C 1 -C 20 ) linear, branched, or cyclic hydrocarbon group (and combinations thereof, inclusively) and may be saturated or unsaturated.
  • C 6 alkyl may refer to an n-hexyl, iso-hexyl, cyclobutylethyl, and the like.
  • Lower alkyl means an alkyl group of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.
  • a “C 0 ” alkyl (as in “C 0 -C 6 -alkyl”) is a covalent bond.
  • alkyl includes alkanyl, alkenyl, alkynyl, and cycloalkyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like.
  • C 4 alkyl is meant to include n-butyl, sec-butyl, isobutyl, t-butyl, cyclobutyl, isobutenyl and but-2-ynyl groups; and for example, “C 3 alkyl” each include n-propyl, propenyl, and isopropyl.
  • Alkanyl means a linear saturated monovalent hydrocarbon radical of one to twenty carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 20 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.
  • “Lower alkanyl” means alkanyl having one to six carbons atoms.
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having three to thirteen carbon atoms.
  • the cycloalkyl can be saturated or partially unsaturated, but cannot contain an aromatic ring. Cycloalkyl includes fused, bridged, and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cycloalkylalkyl means alkyl group substituted with one or two cycloalkyl group(s), as defined herein. Representative examples include cyclopropylmethyl and 2-cyclobutyl-ethyl, and the like.
  • Optionally substituted cycloalkyl means a cycloalkyl radical, as defined herein, that is optionally substituted with one, two, three, or four groups independently selected from C 1 -C 6 alkanyl, C 1 -C 6 alkoxy, halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, carb
  • Alkenyl means a straight or branched hydrocarbon radical having from 2 to 20 carbon atoms and at least one double bond and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. “Lower alkenyl” is alkenyl having 2-6 carbon atoms.
  • Alkynyl means a straight or branched hydrocarbon radical having from 2 to 20 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like. “Lower alkynyl” is alkynyl having 2-6 carbon atoms.
  • Alkylene refers to straight or branched divalent hydrocarbon, containing no unsaturation and having from one to ten carbon atoms. Examples of alkylene include methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), and dimethylpropylene (—CH 2 C(CH 3 ) 2 CH 2 —), and the like.
  • Alkylidyne or “alkynylene” means a straight or branched divalent hydrocarbon having from two to ten carbon atoms, and containing at least one triple bond, for example, propylid-2-ynyl, n-butylid-1-ynyl, and the like.
  • Alkoxy or “alkoxyl” means —O-alkyl, where the alkyl group includes from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include metboxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
  • Alkylamino means a —NHR radical where R is alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, and the like.
  • Alkylaminoalkyl means an alkyl group substituted with one or two alkylamino groups, as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenyl, naphthyl, and indanyl, and the like.
  • Optionally substituted aryl means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyi, optionally substituted heteroaryl, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or heterocyclyl), and —NHS(O) 2 R′ (where R′ is alkyl, aryl, or heteroaryl).
  • Arylalkyl means a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. “Lower arylalkyl” refers to an arylalkyl where the “alkyl” portion of the group has one to six carbons; this can also be referred to as C 1-6 arylalkyl.
  • C 1 -C 6 alkyl-aryl or “C 0 -C 6 alkyl-aryl”
  • an aryl moiety is attached to a parent structure via an alkylene group. Examples include benzyl, phenethyl, and the like.
  • Arylalkyloxy means an —OR group where R is arylalkyl, as defined herein.
  • Carboxy ester means a —C(O)OR group where R is lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which is defined herein. Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like.
  • Dialkylamino means a —NRR′ radical where R and R′ are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylami no, diethylamino, N,N-methylpropylamino or N,N-methylethylamino, and the like.
  • fused-polycyclic or “fused ring system” refers to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.
  • Haloaloxy means an —OR′ group where R′ is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
  • Halogen or “halo” means fluoro, chloro, bromo or iodo.
  • Haloalkyl and haloaryl mean an alkyl and an aryl group, respectively, that are substituted with one or more halogens, preferably one to five halo atoms.
  • haloaryl dihaloaryl
  • dihaloalkyl dihaloalkyl
  • trihaloaryl etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • Heteroatom refers to O, S, N, or P.
  • Heterocyclyl refers to a stable three- to fifteen-membered ring substituent that consists of carbon atoms and from one to five beteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclyl substituent may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems.
  • the terms “heterocycloalkyl” and “heteroaryl” are groups that are encompassed by the broader term “heterocyclyl.”
  • the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl group may be optionally oxidized to various oxidation states.
  • the group —S(O) 0-2 — refers to —S— (sulfide), —S(O)— (sulfoxide), and —SO 2 — (sulfone).
  • nitrogens particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding N-oxide form, although not explicitly defined as such in a particular example.
  • annular nitrogen atoms may be optionally quatemized; and the ring substituent may be partially or fully saturated or aromatic.
  • heterocyclyl groups include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl
  • Optionally substituted heterocyclyl means a heterocyclyl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo (valency rules permitting), lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or heterocyclyl), amino, alkylamino, dialkylamino, and
  • Heteroalicyclic and “heterocycloalkyl” mean a non-aromatic heterocyclyl group, as defined herein.
  • a “heteroalicyclic” or “heterocycloalkyl” may be fully saturated or may contain unsaturation, but is not aromatic.
  • Heteroalicyclic” or “heterocycloalkyl” may be monocyclic or bicyclic (including fused, bridged, and spiro ring systems).
  • Optionally substituted heteroalicyclic and “optionally substituted heterocycloalkyl” mean, respectively, a heteroalicyclic and heterocycloalkyl ring, each as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or beterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or betero
  • Heteroaryl means a 5- to 12-membered, monocyclic aromatic heterocyclyl (where heterocyclyl is defined herein) or bicyclic heterocyclyl ring system (where at least one of the rings in the bicyclic system is aromatic) where the monocyclic ring and at least one of the rings in the bicyclic ring system contains one, two, three, four, or five heteroatom(s) selected from nitrogen, oxygen, phosphorous, and sulfur.
  • Representative examples include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quin
  • Optionally substituted heteroaryl means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, —C(O)NR′R′′ (where R′ is hydrogen or alkyl and R′′ is hydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R′′ (where R′ is hydrogen or alkyl and R′′ is alkyl, aryl, or heterocyclyl), and —NHS(O) 2 R′ (where R′ is alkyl, aryl, or hetero
  • Optionally substituted heterocyclylalkyl means an alkyl group substituted with an optionally substituted heterocyclyl group, as defined herein. Examples include (4-methylpiperazin-1-yl)methyl, (morpholin-4-yl)methyl, (pyridin-4-yl)methyl, 2-(oxazolin-2-yl)ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like.
  • the alkyl portion of a heterocyclylalkyl group may be substituted as described in the definition for “substituted”.
  • “Lower heterocyclylalkyl” means a heterocyclylalkyl where the “alkyl” portion of the group has one to six carbons.
  • Heteroalicyclylalkyl or “lower heterocycloalkylalkyl” means a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and “heteroarylalkyl” means a heterocyclylalkyl where the heterocyclyl portion of the group contains an aromatic ring. Such terms may be described in more than one way, for example, “lower heterocyclylalkyl” and “heterocyclyl C 1-6 alkyl” are equivalent terms.
  • C x -C y the number of annular atoms (including heteroatoms) in a heterocycle
  • x and y are integers.
  • C 5 -C 14 -heterocyclyl refers to a 5 to 14 membered ring system having at least one heteroatom and not a ring system containing 5 to 14 annular carbon atoms.
  • Hydroalkyl means an alkanyl, alkenyl, or alkynyl radical, as defined herein, substituted with at least one, preferably one, two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-bydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl, and the like.
  • “Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class “saturated bridged ring system.”
  • “Spirocyclyl” or “spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B′), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • “Substituted” alkyl, alkylene, alkylidene, and alkylidyne refer respectively to alkyl, alkylene, alkylidene, and alkylidyne where one or more (for example up to about five, in another example, up to about three) hydrogen atoms are replaced by a substituent independently selected from halo, optionally substituted aryl, hydroxy, alkoxy, optionally substituted heterocyclyl, alkylenedioxy, amino, alkylamino, dialkylamino), amidino, aryloxy, arylalkyloxy, carboxy, carboxy ester, alkylcarbonyloxy, carbamyl, alkylaminocarbonyl, dialkylaminocarbonyl, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, nitro, S(O) n1 R′ (where n1 is 0, 1, or 2 and R′ is alkyl, substituted alkyl
  • “Sulfonamido” means a —NRSO 2 R′ or —SO 2 NRR′′ group where R is hydrogen or lower alkyl, R′ is lower alkanyl, lower alkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, and R′′ is hydrogen or R′.
  • the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 8 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 4 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 3 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 2 ⁇ M or less.
  • the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 1.5 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 1 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.750 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.5 ⁇ M or less.
  • the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.3 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.2 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.1 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.075 ⁇ M or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table I having a PI3K-binding affinity of about 0.050 ⁇ M or less.
  • 6-chloropyridine-3-sulfonamide 6-chloropyridine-3-sulfonyl chloride (4.1 g, 19.3 mmol) was stirred in ammonium hydroxide (30 mL) at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (150 mL) and any insoluble material filtered. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous phase was further extracted with EtOAc (1 ⁇ 15 mL).
  • 6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide 2,3-dichloroquinoxaline (1.09 g, 5.48 mmol), 6-chloropyridine-3-sulfonamide (1.05 g, 5.45 mmol), K 2 CO 3 (753 mg, 5.45 mmol) and dry DMSO (30 mL) were combined and heated to 150 C with vigorous stirring for 3-4 hr. The reaction mixture was allowed to cool to room temperature, then poured into 1% AcOH in ice water (300 mL) with vigorous stirring.
  • 6-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide 6-Chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (775 mg, 2.2 mmol), 3,5-dimethoxyaniline (355 mg, 2.3 mmol) and toluene (12 mL) were combined and heated to 125 C with stirring overnight. The reaction was allowed to cool to room temperature and diluted with Et 2 O with vigorous stirring.
  • N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide 100 mg, 0.21 mmol
  • KHCO 3 40 mg, 0.40 mmol
  • N 1 ,N 1 -dimethylethane-1,2-diamine 225 ⁇ l, 2.0 mmol
  • dry DMF 1.0 mL
  • N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide 100 mg, 0.21 mmol
  • 2-(dimethylamino)ethanol 50 ⁇ l, 0.50 mmol
  • dry DMF 60% NaH in oil
  • the reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethoxy)pyridine-3-sulfonamide (23 mg, 21%).
  • N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (220 mg, 0.47 mmol), DMSO (5 mL), and 3N NaOH (5 mL) are combined and heated to 100 C overnight with stirring. Upon cooling to room temperature, the reaction mixture was diluted with H 2 0 and the pH was adjusted to 7.0 with 1N HCl. The resulting solid was filtered, washed with H 2 0, and air-dried.
  • the reaction was stirred for 15 min before N,N-dimethylethane-1,2-diamine (73 mg, 0.83 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL), 1.0 N aqueous hydrochloric acid (30 mL), and saturated aqueous sodium chloride (25 mL).
  • N-(3-(3-methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (700 mg, 1.92 mmol), 3-methoxy-5-nitroaniline (645 mg, 3.84 mmol) and p-xylene (7 mL) were combined and heated to 140° C., then stirred for 16 hours at 130° C. The reaction was allowed to cool, placed in a sep funnel, diluted with DCM, and washed with 2M HCl and brine and concentrated in vacuo.
  • N-(3-(3-Methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide 400 mg, 0.81 mmol was dissolved in 1:1 THF:EtOH (4 mL), to which was added formic acid (938 ⁇ l, 2.42 mmol) and potassium formate (203 mg, 2.42 mmol). The system was flushed with nitrogen, and then 10% wt Pd/C (50 mg) was added. The reaction was then heated to 60° C.
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CA2658725A1 (fr) 2008-02-21
EP2056829B1 (fr) 2012-01-04
JP2016074743A (ja) 2016-05-12
WO2008021389A2 (fr) 2008-02-21
EP2056829B9 (fr) 2012-09-26
US20140100215A1 (en) 2014-04-10
WO2008021389A3 (fr) 2008-07-17
JP2017226702A (ja) 2017-12-28
CN101528231A (zh) 2009-09-09
US8642584B2 (en) 2014-02-04
EP2056829A2 (fr) 2009-05-13
HK1130438A1 (en) 2009-12-31
JP2010500994A (ja) 2010-01-14
CN104784695A (zh) 2015-07-22
US20120302545A1 (en) 2012-11-29
WO2008021389A8 (fr) 2009-03-12
AU2007284562B2 (en) 2013-05-02
JP2014122243A (ja) 2014-07-03
ATE539752T1 (de) 2012-01-15
JP2013151570A (ja) 2013-08-08
AU2007284562A1 (en) 2008-02-21

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