WO2008124085A2 - Méthodes d'utilisation de combinaisons d'inhibiteurs de mek et de jak-2 - Google Patents

Méthodes d'utilisation de combinaisons d'inhibiteurs de mek et de jak-2 Download PDF

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WO2008124085A2
WO2008124085A2 PCT/US2008/004434 US2008004434W WO2008124085A2 WO 2008124085 A2 WO2008124085 A2 WO 2008124085A2 US 2008004434 W US2008004434 W US 2008004434W WO 2008124085 A2 WO2008124085 A2 WO 2008124085A2
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phenyl
amino
pyrimidin
carbonyl
fluoro
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PCT/US2008/004434
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WO2008124085A3 (fr
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Peter Lamb
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Exelixis, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to methods of using certain inhibitors of MEK in combination with certain inhibitors of JAK-2 for the treatment of diseases in mammals, especially humans.
  • 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.
  • 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).
  • Tyrosine 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 (HERl), 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-I 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, AbI, 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, BIk, Hck, Fgr, and Yrk.
  • the Src subfamily of enzymes has been linked to oncogenesis.
  • kinase modulation relates to oncological indications.
  • modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatinib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, NJ) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma capcers.
  • Gleevec is a selective AbI kinase inhibitor.
  • Modulation (particularly inhibition) of cell proliferation and angiogenesis, two cellular processes needed for tumor growth and survival, is an attractive goal for development of small-molecule drugs.
  • Anti-angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis.
  • Cell antiproliferative agents are also desirable to slow or stop the growth of tumors.
  • MEK Another target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is MEK.
  • Inhibition of MEKl is a promising strategy to control the growth of tumors that are dependent on aberrant ERK/MAPK pathway signaling.
  • 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 an effector of Ras function.
  • the ERK/MAPK pathway is upregulated in 30% of all tumors and oncogenic activating mutations in K-Ras and B-Raf have been identified in 22% and 18% of all cancers respectively (Allen et al., 2003; Bamford S, 2004; Davies et al., 2002; Malumbres and Barbacid, 2003).
  • a large portion of human cancers including 66% (B-Raf) of malignant melanomas, 60% (K-Ras) and 4% (B-Raf) of pancreatic cancers, 50% of colorectal cancers (colon, in particular, K-Ras: 30%, B-Raf: 15%), 20% (K-Ras) of lung cancers, 27% (B-Raf) papillary and anaplastic thyroid cancer, and 10-20% (B-Raf) of endometriod ovarian cancers, harbor activating Ras and Raf mutations.
  • MEK-ERK signal transduction pathway is an appropriate pathway to target for therapeutic intervention.
  • Binding of growth factors and cytokines to their cell surface receptors results in activation of intracellular signaling pathways which control cell proliferation, survival and differentiation.
  • Key components of these pathways are protein kinases, which phosphorylate tyrosine, serine or threonine residues and thereby modulate the activity of substrate proteins.
  • Two major signaling pathways which emanate from growth factor and cytokine receptors are the Ras/raf/MEK/Erk and the JAK/STAT pathways.
  • Activation of the small GTPase Ras leads to activation of a cascade of serine / threonine kinases which initiates with Raf and, via activation of MEK, results in stimulation of ERK activity and phosphorylation of numerous substrates that control cellular proliferation and differentiation.
  • Activation of members of the JAK family of cytoplasmic tyrosine kinases results in phosphorylation of members of the STAT family of inducible transcription factors.
  • Phosphorylation of a key regulatory tyrosine residue in STAT proteins by JAKs results in their dimerization, translocation to the nucleus and binding to specific DNA sequences in the promoters and enhancers of regulated genes.
  • the DNA-bound STATs serve to promote the transcription of these genes, many of which are involved in the control of cellular growth.
  • the Ras/Raf/MEK/ERK and JAK/STAT pathways intersect at the levels of the STAT proteins.
  • the STATs are substrates for ERK kinases and are phosphorylated by ERKs in their C-terminal transcriptional activation domain. Phosphorylation at this site is required for efficient transcriptional activation by STAT proteins.
  • Constitutive STAT activation is a feature of a wide variety of human tumors.
  • activation of STAT5 is observed in leukemias, including CML, AML and ALL
  • activation of STAT3 is a common feature of solid tumors including prostate carcinoma, non-small cell lung carcinoma and head and neck tumors.
  • Reduction of STAT3 or STAT5 levels results in a reduction in tumor cell growth and in some case induction of tumor cell apoptosis in preclinical models. It is therefore desirable to develop strategies for pharmacologically inhibiting STAT activity in tumor cells as a method for treating cancers.
  • the methods of the invention involve simultaneous inhibition of both tyrosine and serine phosphorylation of STATs which is intended to maximally inhibit STAT activity thereby providing maximal opportunity to achieve therapeutic benefit in patients whose tumors have activated STATs.
  • the invention relates to a method of treating a disease, such as cancer, comprising administering to a mammal, including humans, a therapeutically effective amount of a MEK inhibitor of Formula I(M) or Formula 1(N) as defined below, or a pharmaceutical composition comprising a therapeutically effective amount of the MEK compound of Formula I(M) or Formula 1(N) and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a JAK-2 inhibitor, as defined below, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 inhibitor and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment.
  • a disease such as cancer
  • the invention in another aspect, relates to a method of treating a disease, such as cancer, comprising administering to a mammal, including humans, a therapeutically effective amount of a JAK-2 compound of Formula I(J), as defined below, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J) and a pharmaceutically acceptable carrier, in combination with a MEK inhibitor, as defined below, or a pharmaceutical composition comprising a therapeutically effective amount of the MEK inhibitor and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment.
  • a disease such as cancer
  • the invention relates to a method of treating a disease, such as cancer, comprising administering to a mammal, including humans, a therapeutically effective amount of a JAK-2 compound of Formula I(J), as defined below, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound and a pharmaceutically acceptable carrier, in combination with a MEK compound of Formula I(M) or Formula 1(N) as defined below, or a pharmaceutical composition comprising a therapeutically effective amount of the MEK compound of Formula I(M) or Formula 1(N) and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment.
  • a disease such as cancer
  • MEK COMPOUNDS The MEK compounds regulate and/or modulate the signal transduction of MEK and are azetidin-l-yl(2-(2-fluorophenylamino)cyclic)methanones derivatives.
  • the MEK compounds described below are non-limiting examples of "MEK inhibitors" defined hereinabove. These MEK compounds are described in a separate section from the JAK-2 compounds. All of the substituents for the MEK compounds described below are defined separately from the JAK-2 compounds so that every substituent in the MEK compounds that also appears in the JAK-2 compounds has a separate and distinct definition for each of these two compounds. For instance, R 1 for the JAK-2 compounds has a separate and distinct definition from R 1 for the MEK compounds. [0022] In one aspect, the MEK compound is of Formula 1(N):
  • A is arylene optionally substituted with one, two, three or four groups selected from R 10 , R 12 , R 14 , and R 16 , wherein R 10 , R 12 , R 14 and R 16 are independently hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, 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' ;
  • X is alkyl, halo, haloalkyl, or haloalkoxy;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently hydrogen, halo, nitro, -NR 8 R 8' , -OR 8 ,
  • R 7 is hydrogen, halo or alkyl
  • R 8 , R 8 and R 8 are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxycarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted ary
  • R 34 is hydrogen or alkyl and R 34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), -SO 2 NR 35 R 353 (wherein R 35 is hydrogen or alkyl and R 35a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), -NR 32 C(O)R 32a
  • R 32 is hydrogen or alkyl and R 32a is alkyl, alkenyl, alkoxy, or cycloalkyl
  • -NR 30 R 30' wherein R 30 and R 30' are independently hydrogen, alkyl, or hydroxyalkyl
  • -C(O)NR 33 R 33a wherein R 33 is hydrogen or alkyl and R 33a is alkyl, alkenyl, alkynyl, or cycloalkyl
  • R 9 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally susbstituted with one, two, three, four, or five groups selected from halo, hydroxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamin
  • A is heteroarylene optionally substituted with one, two, three, or four groups selected from R 10 , R 12 , R 14 , R 16 and R 19 , wherein R 10 , R 12 , R 14 and R 16 are independently hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkylsulfonylamino, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or alkylcarbonylamino; wherein R 19 is hydrogen, alkyl, or alkenyl; and wherein each alkyl and alkenyl, either alone or as part of another group within R 10 ,
  • R 12 , R 14 , R 16 , and R 19 is independently optionally substituted with halo, hydroxy, or alkoxy;
  • X is alkyl, halo, haloalkyl, or haloalkoxy
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently hydrogen, 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' ,
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, 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 1Oa is hydrogen, alkyl, or alkenyl;
  • X is alkyl, halo, haloalkyl, or haloalkoxy;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently hydrogen, halo, nitro, -NR 8 R 8' , -OR 8 ,
  • R 7 is hydrogen, halo or alkyl
  • R 8 , R 8 and R 8" are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, -S(O) n R 31 (wherein n is 0, 1, or 2 and R 31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted hetero
  • R 36 is hydrogen, alkyl, or alkenyl and R 36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
  • -S(O) 2 NR 37 R 37a wherein R 37 is hydrogen, alkyl, or alkenyl and R 37a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
  • R 40 and R 4Oa are independently hydrogen or alkyl;
  • X is alkyl, halo, haloalkyl, or haloalkoxy;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently hydrogen, halo, nitro, -NR 8 R 8' , -OR 8 ,
  • R 7 is hydrogen, halo or alkyl
  • R 8 , R 8 and R 8 - are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, -S(O) n R 31 (wherein n is O, 1, or 2 and R 31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substitute
  • R 36 is hydrogen, alkyl, or alkenyl and R 36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
  • -S(O) 2 NR 37 R 37a wherein R 37 is hydrogen, alkyl, or alkenyl and R 37a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
  • A is phenylene optionally substituted with one or two groups selected from R 10 , R 12 , R 14 , and R 16 wherein R 10 , R 12 , R 14 and R 16 are independently hydrogen or halo; X is halo;
  • R 1 , R 2 , R 5 and R 6 are hydrogen;
  • R 3 is hydrogen, halo, hydroxy, alkoxy, or amino;
  • alkyl alkenyl, cycloalkyl, heterocycloalkyl, or heteroaryl; wherein the alkyl is optionally substituted with one, two, or three groups independently selected from -OR 8 , halo, nitro, -S(O) m R 9 , optionally substituted heterocycloalkyl, -NR 8 R 8' , -NR 8 C(O)R 8' ,
  • cycloalkyl is optionally substituted with one or two groups selected from -OR 8 and -NR 8 R 8 ; wherein the heterocycloalkyl is optionally substituted with one or two groups independently selected from alkyl and -C(O)OR 8 ; and wherein the heteroaryl is optionally substituted with -NR 8 R 8' ; or
  • R 34 is hydrogen or alkyl and R 34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl
  • R and R cycloalkyl are independently optionally substituted with one, two, or three groups indendently selected from hydroxy, hydroxyalkyl, alkoxy, carboxy, -C(O)NR 33 R 333
  • R 33 is hydrogen or alkyl and R 33a is alkyl, alkenyl, alkynyl, or cycloalkyl), and optionally substituted cycloalkyl; and
  • R 9 is alkyl or aryl
  • A is thien-3,4-diyl, benzo[ ⁇ /
  • R 1 , R 2 , R 5 and R 6 are hydrogen; R 3 is hydrogen or hydroxy; R 4 is -NR 8 R 8 , heterocycloalkyl, heteroaryl, or alkyl; wherein the alkyl is optionally substituted with -NR 8 R 8 and wherein the heteroaryl is optionaly substituted with alkyl; R 7 is halo;
  • R 8 is hydrogen or alkyl; and R 8 is hydrogen, alkyl, or cycloalkyl; wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl;
  • R 10 is hydrogen or halo;
  • R 1Oa is hydrogen or alkyl;
  • X is halo;
  • R 1 , R 2 , R 5 and R 6 are hydrogen;
  • R is hydrogen or hydroxy;
  • R is -NR 8 R 8 , heterocycloalkyl, heteroaryl, or alkyl; wherein the alkyl is optionally substituted with -NR 8 R 8 and wherein the heteroaryl is optionaly substituted with alkyl; R 7 is halo; R is hydrogen or alkyl; and
  • R is hydrogen, alkyl, or cycloalkyl; wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl.
  • the MEK compounds can also be used as a pharmaceutical composition which comprises a compound of Formula I(M), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • 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.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • 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 specific embodiment the patient is a mammal, and in a more specific 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 wherein 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).
  • 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
  • “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), pancre
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are nontoxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.
  • Examples of pharmaceutically acceptable acid addition salts include those 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, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 2-
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferable 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.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, iV-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • 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” ⁇ .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.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i. e. , causing regression of the disease, disorder, or syndrome.
  • “Mammal” is intended to mean any various warm-blooded vertebrate animals of the class Mammalia, including humans, dogs, cats, and the like, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • MEK inhibitors are intended to include all MEK inhibitors including the MEK compounds of Formulae I(M) and 1(N) defined hereinbelow.
  • MEK inhibitors, including the MEK compounds include pharmaceutically acceptable salts or solvates throughout this application whether it is explicitly stated or not.
  • JAK-2 inhibitors are intended to include all JAK-2 inhibitors including the JAK-2 compounds of Formula I( J) defined hereinbelow. JAK-2 inhibitors, including the JAK-2 compounds, include pharmaceutically acceptable salts or solvates throughout this application whether it is explicitly stated or not.
  • R 7 is halo and all other substituents are as defined in the above for the compound of Formula I(M) or Formula 1(N) for Group A, Group B, Group C, or Group D.
  • R 7 is iodo or bromo.
  • R 7 is iodo.
  • the MEK compound is that wherein R 7 is iodo or bromo and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A.
  • X is halo and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A, Group B, Group C, or Group D.
  • X is fluoro or chloro.
  • X is fluoro.
  • the MEK compound is that wherein X is fluoro or chloro and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A.
  • R 7 and X are halo and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A, Group B, Group C, or Group D. More specifcally, R 7 is iodo and X is fluoro. Even more specifically, the MEK compound is that wherein R 7 is iodo and X is fluoro and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A.
  • R 1 , R 2 , R 5 , and R 6 are hydrogen and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A, Group B, Group C, or Group D. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A.
  • the substituents of Formula I are as defined in Group A in the compound of Formula I(M) or Formula 1(N).
  • X and R 7 are halo and all other substituents are as defined in Group A in the compound of Formula I(M) or Formula 1(N).
  • the substituents for the compound of Formula I(M) or Formula 1(N) are as defined in Group A, wherein R 10 and R are independently hydrogen or halo.
  • R 10 and R 12 are independently hydrogen or fluoro. More specifically, R 10 is 3-fluoro and R 12 is hydrogen.
  • R 10 and R 12 are fluoro, more specifically, 3-fluoro and 4-fluoro, 4-fluoro and 5-fluoro, or 4-fiuoro and 6-fluoro.
  • the compound is that wherein R 1 , R 2 , R 5 and R 6 are hydrogen and all other substituents are as defined in the compound of Formula I(M) or Formula 1(N) for Group A.
  • the compound of Formula I(M) or Formula 1(N) is as defined in Group A, wherein X, R 7 , and A are as defined in the compound of Formula I(M) or Formula 1(N); and one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 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)OR 8' , -NR 8 C(O)NR 8 R 8" , -NR 8 C(O)OR 8' , -NR 8 C(O)R 8' , -CH 2 N(R 25 .
  • -CH 2 NR 25 C(NR 25a R 25b ) CH(NO 2 ), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 , -NR 8 R 8' , -NR 8 S(O) 2 R 9 , -CN, -S(O) 01 R 9 , -C(O)R 8 , -C(O)
  • the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein X, R 7 , and A are as defined in the compound of Formula I(M) or Formula 1(N); and
  • 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' , -CH 2 N(R 25 )(NR 25a R 25b ),
  • -CH 2 NR 25 C(NR 25a R 25b ) CH(NO 2 ), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 , -NR 8 R 8' , -NR 8 S(O) 2 R 9 , -CN, -S(O) 01 R 9 , -C(O)R 8 , -C(O)
  • R 4 is as defined in the compound of Formula I(M) or Formula 1(N); or R 3 and R 4 , together with the carbon to which they are attached, form -C(O) or -
  • R 1 , R 2 , R 5 and R 6 are as defined in the the compound of Formula I(M) or Formula 1(N).
  • a more specific embodiment of embodiment A5 is that wherein R 1 , R 2 , R 5 and R 6 are hydrogen.
  • the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein X, R 7 , and A are as defined in the compound of Formula I(M) or Formula 1(N); and
  • -CH 2 NR 25 C(NR 25a R 25b ) CH(NO 2 ), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 , -NR 8 R 8' , -NR 8 S(O) 2 R 9 , -CN, -S(O) m R 9 , -C(O)R 8 , -C(O
  • the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein X and R 7 are halo; A is phenylene optionally substituted with R 10 and R 12 , wherein R 10 and R 12 are independently hydrogen or halo; R 1 , R 2 , R 5 and R 6 are hydrogen; R 3 is hydrogen and R 4 is -NR 8 R 8 (wherein R 8 is hydrogen, hydroxy, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl and R 8 is hydroxy, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl), -NHS(O) 2 R 8 , -CN, -S(O) m R 8 ,
  • alkenyl and alkynyl are optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 , -NR 8 R 8' , -NR 8 S(O) 2 R 9 , -CN, -S(O) m R 9 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 8 R 8' , -NR 8 C(O)NR
  • R 8 and R 8 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group A.
  • the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein R 3 is hydrogen, halo, hydroxy, alkoxy, or amino. More specifically, R 3 is hydrogen, fluoro, hydroxy, methoxy, or amino. Even more specifically, R 3 is hydrogen or hydroxy. Yet even more specifically, R 3 is hydroxy.
  • X and R 7 are halo;
  • A is phenylene optionally substituted with R 10 and R 12 , wherein 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 the compound of Formula I(M) or Formula 1(N) for a compound of Group A.
  • Another specific embodiment of the MEK compound (A9) is that wherein the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein 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 , wherein R 8 and R 8 and all other groups are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group A.
  • R 4 is alkyl substituted with -NR 8 R 8 , wherein R 8 and R 8 and all other groups are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group A.
  • the compound is of Formula I(a) or I(b):
  • R 3 is as defined in A9; X 5 R 7 , R 8 , R 8' , R 10 , R 12 , R 14 , and R 16 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group A.
  • R 4 is heterocycloalkyl.
  • the compound is that wherein X and R 7 are halo; A is phenylene optionally substituted with R 10 and R 12 , wherein R 10 and R 12 are independently hydrogen or halo; R 3 is hydroxy; and 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, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, -OR 8 , -NR 8 R 8' , -NR 8 S(O) 2 R 9 , -CN, -S(O)JR 9 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 8 R 8' , -NR
  • alkyl substituted with -S(O) m R 9 (wherein m is O and R 9 is aryl); m) alkyl substituted with optionally substituted heterocycloalkyl; n) alkenyl; o) -NR 8 R 8 (wherein R 8 and R 8 are independently hydrogen; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with one or two -NR 30 R 30 , wherein R 30 and R 30 are independently hydrogen, alkyl, or hydroxyalkyl; alkyl substituted with optionally substituted heteroaryl; or alkyl substituted with optionally substituted cycloalkyl); p) -C(O)NR 8 R 8' (wherein R 8 is hydrogen, alkyl, or alkenyl; and R 8' is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with optionally substituted heterocycloalkyl; alky
  • R 33 is hydrogen or alkyl and R 33a is alkyl, alkenyl, alkynyl, or cycloalkyl; cycloalkyl substituted with optionally substituted cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted with alkyl; heterocycloalkyl substituted with alkoxycarbonyl; heterocycloalkyl substituted with optionally substituted arylalkyl; heterocycloalkyl substituted with one or two hydroxy; heterocycloalkyl substituted with one or two alkoxy; heterocycloalkyl substituted with one or two hydroxyalkyl; heterocycloalkyl substituted with one or two hydroxy, one or two alkoxy, and one or two hydroxyalkyl; alkyl substituted with optionally substituted aryloxy; alkyl substituted with -S(O) n R 31 , wherein n is 0 and R 31 is alkyl
  • R 9 is alkyl or alkenyl; dd) alkyl substituted with -NR 8 C(O)OR 8' , wherein R 8 and R 8' are independently hydrogen, alkyl, or alkenyl; ee) alkyl substituted with one aryl and one -NR R , wherein R and R are independently hydrogen, alkyl, or alkenyl; or ff) alkyl substituted with one or two -OR 8 (wherein R 8 is hydrogen) and one or two -NR 8 R 8 wherein R 8 and R 8 are independently hydrogen, alkyl, or alkenyl.
  • a more specific embodiment of embodiment AlO is that wherein X and R 7 are halo; A is phenylene optionally substituted with R 10 and R 12 , wherein 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.
  • a more specific embodiment of embodiment AlO is that wherein R 3 is hydrogen and R 4 is a) hydrogen; b) -NR R (wherein R and R are independently hydrogen; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with one or two -NR 30 R 30 , wherein R 30 and R 30 are independently hydrogen, alkyl, or hydroxyalkyl; alkyl substituted with optionally substituted heteroaryl; or alkyl substituted with optionally substituted cycloalkyl); c) -C(O)NR 8 R 8 (wherein R 8 is hydrogen, alkyl, or alkenyl; and R 8 is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with heterocycloalkyl; alkyl substituted with -NR 30 R 30' , wherein R 30 and R 30' are independently hydrogen, alkyl, or hydroxyalkyl; or optionally substituted
  • a more specific embodiment of embodiment AlO is that wherein R 3 is alkoxy and R 4 is alkyl substituted with -NR 8 R 8 (wherein R 8 and R 8 are independently hydrogen, alkyl, or alkenyl). More specifically, R 3 is methoxy and R 4 is alkyl substituted with - NR R (wherein R and R are independently hydrogen, alkyl, or alkenyl). [0070] A more specific embodiment of embodiment AlO is that wherein R 3 is halo and R 4 is alkyl substituted with -NR 8 R 8 (wherein R 8 and R 8 are independently hydrogen, alkyl, or alkenyl).
  • R is fluoro and R is alkyl substituted with -NR R (wherein R 8 and R 8 are independently hydrogen, alkyl, or alkenyl).
  • R 8 and R 8 are independently hydrogen, alkyl, or alkenyl.
  • a more specific embodiment of embodiment Al 0 is that wherein R 3 is amino and R 4 is alkyl substituted with -NR 8 R 8' (wherein R 8 and R 8' are independently hydrogen, alkyl, or alkenyl).
  • R 32 is hydrogen or alkyl and R 32a is alkyl, alkenyl, alkoxy, or cycloalkyl; aryl substituted with -NR 34 SO 2 R 343 wherein R 34 is hydrogen or alkyl and R 34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl substituted with one or two hydroxy; cycloalkyl substituted with one or two hydroxy and one or two hydroxyalkyl; cycloalkyl substituted with one or two alkoxy; cycloalkyl substituted with carboxy; cycloalkyl substituted with -C(O)NR 33 R 333 wherein R 33 is hydrogen or alkyl and R 33a is alkyl, alkenyl, alkynyl, or cycloalkyl; cycloalkyl substituted with optionally substituted
  • R 33a is alkyl, alkenyl, alkynyl, or cycloalkyl; v) heterocycloalkyl; w) heterocycloalkyl substituted with one or two alkyl; x) heterocylcloalkyl substituted with -C(O)OR 8 , wherein R 8 is alkyl or alkenyl; y) heteroaryl; z) heteroaryl optionally substituted with -NR 8 R 8' , wherein R 8 and R 8 are independently hydrogen, alkyl, or alkenyl; aa) alkyl substituted with optionally substituted heteroaryl; bb) alkyl substituted with -NR 8 S(O) 2 R 9 , wherein R 8 is hydrogen, alkyl, or alkenyl and
  • R 9 is alkyl or alkenyl; cc) alkyl substituted with -NR 8 C(O)OR 8' , wherein R 8 and R 8' are independently hydrogen, alkyl, or alkenyl; dd) alkyl substituted with one aryl and one -NR 8 R 8 , wherein R 8 and R 8 are independently hydrogen, alkyl, or alkenyl; or ee) alkyl substituted with one or two -OR (wherein R is hydrogen) and one or two -NR 8 R 8 wherein R 8 and R 8 are independently hydrogen, alkyl, or alkenyl.
  • Another specific embodiment of the MEK compound (A 12) is that wherein the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein X and R 7 are halo; A is phenylene optionally substituted with R 10 and R 12 , wherein R 10 and R 12 are independently hydrogen or halo; and R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen.
  • Another specific embodiment of the MEK compound (A 13) is that wherein the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein A is phenylene.
  • MEK compound (A14) Another specific embodiment of the MEK compound (A14) is that wherein the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein R 1 is hydrogen and R 2 is alkyl substituted with -NR 8 R 8' , wherein R 8 and R 8' and all other groups are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group A.
  • MEK compound (Al 5) Another specific embodiment of the MEK compound (Al 5) is that wherein the compound of Formula I(M) or Formula 1(N) is selected from Group A, wherein A is phenylene; R 7 is iodo or bromo; X is fluoro or chloro; and 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.
  • 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.
  • MEK compound is a compound of Formula I(M) or Formula 1(N) selected form Group A, wherein R 3 is hydroxy and R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR R (wherein R is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 3 is hydroxy and R 4 is heterocycloalkyl or alkyl, wherein the alkyl is optionally substituted with -NR R (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with groups independently selected from hydroxy and alkyl).
  • the compound of Formula I(M) or Formula 1(N) is selected from Group B, wherein all groups are as defined in the compound of Formula I(M) or Formula 1(N).
  • X and R 7 are halo; and all other groups are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. Specifically, X is fluoro or chloro and R 7 is iodo or bromo.
  • R 1 , R 2 , R 5 and R 6 are hydrogen; and X and R 7 are halo.
  • the compound is selected from Group B, wherein R 3 and R 4 are independently halo, nitro, -NR 8 R 8 , -OR 8 , -NHS(O) 2 R 8 , -CN,
  • R 1 , R 2 , R 5 and R 6 are hydrogen; and X and R 7 are halo.
  • A is heteroarylene selected from thien-diyl, benzo[cT]isoxazol-diyl, benzo[cf]isothiazol-diyl, lH-indazol-diyl (optionally substituted at the Nl position with R 19 , wherein R 19 is as defined in the compound of Formula I(M) for a compound of Group B), benzo[ ⁇ T]oxazol-diyl, benzo[ ⁇ f]thiazol-diyl, lH-benzo[d]imidazol-diyl (optionally substituted at the Nl position with R 19 , wherein R 19 is as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B), l//-benzo[fiT][
  • A is selected from thien-3,4-diyl, benzo[c(]isoxazol-5,6-diyl, benzo[c/]isothiazol-5,6-diyl, lH-indazol-5,6-diyl (optionally substituted at the Nl position with R 19 , wherein R 19 is alkyl or alkenyl), benzo[ ⁇ xazol- 5,6-diyl, benzo[d]thiazol-5,6-diyl, lH-benzo[d]imidazol-5,6-diyl (optionally substituted at the Nl position with R 19 , wherein R 19 is alkyl or alkenyl), lH-benzo[tf][l,2,3]triazol- 5,6-diyl (optionally substituted at the Nl position with R 19 , wherein R 19 is alkyl or alkenyl), imidazo[l,2- ⁇ ]pyridin
  • the compound of Formula I(M) or Formula 1(N) is selected from Group B, wherein A is thien-diyl and X, R 1 , R 2 , R , R 4 , R 5 , R 6 , R 7 , R 10 , and R 12 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, A 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 (wherein R 8 and R 8 are independently hydrogen or alkyl), heterocycloalkyl, heteroaryl (optionally substituted with alkyl), or alkyl, wherein the alkyl is optionally substituted with -NR 8 R 8' (wherein R 8 is hydrogen or alkyl and R 8' is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl).
  • the MEK compound (B7) is of Formula I(c) or I(d)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 and R 14 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 , R 12 , and R 14 are independently hydrogen, halo, or alkyl.
  • X is fluoro or chloro and R 7 is iodo or bromo;
  • R 10 is hydrogen or halo, more specifically hydrogen or fluoro;
  • R 12 is hydrogen;
  • R 14 is hydrogen or alkyl; and
  • R 3 is hydroxy.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl wherein the cycloalkyl is optionally substituted with groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, l(/?,5)-amino-ethyl, l(i?)-amino-ethyl, 1 (5)-amino-ethyl, 1 (R, 5 r )-(methylamino)-ethyl, 1 ( ⁇ )-(methylamino)-ethyl, l(iS)-(methylamino)-ethyl, l(/?,5)-(dimethylamino)-ethyl, l(/?)-(dimethylamino)-ethyl, 1 (£)-(dimethylamino)-ethyl, 1 (R, S)-(3 ,4-c/5-dihydroxy-cyclopentylamino)-ethyl,
  • the compound is of Formula I(e) or I(f): wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 and R 14 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 , R 12 , and R 14 are independently hydrogen, halo, or alkyl.
  • X is fluoro or chloro and R 7 is iodo or bromo;
  • R 10 is hydrogen or halo, more specifically hydrogen or fluoro;
  • R 12 and R 14 are hydrogen;
  • R is hydroxy;
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • the compound is of Formula I(g) or l(h):
  • the compound is of formula I(g) or I(h), wherein 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 ,
  • cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 , -NR 8 R 8' , -NR 8 S(O) 2 R 9 , -CN, -S(O) m R 9 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 8 R
  • the compound is of formula I(g) or I(h), wherein R 3 is hydroxy and all other groups are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B.
  • the compound is of Formula I(g) or I(h), wherein R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; R 10 , R 12 , and R 14 are independently hydrogen, halo, or alkyl; and R 19 is hydrogen or methyl.
  • X is fluoro or chloro and R 7 is iodo or bromo;
  • R 10 is hydrogen or halo, more specifically hydrogen or fluoro;
  • R 12 and R 14 are hydrogen;
  • R 3 is hydroxy;
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • the compound is of Formula I(i) or I(j):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 and R 14 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 , R 12 , and R 14 are independently hydrogen, halo, or alkyl.
  • X is fluoro or chloro and R 7 is iodo or bromo;
  • R 10 is hydrogen or halo, more specifically hydrogen or fluoro;
  • R 12 and R 14 are hydrogen;
  • R 3 is hydroxy;
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • the compound is of Formula I(k) or I(m):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 and R 14 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B.
  • the compounds of Formula I(M) and Formula I(m) are two different formulae and are defined separately hereinabove. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R , R 1 , and R 14 are independently hydrogen, halo, or alkyl.
  • X is fluoro or chloro and R 7 is iodo or bromo;
  • R 10 is hydrogen or halo, more specifically hydrogen or fluoro;
  • R 12 and R 14 are hydrogen;
  • R 3 is hydroxy;
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • the compound is of Formula I(n) or I(o):
  • X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 , R 14 , and R 19 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B.
  • the compound is of formula I(n) or I(o), wherein R 7 is halo or alkyl; and all other groups are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, R 7 is iodo or bromo.
  • the compound is of formula I(n) or I(o), wherein X is halo, haloalkyl, or haloalkoxy; and all other groups are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, X is halo. Even more specifically X is fluoro or chloro.
  • R 3 is halo, nitro, -NR 8 R 8' , -OR 8 , -NHS(O) 2 R 8 , -CN, -S(O) 01 R 8 , -S(O) 2 NR 8 R 8' , -C(O)R 8 ,
  • the compound is of formula I(n) or I(o), wherein R 19 is alkyl; R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 , R 12 , and R 14 are independently hydrogen or halo. Even more specifically, R 19 is methyl; X is fluoro or chloro and R 7 is iodo or bromo; R 10 is hydrogen or fluoro; R 12 and R 14 are hydrogen; and R 3 is hydroxy.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, l(i?,5)-amino-ethyl, l(i?)-amino-ethyl, 1 (S)-amino-ethyl, l(i?,5)-(methylamino)-ethyl, 1 (/?)-(methylamino)-ethyl, l(,S>(methylamino)-ethyl, l(/?,S)-(dimethylamino)-ethyl, l(i?)-(dimethylamino)-ethyl, 1 (5)-(dimethylamino)-ethyl, l( ⁇ ,5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, l(i?)-(3,4-cis-dihydroxy- cyclopentylamino)-ethyl, or l(S)-
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 , and R 19 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, R 1 , R 2 ,
  • R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 and R 12 are independently hydrogen, halo, or alkyl. Even more specifically, X is fluoro or chloro; R 7 is iodo or bromo; R 10 is hydrogen or halo, more specifically hydrogen or fluoro; R 12 is hydrogen; R 19 is hydrogen or alkyl, more specifically hydrogen or methyl; R 3 is hydroxy.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, l(/?,S)-amino-ethyl, l(/?)-amino-ethyl, 1 (5)-amino-ethyl, l(/?,5)-(methylamino)-ethyl, 1 (i?)-(methylamino)- ethyl, l(5')-(methylamino)-ethyl, l(i?,S)-(dimethylamino)-ethyl, 1 (iJ)-(dimethylamino)- ethyl, l(iS)-(dimethylamino)-ethyl, l(i?,5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1 ( ⁇ )-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1
  • the compound is of Formula I(q):
  • R 3 is halo, nitro, -NR 8 R 8' , -OR 8 , -NHS(O) 2 R 8 , -CN, -S(O)JR 8 , -S(O) 2 NR 8 R 8' , -C(O)R 8 ,
  • the compound is of formula I(q), wherein R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 , R 12 , R 14 , and
  • R are independently hydrogen or halo. Even more specifically, R 10 is halo and R 12 , R 14 , and R are hydrogen. Even more specifically, X is fluoro or chloro; R 7 is iodo or bromo; R is chloro; and R 3 is hydroxy. Even more specifically, R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, benzimidazolyl, l(/?,5)-amino-ethyl, l(/?)-amino-ethyl, 1 (S ⁇ -amino-ethyl, 1 (/?,S)-(methylamino)-ethyl, 1 (i?)-(methylamino)-ethyl, l(S)-(methylamino)-ethyl, l(/?,5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, l(/?)-(3,4- cis-dihydroxy-cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)- ethyl.
  • the compound is of Formula I(r):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 and R 14 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; R 10 and R 12 are independently hydrogen, halo, or alkyl; and R 14 is hydrogen, halo, alkyl, or amino.
  • X is fluoro or chloro; R 7 is iodo or bromo; R 10 is hydrogen or halo, more specifically hydrogen or fluoro; R 12 is hydrogen; R 14 is hydrogen, alkyl, or amino, more specifically hydrogen, methyl, or amino; R 3 is hydroxy.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR R (wherein R is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, l(/?,S)-amino-ethyl, 1 (/?)-amino-ethyl, l(.S)-amino-ethyl, 1 (R, S>(methylamino)-ethyl, 1 (i?)-(methylamino)-ethyl, 1 (S)-(methylamino)-ethyl, l(/?,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, l(/?)-(3,4-cis-dihydroxy- cyclopentylamino)-ethyl, or l(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.
  • the compound is of Formula I(s):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 12 and R 14 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B. More specifically, R 1 , R 2 ,
  • R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 and R 12 are independently hydrogen, halo, or alkyl; and R 14 is hydrogen, halo, alkyl, or amino.
  • X is fluoro or chloro and R 7 is iodo or bromo;
  • R 10 is hydrogen or halo, more specifically hydrogen or fluoro;
  • R 12 is hydrogen;
  • R 14 is hydrogen, methyl, or amino;
  • R 3 is hydroxy;
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8' is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • the compound is of Formula I(u), I(v), I(w), or I(x):
  • the compound is of formula I(u), I(v), I(w), or I(x), wherein R 4 is heterocycloalkyl, heteroaryl (optionally substituted with alkyl), or alkyl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl).
  • R 4 is piperidinyl, pyrrolidinyl, l(7?,S)-amino-propyl, 1 (/?)-amino-propyl, 1 (. ⁇ -amino-propyl, 1 (R, iS)-(methylamino)-propyl,
  • the compound is of formula I(u), I(v), I(w), or I(x), wherein R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 and R 4 are as defined in the compound of Formula I(M) or Formula 1(N) for Group B; and R 10 , R 12 , and R 14 are independently hydrogen, halo, or alkyl.
  • X is fluoro or chloro
  • R 7 is iodo or bromo
  • R 10 is hydrogen or halo, more specifically hydrogen or fluoro
  • R 12 and R 14 are hydrogen
  • R 3 is hydroxy.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B.
  • R 1 , R 2 , R 5 , and R 6 are hydrogen; and X and R 7 are halo. More specifically, X is fluoro or chloro; and R 3 is hydrogen or hydroxy; R 7 is iodo or bromo.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl- benzimidazolyl, methylaminomethyl, l(7?,5)-amino-ethyl, 1 (i?)-amino-ethyl, l(5)-amino- ethyl, l(i?,S>(methylamino)-ethyl, l(i?)-(methylamino)-ethyl, l(S)-(methylamino)-ethyl, 1 (R, S)-(dimethylamino)-ethyl, 1 (/?)-(dimethylamino)-ethyl, 1 (S)-(dimethylamino)-ethyl, l(i?,S)-amino-propyl, l(i?)-amino-propyl, 1 (5)-amino-propyl, l(
  • a specific embodiment (B 19a) of embodiment B 19 is that wherein R 4 is heterocycloalkyl or alkyl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl).
  • R 4 is piperidinyl, pyrrolidinyl, methylaminomethyl, l(i?,S)-amino-ethyl, l(Z?)-amino-ethyl, l(S)-amino-ethyl, l(/?,5)-(methylamino)-ethyl, 1 (/?)-(methylamino)-ethyl, l(5)-(methylamino)-ethyl, l(/?,S)-(dimethylamino)-ethyl, 1 (i?)-(dimethylamino)-ethyl, 1 (S)-(dimethylamino)-ethyl, 1 (i?,S)-amino-propyl, 1 (7?)-amino-propyl, l(5)-amino-propyl, l(/?,5)-(methylamino)-propyl, 1 (/?)-(methyl)-
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group B.
  • R 1 , R 2 , R 5 , and R 6 are hydrogen; and X and R 7 are halo. More specifically, X is fluoro or chloro; R 3 is hydrogen or hydroxy; and R 7 is iodo or bromo.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, benzimidazolyl, iV-methyl-benzimidazolyl, methylaminomethyl, l(/?,S)-amino- ethyl, l(/?)-amino-ethyl, l(5)-amino-ethyl, l(/?,S)-(methylarnino)-ethyl, l(i?)-(methylamino)-ethyl, l(S)-(methylamino)-ethyl, l(7?,S>(dirnethylamino)-ethyl, l(i?)-(dimethylamino)-ethyl, 1 (5)-(dimethylamino)-ethyl, l(i?,5)-amino-propyl, 1 ( ⁇ -amino- propyl, l(5)-amino-propyl,
  • a specific embodiment (B20a) of embodiment B20 is that wherein R 4 is heterocycloalkyl or alkyl, wherein the alkyl is optionally substituted with -NR 8 R 8
  • R 4 is piperidinyl, pyrrolidinyl, methylaminomethyl, l(i?,5)-amino-ethyl, 1 (i?)-amino-ethyl, 1 (5)-amino-ethyl, l(/?,S)-(methylamino)-ethyl, 1 (i?)-(methylamino)-ethyl, 1 (5)-(methylamino)-ethyl, 1 (R, 5)-(dimethylamino)-ethyl, 1 (/?)-(dimethylamino)-ethyl, 1 (5)-(dimethylamino)-ethyl, 1 (R, 5)-amino-propyl,
  • X and R 7 are halo; and all other groups are as defined for a compound selected from Group C.
  • R 1 , R 2 , R 5 and R 6 are hydrogen; and X and R 7 are halo.
  • the compound is selected from Group C, wherein R 3 and R 4 are independently halo, nitro, -NR 8 R 8' , -OR 8 , -NHS(O) 2 R 8 , -CN,
  • -CH 2 NR 25 C(NR 25a R 25b ) CH(NO 2 ), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 , -NR 8 R 8' , -NR 8 S(O) 2 R 9 , -CN, -S(O) m R 9 , -C(O)R 8 , -C(O
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , and R IOa are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group C. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 10 is hydrogen or halo; and R 1Oa is alkyl. Even more specifically, X is fluoro or chloro; R 3 is hydroxy; R 7 is iodo or bromo; R 10 is hydrogen or fluoro; and R 1Oa is methyl.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl, l(/?,5)-amino-ethyl, l(/?)-amino-ethyl, l(S)-amino-ethyl, 1 (/?,5)-(methylamino)-ethyl, 1 (/?)-(methylamino)-ethyl, 1 (S)-(methylamino)-ethyl, 1 (R, S)-(dimethylamino)-ethyl, 1 (i?)-(dimethylamino)-ethyl, 1 (5)-(dimethylamino)-ethyl, l(i?,iS)-amino-propyl, 1 (i?)-amino-propyl, 1 (S)-amino-propyl, l(i?
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , and R 1Oa are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group C. More specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 10 is hydrogen or halo; and R 1Oa is alkyl. Even more specifically, X is fluoro or chloro; R 3 is hydroxy; R 7 is iodo or bromo; R 10 is hydrogen or fluoro; and R 1Oa is methyl.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methylbenzimidazolyl, l ⁇ -amino- ethyl, l( ⁇ )-amino-ethyl, 1 (S)-amino-ethyl, l(i?,S)-amino-propyl, 1 ( ⁇ )-amino-propyl, l(S)-amino-propyl, l(i?,S)-(methylamino)-propyl, l(i?)-(methylamino)-propyl,
  • the compound is of Formula I(y) or I(z):
  • R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; R 3 , R 4 , R 10 , R 1Oa , and Y 1 are as defined in the compound of Formula I(M) or Formula 1(N) for a compound of Group
  • X is fluoro or chloro
  • R 7 is iodo or bromo
  • R is hydrogen, halo, or alkyl, more specifically hydrogen or halo
  • R 1Oa is alkyl, more specifically methyl.
  • R 10 is hydrogen or fluoro
  • R 3 is hydroxy
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR 8 R 8 (wherein R 8 is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • I(M) or Formula 1(N) is selected from Group D, wherein all groups are as defined in the compound of Formula I(M) or Formula 1(N).
  • X and R 7 are halo; and all other groups are as defined for a compound selected from Group D.
  • R 40 is hydrogen or methyl (specifically, R 40 is hydrogen) and all other groups are as defined in the compound of Formula I(M) or Formula 1(N). Specifically, R 1 , R 2 , R 5 , and R 6 are hydrogen; X and R 7 are halo; and R 40 is hydrogen or methyl. More specifically, X is fluoro or chloro; and R 3 is hydrogen or hydroxy; R 7 is iodo or bromo.
  • R 4 is heterocycloalkyl, alkyl, or heteroaryl, wherein the alkyl is optionally substituted with -NR R (wherein R is hydrogen or alkyl and R is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.
  • R 4 is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl, l(i?,S)-amino-ethyl, l( ⁇ )-amino-ethyl, 1 (5>amino-ethyl, l(/?,5)-(methylamino)-ethyl, 1 (i?)-(methylamino)- ethyl, l(5)-(methylamino)-ethyl, l(/?,5)-(dimethylamino)-ethyl, l( ⁇ )-(dimethylamino)- ethyl, l(S)-(dimethylamino)-ethyl, l(i?,S)-amino-propyl, l(/?)-amino-propyl, 1 ( ⁇ -amino- propyl, l
  • a specific embodiment (D4a) of D4 is that wherein R 4 is heterocycloalkyl or alkyl, wherein the alkyl is optionally substituted with -NR R (wherein R is hydrogen or alkyl and R 8 is hydrogen, alkyl, or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl).
  • R 4 is piperidinyl, pyrrolidinyl, methylaminomethyl, l(/?,5)-amino-ethyl, l(i?)-amino-ethyl, l(S)-amino-ethyl, l(/?,5)-(methylamino)-ethyl, 1 ( ⁇ )-(methylamino)- ethyl, l(5)-(methylamino)-ethyl, l(i?,5)-(dimethylamino)-ethyl, l(i?)-(dimethylamino)- ethyl, l(S)-(dimethylamino)-ethyl, l(i?,5)-amino-propyl, l(/?)-amino-propyl, 1 ( ⁇ -amino- propyl, l(/?,S)-(methylamino)-propyl, l(/
  • MEK compound (E) is directed to a compound selected from Group A, Group B, and Group C, wherein
  • A is phenylene optionally substituted with one or two groups selected from R 1 , R , R , and
  • R 16 wherein R 10 , R 12 , R 14 and R 16 are independently hydrogen or halo;
  • X is halo; R 1 , R 2 , R 5 and R 6 are hydrogen;
  • R 3 is hydrogen, halo, hydroxy, alkoxy, or amino
  • R 4 is hydrogen, -NR 8 R 8' , -C(O)NR 8 R 8' , -NR 8 C(O)OR 8' , -NR 8 C(O)R 8' ,
  • R 4 alkyl is optionally substituted with one, two, or three groups independently selected from -OR 8 , halo, nitro, -S(O) m R 9 , optionally substituted heterocycloalkyl, -NR 8 R 8' , -NR 8 C(O)R 8' , -NR 8 S(O) 2 R 9 , -NR 8 C(O)OR 8' , and aryl; wherein the R 4 cycloalkyl is optionally substituted with one or two groups selected from
  • R 34 is hydrogen or alkyl and R 34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl
  • R 8 and R 8 cycloalkyl are independently optionally substituted with one, two, or three groups indendently selected from hydroxy, hydroxyalkyl, alkoxy, carboxy, -C(O)NR 33 R 333 (wherein R 33 is hydrogen or alkyl and R 33a is alkyl, alkenyl, alkynyl, or cycloalkyl), and optionally substituted cycloalkyl
  • R 9 is alkyl or aryl
  • A is thien-3,4-diyl, benzo[f/]isoxazol-5,6-diyl, lH-indazol-5,6-diyl (optionally substituted at the Nl position with R 19 , wherein R 19 is alkyl or alkenyl), benzo[ ⁇ /]oxazol-5,6-diyl, benzo[c/]triiazol-5,6-diyl, l//-benzo[d]imidazol-5,6-diyl (optionally substituted at the Nl position with R 19 , wherein R 19 is alkyl or alkenyl), lH-benzo
  • R 19 is alkyl or alkenyl
  • A is optionally substituted with one, two, or three groups independently selected from R 10 , R 12 , R 14 , R 16 and R 19 , wherein R 10 , R 12 , R 14 and R 16 are independently hydrogen, alkyl, halo, or amino; and R 19 is hydrogen or alkyl;
  • X is halo
  • R 1 , R 2 , R 5 and R 6 are hydrogen
  • R 3 is hydrogen or hydroxy
  • R 4 is -NR 8 R 8 , heterocycloalkyl, heteroaryl, or alkyl; wherein the alkyl is optionally substituted with -NR 8 R 8 and wherein the heteroaryl is optionaly substituted with alkyl; R 7 is halo;
  • R 8 is hydrogen or alkyl
  • R 8 is hydrogen, alkyl, or cycloalkyl; wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl;
  • R 10 is hydrogen or halo
  • R 1Oa is hydrogen or alkyl
  • X is halo
  • R 1 , R 2 , R 5 and R 6 are hydrogen
  • R 3 is hydrogen or hydroxy
  • R 4 is -NR 8 R 8 , heterocycloalkyl, heteroaryl, or alkyl; wherein the alkyl is optionally substituted with -NR R and wherein the heteroaryl is optionaly substituted with alkyl
  • R 7 is halo
  • R is hydrogen or alkyl; and R is hydrogen, alkyl, or cycloalkyl; wherein the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl.
  • the MEK compound can be in the form of a pharmaceutical composition which comprises the MEK compound of Formula I(M) or Formula 1(N) selected from Group A, Group B, Group C and Group D, or a pharmaceutically acceptable salt or solvate therof, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Non- limiting examples of the MEK compound of Formula I which can be used in the pharmaceutical composition include a compound of Formula I(c), I(d), I(e), I(f), I(g), I(h), I(i), IG), I(k), I(m), I(n), I(o), IQp), I(q), I(r), I(s), I(t), I(u), I(v), I(w), I(x), I(cc), or I(dd).
  • 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.
  • 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.
  • two R's on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring (a "spirocyclyl” group) structure with the depicted ring as for example in the formula: [00136]
  • "Acyl” means a -C(O)R radical, wherein R is optionally substituted alkyl, optionally substituted alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g., acetyl, benzoyl, trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like.
  • Acylamino means a -NRR' group, wherein R is acyl, as defined herein, and R' is hydrogen or alkyl.
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkenyl means a means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, l-but-3- enyl, l-pent-3-enyl, l-hex-5-enyl and the like.
  • alkenylcarbonyl means a -C(O)R group, wherein R is alkenyl, as defined herein.
  • alkenyloxycarbonyl means a -C(O)OR group, wherein R is alkenyl, as defined herein.
  • Alkoxy means an -OR group, wherein R is alkyl group as defined herein.
  • Lower-alkoxy refers to groups containing one to six carbons.
  • Alkoxyalkyl means an 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.
  • Alkoxycarbonyl means a -C(O)OR group, wherein R is alkyl as defined herein.
  • Alkoxycarbonylamino means a -NR'R" group, wherein R' is hydrogen, alkyl, hydroxy, or alkoxy and R" is alkoxycarbonyl, as defined herein.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.
  • Alkylamino means a -NHR radical, wherein R is alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino,
  • Alkylaminoalkyl means an alkyl group substituted with one or two alkylamino groups, as defined herein.
  • Alkylaminocarbonyl means a -C(O)R group, wherein R is alkylamino, as defined herien.
  • Alkylcarbonyl means a -C(O)R group, wherein R is alkyl, as defined herein.
  • Alkylcarbonylamino means a -NRR' group, wherein R is hydrogen or alkyl as defined herein and R' is alkylcarbonyl, as defined herein.
  • Alkylcarbonyloxy means an -OC(O)R group, wherein R is alkyl, as defined herein.
  • Alkylsulfonylamino means a -NRS(O) 2 R' group, wherein R is hydrogen or alkyl as defined herein, and R' is alkyl, as defined herein.
  • Alkynyl means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
  • Aminoalkyl means an alkyl group substiuted with at least one, specifically one, two or three, amino groups.
  • Aminocarbonyl means a -C(O)NH 2 group.
  • 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. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting.
  • Representative examples include phenyl, naphthyl, and indanyl, and the like.
  • Arylene means a divalent 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 phenylene, naphthylene, and indanylene, and the like.
  • Arylalkyl means an alkyl group, as defined herein, substituted with one or two aryl groups, as defined herein. Examples include benzyl, phenethyl, and the like.
  • Carboxy ester means a -C(O)OR group, wherein R is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which is defined herein.
  • Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like.
  • Cycloalkyl means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), monovalent hydrocarbon radical of three to ten carbon ring atoms.
  • Fused bicyclic hydrocarbon radical includes bridged ring systems.
  • the valency of the group may be located on any atom of any ring within the radical, valency rules permitting.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.
  • "Dialkylamino" means a -NRR' radical, wherein R and R' are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N, iV-methylpropylamino or iV,iV-methylethylamino, and the like.
  • Dialkylaminoalkyl means an alkyl group substituted with one or two dialkylamino groups, as defined herein.
  • Dialkylaminocarbonyl means a -C(O)R group, wherein R is dialkylamino, as defined herien.
  • fused-polycyclic or "fused ring system” means a polycyclic ring system that contains fused rings and, unless otherwise indicated, can contain bridged rings; that is, wherein 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.
  • Haloalkoxy means an -OR' group, wherein R' is haloalkyl as defined herein, e.g., trifiuoromethoxy or 2,2,2-trifluoroethoxy, and the like.
  • Halogen or “halo” means fluoro, chloro, bromo and iodo.
  • Haloalkyl means an alkyl group, as defined herein, that is substituted with one or more halogens, preferably one to five halo atoms. Representative examples include trifluoromethyl, difluoromethyl, l-chloro-2-fluoro-ethyl, and the like.
  • Heteroaryl means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O) n - (n is 0, 1, or 2), -N-, -N(R X )-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic.
  • R x is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl.
  • the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, R x is absent.
  • heteroaryl includes, but is not limited to, 1 ,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl or 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolin
  • ⁇ eteroarylene means a monocyclic, fused bicyclic, or fused tricyclic, divalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O) n - (n is 0, 1, or 2), -N-, -N(R 19 )-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic.
  • R 19 is hydrogen, alkyl, or alkenyl.
  • the valencies may be located on any atom of any ring of the heteroarylene group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, R x is absent.
  • heteroaryl includes, but is not limited to, thien-diyl, benzo[c/]isoxazol-diyl, benzo[J]isothiazol-diyl, l//-indazol-diyl (optionally substituted at the Nl position with R 19 ), benzo[cT]oxazol-diyl, benzo[fif]thiazol-diyl, lH-benzo[d]imidazol-diyl (optionally substituted at the Nl position with R 19 ), lH-benzo[flf][l,2,3]triazol-diyl (optionally substituted at the Nl position with R 19 ), imidazo[l,2- ⁇ ]pyridin-diyl, cinnolin-diyl, quinolin-diyl, pyridin-diyl, 1 -oxido-pyridin- diyl, [l,
  • ⁇ eterocycloalkyl means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, specifically one, two, three, or four ring heteroatoms independently selected from O, S(O) n (n is 0, 1 , or 2), N, N(R y ) (wherein R y is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon.
  • Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, R y is absent.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2- oxopyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroin
  • Hydroxyalkyl means an alkyl, 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, l-(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, and l-(hydroxymethyl)-2-hydroxyethyl, and the like.
  • "Hydroxyamino" means a -NH(OH) group.
  • Optionally substituted alkoxy means an -OR radical wherein R is optionally substituted alkyl as defined herein.
  • Representative examples include -OCH2CH2OCH3,
  • Optionally substituted alkyl means an alkyl radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, three, four, or five groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, halo, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, -S(O) 0-2 -alkyl, -S(O) 0-2 -alkenyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, -
  • 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, alkyl, alkenyl, alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, -C(O)NR 5 R" (wherein R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR 5 C(O)R" (wherein R 5 is hydrogen or alkyl and R 55 is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O) 2 R' (wherein R' is alkyl, aryl,
  • Optionally substituted arylalkyloxy means an -OR group, wherein R is optionally substituted arylalkyl, as defined herein.
  • Optionally substituted arylalkyloxycarbonyl means a -C(O)R group, wherein R is optionally substituted arylalkyloxy, as defined herein.
  • Optionally substituted aryloxy means an -OR group, wherein R is optionally substituted aryl, as defined herein.
  • Optionally substituted aryloxycarbonyl means a -C(O)R group, wherein R is optionally substituted aryloxy as defined herein.
  • Optionally substituted cycloalkyl means a cycloalkyl radical, as defined herein, that is optionally substituted with one, two, three, or four groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino, mono(C]-C 6 )alkylamino, dialkylamino, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl dialkylaminoalkyl, carboxy, carboxy ester, cycloalkyl, hydroxyalkyl, -C(O)NR 5 R 55 (wherein R' is hydrogen, alkyl, hydroxy
  • Optionally substituted cycloalkyloxycarbonyl means a -C(O)OR group, wherein R is optionally substituted cycloalkyl as defined herein.
  • 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, alkyl, alkenyl, 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 5 R" (wherein R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR 1 C
  • Optionally substituted heterocycloalkyl means a heterocycloalkyl ring, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, alkyl, alkenyl, alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, -C(O)NR 5 R" (wherein R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR 5 C
  • 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- lH-indene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system. 55
  • JAK-2 COMPOUNDS The JAK-2 compounds regulate and/or modulate the signal transduction of JAK-2 aminopyrimidine derivatives.
  • the JAK-2 compounds described below are non- limiting examples of "JAK-2 inhibitors" defined hereinabove. All of the substituents for the JAK-2 compounds described below are defined separately from the MEK compounds so that every substituent in the JAK-2 compounds that also appears in the MEK compounds has a separate and distinct meaning for each of these two compounds. For instance, R for the JAK-2 compounds has a separate and distinct meaning from R 1 for the MEK compounds.
  • the JAK-2 compound is a compound of Formula I(J):
  • E is hydrogen, halo, -CF 3 , heterocycloalkyl or alkyl; or
  • D and E together with the carbon atoms to which they are attached, form a 5-7 membered heteroaryl or a 5-7 membered heterocycloalkyl, wherein the 5-7 membered heteroaryl or 5-7 membered heterocycloalkyl are each fused to the pyrimidinyl moiety to which D and E are attached;
  • L is a bond, -O- or -N(H)-;
  • Z is selected from alkoxy, cycloalkyl, heteroaryl optionally substituted with alkyl, halo,
  • Z and R 25 together with the carbon atoms to which they are attached, join to form a 5 or 6 membered heterocycloalkyl, a 5 or 6 membered heteroaryl, or a 5 or 6 membered cycloalkyl ring, wherein the 5 or 6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, or 5 or 6 membered cycloalkyl ring are fused to the phenyl moiety to which Z and R 25 are attached, and wherein the 5 or 6 membered heterocycloalkyl,
  • 5 or 6 membered heteroaryl, or 5 or 6 membered cycloalkyl ring are each optionally substituted with 1, 2, or 3 groups independently selected from oxo, alkyl, alkoxy and halo; nl is 0, 1, 2, 3, or 4, and each nl is independently selected when more than one nl is present; n2 is 0, 1, 2, 3, or 4, and each n2 is independently selected when more than one n2 is present; n3 is 0, 1, 2, or 3, and each n3 is independently selected when more than one n3 is present; n4 is 0, 1, 2, 3 or 4, and each n4 is independently selected when more than one n4 is present; n5 is 0, 1, 2, 3 or 4, and each n5 is independently selected when more than one n5 is present; p is 0-3; r is 1-3;
  • R 1 is hydrogen
  • R 2 is selected from one of the following groups:
  • R 2 is selected from one of the following groups:
  • ring X in formula (d) of R 2 is a 5 or 6 membered unsaturated heterocyclic ring fused to the two carbon atoms of the phenyl moiety to which ring X is attached, wherein ring X contains 1 or 2 nitrogen atoms;
  • R 7 , R 7' , R 9 , R 10 , R 12 and R 15 are each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl;
  • R is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, hydroxyalkyl, alkoxyalkyl, dihydroxyalkyl, alkylamino, dialkylamino, aminoalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkylaminoalkyl, dialkylaminoalkyl, -(CH 2 ) r -C(O)OR 7 , -(CH 2 ) r -C(O)NR 7 R 7' , aryl, heteroaryl, cycloalkyl, arylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, aryloxyalky
  • R 26 is hydrogen, -C(O)-phenyl or alkyl, wherein the -C(O)-phenyl is optionally substituted at any ring position with 1 , 2 or 3 halo;
  • R 26a is hydrogen, alkyl, heteroaryl, -C(O)R 32 , -C(O)NHR 32a , -S(O) 2 R 9 , -SR 9 , -C(O)OR 32 , or -C(O)NR 323 R 32 ;
  • R 27 and R 28 are each independently selected from alkyl, alkenyl, hydroxy, alkoxy, and alkoxyalkyl;
  • R 27a and R 28a are independently selected from hydrogen, alkyl, alkenyl, alkoxyalkyl, alkoxy carbonylalkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminoalkyl, arylcarbonylalkyl, aryloxyalkyl, dialkylaminoalkyl, alkyl-O-
  • R 27a and R 28a are each independently optionally substituted at any ring position with 1, 2, 3, 4, or 5 groups selected from halo, alkyl, alkoxy, alkylcarbonyl, phenyl, phenoxy, arylcarbonyl, -CF 3 , oxo, -OCF 3 , alkoxyphenyl, and heteroaryl optionally substituted with alkyl or halo; or R 27 and R 27a , together with the nitrogen to which they are attached, form heterocycloalkylamino, heterocycloalkyl or heteroaryl, wherein the
  • R 28 and R 28a together with the nitrogen to which they are attached form heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl and heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 R 31 ;
  • R 29a is hydrogen or alkyl
  • R 29 is selected from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl groups within R 29 are each optionally substituted at any ring position with 1, 2, 3, 4, or 5 groups selected from halo, alkyl, alkoxy, alkylcarbonyl, phenyl, phenoxy, arylcarbonyl, -CF 3 , oxo, -OCF 3 , alkoxyphenyl, and heteroaryl optionally substituted with alkyl or halo; R 3Oa is hydrogen or alkyl;
  • R 30 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonylalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, arylalkyl, phenoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, arylheteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, arylalkyl, phenoxyalkyl, cycloalkyl, arylheteroarylalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, arylalkyl, phenoxyal
  • R 32 is selected from aryl, arylalkyl, arylalkoxy, arylcycloalkyl, alkoxycarbonylalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkylhydroxyalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein the aryl, arylalkyl, cycloalkyl, arylcycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at any ring position with 1 , 2, 3, 4, or 5 groups selected from hydroxy, oxo, alkyl, alkoxy, amino, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, halo, -CF 3 , -OCF 3 , aminoalkyl, alkyla
  • R 34 is hydrogen or alkyl
  • R 34a is selected from hydrogen, alkyl, heteroaryl, aryl, aminoalkyl, aminocarbonylalkyl, heteroarylalkyl, arylalkoxy and arylalkyloxycarbonylalkyl; wherein the heteroaryl, aryl, heteroarylalkyl, arylalkoxy or arylalkyloxycarbonylalkyl are each independently optionally substituted at any ring position with 1, 2, 3, 4, or 5 groups selected from hydroxy, oxo, alkyl, amino, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, halo, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and
  • R 35 is selected from halo, -(CH 2 ) p C(O)ORi 7 , cycloalkyl, heterocycloalkyl, and heterocycloalklylalkyl; wherein the heterocycloalkyl and heterocycloalklylalkyl are each optionally substituted with 1, 2, 3, 4, or 5 groups each independently selected from alkyl, alkoxy, and halo.
  • JAK compound of Formula I(J) is a compound of Formula H(J):
  • JAK compound of Formula I(J) is a compound of Formula HI(J) : wherein E, D, L, Z, R 1 , R 2 and R 25 are as defined above for the compound of Formula
  • JAK compound of Formula I(J) is a compound of Formula IV(J):
  • D, E, R 25 and R 32 are as defined above for Formula I, and R 28 and R 28a , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R 31 , and wherein R ' is as defined above in Formula I(J).
  • JAK compound of Formula I(J) is a compound of Formula VI(J):
  • D, E, R 25 and R 32 are as defined above for Formula 1(J), and R 28 and R 28a , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R 31 , and wherein R 31 is as defined above in Formula I(J).
  • Formula V(J) or Formula VI(J) are each hydrogen.
  • V(J) or Formula VI(J) is alkyl optionally substituted with alkoxy, hydroxy, amino, alkylamino, or dialkylamino.
  • R 27a , R 11 and n2 are as defined above for the compound of Formula I(J).
  • R 2 in Formula I(J), H(J) or IH(J) is
  • R 28 , R 1 ' and n2 are as defined above for the compound of Formula I(J), and R 28a is arylalkyl or heteroarylalkyl, wherein the arylalkyl or heteroarylalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo or lower alkyl.
  • R 2 in Formula 1(J), II(J) or IH(J) is
  • R 28 , R 28a , R 1 ' and n2 are as defined above for the compound of Formula I(J).
  • R 2 in Formula I(J), H(J) or IH(J) is
  • R 28 , R 1 ' and n2 are as defined above for the compound of Formula I(J), and R 28a is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl.
  • R 2 in Formula I(J), H(J) or IH(J) is
  • R 11 and n2 are as defined above for the compound of Formula I(J), and R 28 and R 28a , together with the nitrogen atom to which they are attached, join together to form a ring structure selected from thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrimidinyl, and pyridinyl, wherein the ring structure is optionally substituted with 1, 2, 3, 4 or 5 subsituents selected from halo, lower alkyl or alkoxy.
  • R 2 in Formula I(J), H(J) or IH(J) is wherein R 27a , R 1 ' and n2 are as defined above for the compound of Formula I(J).
  • Other embodiments of the JAK compound are of Formula I(J), H(J) or HI(J),
  • JAK-2 compound 5 ⁇ - N wherein L is a bond, and Z is R26a .
  • Other embodiments of the JAK-2 compound are of Formula I(J), H(J) or IH(J) ,
  • JAK-2 compound are of Formula I(J), H(J) or HI(J),
  • JAK-2 compound is of Formula I(J), H(J) or IH(J), wherein R 25 is on the 3 position.
  • JAK-2 compound is of Formula I(J), II(J) or HI(J),
  • JAK-2 compound is of Formula I(J), H(J) or
  • JAK-2 compound is of Formula I(J), H(J) or
  • JAK-2 compound is of Formula I(J), H(J) or IU(J)
  • R 26 wherein Z is R 26a , R 26a is -C(O)R 32 , R 26 is hydrogen, wherein R 32 selected from aryl, arylalkyl, cycloalkyl, alkoxycarbonylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 32 optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl or halo.
  • Other embodiments of the JAK compound are of Formula I(J), H(J) or IH(J),
  • JAK compound wherein Z is , R 26a is -C(O)R 32 , R 26 is hydrogen, wherein R 32 selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R 32 optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl or halo.
  • R 32 selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R 32 optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl or halo.
  • Other embodiments of the JAK compound are of Formula I(J), H(J) or III(J),
  • R 26a is -C(O)R 32
  • R 26 is hydrogen
  • R 32 is lower alkyl optionally substituted with 1, 2, 3, 4 or 5 groups selected from dialkylaminocarbonyl, hydroxy and -NR 34 R 34a , wherein R 34 and R 34a are as defined above for Formula I(J).
  • R 34 and R 34a are as defined above for Formula I(J).
  • Other embodiments of the JAK-2 compound are of Formula I(J), H(J) or IH(J),
  • R 32 is methyl
  • R 32 is alkyl substituted with
  • JAK-2 compound are of Formula I(J), H(J) or IH(J), wherein R 32 is U or -CH 2 -U, wherein U is selected from pyrolidinyl, thiazolidinyl, morpholinyl, azetidinyl, cyclobutyl, cyclopropyl, tetrahydofuranyl, pyrazinyl, imidazolyl, piperazinyl, thienyl, thienylmethyl, furanyl, phenyl, prolinamidyl, pyridinyl, tetrahydronaphthalene, tetrazolyl, isoindolinyl, pyranyl, cyclopentyl, and octahydro-lH- indolyl.
  • R 32 is U or -CH 2 -U, wherein U is selected from pyrolidinyl, thiazolidinyl, morpholinyl, aze
  • JAK-2 compound is of Formula I(J), H(J) or IH(J), wherein R 11 , when present, is halo or lower alkyl.
  • JAK-2 compound is of Formula I(J), H(J) or IH(J), wherein R 1 ' , when present, is lower alkyl.
  • JAK-2 compound is of Formula I(J), II(J) or IH(J), wherein R 35 is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl.
  • JAK-2 compound is of Formula 1(J), H(J) or IH(J), wherein n2 is 0.
  • JAK-2 compound are of Formula I(J), H(J) or IH(J),
  • JAK-2 compound is of Formula I(J), II(J) or IH(J),
  • JAK-2 compound is of Formula I(J), H(J) or III(J), IV(J) or V(J), wherein R 25 is hydrogen.
  • JAK-2 compounds of Formula I(J) are depicted below in Table 2 (Part A and Part B). The examples are merely illustrative and do not limit the scope of the JAK-2 compounds or JAK-2 inhibitors in any way.
  • Alkyl is intended to include Ci-C 2O , more typically, Ci-C 12 linear or branched structures and combinations thereof, inclusively.
  • Lower alkyl is intended to include Q- C 6 linear or branched structures and combinations thereof, inclusively.
  • C 6 alkyl can refer to an n-hexyl, wo-hexyl, cyclobutylethyl, and the like.
  • Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.
  • Higher alkyl refers to alkyl groups containing more that six carbon atoms.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 14 carbon atoms, 5 to 10 carbon atoms, or 5 to about 7 ring atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like. Cycloalkyls can be fused or bridge ring systems or spirocyclic systems.
  • Alkyl substituted with halo and hydroxy means an alkyl group substituted with 1 , 2, or 3 hydroxy and 1, 2, 3, 4, or 5 halo.
  • Alkylene refers to straight or branched chain 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.
  • alkylene examples include ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), dimethylpropylene (-CH 2 C(CH 3 ) 2 CH 2 - ), and cyclohexylpropylene (-CH 2 CH 2 CH(C 6 Hi 3 )).
  • alkoxy refers to the group -O-alkyl, wherein the term “alkyl” is as defined hereinabove. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like. Lower alkoxy refers to groups containing one to six carbons.
  • Substituted alkoxy refers to the group -O-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy). Another exemplary substituted alkoxy group is hydroxyalkoxy or -O-alkyl-OH.
  • Alkoxy refers to the group -O-alkyl, wherein the term “alkyl” is as defined hereinabove. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like. Lower alkoxy refers to groups containing one to six carbons.
  • Substituted alkoxy refers to the group -O-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy).
  • Another exemplary substituted alkoxy group is hydroxyalkoxy or -O-alkyl-OH.
  • Aryl means a monovalent six - to fourteen-membered mono- or multicyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the multicyclic ring is aromatic.
  • An aryl can also be six- to ten membered, or six membered. Representative non- limiting examples of aryl include phenyl, naphthyl, and the like.
  • Arylalkyl means a residue in which an aryl moiety, as defined above, is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group.
  • Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like.
  • the "alkyl" portion of the group can be one to ten carbons, and in another embodiment, one to six carbons; the latter can also be referred to as C ⁇ . ⁇ arylalkyl.
  • a group is referred to as or "-(Cr C 6 )alkylaryl," an aryl moiety is attached to a parent structure via an alkylene group. Examples include benzyl, phenethyl, and the like.
  • two adjacent groups on an aromatic system can be fused together to form a ring structure.
  • the fused ring structure can contain heteroatoms and can 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” 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 includes non-aromatic and aromatic 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 can themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • "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.
  • Non-limiting examples of "haloalkyl” include -CH 2 F, -CHCl 2 or - CF 3 .
  • 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 can be a monocyclic, bicyclic or tricyclic ring system, which can 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 can be optionally oxidized to various oxidation states.
  • the group -S(O) 0-2 - refers to -S- (sulfide), -S(O)- (sulfoxide), and -SO 2 - (sulfone) respectively.
  • nitrogens particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding iV-oxide form, although not explicitly defined as such in a particular example.
  • annular nitrogen atoms can be optionally quaternized; and the ring substituent can 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
  • Heterocycloalkylalkyl refers to a heterocycloalkyl, as defined herein, attached to the parent moiety through an "alkyl,” as defined herein.
  • One non-limiting example of heterocycloalkyl includes piperadinyl.
  • Another non-limiting example of heterocycloalkyl includes piperadinyl.
  • Another non-limiting example of heterocycloalkyl includes piperazinyl.
  • Another non-limiting example of heterocycloalkyl includes furanyl.
  • Another non-limiting example of heterocycloalkyl includes pyrrolidinyl.
  • Another non-limiting example of heterocycloalkyl includes morpholinyl.
  • Alkylamino refers to -NH(alkyl), wherein “alkyl” is as defined above, and wherein the the parent moiety is attached to the nitrogen atom.
  • Dialkylamino refers to -N(alkyl) 2 , wherein “alkyl” is as defined above, and wherein the parent moiety is attached to the nitrogen atom.
  • Dialkylaminoalkyl refers to -(alkyl)N(alkyl) 2 , wherein “alkyl” is as defined above.
  • dialkylaminoalkyl includes -
  • Aminoalkyl refers to -(alkyl)NH, wherein “alkyl” is as defined above, and wherein the the parent moiety is attached to the alkyl group.
  • aminoalkyl refers to -(alkyl)NH 2 , wherein “alkyl” is as defined above, and wherein the the parent moiety is attached to the alkyl group.
  • the amino group can be attached at any point along the alkyl group.
  • Non-limiting examples of aminoalkyl include -
  • Phenoxy refers to a -alkyl-O-phenyl group, wherein “alkyl” is as defined above, and the parent moiety is attached to the alkyl group.
  • Heteroaryl means a 5- to 12-membered, monocyclic aromatic heterocyclyl
  • heterocyclyl is defined herein
  • bicyclic heterocyclyl ring system where at least one of the rings in the bicyclic system is aromatic
  • 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.
  • the ring containing the heteroatom can be aromatic or non-aromatic.
  • Representative examples include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzdioxolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl
  • Aminocarbonyl refers to the group “-C(O)-NH 2, " wherein the parent moiety is attached to the amino group.
  • Alkoxycarbonyl refers to the group “-C(O)alkoxy,” wherein alkoxy is as defined above, and the parent moiety is attached to the carbonyl.
  • a non-limiting example includes -C(O)-OC(CH 3 ) 3 .
  • heterocyclyl When a group is referred to as "-Ci-C 6 alkyl heterocyclyl" the heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include (4-methylpiperazin-l-yl) methyl, (morpholin-4-yi) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-l-yl)-2-butenyl, and the like. Both the heterocyclyl and the corresponding alkylene, alkylidene, or alkylidyne portion of a heterocyclylalkyl group can be optionally substituted.
  • Hydroxyalkyl means -alkyl-OH, wherein alkyl is as defined hereinabove.
  • “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted” refers to all subsequent modifiers in a term.
  • saturated bridged ring system refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system can contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but can have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7- aza-bicyclo[2.2.1]-heptane, and l,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, aryl, and heterocyclyl refer respectively to alkyl, aryl, and heterocyclyl, 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: alkyl (for example, fluoromethyl), aryl (for example, 4-hydroxyphenyl), arylalkyl (for example, 1- phenyl-ethyl), heterocyclylalkyl (for example, l-pyridin-3-yl-ethyl), heterocyclyl (for example, 5-chloro-pyridin-3-yl or l-methyl-piperidin-4-yl), alkoxy, alkylenedioxy (for example methylenedioxy), amino (for example, alkylamino and dialkylamino), amidino, aryloxy (for example, phenoxy), arylalkyloxy (for example, benzyloxy), carboxy
  • alkyl for
  • an optionally substituted moiety is one that can or can not have one or more substituents, and each of the substituents can or can not have one or more substituents. But, the substituents of the substituents can not be substituted.
  • Some of the compounds of the invention can have imino, amino, oxo or hydroxy substituents off aromatic heterocyclyl systems.
  • imino, amino, oxo or hydroxy substituents can exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
  • compounds of Formula I(M) or 1(N) are useful for treating diseases, particularly cancer in which MEK activity contributes to the pathology and/or symptomatology of the disease.
  • cancer in which MEK activity contributes to its pathology and/or symptomatology include malignant melanomas, colorectal cancer, pancreatic cancer, lung cancer, papillary and anaplastic thyroid cancer, and endometriod ovarian cancers, and the like.
  • Suitable in vitro assays for measuring MEK activity and the inhibition thereof by compounds are known in the art.
  • Suitable in vivo models for cancer are known to those of ordinary skill in the art (including WO 2006/061712).
  • Suitable in vivo models for colorectal cancer, melanoma, breast adenocarcinoma, and lung anaplastic carcinoma see Biological Example 4, infra.
  • the "MEK compounds: described herein can be made by the synthetic procedures described below.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic
  • the starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein take place at atmospheric pressure and over a temperature range from about -78 0 C to about 150 0 C, more preferably from about 0 0 C to about 125 0 C and most preferably at about room (or ambient) temperature, e.g., about 20 0 C. Unless otherwise stated (as in the case of an hydrogenation), all reactions are performed under an atmosphere of nitrogen.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds described herein may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • the MEK compounds, or their pharmaceutically acceptable salts may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure.
  • Compounds of Formula 1(N) or Formula I(M) that may be prepared through the syntheses described herein 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. Some of the compounds described herein may exist as tautomers.
  • the MEK compounds also includes N-oxide derivatives and protected derivatives of compounds of Formula 1(N) or Formula I(M).
  • compounds of Formula I(M) or 1(N) contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.

Abstract

L'invention concerne une méthode destinée au traitement d'une maladie chez un mammifère, consistant à lui administrer une dose thérapeutique d'un composé à base de MEK représenté par la formule générale I(M), ou une composition pharmaceutique comprenant une dose thérapeutique d'un composé à base de MEK représenté par la formule générale I(M) et un excipient de qualité pharmaceutique, conjointement avec une dose thérapeutique d'un composé à base de JAK-2 représenté par la formule générale I(J), ou une composition pharmaceutique comprenant une dose thérapeutique d'un composé à base de JAK-2 représenté par la formule générale I(J) et un excipient de qualité pharmaceutique, le composé à base de MEK représenté par la formule générale I(M) et le composé à base de JAK-2 représenté par la formule générale I(J) étant définis dans la description de la présente demande.
PCT/US2008/004434 2007-04-03 2008-04-03 Méthodes d'utilisation de combinaisons d'inhibiteurs de mek et de jak-2 WO2008124085A2 (fr)

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