WO2009017838A2 - Combinaisons d'inhibiteurs jak-2 et d'autres agents - Google Patents

Combinaisons d'inhibiteurs jak-2 et d'autres agents Download PDF

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Publication number
WO2009017838A2
WO2009017838A2 PCT/US2008/009360 US2008009360W WO2009017838A2 WO 2009017838 A2 WO2009017838 A2 WO 2009017838A2 US 2008009360 W US2008009360 W US 2008009360W WO 2009017838 A2 WO2009017838 A2 WO 2009017838A2
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Prior art keywords
phenyl
amino
pyrimidin
quinoxalin
acetamide
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PCT/US2008/009360
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English (en)
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WO2009017838A3 (fr
Inventor
Peter Lamb
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Exelixis, Inc.
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Publication of WO2009017838A2 publication Critical patent/WO2009017838A2/fr
Publication of WO2009017838A3 publication Critical patent/WO2009017838A3/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This invention relates to methods of using certain inhibitors JAK-2 in combination with other active agents 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).
  • 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.
  • One major signaling pathway which emanate from growth factor and cytokine receptors is the JAK/STAT pathway. Activation of members of the JAK family of cytoplasmic tyrosine kinases results in phosphorylation of members of the STAT family of inducible transcription factors.
  • the JAK/STAT pathway 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.
  • 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 in combination with other active agents.
  • This invention provides methods that inhibit, regulate and/or modulate the signal transduction of JAK-2 using any of the JAK-2 compounds described hereinbelow in combination with any of the other agents described herein. These methods are useful for treating various diseases as described herein.
  • invention refers to an "aspect” or a “non-limiting embodiment” regardless of whether the terms “aspect” or “embodiment” appear in conjunction with the term “invention.”
  • transitional term “comprising” as used herein, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a PI3K inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the PBK inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • the POK inhibitors in this embodiment include any one of more of the PI3K compounds described hereinbelow that inhibit PI3K, or the pharmaceutically acceptable salts thereof, wherein the mammal is in
  • a pharmaceutical composition of any of the compounds or inhibitors in each of these aspects is meant to include the compound or inhibitor and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of a PI3K inhibitor comprises the PI3K inhibitor and a pharmaceutically acceptable carrier.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a PI3K ⁇ inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the PI3K ⁇ inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of the PI3K ⁇ inhibitors in this embodiment include any one or more of the PI3K ⁇ compounds described hereinbelow that inhbit PBK ⁇ , or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Akt inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Akt inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of the Akt inhibitors in this embodiment include any one or more of the Akt compounds described hereinbelow that inhibit Akt, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a VEGFR inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the VEGFR inhibitor as described hereinbelow, or a pharmaceutically acceptable salt
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a c-Met inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the c-Met inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • the c-Met inhibitors in this embodiment include any one or more of the c-Met compounds described hereinbelow that inhibit c-Met, or the pharmaceutically acceptable salts thereof, wherein the ma
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a c-Kit inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the c-Kit inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of the c-Kit inhibitors in this embodiment include any one or more of the c-Kit compounds described hereinbelow that inhibibt c-Kit, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(S), III(S), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Src inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Src inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of the Src inhibitors in this embodiment include any one or more of the Src compounds described hereinbelow that inhibit Src, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Flt3 inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Flt3 inhibitor as described hereinbelow, or a pharmaceutically
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a BCR-AbI inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the BCR-AbI inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of the BCR-AbI inhibitors in this embodiment include any one or more of the BCR-AbI compounds described hereinbelow that inhibit BCR-AbI, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula 1(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a ErbB2 inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the ErbB2 inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of the ErbB2 inhibitors in this embodiment include any one or more of the ErbB2 compounds described hereinbelow that inhibit ErbB2, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a EGFR inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the EGFR inhibitor as described hereinbelow, or a
  • Non-limiting examples of the EGFR inhibitors in this embodiment include any one or more of the EGFR compounds described hereinbelow that inhibit EGFR, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a raf inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the raf inhibitor as described hereinbelow, or a pharmaceutical composition of the r
  • Non-limiting examples of the raf inhibitors in this embodiment include any one or more of the raf compounds described hereinbelow that inhibit raf, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a mTor inhibitor, such as the rapamycins, or a pharmaceutically acceptable salt thereof (including pharmaceutical compositions thereof), wherein the mammal is in need of
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Ret inhibitor as described herein below, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Ret inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • the Ret inhibitors in this embodiment include any one or more of the Ret compounds described hereinbelow that inhibit Ret, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), U(J), 111(3), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a IGFlR inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the IGFlR inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a PI3K compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the PI3K compound as described hereinbelow, or
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a P13K ⁇ compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the PDK ⁇ compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Akt compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Akt compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention in another aspect (19), relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a VEGFR compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the VEGFR compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a c-Met compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the c-Met compound as described hereinbelow, or a pharmaceutically acceptable salt thereof.
  • the c-Met inhibitors in this embodiment include any one or more of the c-Met compounds described hereinbelow that inhibit c-Met, or the pharmaceutically acceptable salts thereof, wherein the mam
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a c-Kit compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the c-Kit compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Src compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Src compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Flt3 compound described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Flt3 compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a BCR-AbI compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the BCR-AbI compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a ErbB2 compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the ErbB2 compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a EGFR compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the EGFR compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a raf compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the raf compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a Ret compound as described herein below, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Ret compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the invention relates to a method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), II(J), III(J), IV(J), V(J), or VI(J), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a IGFlR compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the IGFlR compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
  • the diseases that can be treated in mammals are selected from myeloproliferative disorder, cancer, cardiovascular disease, and/or hematopoitic abnormality wherein the mammal is in need of the treatment.
  • the diseases that can be treated in mammals are selected from cancer, such as prostate cancer, breast cancer, multiple myeloma, leukemia, lymphoma, lung cancer, colorectal cancer, renal cancer, melanoma, hepatocellular, gastric, GIST, pancreatic carcinoma, and papillary thyroid cancer.
  • the diseases that can be treated are selected from myelofibrosis, thrombocythemia, polycythemia vera, essential thrombocythemia, agnogenic myeloid metaplasia, and chronic myelogenous leukemia.
  • the diseases that can be treated are selected from cancers selected from leukemias, lymphomas, multiple myeoloma, prostate cancers, lung cancers, breast cancers, and ovarian cancers.
  • the diseases that are treated are selected from congestive heart failure and hypertension.
  • the diseases that can be treated include those related to hematopoitic abnormality such as thrombocytosis.
  • the disease being treated is selected from prostate cancer, breast cancer, multiple myeloma, leukemia, lymphoma, lung cancer, colorectal cancer, renal cancer, melanoma, hepatocellular, gastric, GIST, pancreatic carcinoma, papillary thyroid cancer, myelofibrosis, thrombocythemia, polycythemia vera, essential thrombocythemia, agnogenic myeloid metaplasia, chronic myelogenous leukemia, and thrombocytosis.
  • 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". All of the substituents for the JAK-2 compounds described below are defined separately from any of the other active agents so that every substituent in the JAK-2 compounds that also appears in any of the other active agents has a separate and distinct meaning. For instance, R 1 for the JAK-2 compounds has a separate and distinct meaning from R 1 that appears in any of the other active agents. All of the following JAK-2 compounds are intended to alternatively include the pharmaceutically acceptable salts of these compounds whether it is explicitely stated or not.
  • the JAK-2 compounds that fall within the scope of any of aspects (I)-(15) of the invention are the following compounds: [0043] The JAK-2 compound is a compound of Formula I(J):
  • D is hydrogen, halo, -CF 3 , heterocycloalkyl or alkyl
  • E is hydrogen, halo, -CF 3 , heterocycloalkyl or alkyl
  • 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)-;
  • 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 8 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, heterocycloal
  • R 12 is hydrogen or alkyl
  • R 12a is hydrogen or alkyl
  • R 13 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
  • R 14 is a bond, heterocycloalkyl or cycloalkyl
  • R 16 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, dialkylaminoalkyl, -(CH 2 ) r -C(O)OR 7 , aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyal
  • R 7 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, dialkylaminoalkyl, -(CH 2 ) r -C(O)OR 7 , -(CH 2 ) r -C(O)NR 7 R 7' , aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyal
  • 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 323 , -S(O) 2 R 9 , -SR 9 ,
  • R and R are each independently selected from alkyl, alkenyl, hydroxy, alkoxy, and alkoxy alkyl;
  • R 27a and R 28a are independently selected from hydrogen, alkyl, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminoalkyl, arylcarbonylalkyl, aryloxyalkyl, dialkylaminoalkyl, alkyl-O- C(O)heterocylcoalkyl, -(CH 2 ) n4 heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -(CH 2 ) n4 -C(O)R 29 , -(CH 2 ) n4
  • 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 31 is selected from alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, -C(O)R 30 , -C(O)NR 30 R 303 , -C(O)OR 30 , -S(O) 2 R 30 , amino, dihydroxy alkyl, arylcarbonyl, alkylcarbonylamino, alkoxyphenyl, phenylalkoxyalkyl, arylheteroarylalkyl, alkylamino, -O-dialkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, oxo, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, spirocyclic cycloalkyl, spir
  • 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)OR] 7 , cycloalkyl, heterocycloalkyl, and heterocycloalklylalkyl; wherein the heterocycloalkyl and heterocycloalklylal
  • the compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • the symbol "-" means a single bond
  • " ⁇ ” means a triple bond.
  • the symbol refers to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous.
  • the " ⁇ " symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural Formula.
  • a substituent "R” may reside on any atom of the fused ring system, assuming replacement of a depicted (for example the -NH- in the Formula above), implied (for example as in the Formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the Formula above, "X" equals -CH-) from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group may reside on either the 5- membered or the 6-membered ring of the fused ring system.
  • R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon).
  • 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:
  • Spiro 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.
  • 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.
  • “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.
  • Carcer 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, mesothelioma; 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. ScL, 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, N-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” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • JAK-2 inhibitors are intended to include all JAK-2 inhibitors including the JAK-2 compounds of Formula I(J), II(J), III(J), IV(J), V(J) and VI(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.
  • JAK compound of Formula I(J) is a compound of Formula II(J):
  • JAK compound of Formula I 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 31 is as defined above in Formula I(J).
  • JAK-2 compound of Formula I is a compound of Formula V(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).
  • R 32 for Formula IV(J), Formula V(J) or Formula VI(J) is heterocycloalkyl.
  • V(J) or Formula VI(J) is alkyl optionally substituted with alkoxy, hydroxy, amino, alkylamino, or dialkylamino.
  • R 2 in Formula I(J), II(J) or III(J) is
  • R 27 a , R 11 and n2 are as defined above for the compound of Formula I(J).
  • R 2 in Formula I(J), II(J) or III(J) is wherein R 28 , R 11 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 I(J), II(J) or III(J) is
  • R 28 , R 28a , R 11 and n2 are as defined above for the compound of Formula I(J).
  • R 2 in Formula I(J), II(J) or III(J) is wherein R , R and n2 are as defined above for the compound of Formula I(J), and R is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl.
  • R 2 in Formula I(J), II(J) or III(J) is
  • R and n2 are as defined above for the compound of Formula I(J), and R 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), II(J) or III(J) is
  • R 27a , R 11 and n2 are as defined above for the compound of Formula I(J).
  • Other embodiments of the JAK compound are of Formula I(J), II(J) or III(J),
  • JAK-2 compound is of Formula I(J), II(J) or III(J) ,
  • JAK-2 compound are of Formula I(J), II(J) or III(J),
  • JAK-2 compound wherein Z is , R 25 is hydrogen and E and D are hydrogen.
  • Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J), wherein R 25 is on the 3 position.
  • Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
  • JAK-2 compound are of Formula I(J), II(J) or III(J),
  • R 26a is -C(O)R 32
  • R 32 is selected from lower alkyl, cylcoalkyl, diaminoalkyl, aminoalkyl, arylalkyl, heterocycloalkyl, alkoxyalkyl, alkylamino, and hydroxyalkyl optionally substituted with amino.
  • Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
  • R 26a is -C(O)R 32
  • R 32 is cycloalkyl
  • JAK-2 compound are of Formula I(J), II(J) or III(J),
  • R 26a is -C(O)R 32
  • R 32 is lower alkyl
  • JAK-2 compound is of Formula I(J), II(J) or III(J)
  • 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), II(J) or III(J),
  • 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), II(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 34 ", wherein 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), II(J) or III(J),
  • R 2 is [0092] In another embodiment of the JAK-2 compound, R 32 is methyl.
  • R 32 is alkyl substituted with
  • JAK-2 compound are of Formula I(J), II(J) or III(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-1H- indolyl.
  • R 32 is U or -CH 2 -U, wherein U is selected from pyrolidinyl, thiazolidinyl, morpholinyl, azeti
  • JAK-2 compound is of Formula I(J), II(J) or III(J), wherein R 1 1 , when present, is halo or lower alkyl.
  • JAK-2 compound is of Formula I(J), II(J) or III(J), wherein R 1 ', when present, is lower alkyl.
  • JAK-2 compound is of Formula I(J), II(J) or III(J), wherein R 35 is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl.
  • JAK-2 compound is of Formula I(J), II(J) or III(J), wherein n2 is 0.
  • JAK-2 compound are of Formula I(J), II(J) or III(J),
  • R 2 is [00100]
  • Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
  • R 2 is , and wherein R 28 and R 28 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
  • JAK-2 compound are of Formula I(J), II(J) or III(J),
  • JAK-2 compounds of Formula I(J) are the compounds depicted below in Table l(J), or the pharmaceutically acceptable salts of any of these compounds. 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 C 1 -C 20 , more typically, C 1 -C 12 linear or branched structures and combinations thereof, inclusively.
  • Lower alkyl is intended to include C 1 -C 6 linear or branched structures and combinations thereof, inclusively.
  • C 6 alkyl can refer to an n-hexyl, iso-hexyl, cyclobutylethyl, and the like.
  • 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.
  • alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like.
  • alkyl residue having a specific number of carbons all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either “butyl” or “C 4 alkyl” is meant to include n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-ynyl groups; and for example, "propyl” or “C 3 alkyl” each include n-propyl, propenyl, and isopropyl.
  • 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 CII(C 6 H 13 )).
  • Alkylidene refers to a straight or branched chain unsaturated divalent group consisting solely of carbon and hydrogen atoms, having from two to ten carbon atoms, for example, ethylidene, propylidene, n-butylidene, and the like. Alkylidene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, double bond unsaturation. The unsaturation present includes at least one double bond.
  • Alkylidyne refers to a straight or branched chain unsaturated divalent group consisting solely of carbon and hydrogen atoms having from two to ten carbon atoms, for example, propylid-2-ynyl, n-butylid-1-ynyl, and the like. Alkylidyne is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, triple bond unsaturation. The unsaturation present includes at least one triple bond.
  • 2-(2-phenylethynyl-but-3-enyl)-naphthalene contains an n- butylid-3-ynyl group with a vinyl substituent at the 2-position of said group.
  • 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.
  • 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 1-6 arylalkyl.
  • a group is referred to as or "-(C 1 -C 6 )alkylaryl," an aryl moiety is attached to a parent structure via an alkylene group.
  • fused ring structure can contain heteroatoms and can 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.
  • 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 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 N-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.
  • Amino refers to -NH 2 .
  • Alkylamino refers to -NII(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 -CH 2 C(CH 3 ) 2 CH 2 N(CH 3 ) 2 .
  • 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 -CII(NH 2 )CH 3 ,
  • Heteroaryl means a 5- to 12-membered, monocyclic aromatic heterocyclyl (where heterocyclyl is defined herein) or bicyclic heterocyclyl ring system (where at least one of the rings in the bicyclic system is aromatic) where the monocyclic ring and at least one of the rings in the bicyclic ring system contains one, two, three, four, or five heteroatom(s) selected from nitrogen, oxygen, phosphorous, and sulfur.
  • 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
  • Carbonyl refers to the group “-C(O)-", which is bivalent.
  • 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 .
  • a group is referred to as "-C 1 -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-1-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4- yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. Both the heterocyclyl and the corresponding alkylene, alkylidene, or alkylidyne portion of a heterocyclylalkyl group 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 may or may 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.
  • other active agents or “other active agents described herein” as used in the combination of JAK-2 inhibitors with other active agents, means any of the Raf inhibitors, PI3K inhibitors, PI3K ⁇ inhibitors, mTor inhibitors, Akt inhibitors, EGFR inhibitors, ErbB2 inhibitors, VEGFR inhibitors, c-Met inhibitors, c-Kit inhibitors, Ret inhibitors, IFGlR inhibitors, BCR-AbI inhibitors, Flt3 inhibitors, Src inhibitors, described within this application, as well as any of the chemotherapeutic agents described herein, such as the taxanes.
  • 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-1H-indene, 7-aza-bicyclo[2.2.1]-heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system.
  • Spirocyclyl or "spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B'), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • Substituted alkyl, 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 (
  • an optionally substituted moiety is one that may or may not have one or more substituents, and each of the substituents may or may not have one or more substituents. But where a first optionally substituted group can be substituted by a second optionally substituted group, the second substituent cannot be further substituted.
  • Some of the compounds described herein can have imino, amino, oxo or hydroxy substituents off aromatic heterocyclyl systems. For purposes of this disclosure, it is understood that such imino, amino, oxo or hydroxy substituents can exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
  • the compounds of Formula I(J) are useful for treating diseases, particularly myeloproliferative disorders, for example, myelofibrosis, thrombocythemia, polycythemia vera (PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM), also referred to as idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML); and cancer, for example, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, glioblastomas, prostrate, colon, melanoma, leukemia and haematopoietic malignancies, as described above, in which JAK-2 activity contributes to the pathology and/or symptomatology of the disease.
  • myeloproliferative disorders for example, myelofibrosis, thrombocythemia, polycythemia vera (PV), essential thrombocythemia (ET), agnogenic
  • Suitable in vitro assays for measuring JAK-2 activity and the inhibition thereof by compounds are known. For further details of an in vitro assay for measuring JAK-2 activity see Biological Examples. [00146] Assays for measurement of efficacy in treatment of various cancers are described in Biological Examples.
  • JAK-2 compounds described herein, or their pharmaceutically acceptable salts can have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.
  • JAK-2 compounds described herein and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds can 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.
  • Enantiomers can be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomer enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization.
  • the JAK-2 compounds can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the JAK-2 compounds are made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
  • Scheme 1 for the JAK-2 compounds below depicts the general synthetic procedure for the JAK-2 compounds. Synthesis of the JAK-2 compounds is not limited by the procedure of Scheme 1.
  • Compounds of Formula Dl can be further transformed to amides of Formula E using standard peptide coupling conditions with carboxylic acids or reaction with acid chlorides.
  • Dl ca be reacted with an intermediate of Formula LG 1 C(O)R 4 where LG 1 is a leaving group under acylation conditions and R 4 is phenyl optionally substituted with 1, 2, 3, 4, or 5 R 11 groups, wherein R 11 is as defined in the Detailed Description of the Invention to yield a compound of Formula E.
  • each example is set out below with a corresponding multi-step synthesis procedure. Following the specific examples is a list of compounds that were made in a similar way.
  • a flask containing a solution of C 1 (500 mg, 2.0 mmol) and 3-boc-amino- aniline F (687 mg, 3.3 mmol) in nBuOH (5 mL) was immersed in an oil bath at 180 °C for 30 mins. The mixture was cooled to ambient temperature and to the black residue was added aqueous HCl and MeOH. The aqueous layer was twice washed with ethylacetate. The aqueous layer was then basified with NaOH and extracted twice with ethylacetate. The organic layer was washed with brine and dried with sodium sulfate.
  • reaction mixture was then cooled to ambient temperature, quenched with saturated NH 4 Cl (aq., 10 mL), extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue.
  • the residue was purified by reverse phase HPLC to yield the product 319 (49.6 mg, 8.10% yield) as a light brown solid.
  • the crude mixture was concentrated on a rotary evaporator and the product was purified by HPLC with NH 4 OAc/ACN as eluent.
  • the resulting solution was concentrated on a rotary evaporator and the final product, 208, was dried by lyophilization.
  • a pressure bottle was charged with l-chloro-2-methoxy-4-nitrobenzene (10.0 g mg, 53.3 mmol, purchased from TCI America) and morpholine (15 mL, 172.0 mmol).
  • the reaction mixture was stirred at 120 °C for 15 hours and it was allowed to cool to room temperature by itself.
  • the resulting solid was suspended in 20 mL of ethyl acetate, filtered, and washed with 20 mL of tert-butyl methyl ether. 8.8 g of yellow solid as the desired product AA was collected (69% yield).
  • a seal tube was charged with intermediate A (500 mg, 2.02 mmol) and 4- morpholinobenzene-1,3-diamine (400 mg, 2.02 mmol, Zerenex Limited). N-butanol (15 mL) was added to the seal tube and stirred at 180°C. The reaction was done in Ih according to LCMS to afford intermediate C as a yellow solid. Intermediate C was placed on a rotary evaporator to remove excess n-butanol. Intermediate C was carried on to the next step without further purification.
  • a seal tube was charged with intermediate A (300 mg, 1.21 mmol) and 3,5- diaminobenzoic acid (204 mg, 1.34 mmol). N-butanol (15 mL) was added to the seal tube and stirred at 180°C. The reaction was done in Ih according to LCMS to afford intermediate D as a yellow solid. Intermediate D was placed on a rotary evaporator to remove excess n-butanol. Intermediate D was carried on to the next step without further purification.
  • intermediate F 200 mg, 0.766 mmol
  • a seal tube was charged with intermediate F (200 mg, 0.766 mmol), anhydrous DMA (15 mL), cesium carbonate (374 mg, 1.15 mmol), racemic-2,2'- Bis(diphenylphosphino)-l,l '-binaphthyl (70 mg, 0.1 15 mmol), and tris(dibenzylideneacetone)dipalladium(0).
  • the reaction was flushed with N 2 gas for five minutes and the seal tube was sealed and stirred at 80°C over night.
  • the reaction was filtered and washed with ethyl acetate and the solid was discarded.
  • the organic solvent was removed using the rotary evaporator.
  • the final product 66 was purified using Preperative HPLC and TFA buffer, free-based and lyophilized to afford the product (95 mg, 0.235 mmol, 28% Yield).
  • a seal tube was charged with intermediate A (200 mg, 0.81 mmol), and intermediate J (235 mg, 0.81 mmol).
  • N-butanol (15 mL) was added to the seal tube and stirred at 180°C.
  • the reaction was done in Ih and concentrated to remove excess n-butanol and then treated with 4N HCl/dioxane.
  • the reaction mixture was stirred at rt for Ih to afford the final product 35.
  • the final product was purified using Preperative HPLC and ammonium acetate buffer, then free-based and lyophilized (90 mg, 0.22 mmol, 27% Yield).
  • a seal tube was charged with intermediate Ai (0.2g, 0.81 mmol), compound C from the previous step (0.56g, 2.0mmol), tris(dibe ⁇ zylideneacetone)dipalladium(0) (0.15g, 0.16 mmol), racemic-2,2'-bis(diphenylphosphino)-l,l 'binaphthyl (0.12g, 0.2mmol), cesium carbonate (0.4g, 1.22mmol). Dimethylacetamide (10ml) was added and the mixture was purged with N 2 for 5 minutes. The tube was sealed and the reaction mixture was stirred at 80°C overnight. LCMS showed the reaction was done (M+H: 493).
  • Intermediate A was isolated by removal of the solvent with a rotary evaporator and purified using glass column chromatography and eluted with ethyl acetate to afford 30.5 g (123.14 mmol, 81% yield) of intermediate A as a yellow solid.
  • a seal tube was charged with intermediate A (400 mg, 1.62 mmol) and 3-(tert- butoxycarbonylamino)aniline (1.99g, 9.57 mmol). N-butanol (50 mL) was added to the seal tube and stirred at 180 C. The reaction was stopped after 2.5h, monitored by LCMS. The reaction mixture was diluted with methanol and the solid precipitate was filtered to afford intermediate B as a yellow solid.
  • Diisoproplyethylamine (10 equiv., 1.24 g, 1.67 ml, 9.631 mmoles) was added in one lot and the reaction mixture was stirred for 5 minutes.
  • 1 -(tert-Butoxycarbonyl)-2- methylpyrrolidine-2-carboxylic acid (4 equiv., 3.852 mmoles, 0.883 g, purchased from Fluka-Sigma Aldrich) was added to the reaction mixture in one lot, followed by 2-(7-aza- 1H-benzotriazole-1-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 4 equiv., 3.852 mmoles, 1.464 g, purchased from Oakland Products).
  • HATU 2-(7-aza- 1H-benzotriazole-1-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate
  • reaction mixture was stirred at room temperature and the progress of the reaction was monitored by LC/MS. After 72 hours, the reaction mixture was quenched with ethyl acetate (20ml), and transferred to separatory runnel. The reaction flask was further rinsed with ethyl acetate (20 ml), transferred to the separatory funnel, shaken and the layered separated off. The aqueous layer was further washed with ethyl acetate (3 x 50 ml). The combined ethyl acetate solutions were washed with cold water (2 x 50 ml) and saturated sodium chloride solution (2 x 50 ml).
  • Diisoproplyethylamine (10 equiv., 0.977 g, 1.31 ml, 7.561 mmoles) was added in one lot and the reaction mixture was stirred for 5 minutes.
  • N-Boc-D-proline (4 equiv., 3.204 mmoles, 0.65 g, purchased from Fluka-Sigma Aldrich) was added to the reaction mixture in one lot, followed by 2-(7-aza-1H-benzotriazole-1-yl)-l,1,3,3-tetramethyl- uronium hexafluorophosphate (HATU, 4 equiv., 3.024 mmoles, 1.149 g, purchased from Oakland Products).
  • HATU 2-(7-aza-1H-benzotriazole-1-yl)-l,1,3,3-tetramethyl- uronium hexafluorophosphate
  • the reaction mixture was stirred at room temperature and the progress of the reaction was monitored by LC/MS. After 72 hours, the reaction mixture was quenched with ethyl acetate (20ml), and transferred to separatory funnel. The reaction flask was further rinsed with ethyl acetate (20 ml), transferred to the separatory funnel, shaken and the layer separated off. The aqueous layer was further washed with ethyl acetate (3 x 50 ml). The combined ethyl acetate solutions were washed with chloride solution (2 x 50 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give an orange oil.
  • reaction mixture was stirred at room temperature, and the progress of the reaction monitored by LC/MS. After 16 hours, additional 4M hydrogen chloride in 1,4-dioxane (0.87, 1.25 mmoles, 5 equivalents) was added. After a total of 48 hours the reaction was complete and the resulting slurry was filtered off. The reaction flask was rinsed with ethyl acetate to ensure complete transfer of product.
  • intermediate B was carried on without further purification.
  • a seal tube was charged with intermediate B (140 mg, 0.536 mmol) and 4-morpholinoaniline (95 mg, 0.536 mmol). N-butanol (15 mL) was added to the seal tube and stirred at 180°C. The reaction was done in Ih according to LCMS to afford 283 as a yellow solid.
  • Compound 283 was purified using preperative HPLC and TFA buffer. Compound 283 was free-based, converted to HCl salt, and lyophilized (20mg, 0.455 mmol).
  • Example 59 (R)-N-(4-(2-(4-morpholino-3-(trifluoromethyl)-phenylamino)pyrimidin-4-yl)-phenyl)- pyrrolidine-2-carboxamide was synthesized in an analogous fashion to Example 3, wherein aniline was substituted with 3-trifluoromethyl-4-rnorpholinoaniline (Zerenex Limited) to afford the title compound.
  • Example 61 N-[4-(2- ⁇ [3-(1,3-dioxan-2-yl)phenyl]amino ⁇ pyrimidin-4-yI)phenyl]acetamide was synthesized in an analogous fashion to Example 3, wherein aniline was substituted 3-(1,3- dioxan-2-yl)aniline (Oakwood Products, Inc.) to afford the title compound.
  • N-(4- ⁇ 2-[(4-morpholin-4-yIphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl ⁇ phenyl)acetamide was synthesized in an analogous fashion to Example 5, wherein pyrimidine was substituted with 5-trifiuoromethyl-2,4-dichloropyrimidine (Astatech, Inc.) to afford the title compound.
  • pyrimidine was substituted with 5-trifiuoromethyl-2,4-dichloropyrimidine (Astatech, Inc.) to afford the title compound.
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)benzamide 1 H-NMR (400 MHz, DMSO): 10.532 (s, 1H), 9.407 (s, 1H), 8.47 (d, 1H) 8.189 (d, 2H), 7.982 (m, 4H), 7.7-7.54 (m, 5H), 7.325 (d, 1H), 6.959 (d, 2H), 3.747 (t, 4H), 3.054 (t, 4H).
  • N-[4-(2- ⁇ [4-(methyloxy)phenyl]amino ⁇ pyrimidin-4-yl)phenyl]acetamide 1 H-NMR (400 MHz, DMSO): 10.532 (s, 1H), 9.407 (s, 1H), 8.47 (d, 1H) 8.189 (d,
  • N-(4- ⁇ 2-[(4- ⁇ 4-[(2S)-pyrrolidin-2-ylmethyl]piperazin-1-yl ⁇ phenyl)amino]- pyrimidin-4-yl ⁇ phenyl)-D-prolinamide 1 H NMR (400 MHz, DMSO): 10.231 (br s, 1H), 9.376 (s, 1H), 8.443 (d, 1H), 8.134 (d, 2H), 7.848 (d, 2H), 7.663 (d, 2H), 7.29 (d, 1H), 6.936 (d, 2H), 3.74 (m, 1H), 3.505 (m, 1H), 3.08-2.89 (m, 6H), 2.64 (m, 2H), 2.374 (m, 1H), 2.069 (m, 1H), 1.938-1.648 (m, 9H), 1.452 (m, 1H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)piperidine-2- carboxamide 1 H NMR (400 MHz, d6-DMSO): 9.85 (s, br, 1H), 9.31 (s, 1H), 8.36 (d, 1H), 8.04 (d, 2H), 7.75 (d, 2H), 7.60 (d, 2H), 7.21 (d, 1H), 6.87 (d, 2H), 3.67 (m, 4H), 3.21 (m, 1H), 2.98 (m, 4H), 2.93 (m, 1H), 2.47 (m, 1H), 1.70 (m, 2H), 1.37 (m, 4H). MS (EI) 2: 459 (MH+). N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)glycinamide:
  • N-(4- ⁇ 2-[(4-morpholin-4-yIphenyl)amino]pyrimidin-4-yl ⁇ phenyl)tetra- hydrofuran-2-carboxamide 1 H NMR (400 MHz, d6-DMSO): 9.91 (s, 1H), 9.36 (s, 1H), 8.41 (d, 1H), 8.09 (d, 2H), 7.84 (d, 2H), 7.67 (d, 2H), 7.22 (d, 1H), 6.91 (d, 2H), 4.41 (dd, 1H), 3.96 (q, 1H), 3.83 (q, 1H), 3.72 (m, 4H), 3.02 (m, 4H), 2.19 (m, 1H), 1.99 (m, 1H), 1.88 (m, 2H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)prolinamide 1 H NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.13 (d, 2H), 7.83 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.71 (m, 1H), 3.04 (m, 4H), 2.90 (t, 2H), 2.05 (m, 1H), 1.80 (m, 1H), 1.66 (m, 2H). MS (EI): 445 (MH+).
  • N-(4-(2-(4-(4-pivaloylpiperazin-1-yl)phenyIamino)pyrimidin-4-yl)phenyl)- tetrahydrofuran-3-carboxamide 1 H NMR (400 MHz, d6-DMSO): 10.30 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 3.96 (t, 1H), 3.74 (m, 6H), 3.19 (m, 2H), 3.05 (m, 4H), 2.10 (q, 2H), 1.23 (s, 9H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl ⁇ phenyl)phenylalaninamide 1 H NMR (400 MHz, d6-DMSO): 9.39 (s, 1H), 8.42-8.46 (d, 1H), 8.09-8.14 (d, 2H), 7.75-7.81 (d, 2H), 7.64-7.70 (d, 2H), 7.23-7.32 (m, 6H), 7.16- 7.22 (m, 2H), 6.90-6.97 (d, 2H), 3.71-3.78 (m, 4H), 3.57-3.63 (m, 1H), 3.02-3.08 (m, 4H), 2.98-3.02 (m, 1H), 2.71-2.79 (m, 1H). MS (EI): 495 (MH+).
  • N- ⁇ l-[4-( ⁇ 4-[4-(acetylamino)phenyl]pyrimidin-2-yl ⁇ amino)phenyl]pyrrolidin- 3-yl ⁇ acetamide NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.20 (s, 1H), 8.60 (s, 1H), 8.15-8.20 (m, 3H), 7.79-7.86 (m, 4H), 7.20 (s, 1H), 6.58 (d, 2H), 4.39 (m, 1H), 3.43 (m, 1H), 3.23 (m, 1H), 3.10 (m, 1H), 2.18 (m, 1H) 3 2.07 (s, 3H), 1.85 (m, 1H), 1.80 (s, 3H).
  • N-[4-(2- ⁇ [4-(3-oxopiperazin-1-yl)phenyI]amino ⁇ pyrimidin-4- yl)phenyl]acetamide NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.41 (s, 1H), 8.06 (d, 2H), 8.02 (s, 1H), 7.65 - 7.80 (m, 4H), 7.25 (s, 1H), 6.97 (d, 2H), 3.64 (s, 2H), 3.35 - 3.40 (m, 4H), 2.05 (s, 3H).
  • N-[4-(2- ⁇ [3-(methyloxy)-4-morpholin-4-ylphenyl]amino ⁇ pyrimidin-4- yl)phenyl]-D-alaninamide NMR (400 MHz, d6-DMSO): 1 1.40 (s, 1H), 10.10 (s, 1H), 8.57 (d, 1H), 8.45(d, 2H), 8.02 (d, 2H), 7.87 (m, 3H), 7.47 (m, 2H), 4.15 (m, 1H), 3.95 -
  • N-[4-(2- ⁇ [3-(methyIoxy)-4-morpholin-4-ylphenyl]amino ⁇ pyi ⁇ midin-4- yl)phenyl]-butanamide NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 9.43 (s, 1H), 8.44 (d, 1H), 8.17 (m, 2H), 7.75 (d, 2H), 7.64 (s, 1H), 7.25 (m, 2H), 6.84 (d, 1H), 3.80 (s, 3H), 3.75 (m, 4H), 2.96 (m, 4H), 2.35 (q, 2H), 1,62 (m, 2H), 0.92 (q, 3H).
  • N-(4- ⁇ 2-[(4- ⁇ 4-[3-(methyloxy)propanoyl]piperazin-1-yl ⁇ phenyI)amino]- pyrimidin-4-yl ⁇ phenyl)butanamide NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 9.40 (s, 1H), 8.41 (d, 1H), 8.17 (d, 2H), 7.78 (d, 2H), 7.68 (d, 2H), 7.24 (s, 1H), 6.94 (d, 2H), 3.60 (m, 6H), 3.21 (s, 3H), 3.0 - 3.09 (m, 4H), 2.60 (q, 2H), 2.35 (m, 2H), 1,60 (m, 2H), 0.95 (q, 3H).
  • N-[4-(2- ⁇ [3-(methyloxy)-4-morpholin-4-ylphenyl]amino ⁇ pyriinidin-4- yl)phenyl]-D-proIinamide NMR (400 MHz, d6-DMSO): 11.57 (s, 1H), 10.25 (br, 1H), 10.06 (s, 1H), 8.76 (br, 1H), 8.60 (d, 1H), 8.22 (d, 2H), 8.05 (s, 1H), 7.87 (m, 3H), 7.50 (m, 2H), 4.18 - 4.52 (m, 5H), 4.08 (m, 2H), 3.99 (s, 3H), 3.62 (m, 4H), 3.30 (m, 2H), 1.95 (m, 2H).
  • N-(4- ⁇ 2-[(4- ⁇ 4-[3-(methyloxy)propanoyl]piperazin-1-yI ⁇ phenyl)amino]- pyrimidin ⁇ -yljphenyljcyclopropanecarboxamide NMR (400 MHz, d6-DMSO): 10.45 (s, 1H), 9.40 (s, 1H), 8.41 (s, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.98 (d, 2H), 3.60 (m, 6H), 3.22 (s, 3H), 3.0 - 3.11 (m, 4H), 6.62 (q, 2H), 0.82 (m, (4H).
  • N- ⁇ 4-[2-( ⁇ 4-[4-(3-thienylmethyl)piperazin-1-yl]phenyl ⁇ amino)pyrimidin-4-yl]- phenyljacetamide 1 H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.1 1 (d, 2H), 7.73 (d, 2H), 7.64 (d, 2H), 7.51-7.45 (m, 1H), 7.35 (d, 1H), 7.29-7.25 (m, 1H), 7.08-7.04 (m, 1H), 6.91 (d, 2H), 3.53 (s, 2H), 3.07 (m, 4H), 2.52 (m, 4H), 2.09 (s, 3H).
  • N-(4-(2-(4-(4-(2-cyclopropylacetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide 1 H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.54 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.59 (m, 4H), 3.04 (m, 4H), 2.30 (d, 2H), 2.09 (s, 3H), 0.97 (m, 1H), 0.45 (m, 2H), 0.14 (m, 2H).
  • N-(4- ⁇ 2-[(4- ⁇ 4-[3-(methyloxy)propanoyl]piperazin-1- yl ⁇ phenyl)amino]pyrimidin-4-yl ⁇ phenyl)acetainide 1 H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.95 (d, 2H), 3.58 (m, 6H), 3.23 (s, 3H), 3.08 (m, 2H), 3.02 (m, 2H), 2.62 (t, 2H), 2.09 (s, 3H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)-L- threoninamide 1 H NMR (400 MHz, d6-DMSO): 11.53 (s, 1H), 10.11 (s, 1H), 8.51 (d, 1H), 8.31 (d, 2H), 8.15 (d, 2H), 7.86 (t, 3H), 7.73 (d, 2H), 7.44 (d, 2H), 4.01 (m, 6H), 3.48 (m, 4H), 1.18 (s, 3H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)-D- norvalinamide 1 H NMR (400 MHz, d6-DMSO): 1 1.50 (s, 1H), 10.15 (s, 1H), 8.56 (m, 3H), 8.24 (d, 2H), 7.94 (d, 2H), 7.76 (m, 3H), 7.51 (d, 2H), 4.08 (m, 4H), 3.67 (d, 1H), 1.97 (m, 4H), 1.43 (m, 2H), 1.19 (m, 2H), 0.94 (m, 3H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)-D- norleucinamide 1 H NMR (400 MHz, d6-DMSO): 11.55 (s, 1H), 10.19 (s, 1H), 8.57 (d, 2H), 8.26 (d, 1H), 8.01 (m, 4H), 7.80 (m, 3H), 7.53 (d, 2H), 4.05 (m, 4H), 3.68 (d, 1H), 1.92 (m, 4H), 1.36 (m, 4H), 1.19 (m, 2H), 0.99 (d, 3H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)-L- alloisoleucinamide 1 H NMR (400 MHz, d6-DMSO): 11.32 (s, 1H), 10.01 (s, 1H), 8.56 (d, 2H), 8.44 (d, 3H), 8.21 (d, 2H), 7.89 (m, 3H), 7.46 (d, 2H), 4.02 (m, 4H), 3.56 (d, 1H), 1.99 (m, 4H), 1.63 (m, 1H), 1.17 (m, 2H), 1.00 (d, 3H), 0.91 (d, 3H).
  • N-(4- ⁇ 2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl ⁇ phenyl)-L- leucinamide 1 H NMR (400 MHz, d6-DMSO): 11.32 (s, 1H), 9.97 (s, 1H), 8.56 (d, 2H), 8.45 (d, 3H), 8.21 (d, 2H), 7.89 (m, 3H), 7.46 (d, 2H), 4.02 (m, 4H), 3.57 (d, 1H), 1.99 (m, 4H), 1.91 (m, 1H), 1.71 (t, 2H), 1.17 (t, 3H), 0.95 (t, 3H). MS (EI): 461.6 (MH+).

Abstract

L'invention concerne un procédé de traitement d'une maladie chez un mammifère. Le procédé consiste à administrer à un mammifère qui en a besoin une quantité thérapeutiquement efficace d'un composé JAK-2 de la formule I (J) tel que décrit dans les spécifications ou d'une composition pharmaceutique comprenant une quantité thérapeutiquement efficace du composé JAK-2 de formule I (J) et d'un support pharmaceutiquement acceptable, en combinaison avec un agent actif sélectionné parmi un inhibiteur Raf, un inhibiteur EGFR, un inhibiteur VEGFR, un inhibiteur ErbB2, un inhibiteur BCR-Abl, un inhibiteur Flt3, un inhibiteur Src, un inhibiteur C Kit, un inhibiteur Akt, un inhibiteur Ret, un inhibiteur IFG1R, un inhibiteur m-Tor, un inhibiteur PI3K, un inhibiteur PI3K-alpha.
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