WO2009017838A2 - Combinations of jak-2 inhibitors and other agents - Google Patents

Combinations of jak-2 inhibitors and other 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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French (fr)
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WO2009017838A3 (en
Inventor
Peter Lamb
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Exelixis, Inc.
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Publication of WO2009017838A2 publication Critical patent/WO2009017838A2/en
Publication of WO2009017838A3 publication Critical patent/WO2009017838A3/en

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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

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) as described in the specification, 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 an active agent selected from of a Raf inhibitor, an EGFR inhibitor, a VEGFR inhibitor, a ErbB2 inhibitor, a BCR-Abl, inhibitor, a Flt3 inhibitor, a Src inhibitor, a c Kit inhibitor, an Akt inhibitor, a Ret inhibitor, an IFG1R inhibitor, an m-Tor inhibitor, a PI3K inhibitior, a PI3Kalpha inhibitor, wherein the mammal is in need of the treatment.

Description

COMBINATIONS OF JAK-2 INHIBITORS AND OTHER AGENTS
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] 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.
State of the Art
[0002] Improvements in the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms.
[0003] Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i.e., virtually all aspects of cell life in one-way or another depend on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer). [0004] 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. 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.
[0005] 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.
[0006] Constitutive STAT activation is a feature of a wide variety of human tumors. In particular, activation of STAT5 is observed in leukemias, including CML, AML and ALL, whereas 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. SUMMARY OF THE INVENTION
[0007] The following only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. All references cited in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this specification and the references incorporated by reference, the express disclosure of this specification shall control.
[0008] 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.
[0009] There are many different aspects of the invention as described hereinbelow, and each aspect is non-limiting in regard to the scope of the invention. The term "invention" is meant to be non-limiting such that "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." The 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.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In aspect (1), 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. Non-limiting examples of 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 need of the treatment.
[0011] In aspects (1) - (29) of this invention, 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. For instance, a pharmaceutical composition of a PI3K inhibitor comprises the PI3K inhibitor and a pharmaceutically acceptable carrier.
[0012] In aspect (2), 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 PI3Kα inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the PI3Kα inhibitor as described hereinbelow, or a pharmaceutically acceptable salt thereof. Non-limiting examples of the PI3Kα inhibitors in this embodiment include any one or more of the PI3Kα compounds described hereinbelow that inhbit PBKα, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
[0013] In aspect (3), 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. [0014] In another aspect (4), 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 thereof. Non-limiting examples of the VEGFR inhibitors in this embodiment include any one or more of the VEGFR compounds described hereinbelow that inhibit VEGFR, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
[0015] In aspect (5), 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. Non-limiting examples of 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 mammal is in need of the treatment.
[0016] In aspect (6), 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.
[0017] In aspect (7), 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. [0018] In aspect (8), 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 acceptable salt thereof. Non-limiting examples of the Flt3 inhibitors in this embodiment include any one or more of the Flt3 compounds described hereinbelow that inhibit Flt3, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment.
[0019] In aspect (9), 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. [0020] In aspect (10), 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. [0021] In aspect (11), 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 pharmaceutically acceptable salt thereof. 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. [0022] In aspect (12), 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 pharmaceutically acceptable salt thereof. 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. [0023] In aspect (13), 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 treatment.
[0024] In aspect (14), 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. Non-limiting examples of 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.
[0025] In aspect (15), 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. Non-limiting examples of the IGFlR inhibitors in this embodiment include any one or more of the IGFlR compounds described hereinbelow that inhibit IGFlR, or the pharmaceutically acceptable salts thereof, wherein the mammal is in need of the treatment. [0026] In aspect (16), 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 a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
[0027] In aspect (17), 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 P13Kα compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the PDKα compound as described hereinbelow, or a pharmaceutically acceptable salt thereof, wherein the mammal is in need of the treatment.
[0028] In aspect (18), 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.
[0029] In another aspect (19), 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 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.
[0030] In aspect (20), 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. Non-limiting examples of 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 mammal is in need of the treatment.
[0031] In aspect (21), 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. [0032] In aspect (22), 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.
[0033] In aspect (23), 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.
[0034] In aspect (24), 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.
[0035] In aspect (25), 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.
[0036] In aspect (26), 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. [0037] In aspect (27), 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. [0038] In aspect (28), 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.
[0039] In aspect (29), 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.
[0040] In other embodiments for any of the aspects described above [including any of aspects (l)-(35)], 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. In other embodiments for any of the aspects described above [including any of aspects (l)-(35)], 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. In other embodiments for any of the aspects described above [including any of aspects (l)-(35)], the diseases that can be treated are selected from myelofibrosis, thrombocythemia, polycythemia vera, essential thrombocythemia, agnogenic myeloid metaplasia, and chronic myelogenous leukemia. In other embodiments for any of the aspects described above, 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. In other embodiments for any of the aspects described above [including any of aspects (l)-(35)], the diseases that are treated are selected from congestive heart failure and hypertension. In other embodiments for any of the aspects described above [including any of aspects (l)-(35)], the diseases that can be treated include those related to hematopoitic abnormality such as thrombocytosis. [0041] In other embodiments in any of the aspects described herein [including any of aspects (l)-(35)] , 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.
JAK-2 COMPOUNDS
[0042] 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, R1 for the JAK-2 compounds has a separate and distinct meaning from R1 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 (described above) are the following compounds: [0043] The JAK-2 compound is a compound of Formula I(J):
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, wherein
D is hydrogen, halo, -CF3, heterocycloalkyl or alkyl; E is hydrogen, halo, -CF3, 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, -C(O)OR26, -C(=N-OH)alkyl, -C(O)R8, -C(O)NR30R30a, -CH2R2,
-(CH2)n5NR26R26a, -CF3, -CN, -SO2R12, -S-R12a, -OR32a, -NHC(O)R32, aryl, and heterocycloalkyl optionally substituted with 1 or 2 oxo, or Z and R25, 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 R25 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;
R1 is hydrogen;
R2 is selected from one of the following groups:
Figure imgf000017_0001
or R2 is selected from one of the following groups:
Figure imgf000018_0001
ring X in Formula (d) of R2 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;
R7, R7 , R9, R10, R12 and R15 are each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl; R8 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, hydroxyalkyl, alkoxyalkyl, dihydroxyalkyl, alkylamino, dialkylamino, aminoalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkylaminoalkyl, dialkylaminoalkyl, -(CH2)r- C(O)OR7, -(CH2)r-C(O)NR7R7', aryl, heteroaryl, cycloalkyl, arylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with one, two, three, four or five groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; each R1 1, when R1 1 is present, is independently selected from alkyl, alkenyl, lower alkynyl, -CF3, alkoxy, halo, haloalkoxy, haloalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkyl, dialkylaminoalkoxy, oxo, thioalkyl, alkylthioalkyl, -(CH2)P-OR17, -CN, -0-CH2-C(O)-R17, -C(O)R16, -(CH2)p-C(O)OR17, -S(O)2R17, -S(O)2NR15R17, aryl, heteroaryl, cycloalkyl, arylalkyl, arylalkoxy, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at any ring position with 1 , 2, 3 or 4 R21;
R12 is hydrogen or alkyl; R12a is hydrogen or alkyl;
R13 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
-(CH2)r-C(O)OR7, -(CH2)r-C(O)NR7R7', aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with 1, 2, 3, 4 or 5 groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; and wherein the alkyl of cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl are independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from halo and hydroxy;
R14 is a bond, heterocycloalkyl or cycloalkyl; R16 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, dialkylaminoalkyl, -(CH2)r-C(O)OR7, aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with one, two, three, four or five groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; and wherein the alkyl of cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from halo and hydroxy;
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, -(CH2)r-C(O)OR7, -(CH2)r-C(O)NR7R7', aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with one, two, three, four or five groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; and wherein the alkyl of cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from halo and hydroxy; each R21, when R21 is present, is independently selected from alkyl, alkenyl, lower alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyloxy, haloalkyl, oxo, -OR13, -NHS(O)2R17, -S(O)2R17, -C(O)R17, -C(O)OR17, -C(O)NR15R17, -NR15C(O)R17, aryl, arylalkyl, heteroarylalkyl, aryloxy, and heteroaryl; wherein each of the aryl, arylalkyl, heteroarylalkyl, aryloxy, and heteroaryl within R21 are optionally substituted at any ring position with 1 , 2, or 3 groups selected from alkyl, lower alkoxy halo, phenyl, heteroaryl and alkylheteroalkyl; R25 is selected from alkyl, alkenyl, lower alkyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, -OR12, cyano, -CH2NHC(O)OR7, -CH2NHC(O)R7, -SR7, -S(O)2R7, -S(O)2NR7R8, -C(O)OR8, -C(O)NR7R8, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one, two or three groups independently selected from alkyl, alkenyl, halo, haloalkoxy, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, -OR8, -NHS(O)2R8, cyano, -C(O)R8, -CH2NHC(O)OR7,
-CH2NHC(O)R7, -SR7, -S(O)2R7, -S(O)2NR7R8, -C(O)OR8, -C(O)NR7R8, -NR7 C(O)-CHR3-OR8, -NR7 C(O)-CHR3-NR7-R8, and -NR7C(O)R8; R26 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; R26a is hydrogen, alkyl, heteroaryl, -C(O)R32, -C(O)NHR323, -S(O)2R9, -SR9,
-C(O)OR32, or -C(O)NR323R32; R and R are each independently selected from alkyl, alkenyl, hydroxy, alkoxy, and alkoxy alkyl; R27a and R28a are independently selected from hydrogen, alkyl, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminoalkyl, arylcarbonylalkyl, aryloxyalkyl, dialkylaminoalkyl, alkyl-O- C(O)heterocylcoalkyl, -(CH2)n4heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -(CH2)n4-C(O)R29, -(CH2)n4NR28R28a, -(CH2)n4NHR28a, -CII(phenyl)2, -S(O)2R29, -C(O)R29, -C(O)OR29, and -C(O)NR293R29, wherein the aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl groups within R27a and R28a 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, -CF3, oxo, -OCF3, alkoxyphenyl, and heteroaryl optionally substituted with alkyl or halo; or R27 and R27a, together with the nitrogen to which they are attached, form heterocycloalkylamino, heterocycloalkyl or heteroaryl, wherein the heterocycloalkylamino and heteroaryl are each independently optionally substituted with 1, 2, 3, 4, or 5 R31; or R28 and R28a 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 R31; R29a is hydrogen or alkyl;
R29 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 R29 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, -CF3, oxo, -OCF3, alkoxyphenyl, and heteroaryl optionally substituted with alkyl or halo; R3Oa is hydrogen or alkyl;
R30 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 groups within R30 are each independently optionally substituted at any ring position with 1, 2, 3, 4, or 5 groups selected from halo, alkyl, alkoxy, alkoxyalkyl, -C(O)OCH3, -CF3, -OCF3, alkylcarbonyl, phenyl, phenoxy, alkylphenoxy, dialkylaminoalkoxy and heteroaryl;
R31 is selected from alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, -C(O)R30, -C(O)NR30R303, -C(O)OR30, -S(O)2R30, 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, spirocyclic heterocycloalkyl, and heterocycloalkylalkyl, wherein the aryl, arylalkyl, cycloalkyl, arylheteroarylalkyl, arylalkoxyalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl groups within R31 are each independently optionally substituted at any ring position with 1, 2, 3, 4, or 5 groups selected from halo, alkyl, -CF3, -OCF3, cyano, alkoxy, alkoxyalkyl, -C(O)OCH3, alkylcarbonyl, phenyl optionally substituted at any ring position with halo, phenoxy, alkylphenoxy, arylalkoxyalkyl, dialkylaminoalkoxy and heteroaryl; R32a is hydrogen, -OCF3, -CF3, or alkyl; R32 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, -CF3, -OCF3, aminoalkyl, alkylaminoalkyl, aryl and dialkylaminoalkyl, and wherein the alkyl portion of the heteroarylalkyl can be substituted with amino; or R32 is alkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from hydroxy, alkoxycarbonyl, alkoxy, -CF3, halo, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonylalkylamino, dialkylaminocarbonyl, -NR34R34a and phenyl optionally substituted with 1, 2, or 3 halo; or R32 is alkylamino or arylalkylamino; R34 is hydrogen or alkyl;
R34a 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 R35 is selected from halo, -(CH2)PC(O)OR]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. Abbreviations and Definitions
[0044] The following abbreviations and terms have the indicated meanings throughout:
Figure imgf000024_0001
Figure imgf000025_0003
[0045] 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.
[0046] It is assumed that when considering generic descriptions of compounds of the invention for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that there can theoretically be some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra). [0047] The atom numbering convention for the quinazoline structure is as follows:
Figure imgf000025_0001
[0048] The symbol "-" means a single bond, "=" means a double bond, "≡" means a triple bond. The symbol
Figure imgf000025_0002
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. When a group is depicted removed from its parent Formula, the " ~" symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural Formula. [0049] If a group "R" is depicted as "floating" on a ring system, as for example in the Formula:
Figure imgf000026_0001
then, unless otherwise defined, 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.
[0050] If a group "R" is depicted as floating on a fused ring system, as for example in the Formulae:
Figure imgf000026_0002
then, unless otherwise defined, 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. In the example depicted, the "R" group may reside on either the 5- membered or the 6-membered ring of the fused ring system. In the Formula depicted above, when y is 2 for example, then 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. [0051] When there are more than one such depicted "floating" groups, as for example in the Formulae:
Figure imgf000026_0003
where there are two groups, namely, the "R" and the bond indicating attachment to a parent structure; then, unless otherwise defined, the "floating" groups may reside on any atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring. [0052] When a group "R" is depicted as existing on a ring system containing saturated carbons, as for example in the Formula:
Figure imgf000027_0001
where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" may reside on the same carbon.
A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon). In another example, 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:
Figure imgf000027_0002
[0053] "Spiro", "Spirocyclyl" or "spiro ring" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, 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.
Figure imgf000027_0003
[0054] "Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield. [0055] "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.
[0056] "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.
[0057] "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, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofϊbroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis defomians), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal Glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above- identified conditions.
[0058] 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, 17th 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.
[0059] 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, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like. [0060] 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. 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. Examples of organic bases 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.
[0061] "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.
[0062] "Metabolite" 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). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, 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. [0063] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, 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. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
[0064] "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. [0065] "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. [0066] In one specific embodiment of the JAK compound of Formula I(J) is a compound of Formula II(J):
Figure imgf000032_0001
wherein E, D, L, Z, R1, R and R are as defined above for the compound of Formula I(J). [0067] In another specific embodiment of the the JAK compound of Formula I(J) is a compound of Formula III( J):
Figure imgf000032_0002
wherein E, D, L, Z, R1, R2 and R25 are as defined above for the compound of Formula I(J).
[0068] Another specific embodiment of the JAK compound of Formula I is a compound of Formula IV(J) :
Figure imgf000032_0003
wherein D, E, R25 and R32 are as defined above for Formula I, and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31, and wherein R31 is as defined above in Formula I(J).
[0069] Another specific embodiment of the JAK-2 compound of Formula I is a compound of Formula V(J):
Figure imgf000033_0001
wherein D, E, R25 and R32 are as defined above for Formula I, and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31, and wherein R31 is as defined above in Formula I(J). [0070] Another specific embodiment of the JAK compound of Formula I(J) is a compound of Formula VI(J):
Figure imgf000033_0002
wherein D, E, R25 and R32 are as defined above for Formula I, and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31, and wherein R ' is as defined above in Formula I(J).
[0071] In other embodiments of the JAK-2 compound, D, E and R25 for Formula
IV(J), Formula V(J) or Formula VI(J) are each hydrogen.
[0072] In other embodiments of the JAK-2 compound, R32 for Formula IV(J), Formula V(J) or Formula VI(J) is heterocycloalkyl.
[0073] In other embodiments of the JAK-2 compound, R32 for Formula IV(J), Formula
V(J) or Formula VI(J) is alkyl optionally substituted with alkoxy, hydroxy, amino, alkylamino, or dialkylamino. [0074] In other embodiments of the JAK-2 compound, R2 in Formula I(J), II(J) or III(J) is
Figure imgf000034_0001
wherein R27 a, R11 and n2 are as defined above for the compound of Formula I(J). [0075] In other embodiments of the JAK-2 compound, R2 in Formula I(J), II(J) or III(J) is
Figure imgf000034_0002
wherein R28, R11 and n2 are as defined above for the compound of Formula I(J), and R28a 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.
[0076] In other embodiments of the JAK compound, R2 in Formula I(J), II(J) or III(J) is
Figure imgf000034_0003
wherein R28 , R28a , R11 and n2 are as defined above for the compound of Formula I(J). [0077] In the embodiments of the JAK-2 compound, R2 in Formula I(J), II(J) or III(J) is
Figure imgf000034_0004
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. [0078] In other embodiments of the JAK-2 compound, R2 in Formula I(J), II(J) or III(J) is
Figure imgf000035_0001
wherein R and n2 are as defined above for the compound of Formula I(J), and R and R28a, 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. [0079] In other embodiments of the JAK-2 compound, R2 in Formula I(J), II(J) or III(J) is
Figure imgf000035_0002
wherein R27a, R11 and n2 are as defined above for the compound of Formula I(J). [0080] Other embodiments of the JAK compound are of Formula I(J), II(J) or III(J),
wherein L is a bond, and Z is
Figure imgf000035_0003
.
[0081] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J) ,
wherein Z is
Figure imgf000035_0004
and R25 is hydrogen.
[0082] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein Z is
Figure imgf000035_0005
, R25 is hydrogen and E and D are hydrogen. [0083] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J), wherein R25 is on the 3 position. [0084] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein Z is
Figure imgf000036_0001
, and R26a is -C(O)R32.
[0085] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein Z is
Figure imgf000036_0002
, R26a is -C(O)R32, and R32 is selected from lower alkyl, cylcoalkyl, diaminoalkyl, aminoalkyl, arylalkyl, heterocycloalkyl, alkoxyalkyl, alkylamino, and hydroxyalkyl optionally substituted with amino. [0086] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein Z is
Figure imgf000036_0003
, R26a is -C(O)R32, and R32 is cycloalkyl.
[0087] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein Z is
Figure imgf000036_0004
, R26a is -C(O)R32, and R32 is lower alkyl.
[0088] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J)
wherein Z is
Figure imgf000036_0005
, R26a is -C(O)R32, R26 is hydrogen, wherein R32 selected from aryl, arylalkyl, cycloalkyl, alkoxycarbonylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R32 optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl or halo. [0089] Other embodiments of the JAK compound are of Formula I(J), II(J) or III(J),
wherein Z is
Figure imgf000036_0006
, R26a is -C(O)R32, R26 is hydrogen, wherein R32 selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R32 optionally substituted with 1 , 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl or halo. [0090] Other embodiments of the JAK compound are of Formula I(J), II(J) or III(J),
wherein Z is , R26a is -C(O)R32, R26 is hydrogen, wherein R32 is lower alkyl
Figure imgf000036_0007
optionally substituted with 1, 2, 3, 4 or 5 groups selected from dialkylaminocarbonyl, hydroxy and -NR34R34", wherein R34 and R34a are as defined above for Formula I(J). [0091] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein R2 is
Figure imgf000037_0001
[0092] In another embodiment of the JAK-2 compound, R32 is methyl.
[0093] In another embodiment of the JAK-2 compound, R32 is alkyl substituted with
-NR34R34a.
[0094] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J), wherein R32 is U or -CH2-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.
[0095] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J), wherein R1 1, when present, is halo or lower alkyl.
[0096] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J), wherein R1 ', when present, is lower alkyl.
[0097] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J), wherein R35 is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl.
[0098] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J), wherein n2 is 0.
[0099] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein R2 is
Figure imgf000037_0002
[00100] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
wherein R2 is
Figure imgf000037_0003
, and wherein R28 and R28 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
[00101] Other embodiments of the JAK-2 compound are of Formula I(J), II(J) or III(J),
IV(J) or V(J), wherein R25 is hydrogen. [00102] Representative 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.
TABLE l(J)
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
JAK-2 Definitions
[00103] The following definitions apply to the JAK-2 compounds described above only. These definitions are not to be considered when determining the scope and meaning of any of the compounds that are not JAK-2 compounds. To the same extent, the definitions for the compounds described herein that are not JAK-2 compounds are not to be considered when determining the scope and meaning of the JAK-2 compounds. [00104] "Alkyl" is intended to include C1-C20, more typically, C1-C12 linear or branched structures and combinations thereof, inclusively. "Lower alkyl" is intended to include C1-C6 linear or branched structures and combinations thereof, inclusively. For example, "C6 alkyl" can refer to an n-hexyl, iso-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. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either "butyl" or "C4 alkyl" is meant to include n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-ynyl groups; and for example, "propyl" or "C3 alkyl" each include n-propyl, propenyl, and isopropyl. [00105] "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. [00106] "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.
[00107] "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. Examples of alkylene include ethylene (- CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CH3)2CH2-), and cyclohexylpropylene (-CH2CH2CII(C6H13)). [00108] "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.
[00109] "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.
[00110] Any of the above groups, "alkylene," "alkylidene" and "alkylidyne," when optionally substituted, can contain alkyl substitution which itself contains unsaturation.
For example, 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an n- butylid-3-ynyl group with a vinyl substituent at the 2-position of said group.
[00111] "Alkoxy" or "alkoxyl" 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. .
[00112] "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.
[00113] "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.
[00114] "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. When a group is referred to as or "-(C1-C6)alkylaryl," an aryl moiety is attached to a parent structure via an alkylene group. Examples include benzyl, phenethyl, and the like. [00115] In some examples, as appreciated by one of ordinary skill in the art, 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. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.
[00116] "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. In this application, fused-polycyclics and fused ring systems includes non-aromatic and aromatic systems. Typically, but not necessarily, 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.
[00117] "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 - CH2F, -CHCl2 or -CF3. [00118] "Heteroatom" refers to O, S, N, or P.
[00119] "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. For purposes of this invention, 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. In a specific example, the group -S(O)0-2-, refers to -S- (sulfide), -S(O)- (sulfoxide), and -SO2- (sulfone) respectively. For convenience, 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. Thus, for a compound of the invention having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included as another compound of the invention. In addition, annular nitrogen atoms can be optionally quaternized; and the ring substituent can be partially or fully saturated or aromatic. Examples of 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, fiiryl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, and tetrahydroquinolinyl. [00120] "Heterocycloalkyl" refers to a stable 4-12 membered monocyclic, bicyclic or tricyclic ring containing one or more heteroatoms.
[00121] "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. [00122] "Amino" refers to -NH2. [00123] "Alkylamino" refers to -NII(alkyl), wherein "alkyl" is as defined above, and wherein the the parent moiety is attached to the nitrogen atom.
[00124] "Dialkylamino" refers to -N(alkyl)2, wherein "alkyl" is as defined above, and wherein the parent moiety is attached to the nitrogen atom. [00125] "Dialkylaminoalkyl refers to -(alkyl)N(alkyl)2, wherein "alkyl" is as defined above. One such non-limiting example of "dialkylaminoalkyl" includes -CH2C(CH3)2CH2N(CH3)2. [00126] "Aminoalkyl" refers to -(alkyl)NH, wherein "alkyl" is as defined above, and wherein the the parent moiety is attached to the alkyl group.
[00127] "Aminoalkyl" refers to -(alkyl)NH2, 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(NH2)CH3,
[00128] Phenoxy refers to a -alkyl-O-phenyl group, wherein "alkyl" is as defined above, and the parent moiety is attached to the alkyl group. [00129] "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, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Fused, bridged, and spiro moieties are also included within the scope of this definition.
[00130] "Carbonyl" refers to the group "-C(O)-", which is bivalent. [00131] "Aminocarbonyl" refers to the group "-C(O)-NH2," wherein the parent moiety is attached to the amino group.
[00132] "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(CH3)3. [00133] When a group is referred to as "-C1-C6 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.
[00134] "Hydroxyalkyl" means -alkyl-OH, wherein alkyl is as defined hereinabove. [00135] "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. So, for example, in the term "optionally substituted arylalkyl," both the "alkyl" portion and the "aryl" portion of the molecule may or may not be substituted. A list of exemplary optional substitutions is presented below in the definition of "substituted." [00136] Unless otherwise specified, the term "optionally substituted" applies to the chemical moiety immediately preceding it. For instance, if a variable group (such as R) is defined as aryl, optionally substituted alkyl, or cycloalkyl, then only the alkyl group is optionally substituted.
[00137] In the case where there is a point of attachment for a monovalent substituent, such as -CH3, -NH2, or -OH, the indication of where the point of attachment is is not necessary. That is, -CH3 has the same meaning as CH3, -NH2 has the same meaning as NH2, and -OH has the same meaning as OH.
[00138] In Table I(J), where there appears to be an empty valence for oxygen or nitrogen for any of the compounds listed in this table, where the name of the structure requires that the empty valence is filled with hydrogen, it is assumed that the missing valence is filled with hydrogen for each of these cases.
[00139] The 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, PI3Kα 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. [00140] "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.
[00141] "Spirocyclyl" or "spirocyclic ring" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, 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.
Figure imgf000111_0001
[00142] "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 (-CO2H), carboalkoxy (that is, acyloxy or -OC(=O)R), carboxyalkyl (that is, esters or -CO2R), carboxamido, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, halogen, hydroxy, nitro, sulfanyl, sulfinyl, sulfonyl, thiol, halogen, hydroxy, oxo, carbamyl, acylamino, and sulfonamido. Thus, 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. [00143] 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.
UTILITY OF JAK-2 COMPOUNDS
[00144] 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.
[00145] 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.
[00147] Suitable in vivo models of various cancers are known to those of ordinary skill in the art. For further details of in vivo assays see Biological Examples.
Synthetic Procedures for JAK-2 Compounds [00148] The 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.
[00149] The 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.
[00150] It is assumed that when considering generic descriptions of JAK-2 compounds for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that theoretically some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra). [00151] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) 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. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can be required to liberate the desired enantiomeric form. Alternatively, specific 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. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization. [00152] In addition, 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. [00153] In addition, it is intended that 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. [00154] 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. One skilled in the art will know that other procedures can be used to synthesize the JAK-2 compounds, and that the procedure described in Scheme 1 is only one such procedure. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of the JAK-2 compounds described herein. Thus, the general synthetic procedure depicted in Scheme 1 in conjunction with the specific examples that follow provide sufficient information and guidance to allow one of ordinary skill in the art to synthesize the JAK-2 compounds. [00155] Compounds of Formula I(J) can be prepared according to Scheme 1 :
Scheme 1
Figure imgf000114_0001
[00156] The synthesis of compounds of Formula I(J) proceeds from commercially available reagents and employs standard techniques. Standard Suzuki coupling reactions conditions can be used to convert dichloropyrimindines of Formula A (commercially available from Sigma Aldrich) and boronic acids of Formula B (commercially available from Sigma Aldrich, Fisher Scientific, or Combi-Blocks Inc.), where R25, Z and and nl are as defined in the Detailed Description of the Invention, to 4-substituted-2- chloropyrimidines of Formula C. Compounds of Formula Dl and I can be generated by reaction of C with the corresponding amines (Fl, available from Fluka) or anilines (F2, available from Sigma Aldrich). 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. For instance, Dl ca be reacted with an intermediate of Formula LG1C(O)R4 where LG1 is a leaving group under acylation conditions and R4 is phenyl optionally substituted with 1, 2, 3, 4, or 5 R11 groups, wherein R11 is as defined in the Detailed Description of the Invention to yield a compound of Formula E.
Synthetic Examples for JAK-2 Compounds
[00157] The following examples serve to more fully describe the manner of making the JAK-2 compounds described herein. These examples in no way serve to limit the scope of the JAK-2 compounds or the JAK-2 inhibitors, but rather are presented for illustrative purposes. All references cited herein are incorporated by reference in their entirety.
Generally, 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.
Example 1
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)acetamide (Compound 58) a) N-(4-(2-chloropyrimidin-4-yl)phenyl)acetamide (C1)
Figure imgf000115_0001
[00158] A flask was charged with 2,4-dichloropyrimindine Ai (650 mg, 4.4 mmol), 4-acetoamidophenylboronic acid Bi (820 mg, 4.6 mmol), dicholor[l ,l '-bis(diphenyl- phosphino)ferrocenepalladium (480 mg, 0.56 mmol, 15 mol %), and triethylamine (1.5 H)L, 11 mmol). Ethyleneglycoldimethylether (30 mL) was added to the flask and the mixture was purged with N2 for 5 minutes. The reaction mixture was stirred under an N2 atmosphere at 80 °C for 12 hours, after which time, ether was added and the reaction mixture was filtered. The product, C1, was isolated by removal of the solvent with a rotary evaporator and used without further purification. LCMS: m/z 248 (M+H)+. b) N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)acetamide (58)
Figure imgf000116_0001
[00159] A flask containing a solution of C1 (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. The solvent was removed on a rotary evaporator and the product was purified by HPLC with TF A/A CN as eluent. The TFA salt was removed by extraction with sodium hydroxide and ethylacetate to afford the title compound 58.
Example 2
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide (Compound 7)
Figure imgf000116_0002
[00160] A flask was charged with 58 (638 mg, 2.0 mmol), 2,6-dichlorobenzoylchloride G (350 μL, 2.4 mmol), diispropylethylamine (1.1 mL, 6 mmol) and THF (50 mL). The reaction mixture was stirred at 70 °C for 6 hours. The crude mixture was concentrated on a rotary evaporator and the crude product was purified by HPLC with TFA/ACN as eluent. The title compound 7 was isolated by precipitation from ACN and washed with ether. 1H-NMR (400MHz, d6-DMSO): 10.718 ppm (s, 1H), 10.269 ppm (s, 1H), 9.678 ppm (s, 1H), 8.507 ppm (d, 1H), 8.419 ppm (s, 1H), 8.215 ppm (d, 2H), 7.758 ppm (d, 2H), 7.608 ppm (d, 2H), 7.532 ppm (t, 1H), 7.472 ppm (d, 1H), 7.380 ppm (d, 1H), 7.301 ppm (t, 1H), 7.216 ppm (d, 1H), 2.085 ppm (s, 3H); MS (EI) C25H]9Cl2N5O2: 492.2 (MH+). Example 3 N-(4-{2-[(4-morpholin-4-ylphenyl)aminoJpyrimidin-4-yl}phenyl)acetamide (18)
Figure imgf000117_0001
[00161] A flask was charged with C1 (500 mg, 2.0 mmol), 4-morpholinoaniline H (540 mg, 3.0 mmol) and nBuOH (10 mL). The flask was immersed in a 180 °C oil bath for 30 minutes. The reaction mixture was cooled to ambient temperature and the black residue dissolved in DMF and MeOH. The product was purified by HPLC with TFA/ACN as eluent. The TFA salt was removed by extracting with sodium hydroxide and ethylacetate to afford the title compound (18).
1H-NMR (400MHz, d6-DMSO): 10.533 ppm (s, 1H), 9.408 ppm (s, 1H), 8.447 ppm (d, 1H), 8.114 ppm (d, 2H), 7.813 ppm (d, 2H), 7.705 ppm (d, 2H), 7.288 ppm (d, 1H), 6.982 ppm (br s, 2H), 4.65 ppm (br s, 4H), 3.072 ppm (br s, 2H), 2.108 ppm (s, 3H); MS (EI) C22H23N5O2: 390.3 (MH+).
Example 4
N-{l-[(2,6-dichlorophenyl)carbonyl]piperidin-4-yl}-4-(4-methyl-2-thienyl)pyrimidin- 2-amine
Figure imgf000117_0002
[00162] To a solution of {4-[4-(5-Methyl-thiophen-2-yl)-phenyl]-pyrimidin-2-yl}- piperidin-4-yl-amine hydrochloride I (274mg, 1 mmoL) and TEA (0.69mL, 5 mmo) in DMF (5 mL) was added 2,6-dichlorobenzoyl chloride G (0.2ImL, 1.5 mmol) and the solution was stirred for 4 h. To the resulting solution was added ethyl acetate (10OmL) and the organic layer was washed with 5% LiCl (3 x 5OmL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue. This residue was purified by reverse phase HPLC to yield the product G2 (195mg, 38.9% yield, acetate salt) as a tan solid. 1H NMR (400 MHz, d6-DMSO): 8.28 (m, 1H), 7.73 (m, 1H), 7.58-7.54 (m, 2H), 7.48-7.46 (m, 1H), 7.32 (s, 1H), 7.27 (m, 1H), 7.01 (m, 1H), 4.47 (m, 1H), 4.03 (m, 1H), 3.30-3.05 (m, 2H), 2.25 (s, 3H), 2.03 (m, 1H), 1.88 (m, 1H), 1.58-1.48 (m, 3H); MS (EI) for C21H20Cl2N4OS: 447 (MH+).
Example 5
N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide (Compound 574) a) N-(4-(2-chloro-5-m ethylpyrim idin-4-yl)phenyl)acetam ide (C 2)
Figure imgf000118_0001
B1 C2 [00163] A flask was charged with 5-methly-2,4-dichloropyrimindine C2 (2.45g, 15.0mmol), 4-acetoamidophenylboronic acid (2.95g, 16.5mmol), dicholor[l,l '- bis(diphenyl-phosphino)ferrocenepalladium Bi (1.22g, 1.5mmol, 10 mol %), and triethylamine (5.23mL, 37.5mmol). Ethyleneglycoldimethylether (20 mL) and H2O (5ml) were added to the flask and the mixture was purged with N2 for 5 minutes. The reaction mixture was stirred under an N2 atmosphere at 90 °C for 2hours, after which time, ether was added and the reaction mixture was filtered. The product, C2, was isolated by removal of the solvent with a rotary evaporator and used without further purification. LCMS: m/z 262 (M+H)+. b) N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)ammo]pyήmidin-4- yl}phenyl)acetam ide
Figure imgf000119_0001
[00164] A flask containing a solution of C2 (523 mg, 2.0 mmol) and H (392 mg, 2.2mmol) in n-BuOH (6 mL) was immersed in an oil bath at 180 °C for 3hr. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by HPLC with Ammonium acetate/ACN as eluent to afford the title compound 574 (531mg, 66%).
1H-NMR (400MHz, d6-DMSO): 10.15 ppm (s, 1H), 9.27 ppm (s, 1H), 8.31 ppm (s, 1H), 7.72 ppm (d, J = 8.8Hz, 2H), 7.66-7.62 ppm (m, 4H), 6.88 ppm (d, J = 8.8Hz, 2H), 3.73 (t, J = 4.8Hz, 4H), 3.01 (t, J = 4.8Hz, 4H), 2.21 ppm (s, 3H), 2.09 (s, 3H); MS (EI) C23H25N5O2: 404 (M+H)+.
Example 6
N-(4-(2-(3,5-dimorpholinophenylamino)-5-methylpyrimidin-4-yl)phenyl)acetamide (Compound 570)
Figure imgf000119_0002
[00165] A flask containing a solution of C2 (288 mg, 1.1 mmol) and Hi (263 mg, 1.Ommol) in n-BuOH (3 mL) was immersed in an oil bath at 180 °C for 4hr. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by HPLC with ammonium acetate/acetonitrile (ACN) as eluent to afford the title compound 570 (205mg, 42%).
1H-NMR (400MHz, d6-DMSO): 10.15 ppm (s, 1H), 9.22 ppm (s, 1H), 8.34 ppm (s, 1H), 7.72 ppm (d, J = 9.2Hz, 2H), 7.69 ppm (d, J = 8.8Hz, 2H), 7.10 ppm (d, J = 2.0Hz, 2H), 6.09 ppm (s, 1H), 3.71 (t, J = 4.8Hz, 8H), 3.03 (t, J = 4.8Hz, 8H), 2.26 ppm (s, 3H), 2.07 (s, 3H); MS (EI) C27H32N6O3: 489 (M+H) +
Example 7
'N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide
Figure imgf000120_0001
[00166] A solution of N-(4-(2-(4-(piperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl) acetamide (300mg, 0.6mmol) and DIPEA (261ul, 1.50mmol) was treated with isobutyryl chloride at room temperature. After stirring for 10 minutes, the reaction mixture was directly concentrated in vacuo and the residue was purified by HPLC TF A/A CN as eluent. TFA salt was removed by using basic resin to afford 11 lmg (40%) of the title compound 572.
1H-NMR (400MHz, (I6-DMSO): 10.21 ppm (s, 1H), 9.40 ppm (s, 1H), 8.44 ppm (d, J = 4.8Hz, 1H), 8.11 ppm (d, J = 9.2Hz, 2H), 8.10 ppm (s, 1H), 7.74 ppm (d, J = 8.8Hz, 2H), 7.68 ppm (d, J = 8.8Hz, 1H), 7.28 ppm (d, J = 5.6Hz, 1H), 6.97 (d, J = 9.6Hz, 2H), 3.65- 3.61 (m, 4H), 3.08-3.02 (m, 4H), 2.92 ppm (penth, J = 6.8Hz, 1H), 2.09 ppm (s, 3H), 1.03 ppm (s, 3H), 1.01 ppm (s, 3H); MS (EI) C26H30N6O2: 459 (M+H)+.
Example 8
Methyl (4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)carbamate (Compound 248)
Figure imgf000121_0001
55 248
[00167] To a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2- amine 55 (100 mg, 0.29 mmol) and DIEA (0.435 mmol, 75 μl) in THF (50 mL) was added methyl chloroformate (0.348 mmol, 27 μl) and the solution was stirred at room temperature for 2 hours. The solution mixture was concentrated, redissolved with MeOH and purified using reverse phase HPLC. The product obtained from the reverse phase HPLC was free base 248, converted to HCl salt using 3 N HCl and lyophilized to yield the product 248 (60mg, 47% yield) as a yellow solid.
1H-NMR (400MHz, d6-DMSO): 10.063 ppm (s, 1H), 9.976 ppm (s, 1H), 8.521 ppm (d, 1H), 8.153 ppm (d, 2H), 7.878 ppm (d, 2H), 7.661 ppm (d, 2H), 7.554 ppm (bs, 2H), 7.432 ppm (d, 1H), 3.983 ppm (bs, 4H), 3.707 ppm (s, 3H), 4.435 ppm (bs, 4H); MS (EI) C22H23N5O3HCl: 475.4 (MH+).
Example 9 4-[4-(dimethylamino)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine (67) a) 4-(2-chloropyrimidin-4-yl)-N,N-dimethylaniline (Ci)
Figure imgf000121_0002
[00168] A flask was charged with A1 (650 mg, 4.4 mmol), 4-
(dimethylamino)phenylboronic acid B2 (797 mg, 4.8 mmol), dicholor[l ,l '- bis(diphenylphosphino)ferrocenepalladium (480 mg, 0.56 mmol, 15 mol %), and triethylamine (1.5 mL, 1 1 mmol). Ethyleneglycoldimethylether (30 mL) was added to the flask and the mixture was purged with N2 for 5 minutes. The reaction mixture was stirred under an N2 atmosphere at 80 °C for 12 hours, after which time, ether was added and the reaction mixture was filtered. The product, C3, was isolated by removal of the solvent with a rotary evaporator and used without further purification. LCMS: m/z 234 (M+H)+. b) 4-[4-(dimethylamino)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine (67)
Figure imgf000122_0001
C3 67
[00169] A flask was charged with C3 (500 mg, 2.1 mmol), 4-morpholinoaniline (573 mg, 3.2 mmol) and nBuOH (10 mL). The flask was immersed in a 180 °C oil bath for 30 minutes. The reaction mixture was cooled to ambient temperature and the black residue dissolved in DMF and MeOH. The product 67 was purified by HPLC with TFA/ACN as eluent. The TFA salt was removed by extracting with sodium hydroxide and ethylacetate to afford the free base of 67.
1H-NMR (400MHz, d6-DMSO): 9.24 ppm (s, 1H), 8.33 (d, 1H), 8.03 (d, 2H), 7.68 (d, 2H), 7.18 (d, 1H), 6.92 (d, 2H), 6.81 (d, 2H), 3.72-3.77 (m, 4H), 3.04-3.08 (m, 4H), 3.00 (s, 6H). MS (EI) C22H25N5O: 376.1 (MH+).
Example 10
4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine (Compound 319) a) 4-(2-chloropyrimidin-4-yl)benzonitrile
Figure imgf000122_0002
A1 B3 C4
[00170] A flask was charged with Ai (763 mg, 5.16 mmol), 4-cyanophenylboronic acid B3 (848 mg, 5.77 mmol), dicholoro[l,r-bis(diphenylphosphino)ferrocenepalladium (375 mg, 0.437 mmol, 10 mol %), and triethylamine (1.76 mL, 12.9 mmol). Ethylene glycol dimethyl ether (5.0 mL) was added to the flask and the mixture was purged with N2. The reaction mixture was stirred under an N2 atmosphere at 90 °C for 1 hour, after which time, it was cooled to ambient temperature and filtered. The product, C4, was isolated by removal of the solvent with a rotary evaporator and used without further purification. LCMS: m/z 216 (M+H)+. b) 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzonitrile (S)
nBuOH
Figure imgf000123_0001
Figure imgf000123_0002
[00171] A flask containing a solution of C4 (400 mg, 1.85 mmol) and 4- morphilinoaniline (362 mg, 2.04 mmol) in 1-butanol (10 mL) was immersed in an oil bath at 180 °C for 2 h. The mixture was cooled to ambient temperature, concentrated, and the crude product S was used without further purification. LCMS: m/z 358 (M+H)+. c) 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid
Figure imgf000123_0003
[00172] A flask containing a solution of S (600 mg, 1.68 mmol) and 10 N HCl (aq., 20 mL) was immersed in an oil bath at 100 °C for 5 hours. The mixture was cooled to ambient temperature, after which time, 5 N LiOH was added until the reaction mixture was pH 6. The white precipitate was filtered and dried to give the product T, which was used without further purification. LCMS: m/z 377 (M+H)+. d) 4-[4-(3-methyl-l, 2, 4-oxadiazol-5-yl)phenyl]-N-(4-morpholin-4- ylphenyl)pyrimidin-2 -amine (323)
Figure imgf000124_0001
[00173] To a flask containing a solution of T (570 mg, 1.47 mmol) and THF (10 mL) was added l,l '-carbonyldiimidazole (475 mg, 2.93 mmol). The reaction mixture was immersed in an oil bath at 60 °C for 2 h, after which time, it was cooled to ambient temperature. A mixture of acetamide oxime (120 mg, 1.62 mmol) and NaH (39 mg, 1.6 mmol) in DMF (5 mL) was added to the reaction mixture, after which time, the reaction mixture was immersed in an oil bath at 80 °C for 2 hours. The reaction mixture was then cooled to ambient temperature, quenched with saturated NH4Cl (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.
1H-NMR (400MHz, d6-DMSO): 9.57 ppm (s, 1H), 8.57 ppm (d, 1H), 8.38 ppm (d, 2H), 8.25 ppm (d, 2H), 7.67 ppm (d, 2H), 7.44 ppm (d, 1H), 6.95 ppm (d, 2H), 3.75 ppm (t, 4H), 3.06 ppm (t, 4H), 2.46 ppm (s, 3H); MS (EI) C23H22N6O2: 415.0 (MH+).
Example 11
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyI)-2-pyrrolidin-1- ylacetamide (Compound 292) a) 2-chloro-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)acetam ide
Figure imgf000124_0002
[00174] To a flask charged with 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin- 2-amine (100 mg, 0.286 mmol) and THF (1 mL) was added chloroacetyl chloride (0.0230 mL, 0.286 mmol). The solution was stirred at ambient temperature for 1 hour. The crude mixture was then concentrated and used without further purification. LCMS: m/z 424 (M+H)+. b) N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2- pyrrolidin-1-ylacetamide (292)
Figure imgf000125_0001
[00175] To a flask charged with U (100 mg, 0.236 mmol), diisopropylethylamine (0.2 mL, 1 mmol), and dimethylacetimide (1 mL) was added pyrrolidine (0.021 mL, 1.3 mmol). The reaction mixture was stirred at 80 °C for 1 hour. The crude mixture was concentrated on a rotary evaporator and the product 292 was purified by reverse phase
HPLC.
1H-NMR (400MHz, dδ-DMSO): 10.90 ppm (s, 1H), 10.20 ppm (br. s, 1H), 9.64 ppm (s,
1H), 8.50 ppm (d, 1H), 8.19 ppm (d, 2H), 7.78 ppm (d, 2H), 7.74 ppm (d, 2H), 7.36 ppm (d, 1H), 7.11 ppm (d, 2H), 4.32 ppm (s, 2H), 3.80 ppm (t, 4H), 3.70-3.65 ppm (m, 2H),
3.19-3.06 ppm (m, 6H), 2.10-1.86 (m, 4H); MS (EI) C26H30N6O2: 459.4 (MH+).
Example 12
3-methoxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)propanamide (Compound 575)
Figure imgf000126_0001
[00176] To a solution of 249(a) (0.18 g, 0.05 mmol), HATU (0.4 g, 1.1 mmol), and DIEA (0.5 mL, 4.0 mmol) in DMA (5 mL) was added 3-methoxypropanoic acid (0.1 mL, 1.05 mmol) and the solution was stirred at 60 °C for 2 hours. The solution mixture was diluted with ethyl acetate and the mixture was extracted with 10% LiCL (3X) and brine (IX). The resulting organic layer was dried with sodium sulfate and concentrated in vacuo. The product was purified by silica column chromatography (5% MeOH/DCM as eluent) to afford 0.1 g of the title compound 575 (49% yield) as a white solid. 1H-NMR (400MHz, d6-DMSO): 10.20 ppm (s, 1H), 9.37 ppm (s, 1H), 8.42 ppm (d, 1H), 8.10 ppm (d, 2H), 7.74 ppm (d, 2H), 7.65 ppm (d, 2H), 7.25pm (d, 1H), 6.91 ppm (d, 2H), 3.72 ppm (m, 4H), 3.61 ppm (t, 2H), 3.23 ppm (s, 3H), 3.03 ppm (m, 4H), 2.57 ppm (t, 2H); MS (EI) C22H23N5O3HCl: 434.3 (MH+).
Example 13 N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)prolinamide (576)
Figure imgf000127_0001
[00177] To a solution of 249(a) (5HC1) (0.2 g, 0.37 mmol) in DMA (5 mL) was added a solution of l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid, (d,l-boc-proline) (0.1 g, 0.46 mmol), Hunigs base (0.5 mL, 2.5 mmol), HATU (0.2 g, 0.52 mmol) and the solution was stirred at RT for 14 hours. The resulting solution was loaded on the silica gel and was purified by silica gel column chromatography (10-100% gradient of ethyl acetate/hexanes) to yield Z (160 mg) in 79% yield as yellow solid. LCMS: m/z 545 (M+H)+. d) N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2- carboxamide (Compound 585)
Figure imgf000127_0002
[00178] A flask containing a solution of Z (160 mg, 0.29 mmol) in 4M HCl in 1,4- dioxane (5 mL) and MeOH (5 mL) was stirred at 50 C for 1 hour. Concentration of the solvent gave a yellow solid that was purified by reverse phase HPLC using an ammonium acetate buffer to yield 105 mg (68%) of 576 as a yellow solid. 1H NMR (400 MHz, ^-MeOD): 8.36 (m, 1H), 8.14 (m, 2H), 7.78 (m, 2H), 7.62 (m, 2H), 7.22 (m, 1H), 6.98 (m, 2H), 4.15 (m, 1H), 3.83 (m, 4H), 3.21 (m, 2H), 3.13 (m, 4H), 2.41 (m, 1H), 2.06-1.91 (m, 3H); LCMS: for C25H28N6O2: 445 (M + H)+.
Example 14
2-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)propanamide (Compound 208)
Figure imgf000128_0001
249(a) 208
[00179] A flask was charged with 249(a) (140 mg, 0.3 mmol), N-(tert-butoxycarbonyl)- alanine (57 mg, 0.3 mmol, purchased from Chem-Impex International), HATU (140 mg, 0.37 mmol), diispropylethylamine (0.6 mL, 3.0 mmol) and DMA (5 mL). The reaction mixture was stirred at RT for 12 hours. The crude mixture was concentrated on a rotary evaporator and the residue was dissolved in 10 mL of MeOH and 5 mL of 4N HCl in dioxane. The reaction mixture was stirred at 70 °C for 1 hour. The crude mixture was concentrated on a rotary evaporator and the product was purified by HPLC with NH4OAc/ACN as eluent. The resulting solution was concentrated on a rotary evaporator and the final product, 208, was dried by lyophilization. 1H-NMR (400MHz, d6-DMSO): 9.387 ppm (s, 1H), 8.443 ppm (d, 1H), 8.127 ppm (d, 2H), 7.825 ppm (d, 2H), 7.676 ppm (d, 2H), 7.287 ppm (d, 1H), 6.939 ppm (d, 2H), 3.747 ppm (m, 4H), 3.457 ppm (q, 1H), 3.050 ppm (m, 4H), 1.896 ppm (s, 3H (AcOH)) 1.243 ppm (d, 3H); MS (EI) C23H26N6O2: 419.1 (MH+). Example 15
N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)acetamide (Compound 341) a) 4-(2-methoxy-4-nitrophenyl)morpholine (AA)
Figure imgf000129_0001
[00180] 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). 1H-NMR (400MHz, d6-DMSO): 7.83 (dd, 1H), 7.67 (d, 1H), 6.98 (d, 1H), 3.88 (s, 3H), 3.71 (m, 4H), 3.16 (m, 4H). MS (EI) CnH14N2O4: 239 (M+H)+. b) 3-methoxy-4-morpholinoaniline
Figure imgf000129_0002
[00181] To a solution of AA (8.8 g, 37.0 mmol) in ethyl acetate (30 mL) and methanol
(10 mL) in a Parr bottle was added 1 g 10% palladium on carbon. The reaction mixture was hydrogenated at 40 PSI H2 for 1 hour, filtered and concentrated. 8.0 g of a pink solid as the product BB was obtained as a crude product and used without further purification. MS (EI) C11Hi6N2O2: 209 (M+H)+. c) N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)acetam ide
nBuOH
Figure imgf000130_0001
Figure imgf000130_0002
[00182] A flask was charged with BB (51 mg, 0.24 mmol), N-(4-(2-chloropyrimidin-4- yl)phenyl)acetamide (50 mg, 0.2 mmol) and nBuOH (2 mL). The flask was immersed in a 180 °C oil bath for 30 minutes, and then cooled to ambient temperature. The residue was suspended in 5 mL of ethyl acetate, stirred for 1 hour, filtered, and washed with 10 mL of ethyl acetate. 50 mg of an off-white powder was obtained as the title compound (341) (60% yield).
1H-NMR (400MHz, d6-DMSO): 10.33 (s, 1H), 9.50 (br, 1H), 8.54 (d, 1H), 8.15 (d, 2H), 7.95 (br, 1H), 7.77 (d, 2H), 7.42 (m, 2H), 3.94 (s, 3H), 3.77 (br, 4H), 3.40 (br, 2H), 2.15 (s, 2H). MS (EI) C23H25N5O3: 420 (M+H)+.
Example 16
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)methanesulfonamide (Compound 326)
Figure imgf000130_0003
[00183] 82 (500 mg, 0.94 mmol) was dissolved in 4 mL of pyridine. Methanesulfonyl chloride (730 μL, 9.4 mmol) was added dropwise to the vigorously stirred pyridine solution. The addition of the sulfonyl chloride was exothermic and caused a significant increase in the temperature of the reaction. The reaction was maintained at 80 °C for several hours. After cooling, the solvent was removed under vacuum and the residue was purified by reverse phase HPLC to afford 200 mg (52% yield) of the title compound (326). 1H-NMR (400MHz, d6-DMSO): 10.16 ppm (s, 1H), 9.41 ppm (s, 1H), 8.45 ppm (d, 1H), 8.13 ppm (d, 2H), 7.67 ppm (d, 2H), 7.33 ppm (d, 2H), 7.28 ppm (d, 1H), 6.94 ppm (d, 2H), 3.74 ppm (br s, 4H), 3.09 ppm (s, 3H), 3.05 ppm (br s, 4H); MS (EI) C2iH23N503S: 426 (MH+).
Example 17 Methyl (4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyI)carbamate (Compound 248)
Figure imgf000131_0001
[00184] To a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2- amine 249(a) (100 mg, 0.29 mmol) and DIEA (0.435 mmol, 75 μl) in THF (50 mL) was added methyl chloroformate (0.348 mmol, 27 μl) and the solution was stirred at room temperature for 2 hours. The solution mixture was concentrated, redissolved with MeOH and purified using reverse phase HPLC. The product obtained from the reverse phase HPLC was free base 248, converted to HCl salt using 3 N HCl and lyophilized to yield the product 248 (60mg, 47% yield) as a yellow solid. 1H-NMR (400MHz, d6-DMSO): 10.063 ppm (s, 1H), 9.976 ppm (s, 1H), 8.521 ppm (d, 1H), 8.153 ppm (d, 2H), 7.878 ppm (d, 2H), 7.661 ppm (d, 2H), 7.554 ppm (bs, 2H), 7.432 ppm (d, 1H), 3.983 ppm (bs, 4H), 3.707 ppm (s, 3H), 4.435 ppm (bs, 4H); MS (EI) C22H23N5O3HCl: 475.4 (MH+). Example 18
(S)-3-hydroxy-N-(4-(2-(4-morphoIinophenylamino)pyrimidin-4- yl)phenyl)butanamide (Compound 363)
Figure imgf000132_0001
[00185] To a solution of (5)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyyl)pyrimidin-2-amine (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at rt for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3X), and washed with brine (IX). The organic layers were dried with sodium sulfate and concentrated. The product was purified by reverse phase HPLC to afford (5)-3-hydroxy-N-(4-(2-(4- morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (0.136 g, 22% yield) as a light brown solid. (363) 1H-NMR (400MHz, DMSO-J6): 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.1 1 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H) ), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Example 19
2-Hydroxy-2-methyl-N-(4-(2-(4-morpholinoplienylamino)pyrimidin-4- yl)phenyl)propanamide (Compound 366)
Figure imgf000132_0002
[00186] To a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyyl)pyrimidin-2- amine (1.0 g, 2.8 mol) 249(a) and DIPEA (0.5 mL, 1 eq.) in anhydrous DMA (5 mL) was added dropwise 2-acetoxy-2-methylpropionyl chloride (3 mol, 1.05 eq., 0.44 mL) at 0 °C. The mixture was stirred for 20 min at room temperature. The solution was diluted with water and EtOAc. The organic layer was concentrated in vacuo. The residue 366(a) was suspended in MeOH (10 mL) and a solution Of LiOH-H2O (8.3 mmol, 3 eq. 0.35 g) in water (3 mL) was added. The reaction was complete within 20 min and then was neutralized. The organic solvent was removed in vacuo. The residue was purified to afford 2-hydroxy-2-methyl-N-(4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)phenyl)- propanamide (366) (1.0 g, 85% yield) as a pale yellow solid. 1H-NMR (400MHz, DMSO- d6): 9.86 (s, 1H), 9.41 (s, 1H), 8.47 (d, 1H), 8.12 (d, 2H), 7.94 (d, 2H), 7.68 (d, 2H), 7.30 pm (d, 1H), 6.94 (d, 2H), 5.82 (s, 1H), 3.75 (m, 4H), 3.08 (m, 4H), 1.38 (s, 6H); MS (EI) m/z for C22H23N5O3HCl: 434.2 (MH+).
Example 20
(Λ)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide (Compound 364)
Figure imgf000133_0001
[00187] To a solution of (R)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g,
1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added and a solution of 4-(4-aminophenyl)-/V-(4-morpholinophenyyl)pyrimidin-2-amine (249(a)) (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3X), washed with brine (IX), and the organic layers were dried with sodium sulfate. The solution was concentrated and the product was purified by reverse phase HPLC to afford (R)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide (364) (0.129 g, 21% yield) as a light brown solid. 1H-NMR (400MHz, OMSO)-d6: 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+). Example 21
(/f)-2-amino-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)- propanamide (Compound 365)
Figure imgf000134_0001
[00188] To a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyyl)pyrimidin-2- amine 249(a) (521mg, 1.5 mmol), N-CBZ-D-Serine (359mg, 1.5mmol), and DIEA (0.653mL, 3.75mol) in DMA (4mL) was added HATU (855mg, 2.25mmol) and the solution was stirred at room temperature for 0.5 hour. Excess H2O was added to the reaction mixture. The precipitate was collected and were redissolved in CH2Cl2, washed with NaHCO3 (aq) (2X), brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica column chromatography (1% MeOH/DCM as eluent) to afford (R)- benzyl 3-hydroxy- 1 -(4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)phenylamino)- 1 - oxopropan-2-ylcarbamate 365(a) (668 mg, 78% yield). [00189] To a stirred solution of (R)-benzyl 3-hydroxy- 1-(4-(2-(4- morpholinophenylamino)-pyrimidin-4-yl)phenylamino)- 1 -oxopropan-2-ylcarbamate from the step above in MeOH (10 mL) was added Pd(OH)2 (134 mg) and ammonium formate (369 mg, 5.85). The mixture was heated at 60 °C for 2 hours, cooled down to room temperature, and filtered on Celite by eluting with MeOH. The filtrate was concentrated in vacuo and the residue was purified by prepatory HPLC (TFA). The TFA salt was removed by using basic resin to afford (R)-2-amino-3-hydroxy-N-(4-(2-(4- morpholinophenylamino)pyrimidin-4-yl)-henyl)ropanamide 365 (346 mg, 68%). 1H- NMR (400MHz, DMSO-d6): 9.39 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.83 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.94pm (d, 2H), 4.94 (m, 1H), 3.75 (m, 4H), 3.60 (m, 2H), 3.46 (m, 1H), 3.05 (m, 4H); MS (EI) m/z for C23H26N6O3: 435.4 (MH+). Example 22
N-{4-[2-({3-[(4-ethylpiperazin-1-yl)methyl]phenyl}amino)pyrimidin-4-yl]phenyl}- acetamide (Compound 122)
Figure imgf000135_0001
[00190] Intermediate A (0.5g) was dissolved in THF (5 ml), 20% aqueous H2SO4 solution (5ml) was then added to the solution. The mixture was stirred at 50° C for 2 hours and monitored by LC/MS (MH+, 333). The solution was then neutralized with 2N NaOH solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to afford 0.38g of the aldehyde B. (90% yield). [00191] A flask was charged with aldehyde B (O.lg, 0.3 mmol), dichloromethane (10 ml), sodiumtriacetoxyborohydride (0.32g, 1.5mmol), and 1-ethylpiperazine (0.19 ml, 1.5mmol). The reaction mixture was stirred at room temperature overnight and checked with LC/MS. The product 122 was isolated by removal of the solvent with a rotary evaporator and then purified with a preparative HPLC.
1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.6 (s, 1H), 8.5 (d, 1H), 8.14 (d, 2H), 7.9 (s, 1H), 7.76 (d, 2H), 7.65 (d, 1H), 7.36 (d, 1H), 7.24 (t, 1H), 6.89 (d, 1H), 3.43 (s, 2H), 2.4 (br, 6H), 2.3 (q, 2H), 2.1 (s, 3H), 0.96 (t, 3H). MS (EI) for C25H30N6O : 431 (MH+). Example 23
2-(3-(1H-imidazol-1-yl)propylamino)-N-(4-(2-(4-morphoIinophenylamino)pyrimidin- 4-yl)phenyl)acetamide (Compound 143)
Figure imgf000136_0001
[00192] A flask was charged with aniline A, (100 mg, 0.29 mmol), and THF (1.0 mL). Chloroacetylchloride (23 μL, 0.29 mmol) was added and the mixture was stirred at ambient temperature for 1 hr, after which time it was concentrated. The product, Bi, was isolated by removal of the solvent with a rotary evaporator and used without further purification.
[00193] A flask was charged with alkyl chloride Bi (20 mg, 0.047 mmol), Na2CO3 (30 mg, 0.28 mmol), l-(3-Aminopropyl)imidazole (5.6 μL, 0.047 mmol), and DMF (1.0 mL). The mixture was stirred at 150 °C for 1 hr, after which time it was concentrated. The product 143 was purified by reverse phase HPLC to afford 9.7 mg (40% yield from Bi) as a white solid.
1H-NMR (400MHz, d6-DMSO): 8.35 (d, 1H), 8.13 (d, 2H), 7.78-7.63 (m, 3H), 7.61 (d, 2H), 7.22 (d, 1H), 7.17 (s, 1H), 7.05-6.95 (m, 2H), 4.62 (s, br, 1H), 4.16 (t, 2H), 3.87-3.77 (m, 4H), 3.49 (s, 1H), 3.34 (s, 1H), 3.15-3.07 (m, 4H), 2.67 (t, 2H), 2.11-2.01 (m, 2H), 1.95 (s, 2H). MS (EI) C28H32N8O2: 513.1 (MH+).
Example 24
N-chloro-N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-2- (1H-tetrazol-1-yl)acetamide (Compound 554)
Figure imgf000137_0001
[00194] 4-(4-aminophenyl)-N-(3-methoxy-4-morpholinophenyl)pyrimidin-2-amine hydrochloride: A flask was charged with tert-butyl 4-(2-chloropyrimidin-4- yl)phenylcarbamate A (12.2 g, 40.0 mmol), 3-Methoxy-4-morpholinoaniline (9.7 g, 40.76 mmol) and 50 mL n-butanol. The reaction mixture was stirred under an N2 atmosphere at 100 °C for 12 hours, after which time, then, cooled to room temperature. 25 mL of 4N HCl in dioxane was added, the reaction mixture was stirred at 50 °C for 5 hours. After cooled to room temperature, it was filtered, washed with ethyl acetate, dried in the air to collect 16 g of yellow-green solid as the desired product. NMR (400 MHz, d6-DMSO): 10.40 (s, 1H), 8.60 (d, 1H), 8.20 (s, 2H), 7.94 (s, 1H), 7.84 (d, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 7.30 (m, 2H), 4.10 (m, 2H), 3.99 (s, 3H), 3.60 (br, 2H), 3.39 (m, 2H), 1.25 - 1.42 (m, 4H). MS (EI) for C2]H23N5O2: 378 (MH+).
[00195] A flask was charged with 4-(4-aminophenyl)-N-(3-methoxy-4- morpholinophenyl)pyrimidin-2-amine hydrochloride B (471.0 mg, 0.84 mmol), 2-(1H- tetrazol-1-yl)acetic acid (216.0 mg, 1.69 mmol), HATU (1276.0 mg, 3.38 mmol) and 2 mL of DMA. The reaction mixture was stirred at room temperature for 24 hours, and then quenched with 50 mL of water, extracted with ethyl acetate (3X50 mL). The combined organics were washed with water and then brine (50 mL each), dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified with a silica gel column (ethyl acetate to 10% methanol in ethyl acetate), 345.0 mg of the desired product 554 was obtained as yellowish powder. NMR (400 MHz, d6-DMSO): 10.85 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.47 (s, 1H), 8.19 (d, 2H), 7.75 (d, 2H), 7.63 (s, 1H), 7.20 (m, 3H), 6.84 (d, 1H), 5.56 (s, 2H), 3.80 (s, 3H), 3.74 (m, 4H), 2.94 (m, 4H). MS (EI) for C24H25N9O3: 488 (MH+).
Example 25
4-[4-(l,l-DioxidoisothiazoIidin-2-yl)phenylJ-N-(4-morpholin-4-ylphenyl)pyriπiidin-2- amine (Compound 374)
Figure imgf000138_0001
A
[00196] Aniline A (300 mg, 0.78 mmol) was dissolved in 4 mL of dry pyridine. 3- Chloropropanesulfonyl chloride (950 uL, 7.8 mmol) was added dropwise. The reaction mixture was heated to 80 °C and stirred overnight under a nitrogen atmosphere. The solvent was removed under vacuum and the residue was re-dissolved in 25 mL of ethyl acetate. The reaction mixture was washed one time each with 10 mL portions of water, 0.1 M HCl, and saturated aqueous NaCl. The organic layer was dried with MgSO4 and concentrated under vacuum. The residue was taken up in DMF (4 mL) and triethylamine (1100 uL, 7.9 mmol). The reaction mixture was heated to 80 °C and stirred overnight. The product was purified by preparative HPLC to give 85 mg of 374. 1H NMR (400 MHz, d6-DMSO): 9.78 (s, 1H), 8.49 (d, 1H), 8.20 (d, 2H), 7.78 (d, 2H), 7.39 (d, 1H), 7.33 (d, 2H), 7.25 (br s, 2H), 3.84 (br s, 4H), 3.73 (t, 2H), 3.60 (t, 2H), 2.54 (m, 2H), 2.45 (m, 2H) 2.01 (m, 2H); MS (EI) for C23H25N5O3S: 452 (MH+). Example 26 N-(4-Morpholin-4-ylphenyl)-4-[4-(1H-tetrazol-1-yl)phenyl]pyrimidin-2-amine
Figure imgf000139_0001
[00197] Aniline A (200 mg, 0.52 mmol), sodium azide (45 mg, 0.69 mmol), triethylorthoformate (280 uL, 1.7 mmol) and acetic acid (480 uL, 8.4 mmol) were combined in a 25 mL round bottom flask. The reaction mixture was stirred for 2 hours at 80 °C. The reaction mixture was allowed to cool to room temperature and then it was cooled further in an ice bath. A solution of 670 uL of 6.0 M HCl in 1.25 mL of water was added to the reaction mixture. After stirring in the ice bath for 5 minutes, another solution of sodium nitrite (50 mg, 0.72 mmol) in water (200 uL) was added slowly. The precipitate was filtered off and purified by reverse phase HPLC to give 24 mg of 375. 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.51 (s, 1H), 8.53 (d, 1H), 8.40 (dd, 2H), 8.10 (d, 2H), 7.65 (d, 2H), 7.43 (d, 1H), 6.92 (d, 2H), 3.73 (m, 4H), 3.03 (m, 4H); MS (EI) for C21H20N8O: 401 (MH+).
Example 27
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}aπiino)propyl]-2-fluoro-6- iodobenzamide (Compound 289)
Figure imgf000140_0001
[00198] A flask was charged with Cl (5.0 g, 20.2388 mmol) and (3-aminopropyl)- carbamicacid-t-butyl ester (6 mL, 30.3582 mmol). n-butanol (40 mL) were added to the flask and heated to 175 °C for an hour. Solvent was evaporated and reaction mixture was checked with LC/MS. The reaction mixture was cooled to room temperature and ethyl acetate was added. The precipitate, B, was filtered and used without further purification. LC/MS: m/z 386 (M+H)+.
[00199] A flask was charged with B. 4 N HCl in dioxane was added and stirred at room temperature for 3 hours. The reaction mixture was checked with LC/MS. The product, E, was isolated by removal of the solvent with a rotary evaporation and used without further purification. LC/MS; m/z 286 (M+H)+.
[00200] A flask was charged with E (254 mg, 0.8902 mmol), 2-fluoro-6-idobenzoyl chloride (90 μL, 0.6231 mmol), tetrahydrofuran (25 mL), and n-ethyldiisopropylamine (108 μL, 0.6231 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was monitored with LC/MS. The product, 289, was isolated by removal of the solvent with a rotary evaporator and purified with a TFA preparative HPLC (10:90, 1 1 m in run).
1H-NMR (400MHz, (d6-DMSO): 10.16 ppm (s, 1H), 8.64 ppm (t, 1H), 8.30 ppm (d, 1H), 8.06 ppm (d, 2H), 7.70 ppm (m, 3H), 7.30 ppm (m, 1H), 7.20 ppm (m, 1H), 7.13 ppm (m, 1H), 7.07 ppm (m, 1H), 3.34 ppm (m, 4H), 2.08 ppm (s, 3H), 1.83 ppm (m, 2H); MS (EI) C22H2IFIN5O2: 533.9 (MH+). Example 28
N-(4-{2-[(3-{[(2,6-dimethylphenyl)methyl]amino}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide (Compound 51)
Figure imgf000141_0001
[00201] A flask was charged with Cl (5.0 g, 20.2388 mmol) and tert-butyl 3- aminophenylcarbamate (4.6 g, 22.2627 mmol). n-butanol (40 mL) were added to the flask and heated to 175 °C for 4 hours. Solvent was evaporated and reaction mixture was checked with LC/MS. The reaction mixture was cooled to room temperature and ethyl acetate was added. The precipitate, D, was filtered and used without further purification. LC/MS: m/z 320 (M+H)+.
[00202] A flask was charged with D (463 mg, 1.4514 mmol), dichloromethane/tetrahydrofuran (2;1, 15 mL), sodium triacetoxyborohydride (615 mg, 2.9028 mmol), and 2,6-dimethylbenzaldehyde (196 μL, 1.4514 mmol) The reaction mixture was stirred at room temperature for 12 hours and monitored with LC/MS. The product, 51, was isolated by removal of the solvent with a rotary evaporator and purified with a TFA preparative HPLC (10:90, 11 min run). 1H-NMR (400MHz, d*- DMSO): 10.20 ppm (s, 1H), 9.36 ppm (s, 1H), 8.47 ppm (d, 1H), 8.16 ppm (d, 2H), 7.72 ppm (d, 2H), 7.35 ppm (s, 1H), 7.31 ppm (d, 1H), 7.12 ppm (m, 1H), 7.07 ppm (m, 2H), 6.99 ppm (m, 3H), 6.38 ppm (d, 1H), 5.46 ppm (t, 1H), 4.14 ppm (d, 2H), 2.36 ppm (s, 6H), 2.08 ppm (s, 3H); MS (EI) C27H27N5O: 438.1 (MH+).
Example 29
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-IV-[2- (dimethylamino)ethyl]benzamide (Compound 9)
Figure imgf000142_0001
[00203] A flask was charged with 2,4-dichloropyrimindine (22.7 g, 152.38 mmol), 4-acetoamidophenylboronic acid (30.0 g, 167.62 mmol), dicholor[l,l '-bis(dipheny- phosphino)-ferrocenepalladium (16.726 g, 22.86 mmol, 15 mol %), and triethylamine (53 mL, 380.95 mmol). Ethyleneglycoldimethylether (500 mL) and H2O (20 mL) was added to the flask. The reaction mixture was stirred at 80 °C for 4 hours. The product, 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. [00204] A seal tube was charged with intermediate A (400 mg, 1.62 mmol) and 3-aminobenzoic acid (222 mg, 1.62 mmol). N-butanol (15 mL) was added to the seal tube and stirred at 180°C. The reaction was done in lhour according to LCMS to afford intermediate B as a yellow solid. Intermediate B was placed on a rotary evaporator to remove excess n-butanol. Intermediate B was carried on to the next step without further purification. [00205] A flask was charged with intermediate B (282 mg, 0.81 mmol), HATU (464 mg, 1.22 mmol), DMF (15 mL) and DIEA (212 μL, 1.22 mmol). The reaction mixture was stirred at rt and completed in 30 min. to afford the final product (9). The final product was purified using Preperative HPLC and ammonium acetate buffer and lyophilized to afford the product as ACE salt (170 mg, 0.41 mmol). 1H-NMR (400MHz, (I6-CD3OD): 8.523 ppm (t, 1H), 8.45 ppm (d, 1H), 8.176 ppm (m, 2H), 7.828 ppm (m, 1H), 7.2 ppm (d, 2H), 7.475-7.404 ppm (m, 2H), 7.326 ppm (d, 1H), 3.738 ppm (t, 2H), 3.244 ppm (t, 2H), 2.877 ppm (s, 6H), 2.162 ppm (s, 3H), 1.955 (s, 3H, ACE). MS (EI) C23H26N6O2: 419.1 (MH+).
Example 30
N-[5-({4-[4-(acetylamino)phenyI]pyrimidin-2-yl}amino)-2-morpholin-4-ylphenyl]-2,6- dichlorobenzamide (Compound 62)
Figure imgf000143_0001
[00206] 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.
[00207] A flask was charged with intermediate C (816 mg, 2.02 mmol), THF (100 mL), DIEA (705 μL, 4.04mmol), and 2,6-dichlorobenzoyl chloride (290 μL, 2.02 mmol). The reaction mixture was stirred at rt over night to afford the final product 62. The final product was purified using Preperative HPLC and TFA buffer, then was free-based and lyophilized (165 mg, 0.28 mmol, 14% Yield).
1H NMR (400 MHz, DMSO): 10.194 (s, 1H), 9.8 (s, 1H), 9.607 (s, 1H), 8.585 (s, 1H),
8.484 (d, 1H), 8.235 (d, 2H), 7.711 (d, 2H), 7.592 (d, 2H), 7.496 (m, 2H), 7.356 (d, 1H),
7.183 (d, 1H), 3.74 (t, 4H)), 2.89 (t, 4H), 2.07 (s, 3H). MS (EI) for C29H26Cl2N6O3: 579.1
(MH+).
Example 31
N-{3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-5-[(4-ethylpiperazin-1- yl)carbonyl]phenyl}-2,6-dichlorobenzamide (Compound 66)
Figure imgf000144_0001
[00208] 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.
[00209] A flask was charged with intermediate D (439 mg, 1.21 mmol), THF (30 mL), DMF(5 mL), DIEA (632 μL, 3.63 mmol), and 2,6-dichlorobenzoyl chloride (174 μL, 1.21 mmol). The reaction mixture was stirred at rt over night. The reaction mixture was quenched with 2 M NaOH (100 mL) and extracted with ethyl acetate (3x) and the organic layer was discarded. The aqueous NaOH layer was neutralized with cone. HCl. The solid formed was collected via filtration and washed with excess water to afford intermediate E (274 mg, 0.51 mmol, 62% yield) as a yellow solid. Intermediate E was carried on to the next step without further purification.
[00210] A flask was charged with intermediate E (274 mg, 0.51 mmol), HATU (291 mg, 0.765 mmol), DMF (25 mL), ethylpiperazine (78 μL, 0.61 mmol) and DIEA (133 μL, 0.765 mmol). The reaction was stirred at rt and completed in 15 min. The final product 66 was purified using Preperative HPLC and TFA buffer, free-based and lyophilized to afford the product (166 mg, 52% yield).
1H NMR (400 MHz, DMSO): 10.896 (s, 1H), 10.33 (s, 1H), 9.881 (s, 1H), 8.533 (d, 1H), 8.374 (s, 1H), 8.202 (d, 2H), 7.776 (d, 2H), 7.636-7.6 (m, 3H), 7.529 (m, 1H), 7.419 (d, 1H), 7.296 (s, 1H), 3.628 (br s, 2H), 3.415 (br s, 2H), 2.427-2.314 (m, 6H), 2.091 (s, 3H), 0.996 (t, 3H). MS (EI) for C32H31Cl 2N7O3: 634.1(MH+).
Example 32
N-methyl-N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetainide (Compound 118):
Figure imgf000145_0001
[00211] A flask was charged with intermediate A (250 mg, 1.01 mmol), DMF (10 mL), NaH (30.0 g, 167.62 mmol), dicholor[l,r-bis(diphenylphosphino)ferrocenepalladium (60 mg, 1.5 mmol), and methyl iodide (94 μL, 1.5 mmol). The reaction mixture was stirred at rt and completed in 30 min. The reaction mixture was quenched with H2O and extracted with ethyl acetate (3X) and washed with 10% LiCl solution (IX), brine (IX), dried over sodium sulfate, and filtered. The organic layer was removed with a rotary evaporator to afford intermediate F (200 mg, 0.766 mmol) as a yellow gelatin. Intermediate F was carried on to the next step without further purification. [00212] 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 N2 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).
1H-NMR (400MHz, d6-DMSO): 9.464 ppm (s, 1H), 8.51 1 ppm (d, 1H), 8.209 ppm (d, 2H), 7.67 ppm (m , 2H), 7.516 ppm (d, 2H), 7.366 ppm (d, 1H), 6.926 ppm (m, 2H), 3.743 ppm (t, 4H), 3.22 ppm (s, 3H), 3.048 ppm (t, 4H). MS (EI) C23H25N5O2: 404.3 (MH+).
Example 33 N-(4-(2-(3-(3-morpholinopropoxy)phenylamino)pyrimidin-4-yl)phenyl)acetamide
(Compound 160)
Figure imgf000146_0001
[00213] A seal tube was charged with intermediate A (500 mg, 2.02 mmol) and 3-benzyloxyaniline (404 mg, 2.02 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 G as a yellow solid. Intermediate G was placed on a rotary evaporator to remove excess n-butanol. Intermediate G was carried on to the next step without further purification. A flask was charged with intermediate G and HBr/ Acetic acid (33%, 10 mL) and stirred at rt over night. The reaction was done and the solid was collected via filtration and washed with ether to afford intermediate H as a yellow and HBr salt solid (800 mg, 1.66 mmol, 82% yield).
[00214] A flask was charged with intermediate H (250 mg, 0.52 mmol), DMF (15mL), Cs2CO3 (847mg, 2.6 mmol) and 4-(3-chloropropyl)morpholine HCl salt (135 mg, 0.676 mmol, purchased from Apin Chemicals, Ltd.) and stirred at 80°C over night. The reaction mixture had approximately 85% desired product and 15% bis-alkylated by-product. The solid was filtered and washed with ethyl acetate and discarded. The filtrate was concentrated using the rotary evaporator. The final product was purified using Preperative HPLC and TFA buffer, free-based, converted to HCl salt and lyophilized to afford the product (115mg, 0.237 mmol, 46% Yield). ' H NMR (400 MHz, DMSO): 11.058 (s, 1H), 10.403 (s, 1H), 9.761 (s, 1H), 8.532 (d,
1H), 8.158 (d, 2H), 7.81 (d, 2H), 7.677 (s, 1H), 7.4-7.345 (m, 2H), 7.231 (t, 1H), 6.569 (m, 1H), 4.081 (t, 2H), 3.962 (m, 2H), 3.82 (t, 2H), 3.46 (m, 2H), 3.267 (m, 2H), 3.123 (m, 2H), 2.254 (m, 2H), 2.104 (s, 3H). MS (EI) for C25H29N5O3: 448.3 (MH+).
Example 34
N-(4-{2-[(2-methyl-4-piperazin-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide
(Compound 35):
Figure imgf000147_0001
[00215] A flask was charged with 5-fluoro-2-nitrotoluene (1 mL, 8.2 mmol), DMF (15 mL), Bocpiperazine (1.68 g, 9.02 mmol), and K2CO3 (2.27 g, 16.4 mmol). The reaction mixture was stirred at 50 °C for about 25 h. The reaction was quenched with H2O and the solid precipitated out of the solution and collected via filtration and washed with excess H2O to obtain intermediate I (1.765g, 5.4 mmol). Intermediate I was carried on to the next step without further purification. A flask was charged with intermediate I (290 mg, 0.9 mmol), ethanol (18 mL), ammonium formate (340 mg, 5.4 mmol) and Pt/S (10.2 mg, 0.04 mmol). The reaction mixture was stirred at 70°C for 3 h and 78°C for 4 h. The reaction mixture was filtered through celite and washed with ethanol. The filtrate was removed using the rotary evaporator and then treated with ethyl acetate and washed with H2O, dried over sodium sulfate, and filtered. The ethyl acetate layer was concentrated using rotary evaporator to afford intermediate J.
[00216] 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). 1H-NMR (400MHz, d6-DMSO): 10.31 ppm (s, 1H), 8.569 ppm (s, 1H), 8.323 ppm (d, 1H), 8.022 ppm (d, 2H), 7.715 ppm (d, 2H), 7.271 ppm (d, 1H), 7.186 ppm (d, 1H), 6.8 ppm (m, 2H), 3.023 ppm (t, 4H), 2.844 ppm (t, 4H), 2.175 ppm (s, 3H), 2.077 ppm (s, 3H), 1.605 ppm (s, 2H); MS (EI) C23H26N6O: 403.1 (MH+).
Example 35 N-[4-({2-[(4-morpholin-4-ylphenyl)amino]-7/T-pyrrolo[2,3-</]pyrimidin-4-yl}amino)- phenyl]acetamide (Compound 306)
Figure imgf000148_0001
[00217] A flask was charged with methylsulfide (2.1g, l l .όmmol) and THF (5OmL). To this, m-CPBA (7.9g, 46mmol) was added and the mixture was stirred at ambient temperature for 20 hours. Volatiles were removed under vacuo. The crude mixture was partitioned between EtOAc and DI H2O. The aqueous layer was extracted with EtOAc (3x15mL). The combined organics were washed with IN NaHCO3 (x2), DI H2O (x2), brine, (xl), dried over sodium sulfate, filtered and concentrated under vacuo. The product (1.8g, 75%) was used without further purification. LCMS: m/z 214(M+H)+.
Figure imgf000149_0001
[00218] A pressure tube was charged with methylsulfone (1.15g, 5.4mmol) and aniline (2.8g, 16.2mmol). The tube was sealed and the mixture heated at 14O°C for 30 minutes. The mixture was cooled. Methanol was added and the resulting solid collected via filtration then washed with methanol. The product (270mg, 8.7%) was used without further purification. LCMS: 312 (M+H)+.
Figure imgf000149_0002
[00219] A flask was charged with pyrrolopyrimidinone (250mg, O.δmmol) and toluene (5mL). Phosphorous oxychloride (218μL, 2.41mmol) and DIPEA (165μL, 0.96mmol) were added and the mixture stirred at HO°C for 6 hours. The volatiles were removed under vacuo and the product used without further purification. LCMS: 330 (M+H)+.
Figure imgf000149_0003
[00220] A flask was charged with pyrrolopyrimidine (lOOmg, 0.3mmol) and isopropanaol (ImL). Aniline (55mg, .036mmol) and two drops of cone. HCl were added and the mixture heated to reflux for 6 hours. Volatiles were removed under vacuo. The product was purified by preparative HPLC to afford the title compound (306) (12.8mg,
9.6%).
1H NMR (400MHz, d6-DMSO): 11.13 (s, 1H), 9.95 (s, 1H), 9.04 (s, 1H), 8.56 (s, 1H),
7.86 (d, 2H), 7.66 (d, 2H), 7.54 (d, 2H), 6.88-6.82 (m, 3H), 6.65-6.61 (m, 1H), 3.78-3.71
(m, 4H), 3.05-2.99 (m, 4H), 2.04 (s, 3H). MS (EI) for C24H25N7O2: 444 (MH+).
Example 36
(N-(4-{2-[(3-{[(2,6-dichlorophenyl)sulfonyl]amino}phenyl)amino)-5-methyl- pyrimidin-4-yl}phenyl)acetamide) (Compound 26)
Figure imgf000150_0001
[00221] To a mixture of 2,4-dichloro-5-methylpyrimidine (4.17g, 25.6mmol) and 4-acetamidophenylboronic acid (5.0g, 27.9mmol) in DME (40ml) was added Et3N (8.92ml, 64.0mmol), H2O (4ml), and dichloro[l,l '- bis(diphenylphosphino)ferrocenepalladium (2.8 Ig, 3.44mmol, 13%). The mixture was allowed to stir at reflux for 5hours. After the mixture was cooled down to rt, the crude mixture was directly filtered on silica gel and eluted with EtOAc. The filtrate was concentrated in vacuo. Further purification was conducted by flash chromatography to afford Intermediate 1 (5.94g, 89%) as a white solid. LCMS: m/z 262 (M+H)+.
Figure imgf000150_0002
[00222] To a stirred solution of chloropyrimidine (1.05g, 4.0mmol) in 1-butanol (10ml) was added N-Boc-amino-3-aniline (920mg, 4.4mmol) and the mixture was heated in the sealed tube at 18O°C for 1.5 hours. The mixture was cooled down to rt and acidified with IN HCl (20ml). The aqueous layer was washed with EtOAc (50ml). The separated aqueous layer was basified with 2N NaOH to pH 8-9 and extracted with EtOAc (50ml*3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography to afford product Intermediate K (943mg, 71% as a light yellow solid. LCMS: m/z 334 (M+H)+.
Figure imgf000151_0001
[00223] To a stirred suspension of aniline (250mg, 0.75mmol) in THF (5ml) was added DIPEA (157ml, 0.90mmol) and 2,6-dichlorobenzenesulfonyl chloride (203mg, 0.83mmol) and the mixture containing intermediate K was stirred at reflux for 2hrs. After cooling down to rt, the mixture was diluted with EtOAc, washed with H2O, brine, and dried over Na2SO4. After concentrated in vacuo, the residue was purified by flash chromatography to give product 26 (299mg, 73%) as a light pink solid.
1H-NMR (400MHz, d6-DMSO): 10.71 (s, 1H), 10.16 (s, 1H), 9.54 (s, 1H), 8.34 (s, 1H), 7.75-7.69 (m, 5H), 7.60 (dd, 2H), 7.51 (dd, 1H), 7.31 (dd, 1H), 7.09 (t, 1H), 6.66 (dd, 1H), 2.25 (s, 3H), 2.08 (s, 3H); MS (EI) C25H2ICl2N5O3S: 542.2 (M+H)+.
Example 37
N-(4-{6-morpholin-4-yl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide (Compound 47)
Figure imgf000151_0002
[00224] The mixture of 2,4,6-trichloropyrimidine (1.72ml, 15mmol) 4-acetamidophenyl-boronic acid (1.79g, lOmmol) in DME (20ml) was added Et3N (3.5ml, 25.0mmol), H2O (2ml), and dichloro[l,r-bis(diphenylphosphino)ferrocenepalladium (1.22g, 1.5mmol, 15%). The mixture was allowed to stir at reflux for 2hrs. After the mixture was cooled down to rt, the crude mixture was directly filtered on silica gel and eluted with EtOAc. The filtrate was concentrated in vacuo. Further purification was conducted by flash chromatography to afford intermediate L (1.91g, 68%) as a white solid. LCMS: m/z 282 (M+H)+.
Figure imgf000152_0001
[00225] To a stirred suspension of pyrimidine (282mg, l.Ommol) in 1-butanol (5ml) was added morpholine (96ml, l .lOmmol) and DIPEA (209μl, 1.2mmol). The mixture was heated at 12O°C for lhr, cooled down to rt, and concentrated in vacuo. The residue was purified by flash chromatography to afford intermediate M (176mg, 53%) as well as isomer (108mg, 32%). LCMS: m/z 333 (M+H)+.
Figure imgf000152_0002
[00226] The mixture of chloropyrimidine (176mg, 0.53mmol) and 4-morpholinoaniline (104mg, 0.58mmol) in 1-butanol (5ml) was heated in the sealed tube at 16O°C for 3hrs. The reaction mixture was cooled down to rt and the crude mixture was directly subjected on silica gel to afford product 47 (122mg, 49%) as a pale pink solid. LCMS: m/z 475 (M+H)+. 1H-NMR (400MHz, d6-DMSO): 10.13 (s, 1H), 8.87 (s, 1H), 8.07 (d, 2H), 7.70-7,64 (m, 4H), 6.90 (d, 2H), 6.71 (d, 1H), 3.74-3.68 (m, 12H), 3.03 (t, 4H), 2.08 (s, 3H); MS (EI) C26H30N6O3: 475 (MH+).
Example 38
N-[6-({4-[4-(acetyIamino)phenyl]pyrimidin-2-yl}ainino)pyridin-2-yl]-2,6-dichloro- benzamide (Compound 299)
Figure imgf000153_0001
[00227] To a mixture of 2,6-diaminopyridine A (9.2 mmol, 1.0 g), and diisopropylethylamine (6.9mmol, 1.2ml) in 20ml of THF, was added 2,6- dichlorobenzoylchloride B (4.6mmol, 0.67ml) dropwise. The mixture was stirred at room temperature for 1 hour and LCMS indicated it was done (M+H: 283). THF was removed and replaced with ethyl acetate. The reaction mixture was then extracted with water, brine, and dried over sodium sulfate. The product, C , was isolated by removal of the solvent with a rotary evaporator and used without further purification. LCMS: 283 (M+H).
Figure imgf000153_0002
[00228] A seal tube was charged with intermediate Ai (0.2g, 0.81 mmol), compound C from the previous step (0.56g, 2.0mmol), tris(dibeπzylideneacetone)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 N2 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). The reaction mixture was partitioned between ethyl acetate and water, the organic layer extracted with 10% LiCl solution, followed by brine, dried over Na2SO4, and then evaporated. The crude product 299 was then purified via prep HPLC. 1H NMR (400 MHz, (I6-DMSO): 11.12 (s, 1H), 10.25 (s, 1H), 9.43 (s, 1H), 8.58 (d, 1H), 8.2-8.13 (m, 3H), 7.9 (t, 1H), 7.83 (d, 1H), 7.78 (d, 2H), 7.55 (d, 2H), 7.52-7.45 (m, 2H), 2.1 (s, 3H). MS (EI) for C24H18Cl2N6O2 : 493 (MH+).
Example 39 N-(3-(4-(4-acetamidophenyl)pyrimidin-2-yIamino)phenyl)-3-(2-morpholinoethoxy)- benzamide (Compound 123)
ate B
Figure imgf000154_0001
Figure imgf000154_0002
[00229] A flask was charged with 2,4-dichloropyrimindine (22.7 g, 152.38 mmol), 4-acetoamido-phenylboronic acid (30.0 g, 167.62 mmol), dicholor[l,l '- bis(diphenylphosphino)-ferrocene-palladium (16.726 g, 22.86 mmol, 15 mol %), and triethylamine (53 mL, 380.95 mmol). Ethyleneglycoldimethylether (500 mL) and H2O (20 mL) were added to the flask. The reaction mixture was stirred at 80 °C for 4 hours. The product, 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. [00230] 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. The filter pad was washed with ethyl-acetate, 72% yield. Intermediate B was carried on to the next step without further purification. [00231] A flask was charged with intermediate B (159mg, 0.5 mmol), 3-(2- morpholinoethoxy)benzoyl chloride (169mg, 0.63 mmol), and Pyridine (8 mL). The reaction mixture was stirred at RT under nitrogen. Reaction was complete after lhour. The final product 123 was purified using Preperative HPLC and trifluoroacetic acid buffer then free based with hydroxide resin in methanol. The filtrate was then concentrated, the yellow oil was then freezed and lyophilized.
1H-NMR (400MHz, d6-DMSO): 10.206(s, br, 2H), 9.665(s, br, 1H), 8.512(d, 1H), 8.502(s, 1H), 8.440(d, 2H), 7.755(d, 2H), 7.582(m, 2H), 7.483(m, 2H), 7.375(d, 1H), 7.287(m, 2H), 7.163(d, 1H), 4.188(m, 2H), 3.595 (m, 4H), 3.174(m, 4H), 2.732(m, 2H), 2.083(s, 3H). MS(EI) for C3iH32N6O4: 553 (MH+).
Example 40
4-[4-(methylamino)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine (Compound 124)
Figure imgf000155_0001
[00232] A flask was charged with 2,4-dichloropyrimidine (810 mg, 5.5 mmol), 4-(tert- butoxycarbonyl(methyl)amino)phenylboronic acid B (4.93 g, 15 mmol), dicholoro[l,l '- bis(diphenylphosphino)ferrocenepalladium (590 mg, 0.81 mmol, 15 mol %), triethylamine (1.8 mL, 13 mmol), and water (2 mL). Ethylene glycol dimethyl ether (5.0 mL) was added to the flask and the mixture was purged with N2. The reaction mixture was stirred under an N2 atmosphere at 90 °C for 1 hour, after which time, it was cooled to ambient temperature and filtered. The product, C, was isolated by removal of the solvent with a rotary evaporator and used without further purification. LCMS: m/z 319 (M+H)+.
1) nBuOH
2) HCI in dioxane
Figure imgf000156_0001
Figure imgf000156_0002
C 124
[00233] A flask containing a solution of C (1.9 g, 5.8 mmol) and 4-morphilinoaniline (1.5 g, 8.2 mmol) in 1-butanol (10 mL) was immersed in an oil bath at 180 °C for 4 h. The mixture was cooled to ambient temperature, concentrated, and the residue was dissolved in dichloromethane (10 mL) and 4N HCl in dioxane (10 mL). A portion of this crude product (200 mg) was purified by reverse phase HPLC to yield the product 124 (20 mg) in > 99% purity.
1H-NMR (400MHz, d6-DMSO): 9.92-9.99 ppm (bs, 1H), 8.20-8.29 (bs, 1H), 8.02 (d, 2H), 7.52-7.68 (bs, 2H), 7.33 (d, 1H), 7.04-7.17 (bs, 1H), 6.67 (d, 2H), 3.71-3.82 (bs, 4H), 3.14-3.24 (bs, 4H), 2.78 (s, 3H). MS (EI) C21H23N5O: 362.1 (MH+).
Example 41
2,6-dichIoro-N-{3-[(4-{[3-chloro-4-(methyloxy)phenyl]oxy}pyrimidin-2- yl)amino]phenyl}-benzamide (Compound 304)
Figure imgf000156_0003
[00234] A flask was charged with 2,4-dichloropyrimidine (500 mg, 3.4 mmol), 2- chloro-4-methoxyphenol (580 mg, 3.7 mmol), and diisopropylethylamine (1.2 mL, 6.9 mmol). Dimethylformamide (20 mL) was added to the flask and the mixture was stirred at 70 °C for 15 hours. The reaction mixture was diluted with water and the mixture was extracted with dichloromethane 2X and 5% LiCL 3X. The crude product, B, was isolated by removal of the solvent with a rotary evaporator and the resultant brown oil was used without further purification. LCMS: m/z 272 (M+H)+.
Figure imgf000157_0001
B
[00235] A flask containing a solution of intermediate B (910 mg, 3.4 mmol) and benzene- 1,3-diamine (540 mg, 5.0 mmol) in nBuOH (5 mL) was immersed in an oil bath at 180 °C for 30 mins. The intermediate, C, was isolated by removal of the solvent with a rotary evaporator and used without further purification. LCMS: m/z 343 (M+H)+.
Figure imgf000157_0002
[00236] A flask was charged with intermediate C (1.1 g, 3.4 mmol), 2,6- dichlorobenzoylchloride (1.2 mL, 8.3 mmol), diispropylethylamine (1.8 mL, 10 mmol) and THF (50 mL). The reaction mixture was stirred at 60 °C for 15 hours. The reaction mixture was diluted with ethylacetate, extracted with 5% LiCl 3X, and the organic fraction was concentrated on a rotary evaporator. The crude product was purified by silica column chromatography (1 :1 ethylacetate :hexanes as eluent) followed by reverse phase HPLC (TFA/ACN as eluent) to yield the product, 304 (24 mg, 1% yield). 1H-NMR (400MHz, d6-DMSO): 10.7 (s, 1H), 9.65 (s, 1H), 8.36 (d, 1H), 7.77 (s, 1H), 7.58-7.47 (m, 3H), 7.36-7.28 (m, 3H), 7.23 (d, 1H), 7.04-6.98 (m, 2H), 6.47 (d, 1H), 3.83 (s, 3H). MS (EI) C24H17C13N4O3: 514.8 (MH-). Example 42
(3S)-1-(2-hydroxyethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)pyrrolidine-3-carboxamide (Compound 510)
Figure imgf000158_0001
249 (a) B [00237] To a solution of 249(a) (300 mg, 0.78 mmol) in DMA (10 mL) was added a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (350 g, 1.6 mmol) diisopropyl-ethylamine (0.5 mL, 2.7 mmol), and HATU (600 mg, 1.6 mmol) in DMA (10 mL) and the solution was stirred at room temperature 15 hours. The solution was diluted with ethyl acetate (100 mL), washed with 10% LiCl (2X) and brine. The resultant solution was dried over Na2SO4, filtered and concentrated to yield a residue that was purified by silica gel column chromatography (3:1 ethyl acetate/hexanes). The Boc intermediate was isolated as a solid (340 mg, 78% yield). LC/MS: m/z 545 (M+H)+. A flask containing the Boc-intermediate was dissolved in 4N HCl in dioxane (10 mL) and dichloromethane (10 mL) and the mixture was stirred at room temperature for 15 hours. Intermediate C was isolated as a yellow solid after filtration and used without purification.
Figure imgf000158_0002
C
[00238] A flask was charged with intermediate C (450 mg, 0.78 mmol), 2-hydroxy- acetaldehyde (45 mg, 0.75 mmol), sodium triacetoxyborohydride (150 mg, 0.71 mmol), diisopropylethylamine (0.7 mL, 3.8 mmol) and dichloromethane (20 mL) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and the solution was extracted with saturated NaHCO3 (2X) and brine. The residue was purified by reverse phase HPLC (ammonium acetate/ACN as eluent) to afford the product 510 (120 mg, 31% yield). 1H-NMR (400MHz, d6-DMSO): 10.2 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.75 (d, 2H), 7.67 (d, 2H), 7.28-7.27 (m, 1H), 6.93 (d, 2H), 4.47 (br 1H), 3.76-3.73 (m, 4H), 3.49 (t, 2H), 3.06-3.03 (m, 4H), 2.91 (t, 1H), 2.70-2.65 (m, 1H), 2.58-2.56 (m, 1H), 2.54-2.49 (m, 4H), 1.99 (t, 2H). MS (EI) C27H32N6O3: 489.2 (MH+).
Example 43
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-7H-pyrroIo[2,3-d]pyrimidin-4- yl}phenyl)acetamide (Compound 329)
POB /DIPEA
Figure imgf000159_0001
[00239] A mixture of 2-[(4-morpholin-4-ylphenyl)amino]-3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidin-4-one A (312 mg, 1 mmol), phosphorous oxybromide (717 mg, 2.5 mmol), and diisopropylethylamine (130 mg, 1 mmol) in anhydrous toluene (15 ml) was heated at reflux under N2 overnight. The mixture was cooled down to room temperature, and the solid was filtered, washed with sat. NaHCO3, water, and dried over MgSO4. The solvent was removed in vacuo to give the product 4-bromo-N-(4-morpholin-4-ylphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine B (284 mg, 76%) as a black solid. This was clean and used as such without further purification.
Figure imgf000159_0002
[00240] A mixture of 4-bromo-N-(4-morpholin-4-ylphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine B (284 mg, 0.76 mmol), 4-acetoamidophenylboronic acid C (340 mg, 2.5 eq), tetrakis(triphenyl-phosphine)palladium(0) (120 mg, 0.1 mmol), and IM Na2CO3 (ImI, 1 mmol) in 1,4-dioxane (15 ml) was heated at reflux overnight. The mixture was cooled, extracted with 3N HCl. The aqueous layer was washed with ethylacetate, and then basified with 6N NaOH. The solid was filtered, and the crude product was purified by preparative HPLC to give the product N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)acetamide D (0.8 mg, 0.25%) as a yellow solid. 1H NMR (400 MHz, CD3OD): 8.10 (d, 2H), 7.75 (d, 2H), 7.68 (d, 2H), 7.12 (d, 1H), 6.98 (d, 2H), 6.70 (d, 1H), 3.85 (t, 4H), 3.09 (t, 4H), 2.17 (s, 3H). MS (EI) for C24H24N6O2: 429 (MH+).
Example 44
2-Methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)prolinamide (Compound 367)
Preparation of tert-butyl 2-methyl-2-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenylcarbamoyl)pyrrolidine-1-carboxylate
Figure imgf000160_0001
[00241] An oven dried 50 ml round bottomed flask fitted with a Teflon stirrer and gas inlet was flushed with dry nitrogen and allowed to cool to room temperature. The flask was charged with 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine pentahydrochloride (1 equiv., 0.52 g, 0.9631 mmoles) and anhydrous dimethylacetamide (15 ml). The mixture was stirred for 10 minutes to allow for the complete dissolution of the amine. 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). 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 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). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give orange oil. The resulting crude material was purified by silica phase flash chromatography (45 mm x 250 mm) using 3:1 ethyl acetate -hexane to give 0.147 g of tert-butyl 2-methyl-2-(4-(2-(4- morpholinophenylamino)pyrimidin-4-yl)phenylcarbamoyl)-pyrrolidine- 1 -carboxylate as a white solid (27% yield). 1H NMR (400 MHz, d6-DMSO) 10.01 (br s, 1H), 9.45 (br s 1H), 8.19 (d, 1H), 7.70 (d, 2H), 7.46 (d, 2H), 6.74 (d, 1H), 6.66 (d, 2H), 6.28 (d, 2H), 3.67 (m, 4H), 3.40 (m, 1H), 3.30 (m, 1H), 2.29 (m, 4H), 1.76 (m, 1H), 1.64 (m, 1H), 1.58 (s, 3H), 1.54 (m, 1H), 1.40 (s, 9H). MS (EI) for C31H38N6O4: 559 (M+).
Preparation of 2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)prolinamide
Figure imgf000161_0001
[00242] tert-Butyl 2-methyl-2-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl-carbamoyl)pyrrolidine-l -carboxylate (0.140 g, 0.250 mmoles), was dissolved in an ethyl acetate (5 ml) and methanol (1 ml) mixture. 4 M hydrogen chloride in 1,4-dioxane (0.625 ml, 2.5 mmoles, 10 equivalents, purchased from Sigma- Aldrich) was then added in a drop wise fashion over 5-10 minutes. Upon completion of addition, the 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 (0.312 ml, 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. The resulting solid was washed with ethyl acetate (3 x 10 ml) and diethyl ether (2 x 25 ml) and dried under reduced pressure to give of 0.061 mg 2- methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)prolinamide 367 as its hydrochloride salt (53% yield). 1H NMR (400 MHz, d6-DMSO): 10.88 (s, 1H), 9.79 (br s, 1H), 8.47 (d, 1H), 8.12 (d, 1H), 8.10 (d, 1H), 7.80 (br d, 2H), 7.75 (d, 2H), 7.37 (d, 2H), 5.26 (br s, 3H), 3.72 (br s, 4H), 3.27 (br s, 4H), 2.80 (m , 1H), 2.70 (m, 1H), 2.01 (m, 1H), 1.76 (m, 1H), 1,64 (m, 1H), 1.54 (m, 1H), 1.38 (s, 3H). MS (EI) for C26H30N6O2: 459 (MH+).
Example 45
2-Methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-pyrimidin-4- yl}phenyl)prolinamide (Compound 360)
Figure imgf000162_0001
[00243] An oven dried 50 ml round bottomed flask fitted with a Teflon stirrer and gas inlet was flushed with dry nitrogen and allowed to cool to room temperature. The flask was charged with 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine pentahydrochloride (1 equiv., 0.4 g, 0.756 mmoles) and anhydrous dimethylacetamide (15 ml). The mixture was stirred for 10 minutes to allow for the complete dissolution of the amine. 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). 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. The resulting crude material was purified by silica phase flash chromatography (45 mm x 250 mm) using 3: 1 ethyl acetate -hexane to give 0.39 g of 1,1-dimethylethyl (2R)-2-{[(4-{2-[(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)amino]carbonyl}pyrrolidine-1-carboxylate as a white solid (94 % yield).
1H NMR (400 MHz, d6-DMSO): 10.26 (br s ,1H), 9.38 (br s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.78 (d, 2H)< 7.68 (d, 2H), 7.28 (d, 1H), 6.94 (d, 2H), 4.22 (m, 1H), 3.74 (m, 4H), 3.43 (m, 1H), 3.34 (m, 1H), 3.04 (m, 4H), 2.20 (m, 1H), 1.90 (m, 1H), 1.81 (m, 1H)< 1.40 (s, 3H), 1.27 (s, 6H). MS (EI) for C30H36N6O4: 545 (MH+).
Figure imgf000163_0001
[00244] 1 , 1 -Dimethylethyl (2R)-2-{ [(4-{2-[(4-moipholin-4-ylphenyl)amino]pyrimidin- 4-yl}-phenyl)amino]carbonyl}pyrrolidine-1-carboxylate (0.38 g, 0.698 mmoles), was dissolved in an ethyl acetate (10 ml) and methanol (2 ml) mixture. 4 M hydrogen chloride in 1,4-dioxane (1.75 ml, 6.98 mmoles, 10 equivalents, purchased from Sigma-Aldrich) was then added in a drop wise fashion over 5-10 minutes. Upon completion of addition, the 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. The resulting solid was washed with ethyl acetate (3 x 10 ml), followed by diethyl ether (3 x 25 ml) and dried under reduced pressure to give of 0.264 mg 2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]- pyrimidin-4-yl}phenyl)prolinamide (68 % yield).
1H NMR (400 MHz, d6-DMSO): 11.43 (br s, 1H), 10.07 (br s, 2H), 8.73 (d, 1H), 8.57 (d, 1H), 8.21 (d, 2H), 7.91 (d, 2H), 7.98 (d, 2H), 7.71 (br s, 2H), 7.48 (d, 1H), 4.48 (m, 1H), 4.08 (s, 4H), 3.74 (m, 4H), 3.42 (m, 1H), 3.36 (m, 1H), 3.04 (m, 4H), 2.22 (m 1H), 1.90 (m, 2H), 1.82 (m, 2H). MS (EI) for C25H28N6O2: 445 (MH+).
Example 46
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(l-methyl-1H-benzimidazol- 2-yl)methyl]benzamide (Compound 83)
Figure imgf000164_0001
[00245] 7.9 grams (11.04 mmol, 1.9 eq) of PL-TFP Resin (source: Polymer Laboratories) was weighed into a pressure tube. 60 ml of DCM was added. 2 g (5.74 mmol) of 3-(4-(3-acetamidophenyl)pyrimidin-2-ylamino)benzoic acid was dissolved in 15 ml of DMF and After 10 min, this solution was added to the pressure tube. Dimethylaminopyridine (4.41 mmol, .6 eq, source: Acros) was added to the pressure tube as a solid, followed by 1,3-diisopropylcarbodiimide (33.08 mmol, 4.5 eq, source: Acros). The pressure tube was sealed and the reaction was placed on a vertical shaker overnight. The resin was filtered, and then washed 3 times with DMF, followed by three times with THF, followed by three times with DCM. The resin was then dried overnight by vaccum. [00246] 300 mg of resin prepared above (loading = 0.6 mmol/g, .18 mmol) was added to a 1 dram vial. 2 ml of DMA were added. 1 ml of (l-methyl-1H-benzo[d]imidazol-2- yl)methanamine (0.12 mmol, 0.67 eq) dissolved in DMA was added to the vial. The reaction was stirred overnight at room temperature. The reaction was filtered and rinsed twice with 4 ml of MeOH. The solution was further purified by HPLC to yield ( 3-(4-(4- acetamidophenyl)pyrimidin-2-ylamino)-N-(( 1 -methyl- 1 H-benzo [d] imidazol-2-yl)methyl) benzamide 83 (10.2 mg, 17%). 1H-NMR (400MHz, (I6-DMSO): 10.23 (s, 1H), 9.80 (s, 1H), 9.01 (t, 1H), 8.52 (t, 2H),
8.17-8.19 (m, 2H), 7.91-7.93 (m, 1H), 7.75 (d, 2H), 7.50-7.59 (m, 3H), 7.39-7.43 (m, 2H), 7.16-7.26 (m, 2H), 4.80 (d, 2H), 3.86 (s, 3H), 2.10 (s, 3H). MS (EI) for C28H25N7O2: 492.4 (MH+).
Example 47
N-(4-morpholin-4-ylphenyl)-4-{4-[(propylamino)methyl]phenyl} pyrimidin-2-amine (Compound 283)
Figure imgf000165_0001
[00247] A flask was charged with 2,4-dichloropyrimindine (1.5 g, 10 mmol), 4-formylphenyl boronic acid (1.65 g, 11 mmol), dicholor[l,l'-bis(diphenylphosphino)- ferrocenepalladium (731 mg, 1 mmol, 10 mol %), and triethylamine (2.6 mL, 15 mmol). Ethyleneglycoldimethylether (50 mL) and H2O (2mL) was added to the flask. The reaction mixture was stirred at 80 °C for 4 hours. The product, 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 1.0 g (4.58 mmol, 46% yield) of intermediate A as a yellow solid. [00248] A flask was charged with intermediate A (150 mg, 0.668 mmol), sodium triacetoxy-borohydride (220 mg, 1.032 mmol), propylamine (63 μl, 0.756 mmol). Dichloromethane (50 mL) was added to the flask and the reaction mixture was stirred at room temperature for 48 h. The reaction was quenched with 2 N NaOH and extracted with ethyl acetate, washed with brine, dried over sodium sultate, and filtered. The solvent was removed using the rotary evaporator to afford intermediate B as a yellow solid (140 mg, 0.536 mmol, 80% Yield). Intermediate B was carried on without further purification. [00249] 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).
1H NMR (400 MHz, DMSO): 9.93 (br s, 1H), 9.396 (br s, 2H), 8.607 (d, 1H), 8.233 (d, 2H), 7.905 (d, 2H), 7.767 (d, 2H), 7.571-7.494 (m, 3H), 4.226 (br s, 2H), 3.998 (br s, 4H), 3.436 (br s, 4H), 2.865 (m, 2H), 1.708 (m, 2H), 0.914 (t, 3H). MS (EI) for C24H29N5O: 404.4 (MH+).
Example 48 N-[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)methyl]acetamide (Compound 282)
Figure imgf000166_0001
[00250] In a 20 ml round bottomed flask, 36 mg (1 mmol) of compound A was dissolved in 5 ml of dichloromethane and 0.5 ml of triethylamine was added. It was cooled in ice bath and 10 mg (1.2 mmol) of acetyl chloride was added and stirred for 30 min. Compound 282 precipitated out and purified in a Waters prep column. Yield 40 mg
(90%).
1H NMR (400MHz, CD3CN): 11.20-1 1.22(b, 1H), 8.40 (d, 2H), 8.05(d,2H), 7.80(d,2H), 7.50 (d, 2H), 7.45 (s, 1H), 7.20 (d, 1H), 7.05-7.10 (b, 1H), 4.40-4.44 (b, 2H), 3.90 (t, 4H),
3.40 (t, 4H),2.01(s,3H); MS (EI) for C23H25N5O2: 404 (MH+). Example 49
N^-II-^-l^^^-dichloropheny^methyllpiperazin-1-ylJpheny^aminolpyrimidin- 4-yl}phenyI)acetamide (Compound 180)
Figure imgf000167_0001
[00251] To a 1 ml vial was added N-(4-{2-[(4-piperazin-1-ylphenyl)amino]pyrimidin- 4-yl}-phenyl)acetamide (38.85 mg, 0.1 mmol), 2,4-dichlorobenzaldehyde (350 mg, 2.0 mmol, 20 eq, source: Aldrich) and 1 ml of DMF. To this mixture was added sodium triacetoxyborohydride (106 mg, 0.5 mmol, 5 eq). The mixture was stirred over night at room temperature. Upon completion of the reaction as determined by LC/MS, 0.1 ml of 2M HCl was added. The residue was purified via reverse phase HPLC (ammonium acetate/ACN) to yield N-(4-{2-[(4-{4-[(2,4-dichlorophenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide 180 (20.2 mg, 37 %) .
1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.80 (s, 1H), 9.10 (t, 1H), 8.53 (d, 2H), 8.18 (d, 2H), 7.94-7.91 (m, 1H), 7.75 (d, 1H), 7.69-7.57 (m, 4H), 7.48-7.39 (m, 2H), 4.58 (d, 6H), 2.50 (m, 4H), 2.09 (s, 3H). MS (EI) for C29H28C12N6O: 548.5 (MH+).
Example 50 5-fluoro-N4-[2-(methyloxy)phenyl]-N2-[3-(methyloxy)phenyl] pyrimidine-2,4-diamine (Compound 306)
Figure imgf000167_0002
306
[00252] A round-bottomed flask was charged with 2,4-dichloro-5-fluoropyrimidine (0.84 g, 5 mmol), 2-methoxylaniline (0.61 g, 5 mmol) and dioxane (5 mL). The reaction mixture was heated at 85 °C overnight. The reaction was cooled down and diluted with acetonitrile/water, stirred for 30 min. and filtered. The collected solid was re-suspended in acetonitrile/water, stirred and filtered to give a 2-chloro-5-fluoro-N-(2- methoxyphenyl)pyrimidin-4-amine (0.9 g, 70% yield). To a seal tube was added 2-chloro- 5-fluoro-N-(2-methoxyphenyl)pyrimidin-4-amine (254 mg), 3-methoxyaniline (500 mg, 4 eq.) and dioxane (5 mL). The mixture was heated to 130 °C overnight. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was concentrated; the residue was triturated with a 1 :1 mixture of dichloromethane and acetonitrile, then filtered to give the title product as a white solid (150 mg). 1H NMR (400 MHz, d6-DMSO): 9.16 (s, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.88 (d, 1H), 7.26 (t, 2H), 7.22-7.16 (m, 2H), 7.12-7.08 (m, 1H), 7.08-6.93 (m, 2H), 3.81 (s, 3H), 3.62 (s, 3H). MS (EI) for C18Hi7FN4O2: 341 (MH+).
Example 51
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)- acetamide (Compound 329)
Figure imgf000168_0001
Figure imgf000169_0001
[00253] To a flask containing a solution of 1 (0.25g, 1 mmol), 4-(4-ethylpiperazin-1- yl)aniline (0.23g, 1.1 mmol), cesium carbonate (0.5g, 1.5 mmol), racemic-2,2' - bis(diphenylphosphino)-l,l '-binaphthyl (95mg, 0.15 mmol) in N,N-dimethylacetamide (5mL) purged with N2 was added tris(dibenzylideneacetone)dipalladium(0) (O.I 4g, 0.15 mmol). This reaction was heated to 90 °C for 16 h under N2. At this time the reaction was concentrated and the residue was purified via silica gel column chromatography. The column was eluted with ethyl acetate to remove the impurities and then with 85:10:5 (ethyl acetate/methanol/7M ammonia in methanol) to elute the desired product. The solid obtained was sonicated first in acetone (5mL) and then in ether (1OmL) to yield intermediate 2 (0,23g, 48% yield) as a yellow solid. LCMS: m/z 417 (MH+). To a flask containing 2 (0.23g, 0.45 mmol) was added 4N HCl in dioxane (5mL) and the solution was heated at 50 °C for 4 h. To the cooled solution was added a 2N aqueous solution of sodium hydroxide (1OmL) and the resulting precipitate was filtered and dried to yield 3 (0.2g, 99% yield) as a yellow solid. LCMS: m/z 375 (M+H)+. To a flask with 3 (0.3g, 0.8 mmol), phenylacetic acid (0.125mL, 1 mmol), triethylamine (0.97mL, 7 mmol), and DMF (5mL) was added O-(7-azabenzotriazole-1-yl)-N,N,N')N'-tetramethyluronium hexafluorophosphate (HATU) (0.46g, 1.2 mmol). The reaction mixture was stirred at ambient temperature for 1 h then diluted with 5% aqueous solution of lithium chloride (10OmL) and extracted with ethyl acetate (3 x 5OmL). The combined organic layers were washed with an aqueous 5% sodium bicarbonate solution, a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography (98:2 ethylacetate/methanol) to provide Compound 329 (0.25g, 63% yield) as an off-white solid.
Example 52
N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-D-prolinamide (Compound 662)
Figure imgf000170_0001
[00254] A solution of chloropyrimidine (1) (0.28g, 0.64 mmol) and tert-butyl 4-(4- aminophenyl)piperazine- 1 -carboxylate (0.18g, 0.6 mmol) in n-butanol (5ml) was heated at 180 °C in a sealed tube for 7 h. The reaction mixture was concentrated, the residue dissolved in methanol (5ml) and treated with HCl (3ml, 4M in dioxane) for 1 hour at room temperature. After concentration, the residue was dissolved in H2O (20OmL) and the pH adjusted to ca. 8-9 with IN NaOH. The aqueous layer was extracted with CH2Cl2 (2 x 10ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (85:15 ethyl acetate/methanol) to afford 2 (0.26g, 69%). C33H35N7O3: 578 (MH+).
Figure imgf000171_0001
[00255] To a solution of 2 (0.4 Ig, 0.7 mmol) and DIPEA (0.31ml, 1.75 mmol) in CH2Cl2 (7ml) was added cyclobutylcarbonyl chloride (0.80ml, 0.7 mmol) at room temperature. After 10 min, the reaction mixture was diluted with H2O (1OmL) and CH2Cl2 (1OmL). The aqueous layer was extracted with CH2Cl2 (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (98:2 ethyl acetate/methanol) to afford 3 (0.3 Ig, 68%) as a white powder. C38H4]N7O4: 660 (MH+).
Figure imgf000171_0002
[00256] The mixture of 3 (0.3 Ig, 0.47 mmol) and Pd/C (0.94g) AcOH (ImL) and MeOH (5mL) was stirred at room temperature for 24 h under a H2 balloon. The palladium was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (90:10 ethyl acetate/methanol) to afford product which was then washed with acetonitrile several times to afford Compound 662 (0.14g, 59% yield). Example 53 N-ethyl-4-[4-({4-[4-(D-prolylamino)phenyl]pyrimidin-2-yI}amino)phenyl]piperazine-
1-carboxamide (Compound 663)
Figure imgf000172_0002
[00257] To a stirred solution of 2 (0.58g, 1 mmol) in DMF (4ml) was added ethyl isocyanate (3mL) at room temperature. After stirring for 30 min, the mixture was diluted with H2O (5mL) and CH2Cl2 (5mL). The separated aqueous layer was extracted with CH2Cl2 (3 x 5mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (98:2 ethyl acetate/methanol) to afford 4 (0.46g, 71%). C36H40N8O4: 649 (M+H)+.
Figure imgf000172_0001
[00258] A solution of 4 (0.46g, 0.71 mmol) and Pd/C (0.14g) in AcOH (ImL) and MeOH (5mL) was stirred for 24 h under a H2 balloon. The palladium was filtered through celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (90:10 ethyl acetate/methanol) to afford product which was then washed with acetonitrile several times to afford N-ethyl-4-[4-({4-[4-(D- prolylamino)phenyl]-pyrimidin-2-yl}amino)phenyl]piperazine-1-carboxamide (663) (0.19g, 51%) as a white powder. -{[2-(dimethylamino)ethyl]oxy}-3-(4-ethylpiperazin-1-yl)aniline
Reduce
Figure imgf000173_0001
[00259] To a solution of 2-(diethylamino)ethanol (0.59g, 5mmol) in DMA (5ml), sodium hydride (0.24g, lOmmol) was added in one portion. Fifteen minute later 2-bromo- 4-nitroaniline (l .lg, 5mmol) was added and the content was stirred for 4 hr. Water (50ml) was added to the reaction mixture followed by chloroform. The organic layer was separated, washed with saturated sodium bicarbonate follow by brine. The organic layer was dried over sodium sulfate and concentrated to oil. The oil was dissolved in methanol and saturated with HCl gas. The resulting solution was concentrated and diethyl ester was added. The resulting precipitate was washed with ether and dried to yield 0.8g of 2-[(2- bromo-4-nitrophenyl)0xy]-N,N-diethylethanamine hydrochloride as a solid. LCMS: m/z 318 (M+H)+.
[00260] A mixture of 2-[(2-bromo-4-nitrophenyl)0xy]-N,N-diethylethanamine hydrochloride (0.5g, 1.4mmol), Pd(dba)2 (0.192g, 021mmol), BINAP (0.139g, 0.21mmol), 1-ethylpiperazine (0.182g, 1.68mmol), and cesium carbonate (0.91g, 2.8mmol) in DMA was heated at 80 °C with stirring for 72 hr. Saturated aqueous sodium bicarbonate and ethyl acetate was added, the phases separated, the solvent was removed under vacuum and the residue chromatographed on silica with ethyl acetate/methanol to give 0.32g of N,N- diethyl-2-{[2-(4-ethylpiperazin-1-yl)-4-nitrophenyl]oxy}ethanamine. LCMS: m/z 351 (M+H)+.
[00261] A solution of N,N-diethyl-2-{[2-(4-ethylpiperazin-1-yl)-4- nitrophenyl]oxy}ethanamine (0.280mg, 0.8mmol) in methanol (10ml) was added 10% Pd/C and stirred in hydrogen atmosphere at ambient temperature for 2hours. The reaction mixture was filtered through a pad of Celite and concentrated in vacuum. The residue was taken up in methanol, ether/HCl was added and the hydrochloride (0.270 mg) was precipitated. LCMS: m/z 321 (M+H)+.
Example 54
(if)-N-(4-(2-(3-(benzyloxy)-4-morpholino-phenylamino)-pyrimidin-4-yl)phenyl)- pyrroIidine-2-carboxamide (Compound 376)
[00262] /?)-N-(4-(2-(3-(benzyloxy)-4-morpholino-phenylamino)-pyrimidin-4- yl)phenyl)-pyiτolidine-2-carboxamide was synthesized in an analogous fashion to Example 3, wherein 4-morpholinoaniline was substituted with 3-(benzyloxy)-4- morpholinoaniline to afford the title compound.
3-(benzyloxy)-4-morpholinoaniline
Figure imgf000174_0001
[00263] 4-(2-(Benzyloxy)-4-nitrophenyl)morpholine: A flask was charged with 2- chloro-5-nitrophenol (3.5 g, 20.2 mmol), potassium carbonate (4.Og, 30.3 mmol), benzyl bromide (2.9 mL, 24.24 mmol,) and acetonitrile (25 mL). The reaction mixture was stirred under an N2 atmosphere at room temperature for 12 hours, after which time, the reaction mixture was filtered through Celite pat and washed with ethyl acetate (50 mL). The product was isolated by removal of the solvent with a rotary evaporator and used without further purification. NMR (400 MHz, CDCl3): 7.80 (m, 2H), 7.27 - 7.58 (m, 6H), 5.24 (s, 2H). MS (EI) for C,3Hi0ClNO3: 264 (MH+). Example 55 (S)-2-amino-N-(4-(2-(3-methyl-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide (Compound 384) was synthesized in an analogous fashion to Example 3, wherein 4-morpholinoaniline was substituted with 3 -methyl -4-morpholino- aniline to afford the title compound.
3-Methyl-4-morpholinoaniline
Figure imgf000175_0001
[00264] A flask was charged with 2-fluoro-5-nitrotuloene (3.0 mL, 20.2388 mmol). Exess amount of morpholine (10 mL) were added to the flask and heated to 40 °C for 6 hours. The reaction mixture was checked with LC/MS. Water was added to the reaction mixture and the precipitate, intermediate 1 , was filtered and used without further purification. LC/MS: m/z 223 (M+H)+. [00265] A hydrogenation flask was charged with intermediate 1 (1.0 g, 4.4209 mmol) and palladium/carbon (200 mg). Ethyl alcohol (50 mL) was added to the flask and hydrogenation technique was used. The reaction mixture was checked with LC/MS. The reaction mixture was filtered through a celite plug and washed with methanol. The product, 3-methyl-4-morpholinoaniline, was isolated by removal of the solvent with a rotary evaporator and used without further purification. LC/MS: m/z 197 (M+H)+.
Example 56 N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-chloro-6-fluoro-3-
(methyloxy)benzamide [00266] (Compound 49) was synthesized in an analogous fashion to Example 2, wherein benzoylchloride was substituted with 2-chloro-3-methoxy-6- fluorobenzoylchloride (JRD Fluroochemicals) to afford the title compound. Example 57 N-(4-{2-[(3-chloro-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide
[00267] (Compound 296) was synthesized in an analogous fashion to Example 3, wherein aniline was substituted with 3-chloro-4-morpholinoaniline (Pfaltz and Bauer, Inc.) to afford the title compound.
Example 58 N-(4-{2-[(3-bromo-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide
[00268] (Compound 315) was synthesized in an analogous fashion to Example 3, wherein aniline was substituted with 3-bromo-4-morpholinoaniline (Ryan Scientific, Inc.) to afford the title compound.
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 60 (/f)-N-(4-(2-(3-fluoro-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-
2-carboxamide was synthesized in an analogous fashion to Example 3, wherein aniline was substituted with 3-fluoro-4-morpholinoaniline (Astatech, Inc.) 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.
Example 62
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. [00269] Using the same or analogous techniques as illustrated in the preceding examples the following compounds herein below were made. The skilled artisan would be able to make the necessary modifications and/or substitutions in the above synthetic procedures to arrive at the following compounds: N-(4-{2-[(3-morpholin^-ylphenyOaminolpyrimidin^-ylJphenyOacetamide
(Compound 21): 1H-NMR (400MHz, d6-DMSO): 10.22 ppm (s, 1H), 9.51 1 ppm (s, 1H), 8.504 ppm (d, 1H), 8.154 ppm (d, 2H), 7.76 ppm (d, 3H), 7.343 ppm (d, 1H), 7.215-7.153 ppm (m, 2H), 6.584 ppm (d, 1H), 3.775 ppm (t, 4H), 3.14 ppm (t, 4H), 2.094 ppm (s, 3H); MS (EI) C22H23N5O2: 390.1 (MH+). N-(4-{2-[(3-piperidin-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide
(Compound 22): 1H-NMR (400MHz, d6-DMSO): 10.231 ppm (s, 1H), 9.466 ppm (s, 1H), 8.497 ppm (d, 1H), 8.16 ppm (d, 2H), 7.765 ppm (d, 3H), 7.337 ppm (d, 1H), 7.1 19 ppm (d, 2H), 6.553 ppm (m, 1H), 3.176 ppm (t, 4H), 2.092 ppm (s, 3H), 1.658 ppm (m, 4H), 1.571 ppm (m, 2H); MS (EI) C23H25N5O: 388.1 (MH+). N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide (Compound 33): 1H-NMR (400MHz, d6-DMSO): 10.269 ppm (s, 1H), 9.317 ppm (s, 1H), 8.411 ppm (d, 1H), 8.089 ppm (d, 2H), 7.743 ppm (d, 2H), 7.638 ppm (d, 2H), 7.243 ppm (d, 1H), 6.908 ppm (d, 2H), 3.048 ppm (br s, 4H), 2.350 ppm (q, 2H), 2.07 ppm (s, 3H), 1.027 ppm (t, 3H); MS (EI) C24H28N6O: 417.4 (MH+).
N-(4-{2-[(4-piperidin-4-ylphenyl)amino]pyriinidin-4-yl}phenyl)acetainide
(Compound 34): 1H-NMR (400MHz, d6-DMSO): 10.229 ppm (s, 1H), 9.53 ppm (s, 1H), 8.481 ppm (d, 1H), 8.135 ppm (d, 2H), 7.76 ppm (t, 4H),1 7.325 ppm (d, 1H), 7.178 ppm (d, 2H), 3.025 ppm (br d, 2H), 2.59 ppm (m, 2H), 2.094 ppm (s, 3H), 2.08 ppm (br d, 2H), 1.54-1.439 ppm (m, 2H); MS (EI) C23H25N5O: 388.3 (MH+). N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}ainino)phenyl]-2,6-dichloro- benzamide (Compound 17): 1H-NMR (400MHz, d6-DMSO): 10.718 ppm (s, 1H), 10.269 ppm (s, 1H), 9.678 ppm (s, 1H), 8.507 ppm (d, 1H), 8.419 ppm (s, 1H), 8.215 ppm (d, 2H), 7.758 ppm (d, 2H), 7.608 ppm (d, 2H), 7.532 ppm (t, 1H), 7.472 ppm (d, 1H), 7.380 ppm (d, 1H), 7.301 ppm (t, 1H), 7.216 ppm (d, 1H), 2.085 ppm (s, 3H); MS (EI) C25H19Cl2N5O2: 492.2 (MH+).
N-{4-[2-({3-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide (Compound 8): 1H-NMR (400MHz, d6-MEOD): 8.455 ppm (d, 1H), 8.15 ppm (m, 3H), 7.76-7.7 ppm (m, 3H), 7.435 ppm (t, 1H), 7.311 ppm (d, 1H), 7.1 ppm (d, 1H), 3.832 ppm (br s, 4H), 3.13 ppm (br s, 4H), 3.016 ppm (q, 2H), 2.162 ppm (s, 3H), 1.975 ppm (s, 3H, ACE), 1.299 ppm (t, 3H); MS (EI) C25H28N6O2: 445.4 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyriinidin-2-yl}amino)phenyI]-2- fluorobenzamide (Compound 10): 1H NMR (DMSO-J6) 10.40 (s, 1H), 10.21 (s, 1H), 9.66 (s, 1H), 8.49 (d, 1H), 8.41 (s, 1H), 8.20 (d, 2H), 7.74 (d, 2H), 7.69 (m, 1H), 7.58 (m, 1H), 7.48 (m, 1H), 7.37 (m, 3H), 7.28 (m, 2H), 2.09 (s, 3H). LCMS: m/z 442 (M+H)+.
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-fluoro-6- iodobenzamide (Compound 11): 1H NMR (DMSO-CZ6) 10.65 (s, 1H), 10.19 (s, 1H), 9.67 (s, 1H), 8.50 (d, 1H), 8.41 (s, 1H), 8.21 (d, 2H), 7.76 (m, 3H), 7.41 (m, 3H), 7.28 (m, 3H), 2.08 (s, 3H). LCMS: m/z 567 (M+H)+. N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2- bromobenzamide (Compound 23): 1H NMR (DMSO-J6) 10.48 (s, 1H), 10.20 (s, 1H), 9.66 (s, 1H), 8.49 (d, 1H), 8.42 (s, 1H), 8.20 (d, 2H), 7.73 (d, 3H), 7.55 (m, 2H), 7.45 (m, 2H), 7.36 (m, 1H), 7.37 (d, 1H), 7.25 (m, 2H), 2.08 (s, 3H). LCMS: m/z 502, 503, 504, 505 (M+H)+.
N-[3-({4-[4-(acetyIamino)phenyl]pyrimidin-2-yl}amino)phenyl]-3- fluorobenzamide (Compound 24): 1H NMR (DMSO-J6) 10.33 (s, 1H), 10.23 (s, 1H), 9.69 (s, 1H), 8.50 (d, 1H), 8.44 (s, 1H), 8.21 (d, 2H), 7.85 (m, 1H), 7.79 (m, 1H), 7.73 (d, 2H), 7.61 (m, 1H), 7.50 (m, 1H), 7.36 (m, 1H), 7.29 (m, 2H), 2.09 (s, 3H). LCMS: m/z 442 (M+H)+.
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyI]-2,6-dimethyl- benzamide (Compound 12): 1H NMR (DMSO-J6) 10.37 (s, 1H), 10.20 (s, 1H), 8.55 (s, 1H), 8.49 (d, 1H), 8.22 (d, 2H), 7.72 (d, 2H), 7.36 (d, 2H), 7.22 (m, 3H), 7.12 (d, 2H), 2.33 (s, 6H), 2.08 (s, 3H). LCMS: m/z 452 (M+H)+.
Λf-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]pyridine-4- carboxamide (Compound 14): 1H NMR (DMSO-J6) 10.59 (s, 1H), 10.34(s, 1H), 9.71 (s, 1H), 8.80 (dd, 2H), 8.50 (m, 2H), 8.21 (d, 2H), 7.90 (dd, 2H), 7.75 (d, 2H), 7.51 (m, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 2.09 (s, 3H). LCMS: m/z 425 (M+H)+.
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,3,4,5,6- pentafluorobenzamide (Compound 15): 1H NMR (DMSO-J6) 10.97 (s, 1H), 10.20 (s, 1H), 9.75 (s, 1H), 8.50 (d, 1H), 8.33 (s, 1H), 8.17 (d, 2H), 7.72 (d, 2H), 7.55 (m, 1H), 7.38 (d, 1H), 7.32 (t, 1H), 7.24 (d, 1H), 2.08 (s, 3H). LCMS: m/z 514 (M+H)+.
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2,6-dichloro- benzamide (Compound 1): 1H NMR (DMSO-J6) 10.15 (s, 1H), 8.68 (t, 1H), 8.27 (d, 1H), 8.04 (d, 2H), 7.67 (d, 2H), 7.49 (d, 2H), 7.41 (m, 1H), 7.13 (t, 1H), 7.06 (d, 1H), 3.41 (m, 2H), 3.30 (m, 2H), 2.06 (s, 3H), 1.80 (m, 2H). LCMS: m/z 458 (M+H)+.
2,6-dichloro-N-(3-{[4-(2,4-dichlorophenyl)pyrimidin-2- yl]amino}propyl)benzamide (Compound 2): 1H NMR (DMSO-J6) 8.63 (s, 1H), 8.36 (d, 1H), 7.73 (s, 1H), 7.58 (d, 1H), 7.52 (d, 1H), 7.47 (m, 2H), 7.40 (m, 2H), 6.79 (d, 2H), 3.37 (m, 2H), 3.27 (m, 2H), 1.75 (t, 2H). LCMS: m/z 471 (M+H)+.
4-(2,4-dichlorophenyl)-N-{3-[(2-piperidin-1-ylethyl)oxy]phenyl}pyrimidin-2- amine (Compound 19): 1H NMR (DMSO-J6) 9.79 (s, 1H), 8.58 (d, 1H), 7.77 (d, 1H), 7.68 (d, 1H), 7.58 (m, 2H), 7.24 (d, 1H), 7.10 (m, 2H), 6.50 (dd, 1H), 3.98 (t, 2H), 2.60 (t, 2H), 2.47 (m, 4H), 1.46 (m, 4H), 1.36 (m, 2H). LCMS: m/z 443 (M+H)+ N-(3-{[4-(4-aminophenyl)pyrimidin-2-yl]ainino}propyl)-2,6- dichlorobenzamide (Compound 6): 1H NMR (400 MHz, DMSO): δ 8.76-8.79 (m, 1H), 8.45 (d, 6.0 Hz, 1H), 7.94-8.06 (m, 3H), 7.56 (m. 1H), 7.52-7.51 (m, 1H), 7.50 (s, 2H), 7.43-7.52 (m, 2H), 7.36-7.42 (m, 1H), 7.22-7.34 (bs, 1H), 3.44-3.64 (bs, 2H), 3.32-3.40 (m, 2H), 1.02-1.52 (bs, 2H). LC/MS MH=416. 2,6-dichloro-N-(3-{[4-(2,3-dihydro-1-benzofuran-6-yl)pyriinidin-2-yl]amino}- propyl)benzamide (Compound 4): 1H NMR (400 MHz, DMSO): δ 8.724 (t, 5.6Hz, 1H), 8.29 (d, 5.6 Hz, 1H), 8.41-8.18 (bs, 1H), 7.92-8.15 (bs, 1H), 7.49-7.52 (m, 2H), 7.41-7.45 (m, 2H), 7.14-7.23 (bs, 1H), 6.88 (d, 8.4Hz, 1H), 4.61-4.65 (m, 2H), 3.62-3.93 (bs, 1H), 3.39-3.51 (bs, 1H), 3.33-3.36 (m, 2H), 3.23-3.27 (m, 2H), 1.80-1.87 (bs, 2H). LC/MS MH=443.
2,6-dichloro-N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2- yl}amino)propyl]-benzamide (Compound 3). 1H NMR (400 MHz, DMSO): δ 8.66 (t, 5.6Hz, 1H), 8.17 (d, 5.2 Hz, 1H), 7.95 (d, 8.8 Hz, 2H), 7.47-7.49 (m, 2H), 7.38-7.42 (m, 1H), 6.95-6.97 (m, 2H), 6.72-6.75 (m, 2H), 3.37-3.43 (m, 2H), 3.26-3.32 (m, 2H), 2.96 (s, 6H), 1.79 (t, 6.8Hz, 2H). LC/MS M-H=442.
N-[3-({4-[4-(acetylamino)phenyl]-5-methylpyrimidin-2-yl}amino)phenyl]- 2,6-dichlorobenzamide (Compound 25): 1H NMR (400MHz, DMSO-d6) δ 10.67 (s, 1H), 10.15 (s, 1H), 9.57 (s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.72 (s, 4H), 7.60-7.50 (m, 4H), 7.26-7.23 (m, 2H), 2.26 (s, 3H), 2.09 (s, 3H). LCMS (EI) C26H22Cl2N5O2: 506 (M+H).
N-[3-({4-[4-(acetylamino)phenyl]-5-fluoropyriinidin-2-yl}ainino)phenyl]-2,6- dichlorobenzamide (Compound 28): 1H NMR (400MHz, DMSO-de) δ 10.72 (s, 1H), 10.25 (s, 1H), 9.78 (s, 1H), 8.59 (d, J = 4.0Hz, 1H), 8.32 (s, 1H), 8.12 (d, J = 8.4Hz, 2H), 7.77 (d, J = 8.8Hz, 2H), 7.61-7.58 (m, 2H), 7.51 (dd, J = 8.8, 6.8Hz, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.28 (t, J = 8.0Hz, 1H), 7.23 (t, J = 8.0Hz, 1H), 2.09 (s, 3H). LCMS (EI) C25H18Cl2FN5O2: 510 (M+H).
N-(4-{2-[(4-{[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]oxy}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide (Compound 64): 1H-NMR (400MHz, d6-DMSO): 10.222 ppm (s, 1H), 9.445 ppm (s, 1H), 8.457 ppm (d, 1H), 8.119 ppm (d, 2H), 7.75 ppm (d, 2H), 7.686 ppm (d, 2H), 7.299 ppm (d, 1H), 6.922 ppm (d, 2H), 4.76 ppm (s, 2H), 3.465 ppm (bs, 4H), 2.4 ppm (m, 4H), 2.31 ppm (m, 2H), 2.091 ppm (s, 3H), 1.02 ppm (t, 3H); MS (EI) C26H30N6O3: 475.4 (MH+). l-ethyl-3-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)urea
(Compound 250 HC1) (Compound 250): 1H-NMR (400MHz, d6-DMSO): 10.064 ppm (s, 1H), 9.305 ppm (s, 1H), 8.483 ppm (d, 1H), 8.105 ppm (d, 2H), 7.832 ppm (bd, 2H), 7.603 ppm (d, 2H), 7.54 ppm (bs, 2H), 7.431 ppm (d, 1H), 6.55 ppm (bs, 1H), 3.89 ppm (bs, 4H), 3.426 ppm (bs, 4H), 3.15 ppm (m, 2H), 1.08 ppm (t, 3H) ); MS (EI) C23H26N6O2HCl: 419.3 (MH+).
N-[6-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)pyrimidin-4-yl]-2,6- dichlorobenzamide (Compound 301): 1H NMR (400MHz, d6-DMSO): 1 1.55 (s, 1H), 10.5 (s, 1H), 10.2 (s, 1H), 9.32 (s, 1H), 8.68 (d, 1H), 8.6 (s, 1H), 8.4 (d, 2H), 7.74 (d, 2H), 7.64 (d, 1H), 7.62-7.5 (m, 3H), 2.03 (s, 3H); MS (EI) for C23H17Cl2N7O2: 494 (MH+).
N-[4-(2-{[4-(morpholin-4-ylmethyl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide (Compound 232): 1H NMR (400MHz, d6-DMSO): 10.3 (s, 1H), 9.6 (s, 1H), 8.46 (d, 1H), 8.13 (d, 2H), 7.78 (t, 4H), 7.35 (d, 1H), 7.47 (d, 1H), 7.23 (d, 2H), 3.58 (t, 4H), 3.4 (s, 2H), 2.33 (t, 4H), 2.1 (s, 3H); MS (EI) for C23H25N5O2: 404 (MH+). 4-(l//-indol-5-yl)-ΛL(4-morpholin-4-ylphenyl)pyr-m-din-2-amine (Compound
254): 1H-NMR (400MHz, d6-DMSO): 1 1.35 ppm (s, 1H), 9.33 ppm (s, 1H), 8.41 ppm (m, 2H), 7.94 ppm (dd, 1H), 7.71 ppm (d, 2H), 7.50 ppm (d, 1H), 7.44 ppm (t, 1H), 7.33 ppm (d, 1H), 6.94 ppm (d, 2H), 6.57 ppm (s,1H), 3.75 ppm (m, 4H), 3.05 ppm (m, 4H), 2.09 ppm (s, 3H); MS (EI) C24H25N5O2: 372.3 (MH+).
N-(3-{2-[(4-morpholin-4-ylphenyl)amino]pyriinidin-4-yl}phenyI)acetainide (Compound 79): 1H-NMR (400MHz, d6-DMSO): 10.14 ppm (s, 1H), 9.45 ppm (s, 1H), 8.49 ppm (d, 1H), 8.40 ppm (s, 1H), 7.77 ppm (d, 1H), 7.70 ppm (d, 3H), 7.45 ppm (t, 1H), 7.20 ppm (d, 1H), 6.93 ppm (d, 2H), 3.74 ppm (m, 4H), 3.04 ppm (m, 4H), 2.09 ppm (s, 3H); MS (EI) C24H25N5O2: 390.1 (MH+).
4-[4-(methyloxy)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-am-iie (Compound 252): 1H-NMR (400MHz, d6-DMSO): 9.37 ppm (s, 1H), 8.42 ppm (d, 1H), 8.13 ppm (d, 2H), 7.67 ppm (d, 2H), 7.27 ppm (d, 1H), 7.08 ppm (d, 2H), 6.92 ppm (d, 2H), 3.84 ppm (s, 3H), 3.74 ppm (m, 4H), 3.04 ppm (m, 4H); MS (EI) C24H25N5O2: 363.1 (MH+).
N-(4-{2-[(3-piperazin-1-ylphenyl)ainino]pyrimidin-4-yl}phenyl)acetaniide (Compound 312): 1H-NMR (400MHz, d6-DMSO): 10.32 ppm (s, 1H), 9.55 ppm (s, 1H), 8.50 ppm (d, 1H), 8.13 ppm (d, 2H), 7.78 ppm (d, 2H), 7.68 ppm (s, 1H), 7.35 ppm (dd, 2H), 7.20 ppm (t, 1H), 6.63 (dd, 1H), 3.38 (m, 4H), 3.25 (m, 4H), 2.13 ppm (s, 3H); MS (EI) C22H24N6O: 389.1 (MH+)
2-amino-N-(4-(2-(4-morpholinophenylamino)pyriinidin-4-yl)phenyl)-2- phenyl-acetamide (Compound 573): 1H-NMR (400MHz, d6-DMSO): 1 1.93 ppm (s, 1H), 10.18 (s, 1H), 9.08 ppm (s, 2H), 8.58 ppm (d, 1H), 8.18 ppm (d, 2H), 7.98-7.88 ppm (m, 2H), 7.82-7.75 ppm (m, 2H), 7.60-7.40 ppm (m, 6H), 7.30 ppm (s, 2H), 5.52-5.46 (m, 1H), 4.10 (t, 4H), 3.57 (t, 4H); MS (EI) C28H28N6O2: 481.3 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- alaninamide (Compound 577): 1H-NMR (400MHz, d6-DMSO): 9.387 ppm (s, 1H), 8.443 ppm (d, 1H), 8.127 ppm (d, 2H), 7.825 ppm (d, 2H), 7.676 ppm (d, 2H), 7.287 ppm (d, 1H), 6.939 ppm (d, 2H), 3.747 ppm (m, 4H), 3.457 ppm (q, 1H), 3.050 ppm (m, 4H), 1.896 ppm (s, 3H (AcOH)), 1.243 ppm (d, 3H); MS (EI) C23H26N6O2: 419.1 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)valinamide (Compound 575): 1H-NMR (400MHz, (d6-DMSO): 9.390 ppm (s, 1H), 8.449 ppm (d, 1H), 8.124 ppm (d, 2H), 7.815 ppm (d, 2H), 7.686 ppm (d, 2H), 7.284 ppm (d, 1H), 6.939 ppm (d, 2H), 3.747 ppm (m, 4H), 3.147 ppm (d, 1H), 3.051 ppm (m, 4H), 1.953 ppm (m, 1H ), 1.864 ppm (s, 3H (AcOH)), 0.943 ppm (d, 3H), 0.871 ppm (d, 3H); MS (EI) C25H30N6O2: 446.2 (MH+).
2-(dimethylamino)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)- phenyl)-acetamide (Compound 197): 1H-NMR (400MHz, d6-DMSC)): 10.001 ppm (s, 1H), 9.384 ppm (s, 1H), 8.440 ppm (d, 1H), 8.1 18 ppm (d, 2H), 7.836 ppm (d, 2H), 7.673 ppm (d, 2H), 7.287 ppm (d, 1H), 6.939 ppm (d, 2H), 3.745 ppm (m, 4H), 3.114 ppm (s, 2H), 3.049 ppm (m, 4H), 2.290 ppm (s, 6H ); MS (EI) C24H28N6O2: 432.5 (MH+).
N-(4-{2-[(4-{4-[3-(dimethylamino)-2,2-dimethylpropyl]piperazin-1-yl}phenyl)- amino]pyrimidin-4-yl}phenyl)acetamide (Compound 578): 1H-NMR (400MHz, d6- DMSO): ): 10.208 ppm (s, 1H), 9.358 ppm (s, 1H), 8.433 ppm (d, 1H), 8.106 ppm (d, 2H), 7.741 ppm (d, 2H), 7.648 ppm (d, 2H), 7.262 ppm (d, 1H), 6.909 ppm (d, 2H), 3.050 ppm (m, 4H), 2.595 ppm (m, 4H), 2.212 ppm (s, 6H ), 2.172 ppm (s, 2H ), 2.091 ppm (m, 5H ), 0.843 ppm (s, 6H ); MS (EI) C29H39N7O: 502.2 (MH+).
N-(4-{2-[(4-{4-[(l-methyl-l/r-imidazol-2-yl)methyl]piperazin-1-yl}phenyl)- amino]-pyrimidin-4-yl}phenyl)acetamide (Compound 576): 1H-NMR (400MHz, d6- DMSO): 10.23 ppm (s, 1H), 9.37 ppm (s, 1H), 8.43 ppm (d, 1H), 8.106 ppm (d, 2H), 7.74 ppm (d, 2H), 7.65 ppm (d, 2H), 7.26 ppm (d, 1H), 7.10 ppm (s, 1H), 6.92 ppm (d, 2H), 6.78 ppm (s, 1H), 3.67 ppm (s, 3H), 3.58 ppm (s, 2H), 3.39-3.34 ppm (m, 4H), 3.02-3.08 ppm (M, 4H), 2.10 ppm (s, 3H); MS (EI) C27H30N8O 482.6 (MH+).
N-(4-(2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenylamino)pyrimidin-
4-yl)phenyl)acetamide (Compound 349): 1H-NMR (400MHz, d6-DMSO): 10.22 ppm (s, 1H), 9.41 ppm, (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.74 ppm (d, 2H), 7.69 ppm (d, 2H), 7.28 ppm (d, 1H), 6.97 ppm (d, 2H), 3.83 ppm (s, 2H), 3.62 ppm (s, 2H), 3.15 ppm (s, 2H), 3.03 ppm (s, 2H), 2.09 ppm (s, 3H), 2.02-2.05 ppm (m, 1H), 0.74-0.76 ppm (m, 4H); MS (EI) C26H28N6O2: 456.5 (MH+).
N-{4-[2-({3-[(4-phenylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4-yl]- phenyl}acetamide (Compound 78): 1H-NMR (400MHz, d6-DMSO): 10.21 ppm (s,1H), 9.83 ppm (s,1H), 8.53 ppm (d, 1H), 8.13 ppm (d, 2H), 8.05 ppm (s, 1H), 7.95 ppm (s, 1H), 7.87 ppm (d, 1H), 7.75 ppm (d, 2H), 7.38-7.43 (m, 2H), 7.20-7.242 (m, 2H), 7.02 ppm (d, 2H) 6.95 ppm (d, 2H), 6.81 ppm (t, 1H), 3.68-3.88 ppm (m, 2H), 3.44-3.65 ppm (m, 2H), 3.02-3.11 ppm (m, 4H), 2.09 ppm (s, 3H); MS (EI) C29H28N6O2: 492.6 (MH+). N-(4-{2>[(4-morphoIin-4-ylphenyI)ainino]pyriinidin-4-yl}phenyl)-D- alaninamide (Compound 578): 1H-NMR (400MHz, dδ-DMSO): 11.13 ppm (s, 1H), 9.89 ppm (s, 1H), 8.53 ppm (d, 1H), 8.35 ppm (d, 3H), 8.20 ppm (d, 2H), 7.85 ppm (d, 4H), 7.49 ppm (br s, 2H), 7.43 ppm (d, 1H), 4.14 ppm (m, 1H), 3.96 ppm (br s, 4H), 3.40 ppm (br s, 4H), 1.50 ppm (s, 3H); MS (EI) C23H26N6O2: 419 (MH+).
(N-(4-{5-methyl-2-[(3-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl- acetamide): 1H-NMR (400MHz, d6-DMSO): 10.17 (s, 1H), 9.41 (s, 1H), 8.38 (s, 1H), 7.84 (s, 1H), 7.72 (s, 4H), 7.09 (d, 2H), 6.51 (dd, 1H), 3.74 (t, 4H), 3.07 (t, 4H), 2.26 (s, 3H), 2.09 (s, 3H); MS (EI) C23H25N5O2: 404.3 (M+H)+. (N-(4-{6-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyI)- acetamide): 1H-NMR (400MHz, (I6-DMSO): 10.18 (s, 1H), 9.31 (s, 1H), 8.09 (d, 2H), 7.74-7,70 (m, 4H), 7.19 (s, 1H), 6.93 (d, 2H), 3.74 (t, 4H), 3.04 (t, 4H), 2.38 (s, 3H), 2.09 (s, 3H); MS (EI) C23H25N5O2: 404.3 (M+H)+.
(N-(4-{2-[(4-morpholin-4-yIphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- phenyl)acetamide): 1H-NMR (400MHz, CDCl3): 8.66 (s, 1H), 7.65-7.59 (m, 4H), 7.51 (d, 2H), 7.33 (d, 2H), 6.93 (d, 2H), 3.87 (t, 4H), 3.14 (t, 4H); MS (EI) C26H30N6O3: 458.1 (M+H)+.
(N-(4-{2-[(3-aminophenyl)amino]-5-methylpyrimidin-4-yl}phenyl)acetamide): 1H-NMR (400MHz, (I6-DMSO): 10.14 (s, 1H), 9.19 (s, 1H), 8.33 (d, 1H), 7.72 (d, 2H), 7.67 (dd, 2H), 7.03 (t, 1H), 6.94 (dd, 1H), 6.87 (t, 1H), 6.17-6.14 (m, 1H), 4.92 (s, 2H), 2.23 (s, 3H), 2.08 (s, 3H); MS (EI) C19H19N5O: 334.0 (M+H)+.
(N-(4-{2-[(3-aminophenyl)amino]-5-fluoropyrimidin-4-yl}phenyl)acetainide): 1H-NMR (400MHz, d6-DMSO): 10.26 (s, 1H), 9.41 (s, 1H), 8.54 (d, 1H), 8.04 (d, 2H), 7.78 (d, 2H), 7.03 (s, 1H), 6.95-6.91 (m, 2H), 6.20 (d, 1H), 5.00 (s, 2H), 2.10 (s, 3H); MS (EI) C18H16FN5O: 338.3 (M+H)+.
(N-[4-(2-{[4-(4-ethyIpiperazin-1-yl)phenyl]amino}-5-fluoropyrimidin-4- yl)phenyl]acetamide): 1H-NMR (400MHz, d6-DMSO): 10.26 (s, 1H), 9.45 (s, 1H), 8.52(d, 1H), 8.02 (d, 2H), 7.78 (d, 2H), 7.59 (d, 2H), 6.91 (d, 2H), 3.35 (bs, 4H), 3.07 (bs, 4H), 2.50 (q, 2H), 2.10 (s, 3H), 1.04 (t, 3H); MS (EI) C24H27FN6O: 435.3 (M+H)+. (N-[3-({4-[4-(acetylamino)phenyl]-5-methylpyrimidin-2-yl}amino)phenyl]-2,6- dimethylbenzamide): 1H-NMR (400MHz, d6-DMSO): 10.32 (s, 1H), 10.15 (s, 1H), 9.51 (s, 1H), 8.37(s, 1H), 8.29 (s, 1H), 7.76-7.70 (m, 4H), 7.42-7.41 (m, 1H), 7.25-7.17 (m, 3H), 7.11 (d, 2H), 2.29 (s, 6H), 2.26 (s, 3H), 2.09(s, 3H); MS (EI) C28H27N5O2: 466.3 (M+H)+.
(N-(4-{2-[(3,5-dimorpholin-4-ylphenyl)amino]-5-fluoropyrimidin-4-yl}- phenyl)-acetamide): 1H-NMR (400MHz, d6-DMSO): 10.27 (s, 1H), 9.45 (s, 1H), 8.58(d, 1H), 8.07 (d, 2H), 7.77 (d, 2H), 7.06 (s, 2H), 6.17 (s, 1H), 3.75 (t, 8H), 3.10 (t, 8H), 2.10 (s, 3H); MS (EI) C26H29FN6O3: 493.4 (M+H)+.
(N-{4-[2-(1H-indazol-6-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide): 1H-NMR (400MHz, d6-DMSO): 12.80 (s, 1H), 10.18 (s, 1H), 9.72 (s, 1H), 8.44(d, 1H), 8.37 (d, 1H), 7.90 (s, 1H), 7.77-7.70 (m, 4H), 7.59 (d, 1H), 7.28 (dd, 1H), 2.27 (s, 3H), 2.10 (s, 3H); MS (EI) C20H18N6O: 359.3 (M+H)+.
(N-{4-[2-(1H-indol-5-ylamino)-5-methylpyrimidin-4-yl]phenyI}acetamide): 1H-NMR (400MHz, d6-DMSO): 10.90 (s, 1H), 10.15 (s, 1H), 9.21 (s, 1H), 8.32(d, 1H), 8.00 (d, 1H), 7.72 (dd, 2H), 7.66 (dd, 2H), 7.36 (dd, 1H), 7.28-7.25 (m, 2H), 6.33 (t, 1H), 2.22 (s, 3H), 2.09 (s, 3H); MS (EI) C2iH19N50: 358.3 (M+H)+. (N-(4-{5-fluoro-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyI)- acetamide): 1H-NMR (400MHz, d6-DMSO): 10.26 (s, 1H), 9.48 (s, 1H), 8.52 (d, 1H), 8.02 (d, 2H), 7.77 (d, 2H), 7.61 (d, 2H), 6.93 (d, 2H), 3.74 (t, 4H), 3.03 (t, 4H); MS (EI) C22H22FN5O2: 408.3 (M+H)+.
N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.41 (s, 1H), 9.28 (s, 1H), 8.31(d, 1H), 7.73 (d, 2H), 7.66-7.62 (m, 4H), 6.89 (d, 2H), 3.73 (bs, 4H), 3.02 (bs, 4H), 2.22 (s, 3H), 1.85-1.79 (m, 1H), 0.84-0.81 (m, 4H); MS (EI) C25H27N5O2: 430 (MH+).
N-{4-[2-(1H-indazol-5-ylamino)-5-methylpyrimidin-4-yI]phenyl}acetamide: 1H-NMR (400MHz, d6-DMSO): 12.88 (s, 1H), 10.16 (s, 1H), 9.49 (s, 1H), 8.37(s, 1H), 8.29 (d, 1H), 7.97 (s, 1H), 7.73 (d, 2H), 7.67 (d, 2H), 7.59 (dd, 1H), 7.44 (d, 1H), 2.24 (s, 3H), 2.10 (s, 3H); MS (EI) C20H18N6O: 359 (MH+).
N-(4-{2-[(3,5-dimorphoIin-4-ylphenyl)amino]pyrimidin-4-yl}phenyI)- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.36 (s, 1H), 8.48 (d, 1H), 8.15 (d, 2H), 7.74 (d, 2H), 7.32 (d, 1H), 7.12 (d, 2H), 6.17 (s, 1H), 3.75 (t, 4H), 3.11 (t, 4H), 2.09 (s, 3H); MS (EI) C26H30N6O3: 475 (MH+). 4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}benzonitrile: 1H-NMR (400MHz, d6-DMSO): 9.60 (s, 1H), 8.57 (d, 1H), 8.32 (d, 2H), 8.03 (d, 2H), 7.65 (d, 2H), 7.44 (d, 1H), 6.94 (d, 2H), 3.75 (t, 4H), 3.05 (t, 4H), ; MS (EI) C2iH,9N50: 358 (MH+).
4-(4-fluorophenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMSO): 9.46 (s, 1H), 8.49 (d, 1H), 8.22 (dd, 2H), 7.66 (d, 2H), 7.38 (t, 2H),
7.33 (d, 1H), 6.93 (dd, 2H), 3.74 (t, 4H), 3.05 (t, 4H), ; MS (EI) C20H19FN4O: 358.3 (M+H)+.
N-(4-morpholin-4-ylphenyl)-4-(4-pyrimidin-5-ylphenyl)pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMSO): 9.50 (s, 1H), 9.26 (s, 2H), 9.24 (s, 1H), 8.53 (d, 1H), 8.32 (d, 2H), 8.02 (d, 2H), 7.69 (d, 2H), 7.44 (s, 1H), 6.94 (d, 2H), 3.75 (t, 4H), 3.06 (t, 4H); MS (EI) C24H22N6O: 411 (MH+).
N-(4-morpholin-4-ylphenyl)-4-[4-(pyridin-2-ylamino)phenyl]pyrimidin-2- amine: 1H-NMR (400MHz, d6-DMSO): 9.42 (s, 1H), 9.33 (s, 1H), 8.40 (d, 1H), 8.23 (dd, 1H), 8.09 (dd, 2H), 7.86 (d, 2H), 7.70 (d, 2H), 7.65-7.61 (m, 1H), 7.25 (d, 1H), 6.96-6.90 (m, 3H), 6.84-6.81 (m, 1H). 3.75 (t, 4H), 3.05 (t, 4H) ; MS (EI) C25H24N6O: 425 (MH+).
N-(4-morpholin-4-ylphenyl)-4-[4-(pyridin-3-ylamino)phenyl]pyrimidin-2- amine: 1H-NMR (400MHz, (I6-DMSO): 9.33 (s, 1H), 8.81 (s, 1H), 8.45 (d, 1H), 8.40 (d, 1H), 8.14 (dd, 1H), 8.08 (d, 2H), 7.68 (d, 2H), 7.63-7.60 (m, 1H), 7.32 (dd, 1H), 7.23 (d, 1H), 7.19 (dd, 2H), 6.93 (d, 2H), 3.74 (t, 4H), 3.05 (t, 4H); MS (EI) C25H24N6O: 425 (MH+).
N-[4-(2-{[4-(4-D-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- D-proIinamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.31 (s, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.69 (d, 2H), 7.30 (d, 1H), 6.97 (d, 2H), 4.09-4.04 (m, 1H), 3.77-3.73 (m, 1H), 3.67-3.61 (m, 4H), 3.09-3.03 (m, 4H), 2.92 (t, 2H), 2.10-2.03 (m, 1H), 1.85-1.77 (m, 1H), 1.71-1.64 (m, 2H), 1.19 (d, 3H); MS (EI) C28H34N8O2: 515 (MH+).
N-[4-(2-{[4-(4-L-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyI]- D-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H),
8.34 (s, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.69 (d, 2H), 7.30 (d, 1H), 6.97 (d, 2H), 4.06-4.01 (m, 1H), 3.77-3.73 (m, 1H), 3.67-3.61 (m, 4H), 3.09-3.02 (m, 4H), 2.92 (t, 2H), 2.10-2.03
(m, 1H), 1.85-1.77 (m, 1H), 1.71-1.64 (m, 2H), 1.18 (d, 3H); MS (EI) C28H34N8O2: 515 (MH+). N-{4-[2-({4-[4-(piperazin-1-ylacetyl)piperazin-1-yl]phenyl}amino)pyriniidin-4- yl]phenyl}-D-proIinamide: 1H-NMR (400MHz, (I6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 3.76-3.73 (m, 1H), 3.69-3.59 (m, 4H), 3.19 (s, 2H), 3.10-3.02 (m, 4H), 2.91 (t, 2H), 2.81 (bs, 4H), 2.44 (bs, 4H), 2.10-2.04 (m, 1H), 1.85-1.77 (m, 1H), 1.71-1.64 (m, 2H); MS (EI) C31H39N9O2: 570 (MH+).
N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyI}-D-alaninamide: 1H-NMR (400MHz, d6-DMSO): 9.43 (s, 1H), 8.47 (d, 1H), 8.17 (d, 2H), 7.80 (d, 2H), 7.69 (d, 2H), 7.31 (d, 1H), 6.98 (d, 2H), 3.82-3.78 (m, 4H), 3.66-3.62 (m, 4H), 3.09-3.03 (m, 4H), 2.97-2.90 (m, 1H), 1.39 (d, 3H), 1.03 (d, 6H); MS (EI) C27H33N7O2: 488 (MH+).
N-[4-(2-{[4-(4-D-alanylpiperazin-1-yI)phenyl]amino}pyrimidin-4-yl)phenyl]- D-alaninamide: 1H-NMR (400MHz, (I6-DMSO): 9.42 (s, 1H), 8.45 (d, 1H), 8.33 (s, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.69 (d, 2H), 7.30 (d, 1H), 6.98 (d, 2H), 4.13-4.07 (m, 1H), 3.70-3.59 (m, 5H), 3.11-3.01 (m, 4H), 1.27 (d, 3H), 1.21 (d, 3H); MS (EI) C26H32N8O2: 489 (MH+).
N-{4-[2-({4-[4-(tetrahydrofuran-3-ylcarbonyl)piperazin-1-yl]phenyl}amino)- pyrimidin-4-yl)phenyl}-D-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.19 (s, 1H), 9.42 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 3.89 (t, 1H), 3.74-3.69 (m, 4H), 3.67-3.63 (m, 4H), 3.45-3.37 (m, 1H), 3.09-3.02 (m, 4H), 2.90 (t, 2H), 2.08-1.99 (m, 3H), 1.84-1.76 (m, 1H), 1.70-1.64 (m, 2H); MS (EI) C30H35N7O3: 542 (MH+).
N-{4-[2-({4-[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]phenyl}amino)- pyrimidin-4-yl]phenyl}-D-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.83 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 4.72 (dd, 1H), 3.82-3.72 (m, 3H), 3.69-3.58 (m, 4H), 3.08-3.02 (m, 4H), 2.91 (t, 2H), 2.11-1.99 (m, 3H), 1.88-1.79 (m, 3H), 1.71-1.66 (m, 2H); MS (EI) C30H35N7O3: 542 (MH+).
N-(4-{5-chloro-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.30 (s, 1H), 9.67 (s, 1H), 8.52 (s, 1H), 7.82 (s, 4H), 7.59 (d, 2H), 6.90 (dd, 2H), 3.84 (dd, 1H), 3.74-3.72 (m, 4H), 3.04-3.02 (m, 4H), 2.97 (t, 2H), 2.15-2.09 (m, 1H), 1.86-1.79 (m, 1H), 1.75-1.69 (m, 2H); MS (EI) C25H27ClN6O2: 479 (MH+).
(R)-N-(4-(2-(4-(4-(2-(pyrrolidin-1-yl)acetyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.95 (d, 2H), 3.75-3.71 (m, 1H), 3.69-3.59 (m, 4H), 3.07-3.01 (m, 4H), 2.91 (t, 2H), 2.50 (t, 4H), 2.48 (s, 2H), 2.1 1-2.02 (m, 1H), 1.86-1.78 (m, 1H), 1.72-1.63 (m, 6H); MS (EI) C3iH38N802: 555 (MH+).
(R)-N-(4-(2-(4-(4-(2-morpholinoacetyl)piperazin-1-yl)phenylamino)pyrimidin- 4-yl)phenyl)pyrrolidine-2-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.19 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.84 (dd, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 3.74-3.69 (m, 3H), 3.61-3.57 (m, 6H), 3.19 (s, 2H), 3.11-3.09 (m, 2H), 33.04-3.01 (m, 2H), 2.90 (t, 2H), 2.41 (bs, 4H), 2.11-2.02 (m, 1H), 1.84-1.76 (m, 1H), 1.70-1.63 (m, 2H); MS (EI) C31H38N8O3: 571 (MH+). N-{4-[2-({4-[2-(methyloxy)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}amino)- pyrimidin-4-yl]phenyl}-D-proIinamide: 1H-NMR (400MHz, d6-DMSO): 10.19 (s, 1H), 9.25 (s, 1H), 8.42 (d, 1H), 8.11 (d, 2H), 7.83 (d, 2H), 7.28-7.25 (m, 2H), 7.17 (dd, 1H), 6.68 (d, 1H), 4.15 (t, 2H), 3.72 (dd, 1H), 3.52 (t, 2H)), 3.41-3.36 (m, 4H), 3.27 (s, 3H), 2.90 (t, 2H), 2.10-2.01 (m, 1H), 1.84-1.75 (m, 1H), 1.70-1.63 (m, 2H); MS (EI) C26H30N6O3: 475 (MH+).
N-(4-{2-[(4-{4-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperazin-1- yl}phenyl)amino)pyrimidin-4-yl}phenyl)-D-prolinamide: 1H-NMR (400MHz, d6- DMSO): 10.20 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 4.72 (dd, 1H), 3.82-3.72 (m, 3H), 3.69-3.58 (m, 4H), 3.08-3.03 (m, 4H), 2.90 (t, 2H), 2.11-1.98 (m, 3H), 1.88-1.75 (m, 3H), 1.70-1.65 (m, 2H); MS (EI) C30H35N7O3: 542 (MH+).
N-(4-{2-[(4-{4-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperazin-1-yl}phenyl)- amino]pyrimidin-4-yl}phenyl)-D-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 4.72 (dd, 1H), 3.82-3.72 (m, 3H), 3.69-3.58 (m, 4H), 3.08-3.03 (m, 4H), 2.91 (t, 2H), 2.09-1.98 (m, 3H), 1.88-1.75 (m, 3H), 1.70-1.63 (m, 2H); MS (EI) C30H35N7O3: 542 (MH+). N-{4-[2-(1,2,3,4-tetrahydroquinolin-6-ylamino)pyrimidin-4-yl]phenyl}-D- prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.17 (s, 1H), 9.05 (s, 1H), 8.38 (d, 1H), 8.10 (dd, 2H), 7.84-7.81 (m, 2H), 7.29 (s, 1H), 7.21-7.18 (m, 2H), 6.40 (d, 1H), 5.36 (s, 1H), 3.72 (dd, 1H), 3.15 (t, 2H), 2.90 (t, 2H), 2.67 (t, 2H), 2.10-2.01 (m, 1H), 1.84-1.76 (m, 3H), 1.69-1.63 (m, 2H) ; MS (EI) C24H26N6O: 415 (MH+).
N-{4-[2-({4-[(phenylmethyl)oxy]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.42 (s, 1H), 8.42 (d, 1H), 8.06 (d, 2H), 7.75-7.65 (m, 4H), 7.42-7.24 (m, 6H), 6.95 (d, 2H), 5.04 (s, 2H), 2.04 (s, 3H). MS (EI) for C25H22N4O2: 41 1 (MH+). 4-(4-aminophenyl)-N-[4-(phenyIoxy)phenyl]pyrimidin-2-amine: 1H-NMR (400
MHz, d6-DMSO): 10.42 (s, 1H), 8.43 (d, 1H), 8.08 (d, 2H), 7.72 (d, 2H), 7.43-7.37 (m, 3H), 7.26-7.15 (m, 3H), 7.07-6.95 (m, 3H). MS (EI) for C22H18N4O: 355 (MH+).
N-[4-(2-{[4-(phenyloxy)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.64 (s, 1H), 8.49 (d, 1H), 8.11 (d, 2H), 7.85 (d, 2H), 7.75 (d, 2H), 7.38-7.32 (m, 3H), 7.10-7.03 (m, 3H), 6.97 (d, 1H). MS (EI) for C24H20N4O2: 397 (MH+).
N-(4-{2-[(4-{[2-(methyloxy)ethyl]amino}phenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 9.08 (s, 1H), 8.38 (d, 1H), 8.05 (d, 2H), 7.73 (d, 2H), 7.43 (d, 2H), 7.19 (d, 1H), 6.58 (d, 2H), 5.20 (t, 1H), 3.43 (t, 2H), 3.25 (s, 3H), 3.16 (t, 2H), 2.04 (s, 3H). MS (EI) for C2iH23N5O2: 378 (MH+).
N-{4-[2-({4-[(pyridin-4-ylmethyl)oxy]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.43 (s, 1H), 8.60 (s, 2H), 8.43 (d, 1H), 8.10 (d, 2H), 7.79-7.72 (m, 4H), 7.43 (d, 1H), 7.30 (d, 1H), 7.01 (d, 2H), 5.08 (s,1H), 2.03 (s, 3H). MS (EI) for C24H21N5O2: 412 (MH+). N-(4-{2-[(4-cyclohexylphenyl)amino]pyrimidin-4-yl}phenyl) acetamide:
1H-NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.53 (s, 1H), 8.45 (d, 1H), 8.15 (d, 2H), 7.78-7.70 (m, 4H), 7.35 (d, 1H), 7.18 (d, 1H), 2.43-2.40 (m, 1H), 2.08 (s, 3H), 1.82-1.68 (m, 4H), 1.42-1.20 (m, 6H). MS (EI) for C24H26N4O: 387 (MH+).
N-{4-[2-({4-[(tetrahydrofuran-2-yImethyl)amino]phenyl}amino) pyrimidin-4- yl]phenyl}acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.18 (s, 1H), 8.39 (d, 1H), 8.08 (d, 2H), 7.76 (d, 2H), 7.45 (d, 2H), 7.20 (d, 1H), 6.60 (d, 2H), 5.23 (t, 1H), 4.02-3.97 (m, 1H), 3.80-3.77 (m, 1H), 3.65-3.60 (m, 1H), 3.08-3.00 (m, 2H), 2.07 (s, 3H), 2.00-1.80 (m, 3H), 1.62-1.57 (m, 1H). MS (EI) for C23H25N5O2: 404 (MH+).
N-{4-[2-({4-[(phenylmethyI)amino]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.17 (s, 1H), 8.05 (d, 2H), 7.72 (d, 2H), 7.44-7.27 (m, 5H), 7.22-7.17 (m, 2H), 6.57 (d, 2H), 6.00 (t, 1H), 4.25 (d, 2H), 2.08 (s, 3H). MS (EI) for C25H23N5O: 410 (MH+). ethyl [4-({4-[4-(acetylamino)phenyl] pyrimidin-2-yl}amino)phenyl] acetate: 1H-NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.53 (s, 1H), 8.45 (d, 1H), 8.15 (d, 2H), 7.78-7.70 (m, 4H), 7.32 (d, 1H), 7.17 (d, 2H), 4.05 (q, 2H), 3.45 (s, 2H), 1.35 (t, 3H). MS (EI) for C22H22N4O3: 391 (MH+).
N-(4-{2-[(3-chloro-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.25 (s, 1H), 9.73 (s, 1H), 8.55 (d, 1H), 8.12 (d, 2H), 8.05 (s, 1H), 7.80-7.70 (m, 3H), 7.37 (d, 2H), 7.20 (d, 2H), 3.75 (t, 4H), 2.95 (t, 4H), 2.05 (s, 3H). MS (EI) for C22H22ClN5O2: 425 (MH+). N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4- yl)phenyl]-L-serinamide: 1H NMR (400 MHz, d6-DMSO): 9.50 (s, 1H), 8.45 (d, 1H), 8.18 (d, 2H), 7.83 (d, 2H), 7.70 (s, 1H), 7.37-7.30 (m, 2H), 6.90 (d, 1H), 3.82 (s, 3H), 3.72 (t, 4H), 3.60-3.57 (m, 2H), 3.43 (t, 1H), 2.92 (t, 4H). MS (EI) : 465 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-(1H- tetrazol-1-yl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.90 (s, 1H), 9.47 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.18 (d, 2H), 7.77 (d, 2H), 7.67 (d, 2H), 7.30 (d, 1H), 6.95 (d, 2H), 5.58 (s, 2H), 3.77 (t, 4H), 3.03 (t, 4H). MS (EI): 458 (MH+).
(3S)-3-hydroxy-N-[4-(2-{[3-(methyloxy)-4-morpholin-4- ylphenyl]amino}pyrimidin-4-yl)phenyl]butanamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.48 (s, 1H), 8.48 (s, 1H), 8.17 (d, 2H), 7.78 (d, 2H), 7.65 (s, 1H), 7.31 (d, 2H), 6.88 (d, 1H), 4.80 (s, 1H), 4.15- 4.07 (m, 1H), 3.81 (s, 3H), 3.75 (t, 4H), 2.96 (t, 4H), 2.44-2.37 (m, 2H), 1.14 (d, 3H). MS (EI): 464 (MH+).
(3R)-3-hydroxy-N-[4-(2-{[3-(methyloxy)-4-morpholin-4- yIphenyl]amino}pyrimidin-4-yl)phenyl]butanamide: 1H-NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.48 (s, 1H), 8.48 (s, 1H), 8.17 (d, 2H), 7.78 (d, 2H), 7.65 (s, 1H), 7.31 (d, 2H), 6.88 (d, 1H), 4.80 (s, 1H), 4.15-4.07 (m, 1H), 3.83 (s, 3H), 3.75 (t, 4H), 2.96 (t, 4H), 2.44-2.37 (m, 2H), 1.14 (d, 3H). MS (EI): 464 (MH+). N-(4-{2-[(4-morpholin-4-yIphenyl)amino]pyrimidin-4-yl}pheny.)-2,5-dihydro- 1H-pyrrole-2-carboxamide: 1H-NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.40 (s, 1H), 8.43 (s, 1H), 8.17 (d, 2H), 7.83 (d, 2H), 7.68 (d, 2H), 7.30 (s, 1H), 6.96 (d, 2H), 6.02- 5.98 (m, 1H), 5.93-5.89 (m, 1H), 4.60 (s, 1H), 3.82 (s, 2H), 3.75 (t, 4H), 3.05 (t, 4H). MS (EI): 443 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-[(2S)- pyrrolidin-2-yl]acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.86 (s, 1H), 10.10 (s, 1H), 9.37 (s, br, 1H), 9.28 (s, br, 1H), 8.55 (d, 1H), 8.20 (d, 2H), 7.95-7.85 (m, 4H), 7.70 (s, 2H), 7.45 (d, 1H), 4.10 (t, 4H), 3.83-3.78 (m, 2H), 3.73 (t, 4H), 3.25-3.18 (m, 1H), 3.03-2.95 (m, 2H), 2.20-2.10 (m, 1H), 2.00-1.80 (m, 2H), 1.68-1.56 (m, 1H). MS (EI): 459 (MH+).
2,3-dihydroxy-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)propanamide: 1H-NMR (400 MHz, d6-DMSO): 9.95 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.90 (d, 2H), 7.68 (d, 2H), 7.25 (s, 1H), 6.96 (d, 2H), 5.95 (s, br, 1H), 4.95 (s, br, 1H), 4.08 (t, 1H), 3.78-3.60 (m, 6H), 3.03 (t, 4H). MS (EI) : 436 (MH+). l-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyl}amino) pyrimidin-4- yl]phenyl}-3-ethylurea: 1H-NMR (400 MHz, d6-DMSO): 9.37 (s, 1H), 9.19 (s, 1H), 9.40 (d, 1H), 8.03 (d, 2H), 7.70 (d, 2H), 7.58 (d, 2H), 7.23 (d, 2H), 6.95 (d, 2H), 6.75 (t, 1H), 3.58 (t, 4H), 3.60 (t, 3H), 3.15-3.00 (m, 8H), 2.18 (s, 6H), 1.05 (t, 3H). MS (EI) : 503 (MH+).
N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyI}amino) pyrimidin- 4-yl]phenyl}-3-(methyloxy)propanamide: 1H-NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.78 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.95 (d, 2H), 3.73-3.58 (m, 6H), 3.24 (s, 3H), 3.14-3.00 (m, 6H), 2.60 (t, 3H), 2.20 (s, 6H). MS (EI): 518 (MH+).
N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyl}amino) pyrimidin- 4-yl]phenyl}cyclopropanecarboxamide: 1H-NMR (400 MHz, d6-DMSO): 10.26 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.14 (d, 2H), 7.78 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.95 (d, 2H), 3.70-3.58 (m, 4H), 3.10-3.00 (m, 6H), 2.20 (s, 6H), 1.84-1.80 (m, 1H), 0.83-0.80 (m, 4H). MS (EI): 500 (MH+). N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenylamino) pyimidin-4- yl]-phenyl}butanamide: 1H-NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.12-8.05 (m, 3H), 7.80-7.68 (m, 3H), 7.28 (d, 1H), 6.99 (d, 2H), 2H), 3.70- 3.60 (m, 4H), 3.28 (s, 2H), 3.14-3.00 (m, 4H), 2.35-2.20 (m, 8H), 1.64-1.58 (m, 2H), 0.95- 0.88 (m, 3H). MS (EI): 502 (MH+).
N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyl}amino) pyrimidin- 4-yl]phenyl}-N2,N2-dimethylglycinamide: 1H-NMR (400 MHz, d6-DMSO): 10.00 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.82 (d, 2H), 7.65 (d, 2H), 7.25 (d, 1H), 6.95 (d, 2H), 3.65-3.57 (m, 4H), 3.23 (s, 2H), 3.12-3.00 (m, 6H), 2.28 (s, 6H), 2.20 (s, 6H). MS (EI): 517 (MH+).
N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyl}amino) pyrimidin- 4-yl]phenyl}-D-alaninamide: 1H-NMR (400 MHz, d6-DMSO): 9.40 (s, 1H), 8.43 (d, 1H), 8.15 (d, 2H), 7.85 (d, 2H), 7.70 (d, 2H), 7.30 (d, 1H), 6.95 (d, 2H), 3.70-3.57 (m, 4H), 3.50 (q, 1H), 3.18-3.00 (m, 6H), 1.83 (s, 6H), 1.21 (d, 3H). MS (EI): 503 (MH+). N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyl}amino) pyrimidin-
4-yl]phenyl}tetrahydrofuran-3-carboxamide: 1H-NMR (400 MHz, d6-DMSO): 10.30 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.15 (d, 2H), 7.78 (d, 2H), 7.68 (d, 2H), 7.25 (d, 1H), 6.95 (d, 2H), 3.97 (t, 1H), 3.82-3.70 (m, 3H), 3.67-3.60 (m, 4H), 3.22-3.17 (m, 1 H), 3.12- 3.00 (m, 4H), 2.35 (s, 6H), 2.12-2.05 (m, 2H). MS (EI): 530 (MH+). (2R)-N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}tetrahydrofuran-2-carboxamide: 1H-NMR (400 MHz, d6-DMSO): 9.95 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.16 (d, 2H), 7.88 (d, 2H), 7.70 (d, 2H), 7.30 (d, 1H), 6.97 (d, 2H), 4.44-4.41 (m, 1H), 4.02-3.98 (m, 1H), 3.85-3.80 (m, 1H), 3.68-3.57 (m, 4H), 3.18-3.00 (m, 6H), 2.20 (s, 6H), 2.05-1.85 (m, 4H). MS (EI): 530 (MH+).
(2S)-N-{4-[2-({4-[4-(N,N-dimethyIglycyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yI]phenyl}tetrahydrofuran-2-carboxamide: 1H-NMR (400 MHz, d6-DMSO): 9.95 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.16 (d, 2H), 7.88 (d, 2H), 7.70 (d, 2H), 7.30 (d, 1H), 6.98 (d, 2H), 4.45-4.42 (m, 1H), 4.02-3.98 (m, 1H), 3.85-3.80 (m, 1H), 3.70-3.57 (m, 4H), 3.20 (s, 2H), 3.10-3.00 (m, 6H), 2.22 (s, 6H), 2.05-1.85 (m, 4H). MS (EI): 530 (MH+). N-(4-{2-[(6-morpholin-4-ylpyridin-3-yl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.38 (s, 1H), 10.10 (s, 2H), 9.03 (s, br, 1H), 8.75 (s, br, 1H), 8.60 (d, 2H), 8.30-8.20 (m, 3H), 7.85 (d, 2H), 7.55 (d, 2H), 4.48-4.42 (m, 1H), 3.82-3.70 (m, 8H), 3.37-3.20 (m, 2H), 2.43-2.40 (m, 1H), 2.10-1.95 (m, 3H). MS (EI): 446 (MH+). l-hydroxy-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- cyclopentanecarboxamide: 1H-NMR (400 MHz, d6-DMSO): 9.95 (s, 1H), 9.45 (s, 1H), 8.42 (d, 1H), 8.10 (d, 2H), 7.95 (d, 2H), 7.70 (d, 2H), 7.30 (d, 1H), 7.05-6.95 (m, 2H), 5.68 (s, br, 1H), 3.80-3.70 (m, 4H), 3.15-3.05 (m, 4H), 2.10-1.97 (m, 3H), 1.87-1.68 (m, 5H). MS (EI) : 460 (MH+).
2-hydroxy-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- acetamide: 1H NMR (400 MHz, d6-DMSO): 9.95 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.90 (d, 2H), 7.70 (d, 2H), 7.28 (d, 1H), 6.95 (d, 2H), 5.75 (t, 1H), 4.03 (d, 2H), 3.78-3.70 (m, 4H), 3.10-3.00 (m, 4H). MS (EI): 406 (MH+). 3-chloro-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)pyridine-4-carboxamide: 1H NMR (400 MHz, d6-DMSO): 1 1.68 (s, 1H), 11.00 (s, 1H), 9.43 (s, 2H), 8.83 (s, 1H), 8.70 (d, 1H), 8.50 (d, 1H), 8.20 (d, 2H), 7.87 (d, 2H), 7.75-7.65 (m, 3H), 7.32 (d, 1H), 6.95 (d, 2H), 3.75 (t, 4H), 3.05 (t, 4H). MS (EI): 487 (MH+). N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.24 (s, br, 1H), 9.41 (s, 1H), 8.44 (d, 2H), 8.13 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.95 (d, 2H), 3.78-3.57 (m, 5H), 3.15-3.00 (m, 6H), 2.93 (t, 2H), 2.18 (s, 6H), 2.08-2.00 (m, 1H), 1.93- 1.88 (m, 1H), 1.90-1.80 (m, 2H). MS (EI) : 529 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyI)amino]pyriniidin-4- yl}phenyl)propanamide: 1H-NMR (400 MHz, d6-DMSO): 10.18 (s, br, 1H), 9.18 (s, 1H), 8.40 (d, 1H), 8.13 (d, 2H), 7.78 (d, 2H), 7.63 (d, 2H), 7.25 (d, 1H), 6.93 (d, 2H), 3.77 (t, 4H), 3.07 (t, 4H), 2.16 (q, 2H), 1.10 (t, 3H). MS (EI): 404 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-pyridin-3- ylacetamide: 1H NMR (400 MHz, d6-DMSO): 10.90 (s, 1H), 9.40 (s, 1H), 8.43 (s, 1H), 8.18 (d, 2H), 7.88 (d, 2H), 7.73-7.45 (m, 5H), 7.32 (d, 1H), 6.95 (d, 2H), 3.77 (t, 4H), 3.03 (t, 4H). MS (EI): 467 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)ammo]pyrimidin-4-yl}phenyl)pyrimidiiie-5- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.82 (s, 1H), 9.42 (s, 1H), 9.38 (s, 1H), 9.31 (s, 2H), 8.45 (d, 1H), 8.20 (d, 2H), 7.97 (d, 2H), 7.70 (d, 2H), 7.33 (d, 1H), 6.95 (d, 2H), 3.77 (t, 4H), 3.03 (t, 4H). MS (EI): 454 (MH+). N-[4-(2-{[3-(morpholin-4-ylmethyl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide: 1H NMR (400MHz, (I6-DMSO): 10.25 (s, 1H), 9.62 (s, 1H), 8.5 (d, 1H), 8.16 (d, 2H), 7.94 (s, 1H), 7.76 (d, 2H), 7.62 (d, 1H), 7.36 (d,1H), 7.26 (t, 1H), 6.9 (d, 1H), 3.6 (t, 4H), 3.45 (s, 2H), 2.39 (t, 4H), 2.1 (s, 3H), 1.86 (s, 3H). MS (EI) for C23H25N5O2 : 404 (MH+). N-[4-(2-{[3-(1,3-dioxan-2-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetainide:
1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.68 (s, 1H), 8.5 (d, 1H), 8.32 (s, 1H), 8.21 (d, 2H), 7.77 (d, 2H), 7.58 (d, 1H), 7.39 (d, 1H), 7.28 (t, 1H), 6.98 (d, 1H), 5,52 (s, 1H), 4.2 (dd, 2H), 4.0 (t, 2H), 2.1 (s, 3H), 2.05 (m, 1H), 1.5 (dd, 1H). MS (EI) for C22H22N4O3 : 391 (MH+). N-(4-{2-[(6-aminopyridin-2-yl)amino]pyrimidin-4-yl}phenyl)acetamide:
1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 8.93 (s, 1H), 8.55 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.57 (d, 1H), 7.45-7.4 (m, 2H), 6.12 (d, 1H), 5.78 (s, 2H), 2.08 (s, 3H). MS (EI) for C17Hi6N6O : 321 (MH+).
N-(4-{2-[(6-aminopyrimidin-4-yl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.25 (s, 1H), 9.72 (s, 1H), 8.6 (d, 1H), 8.2-8.15 (m, 3H), 7.8 (d, 2H), 7.52 (d, 1H), 7.42 (s, 1H), 6.8 (br,2H), 2.08 (s, 3H). MS (EI) for C16H15N7O : 322 (MH+).
N-(4-morpholin-4-ylphenyl)-4-quinolin-6-ylpyrimidin-2-ainine: ' H NMR (400MHz, d6-DMSO): 9.57 (s, 1H), 9.0 (d,1H), 8.8 (s, 1H), 8.58 (d, 1H), 8.52 (d, 2H), 8.18 (d, 1H), 7.72 (d, 2H), 7.63 (q, 1H), 7.51 (d, 1H), 6.96 (d, 2H), 3.75 (t, 4H), 3.07 (4H). MS(EI) for C23H21N5O : 384 (MH+).
N-(4-morpholin-4-ylphenyl)-4-quinoxalin-6-ylpyrimidin-2-amine: ' H NMR (400MHz, d6-DMSO): 9.6 (s, 1H), 9.04 (d, 2H), 8.88 (s, 1H), 8.63 (d, 1H), 8.6 (d, 1H), 8.27 (d, 1H), 7.7 (d, 2H), 7.63 (d, 1H), 6.95 (d, 2H), 3.75 (t, 4H), 3.06 (t, 4H). MS (EI) for C22H20N6O : 385 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-5-methylpyriinidin-4- yl)phenyl]-D-alaninamide: 1H NMR (400MHz, d6-DMSO): 9.25 (s, 1H), 8.3 (s, 1H), 7.7 (d, 2H), 7.66 (d, 2H), 7.6 (d, 2H), 6.85 (d, 2H), 3.5 (q, 1H), 3.03 (t, 4H), 2.5 (t, 4H), 2.35 (q, 2H), 2.21 (s, 3H), 1.23 (d, 3H), 1.02 (t, 3H). MS (EI) for C26H33N7O : 460.5 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-5-methylpyrimidin-4- yl)phenyl]-D-prolinamide: 1H NMR (400MHz, d6-DMSO): 10.27 (s, 1H), 9.25 (s, 1H), 8.3 (s, 1H), 7.8 (d, 2H), 7.65 (d, 2H), 7.61 (d, 2H), 6.86 (d, 2H), 3.73 (m, 1H), 3.03 (t, 4H), 2.9 (t, 2H), 2.5 (t, 4H), 2.36 (q, 2H), 2.2 (s, 3H), 2.1-2.0 (m, 1H), 1.85-1.75 (m, 1H), 1.67 (p,2H), 1.02 (t, 3H). MS (EI) for C28H35N7O : 486 (MH+).
N-ethyl-4-{4-[(4-{4-[(tetrahydrofuran-2-ylcarbonyl)amino]phenyl}pyrimidin- 2-yl)amino]phenyI}piperazine-1-carboxamide: 1H NMR (400MHz, d6-DMS0): 9.93 (s, 1H), 9.4 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.88 (d, 2H), 7.67 (d, 2H), 7.3 (d, 1H), 6.96 (d, 2H), 6.6 (t, 1H), 4.43 (t, 1H), 4.0 (q, 1H), 3.86 (q, 1H), 3.42 (t, 4H), 3.05 (p, 2H), 3.01 (t, 4H), 2.27-2.17 (m, 1H), 2.06-1.97 (m, 1H), 1.88 (p, 2H), 1.02 (t, 3H). MS (EI) for C28H33N7O3 : 516 (MH+).
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-1H-imidazole-4- carboxamide: 1H NMR (400MHz, d6-DMSO): 12.76 (br, 1H), 10.12(s, 1H), 9.39 (s,
1H), 8.43 (d, 1H), 8.13 (d, 2H), 8.01 (d, 2H), 7.87 (s, 2H), 7.7 (d, 2H), 7.3 (d, 1H), 6.93 (d, 2H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C24H23N7O2 : 442 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-1H-pyrroIe- 2-carboxamide: 1H NMR (400MHz, d6-DMSO): 1H NMR (400MHz, (I6-DMSO): 11.75 (s, 1H), 10.0 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.15 (d, 2H), 7.92 (d, 2H), 7.7 (d, 2H), 7.3 (d, 1H), 7.12 (s, 1H), 7.0 (s, 1H), 6.93 (d, 2H), 6.2 (d, 1H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C25H24N6O2 : 441 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yI}phenyl)-1H- imidazole-2-carboxamide: 1H NMR (400MHz, d6-DMSO): 13.2 (br, 1H), 10.65 (s, 1H), 9.4 (s, 1H), 8.44 (d, 1H), 8.15 (d, 2H), 8.04 (d, 2H), 7.68 (d, 2H), 7.4-7.2 (m, 3H), 6.95 (d, 2H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C24H23N7O2 : 442 (MH+).
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-2-(2-(pyridin-3- yl)-ethylamino)acetamide: 1H-NMR (400MHz, d6-DMSO): 9.00 (s, 1H), 8.92 (d, 1H), 8.64 (d, 1H), 8.35 (d, 1H), 8.17-8.14 (m, 3H), 7.75 (d, 2H), 7.61 (d, 2H), 7.22 (d, 1H), 7.00 (d, 2H), 3.89-3.79 (m, 4H), 3.33-3.21 (m, 2H), 3.15-3.07 (m, 4H), 1.92 (s, 2H); MS (EI): 510.4 (MH+). 2-(3-(4-methylpiperazin-1-yl)propylamino)-N-(4-(2-(4-morpholinophenyl- amino)pyrimidin-4-yl)phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 8.36 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.61 (d, 2H), 7.22 (d, 1H), 6.99 (d, 2H), 3.87-3.81 (m, 4H), 3.68 (s, 2H), 3.13-3.07 (m, 4H), 2.98-2.88 (m, 2H), 2.82-2.62 (m, 8H), 2.39 (s, 3H), 1.93 (s, 3H), 1.89-1.79 (m, 2H); MS (EI): 512.6 (MH+).
2-(l-methylpiperidin-4-ylamino)-N-(4-(2-(4-morpholinophenylamino)- pyrimidin-4-yl)phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 8.35 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.61 (d, 2H), 7.22 (d, 1H), 6.99 (d, 2H), 3.87-3.81 (m, 4H), 3.47 (s, 2H), 3.15-3.09 (m, 4H), 3.06-2.95 (m, 2H), 2.69-2.55 (m, 1H), 2.39 (s, 3H), 2.38-2.22 (m, 2H), 2.03-1.93 (m, 2H), 1.90 (s, 2H), 1.63-1.43 (m, 2H); MS (EI): 545.2 (MH+).
2-(2-amino-2-oxoethylamino)-N-(4-(2-(4-morpholinophenylamino)pyrimidin- 4-yl)phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 8.27 (d, 1H), 8.04 (d, 2H), 7.68 (d, 2H), 7.53 (d, 2H), 7.13 (d, 1H), 6.91 (d, 2H), 4.54 (s, 2H), 3.79-3.73 (m, 4H), 3.39 (s, 2H), 3.06-3.00 (m, 4H), 1.86 (s, 2H); MS (EI): 462.1 (MH+). 2-morpholino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)pheiiyl)- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.0 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 3.78-3.70 (m, 4H), 3.69- 3.61 (m, 4H), 3.08-3.02 (m, 4H), 2.56-2.46 (m, 4H); MS (EI): 475.3 (MH+).
2-((2-aminoethyl)(methyl)amino)-N-(4-(2-(4-morpholinophenylamino)- pyrimidin-4-yl)phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 8.36 (d, 1H), 8.13 (d, 2H), 7.76 (d, 2H), 7.62 (d, 2H), 7.22 (d, 1H), 7.00 (d, 2H), 3.89-3.81 (m, 4H), 3.51 (s, 2H), 3.14-3.07 (m, 4H), 3.03-3.96 (m, 2H), 2.94-2.88 (m, 2H), 2.67 (s, 3H); MS (EI) C25H3 IN7O2: 462.4 (MH+).
2-(1H-pyrazol-5-ylamino)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)-phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 8.35 (d, 2H), 8.12 (d, 2H), 7.74 (d, 2H), 7.61 (d, 2H), 7.40 (s, 1H), 7.21 (d, 1H), 6.99 (d, 2H), 5.69 (s, 1H), 3.95 (s, 2H), 3.86-3.80 (m, 4H), 3.14-3.07 (m, 4H), 1.96 (s, 2H); MS (EI): 471.1 (MH+).
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-2-(piperazin-1-yl)- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.39 (s, 1H), 9.53 (s, 1H), 8.87 (s, 2H), 8.48 (d, 1H), 8.17 (d, 1H), 7.80 (d, 2H), 7.10 (d, 2H), 7.33 (d, 1H), 7.04 (d, 2H), 3.82-3.74 (m, 4H), 3.32-3.24 (m, 2H), 3.19-3.09 (m, 4H), 3.08-3.02 (m, 2H), 2.95 (s, 2H), 2.79 (s, 2H), 1.96 (s, 2H); MS (EI): 474.2 (MH+). (S)-benzyl 2-(2-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenylamino)-2-oxocthylamino)propanoate: 1H-NMR (400MHz, CD3OD): 8.25 (d, 2H), 8.01 (d, 2H), 7.61 (d, 2H), 7.51 (d, 2H), 7.30-7.08 (m, 5H), 7.12 (d, 1H), 6.90 (d, 2H), 5.15-5.05 (m, 2H), 3.78-3.73 (m, 4H), 3.43 (q, 1H), 3.33 (d, 2H), 3.05-2.97 (m, 4H), 1.28 (d, 3H); MS (EI): 567.2 (MH+).
N-(4-(2-(4-morpholinophenylamino)pyriinidin-4-yl)phenyl)-2-(pyrimidin-4-yl- amino)acetamide: 1H-NMR (400MHz, CD3OD): 10.90 (s, 1H), 9.63 (s, 1H), 9.18 (d, 2H), 8.78 (s, 1H), 8.50 (s, 1H), 8.26 (d, 1H), 8.18 (d, 2H), 7.82-7.68 (m, 4H), 7.36 (d, 1H), 7.11 (d, 2H), 6.84 (s, 1H), 5.16 (s, 2H), 3.83-3.77 (m, 4H), 2.54-2.47 (m, 4H); MS (EI): 483.2 (MH+).
N-(4-(2-(4-morpholinophenylamino)pyriniidin-4-yl)phenyl)-2-(piperidin-1-yl)- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.98 (s, 1H), 9.84 (s, 1H), 9.65 (s, 1H), 8.50 (d, 1H), 8.20 (d, 2H), 7.90-7.70 (m, 4H), 7.36 (d, 1H), 7.1 1 (d, 2H), 4.12-4.07 (m, 2H), 3.87-3.77 (m, 4H), 3.62-3.42 (m, 2H), 3.23-3.13 (m, 4H), 2.51 (s, 2H), 1.94-1.64 (m, 6H), 1.45-1.38 (m, 2H); MS (EI): 473.4 (MH+).
2-(ethy-amino)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.78 (s, 1H), 9.45 (s, 1H), 8.87 (s, 2H), 8.48 (d, 1H), 8.17 (d, 2H), 7.77 (d, 2H), 7.71 (d, 2H), 7.33 (d, 1H), 7.04 (d, 2H), 4.04-3.97 (m, 2H), 3.82-3.74 (m, 4H), 3.19-3.02 (m, 6H), 1.12 (t, 3H); MS (EI): 433.3 (MH+). 2-(1H-imidazol-1-yl)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)-acetamide: 1H-NMR (400MHz, d6-DMSO): 10.87 (s, 1H), 9.56 (s, 1H), 9.11 (s, 1H), 8.45 (d, 1H), 8.15 (d, 2H), 7.76 (d, 2H), 7.70 (d, 2H), 7.32 (d, 1H), 7.05 (d, 2H), 5.26 (s, 2H), 3.82-3.72 (m, 4H), 3.18-3.08 (m, 4H); MS (EI): 456.3 (MH+).
4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid: 1H-NMR (400MHz, d6-DMSO): 9.56 (s, 1H), 8.55 (d, 1H), 8.27 (d, 2H), 8.09 (d, 2H), 7.68 (d, 2H), 7.41 (d, 1H), 6.97 (d, 2H), 3.80-3.72 (m, 4H), 3.11-3.03 (m, 4H); MS (EI): 377.3 (MH+).
N-(4-(2-(4-morpholinophenyIamino)pyrimidin-4-yl)phenyl)-2-(phenylainino)- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.29 (s, 1H), 9.59 (s, 1H), 8.46 (d, 1H), 8.14 (d, 2H), 7.79 (d, 2H), 7.73 (d, 2H), 7.33 (d ,1H), 7.19-7.00 (m, 4H), 6.70-6.50 (m, 3H), 3.96-3.88 (m, 4H), 3.22-3.12 (m, 4H); MS (EI): 481.1 (MH+).
4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N-(4-morpholinophenyl)- pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMSO): 9.53 (s, 1H), 8.54 (d, 1H), 8.35 (d, 2H), 8.12 (d, 2H), 7.65 (d, 2H), 7.40 (d, 1H), 6.92 (d, 1H), 3.76-3.70 (m, 4H), 3.06-3.00 (m, 4H), 2.59 (s, 3H); MS (EI): 415.3 (MH+).
(R)-4-(4-(4-(4-(2-aminopropanamido)phenyl)pyrimidin-2-ylamino)pheiiyl)-N- ethylpiperazine-1-carboxamide: 1H-NMR (400MHz, d6-DMSO): 9.41 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.96 (d, 2H), 6.59 (t, 1H), 3.54- 3.46 (m, 1H), 3.44-3.36 (m, 4H), 3.12-2.97 (m, 6H), 1.24 (d, 3H), 1.02 (t, 2H), 0.95 (t, 2H); MS (EI): 487.1 (MH-).
(R)-2-amino-N-(4-(2-(4-(4-((R)-pyrrolidine-2-carbonyl)piperazin-1-yl)phenyl- amino)pyrimidin-4-yl)phenyl)propanamide: 1H-NMR (400MHz, d6-DMSO): 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.97-3.92 (m, 1H), 3.72-3.58 (m, 4H), 3.51-3.42 (m, 2H), 3.14-2.99 (m, 4H), 2.68-2.62 (m, 1H), 2.12-2.00 (m, 1H), 1.74-1.70 (m, 1H), 1.70-1.56 (m, 2H), 1.24 (d, 3H); MS (EI): 513.2 (MH-).
(R)-2-amino-N-(4-(2r(4-(4-((S)-pyrrolidine-2-carbonyl)piperazin-1-yl)phenyl- amino)pyrimidin-4-yl)phenyl)propanamide: 1H-NMR (400MHz, d6-DMSO): 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.83 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 4.65 (t, 1H), 3.89-3.81 (m, 1H), 3.75-3.58 (m, 3H), 3.54-3.28 (m, 2H), 3.15-2.98 (m, 4H), 2.72- 2.58 (m, 1H), 2.06-1.97 (m, 2H), 1.74-1.54 (m, 2H), 1.24 (d, 3H); MS (EI): 515.4 (MH+).
N-[4-(2-{[4-(4-L-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- D-alaninamide: 1H-NMR (400MHz, d6-DMSO): 9.40 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.83 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.57 (dd, 1H), 3.68-3.58 (m, 4H), 3.46 (dd, 1H), 3.12-2.98 (m, 4H), 1.23 (d, 3H), 1.12 (d, 3H); MS (EI): 489.4 (MH+).
(R)-2-amino-N-(4-(2-(4-(4-((S)-2-aminopropanoyl)piperazin-1- yl)phenylamino)-pyrimidin-4-yl)phenyl)propanamide: 1H-NMR (400MHz, d6- DMSO): 9.40 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.83 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.17 (s, 2H), 3.12-3.07 (m, 1H), 3.05-2.98 (m, 1H), 2.70-2.64 (m, 4H), 2.36- 2.28 (m, 4H), 1.23 (d, 3H); MS (EI): 544.4 (MH+).
3,3,3-trifluoro-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide: 1H-NMR (400MHz, d6-DMSO): 10.42 (br s, 1H), 9.41 (s, 1H), 8.46 (d, 1H), 8.15 (d, 2H), 7.89 (d, 2H), 7.68 (d, 2H), 7.57 (br s, 1H), 7.31 (d, 1H), 6.94 (d, 2H), 4.83-4.74 (m, 1H), 3.78-3.70 (m, 4H), 3.09-3.01 (m, 4H); MS (EI): 474.3(MH+). (R)-2-hydroxy-2-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide: 1H-NMR (400MHz, d6-DMSO): 9.72 (s, 1H), 9.34 (s, 1H), 8.41 (d, 1H), 8.08 (d, 2H), 7.89 (d, 2H), 7.64 (d, 2H), 7.27 (d, 1H), 6.91 (d, 2H), 5.66 (s, 1H), 4.21-4.13 (m, 1H), 3.72 (q, 1H), 3.15 (d, 3H), 3.12-3.02 (m3 4H), 1.80-1.72 (m, 1H), 1.59- 1.51 (m, 1H), 1.32 (s, 3H), 0.82 (t, 3H); MS (EI): 448.4 (MH+).
(S)-2-hydroxy-2-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)- phenyl)butanamide: 1H-NMR (400MHz, d6-DMSO): 9.72 (s, 1H), 9.34 (s, 1H), 8.41 (d, 1H), 8.08 (d, 2H), 7.89 (d, 2H), 7.64 (d, 2H), 7.27 (d, 1H), 6.91 (d, 2H), 5.66 (s, 1H), 4.21-
4.13 (m, 1H), 3.72 (q, 1H), 3.19-3.11 (d, 3H), 3.07-3.02 (m, 4H), 1.81-1.71 (m, 1H), 1.60- 1.50 (m, 1H), 1.32 (s, 3H), 0.82 (t, 3H); MS (EI): 448.1 (MH+).
(R)-2-methoxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)- propanamide: 1H-NMR (400MHz, d6-DMSO): 10.07 (s, 1H), 9.35 (s, 1H), 8.41 (d, 1H), 8.11 (d, 2H), 7.84 (d, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 6.90 (d, 2H), 3.89 (q, 1H), 3.75-3.67 (m, 4H), 3.30 (s, 3H), 3.04-2.96 (m, 4H), 1.31 (d, 3H); MS (EI): 434.3 (MH+). (S)-2-methoxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)- propanamide: 1H-NMR (400MHz, d6-DMSO): 10.07 (s, 1H), 9.35 (s, 1H), 8.41 (d, 1H), 8.11 (d, 2H), 7.84 (d, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 6.90 (d, 2H), 3.89 (q, 1H), 3.75-3.67 (m, 4H), 3.30 (s, 3H), 3.04-2.96 (m, 4H), 1.31 (d, 3H); MS (EI): 434.3 (MH+). l-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)- cyclopentanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 9.39 (s, 1H), 8.44 (d, 1H),
8.14 (d, 2H), 7.87 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.94 (d, 2H), 3.78-3.70 (m, 4H), 3.08-3.00 (m, 4H), 2.10-2.00 (m, 2H), 1.86-1.75 (m, 2H), 1.74-1.62 (m, 2H), 1.60-1.50 (m, 2H); MS (EI): 459.4 (MH+).
(S)-2-hydroxy-3,3-dimethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide: 1H-NMR (400MHz, d6-DMSO): 9.83 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.11 (d, 2H), 7.89 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 5.85 (d, 1H), 3.78-3.70 (m, 4H), 3.47 (q, 1H), 3.09-3.01 (m, 4H), 0.97 (d, 9H); MS (EI): 462.4 (MH+). (R)-2-cyclohexyl-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 9.91 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.89 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 5.76 (br s, 1H), 3.85 (d, 1H), 3.77-3.69 (m, 4H), 3.10-3.02 (m, 4H), 1.80-1.51 (m, 6H), 1.30-1.02 (m, 5H); MS (EI): 488.1 (MH+). (S)-2-cyclohexyl-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 9.91 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.89 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 5.76 (br s, 1H), 3.85 (d, 1H), 3.77-3.69 (m, 4H), 3.07-2.98 (m, 4H), 1.78-1.50 (m, 6H), 1.25-1.00 (m, 5H); MS (EI): 488.1 (MH+).
(S)-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)- propanamide: 1H-NMR (400MHz, d6-DMSO): 9.95 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H),
8.12 (d, 2H), 7.90 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 5.87 (br s, 1H), 4.23- 4.15 (m, 1H), 3.79-3.71 (m, 4H), 3.08-3.00 (m, 4H), 2.51 (d, 3H); MS (EI): 420.4 (MH+). l-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yI)phenyl)- cyclobutanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 9.39 (s, 1H), 8.44 (d, 1H),
8.13 (d, 2H), 7.87 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 3.79-3.71 (m, 4H), 3.09-3.00 (m, 4H), 2.00-1.85 (m, 4H), 1.84-1.76 (m, 2H); MS (EI): 445.4 (MH+).
4-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N-(4- morpholinophenyl)pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMSO): 9.57 (s, 1H), 8.57 (d, 1H), 8.39 (d, 2H), 8.26 (d, 2H), 7.67 (d, 2H), 7.44 (d, 1H), 6.95 (d, 2H), 3.78-3.72 (m, 4H), 3.09-3.03 (m, 4H), 2.46 (s, 3H); MS (EI): 415.0 (MH+).
N-(4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)-2- phenylacetamide: 1H-NMR (400MHz, d6-DMSO): 10.45 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.76 (d, 2H), 7.64 (d, 2H), 7.38-7.33 (m, 3H), 7.27 (d, 1H), 6.92 (d, 2H), 3.69 (s, 2H), 3.10-3.04 (m, 4H), 2.35 (q, 3 H), 1.89 (s, 2H), 1.03 (t, 2H); MS (EI): 493.1 (MH+). l-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidin-2-one: 1H-NMR (400MHz, d6-DMSO): 8.26 (d, 1H), 8.14 (d, 2H), 7.77 (d, 2H), 7.65 (d, 2H), 7.36 (d, 1H), 7.25 (d, 2H), 3.92-3.84 (m, 5H), 3.82-3.74 (m, 1H), 3.74-3.60 (m, 1H), 3.42- 3.30 (m, 4H), 3.06-3.02 (m, 1H), 2.16-2.06 (m, 2H); MS (EI): 416.1 (MH+).
(S)-2-hydroxy-3-methyI-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide: 1H-NMR (400MHz, d6-DMSO): 9.90 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.90 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 5.76 (d, 1H), 3.86 (dd, 1H), 3.78-3.73 (m, 4H), 3.08-3.02 (m, 4H), 0.96 (d, 3H), 0.87 (d, 3H); MS (EI): 448.3 (MH+). (R)-2-hydroxy-3-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide: 1H-NMR (400MHz, d6-DMSO): 9.90 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.90 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 5.76 (d, 1H), 3.86 (dd, 1H), 3.78-3.73 (m, 4H), 3.08-3.02 (m, 4H), 0.96 (d, 3H), 0.87 (d, 3H); MS (EI): 448.3 (MH+).
(R)-2-amino-N-(4-(2-(4-(4-(cyclobutanecarbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide: 1H-NMR (400MHz, d6- DMSO): 9.41 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 3.63-3.56 (m, 2H), 3.43-3.37 (m, 3H), 3.18 (d, 1H), 3.07-2.98 (m, 4H), 2.25- 2.02 (m, 4H), 1.98-1.83 (m, 1H), 1.82-1.70 (m, 1H), 1.23 (d, 3H); MS (EI): 500.2 (MH+).
(R)-2-amino-N-(4-(2-(4-(4-pivaloylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)propanamide: 1H-NMR (400MHz, d6-DMSO): 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 3.73-3.67 (m, 4H), 3.52-4.42 (m, 1H), 3.08-3.02 (m, 4H), 1.25 (s, 3H), 1.23 (d, 3H); MS (EI): 502.4 (MH+). 4-[4-(ethylamino)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine:
1H-NMR (400 MHz, DMSO): 9.202 (s, 1H), 8.3 (d, 2H), 7.948 (d, 2H), 7.689 (q, 2H), 7.134 (d, 1H), 6.93 (d, 2H), 6.657(d, 2H), 6.285 (t, 1H), 3.754 (t, 4H), 3.132-3.113 (m, 2H), 3.04 (t, 4H), 1.187 (t, 3H). MS (EI) for C22H25N5O: 376.3 (MH+).
N-{4-[2-(phenylamino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, DMSO): 10.233 (s, 1H), 9.63 (s, 1H), 8.513 (d, 1H), 8.147 (d, 2H), 7.854 (d, 2H), 7.774 (d, 2H), 7.362-7.305 (m, 3H), 6.961 (t, 1H), 2.098 (s, 3H). MS (EI) for C18Hi6N4O: 305.3 (MH+).
N-{4-[2-({4-[(4-ethylpiperazin-l yl)carbonyl]phenyl}amino)pyrimidin-4-yl]- phenyljacetamide: 1H NMR (400 MHz, DMSO): 10.236 (s, 1H), 9.889 (s, 1H), 8.549 (d, 1H), 8.167-8.134 (m, 2H), 7.93-7.903 (m, 2H), 7.782 (d, 2H), 7.418-7.369 (m, 3H), 3.509 (br s, 4H), 2.378-2.324 (m, 6H), 2.097 (s, 3H), 1.025 (t, 3H). MS (EI) for C25H28N6O2: 445.4 (MH+).
N-[4-(2-{[3-(morpholin-4-ylcarbonyl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, DMSO): 10.237 (s, 1H), 9.823 (s, 1H), 8.541 (d, 1H), 8.152 (d, 2H), 8.026 (t, 1H), 7.847 (d, 1H), 7.772 (d, 2H), 7.392 (m, 2H), 6.996 (d, 1H), 3.76-3.36 (br s, 8H), 2.094 (s, 3H). MS (EI) for C23H23N5O3: 418.3 (MH+). N-(4-(2-(3-(2-(dimethylamino)ethoxy)phenylamino)pyrimidin-4-yl)phenyl)- acetamide: 1H NMR (400 MHz, DMSO): 10.471 (br s, 1H), 10.42 (s, 1H), 9.816 (s, 1H), 8.534 (d, 1H), 8.158 (d, 2H), 7.804 (d, 2H), 7.7 (t, 1H), 7.413-7.383 (m, 2H), 7.29 (t, 1H), 6.636 (m, 1H), 4.381 (t, 2H), 3.531 (q, 2H), 2.883 (d, 6H), 2.106 (s, 3H). MS (EI) for C22H25N5O2: 392.3 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)benzamide: 1H-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). MS (EI) for C27H25N5O2: 452.1 (MH+). N-[4-(2-{[4-(methyloxy)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide:
1H-NMR (400 MHz, DMSO): 10.222 (s, 1H), 9.433 (s, 1H), 8.455 (s, 1H), 8.121 (d, 2H), 7.725 (q, 4H), 7.293 (d, 1H), 6.91 (d, 2H), 3.739 (s, 3H), 2.093 (s, 3H). MS (EI) for C19Hi8N4O2: 335 (MH+).
4-(4-chlorophenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-aπiine: 1H-NMR (400 MHz, DMSO): 9.488 (s, 1H), 8.514 (d, 1H), 8.185 (d, 2H), 7.665-7.606 (q, 4H), 7.354 (d, 1H), 6.918 (d, 2H), 3.757 (t, 4H), 3.048 (t, 4H). MS (EI) for C20H19ClN4O: 367 (MH+).
N-[4-(2-{[3-(methyloxy)phenyI]amino}pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400 MHz, DMSO): 10.235 (s, 1H), 9.633 (s, 1H), 8.52 (d, 1H), 8.15 (d, 2H), 7.65 (t, 1H), 7.369 (d, 2H), 7.209 (t, 1H), 6.535 (q, 1H), 3.77 (s, 3H), 2.092 (s, 3H). MS (EI) for C19Hi8N4O2: 335 (MH+). l-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yI}phenyl)-3-(phenyI- methyl)urea: 1H NMR (400 MHz, DMSO): 9.347 (s, 1H), 9 (s, 1H), 8.414 (d, 1H), 8.067 (d, 2H), 7.688 (d, 2H), 7.583 (d, 2H), 7.351-7.31 (m, 4H), 7.237 (d, 2H), 6.943 (d, 2H), 6.831 (t, 1H), 4.33 (d, 2H), 3.742 (t, 4H), 3.044 (t, 4H). MS (EI) for C28H28N6O2: 481.4 (MH+).
N-(4-{2-[(4-{4-[(2S)-pyrrolidin-2-ylmethyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)-D-prolinamide: 1H 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). MS (EI) for C30H38N8O: 527.3 (MH+). N-(4-{2-[(4-morphoIin-4-yIphenyl)amino]pyrimidin-4-yl}phenyl)-2,3-dihydro- 1H-isoindole-1-carboxamide: 1H NMR (400 MHz, DMSO): 11.345 (s, 1H), 10.326 (br s, 1H), 9.525 (s, 1H), 9.479 (br s, 1H), 8.474 (d, 1H), 8.19 (d, 2H), 7.799 (d, 2H), 7.7- 7.627 (m, 3H), 7.469-7.415 (m, 3H), 7.323 (d, 1H), 7.025 (d, 2H), 5.688 (br s, 1H), 4.578 (m, 2H), 3.757 (s, 4H), 3.105 (s, 4H). MS (EI) for C29H28N6O2: 492.58 (MH+).
N-{4-[2-({4-[4-(2-piperazin-1-ylacetyI)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, DMSO): 9.938 (s, 1H), 9.412 (s, 1H), 8.456 (d, 1H), 7.135 (d, 2H), 7.886 (d, 2H), 7.691 (d, 2H), 7.304 (d, 1H), 6.975 (d, 2H), 4.45 (m, 1H), 4.01 (q, 1H), 3.878 (q, 1H), 3.705 (br s, 4H), 3.592 (br s, 4H), 3.148 (s, 2H), 3.1 (br s, 2H), 3.02 (br s, 2H), 2.719 (br s, 4H), 2.354 (br s, 4H), 2.21 (m, 1H), 2.021 (m, 1H), 1.862 (m, 2H). MS (EI) for C31H38N8O3: 571 (MH+).
N-(4-{2-[(4-{4-[(4-chloro-1-methyl-1H-pyrazol-3-yI)methyl]piperazin-1-yl}- phenyl)amino]pyrimidin-4-yl}phenyl)-D-prolinamide: 1H NMR (400 MHz, DMSO): 10.215 (s, 1H), 9.363 (s, 1H), 8.439 (d, 1H), 8.131 (d, 2H), 7.901 (s, 1H), 7.841 (d, 2H), 7.651 (d, 2H), 7.286 (d, 1H), 6.916 (d, 2H), 3.802 (s, 3H), 3.7 (m, 1H), 3.47 (s, 2H), 3.048 (br s, 4H), 2.92 (t, 2H), 2.568 (t, 4H), 2.08 (m, 1H), 1.816 (m, 1H), 1.691 (m, 2H). MS (EI) for C30H34ClN9O: 572.4 (MH+).
N-{4-[2-({4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyI}-D-prolinamide: 1H NMR (400 MHz, DMSO): 10.176 (s, 1H), 9.927 (s, 1H), 8.374 (d, 1H), 8.065 (d, 2H), 7.773 (d, 2H), 7.587 (d, 2H), 7.219 (d, 1H), 6.857 (d, 2H), 4.396 (br s, 1H), 3.715 (t, 1H), 3.468 (br s, 4H), 2.996-2.954 (m, 6H), 2.873 (t, 2H), 2.74 (s, 1HO, 2.368 (t, 2H) 2.369 (t, 2H) 2.368 (t, 2H), 2.038 (m, 1H), 1.749 (m, 1H), 1.61 (m, 2H). MS (EI) for C27H33N7O2: 488.3 (MH+).
N-(4-{2-[(4-{4-[(l-methyl-1H-pyrrol-2-yl)methyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyI)-D-prolinaniide: 1H NMR (400 MHz,
DMSO): 10.194 (s, 1H), 9.349 (s, 1H), 8.42 (d, 1H), 8.11 (d, 2H), 7.822 (d, 2H), 7.636 (d, 2H), 7.267 (d, 1H), 7.076 (s, 1H), 6.902 (d, 2H), 6.75 (s, 1H), 3.738 (m, 1H), 3.701 (s, 3H), 3.553 (s, 2H), 3.306 (m, 4H), 3.031 (br s, 4H), 2.892 (t, 2H), 2.728 (s, 1H), 2.054 (m, 1H), 1.803 (m, 1H), 1.647 (m, 2H). MS (EI) for C31H36N8O: 538.3 (MH+). N-(4-{2-[(4-{4-[(2R)-pyrrolidin-2-ylmethyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)-D-prolinamide: 1H NMR (400 MHz, DMSO): 8.319-8.251 (m, 3H), 7.86 (d, 2H), 7.636 (d, 2H), 7.56 (d, 1H), 7.282 (d, 2H), 4.479 (t, 1H), 4.106 (m, 1H), 3.514 (br s, 4H), 3.496-3.303 (m, 1 1H),. 2.252 (m, 1H), 2.342 (m, 1H), 2.19-2.094 (m, 6H), 1.835 (m, 1H). MS (EI) for C30H36N8O: 528.5 (MH+).
(2S,3aS,7aS)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-octahydro-1H-indoIe-2-carboxamide: 1H NMR (400 MHz, DMSO): 10.857 (s, 1H), 9.84 (s, 1H), 9.714 (br s, 1H), 8.531 (d, 1H), 8.207 (m, 3H), 7.816 (d, 4H), 7.42 (d, 1H), 4.448 (m, 1H), 3.874 (t, 4H), 3.681 (br s, 1H), 3.322 (t, 4H), 2.504 (m, 2H), 2.09 (m, 1H), 1.913 (m, 1H), 1.615 (m, 4H), 1.371-1.259 (m, 3H). MS (EI) for C29H34N6O2: 499.5 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- cyclopropane-carboxamide: 1H NMR (400 MHz, DMSO): 10.476 (s, 1H), 9.383 (s, 1H), 8.443 (d, 1H), 8.123 (d, 2H), 7.768 (d, 2H), 7.686 (d, 2H), 7.279 (d, 1H), 6.946 (d, 2H), 3.74 (t, 4H), 3.046 (t, 4H), 1.824 (m, 1H), 0.829 (m, 4H). MS (EI) for C24H25N5O2: 416 (MH+).
N-[4-(2-{[4-(dimethylamino)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.38 (s, br, 1H), 9.92 (s, br, 1H), 8.85 (d, 2H), 8.1 1 (d, 2H), 7.92 (d, 2H), 7.79 (d, 2H), 7.67 (s, 2H), 7.42 (d, 1H), 3.10 (s, 6H), 2.10 (s, 3H). MS (EI): 348 (MH+).
N-(4-{2-[(4-chlorophenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.30 (s, 1H), 9.88 (s, 1H), 8.53 (d, 1H), 8.14 (d, 2H), 7.87 (d, 2H), 7.75 (d, 2H), 7.41 (d, 2H), 7.37 (1H), 2.10 (s, 3). MS (EI): 339 (MH+).
N-^^-l^^1H-pyrroI-1-yOphenyllaminoJpyrimidin^-yOphenyllacetamide: 1H-NMR (400 MHz, d6-DMSO): 10.26 (br s, 1H), 9.78 (br s, 1H), 8.52 (d, 1H), 8.15 (d, 2H), 7.92 (d, 2H), 7.77 (d, 2H), 7.54 (d, 2H), 7.38 (d, 1H), 7.31 (m, 2H), 6.24 (m, 2H). 2.09 (s, 3H). MS (EI): 370 (MH+). ethyl l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]- piperidine-4-carboxylate: 1H NMR (400 MHz, d6-DMSO): 10.25 (s, 1H), 9.49 (br s, 1H), 8.45 (d, 1H), 8.11 (d, 2H), 7.75 (d, 4HO, 7.30 (d, 1H), 4.10 (q, 2H), 3.56 (d, 2H), 2.86 (br s, 2H), 2.09 (s, 3H), 1.97 (br d, 2H), 1.35 (m, 2H), 1.30 (m, 2H), 0.88 (t, 3H). MS (EI): 460 (MH+). N-[4-(2-{[4-(4-phenylpiperazin-1-yl)phenyI]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.28 (s, 1H), 9.68 (br s 1H), 9.49 (d, 1H), 8.14 (d, 2H), 7.82 (br s 1H), 7.70 (d, 2H), 7.35 (d, 1H), 7.28 (t, 2H), 7.08 (d, 2H), 6.88 (t, 1H), 3.45 (br s, 8H), 2.09 (s, 3H). MS (EI): 465 (MH+).
N-{4-[2-({4-[(2R,6S)-2,6-dimethyImorpholin-4-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.28 (s, 1H), 9.79 (br s, 1H), 8.47 (d, 1H), 8.12 (d, 1H), 8.10 (d, 1H), 7.80 (br d, 2H), 7.75 (d, 2H), 7.37 (d, 2H), 3.69 (br s, 4H), 3.54 (d, 2H), 2.07 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H) MS (EI): 418 (MH+).
4-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide: 1H NMR (400 MHz, d6- DMSO): 11.06 (br s, 1H), 9.97 (br s, 1H), 9,29 (s, 2HO), 8.56 (d, 1H), 8.21 (d, 2H), 7.94 (d, 2H), 7.89 (d, 1H), 7.58 (s, 1H), 7.47 (d, 1H), 5.32 (br s, 3H), 3.99 (s, 4H), 3.48 (m, 4H), 3.38 (m, 4H), 2.84 (m, 2H), 2.46 (m, 2H). MS (EI): 523 (MH+).
(2R)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- piperazine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.33 (br s, 1H), 10.31 (br s, 1H), 8.58 (d, 1H), 8.22 (d, 2H), 7.94 (d, 2H), 7.89 (d, 2H), 7.77 (d, 2H), 7.53 (d, 1H), 4.55 (d, 1H), 4.08 (s, 5H), 3.54 (s, 5H), 3.43 (m, 2H), 3.28 (m, 2H). MS (EI): 460 (MH+).
2-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- 1,2,3,4-tetrahydronaphthaIene-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 11.10 (br s, 1H), 10.07 (br s, 1H), , 8.89 (d, 2H), 8.56 (d, 1H), 8.20 (d, 2H), 7.98 (d, 2H), 7.92 (d, 2H), 7.70 (d, 2H), 7.48 (d, 1H), 7.10 (m, 4H), 6.10 (br s, 3H), 4.40 (s, 4H), 3.70 (d, 1H), 3.50 (s, 4H), 3.39 (d, 4H), 2.89 (m, 1H), 2.71 (m, 1H), 2.1 (m, 1H), 1.26 (m, 1H), 1.17 (m, 1H). MS (EI): 521 (MH+).
4-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- tetrahydro-2H-pyran-4-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.85 (br s, 1H), 9.85 (br s , 1H), 8.97 (s, 2H), 8.53 (d, 1H), 8.20 (d, 2H), 7.94 (d, 2H), 7.83 (d, 2), 7.43 (d, 2H), 4.39 (br s, 3H), 3.94 (s, 4H), 3.87 (d, 4H), 3.72 (m, 4H), 2.45 (m, 2H), 1.97 (d, 2H). MS (EI): 475 (MH+).
(4S)-4-hydroxy-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.38 (s, 1H), 10.25 (m, 1H), 10.31 (s, 1H), 8.84 (m, 1H), 8.57 (d, 1H), 8.21 (d, 2H), 7.93 (d, 2H), 7.87 (d, 2H), 7.75 (d, 2H), 7.49 (d, 1H), 6.62 (m, 1H), 4.50 (s, 1H), 4.06 (s, 4H), 3.53 (s, 4H), 3.42 (m, 1H)< 3.17 (m, 1H), 2.45 (t, 1H), MS (EI): 461 (MH+). l-acetyl-4-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)piperidine-4-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.72 (s, 1H), 8.51 (d, 1H), 8.14 (dd, 2H), 8.12 (d, 1H), 8.08 (d, 1H), 7.00 (dd, 1H), 7.39 (d, 1H), 7.17 (d, 1H), 4.15 (d, 1H), 3.70 (m, 4H), 3.68 (d, 1H), 4.41 (m, 4H),3.41 (m, 4H), 3.01 (m,1H), 2.93 (m, 4H), 2.02 (s, 3H), 1.98 (m, 1H), 1.84 (m, 1H). MS (EI): 516 (MH+).
0-methyl-N-(4-{2-[(4-morpholin-4-yIphenyl)amino]pyrimidin-4-yl}phenyl)-D- serinamide: 1H NMR (400 MHz, d6-DMSO): 1 1.51 (br s, 1H), 9.99 (br s, 1H), 8.55 (d, 1H), 8.50 (br s, 2H), 8.19 (d, 2H), 7.88 (m, 4H), 7.46 (d, 1H), 5.19 (br s, 3H), 4.36 M, 1H), 4.02 (br s, 4H), 3.88 (m, 1H), 3.46 br s, 4H), 3.33 (s, 3H). MS (EI): 449 (MH+). N-[4-(2-{[4-(2,6-dimethylmorpholin-4-yl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.30 (br s, 1H), 9.83 (br s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.81 (br s, 1H), 7.77 (d, 2H), 7.39 (d, 1H),4.1O (br s, 4H), 3.56 (d, 2H), 2.10 (s, 3H), 1.18 (s, 3H), 1.71 (s, 3H). MS (EI): 418 (MH+).
N-(4-{2-[(4-piperidin-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400 MHz, d6-DMSO): 10.32 (br s, 1H), 9.89 (br s, 1H), 8.52 (d, 1H), 8.1 1 (d, 2H), 7.94 (d, 2H), 7.76 (d, 4H), 7.40 (d, 1H), 3.45 (Br s, 4H), 3.36 (6H), 2.07 (s, 3H). MS (EI): 388 (MH+).
0-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- serinamide: 1H NMR (400 MHz, d6-DMSO):l 1.51 (br s, 1H), 9.99 (br s, 1H), 8.55 (d, 1H), 8.50 (br s, 2H), 8.19 (d, 2H), 7.88 (m, 4H), 7.46 (d, 1H), 5.19 (br s, 3H), 4.36 M, 1H), 4.02 (br s, 4H), 3.88 (m, 1H), 3.46 br s, 4H), 3.33 (s, 3H). MS (EI): 449 (MH+). l,l-dimethylethyl (2R)-2-{[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin- 4-yl}phenyl)amino]carbonyl}pyrrolidine-1-carboxylate: 1H NMR (400 MHz, d6- DMSO): 10.26 (brs ,1H), 9.38 (br s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.78 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.94 (d, 2H), 4.22 (m, 1H), 3.74 (m, 4H), 3.43 (m, 1H), 3.34 (m, 1H), 3.04 (m, 4H), 2.20 (m, 1H), 1.90 (m, 1H), 1.81 (m, 1H), 1.40 (s, 3H), 1.27 (s, 6H). (MS (EI) 4: 545 (MH+).
4-[4-(methylsulfonyl)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine: 1H-NMR (400 MHz, d6-DMSO): 9.62 (s,1H), 8.59 (d, 1H), 8.39 (d, 2H), 8.09 (d, 2H), 7.68 (d, 2H), 7.45 (d, 1H), 7.0 (s, br, 1H), 3.81-3.71 (m, 4H), 3.29 (s, 3H), 3.04-3.14 (m, 4H). MS (EI): 41 1 (MH+). 4-[3-(methylsulfonyl)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine:
1H-NMR (400 MHz, d6-DMSO): 9.60 (s,1H), 8.72 (s, 1H), 8.57 (d, 1H), 8.47 (d, 1H),
8.10 (d, 1H), 7.85 (d, 1H), 7.66 (d, 1H), 7.46 (d, 1H), 6.92 (d, 1H), 3.81-3.71 (m, 4H),
3.31 (s, 3H), 3.0-3.11 (m, 4H). MS (EI): 411 (MH+). 4-[4-(methylthio)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine:
1H-NMR (400 MHz, d6-DMSO): 9.42 (s.1H), 8.46 (d, 1H), 8.09 (d, 2H), 7.66 (d, 2H),
7.40 (d, 2H), 7.31 (d, 1H), 6.92 (d, 2H), 3.79-3.69 (m, 4H), 3.1-3.0 (m, 4H), 2.55 (s, 3H).
MS (EI): 379 (MH+).
N-(4-{2-[(3-bromo-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s,1H), 9.72 (s, 1H), 8.52 (d, 1H),
8.27 (d, 1H), 8.13 (d, 2H), 7.81-7.71 (m, 3H), 7.42-7.32 (m, 1H), 7.18 (d, 1H), 3.78-3.69
(m, 4H), 2.97-2.87 (m, 4H), 2.09 (s, 3H). MS (EI): 469 (MH+).
N-[4-(2-{[4-{[2-(diethylamino)ethyl]oxy}-3-(4-ethylpiperazin-1-yl)phenyl]- amino}pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.36 (s,1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.73 (d, 2H), 7.54 (s, 1H), 7,36-7.26 (m, 2H),
6,88 (d, 1H), 4.02-3.92 (m, 2H), 2.81-2.71 (m, 2H), 2.59-2.49 (m, 4H), 2.45-2.35 (m, 2H),
1.04 (t, 3H), 0.98 (t, 6H). MS (EI): 533 (MH+).
N2,N2-dimethyl-N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)glycinamide: 1H NMR (400 MHz, d6-DMSO): 9.99 (s,1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.1 1 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.28 (d,
1H), 6.95 (d, 2H), 3.63-3.59 (m, 4H), 3.25 (s, 3H), 3.1 1 (s, 2H), 3.10-3.05 (m, 2H, 3.04-
2.99 (m, 2H), 2.65 (t, 2h), 2.29 (s, 6H). MS (EI): 519 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-cyclobutane- carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.99 (s, 1H), 9.37 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.77 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.75 (m, 4H), 3.32 (m,
1H), 3.05 (m, 4H), 2.24 (m, 2H), 2.12 (m, 2H), 1.93 (m, 1H), 1.82 (m, 1H). MS (EI): 430
(MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)azetidine-3- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.10 (s, 1H), 9.36 (s, 1H), 8.42 (d, 1H), 8.09 (d, 2H), 7.74 (d, 2H), 7.64 (d, 2H), 7.24 (d, 1H), 6.91 (d, 2H), 3.71 (m, 4H), 3.61 (m,
1H), 3.52 (m, 4H), 3.02 (m, 4H). MS (EI): 431 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)piperidine-3- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.35 (s, 1H), 8.40 (d, 1H), 8.08 (d, 2H), 7.73 (d, 2H), 7.64 (d, 2H), 7.24 (d, 1H), 6.90 (d, 2H), 3.72 (m, 4H), 3.41 (m, 4H), 3.02 (m, 4H), 2.83 (m, 1H), 2.62 (m, 1H), 1.58 (m, 2H), 1.37 (m, 1H),. MS (EI): 459 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yI}phenyl)piperidine-4- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.12 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.76 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.37 (m, 1H), 3.03 (m, 4H), 3.00 (m, 1H), 2.50 (m, 2H), 2.47 (m, 1H), 1.73 (m, 2H), 1.54 (m, 2H). MS (EI): 459 (MH+).
2-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.05 (s, 1H), 9.36 (s, 1H), 8.42 (d, 1H), 8.09 (d, 2H), 7.82 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.91 (d, 2H), 4.02 (s, 2H), 3.72 (m, 4H), 3.38 (s, 3H), 3.02 (m, 4H). MS (EI): 420 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)piperidine-2- carboxamide: 1H 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:
1H NMR (400 MHz, d6-DMSO): 9.37 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.82 (d, 2H), 7.66 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.75 (m, 4H), 3.62 (br s, 2H), 3.32 (m, 2H), 3.05 (m, 4H). MS (EI): 405 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyI)amino]pyrimidin-4-yl}phenyI)furan-2- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.44 (s, 1H), 9.40 (s, 1H), 8.46 (d, 1H), 8.16 (d, 2H), 7.98 (m, 1H), 7.93 (m, 2H), 7.68 (d, 2H), 7.39 (d, 1H), 7.30 (d, 1H), 6.93 (d, 2H), 6.74 (d, 1H), 3.75 (m, 4H), 3.05 (m, 4H). MS (EI): 3: 442 (MH+).
N-(4-{2-[(4-morpholin-4-yIphenyl)amino]pyrimidin-4-yl}phenyl)tetra- hydrofuran-2-carboxamide: 1H 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). MS (EI): 446 (MH+). 5-methyl-N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- pyrazine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.90 (s, 1H), 9.38 (s, 1H), 9.17 (s, 1H), 8.71 (s, 1H), 8.43 (d, 1H), 8.16 (d, 2H), 8.08 (d, 2H), 7.66 (d, 2H), 7.31 (d, 1H), 6.92 (d, 2H), 3.71 (m, 4H), 3.03 (m, 4H), 2.62 (s, 3H),. MS (EI): 468 (MH+). 2-(ethyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- acetamide: 1H NMR (400 MHz, d6-DMSO): 9.94 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.80 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.91 (d, 2H), 4.05 (s, 2H), 3.72 (m, 4H), 3.55 (q, 2H), 3.02 (m, 4H), 1.17 (t, 3H). MS (EI): 434 (MH+).
N-(4-{2-[(4-morpholin-4-yIphenyl)amino]pyriinidin-4-yl}phenyl)-2- (phenyloxy)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.37 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.14 (d, 2H), 7.82 (d, 2H), 7.67 (d, 2H), 7.31 (m, 3H), 6.98 (m, 4H), 4.75 (s, 2H),
3.73 (m, 4H), 3.04 (m, 4H). MS (EI): 482 (MH+). methyl 4-[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)amino]-4-oxobutanoate: 1H NMR (400 MHz, d6-DMSO): 10.28 (s, 1H), 9.37 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H),
3.74 (m, 4H), 3.60 (s, 3H), 3.06 (m, 4H), 2.65 (m, 4H). MS (EI): 462 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)butanamide: 1H NMR (400 MHz, d6-DMSO): 10.15 (s, 1H), 9.37 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H),
7.75 (d, 2H), 7.67 (d, 2H), 7.26 (d, 1H), 6.93 (d, 2H), 3.73 (m, 4H), 3.04 (m, 4H), 2.33 (t, 2H), 1.63 (q, 2H), 0.93 (t, 3H). MS (EI): 418 (MH+).
2-(2-methylphenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.44 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.76 (d, 2H), 7.67 (d, 2H), 7.27 (m, 2H), 7.16 (m, 3H), 6.93 (d, 2H), 3.75 (m, 6H), 3.03 (m, 4H), 2.31 (m, 3H). MS (EI): 480 (MH+). N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- cyclopentane-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.14 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.77 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.75 (m, 4H), 3.04 (m, 4H), 2.80 (m, 1H), 1.87 (m, 2H), 1.72 (m, 4H), 1.55 (m, 2H). MS (EI): 444 (MH+). (2S)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- azetidine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.09 (br s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.86 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 4.32 (t, 1H), 3.73 (m, 4H), 3.62 (m, 1H), 3.06 (m, 4H), 2.58 (m, 1H), 2.29 (m, 1H), 0.99 (m, 1H). MS (EI): 431 (MH+).
N-{4-[2-({4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.19 (s, 1H), 8.40 (d, 1H), 8.11 (d, 2H), 7.83 (d, 2H), 7.56 (d, 2H), 7.22 (d, 1H), 6.53 (d, 2H), 3.72 (m, 1H), 3.41 (m, 1H), 3.33 (m, 1H), 3.22 (m, 1H), 3.02 (m, 1H), 2.90 (m, 2H), 2.78 (m, 1H), 2.20 (s, 6H), 2.05 (m, 2H), 1.75 (m, 2H), 1.66 (m, 2H). MS (EI): 472 (MH+).
4-(4-aminophenyl)-N-{4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}- pyrimidin-2-amine: 1H NMR (400 MHz, d6-DMSO): 8.99 (s, 1H), 8.25 (s, 1H), 7.87 (d, 2H), 7.57 (d, 2H), 7.05 (d, 1H), 6.63 (d, 2H), 6.52 (d, 2H), 5.70 (s, 2H), 3.41 (m, 1H), 3.31 (m, 1H), 3.21 (m, 1H), 3.01 (m, 1H), 2.77 (m, 1H), 2.20 (s, 6H), 2.15 (m, 1H), 1.77 (m, 1H). MS (EI): 375 (MH+).
N-{4-[2-({4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}-3-(methyloxy)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.19 (s, 1H), 8.40 (d, 1H), 8.10 (d, 2H), 7.75 (d, 2H), 7.58 (d, 2H), 7.23 (d, 1H), 6.54 (d, 2H), 3.63 (t, 2H), 3.41 (m, 1H), 3.25 (m, 3H), 3.21 (m, 1H), 3.01 (m, 1H), 2.77 (m, 1H), 2.59 (t, 2H), 2.52 (m, 1H) 2.20 (s, 6H), 2.13 (m, 1H), 1.79 (m, 1H). MS (EI): 461 (MH+). l-ethyl-3-(4-{2-[(4-{4-[3-(methyIoxy)propanoyl]piperazin-1-yl}phenyl)- amino]pyrimidin-4-yl}phenyl)urea: 1H NMR (400 MHz, d6-DMSO): 9.35 (s, 1H), 8.76 (s, 1H), 8.41 (d, 1H), 8.04 (d, 2H), 7.68 (d, 2H), 7.54 (d, 2H), 7.23 (d, 1H), 6.95 (d, 2H), 6.26 (t, 1H), 3.59 (m, 4H), 3.56 (q, 2H), 3.23 (s, 3H), 3.14 (m, 2H), 3.07 (m, 2H), 3.01 (m, 2H), 2.61 (t, 2H), 1.06 (t, 3H). MS (EI): 504 (MH+).
3-(methyloxy)-N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1-yl}phenyl)- amino]pyrimidin-4-yl}phenyl)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.76 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.95 (d, 2H), 3.60 (m, 8H), 3.25 (s, 3H), 3.23 (s, 3H), 3.08 (m, 2H), 3.01 (m, 2H), 2.61 (m, 4H). MS (EI): 519 (MH+).
N-{4-[2-({4-[4-(3-hydroxypropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.40 (s,
1H), 8.42 (d, 1H), 8.10 (d, 2H), 7.84 (d, 2H), 7.67 (d, 2H), 7.28 (d, 1H), 6.95 (d, 2H), 3.74 (dd, 1H), 3.66 (t, 2H), 3.62 (m, 4H), 3.09 (m, 2H), 3.03 (m, 2H), 2.91 (t, 2H), 2.52 (m, 2H), 2.05 (m, 1H), 1.79 (m, 1H), 1.66 (m, 2H). MS (EI): 516 (MH+).
N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)-D-alaninamide: 1H NMR (400 MHz, d6-DMSO): 9.40 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.95 (d, 2H), 3.59 (m, 4H), 3.57 (t, 2H), 3.46 (m, 1H), 3.23 (s, 3H), 3.07 (m, 2H), 3.02 (m, 2H), 2.61 (t, 2H), 1.24 (d, 3H). MS (EI): 504 (MH+).
N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.11 (d, 2H), 7.83 (d, 2H), 7.66 (d, 2H), 7.28 (d, 1H), 6.95 (d, 2H), 3.75 (dd, 1H), 3.60 (m, 4H), 3.56 (t, 2H), 3.23 (s, 3H), 3.08 (m, 2H), 3.03 (m, 2H), 2.91 (t, 2H), 2.61 (t, 2H), 2.17 (m, 1H), 1.80 (m, 1H), 1.67 (m, 2H). MS (EI): 530 (MH+).
N-2-,N-2-dimethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)glycinamide: 1H NMR (400 MHz, d6-DMSO): 9.98 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.83 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.11 (s, 2H), 3.05 (m, 4H), 2.29 (s, 6H). MS (EI): 433 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)prolinamide: 1H 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-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyI)-3-phenyl- propanamide: 1H NMR (400 MHz, d6-DMSO): 10.12 (s, 1H), 9.31 (s, 1H), 8.37 (d, 1H), 8.05 (d, 2H), 7.67 (d, 2H), 7.60 (d, 2H), 7.21 (m, 5H), 7.12 (m, 1H), 6.83 (d, 2H), 3.67 (m, 4H), 2.98 (m, 4H), 2.86 (t, 2H), 2.61 (t, 2H). MS (EI): 480 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-phenyl- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.44 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.77 (d, 2H), 7.67 (d, 2H), 7.34 (m, 4H), 7.26 (m, 2H), 6.93 (d, 2H), 3.75 (m, 4H), 3.69 (m, 2H), 3.04 (m, 4H). MS (EI): 466 (MH+). N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2-fluoro-6- iodobenzamide: 1H-NMR (400MHz, dδ-DMSO): 10.16 ppm (s, 1H), 8.64 ppm (t, 1H), 8.30 ppm (d, 1H), 8.06 ppm (d, 2H), 7.70 ppm (m, 3H), 7.30 ppm (m, 1H), 7.20 ppm (m, 1H), 7.13 ppm (m, 1H), 7.07 ppm (m, 1H), 3.34 ppm (m, 4H), 2.08 ppm (s, 3H), 1.83 ppm (m, 2H); MS (EI) C22H21FIN5O2: 533.9 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6-difluoro- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.78 ppm (s, 1H), 10.12 ppm (s, 1H), 9.70 ppm (s, 1H), 8.50 ppm (d, 1H), 8.39 ppm (s, 1H), 8.12 ppm (d, 2H), 7.73 ppm (d, 2H), 7.61 ppm (m, 1H), 7.47 ppm (m, 1H), 7.40 ppm (m, 1H), 7.27 ppm (m, 4H), 2.09 ppm (s, 3H); MS (EI) C25H19F2N5O2: 460 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,4,5- trifluoro-benzamide: 1H-NMR (400MHz, d6-DMSO): 10.52 ppm (s, 1H), 10.29 ppm (s, 1H), 9.71 ppm (s, 1H), 8.50 ppm (d, 1H), 8.36 ppm (s, 1H), 8.20 ppm (d, 2H), 7.87 ppm (m, 1H), 7.75 ppm (d, 3H), 7.51 ppm (m, 1H), 7.37 ppm (d, 1H), 7.28 ppm (m, 2H), 2.09 ppm (s, 3H); MS (EI) C25H18F3N5O2: 478 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl)benzamide: 1H-NMR (400MHz, (I6-DMSO): 10.27 ppm (s, 1H), 10.21 ppm (s, 1H), 9.67 ppm (s, 1H), 8.51 ppm (d, 1H), 8.47 ppm (s, 1H), 8.13 ppm (d, 2H), 8.00 ppm (m, 2H), 7.75 ppm (m, 2H), 7.58 ppm (m, 3H), 7.48 ppm (m, 1H), 7.37 ppm (d, 1H), 7.29 ppm (m, 2H), 2.09 ppm (s, 3H); MS (EI) C25H21N5O2: 424(MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-3,5-difluoro- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.37 ppm (s, 1H), 10.20 ppm (s, 1H), 9.70 ppm (s, 1H), 8.51 ppm (d, 1H), 8.41 ppm (s,1H), 8.21 ppm (d, 2H), 7.73 ppm (m, 4H), 7.55 ppm (m, 2H), 7.37 ppm (d, 1H), 7.29 ppm (m, 2H), 2.08 ppm (s, 3H); MS (EI) C25H19F2N5O2: 468.0 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yI}amino)phenyl]-2-chloro-6- fluoro-4-methylbenzamide: 1H-NMR (400MHz, d6-DMSO): 10.72 ppm (s, 1H), 10.20 ppm (s, 1H), 9.69 ppm (s, 1H), 8.50 ppm (d, 1H), 8.41 ppm (s,1H), 8.21 ppm (d, 2H), 7.74 ppm (d, 2H), 7.50 ppm (m, 2H), 7.37 ppm (d, 1H), 7.28 ppm (m, 8H), 2.38 ppm (s, 3H), 2.08 ppm (s, 3H); MS (EI) C26H21ClFN5O2: 490.0 (MH+).
N-(4-{2-[(3-{[(2,6-dimethylphenyl)methyl]amino}phenyl)amino]pyrimidin-4- yl}-phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.20 ppm (s, 1H), 9.36 ppm (s, 1H), 8.47 ppm (d, 1H), 8.16 ppm (d, 2H), 7.72 ppm (d, 2H), 7.35 ppm (s, 1H), 7.31 ppm (d, 1H), 7.12 ppm (m, 1H), 7.07 ppm (m, 2H), 6.99 ppm (m, 3H), 6.38 ppm (d, 1H), 5.46 ppm (t, 1H), 4.14 ppm (d, 2H), 2.36 ppm (s, 6H), 2.08 ppm (s, 3H); MS (EI) C27H27N5O: 438.1 (MH+).
N-(3-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)thiophene-2- carboxamide: 1H-NMR (400MHz, dό-DMSO): 10.66 ppm (s, 1H), 10.28 ppm (s, br, 2H), 10.10 ppm (s, 1H), 8.74 ppm (s, 1H), 8.63 ppm (d, 1H), 8.25 ppm (m, 2H), 7.94 ppm (m, 3H), 7.75 ppm (t, 1H), 7.55 ppm (t, 1H), 7.45 ppm (m, 2H), 7.26 ppm (m, 1H), 6.97 ppm (m,1H); MS (EI) C21H17N5O2S: 388.0 (MH+).
N- [3-({4- [4-(acety lamino)pheny 1] py rimidin-2-y 1} amino)phenyl] -1 - methylpiperidine-4-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.21 ppm (s, 1H), 9.84 ppm (s, 1H), 9.60 ppm (s, 1H), 8.49 ppm (d, 1H), 8.29 ppm (s, 1H), 8.20 ppm (d,
2H), 7.74 ppm (d, 2H), 7.36 ppm (m, 2H), 7.18 ppm (m, 2H), 2.84 ppm (m, 2H), 2.31 ppm (m, 1H), 2.17 ppm (s, 3H), 2.09 ppm (s, 3H), 1.87 ppm (m, 2H), 1.72 ppm (m, 4H); MS (EI) C25H28N5O2: 445 (MH+).
4-(4-aminophenyl)-N-[3-(morpholin-4-ylsulfonyl)phenyl]pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMSO): 9.94 ppm (s, 1H), 8.76 ppm (s, 1H), 8.42 ppm (d, 1H), 7.98 ppm (d, dH), 7.90 ppm (m, 1H), 7.57 ppm (t, 1H), 7.28 ppm (m, 2H), 6.65 ppm (d, 2H), 5.81 ppm (s, 2H), 3.64 ppm (m, 4H), 2.90 ppm (m, 4H); MS (EI) C20H2iN503S: 412 (MH+).
N-(4-{2-[(3-{[(2-fluorophenyl)methyl]amino}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 ppm (s, 1H), 9.35 ppm (s, 1H), 8.45 ppm (d, 1H), 8.12 ppm (d, 2H), 7.74 ppm (d, 2H), 7.43 ppm (m, 2H), 7.29 ppm (m, 2H), 7.16 ppm (m, 3H), 6.99 ppm (m, 2H), 6.21 ppm (m, 2H), 4.33 ppm (d, 2H), 2.09 ppm (s, 3H); MS (EI) C25H22 FN5O; 428 (MH+).
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyI)acetaιnide: 1H-NMR (400MHz, d6-DMSO): 10.21 ppm (s, 1H), 9.31 ppm (s, 1H), 8.46 ppm (d, 1H), 8.13 ppm (d, 2H), 7.75 ppm (d, 2H), 7.30 ppm (d, 1H), 7.13 ppm (s, 1H), 6.94 ppm (m, 2H), 6.20 ppm (d, 1H), 5.01 ppm (s, 2H), 2.10 ppm (s, 3H); MS (EI) C18Hi7IN5O: 320 (MH+).
N-(4-{2-[(3-{[(4-fluorophenyl)methyl]amino}phenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.26 ppm (s, 1H), 9.33 ppm (s, 1H), 8.45 ppm (d, 1H), 8.13 ppm (d, 2H), 7.75 ppm (d, 2H), 7.37 ppm (m, 2H), 7.31 ppm (m, 3H), 7.21 ppm (m, 2H), 6.97 ppm (m, 2H), 6.23 ppm (m, 2H), 4.48 ppm (d, 2H), 2.09 ppm (s, 3H); MS (EI) C25H23N5O: 410 (MH+). N-(4-{2-[(3-{[(3-fluorophenyl)methyl]amino}phenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.36 ppm (s, 1H), 9.35 ppm (s, 1H), 8.45 ppm (d, 1H), 8.12 ppm (d, 2H), 7.76 ppm (d, 2H), 7.33 ppm (m, 2H), 7.19 ppm (m, 3H), 6.99 ppm (m, 3H), 6.32 ppm (t, 1H), 6.20 ppm (m, 2H), 4.30 ppm (d, 2H), 2.09 ppm (s, 3H); MS (EI) C25H22FN5O: 428 (MH+).
N-(4-{2-[(3-{[(4-fluorophenyl)methyl]amino}phenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H-NMR (400MHz, (I6-DMSO): 10.20 ppm (s, 1H), 9.33 ppm (s, 1H), 8.45 ppm (d, 1H), 8.12 ppm (d, 2H), 7.74 ppm (d, 2H), 7.39 ppm (m, 2H), 7.30 ppm (d, 1H), 7.21 ppm (s, 1H), 7.13 ppm (t, 2H), 6.96 ppm (m, 2H), 6.22 ppm (m, 2H), 2.09 ppm (s, 3H); MS (EI) C25H22FN5O: 428 (MH+).
4-[4-({4-[4-(butanoylamino)phenyI]pyrimidin-2-yl}amino)phenyI]-N-ethyl- piperazine-1-carboxamide: 1H-NMR (400MHz, d<;-DMSO): 10.21 ppm (s, 1H), 9.39 ppm (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.77 ppm (d, 2H), 7.68 ppm (d, 2H), 7.28 ppm (d, 1H), 6.96 ppm (d, 2H), 6.59 ppm (t, 1H), 3.43 ppm (t, 4H), 3.07 ppm (m, 2H), 3.02 ppm (t, 4H), 2.34 ppm (t, 2H), 1.63 ppm (m, 2H), 1.02 ppm (t, 3H), 0.98 ppm (t, 3H); MS (EI) C27H33N7O2: 488 (MH+).
N-{4-[2-({4-[4-(2-piperazin-1-ylacetyl)piperazin-1-yl]phenyI}amino)pyrimidin- 4-yl]phenyl}butanamide: 1H-NMR (400MHz, d6-DMS O): 10.18 ppm (s, 1H), 9.40 ppm (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.77 ppm (d, 2H), 7.68 ppm (d, 2H), 7.28 ppm (d, 1H), 6.97 ppm (d, 2H), 3.72 ppm (m, 2H), 3.59 ppm (m, 2H), 3.13 ppm (m, 4H), 3.01 ppm (m, 2H), 2.67 ppm (m, 4H), 2.33 ppm (m, 4H), 1.63 ppm (m, 2H), 0.93 ppm (t, 3H); MS (EI) C30H38N8O2: 543 (MH+).
N-[4-(2-{[4-(4-L-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- butanamide: 1H-NMR (400MHz, d6-DMSO): 10.15 ppm (s, 1H), 9.40 ppm (s, 1H), 8.44 ppm (d, 1H), 8.1 1 ppm (d, 2H), 7.76 ppm (d, 2H), 7.69 ppm (d, 2H), 7.28 ppm (d, 1H), 6.97 ppm (d, 2H), 3.79 ppm (m, 1H), 3.62 ppm (m, 4H), 3.06 ppm (m, 4H), 2.33 ppm (t, 2H), 1.91 ppm (br. s, 2H), 1.63 ppm (m, 2H), 1.09 ppm (d, 3H), 0.93 ppm (t, 3H); MS (EI) C27H33N7O2: 488 (MH+).
N-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- butanamide: 1H-NMR (400MHz, d6-DMSO): 10.21 ppm (s, 1H), 9.41 ppm (s, 1H), 8.44 ppm (d, 1H), 8.1 1 ppm (d, 2H), 7.77 ppm (d, 2H), 7.69 ppm (d, 2H), 7.28 ppm (d, 1H), 6.97 ppm (d, 2H), 3.85 ppm (m, 1H), 3.62 ppm (m, 4H), 3.04 ppm (m, 5H), 2.62 ppm (m, 1H), 2.34 ppm (t, 2H), 2.00 ppm (m, 1H), 1.62 ppm (m, 6H), 0.93 ppm (t, 3H); MS (EI) C29H35N7O2: 514 (MH+).
(3R)-1-(2-hydroxyethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin- 4-yI}phenyl)pyrrolidine-3-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.22 ppm (s, 1H), 9.38 ppm (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.76 ppm (d, 2H), 7.67 ppm (d, 2H), 7.28 ppm (d, 1H), 6.94 ppm (d, 2H), 4.50 ppm (m, 1H), 3.75 ppm (m, 4H), 3.49 ppm (m, 2H), 3.05 ppm (m, 6H), 2.91 ppm (t, 1H), 2.67 ppm (m, 1H), 2.56 ppm (m, 3H), 1.98 ppm (m, 2H); MS (EI) C27H32N6O3: 489 (MH+).
N-(4-{2-[(3-fluoro-4-morpholin-4-ylphenyI)amino]pyrimidin-4-yl}phenyl)-L- prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.21 ppm (s, 1H), 9.69 ppm (s, 1H), 8.51 ppm (d, 1H), 8.13 ppm (d, 2H), 7.85 ppm (d, 2H), 7.79 ppm (m, 1H), 7.52 ppm (m, 1H), 7.37 ppm (d, 1H), 7.03 ppm (t, 1H), 3.74 ppm (m, 5H), 3.14 ppm (br.s, 1H), 2.95 ppm (m, 4H), 2.91 ppm (m, 2H), 2.06 ppm (m, 1H), 1.80 ppm (m, 1H), 1.66 ppm (m, 2H); MS (EI) C25H27FN6O2: 463 (MH+). N-(4-{2-[(3-fluoro-4-morpholin-4-ylphenyl)aminolpyrimidin-4-yl}phenyl)-D- alaninamide: 1H-NMR (400MHz, d6-DMSO): 9.69 ppm (s, 1H), 8.51 ppm (d, 1H), 8.13 ppm (d, 2H), 7.84 ppm (d, 2H), 7.79 ppm (m, 1H), 7.54 ppm (m, 1H), 7.37 ppm (m, 1H), 7.37 ppm (m, 1H), 7.03 ppm (t, 1H), 3.74 ppm (m, 4H), 3.47 ppm (m, 1H), 2.95 ppm (m, 4H), 1.23 ppm (d, 3H); MS (EI) C23H25FN6O2: 437 (MH+). N-(4-{2-[(3-methyl-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.22 ppm (s, 1H), 9.45 ppm (s, 1H), 8.46 ppm (d, 1H), 8.14 ppm (d, 2H), 7.85 ppm (d, 2H), 7.63 ppm (d, 2H), 7.32 ppm (d, 1H), 7.32 ppm (d, 1H), 3.73 ppm (m, 5H), 3.08 ppm (br.s., 1H), 2.90 ppm (t, 2H), 2.80 ppm (m, 4H), 2.27 ppm (s, 3H), 2.06 ppm (m, 1H), 1.80 ppm (m, 1H), 1.66 ppm (m, 2H); MS (EI) C26H30N6O2: 459 (MH+).
N-(4-{2-[(3-methyl-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- alaninamide: 1H-NMR (400MHz, d6-DMSO): 9.44 ppm (s, 1H), 8.47 ppm (d, 1H), 8.14 ppm (d, 2H), 7.83 ppm (d, 2H), 7.64 ppm (m, 2H), 7.32 ppm (d, 1H), 7.02 ppm (m, 1H), 3.73 ppm (m, 4H), 3.46 ppm (m, 1H), 2.80 ppm (m, 4H), 2.28 ppm (m, 4H), 1.23 ppm (d, 3H); MS (EI) C24H28N6O2: 433 (MH+). l-hydroxy-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.14 ppm (s, 1H), 9.39 ppm (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.94 ppm (d, 2H), 7.68 ppm (d, 2H), 7.29 ppm (d, 1H), 6.94 ppm (d, 2H), 6.81 ppm (s, 1H), 3.74 ppm (m, 4H), 3.05 ppm (m., 4H), 1.18 ppm (m, 2H), 1.00 ppm (m, 2H); MS (EI) C24H25N5O3: 432 (MH+).
N-(4-(2-(4-(4-(4-chloro-2,6-dimethylphenylsulfonyl)piperazin-1-yl)phenyl- amino)pyrimidin-4-yl)phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.42 (s, 1H), 8.41 (m, 1H), 8.08 (d, 2H), 7.77 (s, 1H), 7.71 (d, 2H), 7.64 (m, 2H), 7.57 (s, 1H), 7.27 (m, 1H), 6.93 (m, 2H), 3.41 (m, 4H), 3.15 (m, 4H), 2.53 (s, 3H), 2.37 (s, 3H), 2.06 (s, 3H). MS (EI): 591 (MH+).
N-(4-(2-(4-(4-(2-(piperazin-1-yl)acetyI)piperazin-1-yl)phenylamino)pyrimidin- 4-yl)phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.96 (t, 1H), 3.75 (m, 5H), 3.60 (m, 2H), 3.32 (m, 1H), 3.19 (m, 1H), 3.12 (s, 2H), 3.10 (m, 2H), 3.01 (m, 2H), 2.68 (m, 4H), 2.32 (m, 4H), 2.10 (m, 2H). MS (EI): 571 (MH+). N-(4-(2-(4-(4-pivaloylpiperazin-1-yl)phenyIamino)pyrimidin-4-yl)phenyl)- tetrahydrofuran-3-carboxamide: 1H 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). MS (EI): 529 (MH+). l-ethyl-3-(4-(5-methyI-2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)urea: 1H NMR (400 MHz, d6-DMSO): 9.24 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.64 (d, 2H), 7.59 (m, 2H), 7.53 (m, 2H), 6.88 (d, 2H), 6.41 (m, 1H), 3.73 (m, 4H), 3.12 (m, 2H), 3.02 (m, 4H), 2.23 (s, 3H), 1.06 (t, 3H). MS (EI): 433 (MH+).
3-methoxy-N-(4-(5-methyl-2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.17 (s, 1H), 9.30 (s, 1H), 8.31 (s, 1H), 7.74 (m, 2H), 7.66 (m, 4H), 6.90 (m, 2H), 3.74 (m, 4H), 3.64 (t, 2H), 3.26 (s, 3H), 3.03 (m, 4H), 2.59 (m, 2H), 2.22 (s, 3H). MS (EI): 448 (MH+).
N-(4-(2-(4-(4-(ethylsulfonyl)piperazine-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.38 (s, 1H), 8.42 (d, 1H), 8.08 (d, 2H), 7.72 (d, 2H), 7.66 (d, 2H), 7.26 (d, 1H), 6.95 (d, 2H), 3.36 (m, 4H), 3.12 (m, 4H), 2.48 (m, 2H), 2.07 (s, 3H), 1.22 (t, 3H). MS (EI): 481 (MH+). 4-(4-(4-(4-acetamidophenyl)pyrimidin-2-ylamino)phenyl)-N-ethylpiperazine- 1-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.41 (d, 1H), 8.08 (d, 2H), 7.72 (d, 2H), 7.64 (d, 2H), 7.25 (d, 1H), 6.94 (d, 2H), 6.57 (d, 1H), 3.50 (m, 2H), 3.39 (m, 4H), 2.99 (m, 4H), 2.07 (s, 3H), 1.00 (t, 3H). MS (EI): 460 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)morpholine-
2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.87 (s, 1H), 9.37 (s, 1H), 8.43 (s, 1H), 8.04-8.16 (d, 2H), 7.81-7.93 (d, 2H), 7.60-7.72 (d, 2H), 7.27 (s,1H), 6.85-6.99 (d, 2H), 4.08-4.69 (s, br, 1H), 4.00-4.07 (d, 1H), 3.85-3.94 (d, 1H), 3.72 (s, 3H), 3.51-3.63 (d, 1H), 2.58-2.80 (m, 3H), 1.86 (s, 6H). MS (EI): 461 (MH+). N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-beta- alaninamide: 1H NMR (400 MHz, d6-DMSO): 9.38 (s, 1H), 10.65 (d, 1H), 8.07-8.16 (d, 2H), 7.72-7.81 (d, 2H), 7.62-7.72 (d,2H), 7.28 (s, 1H), 6.89-6.98 (d, 2H). MS (EI): 419 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)phenylalaninamide: 1H 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+).
N2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- glycinamide: 1H NMR (400 MHz, d6-DMSO): 9.39 (s, 1H), 8.45 (s, 1H), 8.09-8.17 (d, 2H), 7.78-7.86 (d, 2H), 7.65-7.73 (d, 2H), 7.29 (s, 1H), 6.90-7.00 (d, 2H), 3.74 (s, 4H), 3.05 (s, 4H), 2.33 (s, 3H), 1.92 (s, 1H). MS (EI):419 (MH+).
2-cyclopentyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.13 (s, 1H), 9.37 (s, 1H), 8.42- 8.45 (d, 1H), 8.07-8.14 (d, 2H), 7.73-7.79 (d, 2H), 7.65-7.71 (d, 2H), 7.25-7.28 (d, 1H), 6.90-6.97 (d, 2H), 3.71-3.77 (m, 4H), 3.02-3.07 (m, 4H), 2.33-2.37 (d, 2H), 2.20-2.30 (m, 1H), 1.71-1.82 (m, 2H), 1.48-1.66 (m, 4H), 1.14-1.25 (m, 2H). MS (EI): 458 (MH+).
6-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)pyridine-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.50 (s, 1H), 9.44 (s, 1H), 8.80-8.83 (d, 1H), 8.44-8.49 (d, 1H), 8.24-8.28 (m, 1H), 8.15-8.21 (d, 2H), 7.92- 7.97 (d, 2H), 7.67-7.72 (d, 2H), 7.30-7.34 (d, 1H), 6.93-7.02 (m, 3H), 3.94-3.96 (s, 3H), 3.72-3.79 (m, 4H), 3.04-3.1 1 (m, 4H). MS (EI): 483 (MH+). N,N-dimethyl-N'-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)butanediamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.36 (s, 1H), 8.43 (s, 1H), 8.05-8.17 (d, 2H), 7.71-7.79 (d, 2H), 7.61-7.71 (d, 2H), 7.26-7.31 (d, 1H), 6.89-7.00 (d, 2H), 3.68-3.79 (m, 4H), 3.02-3.08 (m, 4H), 3.00 (s, 3H), 2.82 (s, 3H), 2.56- 2.66 (m, 4H). MS (EI): 475 (MH+).
N-[4-(2-{[4-morpholin-4-yl-3-(trifluoromethyl)phenyl]amino} pyrimidin-4-yl)- phenyl]-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.94 (s, 1H), 8.53-8.57 (d, 1H), 8.48 (s, 1H), 8.14-8.21 (d, 2H), 7.93-7.98 (m, 1H), 7.82-7.88 (d, 2H), 7.56-7.61 (d, 1H), 7.42-7.46 (d, 1H), 3.79-3.86 (m, 1H), 3.67-3.75 (m, 4H), 2.93-3.00 (m, 2H), 2.79-2.86 (m, 4H), 2.05-2.17 (m, 1H), 1.79-1.89 (m, 1H), 1.65-1.75 (m, 2H). MS (EI): 513 (MH+).
3-(methyloxy)-N-[4-(2-{[4-morpholin-4-yl-3-(trifluoromethyl)phenyl]amino}- pyrimidin-4-yl)phenyl]propanamide: 1H NMR (400 MHz, d6-DMSO): 10.24 (s, 1H), 9.94 (s, 1H), 8.53-8.56 (d, 1H), 8.47 (s, 1H), 8.13-8.19 (d, 2H), 7.94-8.00 (d, 1H), 7.76- 7.81 (d, 1H), 7.56-7.62 (d, 1H), 7.41-7.45 (d, 1H), 3.67-3.74 (m, 4H), 3.60-3.67 (m, 2H), 3.35 (s, 3H), 2.80-2.86 (d, 4H), 2.57-2.63 (m, 2H). MS (EI): 502 (MH+).
N-(4-{2-[(4-{4-[3-(dimethylamino)-2,2-dimethyIpropyl]piperazin-1-yl}phenyl)- amino]pyrimidin-4-yl}phenyl)-5-oxo-L-prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.34 (s, 1H), 9.37 (s, 1H), 8.43-8.46 (d, 1H), 8.12-8.16 (d, 2H), 7.94 (s, 1H), 7.77-7.81 (d, 2H), 7.62-7.67 (d, 2H), 7.26-7.30 (d, 1H), 6.88-6.94 (d, 2H), 4.20-4.26 (m, 1H), 3.02- 3.08 (m, 4H), 2.57-2.64 (m, 4H), 2.21 (s, 6H), 2.17 (s, 2H), 2.10 (s, 2H), 1.89 (s, 4H), 0.84 (s, 6H). MS (EI): 571 (MH+).
(2R)-N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6- DMSO): 9.94 (s, 1H), 9.41 (s, 1H), 8.43-8.46 (d, 1H), 8.09-8.15 (d, 2H), 7.85-7.90 (d,
2H), 7.65-7.71 (d, 1H), 6.92-6.98 (d, 2H), 4.39-4.48 (m, 1H), 3.95-4.05 (m, 1H), 3.79-3.89 (m, 1H), 3.52-3.64 (m, 6H), 3.32 (s, 1H), 3.23 (s, 2H), 2.98-3.11 (m, 4H), 2.58-2.65 (m, 2H), 2.15-2.25 (m, 1H), 1.96-2.07 (m, 1H), 1.83-1.93 (m, 2H). MS (EI): 531 (MH+).
(2S)-N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6- DMSO): 9.94 (s, 1HO, 9.41 (s, 1H), 8.42-8.47 (d, 2H), 8.09-8.16 (d, 2H), 7.84-7.91 (d, 2H), 7.64-7.72 (d, 2H), 7.27-7.37 (d, 1H), 6.93-6.99 (d, 2H), 4.40-4.47 (m, 1H), 3.95-4.05 (m, 1H), 3.80-3.89 (m, 1H), 3.53-3.65 (m, 6H), 3.32 (s, 1H), 3.23 (s, 2H), 2.98-3.10 (m, 4H), 2.59-2.65 (m, 2H), 2.15-2.27 (m, 1H), 1.95-2.07 (m, 1H), 1.83-1.93 (m, 2H). MS (EI): 531 (MH+).
(2R,4S)-4-hydroxy-N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin-1-yl)pheiiyl- amino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide: 1H NMR (400 MHz, d6- DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.42-8.46 (d, 1H), 8.09-8.15 (d, 2H), 7.80-7.86 (d, 2H), 7.65-7.71 (d, 2H), 7.27-7.31 (d, 1H), 6.93-6.98 (d, 1H), 4.20-4.26 (m, 1H), 3.88-3.94 (m, 1H), 3.53-3.64 (m, 6H), 3.17 (s, 1H), 2.99-3.10 (m, 4H), 2.89-2.93 (m, 1H), 2.77-2.84 (m, 1H), 2.58-2.64 (m, 3H), 1.99-2.07 (m, 2H), 1.73-1.83 (m, 2H). MS (EI): 546 (MH+). N-(4-{2-[(3-fluoro-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.07 (s, 1H), 9.89 (s, 1H), 8.46-8.56 (d, 1H), 8.08-8.21 (d, 2H), 7.74-7.91 (m, 3H), 7.47-7.57 (d, 1H), 7.35-7.41 (d, 1H), 6.98-7.08 (m, 1H), 3.70-3.82 (m, 5H), 2.87-3.03 (m, 5H), 2.01-2.16 (m, 1H), 1.92 (s, 2H), 1.75-1.87 (m, 1H), 1.61-1.74 (m, 2H). MS (EI): 463 (MH+). N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.30 (s, 1H), 9.40 (s, 1H), 8.42-8.47 (d, 1H), 8.09-8.15 (d, 2H), 7.74-7.80 (d, 2H), 7.64-7.71 (d, 2H), 7.27-7.30 (d, 1H), 6.92-7.00 (d, 2H), 3.92-3.99 (m, 1H), 3.68-3.84 (m, 4H), 3.53-3.64 (m, 5H), 3.32 (s, 1H), 3.23 (s, 2H), 3.16-3.22 (m, 1H), 2.98-3.10 (m, 4H), 2.59-2.65 (m, 1H), 2.06-2.15 (m, 2H). MS (EI): 531 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3-pyridin-3- ylpropanamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.37 (s, 1H), 8.39-8.51 (m, 3H), 8.08-8.13 (d, 2H), 7.64-7.76 (m, 5H), 7.25-7.35 (m, 2H), 6.91-6.98 (d, 2H), 3.72- 3.77 (m, 4H), 3.01-3.08 (m, 4H), 2.91-2.98 (m, 2H), 2.65-2.75 (m, 2H). MS (EI): 481 (MH+).
N-(3-(4-(4-acetamidophenyl)pyrimidin-2-yIamino)phenyl)-2- chlorobenzamide: 1H-NMR (400MHz, d6-DMSO): 10.497(s, 1H), 10.201 (s, 1H), 9.668 (s, 1H), 8.505 (d, 1H), 8.505 (d, 1H), 8.427 (s, 1H), 8.223 (d, 2H), 7.748 (d, 2H), 7.59 (m, 2H), 7.477 (m, 3H), 7.374 (d, 1H), 7.253 (m, 2H), 2.083 (s, 3H). MS (EI): 458 (MH+). N-(3-(4-(4-acetamidophenyl)pyrimidin-2-ylamino)phenyl)-2- methylbenzamide: 1H-NMR (400MHz, d6-DMSO): 10.284(d, 2H), 9.622 (s, 1H), 8.487(m, 2H), 8.235(d, 2H), 7.749 (d, 2H), 7.352(m, 8H), 2.084(s, 3H). MS (EI): 438 (MH+).
N-(3-(4-(4-acetamidophenyl)pyrimidin-2-ylamino)phenyl)-2,4- dichlorobenzamide: 1H-NMR (400MHz, d6-DMSO): 10.533 (s, 1H), 10.198(s, 1H), 9.687(s, 1H), 8.506(d, 1H), 8.406(s, br, 1H), 8.220(d, 2H), 7.787(d, 1H), 7.747(d, 2H), 7.659(d, 1H), 7.591(d, 1H), 7.464 (d, 1H), 7.377(d, 1H), 7.247(m, 2H), 2.085(s, 3H). MS (EI): 492 (MH+).
N-(3-(4-(4-acetamidophenyl)pyrimidin-2-ylamino)phenyl)-2,5- dichlorobenzamide: 1H-NMR (400MHz, d6-DMSO): 10.510(s, 1H), 10.198(s, 1H), 9.696(s, 1H), 8.507(s, 1H), 8.389(s, 1H), 8.220(d, 2H), 7.744(m, 3H), 7.617(m, 2H), 7.487(d, 1H), 7.379(d, 1H), 7.282(m, 2H), 2.081(s, 3H). MS (EI): 492 (MH+).
N-(3-(4-(4-acetamidophenyl)pyrimidin-2-yIamino)phenyl)-2-chloro-6-fluoro- 3-methoxybenzamide: 1H-NMR (400MHz, d6-DMSO): 10.726(s, 1H), 10.204(s, 1H), 9.709(s, 1H), 8.509(d, 1H), 8.402(s, 1H), 8.217(d, 2H), 7.743(d, 2H), 7.488(d, 1H), 7.386(m, 2H), 7.282(m, 2H), 7.221(d, 1H), 3.904(s, 3H), 2.082(s, 3H). MS (EI): 506 (MH+).
N-(3-(4-(4-acetamidophenyl)pyrimidin-2-yIamino)phenyI)-2,3- dichlorobenzamide: Η-NMR(400MHz, d6-DMSO): 10.6 (s,1H), 10.2(s, 1H), 9.7(s, 1H), 8.5(d, 1H), 8.4(s, 1H), 8.2(d, 2H), 7.8(m, 3H), 7.6(d, 1H), 7.5(m, 2H), 7.4(d, 1H), 7.2(m, 2H), 2.081(s,3H). MS (EI): 492 (MH+).
(R)-N-(4-(2-(4-(4-(pyrroIidine-2-carbonyl)piperazin-1-yl)phenylamino)- pyrimidin-4-yl) phenyl)cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.476(s, 1H), 9.406(s, 1H), 8.448(d, 1H), 8.124(d, 2H), 7.767(m, 4H), 7.287(d, 1H), 6.977(d, 2H), 3.85(m, 1H), 3.65(m, 4H), 3.0(m, 4H), 2.95(m, 1H), 2.6(m, 1H), 2.0(m, 1H), 1.8(m, 1H), 1.613(m, 3H), 0.84(m, 4H). MS (EI): 512 (MH+).
N-(4-(2-(4-(4-(2-(piperazin-1-yl)acetyl)piperazin-1-yl)phenylamino)pyrimidin- 4-yI)phenyl)cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.480(s, 1H), 9.399(s,1H), 8.447(d, 1H), 8.124(d, 2H), 7.769(d, 2H), 7.692(d, 2H), 7.285(d, 1H), 6.975(d, 2H), 3.170(m, 2H), 3.592(m, 2H), 3.134(s, 2H), 3.099(m, 2H), 3.028(m, 2H), 2.694(m, 4H), 2.331(m, 4H), 0.842(m, 4H). MS (EI): 541 (MH+). 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide: 1H-NMR (400MHz, d6-DMSO): 9.5(s, 1H), 8.5(d, 1H), 8.2(d, 2H), 8.15(s, 1H), 8(d, 2H), 7.7(d, Ih), 7.5(s, 1H), 7.4(d, 1H), 6.9(d, 1H), 4.8(m, 4h), 3.0(m, 4H). MS (EI): 376 (MH+).
(R)-N-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)cyclopropanecarboxamide: 1H-NMR
(400MHz, d6-MeOD): 8.355(d, 1H), 8.114(d, 2H), 7.177(d, 2H), 7.639(d, 2H), 7.217(d, 1H), 7.028(d, 2H), 4.394(m, 1H), 3.797 (m, 2H), 3.692(m, 2H), 3.137(m, 4H), 3.1(m, 1H), 2.410(m, 1H), 1.992(m, 2H), 1.827(m, 2H), 0.981(m, 2H), 0.85(m, 2H). MS (EI): 512 (MH+). (S)-N-(4-(2-(4-(4-(2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin-
4-yl)phenyl)cyclopropanecarboxamide: 1H-NMR (400MHz, MeOD): 8.357(d, 1H), 8.116(d, 2H), 7.718(d, 2H), 7.642(d, 2H), 7.221(d, 1H), 7.033(d, 2H), 4.1(m, 1H), 3.85(m, 1H), 3.7(m, 4H), 3.2(m, 4H), 1.8(m, 1H), 1.4(d, 3H), 0.9(m, 2H), 0.85(m, 2H). MS (EI): 486 (MH+). (R)-N-(4-(2-(4-(4-(2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin-
4-yl)phenyl)cyclopropanecarboxamide: 1H-NMR (400MHz, MeOD): 8.4(d, 1H), 8.15(d, 2H), 7.8(d, 2HO, 7.6(d, 2H), 7.2(d,1H), 7.0(d, 2H), 4.0(m, 1H), 3.7(m, 4H), 3.2(m, 4H), 1.8(m, 1H), 1.3(d, 3H), 0.9(m, 2H), 0.85(m, 2H). MS (EI): 486 (MH+).
(R)-N-(4-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)- pyrrolidine-2-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.193(s, 1H), 9.41 l(s, 1H), 8.452-8.439(d, 1H), 8.136-8.144(d, 2H), 7.849-7.828 ((d, 2H), 7.690-7.688(d, 2H), 7.302-7.289(d, 1H), 6.971-6.948(d, 2H), 3.743(m, 1H), 3.588(m, 4H), 3.085-3.016(m, 4H), 2.905(t, 2H), 2.046(s, 3H), 1.808(m, 1H), 1.663(m, 2H). MS (EI): 486 (MH+).
(R)-N-(4-(2-(4-(4-(2-methoxyacetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrroIidine-2-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.198(s, 1H), 9.414(s, 1H), 8.452(d, 1H), 8.136(d, 2H), 7.850(d, 2H), 7.691(d, 2H), 7.302(d, 1H), 6.970(d, 2H), 4.136(s, 2H), 3.744(m, 1H), 3.599-3.535(m, 4H), 3.302(s, 3H), 3.078(m, 4H), 2.905(t, 2H), 2.079(m, 1H), 1.791(m, 1H), 1.646((m, 2H). MS (EI): 516 (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). MS (EI): 431 (MH+).
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). MS (EI): 403 (MH+). ethyl N-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-N- methylglycinate: MS (EI): 420 (MH+). ethyl l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2- yI}amino)phenyl]piperidine-3-carboxylate: NMR (400 MHz, d6-DMSO): 10.40 (s, 1H), 10.00 (s, 2H), 8.65 (d, 1H), 8.14 (d, 2H), 7.78 (d, 2H), 7.50 - 7.62 (m, 4H), 7.40 (d, 1H),
2.09 (s, 3H), 2.00 (s, 3H). MS (EI): 362 (MH+). ethyl l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2- yl}amino)phenyl]piperidine-3-carboxylate: MS (EI): 460 (MH+). N-(4-{2-[(4-{bis[2-(methyloxy)ethyl]amino}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide: MS (EI) for C24H29N5O3: 436 (MH+).
N-[4-(2-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: MS (EI) for C22H23N5O4S: 454 (MH+).
3-hydroxy-3-methyl-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}- pyrimidin-4-yl)phenyl]butanamide: NMR (400 MHz, d6-DMSO): 10.04 (s, 1H), 9.46 (s, 1H), 8.45 (d, 1H), 8.1 1 (d, 2H), 7.75 (d, 2H), 7.65 (s, 1H), 7.29 (d, 1H), 6.91 (d, 1H), 3.79 (s, 3H), 3.68 (m, 4H), 2.89 (m, 4H), 2.44 (s, 2H), 1.23 (s, 6H). MS (EI) for C26H31N5O4: 478 (MH+). l-methyl-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin- 4-yl)phenyl]-D-prolinamide: NMR (400 MHz, d6-DMSO): 10.0 (s, 1H), 9.44 (s, 1H), 8.42 (d, 1H), 8.18 (d, 2H), 7.82 (d, 2H), 7.62 (s, 1H), 7.30 (m, 2H), 6.81 (d, 1H), 3.80 (s, 3H), 3.68 (m, 4H), 2.85 - 3.10 (m, 6H), 2.37 - 2.48 (m, 5H), 2.20 (m, 1H), 1.80 (m, 2H). MS (EI) for C27H32N6O3: 489 (MH+).
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 -
4.10 (m, 7H), 3.58 (m, 4H), 1.48 (d, 3H). MS (EI) for C24H28N6O3: 449 (MH+). N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4- yl)phenyl]-cyclopropanecarboxamide: NMR (400 MHz, d6-DMSO): 10.45 (s, 1H), 9.43 (s, 1H), 8.42 (d, 1H), 8.17 (d, 2H), 7.75 (d, 2H), 7.64 (s, 1H), 7.15 (m, 2H), 6.84 (d, 1H), 3.80 (s, 3H), 3.75 (m, 4H), 2.96 (m, 4H), 2.52 (m, 2H), 0.80 (m, 2H). MS (EI) for C25H27N5O3: 446 (MH+).
N-[4-(2-{[3-(methyIoxy)-4-morpholin-4-ylphenyl]amino}pyiϊmidin-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). MS (EI) for C25H29N5O3 : 448 (MH+).
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). MS (EI) for C28H34N6O3: 503 (MH+).
O-methyl-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin- 4-yl)phenyl]-L-serinamide: NMR (400 MHz, d6-DMSO): 11.60 (s, 1H), 10.1 (s, 1H), 8.60 (s, 1H), 8.55 (m, 2H), 8.20 (m, 2H), 7.98 (s, 1H), 7.90 (d, 2H), 7.80 (s, 1H), 7.48 (m, 2H), 4.35 (m, 1H), 4.04 (m, 5H), 3.98 (s, 3H), 3.85 (m, 4H), 3.60 (m, 4H). MS (EI) for C25H30N6O4: 479 (MH+).
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). MS (EI) for C26H30N6O3: 475 (MH+).
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). MS (EI) for C28H32N6O3: 501 (MH+).
N-{4-[2-({4-[4-(Piperidin-4-ylcarbonyl)piperazin-1-yl]phenyl}amino)- pyrimidin-4-yl]phenyl}-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 1 1.40 (s, 1H), 10.0 (m, 1H), 9.96 (s, 1H), 9.1 1 (br d, 1H), 8.7-8.8 (m, 2H), 8.55 (d, 1H), 8.20 (d, 2H), 7.87 (m, 4H), 7.59 (br s, 2H), 7.45 (d, 1H), 4.48 (m, 1H), 3.4-3.5 (m, 4H), 3.25-3.30 (m, 4H) 3.0-3.1 (m, 1H), 2.9-3.0 (m, 2H), 2.4-2.5 (m, 1H), 1.9-2.0 (m, 3H), 1.7-1.9 (m, 4H); MS (EI) for C3 IH38N8O2: 555 (MH+). 3-(Methyloxy)-N-{4-[2-({4-[4-(piperidin-4-ylcarbonyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}propanamide: 1H NMR (400 MHz, d6- DMSO): 10.49 (s, 1H), 9.93 (s, 1H), 9.07 (m, 1H), 8.72 (m, 1H), 8.50 (d, 1H), 8.13 (d, 2H), 7.85 (d, 2H), 7.79 (d, 2H), 7.56 (br s, 2H), 7.42 (d, 1H), 3.61 (t, 2H), 3.3-3.5 (m, 4H), 3.2-3.30 (m, 5H) 3.0-3.1 (m, 1H), 2.85-3.0 (m, 2H), 2.59 (t, 2H), 1.7-1.9 (m, 4H); MS (EI) for C30H37N7O3: 544 (MH+). l-Ethyl-3-{4-[2-({4-[4-(piperidin-4-ylcarbonyl)piperazin-1-yl]phenyl}amino)- pyrimidin-4-yl]phenyl}urea: 1H NMR (400 MHz, d6-DMSO): 9.96 (s, 1H), 9.20 (s, 1H), 8.93 (m, 1H), 8.65 (m, 1H), 8.46 (d, 1H), 8.09 (d, 2H), 7.79 (m, 2H), 7.58 (d, 2H), 7.41 (m, 3H), 6.51 (br s, 1H), 3.2-3.4 (m, 6H), 3.13 (q, 2H) 3.0-3.1 (m, 1H), 2.9-3.0 (m, 2H), 1.7-1.9 (m, 4H), 1.06 (t, 3H); MS (EI) for C29H36N8O2: 529 (MH+).
N-(4-{2-[(4-{4-[3-(Dimethylamino)-2,2-dimethylpropanoyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, dδ-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 6.57 (br s, 1H), 3.70 (m, 4H), 3.07 (m, 4H) 2.60 (br s, 2H), 2.28 (br s, 6H), 2.09 (s, 3H), 1.23 (s, 6H); MS (EI) for C29H37N7O2: 516 (MH+).
2-(Methyloxy)-N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-ethanesulfonamide: 1H NMR (400 MHz, d6-DMSO): 9.39 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.67 (d, 2H), 7.31 (d, 2H), 7.26 (d, 1H), 6.94 (d, 2H), 3.74 (m, 4H), 3.67 (t, 2H) 3.43 (t, 2H), 3.18 (s, 3H), 3.05 (m, 4H); MS (EI) for C23H27N5O4S: 470 (MH+).
3-(Methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)propane-1-sulfonamide: MS (EI) for C24H29N5O4S: 484 (MH+).
3-({4-[4-(acetylamino)phenyl]pyriinidin-2-yl}ainino)-N-(tetrahydrofuran-2- ylmethyl)benzamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.77 (s, 1H), 8.52 (d, 1H), 8.45 (d, 1H), 8.43 (d, 1H), 8.19 (d, 1H), 8.17 (d,1H), 7.88-7.86 (m,1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.43-7.38 (m, 3H), 4.01-3.98 (m, 1H), 3.81-3.76 (m, 2H), 3.65-3.62 (m, 2H), 2.09 (s, 3H), 1.85-1.80 (m, 3H), 1.64-1.61 (m, 1H). MS (EI): 432.5 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}ainino)-N-[3-(2-oxopyrrolidin-1- yl)propyl]benzamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.78 (s, 1H), 8.52 (d, 1H), 8.49 (s, 1H), 8.41 (t, 1H), 8.19 (dd, 2H), 7.87-7.84 (m,1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.40-7.38 (m, 3H), 3.27-3.23 (m, 6H), 2.22 (t, 2H), 2.09 (s, 3H), 1.96-1.88 (m, 2H), 1.73-1.70 (m, 2H). MS (EI): 473.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(3s,5s,7s)-tricyclo- [3.3.1. l~3,7~]dec-1-yl]benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.73 (s, 1H), 8.52 (d, 1H), 8.35 (s, 1H), 8.16 (d, 2H), 7.84-7.81 (m, 1H), 7.76 (d, 2H), 7.55 (s, 1H), 7.39-7.31 (m, 3H), 2.09 (s, 3H), 1.67 (m, 15H). MS (EI): 482.6 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2-(methyloxy)ethyl]- benzamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.77 (s, 1H), 8.52 (d, 1H), 8.46 (d, 2H), 8.19 (d, 1H), 8.18 (d, 1H), 7.88-7.85 (m,1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.43- 7.39 (m, 3H), 3.48-3.41 (m, 4H), 3.29-3.27 (m, 3H), 2.09 (s, 3H). MS (EI): 406.3 (MH+).
N-[4-(2-{[3-(1,3-thiazolidm-3-ylcarbonyl)phenyI]amino}pyrimidin-4- yl)phenyl]-acetamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.84 (s, 1H), 8.52 (d, 1H), 8.19-8.12 (m, 3H), 7.90-7.87 (m, 1H), 1.11-1.15 (m, 2H), 7.43-7.38 (m, 2H), 7.1 1 (d, 1H), 4.64 (m, 2H), 3.77 (m, 2H), 3.06 (m, 2H), 2.09 (s, 3H). MS (EI): 420.6 (MH+).
N-{4-[2-({3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.83 (s, 1H), 8.53 (d, 1H), 8.14-8.11 (m, 3H), 8.04 (t, 1H), 7.89-7.86 (m, 1H), 7.73 (d, 2H), 7.57-7.53 (m, 1H), 7.43-7.39 (m, 2H), 7.03-7.01 (m, 1H), 6.83 (d, 1H), 6.69-6.66 (m, 1H), 3.74 (m, 4H), 3.49 (m, 4H), 2.08 (s, 3H). MS (EI): 494.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[2-
(methyloxy)phenyl]-methyl}benzamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 8.80 (d, 1H), 8.53-8.49 (m, 2H), 8.19 (dd, 2H), 7.94-7.91 (m, 1H), 7.74 (d, 2H), 7.52-7.49 (m, 1H), 7.44-7.39 (m, 1H), 7.26-7.19 (m, 2H), 6.99 (dd, 1H), 6.93-6.89 (m, 1H), 4.46 (d, 2H), 3.84 (s, 3H), 2.09 (s, 3H). MS (EI): 468.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[3-
(methyloxy)phenyl]-methyl}benzamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 8.97 (t, 1H), 8.53-8.49 (m, 2H), 8.20-8.18 (m, 2H), 7.93-7.90 (m, 1H), 7.75 (d, 2H), 7.48-7.46 (m, 1H), 7.43-7.39 (m, 1H), 7.27-7.23 (m, 1H), 6.92-6.90 (m, 2H), 6.83-6.80 (m, 1H), 4.47 (d, 2H), 3.71 (s, 3H), 2.09 (s, 3H). MS (EI): 468.4 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2- nuorophenyl)methyl]-benzamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 8.97 (t, 1H), 8.53-8.49 (m, 2H), 8.19-8.17 (m, 2H), 7.93-7.90 (m, 1H), 7.75 (d, 2H), 7.50-7 '.47 (m, 1H), 7.43-7.37 (m, 2H), 7.32-7.29 (m, 1H), 7.22-7.16 (m, 2H), 4.40 (d, 2H), 2.09 (s, 3H). MS (EI): 456.4 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(4- fluorophenyl)methyl]-benzamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 9.00 (t, 1H), 8.53-8.50 (m, 2H), 8.19-8.17 (m, 2H), 7.90-7.88 (m, 1H), 7.75 (d, 2H), 7.47-7.36 (m, 4H), 7.19-7.13 (m, 2H), 4.47 (d, 2H), 2.09 (s, 3H). MS (EI): 456.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(3,3-dimethylbutyl)- benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.76 (s, 1H), 8.53-8.51 (d, 1H), 8.41 (s, 1H), 8.33 (t, 1H), 8.18-8.17 (m, 2H), 7.88-7.85 (m, 1H), 7.75 (d, 2H), 7.39- 7.37 (m, 2H), 3.30-3.26 (m, 2H), 2.08 (s, 3H), 1.48-1.44 (m, 2H), 0.94 (s, 9H). MS (EI): 432.4 (MH+).
N-[4-(2-{[3-(thiomorpholin-4-ylcarbonyl)phenyl]amino}pyrimidin-4- yl)phenyl]-acetamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.82 (s, 1H), 8.53 (d, 1H), 8.15-8.20 (m, 2H), 7.99 (t, 1H), 7.85-7.82 (m, 1H), 7.76 (d, 2H), 7.41-7.37 (m, 2H), 6.98-6.96 (m, 1H), 3.88 (m, 4H), 3.60 9m, 4H), 2.09 (s, 3H). MS (EI): 434.5 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(2- thienylmethyl)benzamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 9.09 (t, 1H), 8.53-8.50 (m, 2H), 8.18 (d, 2H), 7.89-7.86 (m, 1H), 7.75 (d, 2H), 7.44-7.38 (m, 3H), 7.03 (m, 1H), 6.98-6.96 (m, 1H), 4.64 (d, 2H), 2.09 (s, 3H). MS (EI): 444.4 (MH+). 3-({4-[4-(acetylamino)phenyI]pyrimidin-2-yl}amino)-N-[3-(dimethylamino)- propyljbenzamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 8.74 (m, 1H), 8.55-8.50 (m, 2H), 8.21-8.18 (m, 2H), 7.95-7.87 (m, 1H), 7.75 (d, 2H), 7.45-7.40 (m, 2H), 3.05 (s, 2H), 2.75 (s, 6H), 2.55-2.54 (m, 2H), 2.09 (s, 3H), 1.25-1.21 (m, 2H). MS (EI): 433.4 (MH+). 3-({4-[4-(acetylamino)phenyI]pyrimidin-2-yl}amino)-N-[2-(2-chlorophenyl)- ethyl]benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.77 (s, 1H), 8.54-8.51 (m, 2H), 8.44 (m, 1H), 8.18 (d, 2H), 7.88-7.86 (m, 1H), 7.75 (d, 2H), 7.45-7.36 (m, 4H), 7.28-7.25 (m, 2H), 3.55-3.50 (m, 2H), 3.01-2.98 (m, 2H), 2.08 (s, 3H). MS (EI): 486.8 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[2-(trifluoromethyl)- phenyl]methyl}benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.81 (s, 1H), 9.07 (t, 1H), 8.53-8.49 (m, 2H), 8.19-8.17 (m, 2H), 7.96-7.94 (m, 1H), 7.75-7.72 (m, 2H), 7.55-7.39 (m, 6H), 4.68 (d, 2H), 2.08 (s, 3H). MS (EI): 506.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[3-(trifluoromethyl)- phenyl]methyl}benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.80 (s, 1H), 9.10 (t, 1H), 8.53-8.49 (m, 2H), 8.19-8.17 (m, 2H), 7.94-7.91 (m, 1H), 7.74 (d, 2H), 7.68- 7.58 (m, 3H), 7.48-7.39 (m, 3H), 4.58 (d, 2H), 2.09 (s, 3H). MS (EI): 506.4 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[4-(trifluoromethyl)- phenyl]methyl}benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.80 (s, 1H), 9.10 (t, 1H), 8.52 (m, 2H), 8.18 (d, 2H), 7.91-7.89 (m, 1H), 7.75-7.69 (m, 4H), 7.55 (d, 2H), 7.49-7.38 (m, 3H), 4.58 (d, 2H), 2.08 (s, 3H). MS (EI): 506.5 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2,4-difluorophenyl)- methyljbenzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.79 (s, 1H), 8.98 (t, 1H), 8.52 (m, 2H), 8.18 (d, 2H), 7.91-7.89 (m, 1H), 7.54 (d, 2H), 7.47-7.38 (m, 4H), 7.27- 7.22 (m, 1H), 7.09-7.04 (m, 1H), 4.48 (d, 2H), 2.09 (s, 3H). MS (EI): 474.4 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}ainino)-N-ethyl-N- methylbenzamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.80 (s, 1H), 8.53 (d, 1H), 8.13 (d, 2H), 7.76-7.74 (m, 2H), 7.40-7.32 (m, 3H), 6.94 (m,2H), 3.28-3.24 (m, 2H), 2.94 (m, 3H), 2.09 (s, 3H), 1.15-1.08 (m, 3H). MS (EI): 390.4 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-({4-[(trifluoromethyl)- oxy]phenyl}methyl)benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.79 (s, 1H), 9.04 (t, 1H), 8.52 (m, 2H), 8.18 (d, 2H), 7.91-7.88 (m, 1H), 7.75 (d, 2H), 7.48-7.39 (m, 4H), 7.34-7.32 (m, 2H), 4.51 (d, 2H), 2.09 (s, 3H). MS (EI): 522.5 (MH+).
N-{4-[2-({3-[(4-acetylpiperazin-1-yl)carbonyl]phenyl}amino)pyriinidin-4-yl]- phenyljacetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.82 (s, 1H), 8.53 (t, 1H), 8.19 (d, 2H), 8.14-8.12 (m, 2H), 7.84-7.84 (m, 1H), 7.75 (d, 2H), 7.40-7.38 (m, 2H), 3.53-3.44 (m, 8H), 2.09 (s, 6H). MS (EI): 459.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyriinidin-2-yl}amino)-N-(cyclopropylmethyl)- benzamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.77 (s, 1H), 8.53-8.50 (m, 2H), 8.48 (d, 1H), 8.19(dd, 2H), 7.86-7.84 (m, 1H), 7.75 (d, 2H), 7.41-7.38 (m, 2H), 3.17- 3.14 (m, 2H), 2.09 (s, 3H), 1.06 (m, 1H), 0.45-0.42 (m, 2H), 0.25-0.23 (m, 2H). MS (EI): 402.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2-(2-fluorophenyI)- ethyl] benzamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.77 (s, 1H), 8.54-8.51 (m, 2H), 8.44 (m, 1H), 8.20-8.17 (m, 2H), 7.88-7.86 (m, 1H), 7.75 (d, 2H), 7.40-7.26 (m, 4H), 7.18-7.13 (m, 2H), 3.52-3.49 (m, 2H), 2.92-3.88 (m, 2H), 2.09 (s, 3H). MS (EI): 470.4 (MH+).
N-[4-(2-{[3-(pyrrolidin-1-ylcarbonyl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.78 (s, 1H), 8.53 (d, 1H),
8.20-8.12 (m, 4H), 7.83 (d, 1H), 7.76-7.73 (m, 2H), 7.39-7.35 (m, 2H), 3.50-3.40 (m, 4H), 2.09 (s, 3H), 1.95-1.80 (m, 4H). MS (EI): 402.5 (MH+).
N-{4-[2-({3-[(4-pyrimidin-2-ylpiperazin-1- yl)carbonyl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6- DMSO): 10.20 (s, 1H), 9.83 (s, 1H), 8.53 (d, 2H), 8.39 (d, 1H), 8.14-8.12 (m, 2H), 8.04 (t, 1H), 7.89-7.87 (m, 1H), 7.74 (d, 1H), 7.43-7.38 (m, 2H), 7.03-7.01 (m, 1H), 6.67 (t, 2H), 3.81 (m, 4H), 3.73 (m, 4H), 2.08 (s, 3H). MS (EI): 495.6 (MH+).
N-{4-[2-({4-[4-(9H-fluoren-2-ylmethyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.87 (t, 2H), 7.73 (d, 2H), 7.65 (d, 2H), 7.59-7.56 (m, 2H), 7.37-7.25 (m, 4H), 6.92 (d, 2H), 3.92 (s, 2H), 3.60 (s, 2H), 3.10 (m, 4H), 2.56 (m, 4H), 2.08 (s, 3H). MS (EI): 567.7 (MH+).
N-(4-{2-[(4-{4-[(3-methyl-2-thienyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.73 (d, 2H), 7.65 (d, 2H), 7.33 (d, 1H), 7.26 (d, 1H), 6.92 (d, 2H), 6.85 (d, 1H), 3.63 (s, 2H), 3.07 (m, 4H), 2.56 (m, 4H),
2.17 (s, 3H), 2.08 (s, 3H). MS (EI): 499.5 (MH+).
N-(4-{2-[(4-{4-[(5-ethylfuran-2-yl)methyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H 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), 7.26 (d, 1H), 6.92 (d, 2H),
6.18 (d, 1H), 6.01 (d, 1H), 3.48 (s, 2H), 3.07 (m, 4H), 2.62-2.56 (m, 6H), 2.09 (s, 3H), 1.16 (t, 3H). MS (EI): 497.6 (MH+). N-(4-{2-[(4-{4-[(3-{[4-(l,l-dimethylethyl)phenyl)oxy}phenyl)methyl]piperazin- l-yl}phenyl)amino|pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.64 (d, 2H), 7.42- 7.38 (m, 2H), 7.33 (t, 1H), 7.26 (d, 1H), 7.08 (d, 1H), 6.97-6.86 (m, 6H), 3.52 (s, 2H), 3.06 (m, 4H), 2.52 (m, 4H), 2.09 (s, 3H), 1.27 (s, 9H). MS (EI): 627.7 (MH+).
N-{4-[2-({4-[4-(3-thienylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyljacetamide: 1H 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). MS (EI): 485.6 (MH+). methyl 4-({4-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)- phenyl]piperazin-1-yl}methyl)benzoate: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.94 (d, 2H), 7.73 (d, 2H), 7.65 (d, 2H), 7.50 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 3.85 (s, 3H), 3.61 (s, 2H), 3.09 (m, 4H), 2.54 (m, 4H), 2.09 (s, 3H). MS (EI): 537.7 (MH+).
N-(4-{2-[(4-{4-[3-(methylthio)propyl]piperazin-1-yl}phenyl)amino]pyrimidin- 4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 3.34 (m, 4H), 3.07 (m, 4H), 2.39 (m, 4H), 2.09 (s, 3H), 2.03 (m, 3H), 1.75-1.68 (m, 2H). MS (EI): 477.5 (MH+).
N-(4-{2-[(4-{4-[(4-{[3-(dimethylamino)propyl]oxy}phenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H 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), 7.26- 7.21 (m, 3H), 6.92-6.87 (m, 4H), 3.97 (t, 2H), 3.44 (m, 6H), 3.06 (m, 4H), 2.37 (t, 2H), 2.16 (s, 6H), 2.09 (s, 3H), 1.87-1.82 (m, 2H). MS (EI): 580.7 (MH+).
N- [4-(2- { [4-(4- {2- [(phenylmethyl)oxy ] ethyl} piperazin-1- yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.38- 7.26 (m, 6H), 6.92 (d, 2H), 4.50 (s, 2H), 3.59 (m, 3H), 3.07 (m, 3H), 2.58 (m, 6H), 2.09 (s, 3H). MS (EI): 523.5 (MH+).
N-(4-{2-[(4-{4-[(2-chloroquinolin-3-yl)methyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.37 (s, 1H), 8.49 (s, 1H), 8.44 (d, 1H), 8.13-8.09 (m, 3H), 7.96 (d, 1H), 7.83-7.79 (m, 1H), 7.74 (d, 1H), 7.69-7.65 (m, 3H), 7.26 (d, 2H), 6.95 (d, 2H), 3.78 (s, 2H), 3.15 (m, 4H), 2.69 (m, 4H), 2.09 (s, 3H). MS (EI): 565.1 (MH+).
N-{4-[2-({4-[4-(2,2'-bithien-5-ylmethyl)piperazin-1-yl]phenyl}amino)- pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.49 (dd, 1H), 1.21-1.25 (m, 2H), 7.15 (d, 1H), 7.09-7.07 (m, 1H), 6.96-6.92 (m, 3H), 3.73 (s, 2H), 3.10 (m, 4H), 2.59 (m, 4H), 2.09 (s, 3H). MS (EI): 567.6 (MH+).
N-[4-(2-{[4-(4-{[4-(2-thienyl)phenyl]methyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.73 (d, 2H), 7.66-7.62 (m, 4H), 7.54-7.50 (m, 2H), 7.38 (d, 2H), 7.26 (d, 1H), 7.15-7.13 (m, 1H), 6.92 (d, 2H), 3.54 (s, 2H), 3.09 (m, 4H), 2.55-2.52 (m, 4H), 2.09 (s, 3H). MS (EI): 561.6 (MH+).
N-(4-{2-[(4-{4-[(4-cyanophenyl)methyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.82 (d, 2H), 7.73 (d, 2H), 7.65 (d, 2H), 7.56 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 3.63 (s, 2H), 3.10-3.08 (m, 4H), 2.54-2.52 (m, 4H), 2.09 (s, 3H). MS (EI): 504.5 (MH+).
N-[4-(2-{[4-(4-{[2,5-bis(methyloxy)phenyl]methyl}piperazin-1-yI)phenyl]- amino}pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s,
1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.95- 6.90 (m, 4H), 6.81-6.78 (m, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.50 (s, 2H), 3.09 (m, 4H), 2.55 (m, 4H), 2.09 (s, 3H). MS (EI): 539.7 (MH+).
N-{4-[2-({4-[4-(2,2-diphenylethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.1 1 (d, 2H), 7.82 (d, 2H), 7.65-7.59 (m, 6H), 7.50-7.46 (m, 4H), 7.26 (d, 1H), 7.21 (d, 2H), 6.92 (d, 2H), 4.45 (t, 1H), 3.61 (t, 2H), 3.09 (m, 4H), 2.54 (m, 4H), 2.09 (s, 3H). MS (EI): 569.6 (MH+).
N-{4-[2-({4-[4-(1H-pyrrol-2-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.71 (s, 1H), 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), 7.26 (d, 1H), 6.91 (d, 2H), 6.65-6.63 (m, 1H), 5.94-5.90 (m, 2H), 3.44 (s, 2H), 3.06 (m, 4H), 2.48 (m, 4H), 2.09 (s, 3H). MS (EI): 468.6 (MH+).
N-[4-(2-{[4-(4-propyIpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.1 1 (d, 2H), 7.73 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 3.06 (m, 4H), 2.27 (m, 4H), 2.08 (s, 3H), 1.80 (s, 2H), 1.48 (m, 2H), 0.88 (t, 3H). MS (EI): 431.6 (MH+).
N-[4-(2-{[4-(4-butylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.74 (d, 2H), 7.64 (d, 2H), 7.25 (d, 1H), 6.92 (d, 2H), 3.07 (m, 4H), 2.31 (m, 4H), 2.09 (s, 3H), 1.87 (m, 2H), 1.44 (m, 2H), 1.30 (m, 2H), 0.90 (t, 3H). MS (EI): 445.6 (MH+).
N-{4-[2-({4-[4-(cyclopropylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.73 (d, 2H), 7.65 (d, 2H), 7.25 (d, 1H), 6.92 (d, 2H), 3.08 (m, 4H), 2.58 (m, 4H), 2.22 (d, 2H), 2.09 (s, 3H), 1.86 (s, 1H), 0.49 (m, 2H), 0.09 (m, 2H). MS (EI): 443.6 (MH+).
N-[4-(2-{[4-(4-pentanoylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.60 (m, 4H), 3.07 (m, 2H), 3.02 (m, 2H), 2.35 (t, 2H), 2.09 (s, 3H), 1.49 (m, 2H), 1.31 (m, 2H), 0.89 (t, 3H). MS (EI): 473.6 (MH+).
N-{4-[2-({4-[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyriinidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.62 (d, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.95 (t, 1H), 7.74 (d, 2H), 7.69 (d, 2H), 7.61 (d, 1H), 7.27 (d, 1H), 6.97 (d, 2H), 3.82 (t, 2H), 3.57 (t, 2H), 3.18 (t, 2H), 3.06 (t, 2H), 2.09 (s, 3H). MS (EI): 494.6 (MH+).
N-{4-[2-({4-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.68 (m, 2H), 8.44 (d, 1H), 8.10 (d, 2H), 7.89 (d, 1H), 7.74 (d, 2H), 7.69 (d, 2H), 7.51 (m, 1H), 7.28 (d, 2H), 3.80 (m, 2H), 3.49 (m, 2H), 3.18 (m, 2H), 3.09 (m, 2H), 2.09 (s, 3H). MS (EI): 494.6 (MH+). N-{4-[2-({4-[4-(pyridin-4-yIcarbonyl)pipera2in-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.69 (d, 2H), 8.44 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.44 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.79 (m, 2H), 3.41 (m, 2H), 3.18 (m, 2H), 3.07 (m, 2H), 2.09 (s, 3H). MS (EI): 494.6 (MH+).
N-{4-[2-({4-[4-(1H-pyrazol-4-ylcarbonyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO):
10.22 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.75-7.68 (m, 4H), 7.28 (d, 2H), 6.97 (d, 3H), 3.75 (m, 4H), 3.1 1 (m, 4H), 2.09 (s, 3H). MS (EI): 483.5 (MH+). N-(4-{2-[(4-{4-[(l-acetylpiperidin-4-yl)carbonyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.26 (d, 1H), 6.97 (d, 2H), 3.65 (m, 4H), 3.02 (m, 8H), 2.62 (m, 1H), 2.09 (s, 3H), 1.99 (s, 3H), 1.66 (m, 2H), 1.56 (m, 2H). MS (EI): 542.7 (MH+). N-(4-(2-(4-(4-(2-cyclopropylacetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide: 1H 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). MS (EI): 471.6 (MH+). N-(4-{2-[(4-{4-[3-(methyloxy)propanoyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetainide: 1H 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). MS (EI): 475.6 (MH+). N-{4-[2-({4-[4-(2-{[2-(methyloxy)ethyl]oxy}acetyl)piperazin-1- yl]phenyl}amino)-pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO):
10.23 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.68 (d, 1H), 7.27 (d, 1H), 6.96 (d, 2H), 4.20 (s, 2H), 3.58 (m, 6H), 3.47 (m, 2H), 3.25 (s, 3H), 3.06 (m, 4H), 2.09 (s, 3H). MS (EI): 505.6 (MH+). N-(4-(2-(4-(4-(2-(pyridin-3-yl)acetyI)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.44 (m, 3H), 8.10 (d, 2H), 7.75 (d, 2H), 7.68 (d, 2H), 7.64 (m, 1H), 7.34 (m, 1H), 7.28 (d, 1H), 6.96 (d, 1H), 3.83 (s, 2H), 3.70 (m, 2H), 3.63 (m, 2H), 3.05 (m, 4H), 2.09 (s, 3H). MS (EI): 508.6 (MH+).
(2R,4S)-4-hydroxy-N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin-1-yl)phenyl- amino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide: 1H NMR (400 MHz, d6- DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.48 (d, 1H), 8.44 (d, 1H), 8.39 (dd, 1H), 8.1 1 (d, 1H), 7.74 (d, 2H), 7.69 (m, 3H), 7.28 (m, 3H), 6.94 (d, 2H), 3.59 (m, 4H), 3.01 (m, 4H), 2.86 (t, 2H), 2.73 (t, 2H), 2.09 (s, 3H). MS (EI): 522.6 (MH+).
N-{4-[2-({3-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl}amino)- pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.45 (s, 1H), 8.47 (d, 1H), 8.1 1 (d, 2H), 7.73 (d, 2H), 7.66 (d, 1H), 7.60 (s, 1H), 7.31 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H), 6.55 (dd, 1H), 3.90 (s, 2H), 3.17 (m, 4H), 2.66 (m, 4H), 2.07 (s, 3H). MS (EI): 486.6 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-5-oxo-L- prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.33 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.14 (d, 2H), 7.93 (s, 1H), 7.79 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.93 (d, 2H), 4.23 (dd, 1H), 3.75 (m, 4H), 3.06 (m, 4H), 2.35 (m, 1H), 2.21 (m, 2H), 2.02 (m, 1H). MS (EI): 459.5 (MH+).
(3S)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyrro- lidine-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.75 (s, 1H), 9.84 (s, 1H), 9.34 (m, 1H), 9.14 (m, 1H), 8.51 (d, 1H), 8.16 (d, 2H), 7.82 (d, 3H), 7.41 (d, 2H), 3.93 (m, 4H), 3.82 (m, 6H), 3.36 (m, 2H), 3.24 (m, 1H), 2.33-2.24 (m, 1H), 2.1 1-2.04 (m, 2H). MS (EI): 445.5 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- threoninamide: 1H 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). MS (EI): 449.5 (MH+).
N-{4-[2-({4-[4-(N,N-diethyl-beta-alanyl)piperazin-1-yl]phenyl}amino)- pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.38 (s, 1H), 8.42 (d, 1H), 8.09 (d, 2H), 7.73 (d, 2H), 7.67 (d, 2H), 7.25 (d, 1H), 6.95 (d, 2H), 3.58 (m, 4H), 3.05 (m, 4H), 2.81 (t, 2H), 2.66-2.55 (m, 6H), 1.93 (s, 3H), 0.99 (t, 6H). MS (EI): 516.7 (MH+). N1-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- glutamamide: 1H NMR (400 MHz, d6-DMSO): 9.36 (s, 1H), 8.42 (d, 2H), 8.11 (d, 3H), 7.80 (d, 2H), 7.66 (d, 2H), 7.26 (d, 2H), 6.92 (d, 3H), 3.72 (m, 4H), 3.32 (m, 1H), 3.02 (m, 4H), 1.93 (s, 2H), 1.82 (s, 2H). MS (EI): 476.6 (MH+). (S)-1-ethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.94 (d, 2H), 3.04 (m, 4H), 2.90 (m, 2H), 2.65 (m, 2H), 2.43 (m, 3H), 1.98 (m, 6H), 1.03 (t, 3H). MS (EI): 473.6 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- norvalinamide: 1H 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). MS (EI): 447.6 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- norleucinamide: 1H 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). MS (EI): 461.6 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- alloisoleucinamide: 1H 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). MS (EI): 461.6 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- leucinamide: 1H 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+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(2- ethylphenyl)benzamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.85 (d, 2H), 8.59 (s, 1H), 8.53 (d, 1H), 8.18 (d, 2 H), 7.93 (m, 1H), 7.73 (d, 2H), 7.57 (d, 1H), 7.46 (t, 1H), 7.40 (d, 1H), 7.30-7.34 (m, 2H), 7.24-7.27 (m, 2H), 2.62-2.67 (m, 2H), 2.08 (s, 3H), 1.13-1.7 (t, 3H). MS (EI) for C27H25N5O2: 452.58 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(phenylmethyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.80 (s, 1H), 8.98-9.01 (t, 1H),
8.52 (d, 1H), 8.50 (s, 1H), 8.18 (d, 2H), 7.9 (dd, 1H), 7.76 (s,1H), 7.74 (s, 1H), 7.47 (d, 1H), 7.39-7.43 (m, 2H), 7.43 (s, 2H), 7.34 (d, 2H), 7.23-7..25 (m, 1H), 4.50( d, 2H), 2.09 (s, 3H). MS (EI) for C26H23N5O2: 438.48 (MH+).
N-{4-[2-({3-[(4-cyclopentylpiperazin-1-yl) carbonyl] phenyl}amino) pyrimidin^-ylJphenylJacetamider'H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.82 (s, 1H), 8.53 (d, 1H), 8.12 (s, 2H), 8.05 (s, 1H), 7.81 (dd, 1H), 7.76 (d, 2H), 7.38 (t, 2H), 6.95 (d, 1H), 2.89 (s, 2H), 2.73 (s, 2H), 2.34-2.45 (m, 5H), 2.09 (s, 3H), 2.73-2.75 (m, 2H), 1.52-1.59 (m, 2H), 1.46-1.50 (m, 2H), 1.27-1.33 (m, 2H): MS (EI) for C28H32N6O2: 485.8 (MH+).
N-{4-[2-({3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H-NMR (400MHz, d6-DMSO): 10.17 (s, 1H), 9.84 (s, 1H), 8.54 (d, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 8.06-8.10 (m, 2H), 7.86-7.88 (m, 2H), 7.73 (d, 2H), 7.42 (d, 1H), 7.39 (d, 1H), 7.02-7.04 (m, 1H), 3.69 (m, 4H), 3.57 (m, 4H), 2.08 (s, 3H). MS (EI) for C27H26N8O2: 495.7 (MH+).
N-(4-{2-[(3-{[4-(3-chlorophenyl)piperazin-1-yl]carbonyl}phenyl)amino]pyri- midin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s,1H), 9.84 (s, 1H),
8.53 (d, 1H), 8.13 (dd, 2H), 8.064 (t, 1H), 7.85-7.87 (m, 1H), 7.74 (d, 2H), 7.39-7.43 (m, 2H), 7.22 (t, 1H), 7.01-7.03 (m, 1H), 6.96 (t, 1H), 6.90 (dd, 1H), 6.81 (dd, 1H), 3.76 (m,
4H), 3.52 (m, 4H), 2.08 (s, 3H). MS (EI) for C29H27ClN6O2: 528.1 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(l-methyl-1H- benzimidazol-2-yl)methyl]benzamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H),
9.80 (s, 1H), 9.01 (t, 1H), 8.52 (t, 2H), 8.17-8.19 (m, 2H), 7.91-7.93 (m, 1H), 7.75 (d, 2H), 7.50-7.59 (m, 3H), 7.39-7.43 (m, 2H), 7.16-7.26 (m, 2H), 4.80 (d, 2H), 3.86 (s, 3H), 2.10
(s, 3H). MS (EI) for C28H25N7O2: 492.4 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-propylbenzainide:
1H-NMR (400MHz, d6-DMSO): 10.22 (s. 1H), 9.77 (s, 1H), 8.52 (d, 1H), 8.46 (s, 1H),
8.40 (t, 1H), 8.18 (d, 2H), 7.83-7.86 (m, 1H), 7.75 (d, 2H), 7.38-7.40 (m, 3H), 3.21-3.26 (m, 2H), 2.09 (s, 3H), 1.52-1.58 (m, 2H), 089-0.93 (t, 3H). MS (EI) for C22H23N5O2:
390.7 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N- cyclopropylbenzamide: 1H-NMR (400MHz, d6-DMSO): 10.24 (s 1H), 9.77 (s, 1H), 8.52 (d, 1H), 8.47 (s, 1H), 8.40 (d, 1H), 8.18 (d, 2H), 7.82-7.85 (m, 1H), 7.76 (d, 2H), 7.39 (d, 1H), 7.36-7.37 (m, 2H), 2.84-2.89 (m, 1H), 2.09 (s, 3H), 0.69-0.73 (m, 2H), 0.56-0.60 (m, 2H). MS (EI) for C22H2IN5O2: 388.7 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(3-fluorophenyl)- methyl]benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.80 (s, 1H), 9.04 (t, 1H), 8.53 (d, 1H), 8.50 (s, 1H), 8.17-8.20 (m, 2H), 7.90-7.93 (m, 1H), 7.74 (d, 2H), 7.46- 7.50 (m, 1H), 7.36-7.43 (m, 3H), 7.08-7.19 (m, 3H), 4.51 (d, 2H), 2.09 (s, 3H). MS (EI) for C26H22FN5O2: 456.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(naphthalen-1- ylmethyl)-benzamide: 1H-NMR (400MHz, (I6-DMSO): 10.21 (s, 1H), 9.79 (s, 1H), 9.03 (t, 1H), 8.52 (d, 2H), 8.15-8.23 (m, 3H), 7.95-7.97 (m, 1H), 7.90-7.93 (m, 1H), 7.85-7.87 (dd, 1H), 7.75 (d, 2H), 7.55-760 (m, 2H), 7.48-7.50 (m, 3H), 7.38-7.42 (m, 2H), 4.97 (d, 2H), 2.08 (s, 3H). MS (EI) for C30H25N6O2: 488.6 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2-
(dimethylamino)ethyl]-N-methylbenzamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.80 (s, 1H), 8.53 (d, 1H), 8.13 (d, 2H), 8.00 (d, 1H), 7.82 (s, 1H), 7.75 (d, 2H), 7.35- 7.39 (m, 2H)6.93 (d, 1H), 3.39-3.419 (m, 2H), 2.94 (s, 3H), 2.21 (m, 2H), 2.09 (s, 6H), 1.95 (s, 3H). MS (EI) for C24H28N6O2: 433.7 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2-methylphenyI)- methyl]benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 8.56 (t, 1H), 8.52 (d,1H), 8.50 (s, 1H), 8.17-8.19 (m, 2H), 7.90-7.90 (m, 1H), 7.75 (d, 2H), 7.45- 7.50 (s, 1H), 7.39-7.43 (m, 2H), 7.25-7.27 (1H), 7.14-7.18 (m, 3H), 4.47 (d, 2H), 2.34 (s, 3H), 2.09(s, 3H). MS (EI) for C27H25N5O2: 452.6 (MH+).
3-({4-[4-(acetyIamino)phenyl]pyrimidin-2-yl}amino)-N-[(3- chlorophenyl)methyl]-benzamide: 1H-NMR (400MHz, d6-DMSO): 10.25 (s, 1H), 9.80 (s, 1H), 9.05 (t, 1H), 8.53 (d, 1H), 8.50 (s, 1H), 8.17-8.20 (m, 2H), 7.91-7.94 (m, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.46-7.48 (m, 1H), 7.43 (d, 1H), 7.36-7.40 (m, 3H), 7.30-7.32 (m, 2H), 4.95 (d, 2H), 2.09 (s, 3H). MS (EI) for C26H22ClN5O2: 472.8 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(2-phenylethyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.78 (s, 1H), 8.51-8.53 (m, 2H), 8.46 (s, 1H), 8.19 (d, 2H), 7.85-7.88 (m, 1H), 7.76 (d, 2H), 7.37-7.38 (m, 3H), 7.27- 7.32 (m, 4H), 7.19-7.23 (m, 1H), 3.47-3.52 (m, 2H), 2.84-2.88 (m, 2H), 2.08 (s, 3H). MS (EI) for C27H25N5O2: 452.6 (MH+).
N-{4-[2-({3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4-yl]- phenyljacetamide: 1H-NMR (400MHz, d6-DMSO): 10.24 (s, 1H), 9.82 (s, 1H), 8.53 (d, 1H), 8.12-8.15(m, 2H), 8.04(s, 1H), 7.80-7.82 (m, 1H), 7.76 (d, 2H), 7.36-7.40 (m, 2H), 6.94-6.96 (m, 1H), 2.94 (s, 2H), 2.78 (s, 2H), 2.37 (s, 2H), 2.27 (s, 2H), 2.18 (s, 3H), 2.09 (s, 3H). MS (EI) for C24H26N6O2: 431.6 (MH+).
N-(4-{2-[(3-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.84 (s, 1H), 8.53 (d, 1H), 8.14 (d, 2H), 8.08 (m, 1H), 7.85 (d, 1H), 7.77 (d, 2H), 7.39-7.43 (m, 2H), 7.05-7.17 (m, 2H), 6.99-7.05 (m, 4H), 3.8 l(s, 2H), 3.55 (s, 2H), 3.09 (s, 2H), 2.98 (s, 2H), 2.09 (s, 3H). MS (EI) for C29H27FN6O2: 511.7 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2-(phenyloxy)ethyl]- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 8.65 (t, 1H), 8.2 (d, 2H), 8.50 (s br, 1H), 8.9 (d, 2H), 7.88-7.90 (m, 1H), 7.76 (d, 2H), 7.38-7.45 (m, 3H), 7.27-7.30 (m, 2H), 6.91-6.98 (m, 3H), 4.11-4.14 (m, 2H), 3.63-3.78 (m, 2H), 2.09 (s, 3H). MS (EI) for C27H25N5O3: 468.4 (MH+). methyl l-{[3-({4-[4-(acetylamino)phenyl]pyrimidin-2- yl}amino)phenyl]carbonyl}-piperidine-4-carboxylate: 1H-NMR (400MHz, d6-
DMSO):10.23 (s, 1H), 9.82 (s, ,1H), 8.53 (d, 1H), 8.14 (d, 2H), 7.97 (t, 1H), 7.86-7.88 (m, 1H), 7.75 (d, 2H), 7.36-7.70 (m, 2H), 6.94-6.96 (m, 1H), 3.61 (s, 3H), 3.30-3.36 (m, 2H), 2.77-3.29 (m, 2H), 2.65-2.70 (m, 1H), 2.09 (s, 3H), 1.99-2.19 (m, 2H), 1.79-1.88 (m, 2H). MS (EI) for C26H27N5O4: 474.6 (MH+). N-[4-(2-{[3-({4-[3-(methyloxy)phenyl]piperazin-1-yl}carbonyl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, dδ-DMSO): 10.21 (s, 1H), 9.83 (s, 1H), 8.53 (d, 1H), 8.14 (d, 2H), 8.04 (m, 1H), 7.86-7.89 (m, 1H), 7.75 (d, 2H), 7.39-7.43 (m, 2H), 7.12 (t, 1H), 7.00-7.03 (m, 1H), 6.53 (dd, 1H), 6.47 (t, 1H), 6.40 (dd, 1H), 3.78- 3.80 (m, 2H), 3.71 (s, 3H), 3.20-3.24 (m, 2H), 3.12-3.19(m, 2H), 2.09 (s, 3H). MS (EI) for C30H30N6O3: 523.5 (MH+).
3-({4-[4-(acetyIamino)phenyl]pyrimidin-2-yl}amino)-N-{2-[2- (methyloxy)phenyl]-ethyl}benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.78 (s, 1H), 8.52-8.53 (m, 1H), 8.45 (s, 2H), 8.19 (d, 2H), 7.88 (s, 1H), 7.75 (d, 2H), 7.38-7.39(m, 3H), 7.17-7.23 (m, 2H), 6.97 (d, 1H), 6.87 (t, 1H), 3.78 (s, 3H), 3.45-3.47 (m, 2H), 2.84-2.87 (m, 2H), 2.09 (s, 3H). MS (EI) for C28H27N5O3: 482.7 (MH+).
N-[4-(2-{[3-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)phenyl]amino}pyrimidin-4- yl)-phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.82 (s, 1H), 8.53 (d, 1H), 8.16 (s, 1H), 8.12-8.14 (m, 2H), 7.94-7.97 (m, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.39-7.45 (m, 3H), 7.27-7.32 (m, 1H), 7.26 (d, 2H), 7.19-7.21 (m, 1H), 7.89 (s, 2H), 4.82 (s, 2H), 2.09 (s, 3H). MS (EI) for C27H23N5O2: 450.7 (MH+).
3-({4-[4-(acetyIamino)phenyl]pyrimidin-2-yl}amino)-N-(biphenyl-4-ylmethyl)- benzaroide: 1H-NMR (400MHz, (I6-DMSO): 10.23 (s, 1H), 9.80 (s, 1H), 9.04 (s br, 1H), 8.53 (d, 2H), 8.19 (d, 2H), 7.89 (d, 1H), 7.76 (d, 2H), 7.64 (m, 4H), 7.35-7.50 (m, 8H), 4.55 (s, 2H), 2.08 (s, 3H). MS (EI) for C32H27N5O2: 514.8 (MH+).
N-(4-{2-[(3-{[4-(phenylcarbonyl)piperazin-1- yl]carbonyl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6- DMSO): 10.25 (s, 1H), 9.83 (s, 1H), 8.53 (d, 1H), 8.14 (d, 2H), 8.04 (s, 1H), 7.86 (d, 1H), 7.76 (d, 2H), 7.44 (m, 5H), 7.39 (d, 2H), 7.00 (d, 1H), 3.56 (m, 8H) 2.09 (s, 3H). MS (EI) for C30H28N6O3 : 521.6 (MH+).
N-[4-(2-{[3-({4-[4-(methyloxy)phenyl]piperazin-1-yl}carbonyl)phenyI]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.83 (s, 1H), 8.53 (d, 1H), 8.13 (m, 2H), 8.05 (m, 1H), 7.86 (m, 1H), 7.75 (d, 2H), 7.37-7.43 (m, 2H), 7.01 (m, 1H), 6.90 (m, 2H), 6.82 (m, 2H), 3.77 (m, 2H), 3.68 (s, 3H), 3.53 (m, 2H), 3.08 (m, 2H), 2.97 (m, 2H), 2.09 (s, 3H). MS (EI) for C30H30N6O3: 523.7 (MH+).
3-({4-[4-(acetylamino)phenyI]pyrimidin-2-yl}amino)-N-methyl-N-{[2- (methyloxy)-phenyl]methyl}benzamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.80 (s, 1H), 8.37 (m, 1H), 8.14 (d, 2H), 7.76 (m, 3H), 7.39 (d, 2H), 7.25-7.32 (m, 2H), 7.14-7.18 (m, 1H), 7.04 (m, 1H), 6.95 (d, 2H), 4.57 (d, 2H), 3.76 (d, 3H), 2.88 (s, 3H), 2.09 (s, 3H). MS (EI) for C28H27N5O3: 482.7 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2- nuorophenyl)methyl]-N-methylbenzamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.08 (s, 1H), 8.52 (m, 1H), 8.14 (d, 2H), 8.01 (m, 1H), 7.89 (m, 1H), 7.75 (d, 2H),
7.38 (m, 4H), 7.21 (m, 2H), 7.01 (m, 1H), 4.67 (d, 2H), 2.91 (s, 3H), 2.09 (s, 3H). MS (EI) for C27H24FN5O2: 470.6 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yI}amino)-N-(2-pyridin-2-ylethyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.78 (s, 1H), 8.51-8.54 (m, 3H), 8.46 (s, 1H), 8.18 (d, 2H), 7.86-7.88 (m, 1H), 7.76 (d, 2H), 7.69-7.73 (m, 1H), 7.37- 7.40 (m, 3H), 7.31 (m, 1H), 7.21-7.24 (m, 1H), 3.61-3.66 (m, 2H), 3.02 (m, 2H), 2.09 (s, 3H). MS (EI) for C26H24N6O2: 453.6 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(pyridin-2-ylmethyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.81 (s, 1H), 9.06 (m, 1H),
8.52 (m, 2H), 8.19 (d, 2H), 7.91 (m, 1H), 7.73-7.79 (m, 3H), 7.51 (d, 1H), 7.40 (m, 2H), 7.30 (d, 1H), 7.25-7.27 (m, 1H), 4.59 (d, 2H), 2.09 (s, 3H). MS (EI) for C25H22N6O2: 439.8 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(pyridin-3-ylmethyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.78 (s, 1H), 8.52 (d, 1H), 8.45 (s br, 1H), 8.25 (d, 1H), 7.18 (d, 3H), 7.82-7.85 (m, 1H), 7.76 (d, 3H), 7.35-7.41 (m, 4H), 4.25 (m, 2H), 2.09 (s, 3H). MS (EI) for C25H22N6O2: 438.6 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(pyridin-4-ylmethyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.80 (s, 1H), 9.08 (t, 1H), 8.50-8.54 (m, 4H), 8.18 (d, 2H), 7.92 (d, 1H), 7.74 (d, 2H), 7.49 (d, 1H), 7.42 (t, 1H), 7.40 (d, 1H), 7.31 (d, 2H), 4.51 (d, 2H), 2.09 (s, 3H). MS (EI) for C25H22N6O2: 438.5 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yI}amino)-N-methyl-N- (phenylmethyl)-benzamide: 1H-NMR (400MHz, d6-DMS0): 10.23 (s, 1H), 9.81 (s, 1H),
8.53 (s br, 1H), 8.14 (d, 2H), 7.46 (d, 2H), 7.23-7.46 (m, 8H), 7.21 (s br, 1H), 7.02 (s br, 1H), 4.56 (d, 2H), 2.95 (s, 3H), 2.09 (s, 3H). MS (EI) for C27H25N5O2: 452.7 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-cyclopentylbenzamide:
1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.75 (s, 1H), 8.52 (d, 1H), 8.45 (s br, 1H), 8.25 (d, 1H), 8.17 (d, 2H), 7.84 (d, 1H) 7.75 (d, 2H), 7.35-7.42 (m, 3H), 4.22-4.27 (m,
1H), 2.09 (s, 3H), 1.88-1.93 (m, 2H), 1.70 (m, 2H), 1.49-1.59 (m, 4H). MS (EI) for
C24H25N5O2: 416.8 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2- chlorophenyl)methyl]-benzamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.80 (s, 1H), 9.00 (t, 1H), 8.53 (d, 1H), 8.50 (s br, 1H), 8.18 (d, 2H), 7.93 (d, 1H), 7.63 (d, 2H),
7.52 (d, 1H), 7.28-7.48 (m, 6H), 4.56 (d, 2H), 2.09 (s, 3H). MS (EI) for C26H22ClN5O2:
473.0 (MH+). 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(4- chlorophenyl)methyl]-benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 9.02 (t, 1H), 8.52 (d, 1H), 8.50 (s br, 1H), 8.18 (d, 2H), 7.90 (d, 1H), 7.74 (d, 2H), 7.46 (d, 1H), 7.41 (m, 2H), 7.38 (s, 2H), 7.36 (m, 2H), 4.48 (d, 2H), 2.09 (s, 3H). MS (EI) for C26H22 ClN5O2: 473.1 (MH+).
3-({4-[4-(acetyIamino)phenyI]pyrimidin-2-yl}amino)-N-(furan-2-ylmethyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.78 (s, 1H), 8.91 (t, 1H), 8.52 (d, 1H), 8.48 (s br, 1H), 8.17 (d, 2H), 7.88 (d, 1H), 7.76 (d, 2H), 7.58 (m, 1H), 7.44 (d, 1H), 7.37-7.41 (m, 2H), 6.41 (m, 1H), 6.28 (dd, 1H), 4.48 (d, 2H), 2.09 (s, 3H). MS (EI) for C24H21N5O3: 428.6 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[4-
(methyloxy)phenyl]-methyl}benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.77 (s, 1H), 8.92 (t, 1H), 8.52 (d, 1H), 8.49 (s br, 1H), 8.19 (d, 2H), 7.88 (d, 1H), 7.76 (d, 2H), 7.45 (d, 1H), 7.37-7.41 (m, 2H), 7.27 (d, 2H), 6.89 (d, 2H), 4.42 (d, 2H), 3.72 (s, 3H), 2.08 (s, 3H). MS (EI) for C27H25N5O3: 468.4 (MH+).
N-[4-(2-{[3-({4-[2-(methyloxy)phenyl]piperazin-1-yl}carbonyl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.82 (s, 1H), 8.53 (d, 1H), 8.14 (d, 2H), 8.06 (s, 1H) 7.86 (d, 1H), 7.76 (d, 2H), 7.40 (m, 2H), 7.01 (d, 1H), 6.59 (m, 2H), 6.88 (s, 2H), 3.78 (s, 3H), 3.55 (m, 2H), 3.03 (m, 2H), 2.94 (s, 2H), 2.79 (s, 2H), 2.09 (s, 3H). MS (EI) for C30H30N6O3: 523.5 (MH+).
3-({4-[4-(acetyIamino)phenyl]pyrimidin-2-yl}amino)-N-[3-(methyloxy)propyl]- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.76 (s, 1H), 8.52 (d, 1H), 8.46 (s br, 1H), 8.40 (t, 1H), 8.18 (d, 2H), 7.85-7.88 (m, 1H), 7.75 (d, 2H), 7.38-7.40 (m, 3H), 3.40 (m, 2H), 3.30 (m, 2H), 3.24 (s, 3H), 2.09 (s, 3H), 1.74-1.80 (m, 2H). MS (EI) for C23H25N5O3: 420.5 (MH+).
N-(4-{2-[(3-{[(2R,6S)-2,6-dimethylmorpholin-4-yI]carbonyl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.81 (s, 1H), 8.53 (d, 1H), 8.13 (d, 2H), 7.99 (m, 1H), 7.86 (d, 1H), 7.76 (d, 2H), 7.37-7.41 (m, 2H), 6.98 (d, 1H), 2.94 (s, 2H), 2.79 (s, 2H), 2.09 (s, 3H), 1.96 (s, 1H), 1.16 (m, 3H), 0.99 (m, 3H). MS (EI) for C25H27N5O3: 445.5 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(6-chloropyridin-3- yl)methyl]benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.79 (s, 1H), 9.06 (t, 1H), 8.52 (d, 1H), 8.49 (s, 1H), 8.40 (d, 1H), 8.18 (d, 2H), 7.91 (m, 2H), 7.81 (dd, 1H), 7.74 (d, 2H), 7.49 (d, 1H), 7.41-7.46 (m, 2H), 7.39 (d, 1H), 4.50 (d, 2H), 2.09 (s, 3H). MS (EI) for C25H2IClN6O2: 474.1 (MH+).
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-butylbenzamide: 1H- NMR (400MHz, d6-DMSO): 10.24 (s, 1H), 9.80 (s, 1H), 8.53 (d, 1H), 8.13 (d, 2H), 8.02 (s br, 1H), 7.78 (m, 1H), 7.75 (d, 2H), 7.39 (d, 1H), 7.35 (d, 1H), 6.91 (d, 2H), 3.26 (m, 2H), 2.09 (s, 3H), 1.62 (m, 2H), 1.32 (m, 2H), 1.08 (m, 3H). MS (EI) for C23H25N5O2: 404.5 (MH+).
N-(4-{2-[(3-{[4-(2-chlorophenyl)piperazin-1-yl]carbonyl}phenyl)amino]- pyrimidin-4-yI}phenyl)acetamide: 1H-NMR (400MHz, (I6-DMSO): 10.22 (s, 1H), 9.83 (s, 1H), 8.53 (d, 1H), 8.14 (d, 2H), 7.90 (s br, 1H), 7.85 (d, 1H), 7.76 (d 2H), 7.38-7.43 (m, 3H), 7.28 (m, 1H), 7.13 (dd, 1H), 7.07 (dd, 1H), 7.03 (m, 1H), 3.81 (m, 4H), 3.58 (m, 4H), 2.09 (s, 3H). MS (EI) for C29H27ClN6O2: 528.1 (MH+).
3-({4-[4-(acetylamino)phenyl)pyrimidin-2-yl}amino)-N-ethyl-N-[2- (methyloxy)-ethyl]benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.80 (s, 1H), 8.53 (d, 1H), 8.13 (d, 2H), 7.99 (m, 2H), 7.82 (m, 1H), 7.76 (d, 2H), 7.39 (d, 2H), 7.36 (d, 2H), 6.92 (d, 1H), 3.57 (m, 2H), 3.12 (m, 2H), 2.94 (s, 3H), 2.09 (s, 3H), 1.10 (m, 3H). MS (EI) for C24H27N5O3: 434.4 (MH+).
N-{4-[2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyljacetamide: 1H-NMR (400MHz, d6-DMS0): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.35 (d, 4H), 7.27 (d, 2H), 6.92 (d, 2H), 3.54 (s, 2H), 3.9 (m, 4H), 2.53 (m, 4H), 2.09 (s, 3H). MS (EI) for C29H30N6O: 479.7 (MH+).
N-(4-{2-[(4-{4-[(5-methyl-3-phenylisoxazol-4-yl)methyl]piperazin-1- yl}phenyl)-amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, dό-DMSO): 10.20 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.93-7.96 (m, 2H), 7.74 (d, 2H), 7.66 (d, 2H), 7.50-7.53 (m, 3H), 7.26 (d, 1H), 6.93 (d, 2H), 3.43 (s, 2H), 3.09 (m, 4H), 2.56 (m, 4H), 2.48 (s, 3H), 2.09 (s, 3H). MS (EI) for C33H33N7O2: 560.4 (MH+).
N-(4-{2-[(4-{4-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]piperazin-1-yI}- phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.56 (s, 1H), 7.53 (d, 4H), 7.40-7.45 (m, 1H), 7.26 (d, 1H), 6.92 (d, 2H), 3.43 (s, 2H), 3.09 (m, 4H), 2.56 (m, 4H), 2.31 (s, 3H), 2.09 (s, 3H). MS (EI) for C33H34N8O: 559.7 (MH+). N-(4-{2-[(4-{4-[(2-phenyl-1,3-thiazol-4-yI)methyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO):
10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.94 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.57 (s, 1H), 7.48-7.53 (m, 3H), 7.26 (d, 1H), 6.93 (d, 1H), 3.73 (s, 2H), 3.11 (m, 4H), 2.65 (m, 4H), 2.09 (s, 3H). MS (EI) for C32H3iN7OS: 562.5 (MH+).
N-[4-(2-{[4-(4-{[6-(phenyloxy)pyridin-3-yl]methyI}piperazin-1- yl)phenyl]amino}-pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, ds-DMSO): 10.23 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 8.07 (d, 1H), 7.81 (dd, 1H), 7.74 (d, 2H), 7.65 (d, 2H), 7.43 (t, 2H), 7.26 (d, 1H), 7.19-7.23 (m, 1H), 7.14 (d, 2H), 7.01 (d, 1H), 6.92 (d, 2H), 3.21 (s, 2H), 3.08 (m, 4H), 2.48 (m, 4H), 2.09 (s, 3H). MS (EI) for C34H33N7O2: 572.4 (MH+).
N-{4-[2-({4-[4-(cyclohexyImethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 3.06 (m, 4H), 2.47 (m, 4H), 2.13 (d, 2H), 2.09 (s, 3H), 1.76 (d, 2H), 1.65 (m, 3H), 1.49-1.54 (m, 1H), 1.12-1.17 (m, 3H), 080-0.89 (m, 2H). MS (EI) for C29H36N6O: 485.8 (MH+).
N-(4-{2-[(4-{4-[(lS,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethyl]piperazin-1- yl}phenyl)-amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO):
10.21 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 6.14-6.16 (m, 1H), 5.95-5.97 (m, 1H), 3.07 (m, 4H), 2.79 (d, 2H), 2.45
(m, 4H), 2.32-2.39 (m, 2H), 2.09 (s, 3H), 1.95-1.99 (m, 1H), 1.81-1.87 (m, 1H), 1.31 (m,
1H), 1.23 (m, 1H), 0.51 (m, 1H). MS (EI) for C30H34N6O: 495.7 (MH+)
N-[4-(2-{[4-(4-pentylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide: 1H-NMR (400MHz, (I6-DMSO): 10.21 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 3.07 (m, 4H),
2.55 (m, 4H), 2.307 (t, 2H), 2.09 (s, 3H), 1.43-1.49 (m, 2H), 1.22-1.34 (m, 4H), 0.88 (t,
3H). MS (EI) for C27H34N6O: 459.7 (MH+).
N-(4-{2-[(4-{4-[(2-chlorophenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d^ DMSO):10.21 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.66 (d, 2H),
7.54 (dd, 1H), 7.45 (dd, 1H), 7.29-7.39 (m, 2H), 7.26 (d, 1H), 6.93 (d, 2H), 3.64 (s, 2H),
3.10 (m, 4H), 2.60 (m, 4H), 2.09 (s, 3H). MS (EI) for C29H29ClN6O: 514.1 (MH+). N- [4-(2-{ [4-(4- { [3,5-bis(methy loxy)pheny 1] methyl} piperazin-1 - yl)phenyl]amino}-pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.93 (d, 2H), 6.51 (d, 2H), 6.39 (t, 1H), 3.75 (s, 6H), 3.46 (s, 2H), 3.09 (m, 4H), 2.61 (m, 4H), 2.09 (s. 3H). MS (EI) for C3]H34N6O3: 539.8 (MH+).
N-(4-{2-[(4-{4-[(4-fluorophenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.36- 7.39 (m, 2H), 7.26 (d, 1H), 7.16 (t, 2H), 6.92 (d, 2H), 3.51 (S, 2H), 3.08 (m, 4H), 2.28 (m, 4H), 2.09 (s, 3H). MS (EI) for C29H29FN6O: 497.8 (MH+).
N-(4-{2-[(4-{4-[(l-methyl-1H-pyrrol-2-yl)methyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyI)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 6.68 (t, 1H), 5.88-5.91 (m, 2H), 3.61 (s, 2H), 3.4 (s, 3H), 3.06 (m, 4H), 2.58 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H3,N7O: 482.8 (MH+).
N-[4-(2-{[4-(4-{[5-(3-chlorophenyl)furan-2-yl]methyl}piperazin-1-yl)phenyl]- amino}pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.72-7.76 (m, 3H), 7.63-7.66 (m, 3H), 7.45 (t, 1H), 7.33 (d, 1H), 7.26 (d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 6.48 (d, 1H), 3.64 (s, 2H), 3.10 (m, 4H), 2.60 (m, 4H), 20.9 (s, 3H). MS (EI) for C33H3iClN6O: 580.3 (MH+).
N-[4-(2-{[4-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazin-1- yl)phenyl]-amino}pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.37 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.84-7.88 (m, 1H), 7.74 (d, 2H), 7.66 (d, 2H), 7.54-7.72 (m, 2H), 7.26 (d, 1H), 6.93 (d, 2H), 3.66 (s, 2H), 3.10 (m, 4H), 2.56 (m, 4H), 2.09 (s, 3H). MS (EI) for C30H28F4N6O: 565.3 (MH+).
N-[4-(2-{[4-(4-{[4-(1H-imidazol-1-yl)phenyl]methyl}piperazin-1- yl)phenyl]amino}-pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6- DMSO):10.21 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.25 (t, 1H), 7.11 (d, 2H), 7.74 (d, 3H), 7.61-7.67 (m, 4H), 7.48 (d, 2H), 7.26 (d, 1H), 7.11 (t, 1H), 6.93 (d, 2H), 3.58 (s, 2H), 3.10 (m, 4H), 2.55 (m, 4H), 20.9 (s, 3H). MS (EI) for C32H32N8O: 545.8 (MH+).
N-[4-(2-{[4-(4-{[2,5-bis(trifluoromethyl)phenyl]methyl}piperazin-1-yI)phenyl]- amino}pyriniidin-4-yl)phenyl|acetamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s, 1H), 9.37 (s, 1H), 8.43 (d, 1H), 8.17 (s, 1H), 8.10 (d, 2H), 8.00 (d, 1H), 7.89 (d, 1H), 7.74 (d, 2H), 7.67 (d, 2H), 7.26 (d, 1H), 6.94 (d, 2H), 3.79 (s, 2H), 3.12 (m, 4H), 2.60 (m, 4H), 2.09 (s, 3H). MS (EI) for C3iH28F6N6O: 615.7 (MH+).
N-(4-{2-[(4-{4-[(2,6-dimethylphenyl)methyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yI}phenyl)acetamide: 1H-NMR (400MHz, (I6-DMSO): 10.20 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.24 (d, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 7.00-7.08 (m, 3H), 6.90 (d, 2H), 3.50 (s, 2H), 3.02 (m, 4H), 2.54 (m, 4H), 2.37 (s, 6H), 2.09 (s, 3H). MS (EI) for C3 IH34N6O: 507.7 (MH+).
N-(4-{2-[(4-{4-[(2,3-dimethylphenyl)methyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, (I6-DMSO): 10.21 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d 2H), 7.65 (d, 2H), 7.26 (d, 1H), 7.01-7.09 (m, 3H), 6.91 (d, 2H), 3.45 (s, 2H), 3.05 (m, 4H), 2.53 (m, 4H), 2.24 (d, 6H), 2.09 (s, 3H). MS (EI) for C3IH34N6O: 507.8 (MH+).
N-[4-(2-{[4-(4-{[2,4-bis(ethyloxy)phenyl]methyl}piperazin-1- yl)pheny]|amino}-pyrimidin-4-vl)phenyl]acetamidc: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.35 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 7.19 (d, 1H), 6.91 (d, 2H), 6.47-6.51 (m, 2H), 3.97-4.04 (m, 4H), 3.46 (s, 2H), 3.06 (m, 4H), 2.52 (m, 4H), 2.09 (s, 3H), 1.30-1.35 (m, 6H). MS (EI) for C33H38N6O3: 567.8 (MH+). N-[4-(2-{[4-(4-{[3-(ethyloxy)phenyl]methyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.36 (s, 1H), 8.45 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.24 (t, 1H), 7.11-7.19 (m, 3H), 7.02-7.09 (m, 3H), 6.91 (d, 2H), 3.96-4.00 (m, 2H), 3.40 (s, 2H), 3.07 (m, 4H), 2.59 (m, 4H), 2.09 (s, 3H), 1.32-1.38 (m, 3H). MS (EI) for C3,H34N6O2: 523.8 (MH+). N-{4-[2-({4-[4-(3-methylbutanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H-NMR (400MHz, d6-DMSO): 10.23 (s, 1H), 9.04 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.27 (d, 1H), 6.96 (d, 2H) 3.67 (m, 4H), 3.06 (m, 2H), 3.02 (m, 2H), 2.24 (d, 2H), 2.09 (s, 3H), 1.97-2.09 (m, 1H), 0.92 (d, 6H). MS (EI) for C27H32N6O2: 473.8 (MH+). N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperaziu-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.27 (d, 1H), 6.95 (d, 2H), 3.59 (m, 2H), 3.46 (m, 2H), 3.39 (t, 1H), 3.02 (m, 4H), 2.11-2.23 (m, 4H), 2.09 (s, 3H), 1.89-1.92 (m, 1H), 1.72-1.78 (m, 1H). MS (EI) for C27H30N6O2: 470.7 (MH+).
N-{4-[2-({4-[4-(cyclopentylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]-phenyI}acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.27 (d, 1H), 6.96 (d, 2H), 3.63 (m, 4H), 3.04 (m, 4H), 2.98 (m, 1H), 2.09 (s, 3H), 1.74-2.09 (m, 2H), 1.51-1.72 (m, 6H). MS (EI) for C28H32N6O2: 485.5 (MH+).
N-[4-(2-{[4-(4-{[2-(methyloxy)phenyl]carbonyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.68 (d, 2H), 7.42 (m, 1H), 7.27 (d, 1H), 7.22 (dd, 1H), 7.10 (d, 1H), 7.02 (m, 1H), 6.96 (d, 2H), 3.81 (s, 3H), 3.77 (m, 2H), 3.27 (m, 2H), 3.12 (m, 2H), 3.01 (m, 2H), 2.09 (s, 3H). MS (EI) for C30H30N6O3: 523.7 (MH+).
N-(4-{2-[(4-{4-[(2-methylphenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.30- 7.36 (m, 2H), 7.28 (d, 2H), 7.19-7.24 (m, 1H), 6.96 (d, 2H), 3.82 (m, 2H), 3.28 (m, 2H), 3.16 (m, 2H), 3.00 (m, 2H), 2.25 (s, 3H), 2.09 (s, 3H). MS (EI) for C30H30N6O2: 507.8 (MH+).
N-[4-(2-{[3-(4-{[2-(methyloxy)phenyI]methyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyI]acetamide: 1H NMR (400 MHz, d6-DMSO): 11.21 (s, 1H), 9.46 (s, 1H), 8.49 (d, 1H), 8.12 (d, 2H), 7.73 (d, 2H), 7.63 (s, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 7.21 (m, 2H), 7.10 (t, 1H), 6.98 (m, 2H), 6.55 (d, 1H), 3.80 (s, 3H), 3.54 (s, 2H), 3.16 (m, 4H), 2.57 (m, 4H), 2.09 (s, 3H). MS (EI) for C30H32N6O2: 509.6 (MH+).
N-{4-[2-({4-[(2R,6S)-2,6-dimethylmorphoIin-4-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.44 (s, 1H), 10.07 (s,
1H), 8.74 (s, 1H), 8.57 (d, 1H), 8.21 (s, 2H), 7.90 (m, 4H), 7.73 (s, 2H), 7.48 (d, 1H), 4.49 (m, 1H), 4.24 (m, 2H), 4.02 (m, 1H), 3.57 (m, 3H), 3.29 (m, 2H), 1.99 (m, 4H), 1.18 (m, 7H). MS (EI) for C27H32N6O2: 473.5 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-5-oxo-D- prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.33 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.14 (d, 2H), 7.93 (s, 1H), 7.79 (d, 2H), 7.67 (d, 2H), 7.28 (d, 1H), 6.93 (d, 2H), 4.23 (m, 1H), 3.75 (m, 4H), 3.05 (m, 4H), 2.35 (m, 1H), 2.21 (m, 2H), 2.03 (m, 1H). MS (EI) for C25H26N6O3: 459.5 (MH+).
N1-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- aspartamide: 1H NMR (400 MHz, d6-DMSO): 11.71 (s, 1H), 10.09 (s, 1H), 8.94 (s, 3H), 8.58 (d, 1H), 8.23 (d, 2H), 7.91 (m, 4H), 7.73 (s br, 2H), 7.49 (d, 1H), 4.52 (m, 4H), 4.05 (m, 5H), 3.33 (d, 1H), 3.29 (d, 1H). MS (EI) for C24H27N7O3: 462.5 (MH+).
N1-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- glutamamide: 1H NMR (400 MHz, d6-DMSO): 9.39 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.83 (d, 2H), 7.67 (d, 2H), 7.35 (s, 1H), 7.29 (d, 1H), 6.93 (d, 2H), 6.77 (s, 1H), 3.75 (m, 4H), 3.37 (t, 1H), 3.05 (m, 4H), 1.88 (m, 2H), 1.70 (m, 1H). MS (EI) for C25H29N7O3: 476.5 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyriniidin-4-yl}phenyl)-D- threoninamide: 1H NMR (400 MHz, d6-DMSO): 11.26 (s, 1H), 9.89 (s, 1H), 8.54 (d, 1H), 8.31 (s, 2H), 8.19 (d, 2H), 7.86 (d, 3H), 7.44 (m, 3H), 4.1 1 (m, 2H), 3.96 (m, 4H), 3.39 (m, 4H), 1.23 (d, 3H) . MS (EI) for C24H28N6O3: 449.5 (MH+).
N-(4-{2-[(3-chloro-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.43 (s, 1H), 9.99 (s, 1H), 8.55 (d, 1H),
8.20 (d, 2H), 8.03 (s, 1H), 7.89 (2H), 7.71 (dd, 1H), 7.46 (d, 2H), 7.20 (d, 1H), 4.49 (m, 1H), 3.76 (m, 4H), 3.28 (m, 2H), 2.96 (m, 4H), 1.97 (m, 4H). MS (EI) for C25H27ClN6O2: 479.9 (MH+).
N-(4-{2-[(3-chloro-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H NMR (400 MHz, d6-DMSO): 1 1.55 (s, 1H), 10.15 (s, 1H), 8.56 (d, 1H),
8.21 (d, 2H), 8.01 (s, 1H), 7.89 (d, 2H), 7.71 (dd, 1H), 7.49 (d, 2H), 7.23 (d, 1H), 4.51 (m, 1H), 3.76 (m, 4H), 3.29 (m, 2H), 2.97 (m, 4H), 1.97 (m, 4H). MS (EI) for C25H27ClN6O2: 479.9 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- leucinamide: 1H NMR (400 MHz, d6-DMSO): 11.41 (s, 1H), 10.05 (s, 1H), 8.56 (d, 1H), 8.60 (m, 3H), 8.25 (d, 2H), 7.96 (m, 3H), 7.69 (m, 2H), 7.47 (d, 1H),4.14 (m, 1H), 4.04 (m, 4H), 3.57 (m, 4H), 1.71 (m, 2H), 1.19 (m, 1H), 1.00 (s, 6H). MS (EI) for C26H32N6O2: 461.5 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- isoleucinamide: 1H NMR (400 MHz, d6-DMSO): 11.41 (s, 1H), 10.10 (s, 1H), 8.56 (d, 1H), 8.47 (m, 2H), 8.20 (d, 2H), 7.92 (m, 3H), 7.73 (m, 2H), 7.47 (d, 1H), 4.12 (m, 4H), 3.57 (m, 4H), 1.65 (m, 2H), 1.18 (m, 2H), 1.00 (d, 3H), 0.89 (t, 3H). MS (EI) for C26H32N6O2: 461.5 (MH+).
(2R)-2-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)aiiiino]pyrimidin-4- yl}phenyl)-butanamide: 1H NMR (400 MHz, d6-DMSO): 11.57 (s, 1H), 10.20 (s, 1H), 8.56 (m, 3H), 8.24 (m, 2H), 7.97 (m, 4H), 7.82 (s, 1H), 7.54 (s, 1H), 4.05 (m, 5H), 1.96 (m, 4H), 1.10 (m, 5H). MS (EI) for C24H28N6O2: 433.5 (MH+).
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)thiophene-2- carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.5 (s, 1H), 9.40 (br s, 1H), 8.55 (d, 1H), 8.23 (d, 2H), 8.09 (dd, 1H), 7.96-7.91 (m, 5H), 7.53 (m, 1H), 7.45 (d, 1H), 7.32-7.25 (m, 3H), 6.74 (br s, 1H). MS (EI): 388.0 (MH+).
N-(3-{[4-(4-aminophenyl)pyrimidin-2-yl]amino}phenyl)-2,6- dichlorobenzamide: 1H-NMR (400MHz, d6-DMSO): 10.7 (s, 1H), 9.67 (s, 1H), 8.37- 8.35 (m, 2H), 8.01 (d, 2H), 7.61-7.58 (m, 2H), 7.51-7.49 (m, 1H), 7.44 (dt, 1H), 7.31-7.22 (m, 3H), 6.69 (d, 2H), 5.95 (br, 2H)); MS (EI): 450.0 (MH+).
4-{[2-chloro-4-(methyloxy)phenyl]oxy}-N-(4-morpholin-4-ylphenyl)pyrimidin- 2-amine: 1H-NMR (400MHz, d6-DMSO): 9.37 (s, 1H), 8.31 (d, 1H), 7.33-7.23 (m, 4H), 7.02 (dd, 1H), 7.00 (br d, 2H), 6.41 (d, 1H), 3.83 (s, 3H), 3.73-3.71 (m, 4H), 2.98-2.96 (m, 4H). MS (EI): 412.8 (MH+). N-[4-({2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}oxy)phenyl]acetamide: 1H-NMR (400MHz, d6-DMSO): 10.2 (s, 1H), 9.92 (br s, 1H),
8.33 (d, 1H), 7.66 (d, 2H), 7.42 (br s, 2H), 7.17 (d, 2H), 7.10 (br s, 2H), 6.50 (d, 1H), 3.86 (br s, 4H), 3.24 (br s, 4H), 2.08 (s, 3H); MS (EI): 406.1 (MH+).
N-[4-(2-{[4-(4-D-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-3- (methyloxy)propanamide: 1H-NMR (400MHz, d6-DMSO): 10.3 (s, 1H), 9.61 (br s, 1H), 8.46 (d, 1H), 8.16-8.12 (m, 4H), 7.78 (d, 2H), 7.72 (d, 2H), 7.34 (d, 1H), 7.12 (br s, 2H), 4.47.4.44 (m, 1H), 3.80 (br s, 4H), 3.64 (t, 2H), 3.64 (s, 3H), 3.07 (br s, 4H), 2.60 (t, 2H),
1.34 (d, 3H); MS (EI): 504.2 (MH+).
3-(methyloxy)-N-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyl]amino}pyriinidin- 4-yl)phenyl]propanamide: 1H-NMR (400MHz, d6-DMSO): 10.3 (s, 1H), 9.51 (s, 1H), 8.54 (m, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.71 (d, 2H), 7.31 (d, 1H), 7.04 (br d, 2H), 4.68 (m, 1H), 4.07 (br s, 4H), 3.64 (t, 2H), 3.25 (s, 3H), 3.17 (br s, 4H), 2.60 (t, 2H), 2.43-2.39 (m, 2H), 1.94-1.81 (m, 4H); MS (EI): 530.2 (MH+).
N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yI]phenyl}amino)pyriinidin-4- yl]phenyl}cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.5 (s, 1H), 9.60 (br s, 1H), 8.46 (d, 1H), 8.12 (d, 2H), 7.78-7.76 (m, 4H), 7.34 (m, 1H), 7.13 (br s, 2H), 3.70 (m, 1H), 3.54 (br s, 4H), 3.41 (m, 1H), 3.16 (br s, 4H), 2.23-2.08 (m, 3H), 1.95- 1.74 (m, 3H), 0.84-0.83 (m, 4H); MS (EI): 497.2 (MH+).
N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.5 (s, 1H), 9.69 (br s, 1H), 8.47 (d, 1H), 8.13 (d, 2H), 7.77 (d, 4H), 7.36 (d, 2H), 7.23 (br s, 1H), 3.76 (br s, 4H), 3.25 (br s, 4H), 2.94 (septet, 1H), 1.84 (p, 1H), 1.03 (d, 6H), 0.84-0.83 (m, 4H). MS (EI): 485.1 (MH+).
2,6-dichloro-N-{3-[(4-{4-[(cyclopropylcarbonyl)amino]phenyl}pyrimidin-2- yl)-amino]phenyl}benzamide: 1H-NMR (400MHz, d6-DMSO): 10.7 (s, 1H), 10.5 (s, 1H), 9.74 (s, 1H), 8.50 (d, 1H), 8.40 (s, 1H), 8.21 (d, 2H), 7.76 (d, 2H), 7.61-7.59 (m, 2H), 7.53-7.49 (m, 1H), 7.47-7.45 (m, 1H), 7.39 (d, 1H), 7.31-7.22 (m, 2H), 1.83 (p, 1H), 0.83- 0.81 (m, 4H); MS (EI): 518.1 (MH+).
2,6-dichloro-N-(3-{[4-(1H-indol-5-yl)pyrimidin-2- yl]amino}phenyl)benzamide: 1H-NMR (400MHz, d6-DMSO): 11.3 (s, 1H), 10.7 (s, 1H), 9.56 (s, 1H), 8.45 (s, 1H), 8.39 (d, 1H), 8.31 (s, 1H), 7.96 (dd, 1H), 7.54-7.52 (m, 2H), 7.46-7.41 (m, 3H), 7.37-7.34 (m, 2H), 7.21 (d, 2H), 6.48-6.48 (m, 1H). MS (EI): 474.0 (MH+).
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)-2-morphoIin-4- ylacetamide: 1H-NMR (400MHz, d6-DMSO): 11.0 (s, 1H), 10.4 (br, 2H), 9.89 (s, 1H), 8.56 (d, 1H), 8.23 (d, 2H), 7.82-7.79 (m, 3H), 7.62 (br, 1H), 7.44 (d, 1H), 7.34 (br, 1H), 6.8 (br, 1H), 4.24 (s, 2H), 3.96-3.84 (m, 8H); MS (EI): 405.3 (MH+).
N-(4-phenylpyrimidin-2-yl)benzene-1,3-diamine: 1H-NMR (400MHz, d6- DMSO): 9.37 (s, 1H), 8.51 (d, 1H), 8.19-8.16 (m, 2H), 7.57-7.53 (m, 3H), 7.37-7.36 (d, 1H), 7.10 (t, 1H), 7.00-6.91 (m, 2H), 6.22-6.20 (m, 1H), 5.00 (s, 2H). MS (EI): 263.3 (MH+).
N-[3-({4-[4-(acetyIamino)-2-chlorophenyl]pyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide: 1H-NMR (400MHz, d6-DMSO): 10.7 (s, 1H), 10.3 (s, 1H), 9.78 (s, 1H), 8.52 (d, 1H), 8.13-8.12 (m, 1H), 7.93 (s, 1H), 7.71 (d, 1H), 7.30-7.21 (m, 5H), 7.30- 7.21 (m, 2H), 7.11 (d, 1H), 2.07 (s, 3H). MS (EI): 527.9 (MH+).
2,6-dichloro-N-{3-[(4-phenylpyrimidin-2-yl)amino]phenyl}benzamide: 1H-NMR (400MHz, d6-DMSO): 10.7 (s, 1H), 9.76 (s, 1H), 8.56 (d, 1H), 8.39 (s, 1H), 8.26-8.23 (m, 2H), 7.61-7.59 (m, 2H), 7.55-7.48 (m, 5H), 7.44 (d, 1H), 7.31-7.24 (m, 2H); MS (EI): 437.0 (MH+).
4-(2,4-dichlorophenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMSO): 9.59 (s, 1H), 8.52 (d, 1H), 7.80 (d, 1H), 7.66 (d, 1H), 7.63-7.58 (m, 3H), 7.00 (d, 1H), 6.88 (d, 2H), 3.74-3.72 (m, 4H), 3.04-3.01 (m, 4H); MS (EI): 401.0 (MH+).
4-(2,4-dichlorophenyl)-N-{3-[(4-ethylpiperazin-1- yl)carbonyl]phenyl}pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMS O): 10.0 (s, 1H), 8.62 (d, 1H), 7.92 (s, 1H), 7.82 (d, 1H), 7.76 (dd, 1H), 7.70-7.68 (m, 1H), 7.62-7.59 (m, 1H), 7.34 (t, 1H), 7.13 (d, 1H), 6.96-6.94 (m, 1H), 3.59 (br s, 2H), 3.32 (br s, 2H), 2.37 (br s, 2H), 2.30 (q, 2H), 2.22 (br s, 2H), 0.99 (t, 3H); MS (EI): 456.0 (MH+).
2,6-dichloro-N-(3-{[4-(2,4-dichlorophenyl)pyrimidin-2- yl]amino}phenyl)benzamide: 1H-NMR (400MHz, d6-DMSO): 10.7 (s, 1H), 9.89 (s, 1H), 8.59 (d, 1H), 8.14-8.13 (m, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.59-7.48 (m, 5H), 7.32-7.23 (m, 2H), 7.14 (d, 1H); MS (EI): 504.9 (MH+). N-(2-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide:
1H-NMR (400MHz, d6-DMSO): 1 1.3 (s, 1H), 9.61 (s, 1H), 8.53 (d, 1H), 8.19 (d, 1H), 7.79 (d, 1H), 7.50 (d, 2H), 7.48-7.44 (m, 1H), 7.22 (td, 1H), 7.14 (d, 1H), 6.94 (d, 2H), 3.75-3.73 (m, 4H), 3.06-3.03 (m, 4H), 1.69 (s, 3H). MS (EI): 390.1 (MH+).
4-[3-(methyloxy)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine: 1H-NMR (400MHz, d6-DMSO): 9.45 (s, 1H), 8.49 (d, 1H), 7.73-7.66 (m, 4H), 7.45 (t, 1H), 7.34 (d, 1H), 7.13-7.10 (m, 1H), 6.92 (d, 2H), 3.86 (s, 3H), 3.75-3.35 (m, 4H), 2.51- 2.50 (m, 4H). MS (EI): 363.1 (MH+).
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine: 1H-NMR (400MHz, d6-DMSO): 9.36 (s, 1H), 8.41 (d, 1H), 7.69-7.64 (m, 4H), 7.25 (d, 1H), 6.99 (d, 1H), 6.92 (d, 2H), 4.33-4.30 (m, 4H), 3.75-3.73 (m, 4H), 3.06-3.03 (m, 4H); MS (EI): 391.1 (MH+). 3-(methyloxy)-N-{4-[2-({4-[4-(piperazin-1-ylacetyl)piperazin-1- yl]phenyl}amino)-pyrimidin-4-yl]phenyl}propanamide: 1H-NMR (400MHz, d6- DMSO): 10.2 (s, 1H), 9.43 (s, 1H), 8.79 (br, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.98 (d, 2H), 3.64 (t, 2H), 3.59 (br s, 2H), 3.25 (s, 3H), 3.22 (br m, 8H), 3.13 (br m, 4H), 3.07 (br m, 4H), 2.60 (t, 2H). MS (EI): 559.3 (MH+).
N2,N2-dimethyl-N-[4-(2-{[4-(4-L-prolylpiperazin-1- yl)phenyl]amino}pyrimidin-4-yl)phenyl]glycinamide • 1.3 AcOH: 1H-NMR (400MHz, d6-DMSO): 10.00 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.84 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.90 (m, 1H), 3.64 (m, 4H), 3.11 (s, 2H), 3.10-2.98 (m, 5H), 2.66 (m, 1H), 2.29 (s, 6H), 2.07-1.99 (m, 1H), 1.89 (s, 4H), 1.73-1.54 (m, 3H); MS (EI) C29H36N8O2: 529.2 (MH+).
N2,N2-dimethyl-N-[4-(2-{[4-(4-D-prolylpiperazin-1- yl)phenyl]amino}pyrimidin-4-yl)phenyl]gIycinamide • 1.4 AcOH: 1H-NMR (400MHz, d6-DMSO): 10.00 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.84 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.97 (m, 1H), 3.64 (m, 4H), 3.12 (s, 2H), 3.11-3.0 (m, 5H), 2.70 (m, 1H), 2.29 (s, 6H), 2.07-1.99 (m, 1H), 1.90 (s, 4H), 1.75-1.55 (m, 3H); MS (EI) C29H36N8O2: 529.2 (MH+).
2-(dimethylamino)-N-(4-(2-(4-(4-(2-(piperazin-1-yl)acetyl)piperazin-1- yl)phenylamino)pyriinidin-4-yl)phenyl)acetamide • 3 AcOH: 1H-NMR (400MHz, d6- DMSO): 10.01 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.96 (d, 1H), 3.71 (m, 2H), 3.59 (m, 2H), 3.15 (s, 2H), 3.12 (s, 2H), 3.10 (m, 2H), 3.02 (m, 2H), 2.71 (m, 4H), 2.35 (m, 4H), 2.29 (s, 6H), 1.84 (s, 9H); MS (EI) C30H39N9O2: 558.5 (MH+).
1,1-dimethylethyl [(4-{2-[(4-morpholin-4-ylphenyI)amino]pyrimidin-4-yl}- phenyl)methyl]carbamate: 1U NMR (400MHz, CDC13): 8.20-8.22 (b, 1H), 8.05 (d, 2H), 7.65(d,1H), 7.50 (d, 2H), 7.25 (s, 1H), 7.23 (d, 2H), 7.05 (d, 2H), 5.01 (d, 1H), 4.40-4.44 (b, 2H), 3.90 (t, 4H), 3.20 (t, 4H), 1.50 (s, 9H); MS (EI) for C26H31N5O3: 462 (MH+).
4-(4-(aminomethyl)phenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine: 1H NMR (400MHz, CD3CN): 10.10-10-20(b,1H), 8.40 (d, 1H), 8.20(d,2H), 7.80 (d, 2H), 7.60 (d, 2H), 7.50 (d, 2H), 7.45(d,1H),7.20-7.22 (b, 2H), 4.40-4.44 (b, 2H), 3.90 (t, 4H), 3.20 (t, 4H); MS (EI) for C2iH23N5O: 362 (MH+). methyl 4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}benzoate:
1H NMR (400MHz, CDC13):8.45(s,1H), 8.20-8.30 (m, 4H), 7.65(d,1H), 7.25 (d, 2H), 7.15 (d, 2H), 6.85 (d, 1H), 4.01(s,3H), 3.90 (t, 4H), 3.20 (t, 4H),; MS (EI) for C22H22N4O3: 391 (MH+). l-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}-3-ethylurea: 1H NMR (400MHz, d6-DMSO): 9.50-9.45 (b, 1H), 8.80(s,1H), 8.40(s,1H), 8.05 (d, 2H), 7.75-7.70 (m,4H), 7.30 (d, 1H), 7.05 (d, 2H),, 6.01 (d, 1H), 4.01(q,2H), 3.90 (m, 2H), 3.20 (m, 6H), 1.20 (s, 9H),1.10(t,3H); MS (EI) for C28H35N7O2: 502 (MH+). l-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyI}amino)pyrimidin-4- yl]phenyl}-3-ethylurea: 1H NMR (400MHz, d6-DMSO): 9.45 (s, 1H), 8.80(s,1H), 8.40(s,1H), 8.05 (d, 2H), 7.75-7.70 (m, 4H), 7.30 (d, 1H), 7.05 (d, 2H),, 6.01 (d, 1H), 3.80 (m, 4H),3.50(q, 2H), 3.40 (m, 4H),3.30 (m, 1H),3.2O (m, 6H),1.10(t,3H); MS (EI) for C28H33N7O2: 500 (MH+). l-ethyl-3-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1- yl]phenyI}amino)pyrimidin-4-yl]phenyl}urea: 1H NMR (400MHz, d6-DMSO): 9.45 (s, 1H), 8.80(s,1H), 8.40(s,1H), 8.05 (d, 2H), 7.75-7.70 (m, 4H), 7.30 (d, 1H), 7.05 (d, 2H),, 6.01 (d, 1H), 3.80 (m, 4H),3.30(q, 2H), 3.20 (m, 4H),3.10 (m, 1H),1.2O (m, 6H),1.10(t,3H); MS (EI) for C27H33N7O2: 488 (MH+). N-ethyl-4-(4-{[4-(4-{[(ethylamino)carbonyl]amino}phenyl)pyrimidin-2- yl]amino}-phenyl)piperazine-1-carboxamide: 1H NMR (400MHz, d6-DMSO): 9.45 (s, 1H), 8.80(s,1H), 8.40(m,1H), 8.05 (d, 2H), 7.75-7.70 (m, 4H), 7.30 (d, 1H), 7.05 (d, 2H),6.50 (s, 1H), 6.20 (d, 1H),3.40-3.50(m, 4H),3.00-3.15 (m, 8H),1.10-1.20(m,6H); MS (EI) for C26H32N8O2: 489 (MH+). l-ethyl-3-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]-urea: 1H NMR (400MHz, d6-DMSO): 10.20-10.25 (b, 1H), 9.45 (s, 1H), 8.40(m,1H), 8.05 (d, 2H), 7.75-7.60 (m, 6H), 7.30 (d, 1H), 7.00-6.90 (m, 2H),3.80-3.81 (m, 1H), 3.70-3.65(m, 4H),3.20-3.25 (m, 2H), 3.15-3.10 (m, 4H), 1.60-1.50 (m, 6H),1.10- 1.20(m,3H); MS (EI) for C28H34N8O2: 515 (MH+). l-[4-(2-{[4-(4-L-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-3- ethyl-urea: 1H NMR (400MHz, d6-DMSO): 9.70-9.65 (b, 1H), 9.25 (s, 1H), 8.40(m,1H), 8.05 (d, 2H), 7.75-7.60 (m, 4H), 7.30 (d, 1H), 7.00-6.90 (m, 2H), 6.80-6.75 (m, 1H),3.8O- 3.81 (m, 1H), 3.70-3.65(m, 4H),3.60-3.55 (b, 2H), 3.25-3.20 (m, 6H),,1.10-1.20(m,6H); MS (EI) for C26H32N8O2: 489 (MH+). l-ethyl-3-{4-[2-({4-[4-(piperazin-1-ylacetyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyI}urea: 1H NMR (400MHz, d4-MeOH): 8.40 (m, 1H), 8.05 (d, 2H), 7.75-7.60 (m, 4H), 7.30 (d, 1H), 7.00-6.90 (m, 2H), 3.80-3.81 (m, 4H), 3.30-3.10(m, 16H), 2.80-2.90 (m, 4H),1.20(t,3H); MS (EI) for C29H37N9O2: 544 (MH+). l-ethyl-3-[4-(2-{[4-(4-D-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]-urea: 1H NMR (400MHz, d6-DMSO): 10.20-10.25 (b, 1H), 9.40-9.35 (b, 1H), 9.20 (s, 1H), 8.40(m,1H), 8.05 (d, 2H), 7.75-7.60 (m, 4H), 7.30 (d, 1H), 7.00-6.90 (m,
2H),6.80-6.75 (b, 1H), 3.80-3.81 (m, 1H), 3.70-3.65(m, 4H),3.20-3.25 (m, 2H), 3.15-3.10 (m, 4H), 1.60-1.50 (m, 6H),1.10-1.20(m,3H); MS (EI) for C28H34N8O2: 515 (MH+). l-[4-(2-{[4-(4-D-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-3- ethyl-urea: 1H NMR (400MHz, d6-DMSO): 11.00-10.90 (b, 1H), 9.25 (s, 1H), 8.40(m,1H), 8.05 (d, 2H), 7.75-7.60 (m, 4H), 7.30 (d, 1H), 7.00-6.90 (m, 2H), 6.80-6.75 (m, 1H),3.8O-3.81 (m, 1H), 3.70-3.65(m, 4H),3.60-3.55 (b, 2H), 3.25-3.20 (m, 6H),,1.10- 1.20(m,6H); MS (EI) for C26H32N8O2: 489 (MH+).
(R)-N-(4-(2-(4-(4-(2-ethoxyacetyl)piperazin-1-yl)phenylamino)pyrimidin-4-yl)- phenyl)pyrrolidine-2-carboxamide: 1H NMR (400MHz, d6-DMSO): 10.20-10.25 (b, 1H), 9.40 (s, 1H), 8.50 (d, 1H), 8.05 (d, 2H), 7.75-7.60 (m, 4H), 7.30 (d, 1H), 7.00-6.90 (m, 2H), 4.20 (s, 2H), 3.80-3.81 (m, 2H), 3.70-3.65(m, 1H),3.20-3.25 (m, 2H), 3.25-2.85 (m, 6H), 2.20 (m, 1H),1.8O-1.6O (m, 6H),1.20(t, 3H); MS (EI) for C29H35N7O3: 530 (MH+).
N-[4-(2-{[4-(4-formylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-D- prolinamide: 1H NMR (400MHz, CDC13): 10.10-10.00 (b, 1H), 8.30 (d, 2H), 8.05 (s, 1H), 8.00 (d, 2H), 7.75-7.60 (m, 4H), 7.30 (d, 1H), 7.00-6.90 (m, 2H), 6.10-6.00 (b, 1H), 4.20 (m, 1H), 3.80-3.60 (m, 4H), 3.20-3.25 (m, 6H), 2.20 (m, 2H),1.90-1.80 (m, 2H); MS (EI) for C26H29N7O2: 472 (MH+).
N-(4-{2-[(4-{4-[4-(dimethylamino)butanoyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)-D-prolinamide: 1H NMR (400MHz, d6-
DMSO): 10.20-10.25 (b, 1H), 9.40 (s, 1H), 8.50 (d, 1H), 8.05 (d, 2H), 1.15-1.6$ (m, 4H), 7.30 (d, 1H), 7.00-6.90 (m, 2H), 4.20 (m, 1H), 3.80-3.60 (m, 4H), 3.20-3.25 (m, 6H), 2.90- 2.85 (m, 4H), 2.40 (s, 3H), 2.30-2.22 (m, 2H), 2.20 (m, 3H), 2.05 (s, 3H), 1.90-1.80 (m, 2H); MS (EI) for C3iH40N8O2: 557 (MH+).
N-(4-(2-(3-aminophenylamino)pyrimidin-4-yl)phenyl)-2-phenoxyacetamide: 1H NMR (400 MHz, d6-DMS0): 10.41 (s, 1H), 12.4 (s, br, 1H), 8..56 (s, 1H), 8.19 (s, Ih), 7.97-7.82 (m, 3H), 7.61-7.26 (m, 5H), 7.07-7.02 (m, 3H), 6.98 (m, 1H), 4.79 (s, 2H). MS (EI): 412 (MH+).
N-(4-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide: 1H NMR (400 MHz, d4-MeOH): 10.22 (s, 1H), 9.41 (m, 1H), 8.12 (m, 2H), 7.75 (m, 2H), 7.68 (m, 2H), 7.27 (m, 1H), 3.72 (m, 4H), 6.94 (m, 2H), 3.58 (m, 4H), 3.09 (m, 2H), 3.02 (m, 2H), 2.09 (s, 3H), 2.03 (s, 3H). MS (EI): 431 (MH+).
N-(4-(2-(3-amino-2,4,5,6-tetrafluorophenylamino)pyrimidin-4- yl)phenyl)acetamide: 1H NMR (400 MHz, d4-MeOH): 8.26 (m, 1H), 8.07 (m, 2H), 7.82 (m, 2H), 7.41 (m, 1H), 2.18 (s, 3H). MS (EI): 392 (MH+).
N-(4-(2-(4-(piperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)acetamide: MS (EI) for C22H24N6O: 389 (MH+). l-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)cyclopropane-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.27 (s 1H), 10.19 (s, 1H), 9.23 (m, 3H), 8.60 (m, 1H), 8.09 (m, 2H), 7.95 (m, 3H), 7.79 (m, 2H), 7.54 (m, 1H), 4.11 (m, 4H), 3.65 (m, 4H), 1.71 (m, 2H), 1.42 (m, 2H). MS (EI): 431 (MH+). (S)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)indoline-2- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 9.50 (m, 1H), 8.43 (m, 1H), 8.08 (m, 2H), 7.92 (m, 2H), 7.84 (m, 2H), 7.31 (m, 1H), 7.10-6.88 (m, 4H), 6.61 (m, 2H), 6.07 (m, 1H), 4.42 (m, 1H), 3.75 (m, 4H), 3.18-2.99 (m, 6H). MS (EI): 493 (MH+).
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)tetrahydrofuran-3- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.34 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.67 (d, 2H), 7.28 (d, 1H), 6.93 (d, 2H), 3.95 (t, 1H), 3.82-3.69 (m, 7H), 3.25-3.16 (m, 1H), 3.05 (t, 4H), 2.13-2.06 (m, 2H). MS (EI): 446 (MH+).
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yI)phenyl)-2-(pyridin-3-yl)- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.53 (s, 1H), 9.34 (s, 1H), 8.54 (s, 1H), 8.47 (d, 1H), 8.33 (d,1H), 8.12 (d, 2H), 7.76 (d,3H), 7.67 (d, 2H), 7.37 (m, 1H), 7.28 (d, 1H), 6.93 (d, 2H), 3.76-3.73 (m, 6H), 3.06-3.03 (m,4H). MS (EI): 467 (MH+). l-(4-(2-(4-(4-(3-(dimethylamino)-2^-dimethylpropyl)piperazin-1-yl)phenyl- amino)pyrimidin-4-yl)phenyl)-3-ethylurea: 1H NMR (400 MHz, d6-DMSO): 9.33 (s, 1H), 9.00 (s, 1H), 8.40 (d,1H), 8.04 (d, 2H), 7.66 (d, 2H), 7.55 (d, 2H), 7.23 (d, 1H), 6.93 (d, 2H), 6.39 (t, 1H), 3.17-3.08 (m, 10H), 2.85 (s, 6H), 2.74 (s, 4H), 1.08-1.04 (m, 9H). MS (EI): 531 (MH+).
(R)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 12.64 (s, 1H), 9.35 (s, 1H), 8.42 (d,1H), 8.10 (d, 2H), 7.69-7.63 (m, 4H), 7.28 (d, 1H), 6.89 (d, 2H), 3.30-3.23 (m, 1H), 3.15 (d, 2H), 3.10-3.04 (m, 4H), 2.62- 2.58 (m, 4H), 2.34-2.28 (m, 1H), 2.21 (s, 6H), 2.18 (s, 2H), 2.10 (s, 2H), 1.82-1.64 (m, 4H), 0.84 (s, 6H). MS (EI): 557 (MH+).
(R)-2-amino-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin- l-yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide: 1H NMR (400 MHz, d6- DMSO): 9.35 (s, 1H), 8.42 (d,1H), 8.10 (d, 2H), 7.80 (d, 2H), 7.63 (d, 2H), 7.27 (d, 1H), 6.89 (d, 2H), 3.49-3.43 (m, 1H), 3.05-3.01 (m, 4H), 2.62-2.58 (m, 4H), 2.19 (s, 6H), 2.15 (s, 2H), 2.07 (s, 2H), 1.21 (d, 3H), 0.82 (s, 6H). MS (EI): 531 (MH+).
N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyI)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)-3-methoxypropanaiiiide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.78 (d, 2H), 7.66 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.63 (t, 2H), 3.34 (s, 4H), 3.25 (s, 3H), 3.13 (s, 4H), 2.84 (s, 6H), 2.74 (s, 4H), 2.60 (t, 2H), 1.05 (s, 6H). MS (EI): 546 (MH+).
2-(dimethylamino)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2- dimethyIpropyl)piperazin-1-yl)phenylamino)pyriπiidin-4-yl)phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 9.98 (s, 1H), 9.33 (s, 1H), 8.41 (d, 1H), 8.08 (d, 2H), 7.81 (d, 2H), 7.62 (d, 2H), 7.24 (d, 1H) 6.88 (d, 2H), 3.09 (s, 2H), 3.05-3.02 (m, 4H), 2.60-2.45 (m, 4H), 2.27 (s, 6H), 2.20 (s, 6H), 2.15 (s, 2H), 2.09 (s, 2H), 0.82 (s, 6H). MS (EI): 545 (MH+).
N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)butyramide: 1H NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 9.36 (s, 1H), 8.41 (d, 1H), 8.08 (d, 2H), 7.75 (d, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 3.12 (s, 4H), 3.07 (s, 4H), 2.84 (s, 6H), 2.73 (s, 4H), 2.31 (t, 2H), 1.66- 1.58 (m, 2H), 1.03 (s, 6H), 0.91 (t, 3H). MS (EI): 530 (MH+). (3S,7S)-7-(hydroxymethyl)-N-(4-(2-(4-morpholmophenylamino)pyrimidin-4- yl)phenyl)quinucIidine-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.25 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.74 (t, 4H), 3.65-3.58 (m, 2H), 3.45-3.37 (m, 3H), 3.05 (t, 4H), 2.94-2.88 (m, 3H), 2.71-2.67 (m, 1H), 2.17 (s, 1H), 1.68-1.63 (m, 2H), 1.50-1.46 (m, 1H), 1.27-1.21 (m, 1H). MS (EI): 515 (MH+).
(R)-N-(4-(2-(3-ethoxy-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)- pyrrolidine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 11.45 (s, 1H), 10.04 (s, 1H), 8.59 (d, 1H), 8.21 (d, 2H), 7.87 (d, 2H), 7.49 (d, 1H), 7.44-7.41 (m, 2H), 7.32 (s, 1H), 7.19 (s, 1H), 4.51-4.45 (m, 2H), 4.28-4.25 (m, 4H), 4.09-4.01 (m, 4H), 3.68-3.52 (m, 3H), 3.33-3.23 (m, 2H), 2.49-2.42 (m, 1H), 2.03-1.91 (m, 3H), 1.49 (t, 3H). MS (EI): 489 (MH+).
N-{4-[2-({4-morpholin-4-yl-3-[(phenylmethyl)oxy]phenyl}amino)pyrimidin-4- yl]-phenyl}-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.57 (s, 1H), 10.17 (s, 1H), 8.59 (d, 1H), 8.23 (d, 2H), 8.09 (s, 1H), 7.90 (m, 3H), 7.59 (m, 2H), 7.48 (m, 5H), 5.34 (s, 2H), 4.51 (m, 4H), 4.06 (m, 5H), 3.29 (m, 3H), 1.98 (m, 3H). MS (EI) for C32H34N6O3: 551.7 (MH+).
4-methyI-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- piperazine-1-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.35 (s, 1H), 8.88 (s, 1H), 8.41 (d, 1H), 8.15 (s, 1H), 8.06 (d, 1H), 7.66 (m, 3H), 7.25 (d, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.53 (m, 8H), 3.04 (m, 4H), 3.32 (m, 3H). MS (EI) for C26H31N7O2: 474.6 (MH+). l-[3-(dimethylamino)propyl]-3-(4-{2-[(4-morpholin-4- ylphenvl)amino)pyrimidin-4-yl}pheny l)urca: 1H NMR (400 MHz, d6-DMSO): 9.34 (s, 1H), 9.22 (s, 1H), 8.40 (d, 1H), 8.05 (d, 2H), 7.67 (d, 2H), 7.57 (d, 2H), 7.24 ( d, 1H), 6.93 (d, 2H), 6.66 (t, 1H), 3.74 (m, 4H), 3.17 (m, 2H), 3.05 (m, 4H), 2.90 (t, 2H), 2.62 (s, 6H), 1.78 (m, 2H). MS (EI) for C26H33N7O2: 476.6 (MH+). l-[3-(methyloxy)propyl]-3-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin- 4-yl}phenyl)urea: 1H NMR (400 MHz, d6-DMSO): 9.3 (s, 1H), 8.87 (s, 1H), 8.40 (d, 1H), 8.05 (d, 2H), 7.67 (d, 2H), 7.55 (d, 2H), 7.24 (d, 1H), 6.93 (d, 2H), 6.37 (t, 1H), 3.74 (m, 4H), 3.38 (d, 2H), 3.25 (s, 3H), 3.15 (m, 2H), 3.04 (m, 4H), 1.68 (m, 2H). MS (EI) for C25H30N6O3: 463.6 (MH+). l-(2-morpholin-4-ylethyl)-3-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin- 4-yl}phenyl)urea: 1H NMR (400 MHz, d6-DMSO): 9.34 (s, 1H), 9.00 (s, 1H), 8.40 (d, 1H), 8.17 (s, 1H), 8.05 (d, 2H), 7.68 (d, 2H), 7.55 (d, 2H), 7.24 (d, 1H), 6.93 (d, 2H), 6.25 (t, 1H), 3.74 (m, 4H), 3.60 (m, 4H), 3.22 (m, 2H), 3.04 (m, 4H), 2.40 (m, 5H). MS (EI) for C27H33N7O3: 504.5 (MH+). l-[2-(dimethylamino)ethyl]-3-(4-{2-[(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)urea: 1H NMR (400 MHz, d6-DMSO): 9.33 (s, 1H), 9.06 (s, 1H), 8.40 (d, 1H), 8.21 (s, 1H), 8.04 (d, 2H), 7.67 (d, 2H), 7.55 (d, 2H), 7.23 (d, 1H), 6.93 (d, 2H), 6.33 (t, 1H), 3.74 (d, 4H), 3.21 (m , 2H), 3.05 (m, 1H), 2.38 (t, 2H), 2.12 (s, 6H). MS (EI) for C25H31N7O2: 462.5 (MH+). l-ethyI-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yI}phenyl)-L- prolinamide: 1H NMR (400 MHz, d6-DMSO): 9.53 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.14 (d, 2H), 7.85 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.93 (d, 1H), 3.75 (m, 4H), 3.21 (m, 1H), 3.09 (m, 4H), 2.65 (m, 1H), 2.54 (m, 2H), 2.35 (m, 1H), 2.14 (m, 1H), 1.79 (m, 3H), 1.08 (t, 3H). MS (EI) for C27H32N6O2: 473.6 (MH+). l-(2-hydroxyethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.81 (d, 2H), 7.67 (d, 2H), 7.30 (d, 1H), 6.93 (d, 1H), 5.05 (s, br, 1H), 3.75 (m, 4H), 3.05 (m, 4H), 2.75 (m, 2H), 2.63 (m, 1H), 2.40 (m, 2H), 2.18 (m, 2H), 1.80 (m, 3H). MS (EI) for C27H32N6O3: 489.5 (MH+).
N-(4-{2-[(4-{4-[3-(dimethylamino)-2,2-dimethylpropyI]piperazin-1-yl}phenyl)- amino]pyrimidin-4-yl}phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.39 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.79 (d, 2H), 7.66 (d, 2H), 7.28 (d, 1H), 6.93 (d, 2H), 3.94 (t, 1H), 3.75 (m, 4H), 3.15 (m, 8H), 2.80 (m, 9H), 2.09 (m, 2H), 1.03 (s, 7H). MS (EI) for C32H43N7O2: 558.7 (MH+).
(2R)-N-(4-{2-[(4-{4-[3-(dimethylamino)-2,2-dimethylpropyl]piperazin-1-yl}- phenyl)amino]pyrimidin-4-yl}phenyl)tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.88 (s, 1H), 9.34 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.00 (s, 1H), 7.56 (m, 2H), 7.22 (d, 1H), 6.96 (d, 2H), 4.43 (m, 1H), 4.00 (m, 1H), 3.86 (m, 1H), 3.05 (m, 7H), 2.60 (m, 7H), 2.20 (m, 10H), 0.85 (s, 6H). C32H43N7O2. MS (EI) for C32H43N7O2: 558.7 (MH+). N-(4-{2-[(4-{4-[3-(dimethylamino)-2,2-dimethylpropyl]piperazin-1-yl}phenyl)- amino]pyrimidin-4-yl}phenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, d6- DMSO): 10.47 (s, 1H), 9.36 (s, 1H), 8.42 (d, 1H), 8.10 (d, 2H), 7.75 (d, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 6.90 (d, 2H), 3.05 (m, 4H), 2.61 (m, 4H), 2.21 (s, 6H), 2.17 (s, 2H), 2.10 (s, 2H), 1.90 (s, 1H), 1.82 (m, 1H), 0.84 (m, 9H). MS (EI) for C31H4]N7O: 528.6 (MH+).
(S)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenyl-amino)pyrimidin-4-yl)phenyl)tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6-DMS0): 9.95 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.88 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.93 (d, 2H), 4.44 (t, 1H), 4.01 (m, 1H), 3.85 (m, 1H), 3.14 (m, 6H), 2.86 (s, 6H), 2.77 (m, 4H), 2.21 (m, 2H), 2.01 (m, 2H), 1.90 (m, 2H), 1.05 (s, 6H). MS (EI) for C32H43N7O2: 558.7 (MH+).
N-(4-(2-(4-(4-(piperidine-4-carbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)-phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.35 (s, 1H), 9.41 (s, 1H), 8.44 (s, 1H), 8.14 (d, 2H), 7.78 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.96 (m, 1H), 3.73 (m, 3H), 3.62 (m, 4H), 3.20 (m, 1H), 3.04 (m, 5H), 2.79 (m, 1H), 2.62 (t, 2H), 2.11 (m, 2H), 2.79 (m, 3H), 1.55 (m, 3H). MS (EI) for C3iH37N7O3: 556.6 (MH+). l-(l-methylethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 9.98 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.14 (m, 1H), 3.05 (m, 4H), 2.81 (1H), 2.54 (m, 2H), 2.08 (m, 1H), 1.77 (m, 1H), 1.75 (m, 2H), 1.05 (m, 6H). MS (EI) for C28H34N6O2: 487.6 (MH+). l-ethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H NMR (400 MHz, d6-DMSO): 9.95 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.85 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 3.74 (m, 4H), 3.20 (m, 1H), 3.07 (m, 5H), 2.64 (m, 1H), 2.54 (m, 1H), 2.35 (m, 1H), 2.14 (m, 1H), 1.79 (m, 3H), 1.08 (t, 3H). MS (EI) for C27H32N6O2: 473.5 (MH+).
2-(2-fluorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyriinidin-4- yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMS0): 10.50 (s, 1H), 9.32 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.76 (d, 2H), 7.67 (d, 1H), 7.41 (m , 1H), 7.34 (m, 1H), 7.28 (d, 1H), 7.18 (m, 2H), 6.93 (d, 2H), 3.79 (s, 2H), 3.74 (m, 4H), 3.05 (m, 4H). MS (EI) for C28H26FN5O2: 484.5 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridine-4- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.76 (s, 1H), 9.42 (s, 1H), 8.82 (d, 2H), 8.47 (d, 1H), 8.20 (d, 2H), 7.96 (s, 2H), 7.89 (d, 2H), 7.68 (d, 2H), 7.32 (d, 1H), 6.95 (d, 2H), 3.75 (m, 4H), 3.07 (m, 4H). MS (EI) for C26H24N6O2: 453.5 (MH+). (R)-N-(4-(5-methyl-2-(4-(4-((l-methyl-1H-imidazol-2-yl)methyl)piperazin-1- yl)-phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, br, 1H), 9.25 (s, br, 1H), 8.31 (s, 1H), 7.81-7.58 (m, 6H), 7.09-6.76 (br m, 3H), 3.79 (m, 3H), 3.66 (s, 3H), 3.02-2.92 (m, 4H), 2.20 (m, 4H), 2.09 (m, 2H), 2.00 (m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 12.4 (s, 3H). MS (EI): 552 (MH+). (R)-2-amino-N-(4-(5-methyl-2-(4-(4-((l-methyl-1H-imidazol-2- yl)methyl)piperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyI)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, br, 1H), 9.24 (s, br, 1H), 8.31 (s, 1H), 7.80 (d, 2H), 7.66- 7.69 (m, 4H), 7.09 (s, 1H), 6.85 (m, 2H), 6.76 (s, 1H), 3.80 (m, 3H), 3.66 (m, 3H), 3.00 (m, 4H), 2.95 (m, 4H), 2.22 (s, 3H), 1.24 (s, 3H). MS (EI): 526 (MH+). (S)-2-amino-N-(4-(5-methyl-2-(4-(4-((l-methyl-1H-imidazol-2- yl)methyl)piperazin-1-yI)phenylamino)pyrimidin-4-yl)phenyl)propanamide: 1H NMR (400 MHz, d6-DMSO): ): 10.20 (s, br, 1H), 9.24 (s, br, 1H), 8.31 (s, 1H), 7.79 (d, 2H), 7.67-7.58 (m, 4H), 7.09 (s, 1H), 6.86 (m, 2H), 6.76 (s, 1H), 3.80 (m, 3H), 3.66 (m, 3H), 3.01 (m, 4H), 2.95 (m, 4H), 2.22 (s, 3H), 1.23 (s, 3H). MS (EI) for C29H35N9O: 526 (MH+).
N-[3-({2-[(4-morpholin-4-ylphenyl)amino]-7/ir-pyrrolo[2,3-rf]pyrimidin-4-yl}- amino)phenyl]acetamide: 1H NMR (400MHz, d6-DMSO): 11.14 (s, 1H), 9.87 (s, 1H), 9.15 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.80-7.73 (m, 1H), 7.70-7.63 (m, 2H), 7.25-7.18 (m, 2H), 6.89-6.81 (m, 3H), 6.67-6.64 (m, 1H), 3.77-3.71 (m, 4H), 3.04-2.98 (m,4H), 2.06 (s, 3H). MS (EI) for C24H25N7O2: 444 (MH+).
N-(4-{2-[(2-methyl-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- acetamide: 1H NMR (400 MHz, Λ6-DMSO): 10.36 (br s, 1H), 9.51 (br s, 1H), 8.34 (d, 1H), 8.08 (d, 2H), 7.74 (d, 2H), 7.39 (d, 2H), 7.05 (br d, 2H), 3.80 (s, 4H), 3.22 (s, 4H), 2.21 (s, 3H), 2.07 (s, 3H). MS (EI): (MH+). N-(4-{2-[(4-pyrroIidin-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide:
1H NMR (400 MHz, J6-DMSO): 10.33 (br s, 1H), 9.72 (br s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7,69 (br s, 2H), 7.34 (d, 1H), 3.37 (m, 4H), 2.10 (s, 3H), 2.03 (s, 4H). MS (EI): 374 (MH+).
N-[4-(2-{[4-(diethylamino)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, ^6-DMSO): 10.34 (br s), 9.99 (br s, 1H), 8.56 (d, 1H), 8.12 (d, 2H), 8.06 (d, 2H), 7.79 (d, 2H), 7.72 (d, 2H), 7.44 (d, 1H), 3.49 (q, 4H), 2.10 (s, 3H), 1.05 (dt, 6H). MS (EI): 376 (MH+).
N-(4-{2-[(4-azepan-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, c/6-DMSO): 10.34 (br s), 9.99 (br s, 1H), 8.56 (d, 1H), 8.12 (d, 2H), 8.06 (d, 2H), 7.79 (d, 2H), 7.72 (d, 2H), 7.44 (d, 1H), 3.54 (m, 4H), 2.09 (s, 3H), 1.91 (m, 2H), 1.70 (m,2H), 1.64 (m, 4H), 1.44 (m, 2H), 1.37 (m, 2H). MS (EI): 402 (MH+).
N-{4-[2-({4-[methyl(2-phenylethyl)amino]phenyl}amino)pyrimidin-4- yl]phenyl} acetamide: 1H NMR (400 MHz, t/6-DMSO): 10.34 (br s, 1H), 9.95 (br s, 1H), 8.54 (d, 1H), 8.15 (d, 2H), 7.98 (m, 1H), 7.79 (d, 2H), 7.43 (d, 1H), 7.31 (m, 3H), 7.23 (m, 4H), 3.71 (m, 2H), 3.13 (m, 2H), 2.10 (s, 1H), 1.99 (s, 3H). MS (EI): 438 (MH+). N-[4-(2-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]amino}pyrimidin-4- yl)phenyl] acetamide: 1H NMR (400 MHz, c/6-DMSO): 10.34 (br s), 9.99 (br s, 1H), 8.56 (d, 1H), 8.12 (d, 2H), 8.06 (d, 2H), 7.79 (d, 2H), 7.72 (d, 2H), 7.44 (d, 1H),3.9O (s, 4H), 2.70 (t, 4H), (2.10 (s, 3H), 1.76 (t, 4H). MS (EI): 446 (MH+).
N-[4-(2-{[4-(2-oxopiperidin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl] acetamide: 1H NMR (400 MHz, d6-DMS0): 10.32 (br s, 1H), 9.86 (br s 1H), 8.51 (d, 1H), 8.14 (d, 2H), 7.85 (t, 4H), 7.40 (d, 1H), 7.22 (d, 2H), 3.59 (m, 2H), 2.38 (t, 2H), 2.09 (s, 3H), 1.85 (m, 4H). MS (EI): 402 (MH+).
N-[4-(2-{[4-(2-methylpiperidin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (br s, 1H), 9.36 (br s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (s, 1H), 6.92 (d, 2H), 2.09 (s, 3H), 3.41 (m, 3H), 1.60 (m, 6H), 0.88 (d, 3H). MS (EI): 402 (MH+).
N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yI}phenyl)-L- valinamide: 1H NMR (400 MHz, d6-DMSO): 11.51 (br s, 1H), 10.16 (br s, 1H), 8.57 (s, 1H), 8.48 (m, 2H), 8.20 (m, 2H), 7.93 (m, 3H), 7.78 (m, 1H), 7.50 (s, 1H), 5.45 (br s, 4H), 4.07 (s, 4H), 3.53 (s, 4H), 3.35 (m, 1H), 2.25 (m, 1H), 1.03 (m, 6H). MS (EI): 447 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyriinidin-4-yl}phenyl)-D- valinamide: 1H NMR (400 MHz, d6-DMSO): 1 1.51 (br s, 1H), 10.16 (br s, 1H), 8.57 (s, 1H), 8.48 (m, 2H), 8.20 (m, 2H), 7.93 (m, 3H), 7.78 (m, 1H), 7.50 (s, 1H), 5.45 (br s, 4H), 4.07 (s, 4H), 3.53 (s, 4H), 3.35 (m, 1H), 2.25 (m, 1H), 1.03 (m, 6H). MS (EI): 447 (MH+).
2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- alaninamide: 1H NMR (400 MHz, d6-DMSO): 10.68 (br s,1H), 10.02 (br s, 1H), 8.53 (m, 2H), 8.18 (d, 2H), 7.95 (d, 2H), 7.89 (d, 2H), 7.66 (m, 1H), 7.47 (d, 1H), 5.20 (br s, 4H), 4.01 (s, 4H), 3.44 (s,4H), 1.66 (6H). MS (EI): 433 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)tryptophanamide: 1H NMR (400 MHz, d6-DMSO): 11.37 (s, 1H), 10.07 (s, 1H), 10.03 (s, 1H), 8.56 (d, 1H), 8.42 (d, 2H), 8.19 (d, 2H), 7.91 (d, 2H), (d, 2H), 7.73 (d, 1H), 7.66 (1H), 7.46 (d, 1H), 7.35 (d, 1H), 7.28 (d, 1H), 7.07 (t, 1H), 6.95 (t, 1H), 4.70 (br s, 4H), 4.34 (m, 1H), 4.03 (s, 4H), 3.49 (s, 4H), 3.36 (dq, 2H). MS (EI): 534 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.43 (br s, 1H), 10.07 (br s, 2H), 8.73 (d, 1H), 8.57 (d, 1H), 8.21 (d, 2H), 7.91 (d, 2H), 7.98 (d, 2H), 7.71 (br s, 2H), 7.48 (d, 1H), 4.48 (m, 1H), 4.08 (s, 4H), 3.74 (m, 4H), 3.42 (m, 1H), 3.36 (m, 1H), 3.04 (m, 4H), 2.22 (m 1H), 1.90 (m, 2H), 1.82 (m, 2H). MS (EI): 445 (MH+). N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-1,2,3,4- tetrahydro-isoquinoline-1-carboxamide: 1H NMR (400 MHz, d6-DMSO): 11.30 (br d, 1H), 10.04 (br s, 1H), 8.56 (d, 1H), 8.39 (s, 3H), 8.20 (d, 2H), 7.90 (m, 2H), 7.87 (m, 2H), 7.67 (m, 3H), 7.47 (d, 1H), 5.00 (br s, 3H), 4.65 (s, 1H), 4.20 (m, 2H), 4.03 (s, 4H), 3.97 (m, 1H), 3.94 (m, 2H), 3.80 (m, 1H), 3.49 (s, 4H). MS (EI): 507 (MH+). 0-(l,l-dimethylethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyriniidin-4- yl}-phenyl)-L-serinamide: 1H NMR (400 MHz, d6-DMSO): 12.1 1 (br s, 1H), 10.65 (br s, 1H), 10.12 (s, 1H), 9.60 (s, 1H), 8.58 (d, 1H), 8.23 (d, 2H), 7.95 (d, 2H),, 7.79 (s, 1H), 7.56 (d, 1H), 7.49 (d, 1H), 7.31 (s, 2H), 5.14 (br s, 4H), 4.06 (s, 4H), 3.79 (m, 1H), 3.54 (s, 4H), 3.45 (m, 1H), 3.15 (q, 1H), 1.21 (s, 9H). MS (EI): 491 (MH+). 3-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl) tetrahydro-furan-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.89 (br s, 1H), 9.92 (br s , 1H), 8.83 (s, 2H), 8.55 (d, 1H), 8.21 (d, 2H), 7.94 (d, 2H), 7.87 (d, 1H), 7.53 (s, 1H), 7.43 (d, 1H), 4.30 (br s, 4H), 4.21 (d, 1H), 4.07 (d, 1H), 4.05 (m, 1H), 4.02 (m, 1H),
3.97 (s, 4H), 3.42 (s, 4H), 2.79 (m, 1H), 2.28 (m, 1H). MS (EI): 461 (MH+). bis(l,l-dimethylethyl) (2R)-2-{[(4-{2-[(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)amino]carbonyl}piperazine-1,4- dicarboxylate: 1H NMR (400 MHz, d6-DMSO): 10.41 (br s, 1H), 9.35 (s, 1H), 8.42 (d, 1H), 8.14 (d, 2H), 8.76 (d, 2H), 7.67 (d, 2H), 7.28 (d, 1H), 6.93 (d, 2H), 4.51 (m, 1H), 3.90 (m, 2H), 3.74 (m, 4H), 3.66 (t, 4H), 3.04 (t, 4H), 1.41 (s, 3H), 1.33 (s, 9H), 1.17 (s, 6H). MS (EI): 660 (MH+).
N-(4-{2-[(4-{4-[2-(2-fluorophenyl)acetyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.70 (d, 2H), 7.29 (m, 3H), 7.16 (m, 2H), 6.98 (d, 2H), 3.80 (s, 2H), 3.69 (m, 2H), 3.63 (m, 2H), 3.09 (m, 2H), 3.04 (m, 2H), 2.09 (s, 3H). MS (EI): 525.5 (MH+).
N-(4-{2-[(4-{4-[2-(2-metb.ylphenyl)acetyI]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.69 (d, 2H), 7.28 (d, 1H), 7.12 (m, 4H), 6.97 (d, 2H), 3.74 (s, 2H), 3.65 (m, 4H), 3.05 (m, 4H), 2.20 (s, 3H), 2.09 (s, 3H). MS (EI): 521.6 (MH+).
N-(4-{2-[(4-{4-[2-(3-fluorophenyl)acetyI]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.69 (d, 2H), 7.35 (m, 1H), 7.28 (d, 1H), 7.08 (m, 3H), 6.96 (d, 2H), 3.81 (s, 2H), 3.64 (m, 4H), 3.02 (m, 4H), 2.09 (s, 3H). MS (EI): 525.4 (MH+).
N-{4-[2-({4-[4-(3-thienylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.83 (m, 1H), 7.75 (d, 2H), 7.70 (d, 2H), 7.64 (m, 1H), 7.25 (m, 2H),
6.98 (d, 2H), 3.68 (m, 4H), 3.11 (m, 4H), 2.09 (s, 3H). MS (EI): 499.4 (MH+).
N-(4-{2-[(4-{4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.53 (m, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.98 (dd, 1H), 7.75 (d, 2H), 7.70 (d, 2H), 7.65 (d, 1H), 7.28 (d, 1H), 6.98 (d, 2H), 3.78 (m,2H), 3.48 (m, 2H), 3.17 (m, 2H), 3.08 (m, 2H), 2.09 (s, 3H). MS (EI): 529.1 (MH+). N-(4-{2-[(4-{4-[(3-methylfuran-2-yl)carbonyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.75-7.68 (m, 5H), 7.28 (d, 1H), 6.98 (d, 2H), 6.52 (d, 1H), 3.73 (m, 4H), 3.11 (m, 4H), 2.17 (s, 3H), 2.09 (s, 3H). MS (EI): 497.6 (MH+). N-(4-{2-[(4-{4-[(3-fluoro-2-methyIphenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: MS (EI) for C3oH29FN602: 525.5 (MH+).
N-(4-{2-[(4-{4-[(imidazol-4-yl)carbonyl]piperazin-1- yI}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: MS (EI) for C26H26N8O2: 483.5 (MH+).
N-(4-{2-[(4-{4-[(2-methoxypyridin-3-yl)carbonyI]piperazin-1- yl}phenyI)amino]-pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.26 (dd, 1H), 8.12 (d, 2H), 7.75-7.67 (m, 5H), 7.28 (d, 1H), 7.09 (dd, 1H), 6.97 (d, 2H), 3.90 (s, 3H), 3.77 (m, 2H), 3.29 (m, 2H), 3.14 (m, 2H), 3.04 (m, 2H), 2.09 (s, 3H). MS (EI): 524.6 (MH+).
N-(4-{2-[(4-{4-[(4-fluoro-3-methylphenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yI}phenyl)acetainide: MS (EI) for C30H^FN6O2: 525.5 (MH+).
N-{4-[2-({4-[4-(naphthaIen-2-ylsulfonyl)piperazin-1- yI]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.37 (s, 1H), 8.50 (d, 1H), 8.42 (d, 1H), 8.22 (dd, 2H), 8.09 (dd, 3H), 7.82- 7.71 (m, 5H), 7.64 (d, 2H), 7.26 (d, 1H), 6.89 (d, 2H), 3.14 (m, 4H), 3.11 (m, 4H), 2.08 (s, 3H). MS (EI): 579.6 (MH+).
N-{4-[2-({4-[4-(quinolin-8-ylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMS0): 10.20 (s, 1H), 9.37 (s, 1H),
9.10 (dd, 1H), 8.56 (dd, 1H), 8.42 (m, 2H), 8.34 (dd, 1H), 8.10 (d, 2H), 7.79 (m, 1H), 7.73 (m, 3H), 7.65 (d, 2H), 7.27 (d, 1H), 6.90 (d, 2H), 3.45 (m, 4H), 3.08 (m, 4H), 2.09 (s, 3H). MS (EI): 580.8 (MH+).
N-[4-(2-{[4-(4-{[4-(l,l-dimethylethyl)phenyl]sulfonyl}piperazin-1- yl)phenyl]amino}-pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.20 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.70 (m, 4H), 7.66 (d, 2H), 7.27 (d, 1H), 6.91 (d, 2H), 3.16 (m, 4H), 3.01 (m, 4H), 2.08 (s, 3H), 1.32 (s, 9H). MS (EI): 585.5 (MH+).
N-[4-(2-{[4-(4-{[5-bromo-2-(methyloxy)phenyl]sulfonyl}piperazin-1- yl)phenyl]-amino}pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.09 (dd, 2H), 7.84 (m, 2H), 7.74 (d, 2H), 7.68 (d, 2H), 7.28 (d, 2H), 6.94 (d, 2H), 3.92 (s, 3H), 3.27 (m, 4H), 3.11 (m, 4H), 2.09 (s, 3H). MS (EI) for C29H29BrN6O4S: 638.6 (MH+).
N-(4-{2-[(4-{4-[(phenylmethyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.69 (d, 2H), 7.42 (m, 5H), 7.28 (d, 1H), 6.96 (d, 2H), 4.50 (s, 2H), 3.20 (m, 4H), 3.06 (m, 4H), 2.08 (s, 3H). MS (EI): 543.6 (MH+).
N-[4-(2-{[4-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}piperazin-1- yl)phenyl]amino}-pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.18-8.08 (m, 4H), 8.02 (s, 1H), 7.97 (d, 1H), 7.74 (d, 2H), 7.67 (d, 2H), 7.27 (d, 1H), 6.92 (d, 2H), 3.15 (m, 4H), 3.10 (m, 4H), 2.09 (s, 3H). MS (EI): 597.7 (MH+).
N-(4-{2-[(4-{4-[(2-methylphenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.09 (dd, 2H), 7.85 (dd, 1H), 7.74 (d, 2H), 7.67- 7.59 (m, 3H), 7.47 (m, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 3.17 (m, 4H), 3.13 (m, 4H), 2.61 (s, 3H), 2.09 (s, 3H). MS (EI): 543.7 (MH+).
N-(4-{2-[(4-{4-[(3-fluorophenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H), 8.10 (dd, 2H), 7.73 (m, 3H), 7.67-7.62 (m, 5H), 7.27 (d, 1H), 6.92 (d, 2H), 3.14 (m, 4H), 3.08 (m, 4H), 2.09 (s, 3H). MS (EI): 547.7 (MH+).
N-(4-{2-[(4-{4-[(2,4-difluorophenyl)sulfonyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: MS (EI) for C28H26F2N6O3S: 565.6 (MH+). N-{4-[2-({3-[4-({4-[(trifluoromethyl)oxy]phenyl}methyl)piperazin-1- yI]phenyI}-amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.47 (s, 1H), 8.49 (d, 1H), 8.14 (dd, 2H), 7.75 (d, 2H), 7.64 (s, 1H), 7.48 (dd, 2H), 7.33 (m, 3H), 7.22 (m, 1H), 7.13 (m, 1H), 6.56 (dd, 1H), 3.57 (s, 2H), 3.16 (m, 4H), 2.54 (m, 4H), 2.09 (s, 3H). MS (EI): 563.6 (MH+).
N-(4-{2-[(3-{4-[(l-methyI-1H-imidazol-2-yl)methyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.45 (s, 1H), 8.49 (d, 1H), 8.13 (dd, 2H), 7.75 (d, 2H), 7.58 (s, 1H), 7.33 (d, 1H), 7.25 (dd, 1H), 7.15-7.09 (m, 2H), 6.77 (d, 1H), 6.56 (dd, 1H), 3.68 (s, 3H), 3.58 (s, 2H), 3.12 (m, 4H), 2.54 (m, 4H), 2.09 (s, 3H). MS (EI): 483.5 (MH+).
N-{4-[2-({3-[4-({2-[(trifluoromethyl)oxy]phenyl}methyl)piperazin-1- yIjphenyl}-amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.47 (s, 1H), 8.50 (d, 1H), 8.13 (dd, 2H), 7.75 (d, 2H), 7.64-7.62 (m, 2H), 7.44-7.36 (m, 4H), 7.23 (dd, 1H), 7.14 (m, 1H), 6.55 (dd, 1H), 3.62 (s, 2H), 3.16 (m, 4H), 2.57 (m, 4H), 2.09 (s, 3H). MS (EI): 563.6 (MH+).
N-(4-{2-[(3-{4-[(3-chlorophenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.69 (d, 2H), 7.44- 7.38 (m, 4H), 7.28 (d, 1H), 6.96 (d, 2H), 4.48 (s, 2H), 3.27 (m, 4H), 3.09 (m, 4H), 2.09 (s, 3H). MS (EI): 514.1 (MH+).
N-{4-[2-({3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.46 (s, 1H), 8.49 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.63 (s, 1H), 7.33 (d, 1H), 7.22 (d, 1H), 7.13 (m, 1H), 6.56 (dd, 1H), 3.67 (s, 2H), 3.14 (m, 5H), 2.60 (m, 4H), 2.45 (m, 1H), 2.30 (m, 1H), 2.09 (s, 3H). MS (EI): 463.6 (MH+).
N-{4-[2-({3-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.46 (s, 1H), 8.49 (d, 1H), 8.12 (m, 2H), 7.75 (d, 2H), 7.62 (s, 1H), 7.33 (d, 1H), 7.23 (dd, 1H), 7.12 (t, 1H), 6.90-6.85 (m, 2H), 6.79 (m, 1H), 6.55 (dd, 1H), 5.99 (s, 2H), 3.44 (s, 2H), 3.15 (m, 4H), 2.52 (m, 4H), 2.09 (s, 3H). MS (EI): 523.5 (MH+).
N-{4-[2-({3-[4-(pyridin-2-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.47 (s, 1H), 8.52- 8.49 (m, 2H), 8.13 (m, 2H), 7.81-7.72 (m, 3H), 7.63 (s, 1H), 7.50 (d, 1H), 7.33 (d, 1H), 7.30-7.21 (m, 2H), 7.13 (t, 1H), 6.57 (dd, 1H), 3.67 (s, 2H), 3.17 (m, 4H), 2.60 (m, 4H), 2.09 (s, 3H). MS (EI): 480.6 (MH+). N-{4-[2-({3-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.47 (s, 1H), 8.54 (d, 1H), 8.49 (d, 2H), 8.12 (m, 2H), 7.78-7.73 (m, 3H), 7.63 (s, 1H), 7.40-7.37 (m, 1H), 7.33 (d, 1H), 7.23 (d, 1H), 7.13 (t, 1H), 6.55 (dd, 1H), 3.58 (s, 2H), 3.16 (m, 4H), 2.55 (m, 4H), 2.10 (s, 3H). MS (EI): 480.5 (MH+).
N-{4-[2-({3-[4-(pyridin-4-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.47 (s, 1H), 8.53 (dd, 2H), 8.49 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.64 (s, 1H), 7.38 (dd, 2H), 7.33 (d, 1H), 7.23 (d, 1H), 7.13 (t, 1H), 6.56 (dd, 1H), 3.59 (s, 2H), 3.18 (m, 4H), 2.56 (m, 4H), 2.09 (s, 3H). MS (EI): 480.7 (MH+).
N-{4-[2-({3-[4-(1H-pyrrol-2-ylmethyl)piperazin-1-yI]phenyl}amino)pyrimidin- 4-yI]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.45 (s, 1H), 8.49 (d, 1H), 8.12 (m, 2H), 7.75 (d, 2H), 7.61 (s, 1H), 7.33 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H), 6.64 (m, 1H), 6.55 (dd, 1H), 5.92 (m, 2H), 3.46 (s, 2H), 3.14 (m, 4H), 2.51 (m, 4H), 2.09 (s, 3H). MS (EI): 468.6 (MH+).
4-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-N- (phenylmethyl)-piperazine-1-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.62 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.70 (d, 2H), 7.48 (dd, 2H), 7.28-7.21 (m, 3H), 7.00 (d, 2H), 6.94 (t, 1H), 4.41 (s, 2H), 3.60 (m, 4H), 310 (m, 4H), 2.09 (s, 3H). MS (EI): 522.4 (MH+).
N-[4-(2-{[3-(4-{[2-(methyloxy)phenyl]carbonyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.50 (s, 1H), 8.50 (d, 1H), 8.13 (d, 2H), 7.74 (d, 2H), 7.64 (s, 1H), 7.41 (m, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 7.23 (dd, 1H), 7.16 (t, 1H), 7.10 (d, 1H), 7.01 (t, 1H), 6.59 (dd, 1H), 3.79 (s, 3H), 3.21 (m, 4H), 3.07 (m, 4H), 2.09 (s, 3H). MS (EI): 523.5 (MH+).
N-{4-[2-({3-[4-(1H-pyrazol-4-ylcarbonyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 13.22 (s, 1H), 10.22 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (d, 3H), 7.76 (d, 3H), 7.66 (s, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 7.17 (t, 1H), 6.59 (dd, 1H), 3.78 (m, 4H), 3.20 (m, 4H), 2.09 (s, 3H). MS (EI): 483.5 (MH+).
N-{4-[2-({3-[4-(3-pyridin-3-ylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.24 (s, 1H), 9.50 (s, 1H), 8.50 (d, 2H), 8.39 (dd, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.69 (dd, 2H), 7.34-7.24 (m, 3H), 7.15 (t, 1H), 6.58 (dd, 1H), 3.61 (m, 4H), 3.10 (m, 4H), 2.86 (t, 2H), 2.74 (t, 2H), 2.09 (s, 3H). MS (EI): 522.7 (MH+).
N-(4-{2-[(3-{4-[3-(methyloxy)propanoyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO):
10.22 (s, 1H), 9.50 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.66 (s, 1H), 7.34 (d, 1H), 7.27 (d, 1H), 7.16 (t, 1H), 6.59 (dd, 1H), 3.63 (m, 4H), 3.58 (t, 2H), 3.23 (s, 3H), 3.12 (m, 4H), 2.63 (t, 2H), 2.09 (s, 3H). MS (EI): 475.6 (MH+).
N-[4-(2-{[3-(4-{2-[(4-fluorophenyl)oxy]acetyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.66 (s, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 7.19-7.10 (m, 3H), 6.96 (m, 2H), 6.60 (dd, 1H), 4.88 (s, 2H), 3.64 (m, 4H), 3.17 (m, 4H), 2.09 (s, 3H). MS (EI): 541.5 (MH+).
N-{4-[2-({3-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.24 (s, 1H), 9.50 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.69 (s, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 7.15 (t, 1H), 6.58 (dd, 1H), 3.61 (m, 2H), 3.48 (m, 2H), 3.41 (t, 1H), 3.10 (m, 4H), 2.18 (m, 2H), 2.09 (s, 3H) 1.92 (m, 2H), 1.75 (m, 2H). MS (EI): 471.4 (MH+).
N-{4-[2-({3-[4-(pyridin-4-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.51 (s, 1H),
8.69 (dd, 2H), 8.50 (d, 1H), 8.14 (d, 2H), 7.74 (d, 2H), 7.66 (s, 1H), 7.45 (dd, 2H), 7.34 (d, 1H), 7.28 (d, 1H), 7.16 (t, 1H), 6.60 (d, 1H), 3.81 (m, 2H), 3.43 (m, 2H), 3.27 (m, 2H), 3.14 (m, 2H), 2.10 (s, 3H). MS (EI): 494.6 (MH+).
N-{4-[2-({3-[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.50 (s, 1H), 8.61 (d, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.95 (t, 1H), 7.74 (d, 2H), 7.66 (d, 2H), 7.50 (t, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 7.16 (t, 1H), 6.60 (d, 1H), 3.84 (m, 2H), 3.59 (m, 2H), 3.26 (m, 2H), 3.14 (m, 2H), 2.09 (s, 3H). MS (EI): 494.6 (MH+). N-(4-{2-[(3-{4-[(2-methylphenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO):
10.23 (s, 1H), 9.49 (s, 1H), 8.49 (d, 1H), 8.13 (d, 2H), 7.74 (d, 2H), 7.63 (s, 1H), 7.34-7.16 (m, 7H), 6.59 (d, 1H), 3.84 (m, 2H), 3.28 (m, 2H), 3.25 (m, 2H), 3.06 (m, 2H), 2.24 (s, 3H), 2.09 (s, 3H). MS (EI): 507.6 (MH+).
N-{4-[2-({3-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.51 (s, 1H), 8.50 (dd, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.68 (s, 1H), 7.34 (d, 1H), 7.26 (d, 1H), 7.16 (t, 1H), 6.59 (d, 1H), 3.72 (m, 4H), 3.13 (m, 4H), 2.09 (s, 3H), 1.23 (s, 9H). MS (EI): 473.5 (MH+).
N-{4-[2-({3-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]-phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.51 (s, 1H), 8.67 (m, 2H), 8.50 (d, 1H), 8.13 (m, 2H), 7.90 (m, 1H), 7.75 (d, 2H), 7.66 (s, 1H), 7.50 (m, 1H), 7.34 (d, 1H), 7.29 (dd, 1H), 7.17 (t, 1H), 6.60 (dd, 1H), 3.82 (m, 2H), 3.50 (m, 2H), 3.29 (m, 2H), 3.16 (m, 2H), 2.09 (s, 3H). MS (EI): 494.7 (MH+).
N-{4-[2-({3-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.24 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (dd, 2H), 7.76 (d, 2H), 7.69 (s, 1H), 7.34 (d, 1H), 7.26 (dd, 1H), 7.16 (t, 1H), 6.60 (dd, 1H), 3.66 (m, 4H), 3.1 1 (m, 4H), 2.90 (m, 1H), 2.09 (s, 3H), 1.03 (s, 6H). MS (EI): 459.6 (MH+).
N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4- yI)phenyl]-tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.32 (s, 1H), 9.48 (s, 1H), 8.48 (d, 1H), 8.16 (d, 2H), 7.78 (d, 2H), 7.67 (s, 1H), 7.32 (d, 1H), 7.29 (dd, 1H), 6.87 (d, 1H), 3.95 (t, 2H), 3.81 (s, 3H), 3.78 (m, 2H), 3.71 (m, 4H), 3.29-3.17 (m, 1H), 2.91 (m, 4H), 2.13-2.07 (m, 2H). MS (EI): 476.5 (MH+).
(2R)-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4-yl)- phenyl]tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.94 (s, 1H), 9.48 (s, 1H), 8.48 (d, 1H), 8.16 (d, 2H), 7.89 (d, 2H), 7.66 (s, 1H), 7.33 (d, 1H), 7.30 (dd, 1H), 6.87 (d, 1H), 4.43 (dd, 1H), 4.01 (m, 1H), 3.86 (m, 1H), 3.81 (s, 3H), 3.72 (m, 4H), 2.91 (m, 4H), 2.22-2.19 (m, 1H), 2.03-1.98 (m, 1H), 1.89 (m, 2H). MS (EI): 476.4 (MH+). (2S)-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4-yl)- phenyl]tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.94 (s, 1H), 9.48 (s, 1H), 8.48 (d, 1H), 8.16 (d, 2H), 7.89 (d, 2H), 7.66 (s, 1H), 7.33 (d, 1H), 7.30 (dd, 1H), 6.87 (d, 1H), 4.43 (dd, 1H), 4.01 (m, 1H), 3.86 (m, 1H), 3.81 (s, 3H), 3.72 (m, 4H), 2.91 (m, 4H), 2.24-2.19 (m, 1H), 2.03-1.98 (m, 1H), 1.89 (m, 2H). MS (EI): 476.5 (MH+). N-(4-{2-[(4-{4-[(2-fluorophenyl)sulfonyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.85-7.77 (m, 2H), 7.74 (d, 2H), 7.68 (d, 2H), 7.56-7.46 (m, 2H), 7.28 (d, 1H), 6.93 (d, 2H), 3.18-3.16 (m, 8H), 2.09 (s, 3H). MS (EI): 547.7 (MH+).
N-(4-{2-[(3-{4-[(3,5-dichlorophenyl)carbonyI]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yI}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.24 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.73 (m, 3H), 7.64 (s, 1H), 7.54 (d, 2H), 7.34 (d, 1H), 7.29 (d, 1H), 7.16 (t, 1H), 6.60 (dd, 1H), 3.79 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 3.15 (m, 2H), 2.09 (s, 3H). MS (EI): 562.5 (MH+). ethyl 3-(4-(2-(4-morpholinophenylamino(pyrimidin-4-yl)phenylamino)-3- oxopropanoate: 1H NMR (400 MHz, d6-DMSO): 10.46 (s, 1H), 9.35 (s, 1H), 8.42 (d, 1H), 8.11 (d, 2H), 7.71 (d, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 6.92 (d, 2H), 4.11 (q, 2H), 3.72 (m, 2H), 3.37 (m, 4H), 3.02 (m, 4H), 1.19 (t, 3H). MS (EI): 462 (MH+). N-(4-(2-(4-(4-isobutyrylpiperazin-1-yl)penylamino)pyriinidin-4-yl)phenyl)- tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.30 (s, 1H), 9.43 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.97 (m, 2H), 3.96 (t, 1H), 3.76 (m, 2H), 3.63 (m, 4H), 3.19 (m, 2H), 3.06 (m, 4H), 2.93 (m, 1H), 2.10 (m, 2H), 1.02 (d, 6H). MS (EI): 515 (MH+). N-(4-(2-(4-(4-(cyclobutanecarbonyI)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.30 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.96 (d, 2H), 3.96 (t, 1H), 3.76 (m, 3H), 3.59 (m, 2H), 3.41 (m, 3H), 3.19 (m, 1H), 3.03 (m, 4H), 2.41 (m, 6H), 1.90 (m, 1H), 1.75 (m, 1H). MS (EI): 527 (MH+). N-ethyl-4-(4-(4-(4-(tetrahydrofuran-3-carboxamido)phenyl)pyrimidin-2-yl- amino(phenyl)piperazine-1-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.30 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.67 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 6.59 (t, 1H), 3.96 (t, 1H), 3.75 (m, 3H), 3.42 (m, 4H), 3.19 (m, 1H), 3.05 (m, 6H), 2.10 (q, 2H), 1.02 (t, 3H). MS (EI): 516 (MH+). N-(4-(2-(4-(4-((R)-2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin-
4-yl)phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.96 (dd, 1H), 3.89 (m, 1H), 3.76 (m, 4H), 3.63 (m, 4H), 3.18 (m, 2H), 3.07 (m, 4H), 2.09 (m, 2H), 1.13 (d, 3H). MS (EI): 516 (MH+).
N-(4-(2-(4-(4-((S)-2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin- 4-yl)phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.96 (t, 1H), 3.85 (q, 1H), 3.76 (m, 3H), 3.63 (m, 4H), 3.19 (m, 1H), 3.07 (m, 4H), 2.10 (m, 2H), 1.11 (d, 3H). MS (EI): 516 (MH+).
N-(4-(2-(4-(4-((R)-pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yI)phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.97 (m, 2H), 3.76 (m, 3H), 3.64 (m, 4H), 3.19 (m, 1H), 3.06 (m, 6H), 2.73 (m, 1H), 2.09 (m, 2H), 1.67 (m, 4H). MS (EI): 542 (MH+).
N-(4-(2-(4-(4-((S)-pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)tetrahydrofuran-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.31 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.77 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.97 (d, 2H), 3.96 (t, 1H), 3.86 (m, 1H), 3.76 (m, 3H), 3.64 (m, 4H), 3.18 (m, 1H), 3.05 (m, 6H), 2.64 (m, 1H), 2.10 (m, 1H), 2.00 (m, 1H), 1.62 (m, 4H). MS (EI): 542 (MH+). N-{4-[2-(1H-benzimidazol-6-ylamino)-5-methylpyrimidin-4- yl]phenyl}acetamide: 1H-NMR (400MHz, d6-DMSO): 10.25 (s, 1H), 8.97 (s, 1H), 8.78 (s, 1H), 8.21(d, 2H), 7.86 (d, 2H), 7.80 (d, 2H), 6.96 (s, 1H), 6.78 (dd, 2H), 2.44 (s, 3H), 2.1 1 (s, 3H); MS (EI) C20H]8N6O: 359.3 (M+H)+.
4-(4-furan-2-ylphenyl)-N-(4-morpholin-4-ylphenyI)pyrimidin-2-amine: 1H- NMR (400MHz, d6-DMSO): 9.46 (s, 1H), 8.49 (d, 1H), 8.22 (d, 2H), 7.87 (d, 2H), 7.84 (dd, 1H), 7.68 (d, 2H), 7.37 (d, 1H), 7.12 (t, 1H), 6.94 (d, 2H), 6.66 (dd, 1H), 3.75 (t, 4H), 3.05 (t, 4H) ; MS (EI) C24H22N4O2: 399.3 (M+H)+.
N-(4-morpholin-4-ylphenyl)-4-[4-(pyrimidin-2-ylamino)phenyl]pyrimidin-2- amine: 1H-NMR (400MHz, d6-DMSO): 10.01 (s, 1H), 9.35 (s, 1H), 8.56 (d, 2H), 8.42 (d, 1H), 8.1 1 (dd, 2H), 7.95 (dd, 2H), 7.69 (d, 2H), 7.27 (d, 1H), 6.96-6.92 (m, 3H), 3.75 (t, 4H), 3.06 (t, 4H); MS (EI) C24H23N7O: 426.3 (M+H)+. N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-5-methylpyrimidin-4- yl)phenyl]-cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.40 (s, 1H), 9.41 (bs, 1H), 9.30 (s, 1H), 8.30 (s, 1H), 7.23-7.70 (m, 2H), 7.65-7.62 (m, 3H), 6.91 (d, 2H), 3.70-3.50 (bs, 2H), 3.21-2.87 (m, 8H), 2.20 (s, 3H), 1.80 (p, 1H), 1.18 (bs, 3H), 0.81 (d, 4H); MS (EI) C24H23N7O: 457.4 (M+H)+.
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- cyclopropanecarboxamide: 1H-NMR (400MHz, (I6-DMSO): 10.48 (s, 1H), 9.37 (s, 1H),
8.44 (d, 1H), 8.1 1 (d, 2H), 7.76 (d, 2H), 7.65 (d, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.09 (bs, 4H), 2.60-2.35 (m, 6H), 1.83 (p, 1H), 1.06 (t, 3H), 0.84-0.82 (m, 4H); MS (EI) C26H30N6O: 443.4 (M+H)+.
N-(4-{2-[(3,5-dimorphoIin-4-ylphenyl)amino]-5-methylpyrimidin-4- yl}phenyl)-N2,N2-dimethylglycinamide: 1H-NMR (400MHz, d6-DMSO): 10.04 (s, 1H), 9.25 (s, 1H), 8.37 (s, 1H), 7.81 (d, 2H), 7.74 (d, 2H), 7.12 (s, 2H), 6.1 1 (s, 1H), 3.73 (t, 8H), 3.20 (bs, 2H), 3.06 (t, 8H), 2.34 (s, 6H), 2.28 (s, 3H); MS (EI) C29H37N7O3: 532.4 (M+H)+.
N2,N2-dimethyl-N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin- 4-yl}-phenyl)glycinamide: 1H-NMR (400MHz, d6-DMSO): 10.43 (s, 1H), 9.28 (s, 1H), 8.33 (s, 1H), 7.77 (d, 2H), 7.69 (d, 2H), 7.63 (d, 2H), 6.88 (d, 2H), 3.73 (t, 4H), 3.35 (bs, 2H), 3.01 (t, 4H), 2.65 (s, 6H), 2.21 (s, 3H); MS (EI) C25H30N6O2: 447.4 (M+H)+. N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H-NMR (400MHz, (I6-DMSO): 10.15 (s, 1H), 9.28 (s, 1H), 8.32 (s, 1H), 7.82-7.79 (m, 2H), 7.64 (t, 4H), 6.88 (d, 2H), 3.75-3.72 (t, 5H), 3.01 (t, 4H), 2.91 (t, 2H), 2.22 (s, 3H), 2.11-2.02 (m, 1H), 1.84-1.75 (m, 1H), 1.70-1.63 (m, 2H); MS (EI) C26H30N6O2: 459.4 (M+H)+. N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}-D-prolinamide: 1H-NMR (400MHz, (I6-DMSO): 10.25 (s, 1H), 9.41 (s, 1H),
8.45 (d, 1H), 8.12 (d, 2H), 7.83 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 3.80-3.77 (m, 1H), 3.65-3.41 (m, 4H), 3.08-3.02 (m, 4H), 2.96-2.89 (m, 3H), 2.13-2.08 (m, 1H), 1.84-1.78 (m, 1H), 1.73-1.68 (m, 2H), 1.02 (d, 6H); MS (EI) C29H35N7O2: 514.4 (M+H)+. N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyI}-D-prolinamide: 1H-NMR (400MHz, d6- DMSO): 10.85 (s, 1H), 9.41 (s, 1H), 8.47 (d, 1H), 8.18 (d, 2H), 7.78 (d, 2H), 7.68 (d, 2H), 7.31 (d, 1H), 6.96 (d, 2H), 4.40-4.34 (m, 1H), 3.70 (t, 4H), 3.32-3.25 (m, 2H), 3.05 (t, 4H), 2.44-2.38 (m, 1H), 2.05-1.94 (m, 3H), 1.23 (s, 9H); MS (EI) C30H37N7O2: 528.4 (M+H)+. N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}-D-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.19 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.84 (d, 2H), 7.67 (d, 2H), 7.30 (d, 1H), 6.95 (d, 2H), 3.74-3.70 (m, 1H), 3.60-3.46 (m, 4H), 3.04-3.00 (m, 4H), 2.91 (t, 2H), 2.22-2.02 (m, 6H), 1.95-1.87 (m, 1H), 1.82-1.73 (m, 2H), 1.70-1.64 (m, 2H); MS (EI) C30H35N7O2: 526.2 (M+H)+.
N-ethyl-4-[4-({4-[4-(D-prolylamino)phenyl]pyrimidin-2-yl}amino)phenyl]- piperazine-1-carboxamide: 1H-NMR (400MHz, (I6-DMSO): 10.19 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.96 (d, 2H), 6.59 (t, 1H), 3.74-3.71 (m, 1H), 3.42 (t, 4H), 3.10-3.05 (m, 2H), 3.01 (t, 4H), 2.91 (t, 2H), 2.22 (s, 3H), 2.09-2.02 (m, 1H), 1.84-1.76 (m, 1H), 1.70-1.63 (m, 2H), 1.02 (t, 3H); MS (EI) C28H34N8O2: 515.5 (M+H)+.
N-[4-(2-{[4-(4-D-prolylpiperazin-1-yl)phenyI]amino}pyrimidin-4-yl)phenyl]- D-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.97 (d, 2H), 3.92-3.89 (m, 1H), 3.75-3.71 (m, 1H), 3.65-3.59 (m, 4H), 3.09-2.98 (m, 5H), 2.91 (t, 2H), 2.69-2.63 (m, 1H), 2.09-2.02 (m, 2H), 1.84-1.76 (m, 1H), 1.70-1.54 (m, 5H); MS (EI) C30H36N8O2: 541.4 (M+H)+. N-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyI]amino}pyrimidin-4-yl)phenyl]-
D-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.20 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.96 (d, 2H), 3.92-3.89 (m, 1H), 3.75-3.71 (m, 1H), 3.65-3.59 (m, 4H), 3.09-2.98 (m, 5H), 2.91 (t, 2H), 2.69-2.63 (m, 1H), 2.09-2.02 (m, 2H), 1.84-1.76 (m, 1H), 1.70-1.56 (m, 5H); MS (EI) C30H36N8O2: 541.4 (M+H)+. l-Methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- prolinamide: 1H NMR (400 MHz, (I6-DMSO): 9.93 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.87 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.12 (m, 1H), 3.05 (m, 4H), 2.95 (m, 1H), 2.36 (m, 4H) 2.17 (m, 1H), 1.80 (m, 3H); MS (EI) for C26H30N6O2: 459 (MH+). l-Methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)piperidine-2-carboxamide: 1H NMR (400 MHz, (I6-DMSO): 9.97 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.85 (d, 2H), 7.67 (d, 2H), 7.28 (d, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.05 (m, 4H), 2.92 (m, 1H), 2.60 (dd, 1H), 2.16 (s, 3H) 2.03 (m, 1H), 1.76 (m, 2H), 1.60 (m, 3H), 1.25 (m, 1H); MS (EI) for C27H32N6O2: 473 (MH+).
N-{4-[2-({4-[4-(Piperidin-4-ylcarbonyl)piperazin-1- yI]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H NMR (400 MHz, dδ-DMSO): 10.25 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.36 (s, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.28 (d, 1H), 6.97 (d, 2H), 3.64 (m, 4H), 3.17 (m, 2H), 3.06 (m, 4H), 2.93 (m, 1H), 2.81 (m, 2H), 2.09 (s, 3H) 1.60-1.75 (m, 4H); MS (EI) for C28H33N7O2: 500 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-pyridin-4- ylacetamide: 1H NMR (400 MHz, d6-DMSO): 10.53 (s, 1H), 9.38 (s, 1H), 8.53 (d, 2H), 8.44 (d, 1H), 8.12 (d, 2H), 7.95 (d, 1H), 7.76 (d, 2H), 7.67 (d, 2H), 7.35 (d, 1H), 6.92 (d, 2H), 3.75 (m, 6H), 3.04 (m, 4H). MS (EI): 467 (MH+).
2-(3-fluorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.44 (s, 1H), 9.36 (s, 1H), 8.42 (m, 1H), 8.09 (d, 2H), 7.74 (d, 2H), 7.64 (d, 2H), 7.35 (m, 1H), 7.24 (m, 1H), 7.15 (d, 2H), 7.07 (m, 1H), 6.90 (d, 2H), 3.71 (m, 6H), 3.04 (m, 4H). MS (EI): 484 (MH+).
3-(4-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.73 (d, 2H), 7.68 (d, 2H), 7.35 (d, 2H), 7.26 (m, 3H), 6.93 (d, 2H), 3.74 (m, 4H), 3.04 (m, 4H), 2.92 (t, 2H), 2.67 (t, 2H). MS (EI): 515 (MH+).
2-(3-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.47 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.66 (d, 2H), 7.43 (s, 1H), 7.32 (m, 4H), 6.93 (d, 2H), 3.74 (m, 6H), 3.04 (m, 4H). MS (EI): 500 (MH+). 2-methyl-N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3- phenyl-propanamide: 1H NMR (400 MHz, d6-DMSO): 10.12 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.09 (d, 2H), 7.72 (d, 2H), 7.67 (d, 2H), 7.25 (m, 4H), 7.17 (m, 2H), 6.93 (d, 2H), 3.74 (m, 4H), 3.06 (m, 4H), 2.99 (m, 1H), 2.81 (m, 1H), 2.64 (m, 1H), 1.12 (d, 3H). MS (EI): 494 (MH+). trans-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2- phenyl-cyclopropanecarboxamide: 1H NMR (400 MHz, d6-DMSO): 10.53 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.77 (d, 2H), 7.67 (d, 2H), 7.28 (m, 3H), 7.21 (m, 3H), 6.93 (d, 2H), 3.74 (m, 4H), 3.04 (m, 4H), 2.39 (m, 1H), 2.1 1 (m, 1H), 1.53 (m, 1H), 1.42 (m, 1H). MS (EI): 492 (MH+).
2-(4-fluorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.44 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.65 (d, 2H), 7.38 (m, 2H), 7.27 (d, 1H), 7.18 (dd, 2H), 6.93 (d, 2H), 3.71 (m, 4H), 3.69 (s, 2H), 3.04 (m, 4H). MS (EI): 484 (MH+).
3-(2-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.67 (d, 2H), 7.45 (dd, 1H), 7.40 (dd, 1H), 7.25 (m, 3H), 6.93 (d, 2H), 3.74 (m, 4H), 3.04 (m, 6H), 2.70 (t, 2H). MS (EI): 515 (MH+).
3-(3-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.19 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.67 (d, 2H), 7.27 (m, 5H), 6.93 (d, 2H), 3.74 (m, 4H), 3.04 (m, 4H), 2.94 (t, 2H), 2.69 (t, 2H). MS (EI): 515 (MH+). 3-(2-fluorophenyl)-N-(4-{2-[(4-morpholin-4-yIphenyl)amino]pyrimidin-4-yl}- phenyl)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.73 (d, 2H), 7.67 (d, 2H), 7.35 (t, 1H), 7.26 (d, 2H), 7.11 (m, 2H), 6.93 (d, 2H), 3.74 (m, 4H), 3.04 (m, 4H), 2.95 (t, 2H), 2.68 (t, 2H). MS (EI): 498 (MH+).
Nalpha,Nalpha-dimethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]- pyrimidin-4-yl}phenyl)-L-phenylalanmainide: 1H NMR (400 MHz, d6-DMSO): 10.04 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.09 (d, 2H), 7.74 (d, 2H), 7.67 (d, 2H), 7.24 (m, 5H), 7.17 (m, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.48 (dd, 1H), 3.06 (m, 5H), 2.86 (dd, 1H), 2.49 (s, 6H). MS (EI): 523 (MH+).
2-(2-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.54 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.76 (d, 2H), 7.67 (d, 2H), 7.46 (m, 2H), 7.33 (m, 2H), 7.29 (d, 1H), 6.93 (d, 2H), 3.89(s, 2H), 3.74 (m, 4H), 3.04 (m, 4H). MS (EI): 500 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-pyridin-2- yl-acetamide: 1H NMR (400 MHz, d6-DMSO): 10.51 (s, 1H), 9.35 (s, 1H), 8.49 (d, 1H), 8.41 (d, 1H), 8.10 (d, 2H), 7.77 (m, 3H), 7.64 (d, 2H), 7.39 (d, 1H), 7.26 (m, 2H), 6.92 (d, 2H), 3.87 (s, 2H), 3.71 (m, 4H), 3.02 (m, 4H). MS (EI): 467 (MH+). 2-(4-chlorophenyl)-N-(4-{2-[(4-morpholin-4-yIphenyl)amino]pyrimidin-4-yl}- phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.47 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.66 (d, 2H), 7.39 (m, 4H), 7.26 (m, 1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.70 (s, 2H), 3.04 (m, 4H). MS (EI): 500 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-{4-
[(trifluoro-methyl)oxy] phenyl} acetamide: 1H NMR (400 MHz, d6-DMSO): 10.50 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.75 (d, 2H), 7.66 (d, 2H), 7.47 (d, 2H), 7.35 (d, 2H), 7.27(d, 1H), 6.93 (d, 2H), 3.74 (m, 6H), 3.04 (m, 4H). MS (EI): 550 (MH+).
2-[2-(methyloxy)phenyl]-N-(4-{2-[(4-morpholin-4-ylphenyI)amino]pyrimidin- 4-yl}-phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.34 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.76 (d, 2H), 7.67 (d, 2H), 7.26 (m, 3H), 7.00 (d, 1H), 6.91 (m, 3H), 3.77 (s, 3H), 3.74 (m, 4H), 3.67 (s, 2H), 3.04 (m, 4H). MS (EI): 496 (MH+).
2-[3-(methyloxy)phenyl]-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin- 4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.44 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.1 1 (d, 2H), 7.76 (d, 2H), 7.67 (d, 2H), 7.26 (m, 2H), 6.93 (m, 4H), 6.82 (dd, 1H), 3.74 (m, 7H), 3.55 (s, 2H), 3.04 (m, 4H). MS (EI): 496 (MH+).
2-[4-(methyloxy)phenyl]-N-(4-{2-[(4-morpholin-4-ylphenyl)amino)pyrimidin- 4-yl}phenyI)acetamide: 1K NMR (400 MHz, d6-DMSO): 10.38 (s, 1H), 9.38 (s, 1H), 8.43 (d, 1H), 8.11 (d, 2H), 7.75 (d, 2H), 7.67 (d, 2H), 7.26 (m, 3H), 6.93 (m, 4H), 3.74 (m, 7H), 3.60 (s, 2H), 3.04 (m, 4H). MS (EI): 496 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-D- alaninamide: 1H NMR (400 MHz, d6-DMSO): 9.35 (s, 1H), 8.43 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.63 (d, 2H), 7.28 (d, 1H), 6.92 (d, 2H), 3.48 (m, 1H), 2.35 (q, 2H), 1.86 (br s, 8H), 1.24 (d, 3H), 1.03 (t, 3H). MS (EI): 446 (MH+). N-{4-[2-({4-[4-(N,N-dimethylglycyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.75 (d, 2H), 7.67 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.68 (m, 4H), 3.10 (s, 2H), 3.07 (m, 4H), 2.18 (s, 6H), 2.09 (s, 3H). MS (EI): 474 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-3- (methyloxy)propanamide: 1H NMR (400 MHz, d6-DMSO): 10.23 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.1 1 (d, 2H), 7.75 (d, 2H), 7.65 (d, 2H), 7.25 (d, 1H), 6.92 (d, 2H), 3.63 (t, 2H), 3.25 (s, 3H), 3.09 (m, 4H), 2.60 (t, 2H), 2.58 (m, 6H), 1.05 (t, 3H). MS (EI): 461 (MH+).
(2R)-2-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-2-phenylethanamide: 1H NMR (400 MHz, d6-DMSO): 9.37 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.80 (d, 2H), 7.66 (d, 2H), 7.49 (d, 2H), 7.34 (t, 2H), 7.26 (m, 2H), 6.92 (d, 2H), 4.56 (s, 1H), 3.75 (m, 4H), 3.04 (m, 4H). MS (EI): 481 (MH+).
N'2',N'2'-dimethyl-N-(4-{2-[(4-morphoIin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyO-D-alaninamide: 1H NMR (400 MHz, d6-DMS0): 10.02 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.84 (d, 2H), 7.66 (d, 2H), 7.28 (d,1H), 6.92 (d, 2H), 3.75 (m, 4H), 3.21 (q, 1H), 3.04 (m, 4H), 2.25 (s, 6H), 1.19 (d, 3H). MS (EI): 447 (MH+). l-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide: 1H NMR (400 MHz, d6-DMSO): 9.94 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.87 (d, 2H), 7.67 (d, 2H), 7.30(d,1H), 6.94 (d, 2H), 3.76 (m, 4H), 3.12 (m, 1H), 3.05 (m, 4H), 2.95 (m, 1H), 2.36 (s, 3H), 2.30 (m, 1H), 2.18 (m, 1H), 1.78 (m, 3H). MS (EI): 459 (MH+).
N'2',N'2'-dimethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyO-L-alaninamide: 1H NMR (400 MHz, d6-DMS0): 10.03 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.84 (d, 2H), 7.67 (d, 2H), 7.28 (d,1H), 6.92 (d, 2H), 3.75 (m, 4H), 3.21 (q, 1H), 3.05 (m, 4H), 2.25 (s, 6H), 1.19 (d, 3H). MS (EI): 447 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-1-phenyl- cyclopropanecarboxamide: 1H NMR (400 MHz, d6-DMSO): 9.38 (s, 1H), 8.43 (d, 1H), 8.09 (d, 2H), 7.72 (d, 2H), 7.65 (d, 2H), 7.40 (m, 4H), 7.28 (m, 2H), 6.92 (d, 2H), 3.74 (m, 4H), 3.04 (m, 4H), 1.74 (dd, 2H), 1.15 (dd, 2H). MS (EI): 492 (MH+).
2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyI)- butanamide: 1H NMR (400 MHz, d6-DMSO): 10.12 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.78 (d, 2H), 7.67 (d, 2H), 7.27 (d,1H), 6.93 (d, 2H), 3.75 (m, 4H), 3.04 (m, 4H), 2.46 (q, 1H), 1.65 (m, 1H), 1.41 (m, 1H), 1.10 (d, 3H), 0.87 (t, 3H). MS (EI): 432 (MH+).
(2S)-1-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-azetidine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.88 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.89 (d, 2H), 7.67 (d, 2H), 7.29 (d,1H), 6.93 (d, 2H), 3.74 (m, 4H), 3.56 (t, 1H), 3.36 (m, 1H), 3.04 (m, 4H), 2.93 (q, 1H), 2.33 (s, 3H), 2.30 (m, 1H), 2.12 (m, 1H). MS (EI): 445 (MH+).
2,4,6-trichloro-N-(3-{[4-(4-methyl-2-thienyl)pyrimidine-2-yl]amino}propyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 8.68 (br s, 1H), 8.24 (d, 1H), 7.72-7.70 (m, 3H), 7.29 (s, 1H), 7.17 (t, 1H), 6.98 (d, 1H), 3.37-3.35 (m, 2H), 3.28-3.27 (m, 2H), 2.22 (s, 3H), 1.77 (br t, 2H). MS (EI): 457.0 (MH+).
N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}cyclopropanecarboxamide: MS (EI) C29H34N6O2: 499 (MH+). 4-{4-[(4-{4-[(cyclopropylcarbonyl)amino]phenyl}pyrimidin-2- yl)amino]phenyl}-N-ethylpiperazine-1-carboxamide: MS (EI) C27H3iN7O2: 486 (MH+).
N-[3-({4-[3,4-bis(mehtyloxy)phenyl]pyrimidine-2-yl}amino)propyl]-2,6- dichloro-benzamide: 1H-NMR (400MHz, d6-DMSO): 8.67 (br s, 1H), 8.26 (d, 1H), 7.69- 7.67 (m, 2H), 7.49-7.35 (m, 3H), 7.14-7.09 (m, 2H), 7.03 (d, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.42 (m, 2H), 3.32 (m, 2H), 1.80 (m, 2H). MS (EI): 461.2 (MH+).
2,6-dichloro-N-[3-({4-[(4-morpholino-4-ylphenyl)amino]pyrimidin-2- yl}amino)-propyl]benzamide: 1H-NMR (400MHz, d6-DMSO): 8.85 (br s, 1H), 8.63 (t, 1H), 7.69 (d, 1H), 7.48 (d, 2H), 7.44 (d, 1H), 7.42 (s, 1H), 7.37-7.33 (m, 1H), 6.81 (d, 2H), 6.59 (br s, 1H), 5.83 (d, 1H), 3.67-3.65 (m, 4H), 3.23-3.20 (m, 4H), 2.97-2.94 (m, 4H), 1.70 (t, 2H). MS (EI): 501.2 (MH+).
2,6-dichloro-N-(3-{[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-fluoropyrimidin- 2- yl]amino}proypyl)benzamide: 1H-NMR (400MHz, d6-DMSO): 8.62 (t, 1H), 8.29 (d, 1H), 7.49-7.42 (m, 4H), 7.37-7.33 (m, 1H), 7.15 (t, 1H), 6.94-6.92 (m, 1H), 4.27-4.21 (m, 4H), 3.33-3.22 (m, 4H), 1.74 (t, 2H); MS (EI): 477.1 (MH+).
2,6-dichloro-N-{3-[(4-{3-[(dimethylamino)methyl]phenyl}pyrimidin-2- yl)amino]propyl}benzamide: 1H-NMR (400MHz, d6-DMSO): 8.68 (t, 1H), 8.31 (d, 1H), 8.01-7.95 (m, 2H), 7.49-7.38 (m, 5H), 7.23 (br s, 1H), 7.10 (d, 1H), 3.43 (m, 2H), 3.33- 3.29 (m, 4H), 2.14 (s, 6H), 1.82 (t, 2H); MS (EI): 460.2 (MH+). 2,6-dichIoro-N-[3-({4-[3-(l-methylethyl)phenyl]pyrimidin- 2-yl}amino)- propyl]-benzamide: 1H-NMR (400MHz, d6-DMSO): 8.66 (t, 1H), 8.31 (d, 1H), 7.95- 7.88 (m, 2H), 7.55 (br s, 1H), 7.45-7.43 (m, 2H), 7.40-7.34 (m, 3H), 7.20 (br s, 1H), 3.30 (br s, 2H), 3.29-3.25 (m, 2H), 2.92 (septet, 1H), 1.78 (m, 2H), 1.18 (d, 6H); MS (EI): 443.0 (MH+).
2,6-dichloro-N-{3-[(4-{4-[(l-methylethyl)oxy]phenyl}pyrimidin-2- yl)amino]propyl}-benzamide: 1H-NMR (400MHz, d6-DMSO): 8.68 (t, 1H), 8.25 (d, 1H), 8.03 (d, 2H), 7.49-7.47 (m, 2H), 7.42-7.38 (m, 1H), 7.10 (t, 1H), 7.03 (d, 1H), 6.98 (d, 2H), 4.69 (septet, 1H), 3.42 (m, 2H), 3.30 (m, 2H), 1.80 (t, 2H), 1.27 (d, 6H); MS (EI): 459.0 (MH+).
N-[3-({4-[3-(acetylamino)phenyl]pyrimidin- 2-yl}amino)propyl]-2,6-dichloro- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.1 (s, 1H), 8.70 (t, 1H), 8.33-8.27 (m, 2H), 7.70 (m, 2H), 7.49-7.46 (m, 2H), 7.42-7.37 (m, 2H), 7.37 (br s, 1H), 7.01 (d, 1H), 3.43 (m, 4H), 2.02 (s, 3H), 1.97 (m, 2H). MS (EI): 458.2 (MH+).
2,6-dichloro-N-[3-({4-[(E)-2-phenyIethenyl]pyrimidin-2-yl}amino)propyl]- benzamide: 1H-NMR (400MHz, d6-DMSO): 8.71 (t, 1H), 8.27 (d, 1H), 7.76 (d, 1H), 7.67-7.65 (m, 2H), 7.51-7.49 (m, 2H), 7.44-7.34 (m, 4H), 7.12-7.06 (m, 2H), 6.72 (d, 1H), 3.36 (m, 2H), 3.33 (m, 2H), 1.81 (t, 2H). MS (EI): 427.0 (MH+). phenyl (4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)carbamate: 1H-NMR (400MHz, d6-DMSO): 8.59 (d, 1H), 7.90 (d, 2H), 7.69 (d, 1H), 7.44-7.40 (m, 2H), 7.28-7.20 (m, 5H), 6.97 (d, 2H), 6.62 (d, 2H), 5.90 (s, 2H), 3.74-3.72 (m, 4H), 3.13-3.11 (m, 4H). MS (EI): 468.1 (MH+). phenylmethyl (4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- carbamate: 1H-NMR (400MHz, d6-DMSO): 8.55 (d, 1H), 7.85 (d, 2H), 7.64 (d, 1H), 7.33-7.30 (m, 5H), 7.13 (d, 2H), 6.92 (d, 2H), 6.62 (d, 2H), 5.88 (s, 2H), 5.88 (s, 2H), 3.74-3.71 (m, 4H), 3.11-3.09 (m, 4H). MS (EI): 428.3 (MH+). N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}-3-(methyloxy)propanamide: 1H-NMR
(400MHz, d6-DMSO): 10.2 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.95 (d, 2H), 3.71-3.69 (m, 4H), 3.65 (t, 2H), 3.25 (s, 3H), 3.06-3.03 (m, 4H), 2.59 (t, 2H), 1.23 (s, 9H). MS (EI): 517.4 (MH+).
N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-3-(methyloxy)propanamide: 1H-NMR (400MHz, d6-DMSO): 10.2 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.65-3.60 (m, 4H), 3.47-3.37 (m, 4H), 3.25 (s, 3H), 3.03-3.02 (m, 3H), 2.60 (t, 2H), 2.21-2.07 (m, 4H), 1.94-1.87 (m, 1H), 1.78-1.73 (m, 1H). MS (EI): 515.2 (MH+).
3-(methyloxy)-N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1- yl]phenyl}amino)-pyrimidin-4-yl]phenyl}propanamide: 1H-NMR (400MHz, d6- DMSO): 10.2 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.76 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.96 (d, 2H), 3.65-3.62 (m, 6H), 3.25 (s, 3H), 3.08-3.02 (m, 4H), 2.92 (m, 1H), 2.59 (t, 2H), 1.02 (d, 6H). MS (EI): 503.4 (MH+).
N-ethyl-4-(4-{[4-(4-{[3-(methyIoxy)propanoyl]amino}phenyl)pyrimidin-2-yl]- amino}phenyl)piperazine-1-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.2 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 6.97 (d, 2H), 6.59 (t, 1H), 3.64 (t, 2H), 3.43 (m, 4H), 3.25 (s, 3H), 3.10-3.03 (m, 6H), 2.61 (t, 2H), 1.02 (t, 3H). MS (EI): 504.4 (MH+).
N-(4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)-2- phenyl-acetamide: 1H-NMR (400MHz, d6-DMSO): 10.45 (s, 1H), 9.36 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.76 (d, 2H), 7.64 (d, 2H), 7.38-7.33 (m, 3H), 7.27 (d, 1H), 6.92 (d, 2H), 3.69 (s, 2H), 3.10-3.04 (m, 4H), 2.35 (q, 3 H), 1.89 (s, 2H), 1.03 (t, 2H); MS (EI): 493.1 (MH+). l-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidin-2-one: 1H-NMR (400MHz, d6-DMSO): 8.26 (d, 1H), 8.14 (d, 2H), 7.77 (d, 2H), 7.65 (d, 2H), 7.36 (d, 1H), 7.25 (d, 2H), 3.92-3.84 (m, 5H), 3.82-3.74 (m, 1H), 3.74-3.60 (m, 1H), 3.42- 3.30 (m, 4H), 3.06-3.02 (m, 1H), 2.16-2.06 (m, 2H); MS (EI): 416.1 (MH+).
(R)-2-amino-N-(4-(2-(4-(4-(cyclobutanecarbonyI)piperazin-1-yl)phenylamino)- pyrimidin-4-yl)phenyl)propanamide: 1H-NMR (400MHz, d6-DMSO): 9.41 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 3.63-3.56 (m, 2H), 3.43-3.37 (m, 3H), 3.18 (d, 1H), 3.07-2.98 (m, 4H), 2.25-2.02 (m, 4H), 1.98-1.83 (m, 1H), 1.82-1.70 (m, 1H), 1.23 (d, 3H); MS (EI): 500.2 (MH+).
(R)-2-amino-N-(4-(2-(4-(4-pivaloylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)propanamide: 1H-NMR (400MHz, d6-DMSO): 9.41 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 3.73-3.67 (m, 4H), 3.52-4.42 (m, 1H), 3.08-3.02 (m, 4H), 1.25 (s, 3H), 1.23 (d, 3H); MS (EI): 502.4 (MH+).
(S)-2-hydroxy-3-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)- phenyl)butanamide: 1H-NMR (400MHz, d6-DMSO): 9.90 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.90 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 5.76 (d, 1H), 3.86 (dd, 1H), 3.78-3.73 (m, 4H), 3.08-3.02 (m, 4H), 0.96 (d, 3H), 0.87 (d, 3H); MS (EI): 448.3 (MH+).
(R)-2-hydroxy-3-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-y.)- phenyl)butanamide: 1H-NMR (400MHz, d6-DMSO): 9.90 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.90 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.94 (d, 2H), 5.76 (d, 1H), 3.86 (dd, 1H), 3.78-3.73 (m, 4H), 3.08-3.02 (m, 4H), 0.96 (d, 3H), 0.87 (d, 3H); MS (EI): 448.3 (MH+).
N-{4-[2-({4-[4-(cyclopropylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yI]-phenyl}-D-alaninamide: 1H NMR (400 MHz, d6-DMSO): 11.17 (s, 1H), 10.04 (s, 1H), 8.58 (s, 1H), 8.40 (s, 2H), 8.11-8.09 (m, 2H), 7.96-7.82 (m, 3H), 7.76-7.65 (m, 1H), 7.45 (d, 1H), 4.05 (t, 4H), 3.75-3.70 (m, 1H), 3.50 (t, 4H), 2.10-2.00 (m, 1H), 1.45 (d, 3H), 0.82-0.72 (m, 4H). MS (EI): 486 (MH+).
(2S)-2-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-2-phenylethanamide: 1H NMR (400 MHz, d6-DMSO): 11.73 (s, 1H), 10.08 (s, 1H), 8.99 (s, br, 3H), 8.58 (s, 1H), 8.19 (d, 2H), 7.96-7.83 (m, 3H), 7.76-7.65 (m, 3H), 7.45-7.40 (m, 3H), 5.40 (s, br, 1H), 3.85 (s, br, 4H), 3.50 (s, br, 4H). MS (EI): 481 (MH+).
2-amino-2-(4-chlorophenyl)-N-(4-{2-[(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 11.80 (s, 1H), 10.00 (s, 1H), 9.00 (s, 2H), 8.57 (d, 1H), 8.20 (d, 2H), 7.95-7.83 (m, 4H), 7.80-7.60 (m, 3H), 7.58 (d, 2H), 7.43 (d, 1H), 5.50 (s, 1H), 4.00 (t, 4H), 3.50 (t, 4H). MS (EI): 515 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)morpholine- 3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 11.60 (s, 1H), 10.20 (s, 1H), 10.00 (s, 1H), 9.40 (s, br, 1H), 8.58 (d, 1H), 8.20 (d, 2H), 7.95-7.88 (m, 3H), 7.60-7.20 (m, 4H), 4.42-4.30 (m, 2H), 4.05-3.90 (m, 2H), 3.85-3.70 (m, 4H), 3.60-3.45 (m, 4H), 3.25-3.10 (m, 3H). MS (EI): 461 (MH+). l-ethyl-3-[4-(2-{[4-(4-ethylpiperazin-1-yl)-3-
(methyloxy)phenyl]amino}pyrimidin-4-yl)phenyI]urea: 1H NMR (400 MHz, d6- DMSO): 9.40 (s, 1H), 8.90 (s, 1H), 8.42 (d, 1H), 8.20 (s, 1H), 8.05 (d, 2H), 7.56 (d, 2H), 7.28 (d, 2H), 6.83 (d, 1H), 6.36 (t, 1H), 3.80 (s, 3H), 3.12 (q, 2H), 2.98 (s, br, 4H), 2.58 (s, br, 4H), 2.42 (q, 2H), 1.08-1.00 (m, 6H). MS (EI): 476 (MH+). N-[4-(2-{[4-(4-ethylpiperazin-1-yl)-3-(methyloxy)phenyl]amino} pyrimidin-4- yl)-phenyl]-D-prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.23 (s, 1H), 11.05 (s, 1H), 10.18 (s, br, 1H), 10.00 (s, 1H), 8.75 (s, br, 1H), 8.57 (d, 1H), 8.21 (d, 2H), 7.85 (d, 2H), 7.63 (s, 1H), 7.44 (d, 1H), 7.33 (dd, 1H), 7.03 (d, 1H), 4.55-4.50 (m, 1H), 3.82 (s, 3H), 3.80-3.60 (m, 4H), 3.35-3.05 (m, 7H), 2.50-2.45 (m, 2H), 2.02-1.95 (m, 3H), 1.30 (t, 3H). MS (EI): 502 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)-3-(methyloxy)phenyl]amino} pyrimidin-4- yl)-phenyl]acetamide: 1H NMR (400 MHz, d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (s, 1H), 8.15 (d, 2H), 7.80-7.60 (m, 3H), 7.33 (d, 2H), 6.85 (d, 1H), 3.80 (s, 3H), 2.90 (s, br, 4H), 2.35 (q, 2H), 2.05 (s, 4H), 1.95 (s, 3H), 1.00 (s, 3H). MS (EI): 447 (MH+). l-(2,6-dichlorophenyl)-3-(3-{[4-(4-methyl-2-thienyI)pyrimidin-2- yl]amino}propyl)-urea: 1H NMR (400 MHz, d6-DMSO): 8.26 (d, 1H), 8.02 (br, 1H), 7.71 (s, 1H), 7.48 (d, 2H), 7.31 (s, 1H), 7.26 (t, 1H), 7.16 (t, 1H), 6.99 (d, 1H), 6.39 (t, 1H), 3.38 (t, 2H), 3.15 (t, 2H), 2.21 (s, 3H), 1.65 (m, 2H). MS (EI) for C19H19Cl2N5OS : 436 (MH+). l-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-(4-methyl-2-thienyl)pyrimidin- 2-yl]amino}propyl)urea: 1H NMR (400 MHz, d6-DMSO): 8.65 (d, 2H), 8.23 (s, 1H), 7.7 (s, 1H), 7.4 (t, 1H), 7.38-7.15 (m, 3H), 7.0 (s, 1H), 6.8 (t, 1H), 3.38 (t, 2H), 3.2 (t, 2H), 2.21 (s, 3H), 1.75 (m, 2H). MS (EI) for C20H19F4N5OS : 454 (MH+). 2,6-dichloro-N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2- yl}amino)propyl]-benzenesulfonamide: 1H NMR (400 MHz, d6-DMSO): 8.16 (d, 1H), 8.12 (t, 1H), 7.94 (d, 2H), 7.58 (d, 2H), 7.48 (t,1H), 6.97 (d, 1H), 6.92 (t, 6.76 (d, 2H)3.28 (m, 2H), 3.022.96 (m, 8H), 1.68 (m, 2H). MS (EI) for C21H23Cl2N5O2S : 480 (MH+).
N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2,6- difluoro-benzenesulfonamide: 1H NMR (400 MHz, d6-DMSO): 8.25 (T, 1H), 8.16 (d, 1H), 7.94 (d, 2H), 7.66 (m, 1H), 7.24 (t, 2H), 6.98 (d, 1H), 6.95 (t, 1H), 6.76 (d, 2H), 3.33(t, 2H), 3.0 (t, 2H), 2.98 (s, 6H), 1.68 (m, 2H). MS (EI) for C2iH23F2N5O2S : 448 (MH+).
N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2- yl}amino)propyl]naphthalene-2-sulfonamide: 1H NMR (400 MHz, d6-DMSO): 8.42 (br, 1H), 8.15-8.06 (m, 3H), 8.02 (d, 1H), 7.94 (d, 2H), 7.8 (dd, 1H), 7.74-7.62 (m, 3H), 6.96 (d, 1H), 6.92 (t, 1H), 6.74 (d, 2H), 3.3 (t, 2H), 2.98 (s, 6H), 2.83 (t, 2H), 1.63 (m, 2H). MS (EI) for C25H27N5O2S : 462 (MH+).
N-[3-({4-[4-(dimethyIamino)phenyl]pyrimidin-2-yI}amino)propyl]-3,4- bis(methyloxy)benzenesulfonamide: 1H NMR (400 MHz, d6-DMSO): 8.17 (d, 1H), 7.94 (d, 2H), 7.46 (t, 1H), 7.34 (dd, 1H), 7.27 (d, 1H), 7.06 (d, 1H), 6.97 (d, 1H), 6.93 (t, 1H), 6.76 (d, 2H), 3.8 (s, 6H), 3.3 (t, 2H), 2.98 (s, 6H), 2.8 (t, 2H), 1.65 (m, 2H). MS (EI) for C23H29N5O4S : 472 (MH+).
3-chloro-N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2- yl}amino)propyl]propane-1-sulfonamide: 1H NMR (400 MHz, d6-DMSO): 8.2 (s, 1H), 7.98 (d, 2H), 7.2 (t, 1H), 7.0 (t, 2H), 6.8-6.7 (m, 2H), 3.7 (t, 2H), 3.1-2.9 (m, 10H), 2.05 (t, 2H), 1.7 (m, 2H), 1.2 (m, 2H). MS (EI) for C,8H26C1N5O2S : 412 (MH+).
N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2-yl}amino)propyl]propane-1- sulfonamide: 1H NMR (400 MHz, d6-DMSO): 8.2 (d, 1H), 7.96 (d, 2H), 7.0-6.95 (m, 3H), 6.76 (d, 2H), 3.38 (t, 2H), 3.0-2.9 (m, 10H), 1.75 (t, 2H), 1.6 (q, 2H), 0.95 (t, 3H). MS (EI) for C18H27N5O2S : 378 (MH+). methyl (3-{[4-(2,4-dichlorophenyl)pyrimidin-2-yl]amino}propyl)carbamate: 1H MR (400 MHz, d6-DMSO): 8.4 (d, 1H), 7.75 (s, 1H), 7.63-7.55 (m, 2H), 7.35 (t, 1H), 7.12 (t, 1H), 6.8 (d, 1H), 3.5 (s, 3H), 3.28 (t, 2H), 3.03 (t, 2H), 1.65 (m, 2H). MS (EI) for C15H16Cl2N4O2 : 355 (MH+). 1-methylethyl (3-{[4-(2,4-dichIorophenyl)pyrimidin-2-yl]amino}propyl)- arbamate: 1H NMR (400 MHz, d6-DMSO): 8.38 (d, 1H), 7.75 (s, 1H), 7.63-7.55 (m, 2H),7.35 (t, 1H), 7.0 (t, 1H), 6.8 (d, 1H), 4.72 (m, 1H), 3.28 (q, 2H), 3.0 (q, 2H), 1.65 (p, 2H), 1.12 (d, 6H). MS (EI) for C]7H20Cl2N4O2: 383 (MH+). phenylmethyl (3-{[4-(2,4-dichlorophenyl)pyrimidin-2- yl]amino}propyl)carbamate: 1H NMR (400 MHz, d6-DMSO): 8.46 (d, 1H), 8.2 (br, 1H), 7.8 (d, 1H), 7.66 (br, 1H), 7.6 (dd, 1H), 7.4-7.28 (m, 5H), 7.04 (br, 1H), 5.0 (s, 2H), 3.4 (t, 2H), 3.1 (t, 2H), 1.7 (m, 2H). MS (EI) for C21H20Cl2N4O2: 431 (MH+).
N-{4-[2-({[3-(3-chlorophenyl)isoxazol-5-yl]methyl}amino)pyrimidin-4-yl]- henyl}acetamide:'H NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 8.37 (d, 1H), 8.06 (d, 2H), 7.92 (t, 1H), 7.88-7.82 (m, 2H), 7.7 (d, 2H), 7.56-7.48 (m, 2H), 7.2 (d, 1H), 7.0 (s, 1H), 4.7 (s, 2H), 2.05 (s, 3H). MS (EI) for C22H18ClN5O2: 420 (MH+). ethyl 4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)piperidine-1- carboxylate: 1H MR (400 MHz, (I6-DMSO): 10.18 (s, 1H), 8.3 (d, 1H), 8.04 (d, 2H), 7.7 (d, 2H), 7.13 (d, 1H), 7.06 (d, 1H), 4.05 (q, 3H), 3.95 (br, 2H), 2.96 (br, 2H), 2.08 (s, 3H), 1.9 (br, 2H), 1.4 (q, 2H), 1.2 (t, 3H). MS (EI) for C20H25N5O3: 384 (MH+). 1,1-dimethylethyI 4-({4-[4-(acetylamino)phenyl]pyrimidin-2- yl}amino)piperidine-1-carboxylate: 1H NMR (400 MHz, d6-DMSO): 10.18 (s, 1H), 8.3 (d, 1H), 8.05 (d, 2H), 7.7 (d, 2H), 7.2 (br, 1H), 7.1 (d, 1H), 3.92 (br, 3H), 2.9 (br, 2H), 2.08 (s, 3H), 1.87 (br, 2H), 1.46-1.36 (m, HH). MS (EI) for C22H29N5O3: 412 (MH+).
N-{4-[2-(3,5-diamino-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]phenyl}acetamide: 1H MR (400 MHz, d6-DMSO): 10.28 (s, 1H), 8.7 (d, 1H), 8.16 (d, 2H), 7.78 (d, 2H), 7.7 (d, 1H), 7.58 (s, 2H), 2.03(s, 3H). MS (EI) for C14H14N8O: 311 (MH+).
N-{4-[2-({5-[(4-ethylpiperazin-1-yl)carbonyl]pyridin-2-yl}amino)pyrimidin-4- yl]-henyl}acetamide:'H NMR (400 MHz, d6-DMSO): 10.26 (s, 1H), 10.12 (s, 1H), 8.6 (d, 1H), 8.46 (d, 1H), 8.36 (d, 1H), 8.18 (d, 2H), 7.9 (dd, 1H), 7.77 (d, 2H), 7.54 (d, 1H), 2.46-2.32 (m, 6H), 2.1 (s, 3H), 1.0 (t, 3H). MS (EI) for C24H27N7O2: 446 (MH+).
N-(4-{2-|(4-cyanophenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H MR (400 MHz, d6-DMSO): 10.24 (d, 2H), 8.6 (d, 1H), 8.17 (d, 2H), 8.06 (d, 2H), 7.78 (d, 4H), 7.5 (d, 1H), 2.05 9s, 3H). MS (EI) for C19Hi5N5O: 330 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyridin-4-yl}phenyl)acetamide: 1H MR (400 MHz, d6-DMSO): 10.14 (s, 1H), 8.82 (s, 1H), 8.12 (d, 1H), 7.72 9d, 2H), 7.62 (d, 2H), 7.53 (d, 2H), 6.97-6.92 (m, 2H), 6.9 (d, 2H), 3.74 (t, 4H), 3.02 (t, 4H), 2.07 (s, 3H). MS (EI) for C23H24N4O2: 389 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-5-methylpyrimidin-4- yl)phenyl]-3-(methyloxy)propanamide: 1H NMR (400 MHz, (I6-DMSO): 10.18 (s, 1H), 9.25 (s, 1H), 8.3 (s, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.61 (d, 2H), 6.86 (d, 2H), 3.64 (t,
2H), 3.25 (s, 3H), 3.03 (t, 4H), 2.6 (t, 2H), 2.38 (br, 2H), 2.2 (s, 3H), 1.03 (t, 3H). MS (EI) for C72H34N6O2: 475 (MH+). tert-buryl l-(4-(4-(4-acetamidophenyl)pyrimidin-2-ylamino)phenyl)piperidin- 4-ylcarbamate: 1H NMR (400 MHz, d6-DMSO): 10.21 (s, 1H), 9.38 (s, br, 1H), 8.43 (s, 1H), 8.08 (m, 2H), 7.74 (m, 2H), 7.62 (m, 2H), 7.23 (m, 1H), 6.98 (m, 3H), 3.77 (m, 2H), 3.63 (m, 2H), 2.09 (s, 3H), 1.80 (m, 2H), 1.49 (m, 2H), 1.30 (s, 9H). MS (EI) for C28H34N6O3: 503 (MH+). 4-(4-aminophenyl)-N-(4-(4-aminopiperidin-1-yl)phenyl)pyrimidin-2-amine:
1H MR (400 MHz, d6-DMSO): 9.19 (s, 1H), 8.3 (m, 1H), 7.87 (m, 2H), 7.63 (m, 2H), 7.14 (m, 1H), 6.92 (m, 2H), 6.62 (m, 2H), 5.74 (m, 2H), 3.57 (m, 2H), 2.67 (m, 2H), 1.81 (m, 2H), 1.38 (m, 2H). MS (EI) for C2iH24N6: 361 (MH+). N-(l-(4-(4-(4-acetamidophenyl)pyrimidin-2-ylamino)phenyl)piperidin-4-yl)- acetamide: 1H NMR (400 MHz, d6-DMSO): 10.26 (s, 1H), 9.34 (s, 1H), 8.43 (d, 1H), 8.1 (d, 2H), 7.85 (d, 1H), 7.75 (d, 2H), 7.64 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 3.67 (m, 1H), 3.55 (m, 2H), 2.72 (t, 2H), 2.09 (s, 3H), 1.88-1.76 (m, 5H), 1.48 (m, 2H). MS (EI) for C25H28N6O2: 445 (MH+). N-(4-(2-(4-(4-(cycIopropanecarbonyl)piperazin-1-yl)phenylamino)pyriinidin-
4-yI)-phenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, d6-DMSO): 10.51 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.87 (d, 2H), 7.69 (d, 2H), 7.28 (d, 1H), 6.97 (d, 2H), 3.82 (m, 2H), 3.61 (m, 2H), 3.25-2.99 (m, 4H), 2.04 (m, 1H), 1.83 (m, 1H), 0.89- 0.68 (m, 8H).. MS (EI) for C28H30N6O2: 483 (MH+). N-(4-(2-(4-(4-isobutyrylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)- tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.94 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.87 (d, 2H), 7.68 (d, 2H), 7.31 (d, 1H), 6.96 (d, 2H), 4.42 (m, 1H), 3.99 (m, 1H), 3.85 (m, 1H), 3.62 (m, 4H), 3.08 (m, 2H), 3.02 (m, 2H), 2.92 (m, 1H) 2.21 (m, 1H), 2.01 (m, 1H), 2.73 (m, 2H), 1.03 (d, 6H). MS (EI) for C29H34N6O3: 515 (MH+).
N-(4-(2-(4-(4-(cyclobutanecarbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yDpheny l)tctrahy drofuran-2-carboxaniidc: 1H NMR (400 MHz, d6-DMSO): 9.94 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.87 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 6.95 (d, 2H), 4.43 (m, 1H), 3.99 (m, 1H), 3.84 (m, 1H), 3.59 (m, 2H), 3.43 (m, 2H), 3.01 (m, 4H), 2.28-1.69 (m, 10H). MS (EI) for C30H34N6O3: 527 (MH+).
N-(4-(2-(4-(4-pivaloylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)- tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.95 (s, 1H), 9.42 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.88 (d, 2H), 7.69 (d, 2H), 7.30 (d, 1H), 6.95 (d, 2H), 4.43 (m, 1H), 4.0 (m, 1H), 3.84 (m, 1H), 3.7 (m, 4H), 3.04 (m, 4H), 2.22 (m, 1H), 2.02 (m, 1H), 1.86 (m, 2H), 1.23 (s, 9H). MS (EI) for C30H36N6O3: 529 (MH+).
N-cyclopropyl-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide: 1H NMR (400 MHz, d6-DMSO): 9.51 (s, br, 1H), 8.58 (s, br, 1H), 8.52 (d, 1H), 8.21 (d, 2H), 7.96 (d, 2H), 7.67 (d, 2H), 7.39 (d, 1H), 6.93 (d, 2H), 3.76 (m, 4H), 3.05 (m, 4H), 2.89 (m, 1H), 0.71 (m, 2H), 0.60 (m, 2H). MS (EI): 416 (MH+).
N-(2-methoxyethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)benzamide: 1H NMR (400 MHz, d6-DMSO): 9.51 (s, br, 1H), 8.68 (s, br, 1H), 8.52 (d, 1H), 8.23 (d, 2H), 8.00 (d, 2H), 7.67 (d, 2H), 7.40 (d, 1H), 6.94 (d, 2H), 3.75 (m, 4H), 3.47 (m, 4H), 3.28 (s, 3H), 3.05 (m, 4H). MS (EI): 434 (MH+).
2,6-dichloro-n-{3-[(4-pyridin-3-ylpyrimidin-2-yI)amino]propyl}-benzamide: 1H-NMR (400MHz, d6-DMSO): 9.25 (br s, 1H), 8.68-8.66 (m, 2H), 8.37 (m, 2H), 7.49- 7.47 (m, 3H), 7.42-7.38 (m, 1H), 7.32 (m, 1H), 7.21-7.20 (m, 1H), 3.44 (m, 2H), 3.29 (m, 2H), 1.82 (m, 2H). MS (EI): 402.0 (MH+).
2,6-dichloro-n-(3-{[4-(4-methyl-3,4-dihydro-2h-1,4-benzoxazin-7- yl)pyrimidin-2-yl]amino}propyl)benzamide: 1H-NMR (400MHz, d6-DMSO): 8.69 (t, 1H), 8.18 (d, 1H), 7.58 (dd, 1H), 7.51-7.40 (m, 4H), 7.02-6.97 (m, 2H), 6.73 (d, 1H), 4.25- 4.23 (m, 2H), 3.41 (m, 2H), 3.32-3.29 (m, 4H), 2.91 (s, 3H), 1.81 (t, 2H). MS (EI): 472.3 (MH+).
2,6-dichloro-n-(3-{[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-methyl-pyrimidin- 2-yl]amino}propyl)benzamide: 1H-NMR (400MHz, d6-DMSO): 8.68 (t, 1H), 7.62-7.59 (m, 2H), 7.51-7.49 (m, 2H), 7.44-7.40 (m, 1H), 7.02 (t, 1H), 6.97-6.92 (m, 2H), 4.30-4.28 (m, 4H), 3.44-3.43 (m, 2H), 3.32-3.29 (m, 2H), 2.27 (s, 3H), 1.80 (t, 2H); MS (EI): 473.3 (MH+).
N-(4-{2-[(3-{[(2,6-dichlorophenyl)carbonyl]amino}propyl)-amino]pyrimidin- 4-yl}phenyl)morpholine-4-carboxamide: 1H-NMR (400MHz, d6-DMSO): 8.69 (m, 2H), 8.33 (d, 1H), 8.18 (m, 1H), 7.60 (m, 2H), 7.51-7.49 (m, 2H), 7.44-7.34 (m, 2H), 7.20 (m, 1H), 7.01 (d, 1H), 3.62-3.61 (m, 4H), 3.43 (m, 6H), 3.32 (m, 2H), 1.83 (m, 2H). MS (EI): 529.1 (MH+).
2,6-dichloro-n-{3-[(4-{4-[(cyclopropylcarbonyl)amino]-phenyl}pyrimidin-2- yl)amino]propyl}benzamide: 1H-NMR (400MHz, d6-DMSO): 10.4 (s, 1H), 8.72 (t, 1H), 8.36-8.33 (m, 2H), 7.73 (m, 2H), 7.51-7.39 (m, 4H), 7.24 (m, 1H), 7.03 (d, 1H), 3.45 (m, 2H), 3.33 (m, 4H), 1.84-1.78 (m, 2H), 0.81-0.78 (m, 3H). MS (EI): 484.0 (MH+). N-(4-{2-[(3-{[(2,6-dichlorophenyl)carbonyl]amino}propyl)-amino]pyrimidin-
4-yl}phenyl)thiophene-2-carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.4 (s, 1H), 8.72 (t, 1H), 8.44 (t, 1H), 8.37 (d, 1H), 8.05 (s, 1H), 7.90-7.81 (m, 3H), 7.50-7.39 (m, 4H), 7.25-7.23 (m, 2H), 7.07 (d, 1H), 3.47 (m, 2H), 3.34 (m, 2H), 1.85 (m, 2H). MS (EI): 526.0 (MH+).
2,6-dichloro-n-(3-{[4-(4-{[n-(2-morphoIin-4-ylethyl)gIycyl]- amino}phenyl)pyrimidin-2-yl]amino}propyl)benzamide: 1H-NMR (400MHz, d6- DMSO): 10.0 (br s, 1H), 8.72 (t, 1H), 8.35-8.32 (m, 2H), 7.82-7.75 (m, 2H), 7.51-7.40 (m, 4H), 7.22 (s, 1H), 7.05 (d, 1H), 3.56 (m, 4H), 3.45 (m, 2H), 3.30 (m, 3H), 2.64 (m, 2H), 2.41-2.35 (m, 8H), 1.84 (br s, 2H). MS (EI): 586.1 (MH+). l-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-ethanone: 1H-NMR (400MHz, d6-DMSO): 8.50 (d, 1H), 8.26-8.24 (m, 2H), 8.12-8.10 (m, 2H), 7.30 (s, 1H), 7.64-7.62 (m, 2H), 7.31 (d, 1H), 7.00-6.98 (m, 2H), 3.82-3.80 (m, 4H), 3.12-3.10 (m, 4H), 2.64 (s, 3H). MS (EI): 375.1 (MH+).
(Ie)-I -(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}-phenyl)ethanone oxime: 1H-NMR (400MHz, d6-DMSO): 11.4 (s, 1H), 9.82 (br s, 1H), 8.55 (d, 1H), 8.20 (d, 2H), 7.85-7.82 (m, 4H), 7.45 (d, 1H), 7.36 (br s, 1H), 4.69 (br, 1H), 3.91 (m, 4H), 3.34 (m, 4H), 2.21 (s, 3H). MS (EI): 388.1 (MH-).
N-{4-[2-({4-[4-(cyclopropyIcarbonyl)piperazin-1-yl]phenyl}-amino)pyrimidin- 4-yl]phenyl}-2-phenyIacetamide: 1H-NMR (400MHz, d6-DMSO): 10.4 (s, 1H), 9.43 (br s, 1H), 8.42 (d, 1H), 8.10 (d, 2H), 7.75 (d, 2H), 7.67 (d, 2H), 7.33-7.20 (m, 2H), 7.07 (s, 2H), 6.97-6.95 (m, 4H), 3.82 (m, 4H), 3.67 (s, 2H), 3.03 (m, 4H), 2.07 (m, 1H), 0.75-0.69 (m. 4H). MS (EI): 533.2 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}ainino)propyl]-2- bromobenzamide: 1H-NMR (400MHz, d6-DMSO): 10.14 ppm (s, 1H), 8.42 ppm (t, 1H), 8.29 ppm (d, 1H), 8.06 ppm (d, 1H), 7.70 ppm (d,2H), 7.65 ppm (m, 1H), 7.39 ppm (m, 3H), 7.12 ppm (t, 1H), 7.07 ppm (d, 1H), 3.33 ppm (br. m, 2H), 3.31 ppm (m, 2H), 2.07 ppm (s, 3H), 1.81 ppm (m, 2H); MS (EI) C22H22BrN5O2: 468 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2- fluorobenzamide: 1H-NMR (400MHz, d6-DMSO): 10.17 ppm (s, 1H), 8.37 ppm (t, 1H), 8.30 ppm (d, 1H), 8.06 ppm (d, 2H), 7.70 ppm (d,2H), 7.61 ppm (m, 1H), 7.50 ppm (m, 1H), 7.26 ppm (m, 2H), 7.16 ppm (t, 1H), 7.08 ppm (d, 1H), 3.41 ppm (br. m, 2H), 3.33 ppm (m, 2H), 2.08 ppm (s, 3H), 1.81 ppm (br. m, 2H); MS (EI) C22H22FN5O2: 408 (MH+). N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}aiiiino)propyl]-2- chlorobenzamide: 1H-NMR (400MHz, 4-DMSO): 10.14 ppm (s, 1H), 8.45 ppm (t, 1H), 8.28 ppm (d, 1H), 8.04 ppm (d, 2H), 7.68 ppm (d,2H), 7.68 ppm (d, 2H), 7.47 ppm (m, 1H), 7.41 ppm (m, 2H), 7.35 ppm (m, 1H), 7.13 ppm (t, 1H). 7.06 ppm (d, 1H), 3.42 ppm (br. m, 2H), 3.29 ppm (m, 2H), 2.05 ppm (s, 3H), 1.78 ppm (br m, 2H); MS (EI) C22H22BrN5O2: 468 (MH+).
N-[4-(2-{[3-(morpholin-4-ylsulfonyl)phenyl]amino}pyrimidin-4-yl)pheiiyl]- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.23 ppm (s, 1H), 10.12 ppm (s, 1H), 8.74 ppm (s, 1H), 8.58 ppm (d, 1H), 8.21 ppm (d,2H), 7.93 ppm (m, 1H), 7.76 ppm (d, 2H), 7.60 ppm (t, 1H), 7.47 ppm (d, 1H), 7.30 ppm (m, 1H), 3.64 ppm (m, 4H), 2.90 ppm (m, 4H), 2.10 ppm (s, 3H); MS (EI) C22H23N5O4S: 454 (MH+).
N-{4-[2-({3-[(cyclohexylmethyl)amino]phenyl}amino)pyrimidin-4-yl]phenyl}- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.43 ppm (s, 1H), 9.32 ppm (s, 1H), 8.46 ppm (d, 1H), 8.13 ppm (d, 2H), 7.77 ppm (d,2H), 7.30 ppm (d, 2H), 7.17 ppm (s, 1H), 6.94 ppm (m, 2H), 6.22 ppm (m, 1H), 5.56 ppm (t, 1H), 2.87 ppm (t, 2H), 2.09 ppm (s, 3H), 1.85 ppm (br d, 2H), 1.69 ppm (br m, 2H),1.64 ppm (br m, 1H), 1.19 ppm (m, 3H), 0.94 ppm (m, 2H); MS (EI) C25H29N5O: 416 (MH+).
N-(4-{2-[(3-{[(5-bromo-2- fluorophenyl)methyl]amino}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H- NMR (400MHz, d6-DMSO): 10.21 ppm (s, 1H), 9.37 ppm (s, 1H), 8.45 ppm (d, 1H), 8.12 ppm (d, 2H), 7.74 ppm (d, 2H), 7.55 ppm (m, 1H), 7.47 ppm (m, 1H), 7.31 ppm (d, 1H), 7.20 ppm (m, 1H), 7.05 ppm (m, 1H), 7.00 ppm (t, 1H), 6.28 ppm (t, 1H), 6.22 ppm (m, 1H), 4.32 ppm (d, 2H), 2.09 ppm (s, 3H); MS (EI) C25H2iBrFN50: 507 (MH+).
N-(4-{2-[(3-{[(2,5-dimethyIphenyl)methyl]amino}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide: 1H-NMR (400MHz, dδ-DMSO): 10.20 ppm (s, 1H), 9.33 ppm (s, 1H), 8.45 ppm (d, 1H), 8.13 ppm (d, 2H), 7.73 ppm (d, 2H), 7.30 ppm (d, 1H), 7.16 ppm (m, 2H), 7.06 ppm (d, 1H), 6.97 ppm (m, 3H), 6.23 ppm (m, 1H), 5.99 ppm (t, 1H), 4.17 ppm (d, 2H), 2.28 ppm (s, 3H), 2.21 ppm (s, 3H), 2.08 ppm (s, 3H); MS (EI) C27H27N5O: 438 (MH+). N-(4-{2-[(3,4-dimorpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 ppm (s, 1H), 9.43 ppm (s, 1H), 8.46 ppm (d, 1H), 8.14 ppm (d, 2H), 7.74 ppm (d, 2H), 7.65 ppm (s, 1H), 7.34 ppm (m, 2H), 7.29 ppm (d, 2H), 6.88 ppm (d, 1H), 3.75 ppm (m, 8H), 3.15 ppm (br s, 4H), 3.05 ppm (br s, 4H), 2.09 ppm (s, 3H); MS (EI) C26H30N6O3: 475 (MH+).
N-{4-[2-({4-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}cyclopropanecarboxamide: 1H-NMR (400MHz, d6-DMSO): 10.47 ppm (s, 1H), 9.41 ppm (s, 1H), 8.67 ppm (m, 2H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.89 ppm (m, 1H), 7.76 ppm (d, 2H), 7.69 ppm (d, 2H), 7.51 ppm (m, 1H), 7.28 ppm (d, 1H), 6.97 ppm (d, 2H), 3.80 ppm (s, 2H), 3.49 ppm (s, 2H), 3.13 ppm (br d, 4H), 1.83 ppm (m, 1H), 0.84 ppm (m, 4H); MS (EI) C30H29N7O2: 520 (MH+).
N-{4-[2-({4-[4-(2-methylpropanoyI)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}butanamide: 1H-NMR (400MHz, d6-DMSO): 10.16 ppm (s, 1H), 9.41 ppm (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.77 ppm (d, 2H), 7.68 ppm (d, 2H), 7.28 ppm (d, 1H), 6.96 ppm (d, 2H), 3.63 ppm (m, 4H), 3.05 ppm (m, 4H), 2.92 ppm (m, 1H), 2.33 ppm (t, 1H), 1.63 ppm (m, 2), 1.02 ppm (d, 6H), 0.93 ppm (t, 3H); MS (EI) C28H34N6O2: 487 (MH+). N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}butanainide: 1H-NMR (400MHz, d6-DMSO): 10.15 ppm (s, 1H), 9.41 ppm (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.77 ppm (d, 2H), 7.68 ppm (d, 2H), 7.28 ppm (d, 1H), 6.95 ppm (d, 2H), 3.70 ppm (m, 4H), 3.05 ppm (m, 4H), 2.33 ppm (t, 2H), 1.63 ppm (m, 2H), 1.23 ppm (s, 9H), 0.93 ppm (t, 3H); MS (EI) C29H36N6O2: 501 (MH+).
N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}butanamide: 1H-NMR (400MHz, d6-DMS O): 10.28 ppm (s, 1H), 9.41 ppm (s, 1H), 8.44 ppm (d, 1H), 8.11 ppm (d, 2H), 7.79 ppm (d, 2H), 7.68 ppm (d, 2H), 7.28 ppm (d, 1H), 6.95 ppm (d, 2H), 3.59 ppm (m, 2H), 3.46 ppm (m, 2H), 3.40 ppm (m, 1H), 3.02 ppm (m, 4H), 2.35 ppm (t, 2H), 2.14 ppm (m, 4H), 1.91 ppm (m, 1H), 1.75 ppm ( m, 1H), 1.63 ppm (m 2H), 0.93 ppm (t, 3H); MS (EI) C29H34N6O2: 499 (MH+).
N-(4- {2- [(4-morphoIin-4-y lphenyl)amino] pyrimidin-4-yl} phenyl) pyridine-2- carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.91 (s, 1H), 9.41 (s, 1H), 8.78 (d, 1H), 8.47 (d, 2H), 8.17 (m, 4H), 7.69 (m, 2H), 7.33 (d, 1H), 6.95 (d, 2H), 6.80 (s, 2H), 3.75 (m, 4H), 3.06 (m, 4H). MS (EI) for C26H24N6O2: 453.5(MH+).
2-hydroxy-N-(4-{2-[(4-morpholin-4-yIphenyl)amino]pyrimidin-4-yl}phenyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.39 (s, 1H), 9.51 (s, 1H), 8.47 (s, 1H), 8.16 (d, 2H), 7.91 (d, 2H), 7.17 (m, 3H), 7.53 (t, 1H), 7.34 (s, 2H) 7.20 (d, 1H), 7.07 (m, 3H), 3.91 (m, 4H), 3.12 (m, 4H). MS (EI) for C27H25N5O3: 468.5(MH+).
3-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-benzamide: 1H-NMR (400MHz, d6-DMSO): 10.49 (s, 2H), 8.19 (m, 3H), 7.97 (m, 3H), 7.55 (m, 2H), 7.50 (m, 3H), 7.20 (dd, 3H), 3.86 (m, 8H), 3.77 (s, 3H). MS (EI) for C28H27N5O3: 482.6(MH+).
4-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-benzamide: 1H-NMR (400MHz, d6-DMS0): 10.35 (s, 1H), 9.40 (s, 1H), 8.45 (s, 1H), 8.16 (d, 2H), 7.98 (m, 4H), 7.68 (d, 2H), 7.31 (d, 1H), 7.09 (d, 2H), 6.94(d, 2H), 3.83 (s, 3H), 3.75 (m, 4H), 3.05 (m, 4H). MS (EI) for C28H27N5O3: 482.6(MH+).
4-chIoro-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- benzamide: 1H-NMR (400MHz, d6-DMSO): 10.58 (s, 1H), 9.41 (s, 1H), 8.46 (s, 1H),
8.17 (d, 2H), 8.01 (d, 2H), 7.95 (d, 2H), 7.66 (m, 4H), 7.32 (d, 1H), 6.94 (d, 2H), 3.75 (m, 4H), 3.05 (m, 4H). MS (EI) for C27H24ClN5O2: 487.0(MH+). (2R)-N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- tetrahydrofuran-2-carboxamide: 1H-NMR (400MHz, d6-DMSO):9.95 (s, 1H), 9.38 (s, 1H), 8.45 (s, 1H), 8.12 (d, 2H), 7.89 (d, 2H), 7.66 (d, 2H), 7.29 (s, 1H), 6.92 (d, 2H), 4.44 (t, 2H), 4.00 (m, 2H), 3.85 (m, 2H), 2.41 (m, 4H), 2.20 (m, 2H), 2.02 (m, 2H), 1.88 (m, 2H), 1.05 (m, 4H). MS (EI) for C27H32N6O2: 473.6(MH+). (2S)-N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- tetrahydrofuran-2-carboxamide: 1H-NMR (400MHz, d6-DMSO):9.94 (s, 1H, 9.38 (s, 1H), 8.44 (s, 1H), 8.12 (d, 2H), 7.87 (d, 2H), 7.65 (d, 2H), 7.29 (s, 1H), 6.99 (d, 2H), 4.43 (m, 2H), 3.99 (m, 2H), 3.86 (m, 2H), 2.43 (m, 2H), 2.22 (m, 2H), 2.02 (m, 2H), 1.88 (m, 3H), 1.05 (m, 5H) . MS (EI) for C27H32N6O2: 473.6(MH+). l-(2-hydroxyethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}- phenyl)-L-prolinamide: 1H-NMR (400MHz, d6-DMSO): 10.31 (s, 1H), 9.39 (s, 1H), 8.44 (d, 1H), 8.14 (d, 2H), 7.81 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 5.05 (s, br, 1H), 3.74 (m, 4H), 3.59 (m, 1H), 3.49 (m, 1H), 3.23 (m, 2H), 3.05 (m, 4H), 2.77 (m, 1H), 2.63 (m, 1H), 2.41 (m, 1H), 2.16 (m, 1H), 1.80 (m, 3H). MS (EI) for C27H32N6O3: 489.6(MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)thiophene-2- carboxamide: 1H-NMR (400MHz, d6-DMSO): 10.47 (s, 1H), 9.45 (s, 1H), 8.47 (s, 1H), 8.17 (d, 2H), 8.08 (s, 1H), 7.92 (m, 3H), 7.70 (s, 2H), 7.32 (s, 1H), 7.26 (t, 1H), 6.99 (s, 2H), 3.76 (m, 4H), 3.09 (m, 4H). MS (EI) for C25H23N5O2S: 458.6(MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)pb.enyl]- tetrahydrofuran-3-carboxamide: 1H-NMR (400MHz, d6-DMS0): 10.31 (s, 1H), 9.37 (s, 1H), 8.44 (s, 1H), 8.14 (m, 2H), 7.79 (d, 2H), 7.65 (d, 2H), 7.27 (d, 1H), 6.92 (d, 2H), 3.96 (t, 1H), 3.76 (m, 3H), 3.19 (m, 1H), 3.09 (m, 4H), 2.55 (m, 4H), 2.42 (m, 2H), 2.10 (m, 2H), 1.05 (t, 3H). MS (EI) for C27H32N6O2: 473.6(MH+).
N-(4-{2-[4-(4-nicotynoylpiperazin-1-yl)phenylamino]pyrimidin-4-yl}phenyl)- 2-phenyIacetamide: 1H NMR (400MHz, d6-DMSO): 8.8 (d, 2H), 8.40 (s, 1H), 8.05 (d, 2H), 7.80 (d,1H),7.60-7.2 (m, 10H), 7.1-6.90 (m, 5H), 3.80-3.60 (m, 4H), 3.7 (s, 2H)3.20- 3.25 (m, 4H); MS (EI) for C34H3iN7O2: 570 (MH+).
3-({4-[4-(acetyIamino)phenyl]pyrimidin-2-yl}amino)-N-
(diphenylmethyl)benzamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.78 (s, 1H), 9.24 (d, 1H), 8.52 (d, 1H), 8.39 (s br, 1H), 8.16 (d, 2H), 7.95 (d, 1H), 7.75 (d, 2H), 7.53 (d t, 1H), 7.39-7.43 (m, 3H), 7.38 (d, 3H), 7.32-7.36 (m, 4H), 7.24-7.28 (m, 2H), 6.43 (d, 1H), 2.10 (s, 3H). MS (EI) for C32H27N5O2: 514.3 (MH+).
N-[4-(2-{[4-(4-methyIpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H-NMR (400MHz, d6-DMSO): 10.24 (s, 1H), 9.35 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.65 (d, 2H), 7.26 (d, 1H), 6.93 (d, 2H), 3.07 (m, 4H), 2.45 (m, 4H), 2.22 (s, 3H), 2.09 (s, 3H). MS (EI) for C23H26N6O: 403.4(MH+).
N-{4-[2-({4-[4-(phenylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyl}acetamide: 1H-NMR (400MHz,d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.45 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.73-7.79 (m, 5H), 7.28 (d, 1H), 6.98 (d, 2H), 3.78 (m, 2H), 3.48 (m, 2H), 3.15 (m, 2H), 3.07 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H28N6O2: 493.4 (MH+).
N-{4-[2-({4-[4-(2-cyclopentylacetyl)piperazin-1-yl]phenyl}aniino)pyrimidin-4- yl]-phenyl}acetamide: 1H-NMR (400MHz,d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.68 (d, 2H), 7.27 (s, 1H), 6.96 (d, 2H), 3.60 (m, 4H), 3.04 (m, 4H), 2.37 (d, 2H), 2.15 (m, 1H), 2.09 (s, 3H), 1.61-1.78 (m, 2H), 1.53-1.59 (m, 2H), 1.46-1.52 (m, 2H), 1.09-1.77 (m, 2H). MS (EI) for C29H34N6O2: 499.3 (MH+).
N-{4-[2-({4-[4-(cyclohexylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H)3 7.68 (d, 2H), 7.27 (d, 1H), 6.96 (d, 2H), 3.61 (m, 4H), 3.04 (m, 4H), 2.09 (s, 3H), 1.62-1.70 (m, 6H), 1.26-1.38 (m, 5H). MS (EΙ)for C29H34N6O: 499.2 (MH+).
N-(4-{2-[(4-{4-[(2-chlorophenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz,d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.69 (d. 2H), 7.56 (d, 1H), 7.41-7.49 (m, 3H), 7.27 (d, 1H), 6.96 (d, 2H), 3.81 (m, 2H), 3.28 (m, 2H), 3.16 (m, 2H), 3.05 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H27ClN6O2: 527.8 (MH+). N-(4-{2-[(4-{4-[(3-fluorophenyl)carbonyl]piperazin-1- yI}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.53 (m, 1H), 7.27-7.35 (m, 4H), 6.97 (d, 2H), 3.77 (m, 2H), 3.46 (m, 2H), 3.16 (m, 2H), 3.07 (m, 2H), 2.09 (s, 3H).MS(EI) for C29H27FN6O2: 51 1.5 (MH+).
N-(4-{2-[(4-{4-[(3-fluoro-4-methylphenyl)carbonyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.38 (m, 1H), 7.28 (d, 1H), 7.25 (d, 1H), 7.18 (d, 1H), 6.56 (d, 2H), 3.75 (m, 2H), 3.49 (m, 2H), 3.14 (m, 2H), 3.07 (m, 2H), 2.28 (d, 3H), 2.09 (s, 3H). MS(EI) for C30H29FN6O2: 525.7 (MH+). N-(4-{2-[(4-{4-[(3,4-dichlorophenyl)carbonyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.45 (s, 1H), 8.11 (d, 2H), 7.75 (m, 3H), 7.69 (d, 2H), 7.45 (dd, 1H), 7.28 (d, 1H), 6.97 (d, 2H), 3.77 (m, 2H), 3.47 (m, 2H), 3.16 (m, 2H), 3.07 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H26Cl2N6O2: 562.3(MH+). N-(4-{2-[(4-{4-[(3,5-dichlorophenyl)carbonyl]piperazin-1-yl}phenyl)amino]- pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.75 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.54 (d, 2H), 7.28 (d, 1H), 6.97 (d, 2H), 3.77 (m, 2H), 3.45 (m, 2H), 3.17 (m, 2H), 3.08 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H26Cl2N6O2: 562.6(MH+). N-[4-(2-{[4-(4-{[3-(methyloxy)phenyl]carbonyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: Η-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.38 (t, 1H), 7.28 (d, 1H), 7.04 (dd, 1H), 6.95-6.99 (m, 4H), 3.79 (s, 3H), 3.77 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 3.06 (m, 2H), 2.09 (s, 3H). MS(EI) for C30H30N6O3: 523.5(MH+). N-(4-{2-[(4-{4-[(4-chlorophenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.1 1 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.53 (d, 2H), 7.49 (d, 2H), 7.27 (d, 1H), 6.97 (d, 2H), 3.77 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 3.06 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H27ClN6O2: 527.8(MH+).
N-(4-{2-[(4-{4-[(4-methylphenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.44 )d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.34 (d, 2H), 7.27 (m, 3H), 6.97 (d, 2H), 3.75 (m, 2H), 3.51 (m, 2H), 3.10 (m, 4H), 2.36 (s, 3H), 2.09 (s, 3H). MS (EI) for C30H30N6O2: 507.3 (MH+).
N-(4-{2-[(4-{4-[(l-methyl-1H-pyrrol-2-yl)carbonyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyl)acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.27 (d, 1H), 6.98 (d, 2H), 6.92 (t, 1H), 6.37 (dd, 1H), 6.05 (dd, 1H), 3.76 (m, 4H), 3.69 (s, 3H), 3.11 (m, 4H), 2.09 (s, 3H), MS (EI) for C28H29N7O2: 496.4(MH+).
N-{4-[2-({4-[4-(furan-2-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H-NMR(400MHz,d6-DMSO): 10.22 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.87 (d, 1H), 7.74 (d, 2H), 7.69 (d, 2H), 7.28 (d, 1H), 7.04 (d, 1H), 6.98 (d, 2H), 6.66 (dd, 1H), 3.82 (m, 4H), 3.14 (m, 4H), 2.09 (s, 3H). MS (EI ) for C27H26N6O3: 483.3 (MH+).
N-[4-(2-{[4-(4-{2-[(4-fluorophenyl)oxy]acetyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H-NMR (400MHz, d6-DMS0): 10.22 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.27 (d, 1H), 7.12 (m, 2H), 6.94-6.99 (m, 4H), 4.87 (s, 2H), 3.61 (m, 4H), 3.13 (m, 2H), 3.06 (m, 2H), 2.09 (s, 3H). MS (EI) for C30H29FN6O3: 541.4(MH+).
N-(4-{2-[(4-{4-[(3-methylphenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: MS (EI) for C29H30N6O3S: 543.5 (MH+).
N-{4-[2-({4-[4-(phenylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyljacetamide: Η-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.80 (m, 1H), 7.78 (d, 1H), 7.74-7.77 (m, 2H), 7.70-7.73 (m, 2H), 7.67- 7.69 (m, 1H), 7.65 (d, 2H), 7.27 (d, 1H), 6.90 (d, 2H), 3.15 (m, 4H), 3.02 (m, 4H), 2.09 (s,3H). MS (EI) for C26H26N6O3S2: 529.4(MH+).
N-{4-[2-({4-[4-(2-thienylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.10 (m, 3H), 7.74 (d, 2H), 7.70 (dd, 1H), 7.66 (d, 2H), 7.33 (dd, 1H), 7.27 (d, 1H), 6.93 (d, 2H), 3.19 (m, 4H), 3.07 (m, 4H), 2.09 (s, 3H). MS (EI) for C26H26N6O3S2: 535.6(MH+).
N-(4-{2-[(4-{4-[(4-fluorophenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR(400MHz,d6-
DMSO):10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.10 (d, 2H), 7.87 (m, 2H), 7.74 (d, 2H), 7.66 (d, 2H), 7.53 (m, 2H), 7.27 (d, 1H), 6.91 (d, 2H), 3.15 (m, 4H), 3.04 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H27FN6O3S: 547.4 (MH+).
N-[4-(2-{[4-(4-{[4-(methyloxy)phenyl]sulfonyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: Η-NMR(400MHz,d6-DMSO): MS (EI) for C29H30N6O4S: 559.9 (MH+).
N-(4-{2-[(4-{4-[(4-chlorophenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetaiiiide: !H-NMR(400MHz,d6- DMSO):10.21 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 1.12-1X2 (d, 6H), 7.66 (d, 2H), 7.27 (d, 1H), 6.91 (d, 2H), 3.15 (m, 4H), 3.05 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H27ClN6O3S: 563.9 (MH+).
N-(4-{2-[(4-{4-[(3-chlorophenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: Η-NMR(400MHz,d6- DMSO):10.21 (s, 1H), 9.40 (s, 1H), 8.43 (d, 1H), 8.10 (d, 2H), 7.85 (m, 1H), 7.76-7.81 (m, 2H), 7.73 (d, 3H), 7.66 (d, 2H), 7.27 (d, 1H), 6.91 (d, 2H), 3.14 (m, 4H), 3.09 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H27ClN6O3S: 5640 (MH+).
N-{4-[2-({4-[4-(biphenyl-4-ylsulfonyl)piperazin-1-yI]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H-NMR(400MHz,d6-DMSO):10.21(s, 1H), 9.39 (s, 1H), 8.43 (d, 1H), 8.08 (d, 2H), 7.96 (d, 2H), 7.86 (d, 2H), 7.77 (d, 2H), 7.73 (d, 2H), 7.66 (d, 2H), 7.51-7.55 (m, 2H), 7.46 (m, 1H), 7.26 (d, 1H), 6.91 (d, 2H), 3.18 (m, 4H), 3.08 (m, 4H), 2.09 (s, 3H). MS (EI) for C34H32N6O3S: 605.8 (MH+). N-{4-[2-({4-[4-(naphthalen-1-ylsulfonyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.38 (s, 1H), 8.72 (d, 1H), 8.42 (d, 1H), 8.33 (d, 1H), 8.20 (dd, 1H), 8.14 (d, 1H), 8.09 (d, 2H), 7.74-7.79 (m, 1H), 7.73 (d, 2H), 7.62-7.70 (m, 2H), 7.64 (d, 2H), 7.26 (d, 1H), 6.88 (d, 2H), 3.21 (m, 4H), 3.09 (m, 4H), 2.09 (s, 3H). MS (EI) for C32H30N6O3S: 579.6 (MH+).
N-(4-{2-[(3-{4-[(2-chlorophenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.46 (s, 1H), 8.49 (d, 1H), 8.14 (d, 2H), 7.74 (d, 2H), 7.64 (s br, 1H), 7.36 (dd, 1H), 7.33 (d, 1H), 7.20-7.27 (m, 2H), 7.13 (t, 1H), 6.92-7.00 (m, 2H), 6.55 (d, 1H), 3.54 (s, 2H), 3.16 (m, 4H), 2.57 (m, 4H), 2.09 (s,3H). MS (EI) for C29H29CIN6O: 513.8 (MH+).
N-[4-(2-{[3-(4-{[3-(methyloxy)phenyl]methyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: Η-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.46 (s, 1H), 8.48 (d, 1H), 8.13 (d, 2H), 7.74 (d, 2H), 7.62 (s, 1H), 7.33 (d, 1H), 7.22-7.27 (m, 2H), 7.13 (t, 1H), 6.19 (m, 2H), 6.83 (d, 1H), 6.55 (d, 1H), 3.74 (s, 3H), 3.52 (s, 2H), 3.16 (m, 4H), 2.55 (m, 4H), 2.09 (s, 3H). MS (EI) for C30H32N6O2: 509.8(MH+).
N-{4-[2-({3-[4-(3-methylbutyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyljacetamide: Η-NMR(400MHz,d6-DMSO): 10.22 (s, 1H), 9.47 (s, 1H), 8.49 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.68 (s, 1H), 7.33 (d, 1H), 7.19 (d, 1H), 7.13 (t, 1H), 6.55 (d, 1H), 3.15 (m, 4H), 2.54 (m, 4H), 2.34 (t, 2H), 2.09 (s, 3H), 1.57-1.62 (m, 1H), 1.34- 1.40 (m, 2H), 0.90 (d, 6H). MS (EI) for C27H34N6O: 459.7 (MH+).
N-{4-[2-({3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H-NMR(400MHz,d6-DMSO): MS (EI) for C31H32N6O3: 537.5 (MH+).
N-{4-[2-({3-[4-(cyclopropylmethyl)piperazin-1-yl]phenyI}amino)pyrimidin-4- yl]phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.22 (s, 1H), 9.47 (s, 1H), 8.49 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.69 (s, 1H), 7.33 (d, 1H), 7.19 (d, 1H), 7.13 (t, 1H), 6.56 (d, 1H), 3.17 (m, 4H), 2.60 (m, 4H), 2.24 (d, 2H), 2.09 (s, 3H), 0.88 (m, 1H), 0.47-0.51 (m, 2H), 0.11-0.13 (m, 2H). MS (EI) for C26H30N6O: 443.8 (MH+).
N-(4-{2-[(3-{4-[3-(methylthio)propyl]piperazin-1-yl}phenyl)amino]pyrimidin- 4-yI}phenyl)acetamide: Η-NMR(400MHz,d6-DMSO): 10.22 (s, 1H), 9.47 (s, 1H), 8.49 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.68 (s, 1H), 7.33 (d, 1H), 7.20 (d, 1H), 7.14 (t, 1H), 6.56 (d, 1H), 3.15 (m, 4H), 2.56 (m, 4H), 2.41 (t, 4H), 2.09 (s, 3H), 2.06 (s, 3H), 1.71-1.78 (m, 2H). MS (EI) for C26H32N6OS: 477.5(MH+).
N-(4-{2-[(3-{4-[(4-{[3-(dimethylamino)propyl]oxy}phenyI)methyl]piperazin-1- yl}-phenyl)amino]pyrimidin-4-yl}phenyl)acetainide: 1H-NMR(400MHz,d6-
DMSO):10.22 (s, 1H), 9.46 (s, 1H), 8.48 (d, 1H), 8.13 (d, 2H), 7.74 (d, 2H), 7.62 (s, 1H), 7.33 (d, 1H), 7.23 (m 3H), 7.13 (t, 1H), 6.88 (d, 2H), 6.55 (d, 1H), 3.97 (t, 2H), 3.46 (s, 2H), 3.14 (m, 4H), 2.55 (m, 4H), 2.34 (t, 2H), 2.14 (s, 6H), 2.10 (s, 3H), 1.80-1.85 (m, 2H). MS (EI) for C34H41N7O2: 580.5(MH+). N-{4-[2-({3-[4-({3-[(trifluoromethyl)oxy]phenyl}methyl)piperazin-1- yl]phenyl}-amino)pyrimidin-4-yl]phenyl}acetamide: 1H-NMR(400MHz,d6- DMSO): 10.21 (s, 1H), 9.47 (s, 1H), 8.49 (d, 1H), 8.13 (d, 2H), 7.74 (d, 2H), 7.63 (s, 1H), 7.47 (t, 1H), 7.41 (d, 1H), 7.33 (d, 2H), 7.22-7.28 (m, 2H), 7.13 (t, 1H), 6.56 (dd, 1H), 3.62 (s, 2H), 3.16 (m ,4H), 2.56 (m, 4H), 2.09 (s, 3H). MS (EI) for C30H29F3N6O2: 563.7(MH+).
4-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-N- phenylpiperazine-1-carboxamide: 1H-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.63 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.75 (d, 2H), 7.70 (d, 2H), 7.48 (d, 2H), 7.21- 7.28 (m, 3H), 7.00 (d, 2H), 6.94 (t, 1H), 3.61 (m, 4H), 3.11 (m, 4H), 2.09 (s, 3H). MS (EI) for C29H29N7O2: 508.6 (MH+).
N-[4-(2-{[3-(4-propanoylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H-NMR(400MHz,d6-DMSO): 10.24 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.68 (s, 1H), 7.34 (d, 1H), 7.26 (d, 1H), 7.16 (t, 1H), 6.59 (dd, 1H), 3.62 (m, 4H), 3.13 (m, 4H), 2.35-2.39 (m, 2H), 2.09 (s, 3H), 1.02 (t, 3H). MS (EI) for C2,H28N6O2: 445.4 (MH+).
N-{4-[2-({3-[4-(phenylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.48 (s, 1H), 8.47 (d, 1H), 8.1 1 (d, 2H), 7.72 (d, 2H), 7.63 (s, 1H), 7.41-7.47 (m, 5H), 7.31 (d, 1H), 7.26 (d, 1H), 7.14 (t, 1H), 6.56 (dd, 1H), 3.78 (m, 2H), 3.48 (m, 2H), 3.27 (m, 2H), 3.12 (m, 2H), 2.08 (s, 3H). MS (EI) for C29H28N6O2: 493.7 (MH+).
N-{4-[2-({3-[4-(2-phenylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]- phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.25 (s, 1H), 9.50 (s, 1H), 8.49 (d, 1H), 8.13 (d, 2H), 7.76 (d, 2H), 7.63 (s, 1H), 7.33 (d, 1H), 7.30 (d, 2H), 7.26 (m, 3H), 7.22 (m, 1H), 7.15 (t, 1H), 6.56 (dd, 1H), 3.79 (s, 2H), 3.66 (m, 4H), 3.11 (m, 2H), 3.05 (m, 2H), 2.09 (s, 3H). MS (EI) for C30H30N6O2: 507.7 (MH+).
N-{4-[2-({3-[4-(cyclopentylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H-NMR(400MHz,d6-DMSO): 10.24 (s, 1H), 9.52 (s, 1H), 8.49 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.71 (s, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 7.16 (t, 1H), 6.59 (dd, 1H), 3.66 (m, 4H), 3.13 (m, 4H), 3.00-3.07 (m, 1H), 2.09 (s, 3H), 1.80 (m, 2H), 1.51-1.71 (m, 6H). MS (EI) for C28H32N6O2: 485.7 (MH+).
N-{4-[2-({3-[4-(2-pyridin-3-ylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]-phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.24 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.43-8.46 (m, 2H), 8.14 (d, 2H), 7.76 (d, 2H), 7.63-7.67 (m, 2H), 7.32-7.35 (m, 2H), 7.26 (d, 1H), 7.16 (t, 1H), 6.59 (dd, 1H), 3.84 (s, 2H), 3.73 (m, 2H), 3.66 (m, 2H), 3.15 (m, 4H), 2.08 (s, 3H). MS (EI) for C29H29N7O2: 508.4 (MH+).
N-{4-[2-({3-[4-(2-cyclopentylacetyl)piperazin-1-yI]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.24 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.70 (s, 1H), 7.34 (d, 1H), 7.25 (d, 1H), 7.16 (t, 1H), 6.59 (dd, 1H), 3.61 (m, 4H), 3.12 (m, 4H), 2.39 (d, 2H), 2.1 1-2.19 (m, 1H), 2.09 (s, 3H), 1.72- 7.78 (m, 2H), 1.52-1.59 (m, 2H), 1.47-1.52 (m, 2H), 1.09-1.18 (m, 2H). MS (EI) for C29H34N6O2: 499.4 (MH+). N-(4-{2-[(3-{4-[(2-chlorophenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: Η-NMR(400MHz,d6-DMSO): 10.24 (s, 1H), 9.50 (s, 1H), 8.49 (d, 1H), 8.13 (d, 2H), 7.74 (d, 2H), 7.63 (s, 1H), 7.56 (d, 1H), 7.42-7.50 (m, 3H), 7.33 (d, 1H), 7.29 (d, 1H), 7.16 (t, 1H), 6.59 (dd, 1H), 3.79 (m, 2H), 3.50 (m, 2H), 3.24 (m, 2H), 3.15 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H27CIN6O2: 527.9 (MH+).
N-(4-{2-[(3-{4-[(4-chlorophenyI)carbonyl]piperazin-1- yI}phenyI)amino]pyrimidin-4-yl}phenyl)acetamide: Η-NMR(400MHz,d6-DMSO): 10.23 (s, 1H), 9.51 (s, 1H), 8.49 (d, 1H), 8.14 (d, 2H), 7.74 (d, 2H), 7.66 (s, 1H), 7.53 (d, 2H), 7.49 (d, 2H), 7.34 (d, 1H), 7.27 (d, 1H), 7.17 (t, 1H), 6.59 (dd, 1H), 3.79 (m, 2H), 3.50 (m, 2H), 3.24 (m, 2H), 3.15 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H27CIN6O2: 528.1 (MH+). N^-ll-^S-I^ICS^-dichlorophenyOcarbonyllpiperazin-1-ylJpheny^aniino]- pyrimidin-4-yl}phenyl)acetamide: 'H-NMR(400MHz,d6-DMSO): 10.23 (s, 1H), 9.51 (s, 1H), 8.49 (d, 1H), 8.13 (d, 2H), 7.74 (m, 4H), 7.60 (s, 1H), 7.46 (dd, 1H), 7.34 (d, 1H), 7.27 (d, 1H), 7.17 (t, 1H), 6.59 (dd, 1H), 3.79 (m, 2H), 3.50 (m, 2H), 3.24 (m, 2H), 3.15 (m, 2H), 2.09 (s, 3H). MS (EI) for C29H26CI2N6O2: 562.7 (MH+).
N-(4-{2-[(3-{4-[(l-methyI-1H-pyrrol-2-yl)carbonyl]piperazin-1- yl}phenyl)amino]-pyrimidin-4-yl}phenyl)acetamide: Η-NMR(400MHz,d6-DMSO): 10.23 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.75 (d, 2H), 7.67 (s, 1H), 7.34 (d, 1H), 7.28 (d, 1H), 7.17 (t, 1H), 6.92 (m, 1H), 6.59 (dd, 1H), 6.37 (dd, 1H), 6.05 (m, 1H), 3.80 (m, 4H), 3.69 (s, 3H), 3.19 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H29N7O2: 450.7 (MH+).
N2,N2-dimethyl-N-[4-(2-{[3-(methyloxy)-4-morpholin-4- ylphenyl]amino}pyrimidin-4-yl)phenyl]glycinamide: ]H-NMR(400MHz,d6- DMSO):10.0 (s, 1H), 9.48 (s, 1H), 8.48 (d, 1H), 8.15 (d, 2H), 7.84 (d, 2H), 7.65 (s, 1H), 7.29-7.33 (m, 2H), 6.86 (d, 1H), 3.81 (s, 3H), 3.72 (m, 4H), 3.11 (s, 2H), 2.92 (m, 4H), 2.29 (s, 6H). MS (EI) forC2,H3oN603: 463.8 (MH+).
3-(methyloxy)-N-[4-(2-{[3-(methyloxy)-4-morpholin-4- yIphenyl]amino}pyrimidin-4-yl)phenyl]propanamide: 1H-NMR(400MHz,d6-DMSO): 10.21 (s, 1H), 9.46 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.74 (d, 2H), 7.64 (s, 1H), 7.26-7.30 (m, 2H), 6.84 (d, 1H), 3.79 (s, 3H), 3.70 (m, 4H), 3.61 (t, 2H), 3.23 (s, 3H), 2.89 (m, 4H), 2.57 (t, 2H). MS (EI) for C2,H29N,O4: 464.8 (MH+).
N-(4-{2-[(4-{4-[(2-chlorophenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide: Η-NMR(400MHz,d6-DMSO): 10.19 (s, 1H), 9.38 (s, 1H), 8.42 (d, 1H), 8.08 (d, 2H), 8.00 (dd, 1H), 7.68-7.74 (m, 4H), 7.65 (d, 2H), 7.58 (m, 1H), 7.25 (d, 1H), 6.91 (d, 2H), 3.15 (m, 4H), 3.02 (m, 4H), 2.07 (s, 3H). MS (EI) for C28H27CIN6O3S: 563.9 (MH+).
N-{4-[2-({3-[4-(cyclopropylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: Η-NMR(400MHz,d6-DMSO): 10.24 (s, 1H), 9.52 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.71 (s, 1H), 7.34 (d, 1H), 7.25 (d, 1H), 7.17 (t, 1H), 6.60 (dd, 1H), 3.56 (m, 2H), 3.65 (m, 2H), 3.20 (m, 2H), 3.13 (m, 2H), 2.09 (s, 3H), 2.04 (m, 1H), 0.77-0.49 (m, 4H). MS (EI) for C26H28N6O2: 457.5(MH+). N-{4-[2-({3-[4-(2-cyclopropylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H-NMR(400MHz,d6-DMSO): 10.24 (s, 1H), 9.51 (s, 1H), 8.50 (d, 1H), 8.14 (d, 2H), 7.76 (d, 2H), 7.70 (s, 1H), 7.34 (d, 1H), 7.25 (d, 1H), 7.16 (t, 1H), 6.58 (dd, 1H), 3.62 (m, 4H), 3.13 (m, 4H), 2.32 (d, 2H), 2.09 (s, 3H), 0.99 (m, 1H), 0.45 (m, 2H), 0.14 (m, 2H). MS (EI) for C27H30N6O2: 477.5(MH+).
N-[4-(2-{[3-(4-{[3-(methyloxy)phenyl]carbonyl}piperazin-1-yl)phenyl]amino}- pyrimidin-4-yl)phenyl]acetamide: 1H-NMR(400MHz,d6-DMSO): 10.22 (s, 1H), 9.48 (s, 1H), 8.47 (d, 1H), 9.11 (d, 2H), 7.72 (d, 2H), 7.62 (s, 1H), 7.35 (t, 1H), 7.31 (d, 1H), 7.26 (d, 1H), 7.14 (t, 1H), 7.01 (m, 1H), 6.97 (m, 2H), 6.56 (dd, 1H), 3.76 (s, 3H), 3.73 (m, 2H), 3.47 (m, 2H), 3.14 (m, 4H), 2.07 (s, 3H). MS (EI) for C30H30N6O3: 523.7 (MH+).
N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide: 1H-NMR (400MHz, d6-DMSO): 10.21 (s, 1H), 9.40 (s, 1H), 8.44 (d, 1H), 8.11 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.27 (d, 1H), 6.96 (d, 2H), 3.70 (m, 4H), 3.05 (m, 4H), 2.09 (s, 3H), 1.23 (s, 9H), MS(EI) for C27H32N6O2: 473.4(MH+).
2,6-dichloro-N-(3-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2- ylamino)propyl)benzamide: (400 MHz, CDC13): 8.16 (br, 1H), 8.0 - 8.8 (m, 2H), 7.26 (m, 4H), 6.82 (d, 1H), 6.75 (br, 1H), 5.4 (t, 1H), 4.29 (m, 4H), 3.68 (m, 2H), 3.56 (m, 2H), 1.92 (m, 2H). MS (EI): 459 (MH+). l-(4-(4-(4-acetamidophenyl)pyrimidin-2-ylamino)phenyl)piperidine-3- carboxylic acid: MS (EI) for C24H25N5O3: 432 (MH+). tert-butyl methyl(2-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenylamino)-2-oxoethyl)carbamate: MS (EI) for C28H34N6O4: 519 (MH+). tert-butyl 4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl- carbamate: MS (EI) for C27H34N6O2: 475 (MH+).
2-(dimethylamino)-N-(4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin- 4-yl)phenyl)acetamide: NMR (400 MHz, d6-DMSO): 10.0 (s, 1H), 9.37 (s, 1H), 8.41 (d, 1H), 8.11 (d, 1H), 7.85 (d, 2H), 7.63 (f, 2H), 7.46 (d, 1H), 7.25 (d, 1H), 6.83 - 6.92 (m, 2H), 3.11 (m, 4H), 2.51 (m, 4H), 2.37 (q, 2H), 2.36 (s, 6H), 2.26 (s, 2H), 1.05 (t, 3H). MS (EI): 460 (MH+).
4-(4-aminophenyl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)pyrimidin-2-amine: MS (EI) for C22H26N6: 375 (MH+). (S)-tert-butyl l-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate: MS (EI) for C34Ha8N6O4: 595 (MH+).
(R)-tert-butyl l-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate: MS (EI) for C34H38N6O4: 595 (MH+).
(R)-2-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-3- phenylpropanamide: NMR (400 MHz, d6-DMSO): 11.40 (s, 1H), 10.20 (s, 1H), 8.43 - 8.62 (m, 3H), 8.17 (d, 2H), 7.91 (d, 2H), 7.89 (d, 2H), 7.84 (m, 2H), 7.20 - 7.38 (m, 4H), 4.10 (m, 4H), 3.63 (m, 2H), 3.40 - 3.57 (m, 6H), 3.20 (m, 1H), MS (EI): 495 (MH+).
(S)-2-amino-N-(4-(2-(4-morpholinophenylamino)pyriinidin-4-yl)phenyI)-3- phenylpropanamide: NMR (400 MHz, d6-DMSO): 11.40 (s, 1H), 10.20 (s, 1H), 8.43 - 8.62 (m, 3H), 8.17 (d, 2H), 7.91 (d, 2H), 7.89 (d, 2H), 7.84 (m, 2H), 7.20 - 7.38 (m, 4H), 4.10 (m, 4H), 3.63 (m, 2H), 3.40 - 3.57 (m, 6H), 3.20 (m, 1H), MS (EI): 495 (MH+). (S)-2-amino-N-(4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)-3-methylbutanamide: MS (EI) for C27H35N7O: 474 (MH+).
(R)-2-amino-N-(4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)-3-methyIbutanamide: MS (EI) for C27H35N7O: 474 (MH+). l-ethyI-3-(4-(2-(3-methoxy-4-morpholinophenylamino)pyriinidin-4- yl)phenyl)urea: NMR (400 MHz, d6-DMSO): 9.41 (s, 1H), 8.75 (s, 1H), 8.42 (d, 1H), 8.10 (d, 2H), 7.64 (s, 1H), 7.54 (d, 2H), 7.26 (m, 2H), 6.85 (d, 1H), 6.21 (br, 1H), 3.79 (s, 3H), 3.70 (m, 4H), 3.11 (q, 2H), 2.89 (m, 4H), 1.06 (t, 3H). MS (EI): 449 (MH+).
(R)-N-(4-(2-(4-morpholinophenyIamino)pyrimidin-4-yI)phenyl)piperidine-2- carboxamide: NMR (400 MHz, d6-DMSO): 11.36 (s, 1H), 10.0 (s, 1H), 9.4 (d, 1H), 8.84 (m, 1H), 8.57 (d, 1H), 8.2 (d, 2H), 7.82 (m, 4H), 7.6 (br, 1H), 7.4 (d, 1H), 4.0 (m, 4H),
3.82 (m, 1H), 3.42 (m, 4H), 3.23 (m, 1H), 2.94 (m, 1H), 2.3 (m, 1H), 1.82 (m, 1H), 1.54 - 1.92 (m, 4H). MS (EI): 458 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yI)phenyl]amino}-5-methylpyrimidin-4- yl)phenyl]-acetamide: 1H NMR (400 MHz, d6-DMSO): 10.1 (s,1H), 9.23 (s, 1H), 8.31 (s, 1H), 7.6-7.7 (m, 6H), 6.87 (d, 2H), 3.04 (m, 4H), 2.48 (m, 4H), 3.05 (m, 4H), 2.36 (q, 2H), 2.2 (s, 3H), 2.08 (s, 3H), 1.03 (s, 3H). MS (EI): 431 (MH+). 4-{4-[(4-{4-[(N,N-dimethylglycyl)amino]phenyl}pyrimidin-2- yI)amino]phenyl}-N-ethylpiperazine-1-carboxamide: 1H NMR (400 MHz, dό-DMSO): 10.0 (s, 1H), 9.4 (s, 1H), 8.43 (d, 1H), 8.12 (d, 2H), 7.82 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.97 (d, 2H), 3.42 (m, 4H), 3.12 (s, 2H), 3.06 (q, 2H), 3.02 (m, 4H), 2.3 (s, 6H), 1.11 (t, 3H). MS (EI): 503 (MH+).
N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}-N2, N2-dimethylglycinamide: 1H NMR (400 MHz, d6-DMSO): 10.0 (s,1H), 9.4 (s, 1H), 8.44 (d, 1H), 8.1 l(d, 2H), 7.83 (d, 2H), 7.69 (d, 2H), 7.29 (d, 1H), 6.96 (d, 2H), 3.7 (m, 4H), 3.16 (s, 2H), 3.05 (m, 4H), 2.31 (s, 6H), 1.2 (s, 9H). MS (EI): 516(MH+).
N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyI}amino)pyrimidin-4- yl]phenyl}-N2,N2-dimethylglycinamide: 1H NMR (400 MHz, d6-DMSO): 10.0 (s,1H), 9.4 (s, 1H), 8.45 (d, 1H), 8.12(d, 2H), 7.84 (d, 2H), 7.67 (d, 2H), 7.30 (d, 1H), 6.95 (d, 2H), 3.56-3.62 (m, 4H), 3.1 (s, 2H), 2.99-3.05 (m, 4H), 2.31 (s, 6H), 1.8-2.25 (m, 7H). MS (EI): 514(MH+).
N2,N2-dimethyl-N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1- yl]phenyl}amino)-pyrimidin-4-yl]phenyl}glycinamide: 1H NMR (400 MHz, dό- DMSO): 10.0 (s,1H), 9.4 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.84 (d, 2H), 7.68 (d, 2H), 7.29 (d, 1H), 6.95 (d, 2H), 3.58-3.67 (m, 4H), 3.1 1 (s, 2H), 2.99-3.10 (m, 4H), 2.92 (m, 1H), 2.29 (s, 6H), 1.02 (d, 6H). MS (EI): 502(MH+).
N-{4-[2-({4-[4-(cyclopropylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}-N2,N2-dimethylglycinamide: 1H NMR (400 MHz, d6-DMSO): 10.0 (s,1H), 9.4 (s, 1H), 8.43 (d, 1H), 8.14 (d, 2H), 7.68 (d, 2H), 7.26 (d, 1H), 6.97 (d, 2H), 3.8 (m, 2H), 3.6 (m, 2H),3.18 (m, 4H),3.07 (m, 2H), 2.28 (s, 6H), 2.02 (m, 1H), 0.78 (m, 4H). MS (EI): 501 (MH+).
N-[4-(2-{[4-(4-D-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yI)phenyl]- ^^-dimethylglycinamidei'H NMR (400 MHz, d6-DMSO): 10.0 (s,1H), 9.4 (s, 1H), 8.55 (d, 1H), 8.23 (d, 2H), 7.84 (d, 2H), 7.71 (d, 2H), 7.28 (d, 1H), 6.97 (d, 2H), 3.8 (m, 2H), 3.84 (q, 1H), 3.62 (m, 4H), 3.12 (s, 2H),3.05 (m, 4H), 2.31 (s, 6H), 1.12 (d, 3H). MS (EI): 504(MH+).
N-[4-(2-{[4-(4-L-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- N2,N2-dimethylglycinamide:1H NMR (400 MHz, d6-DMSO): 10.0 (s,1H), 9.4 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.84 (d, 2H), 7.69 (d, 2H), 7.28 (d, 1H), 6.97 (d, 2H), 3.8 (m, 2H), 3.84 (q, 1H), 3.62 (m, 4H), 3.12 (s, 2H),3.05 (m, 4H), 2.31 (s, 6H), 1.12 (d, 3H). MS (EI): 504(MH+).
2,6-dichloro-N-(3-{[4-(4-fluorophenyl)pyrimidin-2- yl]amino}propyl)benzamide: 1H NMR (400 MHz, DMSO): 8.705 (t, 1H), 8.354(d, 1H), 7.136 (br s, 2H), 7.515 (d, 2H), 7.5 (d, 2H), 7.425 (m, 1H), 7.34 (t, 2H), 7.26 (t, 1H), 7.14 (d, 1H), 3.456 (br s, 2H), 3.355 (m, 2H), 1.827 (t, 2H). MS (EI): 420.1 (MH+).
N-(4-{2-[({l-[(2,6-dichlorophenyl)carbonyl]azetidin-3- yl}methyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, DMSO): 11.031 (s, 1H), 8.344 (d, 1H), 8.137 (d, 2H), 7.839 (d, 2H), 7.621 (d, 2H), 7.531 (m, 1H), 7.45 (t, 1H), 7.146 (d, 1H), 4.157 (m, 1H), 3.867 (t, 2H), 3.626-3.556 (m, 3H), 2.842 (br s, 1H), 1.725 (s, 3H). MS (EI) for C23H21Cl2N5O2: 470.2 (MH+).
N-(4-{2-[(3-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide: 1H NMR (400 MHz, DMSO): 10.22 (s, 1H), 9.511 (s, 1H), 8.504 (d, 1H), 8.154 (d, 2H), 7.76 (d, 3H), 7.343 (d, 1H), 7.215-7.153 (m, 2H), 6.584 (d, 1H), 3.775 (t, 4H), 3.14 (t, 4H), 2.094 (s, 3H). MS (EI) for C22H23N5O2: 390.1 (MH+).
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}ainino)cyclohexyl]-2,6- dichloro-benzamide: 1H NMR (400 MHz, MeOD): 8.25 (d, 1H), 8.08 (d, 2H), 7.7 (d, 2H), 7.45-7.35 (m, 3H), 7.05 (d, 1H), 4.05 (m, 2H), 2.5 (m, 1H), 2.1 (m, 3H), 2.05 (s, 3H), 1.5 (m, 1H), 1.3 (m, 3H). MS (EI) for C25H25Cl2N5O2: 498.3 (MH+).
N-{4-[2-({[4-(4-methylpiperazin-1-yl)phenyl]methyl}amino)pyrimidin-4- yl]phenyl}-acetamide: 1H NMR (400 MHz, DMSO): 10.192 (s, 1H), 8.294 (d, 1H), 8.062 (d, 2H), 7.713 (d, 2H), 7.653 (t, 1H), 7.285 (br d, 2H), 7.09 (d, 1H), 6.953 (d, 2H), 4.485 (d, 2H), 3.3 (br s, 8H), 2.827 (s, 3H), 2.079 (s, 3H). MS (EI) for C24H28N6O: 417.4 (MH+).
N-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6-dichloro- benzamide 1H NMR (400 MHz, DMSO): 10.66 (s, 1H), 10.324 (s, 1H), 9.638 (s, 1H), 8.501 (d, 1H), 8.144 (d, 2H), 7.782 (m, 4H), 7.65 (d, 2H), 7.597 (d, 2H), 7.498 (m, 1H), 7.349 (d, 1H), 2.11 (s, 3H). MS (EI) for C25H19Cl2N5O2: 492 (MH+). N-{4-[2-(piperidin-4-ylamino)pyriinidin-4-yl]phenyl}acetamide: 1H NMR (400
MHz, DMSO): 10.184 (s, 1H), 8.288 (d, 1H), 8.044 (d, 2H), 7.71 (d, 2H), 7.049 (t, 2H), 3.8 (br s, 1H), 2.962 (d, 2H), 2.077 (s, 3H), 1.838 (br d, 2H), 1.372-1.334 (m, 2H). MS (EI) for C17H21N5O: 312.3 (MH+).
N-{4-[2-({l-[(2,6-dichlorophenyl)carbonyl]piperidin-4-yl}amino)pyrimidin-4- yl]-phenyl}acetamide: 1H NMR (400 MHz, DMSO): 10.171 (s, 1H), 8.312 (d, 1H), 8.067 (d, 2H), 7.71 9d, 2H), 7.584-7.546 (m, 2H), 7.461 (t, 1H), 7.246 (d, 1H), 7.093 (d, 1H), 4.468 (m, 1H), 4.1 (br s, 1H), 3.25-3.05 (m, 2H), 2.077 (s, 3H), 2.05 (m, 1H), 1.915 (br s, 1HO, 1.58-1.532 (m, 2H). MS (EI) for C24H23Cl2N5O2: 485.3 (MH+).
N-{4r[2-({4-[(2-hydroxyethyl)oxy]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide: 1H NMR (400 MHz, DMSO): 10.211 (s, 1H), 9.43 (s, 1H), 8.455 (d, 1H), 8.12 (d, 2H), 7.754-7.69 (m, 4H), 7.292 (d, 1H), 6.93 (m, 2H), 4.865 (t, 1H), 3.97 (t, 2H), 3.715 (q, 2H), 2.09 (s, 3H). MS (EI) for C20H20N4O3: 365.1 (MH+). l-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3- phenylurea: 1H NMR (400 MHz, DMSO): 9.371 (s, 1H), 8.986 (s, 1H), 8.795 9s, 1H), 8.436 (d, 1H), 8.121 (d, 2H), 7.697 (d, 2H), 7.633 (d, 2H), 7.49 (d, 2H), 7.321-7.265 (m, 3H), 7.014-6.928 (t d, 3H), 3.758 (t, 4H), 3.063 (t, 4H). MS (EI) for C27H26N6O2: 467.3 (MH+).
N-[5-({4-[4-(acetylamino)phenyI]pyrimidin-2-yl}amino)-2-(4-ethylpiperazin-1- yl)phenyl]-2,6-dichlorobenzamide: 1H NMR (400 MHz, DMSO): 10.224 (s, 1H), 9.623 (d, 2H), 8.6 (br s, 1H), 8.48 (d, 1H), 8.237 (d, 2H), 7.735 (d, 2H). 7.598 (d, 2H), 7.521 (m, 2H), 7.35 (d, 1H), 7.181 (d, 1H), 3.36 (br s, 4H), 2.877 (t, 4H), 2.344 (q, 2H), 2.071 (s, 3H), 1.005 (t, 3H). MS (EI) for C3]H31Cl2N7O2: 604.3 (MH+). l-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yI)phenyl]-3- (phenylmethyl)urea: 1H NMR (400 MHz, MeOD): 8.082 (t, 3H), 7.53 (d, 2H), 7.422 (m, 3H), 7.236 (m, 4H), 7.159 (m, 1H), 7.037 (d, 2H), 4.32 (s, 2H), 3.971 (d, 2H), 3.608 (d, 2H), 3.195 (t, 2H), 3.126 (d, 2H), 3.045 (t, 2H), 1.3 (t, 3H). MS (EI) for C30H33N7O: 508.4 (MH+).
N2,N2-dimethyl-N-{4-[2-({4-[4-(pyridin-3-ylcarbonyI)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}glycinamide: 1H NMR (400 MHz, DMSO): 9.994 (s, 1H), 9.418 (s, 1H),<8.667 (m, 2H), 8.454 (d, 1H), 8.127 (d, 2H), 7.907-7.827 (m d, 3H), 7.7 (d, 2H), 7.513 (m, 1H), 7.298 (d, 1H), 6.98 (d, 2H), 3.799 (br s, 2H), 3.489 (br s, 2H), 3.179 (br s, 2H), 3.1 13 (br s, 4H), 2.289 (s, 6H). MS (EI) for C30H32N8O2: 537.4 (MH+). N-(3-fluoro-4-{2-[(4-morpholin-4-ylphenyI)amino]pyriinidin-4-yl}phenyl)- cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO): 10.671 (s, 1H), 9.452 (s, 1H), 8.47 (d, 1H), 8.045 (t, 1H), 7.758 (d, 1H), 7.656 (d, 2H), 7.46 (d, 1H), 7.12 (q, 1H), 6.932 (d, 2H), 3.749 (t, 4H), 3.052 (t, 4H), 1.813 (m, 1H), 0.847 (d, 4H). MS (EI) for C24H24FN5O2: 434.3(MH+).
N-(4-{2-[(4-{4-[(l-methyMH-imidazol-2-yl)methyl]piperazin-1- ylJphenyOaminoj-pyrimidin^-ylJpheny^cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO): 7.851 (d, 1H), 7.67 (d, 2H), 7.452 (br d, 2H), 7.285 (d, 2H), 7.091 (d, 1H), 7.763 (d, 1H), 6.688 (d, 2H), 6.291 (br s, 1H), 3.668 (s, 3H), 3.561 (s, 2H), 2.946 (br s, 4H), 2.5 (br s, 4H), 1.413 (m, 1H), 0.541 (m, 2H), 0.3 (m, 2H). MS (EI) for C29H32N8O: 509.4(MH+).
N-[4-(2-{[4-(4-L-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, DMSO): 10.212 (s, 1H), 9.407 (s, 1H), 8.449 (d, 1H), 8.121 (d, 2H), 7.732 (d, 2H), 7.698 (d, 2H), 7.282 (d, 1H), 6.978 (d, 2H), 3.804 (q, 1H), 3.621 (m, 4H), 3.037 (br m, 4H), 2.091 (s, 3H), 1.864 (br s, 2H), 1.10 (d, 3H). MS (EI) for C25H29N7O2: 460.4(MH+).
N-[4-(2-{[4-(4-L-prolyIpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, DMSO): 10.234 (s, 1H), 9.409 (s, 1H), 8.449 (d, 1H), 8.121 (d, 2H), 7.757 (d, 2H), 7.699 (d, 2H), 7.282 (d, 1H), 6.979 (d, 2H), 3.849 (m, 1H), 3.619 (m, 4H), 2.992 (m, 6H), 2.625 (m, 1H), 2.092 (s, 3H), 1.986 (m, 1H), 1.685-1.536 (m, 3H). MS (EI) for C27H3]N7O2: 486.2(MH+).
N-[4-(2-{[4-(4-D-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl- acetamide: 1H NMR (400 MHz, DMSO): 10.22 (s, 1H), 9.406 (s, 1H), 8.449 (d, 1H), 8.12 (d, 2H), 7.755 (d, 2H), 7.697 (d, 2H), 7.282 (d, 1H), 6.978 (d, 2H), 3.791 (q, 1H), 3.621 (br s, 4H), 3.081 (br d, 4H), 2.091 (s, 3H), 1.709 (br s, 2H), 1.096 (d, 3H). MS (EI) for C25H29N7O2: 460.4(MH+).
N-[4-(2-{[4-(4-D-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- acetamide: 1H NMR (400 MHz, DMSO): 10.211 (s, 1H), 9.407 (s, 1H), 8.449 (d, 1H), 8.121 (d, 2H), 7.754 (d, 2H), 7.698 (d, 2H), 7.282 (d, 1H), 6.979 (d, 2H), 3.872 (t, 1H), 3.621 (m, 4H), 3.082-2.979 (m, 6H), 2.656 (m, 1H), 2.091 (s, 3H), 2.013 (m, 2H), 1.676- 1.522 (m, 3H). MS (EI) for C27H3 ,N7O2: 486.4(MH+). N-{4-[2-({4-[4-(2-piperazin-1-ylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin- 4-yl]phenyl}acetamide: 1H NMR (400 MHz, DMSO): 10.219 (s, 1H), 9.401 (s, 1H), 8.448 (d, 1H), 8.121 (d, 2H)3 7.754 (d, 2H), 7.694 (d, 2H), 7.281 (d, 1H), 6.977 (d, 2H), 3.707 (t, 2H), 3.59 (t, 2H), 3.319 (s, 2H), 3.1 (t, 2H), 3.018 (t, 2H), 2.702 (s, 4H), 2.336 (br s, 4H), 2.090 (s, 3H). MS (EI) for C28H34N8O2: 515.2(MH+).
N-[4-(2-{[4-(4-L-alanylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, DMSO): 9.938 (s, 1H), 9.417 (s, 1H), 8.457 (d, 1H), 8.135 (d, 2H), 7.885 (d, 2H), 7.693 (d, 2H), 7.305 (d, 1H), 6.976 (d, 2H), 4.436 (q, 1H), 3.991 (q, 1H), 3.878-3.761 (q q, 4H), 3.622 (br s, 4H), 3.083 (br d, 4H), 2.222 (m, 1H), 2.019 (m, 1H), 1.913 (m, 2H), 1.843 (br s, 2H). MS (EI) for C28H33N7O3: 516.3(MH+).
N-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, DMSO): 9.945 (s, 1H), 9.419 (s, 1H), 8.458 (d, 1H), 8.135 (d, 2H), 7.887 (d, 2H), 7.696 (d, 2H), 7.306 (d, 1H), 6.978 (d, 2H), 4.452 (q, 1H), 4.011 (q, 1H), 3.861 (q, 2H), 3.633 (m, 4H), 3.084-2.968 (m, 6H), 2.62 (m, 1H), 2.191 (m, 1H), 2.002 (m, 2H), 1.897 (m, 2H), 1.691-1.544 (m, 3H). MS (EI) for C30H35N7O3: 542.3(MH+).
N-[4-(2-{[4-(4-D-alanylpiperazin-1-yl)phenyl]amino}pyriinidin-4-yl)phenyl]- tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, DMSO): 9.945 (s, 1H), 9.418 9s, 1H), 8.457 (d, 1H), 8.135 (d, 2H), 7.887 (d, 2H), 7.694 (d, 2H), 7.305 (d, 1H), 6.976 (d, 2H), 4.452 (q, 1H), 4.028 (q, 1H), 3.878-3.768 (m, 2H), 3.633 (m, 4H), 3.083 (br d, 4H), 2.209 (m, 1H), 2.002 (m, 1H), 1.862 (m, 3H), 1.1 (d, 3H). MS (EI) for C28H33N7O3: 516.3(MH+).
N-[4-(2-{[4-(4-D-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- tetrahydrofuran-2-carboxamide: 1H NMR (400 MHz, DMSO). 9.954 (s, 1H), 9.421 (s, 1H), 8.458 (d, 1H), 8.136 (d, 2H), 7.889 (d, 2H), 7.697 (d, 2H), 7.306 (d, 1H), 6.978 (d, 2H), 4.454 (q, 1H), 4.028 (q, 1H), 3.889 (m, 2H), 3.645 (m, 4H), 3.083-2.985 (m, 6H), 2.669 (m, 1H), 2.209 (m, 1H), 2.002 (m, 2H), 1.879 (m, 2H), 1.681-1.548 (m, 3H), MS (EI) for C30H35N7O3: 542.3(MH+). (2,6-dichlorophenyl)(4-(4-(4-methylthiophen-2-yl)pyrimidin-2- ylamino)piperidin-1-yl)methanone: 1H-NMR (400MHz, d6-DMSO): 8.28 (d, 1H), 7.72 (m, 1H), 7.57 (m, 2H), 7.47 (m, 1H), 7.32 (s, 1H), 7.27 (m, 1H), 7.01 (m, 1H), 4.45 (m, 1H), 4.03 (m, 1H), 3.28-3.05 (m, 3H), 2.45 (s, 3H), 2.03-1.80 (m, 2H), 1.59-1.48 (m, 2H); MS (EI): 447 (MH+).
(2,6-dichlorophenyl)(4-(4-(pyridin-3-yl)pyrimidin-2-ylamino)piperidin-1-yl)- methanone: 1H-NMR (400MHz, d6-DMSO): 9.28 (br. s, 1H), 8.69 (m, 1H), 8.41 (m, 2H), 7.59-7.52 (m, 2H), 7.46 (m, 2H), 7.25 (d, 1H), 4.46 (m, 1H), 4.14 (m, 1H), 3.32-3.10 (m, 3H), 2.06-1.89 (m, 2H), 1.63-1.54 (m, 3H); MS (EI): 428 (MH+).
(2,6-dichlorophenyl)(4-(4-(5-methylthiophen-2-yl)pyrimidin-2- ylamino)piperidin-1-yl)methanone: 1H-NMR (400MHz, d6-DMSO): 8.24 (d, 1H), 7.70 (m, 1H), 7.57 (m, 2H), 7.47 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.88 (m, 1H), 4.45 (m, 1H), 4.02 (m, 1H), 3.28-3.05 (m, 3H), 2.47 (s, 3H), 2.03-1.80 (m, 2H), 1.57-1.50 (m, 2H); MS (EI): 447 (MH+). l-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- 1H-pyrrole-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.99 (s, 1H), 9.39 (s, 1H), 8.45 (d, 1H), 8.13 (d, 2H), 7.90 (d, 2H), 7.68 (d, 2H), 7.30 (d, 1H), 7.09-7.08 (m, 1H), 7.05 (t, 1H), 6.97 (d, 2H), 6.13-6.11 (m, 1H), 3.90 (s, 3H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C26H26N6O2: 455 (MH+).
3-fluoro-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)pyridine-4-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.96 (s, 1H), 9.43 (s, 1H), 8.79 (s, 1H), 8.62 (d, 1H), 8.47 (d, 1H), 8.20 (d, 2H), 7.88 (d, 2H), 7.76-7.67 (m, 2H), 7.32 (d, 1H), 6.94 (d, 2H), 6.56 (s, 1H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C26H23FN6O2: 471 (MH+).
6-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)pyridine-3-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.61 (s, 1H),
9.41 (s, 1H), 9.03 (d, 1H), 8.47 (d, 1H), 8.23 (dd, 1H), 8.19 (d, 2H), 7.95 (d, 2H), 7.68 (d, 2H), 7.45 (d, 1H), 7.31 (d, 1H), 6.94 (d, 2H), 3.74 (t, 4H), 3.05 (t, 4H), 2.57 (s, 3H). MS
(EI) for C27H26N6O2: 467 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)ammo]pyrimidin-4-yl}phenyl)pyridazine-4- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.98 (s, 1H), 9.67 (s, 1H), 9.52 (d, 1H),
9.42 (s, 1H), 8.47 (d, 1H), 8.21 (d, 2H), 8.16-8.14 (m, 1H), 7.96 (d, 2H), 7.68 (d, 2H), 7.33 (d, 2H), 7.33 (d, 1H), 6.95 (d, 2H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C25H23N7O2:
454 (MH+). 2-cyclopropyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide: 1H NMR (400 MHz, d6-DMSO): 10.09 (s, 1H), 9.45 (s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.78 (d, 2H), 7.69 (d, 2H), 7.30 (d, 1H), 7.00 (s, 2H), 3.76 (s, 4H), 3.09 (s, 4H), 2.25 (d, 2H), 1.12-1.02 (m, 1H), 0.50-0.48 (m, 2H), 0.22-0.20 (m, 2H). MS (EI) for C25H27N5O2: 430 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)isoxazole-5- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.99 (s, 1H), 9.42 (s, 1H), 8.47 (d, 1H), 8.19 (d, 2H), 7.95 (d, 2H), 7.68 (d, 2H), 7.33-7.31 (m, 2H), 6.95 (d, 2H), 6.55 (s, 1H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C24H22N6O3: 443 (MH+). N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridine-3- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.69 (s, 1H), 9.41 (s, 1H), 9.14 (s, 1H), 8.79 (d, 1H), 8.47 (d, 1H), 8.34-8.31 (m, 1H), 8.20 (d, 2H), 7.97 (d, 2H), 7.70 (d, 2H), 7.67-7.58 (m, 1H), 7.33 (d, 1H), 6.95 (d, 2H), 3.78 (t, 4H), 3.05 (t, 4H). MS (EI) for C26H24N6O2: 453 (MH+). 4-methyl-N-(4-{2-[(4-morpholin-4-yIphenyI)amino]pyrimidin-4-yl}phenyl)- benzamide: 1H NMR (400 MHz, d6-DMSO): 10.42 (s, 1H), 9.53 (s, 1H), 8.47 (s, 1H), 8.17 (d, 2H), 7.98 (d, 2H), 7.91 (d, 2H), 7.72 (s, 2H), 7.37 (d, 3H), 7.05 (s, 2H), 3.78 (s, 4H), 3.14 (s, 4H), 2.40 (s, 3H). MS (EI) for C28H27N5O2: 466 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyI]-D- prolinamide: 1H NMR (400 MHz, d6-DMSO): 11.55 (s, 1H), 11.15 (s, 1H), 10.16 (s, 2H), 8.74 (s, 1H), 8.52 (s, 1H), 8.23 (d, 2H), 7.89 (d, 2H), 7.67 (d, 2H), 7.48 (s, 1H), 7.1 1 (d, 2H), 4.50 (s, br, 1H), 3.81 (d, 2H), 3.57 (d, 2H), 3.28-3.11 (m, 8H), 2.05-1.92 (m, 3H), 1.30 (t, 3H). MS (EI) for C27H33N7O: 472 (MH+).
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]- butanamide: 1H NMR (400 MHz, d6-DMSO): 10.25 (s, 1H), 9.37 (s, 1H), 8.43 (s, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.29 (s, 1H), 6.93 (d, 2H), 3.08 (s, 4H), 2.42-2.30 (m, 4H), 1.68-1.58 (m, 2H), 1.05 (t, 3H), 0.93 (t, 3H). MS (EI) for C26H32N6O: 445 (MH+). l-ethyl-3-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]urea: 1H NMR (400 MHz, d6-DMSO): 9.32 (s, 1H), 8.85 (s, 1H), 8.40 (d, 1H), 8.05 (d, 2H), 7.68 (d, 2H), 7.54 (d, 2H), 7.23 (d, 1H), 6.92 (d, 2H), 6.36 (t, 1H), 3.18-3.05 (m, 6H), 2.54 (t, 4H), 2.46-2.38 (m, 2H), 1.09-1.02 (m, 6H). MS (EI) for C25H3|N7O: 446 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)furan-3- carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.17 (s, 1H), 9.46 (s, 1H), 8.47-8.43 (m, 2H), 8.18 (d, 2H), 7.91 (d, 2H), 7.83 (d, 1H), 7.70 (s, 2H), 7.32 (s, 1H), 7.03-6.95 (m, 3H), 3.76 (s, 4H), 3.09 (s, 4H). MS (EI) for C25H23N5O3: 442 (MH+).
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyriinidin-4-yl}phenyl)-1,3-thiazole- 4-carboxamide: 1H NMR (400 MHz, d6-DMSO): 10.61 (s, 1H), 9.40 (s, 1H), 9.30 (d, 1H), 8.56 (d, 1H), 8.46 (d, 1H), 8.16 (d, 2H), 8.06 (d, 2H), 7.69 (d, 2H), 7.32 (d, 1H), 6.96 (d, 2H), 6.56 (s, 1H), 3.74 (t, 4H), 3.05 (t, 4H). MS (EI) for C24H22N6O2S: 459 (MH+).
[00270] Based on the synthetic examples described hereinabove, the skilled artisan would be able to make the remainder of the compounds intended to be within the scope JAK-2 compounds.
ASSAYS FOR JAK-2 COMPOUNDS Assay Example 1
Measurement of JAK-2 Kinase Activity by ATP Hydrolysis
[00271] JAK-2 kinase activity was measured by monitoring peptide substrate dependent hydrolysis of ATP via quantitation of remaining ATP with luciferase based chemiluminescence. For compound evaluation, 0.5 μl of the compound dissolved in DMSO was added to 10 μl of JAK-2 dissolved in assay buffer (20 mM HEPES pH 7.5, 10 mM MgCl2, 0.03% Triton and ImM DTT). After preincubation for 30 minutes at room temperature, the reaction was initiated by addition of 10 μl of ATP and the substrate peptide poly-Glu-Tyr in assay buffer. Final enzyme, ATP, and peptide concentrations were 3 nM, 1 μM, and 2 μM, respectively. After incubation for 60 minutes at room temperature, reaction progress was quantitated by addition of 10 μl Kinase-Glo (Promega) and measurement of chemiluminescence in a Victor reader (Perkin Elmer). A reaction in which compound was omitted was used to determine maximum reaction progress. Omission of compound and enzyme from the reaction was used to determine zero reaction progress. Assay Example 2
Measurement of JAK-3 Kinase Activity by ATP Hydrolysis
[00272] JAK-3 was assayed similarly as JAK-2 (see Assay Example 1) except that the enzyme reaction was carried out for 180 minutes and enzyme, ATP, and peptide concentrations were 30 nM, 2 μM, and 4 μM, respectively.
Biological Activity
[00273] JAK compounds in Table l(J) were determined to have inhibitory activity for JAK-2 of less than 10 μM. Other more preferred compounds JAK-2 compounds have inhibitory activity for JAK-2 of less than 100 nm. One of ordinary skill in the art can use the disclosures herein as well as what is known in the art to test the inhibitory activity of a particular compound.
Pharmaceutical Composition Examples [00274] The following are representative pharmaceutical Formulations containing a compound of Formula I(J).
Tablet Formulation [00275] The following ingredients are mixed intimately and pressed into single scored tablets.
Figure imgf000306_0001
Capsule Formulation [00276] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Figure imgf000306_0002
Suspension Formulation
[00277] The following ingredients are mixed to form a suspension for oral administration.
Figure imgf000307_0001
Injectable Formulation
[00278] The following ingredients are mixed to form an injectable Formulation.
Figure imgf000307_0002
[00279] All of the above ingredients, except water, are combined and heated to 60-70 °C. with stirring. A sufficient quantity of water at 60°C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.
Suppository Formulation [00280] A suppository of total weight 2.5 g is prepared by mixing the compound of the
JAK-2 compound described herein with Witepsol® H- 15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Figure imgf000307_0003
General Administration
[00281] The combinations of JAK-2 compounds in combination with any of the other active agents described herein can be used to treat diseases in mammals such myeloproliferative disorder, cancer, cardiovascular disease, and/or hematopoitic abnormality wherein the mammal is in need of the treatment. In another embodiment, combinations of JAK-2 and with any of the other active agents described herein can be used to to treat cancer in mammals, such as a cancer prostate cancer, breast cancer, multiple myeloma, leukemia, lymphoma, lung cancer, colorectal cancer, renal cancer, melanoma, hepatocellular, gastric, GIST, pancreatic carcinoma, and papillary thyroid cancer. In another embodiment, combinations of JAK-2 and with any of the other active agents described herein can be used to to treat cancer in mammals, such as a cancer prostate cancer, breast cancer, multiple myeloma, leukemia, lymphoma, lung cancer, colorectal cancer, renal cancer, melanoma, hepatocellular, gastric, GIST, pancreatic carcinoma, and papillary thyroid cancer. In another embodiment, combinations of JAK-2 and with any of the other active agents described herein can be used to treat myelofibrosis, thrombocythemia, polycythemia vera, essential thrombocythemia, agnogenic myeloid metaplasia, and chronic myelogenous leukemia. In another embodiment, combinations of JAK-2 with any of the other active agents described herein can be used to to treat cancers selected from leukemias, lymphomas, multiple myeoloma, prostate cancers, lung cancers, breast cancers, and ovarian cancers. In another embodiment, combinations of JAK-2 and with any of the other active agents described herein can be used to to treat congestive heart failure or hypertension. In another embodiment, combinations of JAK-2 and with any of the other active agents described herein can be used to to treat a hematopoitic abnormality such as thrombocytosis. [00282] In one aspect, the JAK-2 compounds in combination with any of the other active agents described herein can be in the form of pharmaceutical compositions comprising an inhibitor of JAK-2 according to Formula I(J), II(J), III(J), IV(J), V(J) or VI(J) as described herein in combination with any of the inhibitors of Raf, PBK, mTor, Akt, EGFR, ErbB2, VEGFR, c-Met, c-Kit, BCR-AbI, Flt3 and Src, as described herein, each with a pharmaceutically acceptable carrier. The pharmaceutical Formulations can also include one or more excipients and/or one or more diluents. The JAK-2 compounds and any of the other active agents described herein can be administered together in one pharmaceutical composition, or separately as two separate pharmaceutical compositions. [00283] When the pharmaceutical compositions include both of the JAK-2 compounds with any of the other active agents described herein, the weight percentage of the JAK-2 compounds can range from about 0.01% by weight to about 0.99% by weight, or from about 0.05% by weight to about 0.95% by weight, or from about 0.1% by weight to about 0.90% by weight, or from about 0.20% by weight to about 0.80% by weight, or from about 0.30% by weight to about 0.70% by weight, or from about 0.40% by weight to about 0.60% by weight, or from about 0.1% by weight to about 0.2% by weight, or from about 0.20% by weight to about 0.30% by weight, or from about 0.30% by weight to about
0.40% by weight, or from about 0.40% by weight to about 0.50% by weight, or from about 0.50% by weight to about 0.60% by weight, or from about 0.60% by weight to about 0.70% by weight, or from about 0.70% by weight to about 0.80% by weight, or from about 0.80% by weight to about 0.90% by weight. [00284] In another embodiment, when the pharmaceutical compositions include both of the JAK-2 compounds and any of the other active agents described herein, the weight percentage of the other active agents described herein can range from about 0.01% by weight to about 0.99% by weight, or from about 0.05% by weight to about 0.95% by weight, or from about 0.1% by weight to about 0.90% by weight, or from about 0.20% by weight to about 0.80% by weight, or from about 0.30% by weight to about 0.70% by weight, or from about 0.40% by weight to about 0.60% by weight, or from about 0.1% by weight to about 0.2% by weight, or from about 0.20% by weight to about 0.30% by weight, or from about 0.30% by weight to about 0.40% by weight, or from about 0.40% by weight to about 0.50% by weight, or from about 0.50% by weight to about 0.60% by weight, or from about 0.60% by weight to about 0.70% by weight, or from about 0.70% by weight to about 0.80% by weight, or from about 0.80% by weight to about 0.90% by weight.
[00285] In another embodiment, when the pharmaceutical compositions include both of the JAK-2 compounds and any of the other active agents described herein, and the weight ratio of "JAK-2 compounds":"other active agents" is about 0.01 :100, 0.05:50, 0.1 :50, 0.2:30, 0.4:25, 0.5:20, 0.6:15, 0.8: 10, 1 :5, 1 :2, or 1 :1. [00286] In another embodiment, when the pharmaceutical compositions includes both of the JAK-2 compound and any of the other active agents described herein, the weight ratio of "other active agents":"JAK-2 compounds" is about 0.01 :100, 0.05:50, 0.1 :50, 0.2:30, 0.4:25, 0.5:20, 0.6:15, 0.8: 10, 1 :5, 1 :2, or 1 : 1. [00287] In certain other embodiments, administration can be by the oral route. Administration of the combination compounds of the JAK-2 compounds and any of the other active agents described herein, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
[00288] The compositions described herein can include a conventional pharmaceutical carrier or excipient and a JAK-2 compound or any other agent described herein as the/an active agent, and, in addition, may include carriers and adjuvants, etc. [00289] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[00290] If desired, a pharmaceutical composition described herin can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc. [00291] The choice of Formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, Formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical Formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical Formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical Formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical Formulation that exhibits remarkably high bioavailability. [00292] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. [00293] One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[00294] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. [00295] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active JAK-2 compounds and/or any of the other active agents described herein can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[00296] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a JAK-2 compound and/or any of the other active agents described herein, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension. [00297] Suspensions, in addition to the active JAK-2 compounds and/or any of the other active agents described herein may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. [00298] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the JAK-2 compounds and/or any of the other active agents described herein, with for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethylene-glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
[00299] Dosage forms for topical administration of a JAK-2 compounds and/or any of the other active agents described herein include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic Formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. [00300] Compressed gases can be used to disperse the JAK-2 compounds and/or any of the other active agents described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
[00301] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a JAK-2 compound and/or any of the other active agents described herein, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a JAK-2 compound and/or any of the other active agents described herein, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients. [00302] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition or compositions to be administered will, in any event, contain a therapeutically effective amount of a JAK-2 compound and/or any of the other active agents described herein, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
[00303] The JAK-2 compounds and/or any of the other active agents described herein, or their pharmaceutically acceptable salts or hydrates, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compounds employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease- states, and the host undergoing therapy. The JAK-2 compounds and/or any of the other active agents described herein can be administered to a patient at dosage levels in the range of about 0.1 to about 1 ,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art. [00304] If formulated as a fixed dose, such combination products employ the JAK-2 compounds and any of the other active agents described herein within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. The JAK-2 compounds and any of the other active agents described herein may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when combined with other chemotherapeutic, or otherwise active agents.
ADDITIONAL EMBODIMENTS
[00305] In another aspect of the invention, the combination of JAK-2 compounds and optionally any of the additional agents described herein, can be further combined with one or more additional treatments selected from one or more chemotherapeutic agents, one or more antibodies, radiation therapy, surgery, hormone therapy, and hypothermia therapy, wherein the chemotherapeutic agent is selected from one or more taxanes, one or more platin(s), one or more topoisomerase inhibitor(s), one or more alkylating agent(s), one or more antimetabolite(s), one or more antimicrotubule agent(s), one or more bcr-abl inhibitor(s), rapamycin, carboplatin, cisplatin, oxaliplatin, gemcitabine, dacarbazine, topotecan, irinotecan, one or more HSP90 inhibitors, and one or more IGFlR inhibitors.
[00306] In another embodiment, the one or more of the chemotherapeutic agent(s) is selected from a taxane(s), a platin(s), a topoisomerase inhibitor(s), an alkylating agent(s), an antimetabolite(s), an antimicrotubule agent(s), and a bcr-abl inhibitor(s). Non-limiting examples of chemotherapeutic agent(s) include an antimicrotubule agent(s) selected from
Vincristine,Vinblastine, Vinorelbine, and Vindesine.
[00307] In another embodiment, the one or more of the chemotherapeutic agent is a taxane. [00308] In another embodiment, the chemotherapeutic agent is a platin.
[00309] In another embodiment, the one or more of the chemotherapeutic agent(s) is selected from rapamycin, carboplatin, cisplatin, oxaliplatin, gemcitabine, dacarbazine, topotecan, and irinotecan. [00310] In another embodiment, the one or more of the chemotherapeutic agent(s) is an
EGFR inhibitor. Non-limiting examples of EGFR inhibitors include Lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE778, HKI-272, EKB-
569 and CI1033.
[00311] In another embodiment, the one or more of the chemotherapeutic agent(s) is an ErbB2 inhibitor. Non-limiting examples of ErbB2 inhibitors include lapatinib, EXB-569,
HKI272, and CI 1033.
[00312] In another embodiment, the one or more of the chemotherapeutic agent(s) is an
HSP90 inhibitor. Non-limiting examples of the HSP90 inhibitor include 17- AAG, 17-
DMAG, Geldanamycin, CNF2024, and SNX-21 12. [00313] In another embodiment, the one or more of the chemotherapeutic agent(s) is an
IGFlR inhibitor.
[00314] In another embodiment, the one or more of the chemotherapeutic agent(s) is a
Raf inhibitor such as, for example, sorafenib.
[00315] In another embodiment, the one or more of the chemotherapeutic agent(s) is selected from rapamycin, a rapamycin analogue, PI 103, PI504, and SFl 126. Non-limiting examples of the chemotherapeutic agent(s) include rapamycin, CCI-779, AP23573,
RADOOl, TAFA93, PI103, PI504, and SFl 126. In another embodiment, the chemotherapeutic agent is rapamycin.
[00316] In another embodiment, the one or more of the treatment(s) is selected from radiation and hypothermia therapy. In another embodiment, the treatment is radiation.
[00317] In another embodiment, the one or more of the treatment(s) is one or more antibody(s). Non-limiting examples include one or more of the antibody(s) selected from an IGFlR antibody (including, for example, <*IGF-1R Al 2 MoAb, 19Dl 2, h7C10 and CP-
751871), Alemtuzumab, Bevacizumab (Avastin®), Cetuximab (Erbitux®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab,
Tositumomab, and Trastuzumab (Herceptin®).
[00318] In another embodiment, the one or more of the treatment(s) is surgery. [00319] In another embodiment, the one or more of the treatment(s) is one or more hormone therapy(s). Non-limiting examples of hormone treatments include tamoxifen and an aromatase inhibitor.
[00320] In another embodiment, the one or more of the chemotherapeutic agent(s) is gemcitabine.
[00321] In another embodiment, the one or more of the chemotherapeutic agent(s) is Imatinib (i.e. Gleevec®).
[00322] In another embodiment, the cancer is primary or relapsed CML and/or acute myelogenous leukemia (AML) and one or more of the treatment(s) is selected from one or more of the chemotherapeutic agent(s) and one or more antibody(s). Non-limiting examples of the chemotherapeutic agent(s) in this embodiment include Imatinib (i.e. Gleevec®) and PKC412. In another embodiment, the one or more of the chemotherapeutic agent(s) is Imatinib (i.e. Gleevec®). Non-limiting examples of the one or more antibody(s) in this embodiment include "IGF-IR Al 2 MoAb and trastuzumab. [00323] In another embodiment, the cancer is prostate cancer and the one or more of the treatment(s) is selected from one or more antibody(s). Non-limiting examples of the one or more of the antibody(s) in this embodiment include αIGF-IR A12 MoAb. [00324] In another embodiment, the cancer is malignant melanoma and one or more of the treatment(s) is selected from surgery and one or more chemotherapeutic agent(s). Non-limiting examples of chemotherapeutic agent(s) in this embodiment include an alkylating agent(s), a taxane(s), a platin(s), and a Raf inhibitor(s). In another embodiment, the one or more chemotherapeutic agent(s) is selected from sorafenib, Paclitaxel (Taxol®), Docetaxel (Taxotere®), dacarbazine, rapamycin, imatinib mesylate (Gleevec®), sorafenib, and carboplatin. [00325] In another embodiment, the cancer is colon or rectal cancer and one or more of the treatment(s) is selected from surgery, radiation, one or more chemotherapeutic agent(s), and one or more antibody(s). Non-limiting examples of the chemotherapeutic agent(s) include cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, Capecitabine (Xeloda), Irinotecan (Camptosar), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), and leucovorin. Non- limiting examples of the one or more of the antibody(s) include bevacizumab and cetuximab. [00326] In another embodiment, the cancer is pancreatic cancer and one or more of the treatment(s) include surgery, radiation, and one or more chemotherapeutic agent(s). Non- limiting examples of the one or more of the chemotherapeutic agent(s) include erlotinib (Tarceva®), gemcitabine, 5-fluorouracil, leucovorin, cisplatin, oxaliplatin, carboplatin, gemcitabine, irinotecan, paclitaxel, capecitabine, and streptozocin.
[00327] In another embodiment, the cancer is breast cancer and one or more of the treatment(s) is selected from surgery, radiation, one or more chemotherapeutic agent(s), one or more hormone therapy(s), and one or more antibody(s). Non-limiting examples of the chemotherapeutic agent(s) in this embodiment include lapatinib (Tykerb®), Paclitaxel (Taxol®), docetaxel, capecitabine, Cyclophosphamide (Cytoxan), methotrexate, fluorouracil, doxorubicin, epirubicin, gemcitabine, carboplatin (Paraplatin), cisplatin (Platinol), vinorelbine (Navelbine), capecitabine (Xeloda), pegylated liposomal doxorubicin (Doxil), and albumin-bound paclitaxel (Abraxane). Specifically one or more of the antibody(s) is selected from αIGF-lR A12 MoAb, bevacizumab (Avastin), and trastuzumab. Non-limiting examples of the hormone therapy(s) in this embodiment include tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, and an aromatase inhibitor(s). Non-limiting examples of the aromatase inhibitor(s) include selected from etrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). [00328] In another embodiment, the cancer is non-small cell lung cancer and one or more of the treatment(s) is selected from surgery, radiation, one or more antibody(s), and one or more chemotherapeutic agent(s). Non-limiting examples of the chemotherapeutic agent(s) in this embodiment include cisplatin, oxaliplatin, carboplatin, Zactima (ZD6474), Paclitaxel, Docetaxel (Taxotere®), Gemcitabine (Gemzar®), Vinorelbine, Irinotecan, Etoposide, Vinblastine, Erlotinib (Tarceva®), and Pemetrexed. Non-limiting examples of the antibody(s) include Bevacizumab.
[00329] In another embodiment, the cancer is small cell lung cancer and one or more of the treatment(s) is selected from surgery, radiation, and one or more chemotherapy agent(s). Non-limiting examples of the chemotherapy agent(s) in this embodiment include cisplatin, oxaliplatin, carboplatin, etoposide, irinotecan, fosfamide, paclitaxel, docetaxel, gemcitabine, Topotecan, cyclophosphamide/doxorubicin/vincristine (CAV), methotrexate, and vinorelbine. [00330] In another embodiment, the cancer is papillary or anaplastic thyroid cancer, and one or more of the treatment(s) is selected from surgery, radiation, radioactive iodine therapy, one or more hormone therapy(s), and one or more chemotherapeutic agent(s). Non-limiting example of the chemotherapeutic agent(s) in this embodiment include thyroid hormone pills, Doxorubucin and a platin(s).
[00331] In another embodiment, the cancer is endometrial cancer and one or more of the treatment(s) is selected from surgery, radiation, hormone therapy, and one or more chemotherapeutic agent(s). Non-limiting examples of the one or more of the chemotherapeutic agent(s) in this embodiment include paclitaxel, doxorubicin, and cisplatin. Nonlimiting examples of the one or more of the hormone therapies in this embodiment include medroxyprogesterone acetate, megestrol acetate, and Tamoxifen. [00332] In another embodiment, the cancer is ovarian cancer and one or more of the treatment(s) is selected from surgery, radiation, and one or more chemotherapeutic agent(s). Non-limiting examples of chemotherapeutic agent(s) in this embodiment include a platin(s) compound (such as cisplatin, oxaliplatin and carboplatin), a taxane (such as paclitaxel or docetaxel), topotecan, anthracyclines (such as doxorubicin (Adriamycin) and liposomal doxorubicin (Doxil)), gemcitabine, cyclophosphamide, vinorelbine (Navelbine), hexamethylmelamine, ifosfamide, and etoposide. [00333] In another embodiment, one or more of the treatment(s) is selected from one or more chemotherapeutic agent(s), radiation, hypothermia therapy, one or more antibody(s), and surgery.
[00334] In another embodiment one or more of the treatment(s) is selected from radiation and surgery. [00335] In another embodiment of the invention, one or more of the treatments is selected from CCI-779, AP23573, RADOOl, TAF A93, carboplatin, cisplatin, oxaliplatin, gemcitabine, dacarbazine, topotecan, irinotecan, sorafenib, paclitaxel, docetaxel, Lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), 5-fluorouracil, Capecitabine (Xeloda), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), streptozocin, Cyclophosphamide (Cytoxan), methotrexate, doxorubicin, epirubicin, vinorelbine (Navelbine), pegylated liposomal doxorubicin (Doxil), albumin-bound paclitaxel (Abraxane), Etoposide, Vinblastine, Pemetrexed, leucovorin, fosfamide, cyclophosphamide/doxorubicin/vincristine (CAV), thyroid hormone pills, hexamethylmelamine, ifosfamide, Imatinib (i.e. Gleevec®), 0IGF-IR Al 2 MoAb, IGF-IR 19Dl 2, IGF-IR h7C10, IGF-IR CP-751871, Alemtuzumab, Bevacizumab (Avastin®), Cetuximab (Erbitux®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Trastuzumab (Herceptin®), tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, medroxyprogesterone acetate, megestrol acetate, and an aromatase inhibitor. [00336] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.
VEGFR Compounds [00337] In the methods of the invention, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with any VEGFR, EGFR, Flt3 c-Met, or c-Kit inhibitor known in the art. Non- limiting examples of VEGFR inhibitors (VEGFR inhibitors fall within the scope of aspect (2) of this invention) that can be combined with the JAK-2 compounds described hereinabove include bevacizumab, axitinib and any of the VEGFR compounds described below that inhibit VEGFR. The VEGFR inhibitors regulate and/or modulate the signal transduction of VEGFR. Non-limiting examples of Flt3 inhibitors (Flt3 inhibitors fall within the scope of aspect (8) of this invention) that can be combined with the JAK-2 compounds described hereinabove include sunitinib and any of the VEGFR compounds described below that inhibit Flt3. Non-limiting examples of c-Met inhibitors (c-Met inhibitors fall within the scope of aspect 5 of this invention) that can be combined with the JAK-2 compounds described hereinabove include any of the VEGFR compounds described below that inhibit c-Met. Non-limiting examples of c-Kit inhibitors (c-Kit inhitiors fall within the scope of aspect 5 of this invention) that can be combined with the JAK-2 compounds described hereinabove include imatinib, axitinib, and any of the VEGFR compounds described below that inhibit c-Kit. Non-limiting examples of EGFR inhibitors (EGFR inhibitors fall within the scope of aspect (11) of this invention) that can be combined with the JAK-2 compounds described hereinabove include any of the VEGFR compounds described below that inhibit EGFR.
[00338] All of the VEGFR compounds described below are intended to alternatively include pharmaceutically acceptable salts of these compounds whether it is explicitely stated or not. All of the VEGFR compounds described below fall within the scope of aspect (19) of this invention.
[00339] In another embodiment the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with any of the following VEGFR compounds (which can inhibit one or more of VEGFR, EGFR, Flt3 c-Met, or c-Kit) in Table I(Vl), or a pharmaceutically acceptable salt thereof.
Table 1(Vl)
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Synthetic Procedures for the Compounds of Table 1(Vl),
[00340] The compounds of Table I(Vl), can be made by the synthetic schemes and examples described in publication WO 2004/050681, which is incorporated herein by reference in its entirety. The utility of the compounds in Table I(VI) is also described in WO 2004/050681.
[00341] In other embodiments of the above method of combining the compounds in Table I(Vl) with the JAK-2 inhibitors of Formula I(J), one or more of any of the compounds in Table I(VI) can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the above method of combining the compounds in Table I(Vl) with the JAK-2 inhibitors of Formula I(J), one or more of any of the compounds in Table I(VI) can be combined with one or more of any of the compounds in Table I(J).
[00342] Another aspect 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 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a compound selected from Table 1(VI).
EFGR Compounds
[00343] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with any of the following EGFR compounds (that are inhibitors of VEFGR and/or EGFR) described hereinbelow. Non-limiting examples of EGFR inhibitors (EGFR inhibitors fall within the scope of aspect (11) of this invention) that can be combined with any of the JAK-2 compounds described hereinabove include any of the EGFR compounds described below that can inhibit EGFR. Non-limiting examples of VEGFR inhibitors (VEGFR inhibitors fall within the scope of aspect (2) of this invention) that can be combined with any of the JAK-2 compounds described hereinabove include any of the EGFR compounds described below that can inhibit VEGFR. All of the EGFR compounds described below are intended to alternatively include pharmaceutically acceptable salts of these compounds whether it is explicitely stated or not. All of the EGFR compounds described below fall within the scope of aspect (26) of this invention.
[00344] Non-limiting examples of EGFR compounds include the compounds according to Formula I(V2):
Figure imgf000327_0001
or a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt or hydrate thereof, wherein, R1 is C1-C3 alkyl optionally substituted with between one and three R50 substituents; R2 is selected from halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -N(R3)R4,
-S(O)0-2R4, -SO2N(R3)R4, -CO2R3, -C(=O)N(R3)R4, -N(R3)SO2R4, -N(R3)C(=O)R3,
-N(R3)CO2R4, -C(=O)R3, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted lower alkynyl; R3 is -H or R4;
R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or
R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; q is 0, 1, 2, 3, 4, or 5;
Z is selected from -OCH2-, -O-, -S(O)0-2-, -N(R5)CH2-, and -NR5-; R5 is -H or optionally substituted lower alkyl;
R50 is -H, halo, trihalomethyl, -OR3, -N(R3)R4, -S(O)0-2R4, -SO2N(R3)R4, -CO2R3,
-C(=O)N(R3)R4, -C(=NR25)N(R3)R4, -C(=NR25)R4, -N(R3)SO2R4, -N(R3)C(O)R3,
-NCO2R3, -C(=O)R3, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or two of R50, when taken together on the same carbon are oxo; or two of R50, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; R25 is selected from -H, -CN, -NO2, -OR3, -S(O)0-2R4, -CO2R3, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted lower alkynyl; M '-M2 -M3 -M4- together are according to Formula H(VZ):
Figure imgf000328_0001
II(V2) wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system containing up to three annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -O-, -S(O)0-2-, and -NR8-; each X is independently a bridgehead methine optionally substituted with R6, or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(O)0-2-, and -NR8-; provided, for X1, X2, and X3, there are no nitrogen-nitrogen annular bonds nor geminal di-nitrogen substitutions;
E is selected from -NR9-, -0-, and absent; Y is either: a C1-3 alkyl ene linker, between the oxygen at the 7-position of the quinazoline ring system of 1(VT) and either E, or when E is absent, any ring atom of the saturated bridged ring system except X2, when X2 is a bridgehead nitrogen; provided there are at least two carbon atoms between the oxygen at the 7-position of the quinazoline ring system of I(V2) and either E, or when E is absent, any heteroatom represented by X1, X2 or X3; or
Y is absent, when Y is absent, E is also absent; said saturated bridged ring system is directly attached to the oxygen at the 7-position of the quinazoline ring system of I(V2) via a carbon atom of said saturated bridged ring system; m and p are each independently from one to four; n is from zero to two, when n is zero, then there is a direct single bond between the two bridgehead X2 's;
R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -N(R3)R4, -S(O)0-2R4, -SO2N(R3)R4, -CO2R3, -C(O)N(R3)R4, -N(R3)SO2R4, -N(R3)C(O)R3, -NCO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl; or R6 and R7, when taken together are oxo; or
R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
R8 is selected from R3, -SO2N(R3)R4, -CO2R3, -C(O)N(R3)R4, -SO2R4, and
-C(O)R3; R9 is -H or optionally substituted lower alkyl; with the proviso that when Y is a C1-3 alkylene linker, E is absent, Z is -NH- or -N(CH3)-, R1 is a C1-3 alkyl, R2 is -H or halogen, n = O, and the atoms X1 of one bridge of the saturated bridged ring system, when combined with both bridgehead atoms, X , of the saturated bridged ring system, represent: either a pyrrolidine ring or a piperidine ring, and any atom, X1 or X2, of either of said pyrrolidine ring or said piperidine ring is attached to Y; then the other bridge of said saturated bridged ring system cannot be any one Of -OC(O)CH2-, -CH2OC(O)-, -OC(O)CH2CH2-, -CH2OC(O)CH2-, -CH2CH2OC(O)-, -OC(O)CH2NH-, -OC(O)CH2N(C Malkyl)-, and -OC(O)CH2O-; or either a piperazine ring or a 4-(C1-4 alkyl)-piperazine ring, and any atom, X1 or X2, of either of said piperazine ring or said 4-(C1-4 alkyl)-piperazine ring is attached to Y; then the other bridge of said saturated bridged ring system, only when attached via the 2- and the 3-position of either of said piperazine ring or said 4-(C1-4 alkyl)-piperazine ring, cannot be one of -CH2OC(O)CH2-, -CH2CH2OC(O)-, and either of the two aforementioned bridges cannot be optionally substituted by one or two C1-2alkyl groups; or a piperazine ring, and any atom, X1 or X2, of said piperazine ring is attached to Y; then the other bridge of said saturated bridged ring system, only when attached via the 3- and the 4-position of said piperazine ring, cannot be one of -C(O)OCH2CH2- or -CH2OC(O)CH2- (and only when either of -C(O)OCH2CH2- or -CH2OC(O)CH2- is attached to the 3-position of said piperazine ring via their left-hand end as depicted above), and either of the two aforementioned bridges cannot be optionally substituted by one or two C1-2 alkyl groups, and ; or a 2-oxomorpholine ring, said 2-oxomorpholine ring attached to Y via its 4-position; then the other bridge of said saturated bridged ring system, only when attached via the 5- and the 6-position of said 2-oxomorpholine ring, cannot be one of -(CH2)g-, -CH2WCH2-, -CH2WCH2CH2-, and -CH2CH2WCH2-, wherein W is -0-, -S(O)0-2-, -NH-, or -N(C1-4 alkyl)- and wherein g is 2, 3, or 4.
[00345] In another embodiment of the compound of Formula I(V2), Z is -NR5-. [00346] In another embodiment of the compound of Formula I(V2), R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR3, and optionally substituted lower alkyl. [00347] In another embodiment of the compound of Formula I(V2), R1 is an unsubstituted C1-3 alkyl.
[00348] In another embodiment of the compound of Formula I(V2), the saturated bridged ring system has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1]. [00349] In another embodiment of the compound of Formula I(V2), Y is selected from -CH2CH2-, -CH2-, and absent.
[00350] In another embodiment of the compound of Formula I(V2), q is 1, 2, or 3. [00351] In another embodiment of the compound of Formula I(V2), R5 is -H. [00352] In another embodiment of the compound of Formula I(V2), R1 is methyl. [00353] In another embodiment of the compound of Formula I(V2), the saturated bridged ring system has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0].
[00354] In another embodiment of the compound of Formula I(V2), the saturated bridged ring system contains one or two annular nitrogens, said one or two annular nitrogens are selected from -NR8-, when X1, and a bridgehead nitrogen, when X2.
[00355] In another embodiment of the compound of Formula I(V2), E is absent.
[00356] In another embodiment of the compound of Formula I(V2), the saturated bridged ring system is according to Formula III(V2);
Figure imgf000331_0001
wherein A is selected from -O-, -S(O)0-2-, -NR -, and absent; and e is 0 or 1.
[00357] In another embodiment of the compound of Formula I(V2), Y is -CH2-.
[00358] In another embodiment of the Formula III(V2), A is selected from -NR8-, wherein R8 is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(O)N(R3)R4, -SO2R4, and -C(O)R3; -O-; and absent.
[00359] In another embodiment of the compound of Formula I(V2),
Figure imgf000331_0002
of
I(V2) is selected from:
Figure imgf000331_0003
wherein R2a, R2b, and R2c are each independently selected from F, Cl, and Br. [00360] In another embodiment of the compound of Formula I(V2), R2a is F, R2b is Cl, and R2c is either Cl or Br.
[00361] In another embodiment of the compound of Formula I(V2), the saturated bridged ring system is according to either Formula V(V2) or Formula VI (V2);
Figure imgf000332_0001
wherein R8 is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(O)N(R3)R4, -SO2R4, and -C(O)R3.
[00362] In another embodiment of the compound of Formula I(V2), Y is either -CH2- or absent.
[00363] In another embodiment of the compound of Formula V(V2) or VI(V2), R is methyl or ethyl.
[00364] In another embodiment of the compound of Formula I(V2), the saturated
bridged ring system is according to Formula VII(V2);
Figure imgf000332_0002
VII(V2) wherein A is selected from -O-, -S(O)0-2-, -NR8-, -CR6R7-, and absent.
[00365] In another embodiment of the Formula VII(V2), R3 is selected from -H and optionally substituted alkyl.
[00366] In another embodiment of the compound of Formula I(V2), A is either -C(R6)R7- or absent.
[00367] In another embodiment of Formula I(V2), A is either -CH2- or absent. [00368] In another embodiment of Formula I(V2), Y is -CH2-.
[00369] In another embodiment of Formula I(V2), q is 3. [00370] In another embodiment of Formula I(V2), the saturated bridged ring system has a geometry selected from the group consisting of [3.3.1], [3.2.1], and [2.2.1].
[00371] In another embodiment of Formula I(V2), the saturated bridged ring system contains one or two annular nitrogens, said one or two annular nitrogens are selected from -NR8-, when X1, and a bridgehead nitrogen, when X2.
[00372] In another embodiment of Formula I(V2), the saturated bridged ring system is according to Formula VIII(V2) or Formula IX(V2);
Figure imgf000333_0001
( ) ( ) wherein R8 is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(O)N(R3)R4, -SO2R4, and -C(O)R3; and R26 is C1-3 alkyl.
[00373] In another embodiment of Formula I(V2), Y is -CH2CH2-; and E is either absent or -N(R9)-.
[00374] In another embodiment of Formula I(V2), q is 3. [00375] In another embodiment of Formula VIII(V2) or IX(V2), R8 is methyl or ethyl. [00376] In another embodiment of Formula I(V2), the compound is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:
Figure imgf000333_0002
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0003
Definitions for the compounds of Formula I(V2)
[00377] The atom numbering convention for the quinazoline structure is as follows:
Figure imgf000339_0001
[00378] The symbol "-" means a single bond, "=" means a double bond, "≡" means a triple bond. The symbol
Figure imgf000339_0002
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. When a group is depicted removed from its parent Formula, the " ~" symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural Formula.
[00379] If a group "R" is depicted as "floating" on a ring system, as for example in the Formula:
Figure imgf000340_0001
then, unless otherwise defined, 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.
[00380] If a group "R" is depicted as floating on a fused ring system, as for example in the Formulae:
Figure imgf000340_0002
then, unless otherwise defined, 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. In the example depicted, the "R" group may reside on either the 5- membered or the 6-membered ring of the fused ring system. In the Formula depicted above, when y is 2 for example, then 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.
[00381] When there are more than one such depicted "floating" groups, as for example in the Formulae:
Figure imgf000340_0003
where there are two groups, namely, the "R" and the bond indicating attachment to a parent structure; then, unless otherwise defined, the "floating" groups may reside on any atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring. [00382] When a group "R" is depicted as existing on a ring system containing saturated carbons, as for example in the Formula:
Figure imgf000341_0001
where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" may reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon). In another example, 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:
Figure imgf000341_0002
[00383] "Alkyl" is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively. For example, "C8 alkyl" may refer to an n-octyl, iso-octyl, cyclohexylethyl, and the like. Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. Higher alkyl refers to alkyl groups containing more that eight carbon atoms. Exemplary alkyl groups are those of C2o or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c- propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either "butyl" or "C4 alkyl" is meant to include n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2- yne radicals; and "propyl" or "C3 alkyl" each include n-propyl, propenyl, and isopropyl. [00384] "Alkylene" refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, n-butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CH3)2CH2-), and cyclohexylpropylene (-CH2CH2CII(C6H13)).
[00385] "Alkylidene" refers to a straight or branched chain unsaturated divalent radical 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 and a double bond can exist between the first carbon of the chain and a carbon atom of the rest of the molecule to which it is attached. [00386] "Alkylidyne" refers to a straight or branched chain unsaturated divalent radical 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 and a triple bond can exist between the first carbon of the chain and a carbon atom of the rest of the molecule to which it is attached.
[00387] Any of the above radicals, "alkylene," "alkylidene" and "alkylidyne," when optionally substituted, may contain alkyl substitution which itself contains unsaturation. For example, 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an n-butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical.
[00388] "Alkoxy" or "alkoxyl" refers to the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
[00389] "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). One exemplary substituted alkoxy group is "polyalkoxy" or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH2CH2OCH3, and glycol ethers such as polyethyleneglycol and -0(CH2CH2O)xCH3, where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five. Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
[00390] "Acyl" refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.
[00391] "α-Amino Acids" refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available α- amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A "side chain of an α-amino acid" refers to the radical found on the α-carbon of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like. [00392] "Amino" refers to the group -NH2. "Substituted amino," refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino. [00393] "Aryl" refers to aromatic six- to fourteen-membered carbocyclic rings include, for example, benzene, naphthalene, indane, tetralin, fluorene and the like. [00394] "Arylalkyl" refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. The aryl, alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted. "Lower arylalkyl" refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons. [00395] "Exo-alkenyl" refers to a double bond that emanates from an annular carbon, and is not within the ring system, for example the double bond depicted in the Formula below.
Figure imgf000344_0001
[00396] "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. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms. Typically, a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the compounds described above may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. [00397] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3 -fluorophenyl is within the scope of dihaloaryl. [00398] "Heteroatom" refers to O, S, N, or P.
[00399] "Heterocyclyl" refers to a stable three- to fifteen-membered ring radical that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems, and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. Examples of such heterocyclyl radicals 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl. [00400] "Heteroalicyclic" refers specifically to a non-aromatic heterocyclyl system radical. [00401] "Heteroaryl" refers specifically to an aromatic heterocyclyl system radical.
[00402] "Heterocyclylalkyl" refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include (4-methylpiperazin-1-yl) methyl, (morpholin-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. The heterocyclyl, alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted. "Lower heterocyclylalkyl" refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons.
[00403] "Hydrocarbyl" refers to a hydrocarbon residue, generally. The term "hydrocarbyl" can be modified to mean more specific structures, for example "a saturated or mono- or poly-unsaturated C3-C14 mono- or fused-polycyclic hydrocarbyl optionally containing one, two, or three annular heteroatoms per ring" means a mono- or polycyclic (for example a bridged bicyclic) ring system, having between three and fourteen-ring atoms, that contains only carbon ring atoms, but optionally can contain up to three heteratoms per ring and/or unsaturation. [00404] "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. It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (for example, substituted alkyl includes optionally substituted cycloalkyl groups. But where a first optionally substituted group can be substituted by a second optionally substituted group, the second substituent cannot be further substituted. Optional subsituents do not include groups that are sterically impractical and/or synthetically non-feasible. [00405] "Optionally substituted" refers to all subsequent modifiers in a term, for example in the term "optionally substituted arylC1-s alkyl," optional substitution may occur on both the "C1-8 alkyl" portion and the "aryl" portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups, however, optionally substituted groups cannot be further optionally substituted more than once. Examples of optional substitution include, but are not limited to alkyl, halogen, alkoxy, hydroxy, oxo, carbamyl, acylamino, sulfonamido, carboxy, alkoxycarbonyl, acyl, alkylthio, alkylsulfonyl, nitro, cyano, amino, alkylamino, cycloalkyl and the like.
[00406] Unless otherwise specified, the term "optionally substituted" applies to the chemical moiety immediately preceding it. For instance, if a variable group (such as R) is defined as aryl, optionally substituted alkyl, or cycloalkyl, then only the alkyl group is optionally substituted. [00407] In the case where there is a point of attachment for a monovalent substituent, such as -CH3, -NH2, or -OH, the indication of where the point of attachment is is not necessary. That is, -CH3 has the same meaning as CH3, -NH2 has the same meaning as NH2, and -OH has the same meaning as OH. [00408] "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, 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." [00409] "Spirocyclyl" or "spirocyclic ring" refers to a ring originating from a particular annular carbon of another ring. For example, a ring atom of the aforementioned saturated bridged ring system, but not a bridgehead atom, can be a shared atom between the saturated bridged ring system (rings B and B') and a spirocyclyl (ring A) attached thereto, as depicted below. A spirocyclyl can be either carbocyclic or heterocyclic
Figure imgf000347_0001
[00410] "Substituted" alkyl, aryl, and heterocyclyl, refer respectively to alkyl, aryl, and heterocyclyl, wherein 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 the group: optionally substituted alkyl (for example, fluoroalkyl), optionally substituted alkoxy, alkylenedioxy (for example methylenedioxy), optionally substituted amino (for example, alkylamino and dialkylamino), optionally substituted amidino, optionally substituted aryl (for example, phenyl), optionally substituted arylalkyl (for example, benzyl), optionally substituted aryloxy (for example, phenoxy), optionally substituted arylalkyloxy (for example, benzyloxy), carboxy (-COOH), carboalkoxy (i.e., acyloxy or -OOCR), carboxyalkyl (i.e., esters or -COOR), carboxamido, aminocarbonyl, benzyloxycarbonylamino (CBZ-amino), cyano, carbonyl, halogen, hydroxy, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl, nitro, sulfanyl, sulfinyl, sulfonyl, and thio. [00411] "Sulfanyl" refers to the groups: -S-(optionally substituted alkyl), -S -(optionally substituted aryl), and -S-(optionally substituted heterocyclyl). [00412] "Sulfinyl" refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-optionally substituted aryl), and -S(O)-(optionally substituted heterocyclyl). [00413] "Sulfonyl" refers to the groups: -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-optionally substituted aryl), -S(O2)-(optionally substituted heterocyclyl), -S(O2)-(optionally substituted alkoxy), -S(O2)-optionally substituted aryloxy), and -S(O2)-(optionally substituted heterocyclyloxy).
Synthetic Procedures for the Compounds of Formulae I(V2) [00414] The compounds of Formulae I(V2), can be made by the synthetic schemes and examples described in publication WO 2004/006846, which is incorporated herein by reference in its entirety. The utility of these compounds are also described in WO 2004/006846.
[00415] Aspect (30) 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 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of the compound of Formula I(V2), or a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula I(V2), and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment.
[00416] In other embodiments of aspect (2), aspect (1 1), aspect (26), and aspect (30) of this invention, R2 of Formula I(J) is
Figure imgf000348_0001
[00417] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, R2 of Formula I(J) is
Figure imgf000348_0002
wherein R28a is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl.
[00418] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, R2 of Formula I(J) is
Figure imgf000348_0003
[00419] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of
this invention, L of Formula I(J) is a bond, Z is , R25 is hydrogen and E and D
Figure imgf000349_0003
are hydrogen.
[00420] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of 6 this invention, Z of Formula I(J) is
Figure imgf000349_0004
, R26a is -C(O)R32, R26 is hydrogen, and R32 is selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R32 is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl and halo. [00421] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of
this invention, R2 of Formula I(J) is
Figure imgf000349_0001
[00422] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, R32 of Formula I(J) is U or -CH2-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.
[00423] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, R1 ' of Formula I(J), when present, is halo or lower alkyl. [00424] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, R35 of Formula I(J) is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl.
[00425] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, n2 of Formula I(J) is 0. [00426] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of
this invention, R2 of Formula I(J) is
Figure imgf000349_0002
, and wherein R28 and R28a together with the nitrogen atom to which they are attached, form a heterocycloalkyl. [00427] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, the JAK-2 compound has Formula IV(J):
Figure imgf000350_0001
wherein and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00428] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, the JAK-2 compound has Formula V(J):
Figure imgf000350_0002
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00429] In other embodiments of aspect (2), aspect (11), aspect (26), and aspect (30) of this invention, the JAK-2 compound has Formula VI(J):
Figure imgf000350_0003
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two
R31 C-Met Compounds
[00430] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can also be combined with any of the c-MET compounds (which can inhibit VEFGR, Flt3, Ret, c-Kit, and/or c-Met) described below. Non-limiting examples of c-Met inhibitors (c-Met inhibitors fall within the scope of aspect (5) of this invention) include any of the c-Met compounds described below that can inhibt c-Met. Non-limiting examples of VEGFR inhibitors (VEGFR inhibitors fall within the scope of aspect (2) of this invention) include any of the c-Met compounds below that can inhibt VEGFR. Non- limiting examples of Flt3 inhibitors (Flt3 inhibitors fall within the scope of aspect (8) of this invention) include any of the c-Met Compounds below that can inhibt Flt3. Non- limiting examples of Ret inhibitors (Ret inhibitors fall within the scope of aspect (14) of this invention) include any of the c-Met Compounds below that can inhibt Ret. Non- limiting examples of c-Kit inhibitors (c-Kit inhibitors fall within the scope of aspect (6) of this invention) include any of the c-Met Compounds below that can inhibt c-Kit. All of the c-Met compounds described herein are meant to alternatively include pharmaceutically acceptable salts of these c-Met compounds whether it is explicitely stated or not. All of the c-Met compounds described herein fall within the scope of aspect (20) of this invention.
[00431] In one non-limiting embodiment, the c-Met Compound is a compound of Formula I(V3):
Figure imgf000351_0001
or a pharmaceutically acceptable salt thereof, wherein,
R1 is selected from -H, halogen, -OR3, -NO2, -NH2, -NR3R4 and optionally substituted lower alkyl; A1 is selected from =N- and =C(H)-;
Z is -0-;
Ar is either a group of Formula II, or of Formula III,
Figure imgf000352_0001
wherein,
R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl; q is O to 4;
G is selected from:
Figure imgf000353_0001
Figure imgf000354_0001
each E is selected from -O-, -N(R13)-, -CH2- and -S(O)0-2-; M is selected from -O-, -N(R13)-, -CH2- and -C(=O)N(R13)-; each V is independently either =N- or =C(H)-; each methylene in any of the above Formulae is independently optionally substituted with one or two R25;
R25 is selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4,
-S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3,
-N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or two of R25 on a single carbon can be oxo; J is selected from -S(O)0-2-, -0-, and -NR15-; R3 is -H or R4; R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl and optionally substituted lower heterocyclylalkyl; or R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S and
P;
A2 and A3 are each independently selected from =N- and =C(R2)-;
D is selected from -O-, -S(O)0-2- and -NR I5-;
R50 is R3; R13 is selected from -H, -C(=O)R3, -C(=O)OR3, -C(K))SR3, -SO2R4, -C(=O)N(R3)R3 and optionally substituted lower alkyl; or, two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic can have up to four annular heteroatoms, and said heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60;
R14 is selected from -H, -NO2, -NH2, -N(R3)R4, -CN, -OR3, optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic;
R15 is a group -M'-M2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=0)N(R13)-, -C(=O)C(=O)N(R13)-, -C0-4alkylene-, -C(=O)- and an optionally substituted four to six-membered hetercyclyl annular containing between one and three heteratoms including at least one nitrogen; and M2 is selected from -H, -Co-6alkyl, alkoxy, -C(=O)C0- 4alkylQ, -C0-4alkylQ, -OC0-4alkylQ-, -N(R13)C0-4alkylQ- and -C(=O)N(Rl3)C0-4alkylQ;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20; R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl; and
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4,
-S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted arylalkyl; or two of R60, when attached to a non-aromatic carbon, can be oxo; with the proviso that the conditions of:
Z is -0-; Ar is according to Formula II; and the portion of G directly attached to Ar selected from the table below:
Figure imgf000356_0003
are not met at the same time; and with the proviso that when Ar is phenylene or substituted phenylene, then the portion of
G directly attached to Ar cannot contain , wherein R70 is
Figure imgf000356_0002
selected from -H, C1-4alkyl, and C1-4alkoxyl.
[00432] In another embodiment of the compound of Formula I(V3), Ar is according to one of Formula Ha, lib and Ilia:
Figure imgf000356_0001
[00433] In another embodiment of the compound of Formula I(V3), A1 is =C(H)-. [00434] In another embodiment of the compound of Formula I(V3), Ar is of Formula Ha and A1 is =N-. [00435] In another embodiment of the compound of Formula I(V3), D is -O- and R1 is -OR3
[00436] In another embodiment of the compound of Formula I(V3), -O-R50 and R1 are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to Formula I. [00437] In another embodiment of the compound of Formula I(V3), R1 is -OH or -OC1-6alkyl.
[00438] In another embodiment of the compound of Formula I(V3), G is selected from:
Figure imgf000357_0001
wherein Q, R13, E and R60 are as defined above; each methylene in any of the above Formulae, other than those in a depicted ring, is independently optionally substituted with one or two R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2,
-OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3,
-N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic. [00439] In another embodiment of the compound of Formula I(V3), Q is selected from:
wherein R20 is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
[00440] In another embodiment of the compound of Formula I(V3), Ar is according to Formula Hb, and G is selected from:
Figure imgf000358_0002
wherein Q, R13, E, and R60 are as defined above, and each methylene in any of the above Formulae, other than those depicted in a ring, is independently optionally substituted with one or two R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic. [00441] In another embodiment of the compound of Formula I(V3), the methylene between the two carbonyls of G is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle. [00442] In another embodiment of the compound of Formula I(V3), R50 is a heteroalicylic or a C1-6alkyl-heteroalicylic.
[00443] In another embodiment of the compound of Formula I(V3), at least one of R2 is halogen.
[00444] In another embodiment, the compound of Formula I(V3) is selected from one or more of the following compounds, or a pharmaceutically acceptable salt thereof:
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
[00445] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can also be combined with any of the following c-Met compounds (that fall within the scope of aspect 20 of this invention) of Formula A-B-C (version 3), or a pharmaceutically acceptable salt thereof, wherein A is selected from:
Figure imgf000362_0001
B is selected from:
Figure imgf000362_0002
C is selected from:
Figure imgf000362_0003
Figure imgf000363_0001
wherein:
R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl; q is 0 to 2; each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl; or, two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5 and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=O)R3, -C(=O)OR3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; or, two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R60; A1 is selected from =N- and =C(H)-;
A2 is either =N- or =C(H)-; R5 is -H or optionally substituted lower alkyl; R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3 and -C(O)R3, or an R8 is absent and the alkylene linker of A is covalently bonded to the nitrogen atom in which R is absent;
E1 is selected from -0-, -CH2-, -N(R5)- and -S(O)0-2-; Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl; R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3,
-S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted arylalkyl; or, two of R60, when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above Formulae is independently optionally substituted with one or two R 5; and each R25 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or two of R25 on a single carbon can be oxo; with the proviso that the conditions of:
C contains
Figure imgf000364_0001
and the remaining portion of C contains one of:
Figure imgf000365_0003
are not met at the same time; and
with the proviso that when C contains directly attached to
Figure imgf000365_0002
Figure imgf000365_0001
and R70 is selected from -H, C1-4alkyl, and C1-4alkoxyl, then A2 is N.
[00446] In another embodiment of the compound of Formula A-B-C (version 3), Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl and oxadiazolyl; each optionally substituted with between one and four of R20; wherein each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl. [00447] In another embodiment of the compound of Formula A-B-C (version 3), B is:
Figure imgf000366_0001
wherein A1 is =N- or =C(H)-.
[00448] In another embodiment of the compound of Formula A-B-C (version 3), R3 is methyl.
[00449] In another embodiment of the compound of Formula A-B-C (version 3), C is selected from:
Figure imgf000366_0002
Figure imgf000367_0001
Figure imgf000367_0002
[00450] In another embodiment of the compound of Formula A-B-C (version 3), R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl.
[00451] In another embodiment of the compound of Formula A-B-C (version 3), R is halogen.
[00452] In another embodiment of the compound of Formula A-B-C (version 3), R2 is fluorine or chlorine.
[00453] In another embodiment of the compound of Formula A-B-C (version 3), the compound is according to Formula XI(V3),
Figure imgf000368_0001
Xl(V3) or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR3R4, -D- R50 and optionally substituted C1-6alkyl;
Q is selected from =N- or =C(H)-; Z is -0-;
Ar is either a five- or six-membered arylene or a five- or six-membered heteroarylene containing between one and three heteroatoms; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R2 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted C1-6alkyl; each R3 is independently -H or R4; each R4 is independently selected from optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl and optionally substituted heterocyclyl Cι-6alkyl; or
R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S and P;
R5 is -H or optionally substituted C1-6alkyl; each D is independently selected from -0-, -S(O)0-2- and -NR5-; each R30 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted Chalky.;
each R50 is R3; and R70 is selected from -H, halogen, -OR3, -S(O)0-2R3, -NO2, -NH2, -NR3R4 and optionally substituted C1-6alkyl.
[00454] In another embodiment of the compound of Formula XI(V3), R70 is hydrogen.
[00455] In another embodiment of the compound of Formula XI(V3), at least one of R1 is -D-R50.
[00456] In another embodiment of the compound of Formula XI(V3), D is -O- and at least one other R1 is -OR3.
[00457] In another embodiment of the compound of Formula A-B-C (version 3), the compound is according to Formula XIIIa(V3) or X1Hb(V3):
Figure imgf000369_0001
Figure imgf000370_0001
wherein Q1 is either =N- or =C(H)-, R3a is C1-6alkyl, and -N(R3b)R4 is selected from the following:
Figure imgf000370_0002
wherein:
J is a five- to ten-membered ring, optionally substituted with between zero and five of R20, wherein each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted C1^Ucyl, optionally substituted aryl, optionally substituted aryl C1- 6alkyl, optionally substituted heterocyclyl and optionally substituted heterocyclyl C1-6alkyl, or two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to J or fused to J;
E is selected from -O-, -N(R5)-, -CH2- and -S(O)0-2-; each R60 is independently selected from halogen, trihalomethyl, -CN, -NO2,
-NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted heteroaryl C1-6alkyl and optionally substituted aryl C]-6alkyl; each methylene in any of the above Formulae, other than those in a depicted ring, is independently optionally substituted with one or two R25, wherein R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted aryl C1- 6alkyl, heteroaryl C1-6alkyl and optionally substituted C1-6alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; and
R3b has the same meaning as R3.
[00458] In another embodiment of the compound of Formula XIIIa(V3) or XIIIb(V3), R50 is selected from C1-6alkyl optionally substituted with at least one of optionally substituted amino, optionallysubstituted C1-6alkyl amino, optionally substituted C1-6dialkyl amino, optionally substituted heteroalicylic and a group of Formula XII.
[00459] In another embodiment of the compound of Formula A-B-C (version 3), the compound is according to Formula XIIIa(V3) or XIIIb(V3), G is selected from cyclopropyl, aziradine, cyclobutyl and azetidine, each optionally substituted with between zero and four of R30.
[00460] In another embodiment of the compound of Formula A-B-C (version 3), the compound is according to Formula XIIIa(V3) or XIIIb(V3), wherein R2 is selected from -H, halogen, C1-6 alkyl and perfluoro C1-6 alkyl. [00461] In another embodiment of the compound of Formula A-B-C (version 3), the compound is according to Formula XIIIa(V3) or XIIIb(V3), wherein (R30)0-4 is (R30)0 or methyl.
[00462] In another embodiment of the compound of Formula A-B-C (version 3), the compound is according to Formula XIVa(V3) or XIVb(V3):
(R3V
20\
(R'υ)o-
Figure imgf000372_0001
XIVa(V3)
Figure imgf000372_0002
or a pharmaceutically acceptable salt thereof, wherein R50 is C1-6alkyl substituted with a group selected from optionally substituted amino, optionally substituted alkylamino, optionally substituted dialkylamino and optionally substituted heteroalicylic.
[00463] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3), Q is -CH=.
[00464] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3), the heteroalicyclic portion of R50 is selected from piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1 -oxide, thiomorpholine 1,1 -dioxide, 2-oxo-morpholine, pyrrolidine and azepine. [00465] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3),
(R30)0-4 is (R30)0 or methyl.
[00466] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3),
R2 is selected from C1-6 alkyl, perfluoro C1-6 alkyl, hydrogen and halogen.
[00467] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3), R2 is halogen.
[00468] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3), R2 is hydrogen.
[00469] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3), R20 is selected from halogen, -CN, -NO2, -NH2, -OR3, -NR3R4, -N(R3)SO2R3,
-N(R3)C(O)R3, -N(R3)CO2R3, optionally substituted heterocyclyl and optionally substituted heterocyclyl C1-6alkyl, and (two of R20) together with the atom or atoms to which they are attached, form an optionally substituted three- to six-membered heteroalicyclic, said optionally substituted three- to six-membered heteroalicyclic fused to the phenyl as in XIVa(V3) or XIVb(V3).
[00470] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3), R20 is selected from halogen, -NR3R4, optionally substituted heterocyclyl and optionally substituted heterocyclyl C1-6alkyl, and (two of R20) together with the atom or atoms to which they are attached, form an optionally substituted five- to six-membered heteroalicyclic, said optionally substituted five- to six-membered heteroalicyclic fused to the phenyl as in XIVa(V3) or XIVb(V3).
[00471] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3),
R2 is selected from C1-6 alkyl, perfluoro C1-6 alkyl and halogen.
[00472] In another embodiment of the compound of Formula XIVa(V3) or XIVb(V3), R2 is selected from perfluoro C1-3 alkyl and halogen.
[00473] In another embodiment, the compounds of Formula A-B-C (version 3) is selected from one or more of the following compounds, or a pharceutically acceptable salt thereof:
Figure imgf000374_0001
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
[00474] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can also be combined with c-Met compounds (that are VEFGR, Flt3, Ret, and/or c-Met inhibitors) of Formula I(V4):
Figure imgf000379_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from -H, halogen, -OR3, -NO2, -NH2, -NR3R4, and optionally substituted lower alkyl;
A1 is selected from =N- and =C(H)-;
Z is -O- or -NR5-;
Ar is either a group of Formula II, or of Formula III,
Figure imgf000379_0002
wherein,
R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is 0 to 4;
G is selected from:
Figure imgf000380_0001
Figure imgf000381_0001
each E is selected from -O-, -N(R13)-, -CH2-, and -S(O)0-2-; M is selected from -0-, -N(R13)-, -CH2-, and -C(=O)N(R13)-; each V is independently either =N- or =C(H)-; each methylene in any of the above Formulae is independently optionally substituted with one or two R25;
R25 is selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic; or two of R25 on a single carbon can be oxo;
J is selected from -S(O)0-2-, -0-, and -NR15-; R3 is -H or R4;
R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or
R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
A2 and A3 are each independently selected from =N- and =C(R2)-; R5 is -H or optionally substituted lower alkyl; D is selected from -0-, -S(O)0-2-, and -NR15-;
R50 is R3;
R13 is selected from -H, -C(=O)R3, -C(=O)OR3, -C(=O)SR3, -SO2R4, -C(=O)N(R3)R3, and optionally substituted lower alkyl; or, two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic can have up to four annular heteroatoms, and said heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four ofR60; R14 is selected from -H, -NO2, -NH2, -N(R3)R4, -CN, -OR3, optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic;
R15 is a group -M'-M2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=O)N(R13)-, -C(=O)C(=O)N(R13)-;
-C0-4alkylene-, -C(=0)-, and an optionally substituted four to six-membered hetercyclyl annular containing between one and three heteratoms including at least one nitrogen; and M2 is selected from -H, -C0-6alkyl, alkoxy, -C(=O)C0-4alkylQ, -C0-4alkylQ, -OC0-4alkylQ-, -N(R13)C0-4alkylQ-, and -C(=O)N(R13)C0-4alkylQ; and
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R ,20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -0Rj, -NR 33rR,44, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; and
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; or, two of R60, when attached to a non-aromatic carbon, can be oxo; with the proviso that the conditions of: Z is-O-; and
Ar is according to Formula II; and the portion of G directly attached to Ar selected from the table below:
Figure imgf000383_0001
Figure imgf000384_0003
are not met at the same time; and with the proviso that when Ar is phenylene or substituted phenylene and Z is -O-,
then the portion of G directly attached to Ar cannot contain
Figure imgf000384_0001
wherein R70 is selected from -H, C1-4alkyl, and C1-4alkoxyl.
[00475] In another embodiment of the compound of Formula I(V4), Ar is according to one of Formula Ha, Hb, and IIIa:
Figure imgf000384_0002
[00476] In another embodiment of the compound of Formula I(V4), A1 ; is - =C(H)-.
[00477] In another embodiment of the compound of Formula I(V4), Ar is of Formula IIa and A1 is =N-.
[00478] In another embodiment of the compound of Formula I(V4), D is -O- and R1 is -OR3.
[00479] In another embodiment of the compound of Formula I(V4), -O-R50 and R1 are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to Formula I.
[00480] In another embodiment of the compound of Formula I(V4), R1 is -OH or -OC1- 6alkyl. other embodiment of the compound of Formula I(V4), G is selected from:
Figure imgf000385_0001
wherein Q, R13, E, and R60 are as defined above; each methylene in any of the above Formulae, other than those in a depicted ring, is independently optionally substituted with one or two R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic.
[00482] In another embodiment of the compound of Formula I(V4), Q is selected from:
Figure imgf000386_0002
wherein R is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
[00483] In another embodiment of the compound of Formula I(V4), Ar is according to Formula Hb, and G is selected from:
Figure imgf000386_0001
wherein Q, R13, E, and R60 are as defined above, and each methylene in any of the above Formulae, other than those depicted in a ring, is independently optionally substituted with one or two R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic.
[00484] In another embodiment of the compound of Formula I(V4), the methylene between the two carbonyls of G is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle.
[00485] In another embodiment of the compound of Formula I(V4), R50 is a heteroalicylic or a C1-όalkyl-heteroalicylic.
[00486] In another embodiment of the compound of Formula I(V4), at least one of R2 is halogen.
[00487] In another embodiment, the compound of Formula I(V4) is selected from one or more of the following compounds, or a pharmaceutically acceptable salt thereof:
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
[00488] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can also be combined with c-MET compounds (that are VEFGR, Flt3, Ret, and/or c-Met inhibitors) of Formula A-B-C (version 4), or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
Figure imgf000391_0001
B is selected from:
Figure imgf000391_0002
C is selected from:
Figure imgf000391_0003
Figure imgf000392_0001
wherein:
R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is 0 to 2; each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or, two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5, and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=0)R3, -C(=O)OR3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; or, two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R ; A1 is selected from =N- and =C(H)-;
A2 is either =N- or =C(H)-;
R5 is -H or optionally substituted lower alkyl;
R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3, or an R is absent and the alkylene linker of A is covalently bonded to the nitrogen atom in which R8 is absent;
E1 is selected from -0-, -CH2-, -N(R5)-, and -S(O)0-2-;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20; R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3,
-S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3,
-S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; or, two of R60, when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above Formulae is independently optionally substituted with one or two R25; and each R25 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2,
-OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or two of R25 on a single carbon can be oxo; with the proviso that the conditions of:
C contains
Figure imgf000393_0001
; and the remaining portion of C contains one of:
Figure imgf000394_0003
are not met at the same time; and
A with the proviso that when C contains
Figure imgf000394_0002
directly attached to
Figure imgf000394_0001
and R70 is selected from -H, C1-4alkyl, and C1-4alkoxyl, then A2 is N.
[00489] In another embodiment of the compound of Formula A-B-C (version 4), Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted with between one and four of R20; wherein each R2 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
[00490] In another embodiment of the compound of Formula A-B-C (version 4), B is:
Figure imgf000395_0001
wherein A is either =N- or =C(H)-.
[00491] In another embodiment of the compound of Formula A-B-C (version 4), B is
Figure imgf000395_0002
[00492] In another embodiment of the compound of Formula A-B-C (version 4), C is selected from:
Figure imgf000395_0003
Figure imgf000396_0001
and
Figure imgf000396_0002
[00493] In another embodiment of the compound of Formula A-B-C (version 4), R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
[00494] In another embodiment of the compound of Formula A-B-C (version 4), R2 is halogen.
[00495] In another embodiment of the compound of Formula A-B-C (version 4), R2 is fluorine or chlorine.
[00496] In another embodiment of the compound of Formula A-B-C (version 4), the compound is according to Formula XI(V4),
Figure imgf000397_0001
XI or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR3R4, -D- R50 and optionally substituted C1-6alkyl;
Q is =N-, or =C(H)-; Z is -O- or -NR5-;
Ar is either a five- or six-membered arylene or a five- or six-membered heteroarylene containing between one and three heteroatoms; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R2 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted C1-6alkyl; each R3 is independently -H or R4; each R4 is independently selected from optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; or
R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
R5 is -H or optionally substituted C1-6alkyl; each D is independently selected from -0-, -S(O)0-2-, and -NR5-; each R30 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted C!-6alkyl; each R50 is R3; and R70 is selected from -H, halogen, -OR3, -S(O)0-2R3, -NO2, -NH2, -NR3R4, and optionally substituted C1-6alkyl.
[00497] In another embodiment of the compound of Formula XI(V4), R70 = H.
[00498] In another embodiment of the compound of Formula XI(V4), at least one of R1 is -D-R50.
[00499] In another embodiment of the compound of Formula XI(V4), D is -O- and at least one other R1 is -OR3.
[00500] In another embodiment of the compound of Formula A-B-C (version 4), the compound is according to Formula XIIIa(V4) or XIIIb(V4):
Figure imgf000398_0001
Figure imgf000398_0002
XIIlb(V4) or a pharmaceutically acceptable salt thereof, wherein Q1 is either =N- or =C(H)-, R3a is C1-6alkyl, and -N(R3b)R4 is selected from the following:
Figure imgf000399_0001
wherein:
J is a five- to ten-membered ring, optionally substituted with between zero and five of R20, wherein each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1- 6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-όalkyl; or two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to J or fused to J;
E is selected from -O-, -N(R5)-, -CH2-, and -S(O)0-2-; each R60 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted heteroaryl C1-6alkyl, and optionally substituted aryl C1-6alkyl; each methylene in any of the above Formulae, other than those in a depicted ring, is independently optionally substituted with one or two R 5; R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted aryl C1-6alkyl, heteroaryl C1-6alkyl, and optionally substituted C1-6alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; and
R3b has the same meaning as R3.
[00501] In another embodiment of the compound of Formula XIIIa(V3) or XIIIb(V3),
R50 is selected from C1-6alkyl optionally substituted with at least one of optionally substituted amino, optionally substituted C1-6alkyl amino, optionally substituted C1- 6dialkyl amino, optionally substituted heteroalicylic, and a group of Formula XII.
[00502] In another embodiment of the compound of Formula XIIIa(V3) or XIIIb(V3),
G is selected from cyclopropyl, aziradine, cyclobutyl, and azetidine, each optionally substituted with between zero and four of R30.
[00503] In another embodiment of the compound of Formula XIIIa(V3) or XIIIb(V3), R2 is selected from -H, halogen, C1-6 alkyl and perfluoro C1-6 alkyl.
[00504] In another embodiment of the compound of Formula XIIIa(V3) or XIIIb(V3),
(R3O)o-4 is (R30)0 or methyl.
[00505] In another embodiment of the compound of Formula A-B-C (version 4), the compound is according to Formula XIVa(V4) or XIVb(V4):
Figure imgf000400_0001
or a pharmaceutically acceptable salt thereof, wherein R50 is unsubstituted C1-6alkyl. [00506] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4), Q is -CH=.
[00507] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4),
(R30)0-4 = (R3O)o or methyl.
[00508] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4), R2 is selected from C1-6 alkyl, perfluoro C1-6 alkyl, hydrogen, and halogen.
[00509] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4),
R is hydrogen.
[00510] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4), R2 is halogen.
[00511] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4),
R20 is selected from halogen, -CN, -NO2, -NH2, -OR3, -NR3R4, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl, and (two of R20) together with the atom or atoms to which they are attached, an optionally substituted three- to six-membered heteroalicyclic, said optionally substituted three- to six-membered heteroalicyclic fused to the phenyl as in XIVa(V4) or XIVb(V4).
[00512] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4), R20 is selected from halogen, -NR3R4, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl, and (two of R20) together with the atom or atoms to which they are attached, an optionally substituted five- to six-membered heteroalicyclic, said optionally substituted five- to six-membered heteroalicyclic fused to the phenyl as in XIVa(V4) or XIVb(V4).
[00513] In another embodiment of the compound of Formula XIVa(V 4) or XIVb(V4), R2 is selected from C1-6 alkyl, perfluoro C1-6 alkyl, and halogen.
[00514] In another embodiment of the compound of Formula XIVa(V4) or XIVb(V4), R2 is selected from perfluoro C1-3 alkyl and halogen. [00515] In another embodiment, the compounds of Formuia-A-B-C (version 4) is selected from one or more of the following compounds, or a pharmaceutically acceptable salt thereof:
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0002
[00516] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can also be combined with c-Met compounds (that are VEFGR, Flt3, c-Kit, and/or c-Met inhibitors) of Formula I(V5):
Figure imgf000404_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from -H, halogen, -OR3, -NO2, -NH2, -NR3R4, and optionally substituted lower alkyl;
A1 is selected from =N- and =C(H)-; Z is -O-; Ar is either a group of Formula II, or of Formula III,
III
Figure imgf000405_0001
wherein:
R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is 0 to 4;
G is selected from one of the following:
Figure imgf000405_0002
each E is selected from -0-, -N(R13)-, -CH2-, and -S(O)0-2-; each methylene in any of the above Formulae is independently optionally substituted with one or two R25;
R25 is selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic, or, two of R25 on a single carbon can be oxo;
J is selected from -S(O)0-2-, -O-, and -NR15-; R3 is -H or R4;
R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or, R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
A2 and A3 are each independently selected from =N- and =C(R2)-; D is selected from -O-, -S(O)0-2-, and -NR15-; R50 is R3;
R13 is selected from -H, -C(=O)R3, -C(=O)OR3, -C(=O)SR3, -SO2R4, -C(=O)N(R3)R3, and optionally substituted lower alkyl, or two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic can have up to four annular heteroatoms, and said heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60;
R14 is selected from -H, -NO2, -NH2, -N(R3)R4, -CN, -OR3, optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic;
R15 is a group -M'-M2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=O)N(R13)-, -C(=O)C(=O)N(R13)-, -C0- 4alkylene-, -C(=O)-, and an optionally substituted four to six-membered hetercyclyl annular containing between one and three heteratoms including at least one nitrogen; and M2 is selected from -H, -C0-6alkyl, alkoxy, -C(=O)C0-4alkylQ, -C0-4alkylQ, -OC0-4alkylQ-, -N(R13)C0-4alkylQ-, and -C(=O)N(R13)C0-4alkylQ;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20; R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4,
-S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; and
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4,
-S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; or, two of R60, when attached to a non-aromatic carbon, can be oxo.
[00517] In another embodiment of the compound of Formula I(V5), Ar is according to one of Formula Ila, Hb, and IIIa:
Figure imgf000407_0001
[00518] In another embodiment of the compound of Formula I(V5), A1 is =C(H)-.
[00519] In another embodiment of the compound of Formula I(V5), Ar is of Formula IIa and A1 is =N-. [00520] In another embodiment of the compound of Formula I(V5), D is -O- and R1 is -OR3.
[00521] In another embodiment of the compound of Formula I(V5), -O-R50 and R1 are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to Formula I. [00522] In another embodiment of the compound of Formula I(V5), R1 is -OH or -OC1-6alkyl.
[00523] In another embodiment of the compound of Formula I(V5), G is selected from: R13 O R13 * R13
V
O R13 O O O O
R13
I
Figure imgf000408_0001
< ,N t 0-2
O O wherein Q, R20, R13, E, and R60 are as defined above; each methylene in any of the above Formulae, other than those in a depicted ring, is independently optionally substituted with
R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -0R3,
-NR3 R4, -S(O)0-2R3, -SO2NR3R3 -CO2R3, -C(0)NR 33R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
[00524] In another embodiment of the compound of Formula I(V5), Q is selected from:
Figure imgf000408_0002
wherein R20 is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
[00525] In another embodiment of the compound of Formula I(V5), Ar is according to
Formula Ha, and G is selected from:
Figure imgf000409_0002
wherein Q, R2 , R13, E, and R60 are as defined above, and each methylene in any of the above Formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
[00526] In another embodiment of the compound of Formula I(V5), R50 is a heteroalicyclic or a C1-6alkyl-heteroalicylic.
[00527] In another embodiment of the compound of Formula I(V5), at least one of R2 is halogen.
[00528] In another embodiment, the compound of Formula I(V5) is selected from one or more of the following compounds, or a pharmaceutically acceptable salt thereof:
Figure imgf000409_0001
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2- phenylethyl)ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'- phenylethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2-morpholin- 4-ylethyl)ethanediamide
N-(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } -3 -fluorophenyl)-N'- { 2- [4-
(methyloxy) phenyl] ethyl } ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2,3-dihydro- 1 H-inden- 1 -yl)ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2,3-dihydro- 1 H-inden-2-yl)ethanediamide
N-(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } -3 -fluorophenyl)-N'-( 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[(2S)-1,2,3,4- tetrahydronaphthalen-2-yl]ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-(4- methylphenyl) ethyl] ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2- phenylpropyl) Ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-(4- chlorophenyl) ethyl] ethanediamide ethyl [(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)amino] (oxo)acetate
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(2- phenylethyl) Ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(1,2,3,4- tetrahydronaphthalen-2-yl)ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-(l- methylpyrrolidin-2-yl)ethyl]ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-
(phenyloxy) ethyljethanediamide
N'-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-N-(2- phenylethyl) Ethanediamide
N-(4- { [6,7-bis(methyloxy)quinolin-4-y 1] oxy } -3 -fluorophenyl)-N'- { [3 -
(trifluoromethyl) phenyl] methyl } ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-{2-[3-
(trifluoromethyl) phenyl]ethyl} ethanediamide N- { 3-fluoro-4- [(6-(methyloxy)-7- { [( 1 -methylpiperidin-4- yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N'-(2-phenylethyl)ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(l, 2,3,4- tetrahydroisoquinolin- 1 -ylmethyl)ethanediamide
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[(2-methyl- 1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]ethanediamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-phenethyl-oxalamide
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N'-(2-isopropyl- 1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-oxalamide
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N'-(2-ethyl- 1,2,3,4- tetrahydro-isoquinolin- 1 -ylmethyl)-oxalamide
N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl } -N'-phenethyl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]- phenyl } -N'-phenethyl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl} -N'-phenethyl-oxalamide
N-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl } -N'-phenethyl-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-( 1 -methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl }-N'-methyl-N'-phenethyl-oxalamide
2-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-{3-fluoro-4-[6-methoxy-7-(l-methyl- piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -2-oxo-acetamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl} -2-oxo-2-(3-phenyl-pyrrolidin-1-yl)-acetamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide
N-(2-Dimethylamino-2-phenyl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-oxo-2-phenyl-ethyl)-oxalamide
N-Benzyl-N'-{3-fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- ^ phenyl } -N'- [2-(2-fluoro-phenyl)-ethyl] -oxalamide
N-[2-(3-Chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'- [2-(2-methoxy-phenyl)-ethyl] -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-N'-(2-pyridin-3-yl-ethyl)-oxalamide
N-Benzyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -oxalamide N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-Nl-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'- [2-(2-trifluoromethyl-phenyl)-ethyl3 -oxalamide
N-[2-(2-Ethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-[2-(2,4-Dimethyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-( 1 S -phenyl-2-p-tolyl-ethyl)-oxalamide
N-[2-(4-Chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl }-oxalamic acid
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'- [2-(3-fluoro-phenyl)-ethyl] -oxalamide
N-[2-(2-Chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'- [2-(3-methoxy-phenyl)-ethyl] -oxalamide
N-(1,2-Diphenyl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-y loxy] -phenyl } -oxalamide
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(3 ,4-Dimethoxy-phenyl)-ethyl] -N'- { 3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-[2-(4-Ethyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(4-Ethoxy-phenyl)-ethyl] -N'- { 3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl } -oxalamide
N- [2-(4-Ethoxy-3 -methoxy-phenyl)-ethyl] -N'- { 3 -fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl } -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'- [2-(4-phenoxy-phenyl)-ethyl] -oxalamide
N-[2-(3-Ethoxy-4-methoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl }-N'-(2-pyridin-2-yl-ethyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-(2-pyridin-4-yl-ethyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'- [2-(4-fluoro-phenyl)-ethyl] -oxalamide
N-[2-(2-Bromo-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-(2i?-phenyl-propyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-indan- 1 -yl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N'-isobutyl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N'-(3-methyl-butyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N'-(2/?-phenyl-propyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N'-(2-phenyl-propyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl }-N'-indan-2-yl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-( 1 i?-phenyl-ethyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl }-N'-(15'-phenyl-ethyl)-oxalamide
N-[2-(3-Bromo-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-[2-(2,6-Dichloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(2,4-Dichloro-phenyl)-ethyl] -N'- { 3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-[2-(3-Bromo-4-methoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(3 ,5 -Dimethoxy-pheny l)-ethyl] -N1- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-N'-(2-o-tolyl-ethyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-m-tolyl-ethyl)-oxalamide
N-[2-(3-Ethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(3 ,4-Dimethyl-phenyl)-ethyl] -N1- { 3 -fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yIoxy] -phenyl } -oxalamide
N-[2-(2,5-Dimethyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide
N-[2-(3-Chloro-4-propoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide
N-[2-(4-Butoxy-3-chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy (piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(4-tert-Butyl-phenyl)-ethyl] -N'- { 3 -fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'- [2-(4-sulfamoyl-phenyl)-ethyl] -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-[2-(4-hydroxy-3 -methoxy-phenyl)-ethyl] -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-[2-(3 -hydroxy-4-methoxy-phenyl)-ethyl] -oxalamide
N-(2,4-Dichloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-(4-fluoro-2-trifluoromethyl-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-( 1 -p-tolyl-ethyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl}-N'-(3-fluoro-4-trifluoromethyl-benzyl)-oxalamide
N-(3-Chloro-4-fluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'- [ 1 -(3-methoxy-phenyl)-ethyl] -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl }-N'-(l-naphthalen-2-yl-ethyl)-oxalamide
N-(4-Chloro-3 -trifluoromethyl-benzyl)-N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-( 1 -p-tolyl-ethyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-(6-trifluoromethyl-pyridin-3 -ylmethyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-(2 -methyl -benzyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl }-N'-(3-methyl-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(4-fluoro-3-trifluoromethyl-benzyl)-oxalamide
N-(3 ,5 -Dichloro-benzyl)-N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-( 1 R,2,3,4-tetrahydro-naphthalen- 1 -yl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-( 1 S ,2,3 ,4-tetrahydro-naphthalen- 1 -yl)-oxalamide
N-Cyclopentyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin- 4-yloxy] -phenyl } -oxalamide
N-[l-(4-Bromo-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-(2-Fluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(3 ,4-Dichloro-phenyl)-ethyl] -N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide N-(4-Fluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy|-phenyl}-oxalamide
N-(2,3-Difluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-phenoxy-ethyl)-oxalamide
N-(2,2-Diphenyl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'- [2-(4-methoxy-phenyl)-ethyl] -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl} -N'-(2-phenyl-propyl)-oxalamide
N-[2-(4-Bromo-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{4-[7-(l-Ethyl-piperidin-4-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3- fluoro-phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(3 -fluoro-5 -trifluoromethyl-benzyl)-oxalamide
N-(3,5-Difluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-(2-Chloro-5-trifluoromethyl-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N'-(2-dimethylamino- 2-phenyl-ethyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(4-methoxy-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(4-trifluoromethyl-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(3 -methoxy-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(3 -trifluoromethyl-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(3 -trifluoromethoxy-benzyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-(2-methoxy-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-trifluoromethyl-benzyl)-oxalamide
N-(3-Chloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-N'-(2-trifluoromethoxy-benzyl)-oxalamide
N-(2-Chloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(4-trifluoromethoxy-benzyl)-oxalamide N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N'-(4-methoxy-benzyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-( 1 -methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N'-(4-trifluoromethyl-benzyl)-oxalamide
N-{4-[7-(Azetidin-3-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl } -N'-phenethyl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-azetidin-3-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N'-phenethyl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-hydroxy-2-phenyl-ethyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-( 1 R-phenyl-propyl)-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-( 1 R-pheny l-propyl)-oxalamide
N-(3,4-Difluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-(2,6-Difluoro-benzyl)-N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N'- [2-(4-fluoro-phenyl)-ethyl] -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N'-phenyl-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-(3 -fluoro-phenyl)-oxalamide
N-(4-Chloro-3-fluoro-phenyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-(3,4-Dimethoxy-phenyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(3 -methyl-butyl)-oxalamide
N-(3 ,3 -Dimethyl-butyl)-N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-(4-Chloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-(3,5-Dimethoxy-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-(4-Butyl-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-p-tolyl-ethyl)-oxalamide
N-(3,5-Bis-trifluoromethyl-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-pyrazin-2-ylmethyl-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-pyridin-2-ylmethyl-oxalamide N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy] - phenyl } -N'-phenethyl-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-( 1 -methyl-piperidin-4-ylmethoxy)-quinazolin-4- yloxy] -phenyl } -N'-phenethyl-oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl}-N'-(2-fluoro-3-trifluoromethyl-benzyl)-oxalamide
N-[2-(2-Bromo-6-methoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -N-methyl-oxalamide
N- [2-(5 -Bromo-2-methoxy-phenyl)-ethyl] -N1- { 3 -fluoro-4- [6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-fluoro-5 -trifluoromethyl-benzyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-[ 1 -(4-fluoro-phenyl)-ethyl] -oxalamide
N-(lS-Benzyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
N- [2-(4- Amino-phenyl)-ethyl] -N'- { 3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide
2-(4-Benzyl-piperidin-1-yl)-N-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -2-oxo-acetamide
N-Ethyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl} -N'-isopropyl-oxalamide
N-Butyl-N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -oxalamide
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl}-N'-(2-methoxy-ethyl)-oxalamide
N-Cyclopropylmethyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2-morpholin-4-yl-ethyl)-oxalamide
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl }-2-oxo-2-pyrrolidin-1-yl-acetamide
N-Ethyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -N-methyl-oxalamide
[00529] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can also be combined with c-Met compounds (that are VEFGR, Flt3 and/or c- Met inhibitors) of Formula A-B-C (version 5), or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
Figure imgf000418_0001
B is selected from:
Figure imgf000418_0002
C is selected from:
Figure imgf000418_0003
wherein:
R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is O to 2; each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or, two R , together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5, and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=0)R3, -C(=0)0R3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; or, two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R , said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R60; A1 is selected from -N- and =C(H)-;
A2 is either =N- or =C(H)-; R5 is -H or optionally substituted lower alkyl;
R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3, or wherein the A group contains at least one R8, R8 is absent and the alkylene linker is bonded to the corresponding nitrogen atom;
E1 is selected from -0-, -CH2-, -N(R5)-, and -S(O)0-2-;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, or two of R , when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above Formulae is independently optionally substituted with one or two R25; and each R25 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2,
-OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic; or, two of R25 on a single carbon can be oxo.
[00530] In another embodiment of the compound of Formula A-B-C (version 5), Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted with between one and four of R20; wherein each R2 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
[00531] In another embodiment of the compound of Formula A-B-C (version 5), B is:
Figure imgf000420_0001
wherein A1 is =N- or =C(H)-. [00532] In another embodiment of the compound of Formula A-B-C (version 5), B is
Figure imgf000421_0001
[00533] In another embodiment of the compound of Formula A-B-C (version 5), C is selected from:
Figure imgf000421_0002
wherein E, R >2z, r R>3J, τ R,53, r R,2z0υ a Ώn_dJ D R6o0υ are as defined above. [00534] In another embodiment of the compound of Formula A-B-C (version 5), C is
Figure imgf000422_0001
[00535] In another embodiment of the compound of Formula A-B-C (version 5), R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
[00536] In another embodiment of the compound of Formula A-B-C (version 5), R2 is halogen.
[00537] In another embodiment of the compound of Formula A-B-C (version 5), R2 is either fluorine or chlorine.
[00538] In another embodiment of the compound of Formula A-B-C (version 5), R2 is hydrogen.
Definitions for Compounds of Formulae I(V3),
I(V4), I(V5), A-B-C (version 3), A-B-C (version 4) and A-B-C (version 5) [00539] The following abbreviations and terms apply to compounds of Formulae I(V3), I(V4), I(V5), A-B-C (version 3), A-B-C (version 4) and A-B-C (version 5) described above only. These definitions are not to be considered when determining the scope and meaning of the JAK-2 compounds. To the same extent, the JAK-2 definitions are not to be considered when determining the scope and meaning of the compounds of Formulae I(V3), I(V4), IQ/ S), A-B-C (version 3), A-B-C (version 4) and A-B-C (version 5).
[00540] Some ring structures are depicted generically and will be described textually. For example, in the schematic below, if in the structure on the left, ring A is used to describe a "spirocyclyl," then if ring A is cyclopropyl, there are at most four hydrogens on ring A (when "R" can also be -H). In another example, as depicted on the right side of the schematic below, if ring B is used to describe a "phenylene" then there can be at most four hydrogens on ring B (assuming depicted cleaved bonds are not C-H bonds).
Figure imgf000423_0001
[00541] If a group "R" is depicted as "floating" on a ring system, as for example in the Formula:
Figure imgf000423_0002
then, unless otherwise defined, 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.
[00542] If a group "R" is depicted as floating on a fused ring system, as for example in the Formulae:
Figure imgf000423_0003
then, unless otherwise defined, 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. In the example depicted, the "R" group may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the Formula depicted above, when y is 2 for example, then 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.
[00543] When there are more than one such depicted "floating" groups, as for example in the Formulae:
Figure imgf000423_0004
where there are two groups, namely, the "R" and the bond indicating attachment to a parent structure; then, unless otherwise defined, the "floating" groups may reside on any atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
[00544] When a group "R" is depicted as existing on a ring system containing saturated carbons, as for example in the Formula:
Figure imgf000424_0001
where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" may reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon). In another example, 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:
Figure imgf000424_0002
[00545] "Alkyl" is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively. For example, "C8 alkyl" may refer to an n-octyl, iso-octyl, cyclohexylethyl, and the like. Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. Higher alkyl refers to alkyl groups containing more that eight carbon atoms. Exemplary alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c- propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either "butyl" or
"C4 alkyl" is meant to include n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2- yne radicals; and for example, "propyl" or "C3 alkyl" each include ^-propyl, propenyl, and isopropyl.
[00546] "Alkylene" refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, n-butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CH3)2CH2-), and cyclohexylpropylene (-CH2CH2CII(C6H13)). [00547] "Alkylidene" refers to a straight or branched chain unsaturated divalent radical 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.
[00548] "Alkylidyne" refers to a straight or branched chain unsaturated divalent radical 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.
[00549] Any of the above radicals, "alkylene," "alkylidene" and "alkylidyne," when optionally substituted, may contain alkyl substitution which itself contains unsaturation. For example, 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an n-butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical.
[00550] "Alkoxy" or "alkoxyl" refers to the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons. [00551] "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). One exemplary substituted alkoxy group is "polyalkoxy" or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH2CH2OCH3, and glycol ethers such as polyethyleneglycol and -0(CH2CH2O)xCH3, where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five. Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
[00552] "Acyl" refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.
[00553] "α-Amino Acids" refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available α- amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A "side chain of an α-amino acid" refers to the radical found on the α-carbon of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like.
[00554] "Amino" refers to the group -NH2. "Substituted amino," refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino. [00555] "Aryl" refers to aromatic six- to fourteen-membered carbocyclic ring, for example, benzene, naphthalene, indane, tetralin, fluorene and the like, univalent radicals. As univalent radicals, the aforementioned ring examples are named, phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl. [00556] "Arylene" generically refers to any aryl that has at least two groups attached thereto. For a more specific example, "phenylene" refers to a divalent phenyl ring radical. A phenylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.
[00557] "Arylalkyl" refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Both the aryl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted. "Lower arylalkyl" refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons; this can also be refered to as C1-6 arylalkyl. [00558] "Exo-alkenyl" refers to a double bond that emanates from an annular carbon, and is not within the ring system, for example the double bond depicted in the Formula below.
Figure imgf000427_0001
[00559] In some examples, as appreciated by one of ordinary skill in the art, 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.
[00560] "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. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, 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 the compounds described above may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
[00561] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. "Haloalkyl" and "haloaryl" refer generically to alkyl and aryl radicals that are substituted with one or more halogens, respectively. Thus, "dihaloaryl," "dihaloalkyl," "trihaloaryl" etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
[00562] "Heteroarylene" generically refers to any heteroaryl that has at least two groups attached thereto. For a more specific example, "pyridylene" refers to a divalent pyridyl ring radical. A pyridylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.
[00563] "Heteroatom" refers to O, S, N, or P.
[00564] "Heterocyclyl" refers to a stable three- to fifteen-membered ring radical that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states. In a specific example, the group -S(O)0-2-, refers to -S- (sulfide), -S(O)- (sulfoxide), and -SO2- (sulfone). For convenience, 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. Thus, for a compound described above having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included. In addition, annular nitrogen atoms may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. Examples of heterocyclyl radicals 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.
[00565] "Heteroalicyclic" refers specifically to a non-aromatic heterocyclyl radical. A heteroalicyclic may contain unsaturation, but is not aromatic.
[00566] "Heteroaryl" refers specifically to an aromatic heterocyclyl radical.
[00567] "Heterocyclylalkyl" refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. 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 radical portion of a heterocyclylalkyl group may be optionally substituted. "Lower heterocyclylalkyl" refers to a heterocyclylalkyl where the "alkyl" portion of the group has one to six carbons.
"Heteroalicyclylalkyl" refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and "heteroarylalkyl" refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is aromatic Such terms may be described in more than one way, for example, "lower heterocyclylalkyl" and "heterocyclyl C1-6alkyl" are equivalent terms.
[00568] "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, that only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted" refers to all subsequent modifiers in a term, for example in the term "optionally substituted arylC1-8 alkyl," optional substitution may occur on both the "C1-8 alkyl" portion and the "aryl" portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups, however. But where a first optionally substituted group can be substituted by a second optionally substituted group, the second substituent cannot be further substituted. Optional subsituents do not include groups that are sterically impractical and/or synthetically non-feasible. A list of exemplary optional substitution are listed below in the definition of "substituted."
[00569] Unless otherwise specified, the term "optionally substituted" applies to the chemical moiety immediately preceding it. For instance, if a variable group (such as R) is defined as aryl, optionally substituted alkyl, or cycloalkyl, then only the alkyl group is optionally substituted.
[00570] In the case where there is a point of attachment for a monovalent substituent, such as -CH3, -NH2, or -OH, the indication of where the point of attachment is is not necessary. That is, -CH3 has the same meaning as CH3, -NH2 has the same meaning as NH2, and -OH has the same meaning as OH.
[00571] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro- 1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system."
[00572] "Spirocyclyl" or "spirocyclic ring" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, 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.
Figure imgf000430_0001
[00573] "Substituted" alkyl, aryl, and heterocyclyl, refer respectively to alkyl, aryl, and heterocyclyl, wherein 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: optionally substituted alkyl (for example, fluoromethyl), optionally substituted aryl (for example, 4-hydroxyphenyl), optionally substituted arylalkyl (for example, 1 -phenyl-ethyl), optionally substituted heterocyclylalkyl (for example, l-pyridin-3-yl -ethyl), optionally substituted heterocyclyl (for example, 5-chloro-pyridin-3-yl or 1 -methyl -piperidin-4-yl), optionally substituted alkoxy, alkylenedioxy (for example methylenedioxy), optionally substituted amino (for example, alkylamino and dialkylamino), optionally substituted amidino, optionally substituted aryloxy (for example, phenoxy), optionally substituted arylalkyloxy (for example, benzyloxy), carboxy (-CO2H), carboalkoxy (that is, acyloxy or -OC(=O)R), carboxyalkyl (that is, esters or -CO2R), carboxamido, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, halogen, hydroxy, nitro, sulfanyl, sulfinyl, sulfonyl, thiol, halogen, hydroxy, oxo, carbamyl, acylamino, and sulfonamido. [00574] "Suitable leaving group" is defined as the term would be understood by one of ordinary skill in the art; that is, a carbon with such a group attached, upon reaction wherein a new bond is to be formed, loses such a group upon formation of the new bond. The compounds described above pertains particularly with respect convergent synthesis, to reactions where such a leaving group is bonded to a reaction partner that is aromatic, undergoes a bond-forming reaction and remains aromatic. A typical example of such a reaction is a nucleophilic aromatic substitution reaction, as would be understood by one of ordinary skill in the art. However, the compounds described above are not limited to such mechanistic restrictions; for example, reactions where there is, for example, an insertion reaction (for example by a transition metal) into the bond between the aromatic reaction partner and its leaving group followed by reductive coupling can also be used within the scope of the compounds described above. Examples of suitable leaving groups include halogens, optionally substituted aryl or alkyl sulfonates, phosphonates, azides, RS(O)0-2- where R is, for example optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. [00575] "Sulfanyl" refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), and -S-(optionally substituted heterocyclyl). [00576] "Sulfinyl" refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-optionally substituted aryl), and -S(O)-(optionally substituted heterocyclyl). [00577] "Sulfonyl" refers to the groups: -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(02)-optionally substituted aryl), -S(O2)-(optionally substituted heterocyclyl), -S(O2)-(optionally substituted alkoxy), -S(O2)-optionally substituted aryloxy), and -S(O2)-(optionally substituted heterocyclyloxy).
Synthetic Procedures for the Compounds of Formulae I(V3), I(V4), I(V5), A-B-C (version 3), A-B-C (version 4) and A-B-C (version 5) [00578] The Compounds of the Compounds of Formulae I(V3), I(V4), I(V5), A-B-C (version 3), A-B-C (version 4) and A-B-C (version 5) can be made by the synthetic schemes and examples described in publication WO 2005/030140, which is incorporated herein by reference in its entirety. The utility of these compounds are also described in WO 2005/030140. [00579] Aspect (31 ) 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 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a compound of Formulae I(V3), I(V4), I(V5), A-B-C (version 3), A-B-C (version 4) or A-B-C (version 5), or a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formulas I(V3), I(V4), I(V5), A-B-C (version 3), A-B-C (version 4) or A-B- C (version 5), and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment.
[00580] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R2 of Formula I(J) is
Figure imgf000432_0001
[00581] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R2 of Formula I(J) is
Figure imgf000433_0001
wherein R28a is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl.
[00582] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R2 of Formula I(J) is
Figure imgf000433_0002
[00583] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, L of Formula I(J) is a bond, Z is
Figure imgf000433_0003
, R25 is hydrogen and E and D are hydrogen. In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14),
aspect (20), and aspect (31 ) of this invention, Z of Formula I(J) is
Figure imgf000433_0005
, R26a is -C(O)R32, R26 is hydrogen, and R32 is selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R32 is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl and halo.
[00584] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R2 of Formula I(J) is
Figure imgf000433_0004
[00585] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R32 of Formula I(J) is U or -CH2-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.
[00586] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R11 of Formula I(J), when present, is halo or lower alkyl. [00587] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R35 of Formula I(J) is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl. [00588] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, n2 of Formula I(J) is 0.
[00589] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, R2 of Formula I(J) is
Figure imgf000434_0001
, and wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. [00590] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, the JAK-2 compound has Formula IV(J):
Figure imgf000434_0002
wherein and R28 and R28a, 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 [00591] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, the JAK-2 compound has Formula V(J):
Figure imgf000435_0001
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00592] In other embodiments of aspect (2), aspect (5), aspect (6), aspect (8), aspect (14), aspect (20), and aspect (31) of this invention, the JAK-2 compound has Formula VI(J):
Figure imgf000435_0002
wherein R28 and R28a, 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
Figure imgf000436_0001
wherein R28 and R2 a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
PI3K COMPOUNDS OF FORMULA I(P)
[00593] The PI3K compounds regulate and/or modulate the signal transduction of phosphatidylinositol 3-kinase (PI3K or PIK3CA), a protein kinase. In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with any of the PI3K inhibitors known in the art, including the pharmaceutically acceptable salts thereof. The PI3K compounds described below are non-limiting examples of PI3K inhibitors that fall within the scope of aspect (1) of this invention. All of the substituents for the PI3K compounds described below are defined separately from all of the other compounds described herein that are not PI3K compounds so that every substituent in the PI3K compounds that also appears in any of the other compounds described herein has a separate and distinct meaning for each of these two compounds. For instance, R1 for the JAK-2 compounds has a separate and distinct meaning from R1 for the PI3K compounds of Formula 1(P). All of the PI3K compounds disclosed herein include either their free base form or their pharmaceutically acceptable salts whether it is stated in the specification that these compounds can exist as their pharmaceutically acceptable salts or not. All of the PI3K compounds disclosed herein fall within the scope of aspect (16) of this invention. [00594] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with compounds that are PI3K compound according to Formula I(P):
Figure imgf000437_0001
or a pharmaceutically acceptable salt thereof, where
W1, W2, W3, and W4 are -C(R1)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1)=; and where each R1 is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino; R51 is hydrogen or alkyl; R52 is hydrogen or halo; R50, R53, and R54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C i -C6-alkylene-N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R55a, or alkylcarbonylamino and where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R53 and R54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl; B is phenyl substituted with R3a and optionally further substituted with one, two, or three
R3; or B is heteroaryl optionally substituted with one, two, or three R3;
R3a is cyano; hydroxyamino; carboxy; alkoxycarbonyl; alkylamino; dialkylamino; r alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C1-C6-alkylene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR R where R is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R9a where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(R10)-C,-C6-alkylene-N(Rl0a)R10b where R1Oa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl and R10 and R1Ob are independently hydrogen, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl; e) -NR1 1C(O)NR11aR1 lb where R1 1a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R11 and Rl lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl; g) -NR13C(O)OR13a where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl; h) -C(O)N(R14)N(R14a)(R14b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-C1-C6-alkylene-N(R15a)R15b where R15, R15a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-C,-C6-alkylene-C(O)OR16a where R16 is hydrogen, alkyl, or alkenyl and R16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
1) -N(R17)-C(=N(R17b)(R17a))(NRI 7cR17d) where R17, R17a, R17b, R17c, and R17d are independently hydrogen, alkyl, or alkenyl; m) -N(R18)C(O)-C1-C6-alkylene-N(R18b)C(O)R18a where R18a is hydrogen, alkyl, alkenyl, or alkoxy and R18 and R18b are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(RI9)-C1-C6-alkylene-C(O)R19a where R19 is hydrogen, alkyl, or alkenyl and R19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-C,-C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and R20a is cycloalkyl or heterocycloalkyl; p) -NR21S(O)2R-C,.C6-alkylene-N(R21b)R21a where R21 is hydrogen, alkyl, or alkenyl and R21a and R21b are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-C1.C6-alkylene-N(R22b)-N(R22c)(R22a) where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0-C6-alkylene-N(R23)-C1-C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C,.C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and
R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; and where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and each R3 (when R3 is present) is independently alkyl; alkenyl; alkynyl; halo; hydroxy; oxo; alkoxy; cyano; hydroxyamino; carboxy; alkoxycarbonyl; amino; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR8R8a where R8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R93 where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl
(optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(R10)-C1-C6-alkylene-N(R10a)R10b where R1Oa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or hydroxyalkyl and R10 and R1Ob are independently hydrogen, alkyl, alkenyl, haloalkyl, or hydroxyalkyl; e) -NR11C(O)NR113R115 where Rl la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R11 and Rl lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminooalkyl, dialkylaminoalkyl ; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl; g) -NR13C(O)OR133 where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl); h) -C(O)N(R14)N(R14a)(R14b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-C,-C6-alkylene-N(R15a)R15b where R15, R15a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-C1-C6-alkylene-C(O)OR16a where R16 is hydrogen, alkyl, or alkenyl and R16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl ; 1) -N(R17)-C(=N(R17b)(R17a))(NR17cR17d) where R17, R17a, R17b, R17c, and R17d are independently hydrogen, alkyl, or alkenyl; m) -N(R18)C(O)-C,-C6-alkylene-N(R18b)C(O)R18a where Rl8a is hydrogen, alkyl, alkenyl, or alkoxy and R and R are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(R19)-C,-C6-alkylene-C(O)R19a where R19 is hydrogen, alkyl, or alkenyl and R19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-C,-C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and R20a is cycloalkyl or heterocycloalkyl; p) -NR^SCO^R-C1-Ce-alkylene-NCR2"')^13 where R21 is hydrogen, alkyl, or alkenyl and R21a and R21b are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-C1.C6-alkylene-N(R22b)-N(R22c)(R22a), where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0-C6-alkylene-N(R23)-C1-C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C i.C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; wherein each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and provided that when R50 and R52 are hydrogen, R51 is hydrogen or methyl, R53 is hydrogen or methoxy, and R54 is hydrogen or methoxy, then B is not 2,3-dihydro-1,4- benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R3 where R3 is halo. [00595] Another aspect of the PI3K compound is a compound of Formula II(P):
Figure imgf000442_0001
( ) or a pharmaceutically acceptable salt or solvate thereof, wherein W1, W2, W3, and W4 are -C(Rla)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(Rla)=;
X1 is -N(R5a)-; A is aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, or -alkyl-N(R7)R7a, where each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl and alkoxy groups, each either alone or as part of another group within A, are independently optionally substituted with one, two, three, or four R2a; or B1 is aryl, arylalkyl, alkyl, heteroaryl, or heteroary alkyl, wherein each of the aryl, heteroaryl and alkyl groups are independently optionally substituted with one, two, three, or four R3d; each Rla is independently selected from hydrogen, alkoxy, alkyl, nitro, halo, cyano, and - C0-C6-alkyl-N(R7)R7a, wherein each of the alkyl and alkoxy groups is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, and -C(O)OR6; each R2a (when R2a is present) is independently selected from alkyl, alkenyl, -alkenyl- C(O)OR6, -OR6, -N(R7)C(O)R6, -N(R7)C(O)-C0-C6 alkyl-N(R7b)R7a, -OC(O)-C0-C6 alkyl-N(R7)R7a, -N(R7)C(O)-C,-C6 alkylC(O)OR6, C0-C6-alkyl-C(O)R6 oxo, dioxo, -S(O)2-N(R7)R7a, -C(O)OR6, -CII(R6)2-C(O)OR6, -S(O)2R6, cycloalkyl, heterocycloalkyl, heteroaryl, -C(O)N(R7)-alkyl-OR6, -C0-C6 alkyl-C(O)N(R7)-C0- C6-alkyl-C(O)OR6, -C0-C6-alkyl-C(O)N(R7)R7a, aryl, arylalkyl, -S-(C1-C6 alkyl), halo, oxo, nitro, -SCN, cyano, and -C0-C6 alkyl-N(R7)R7a, wherein each of the alkyl (including, for example the alkyl within alkoxy), aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R2, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, oxo, nitro, cyano, hydroxy, -N(R8)R8a, alkoxy, and
-C(O)OR9; each R3d (when R3d is present) is independently oxo, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, C3-C6-cycloalkyl, -C0-C6-alkyl-heterocycloalkyl, -C0-C6 alkyl- N(R7)C(O)-C0-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)C(0)-Co-C6-alkyl- N(R7b)C(O)R7a, -C0-C6 alkyl-C(O)-C0-C6-alkyl-N(R7)R7a, -C0-C6-alkyl-C(O)N(R7)-
C0-C6-alkyl-N(R7b)R7a, -C0-C6-alkyl-C(O)N(R7)-C,-C6alkylC(O)OR7a, -C0-C6 alkyl- N(R7)C(O)-C0-C6-alkyl-(R7a), -C0-C6 alkyl-N(R7)-C0-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)C(O)-C0-C6-alkyl-N(R7b)-N(R7c)R7a, -C0-C6 alkyl-N(R7)C(O)O-C0-C6- alkyl-aryl, -C0-C6 alkyl-C(O)N(R7)-C0-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)-C0-C6 alkyl-C(=N(R7b)(R7a))(NR7cR7d), -Co-Q-alkyl-aryl, -Co-Q-alkyl-heteroaryl, -C0-C6 alkyl-heterocycloalkyl, -0-C0-C6 alkyl-N(R7)R7a, -C0-C6 alkyl-ORg, -C0-C6 alkyl- C(O)OR6, C0-C6-alkyl-N(R7)R7a, -C0-C6 alkyl-C(O)NR7R7a, -C0-C6 alkyl-C(O)R7, -SR7, -S(O)2R7, -S(O)3R7, -S(O)R7, -SO2N(R7)R7a, -SO2N(R7)-C0-C6 alkyl- N(R7b)R7a, -C0-C6-alkyl-N(R7)-aryl, -C0-C6-alkyl-N(R7)-heteroaryl, -C0-C6-alkyl- N(R7)-heterocycloalkyl, -C0-C6-alkyl-C(O)N(R7)-C0-C6-alkyl-cycloalkyl, C0-C6- alkyl-C(O)N(R7)-C0-C6-alkyl-aryl, C0-C6 alkyl-C(O)N(R7)-C0-C6 alkyl-heteroaryl, C0-C6 alkyl-C(O)N(R7)-C0-C6-alkyl-heterocycloalkyl, -C0-C6-alkyl-N(R7)C(O)- C0-C6-alkyl-cycloalkyl, -C0-C6-alkyl-N(R7)C(O)-C0-C6-alkyl-aryl, C0-C6-alkyl- N(R7)C(0)-Co-C6-alkyl-heteroaryl, -C0-C6-alkyl-N(R7)C(0)-Co-C6-alkyl- heterocycloalkyl, Co-C6-alkyl-N(R7)C(0)-C0-C6-alkyl-heterocycloalkyl-aryl, -N(R7)C(O)OR6, or -NHC(O)H, wherein each of the alkyl, alkenyl, cycloalkyl, aryl, (including, for example the alkyl within alkoxy), heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R3d, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkenyl, -Co- Cό-alkyl-OR9, cycloalkyl, halo, haloalkyl, haloalkoxy, -C(O)R9, nitro, cyano, oxo, -C0-C6-alkyl-N(R8)R8a, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)OR9, alkylthio, and hydroxyalkyl;
R4 is hydrogen, aryl, -Co-C6-alkyl-N(R7)R7a, alkoxy, or C1-C6 alkyl, wherein each of the alkyl and aryl groups, either alone or as part of another group in R4, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, alkoxy, and -C(O)OR6; or R4 and X1 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein R5a is absent when X is -N(R5a)-, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R7)R7a, alkoxy, and -C(O)OR6; R5a is hydrogen, -C1-C6 alkyl-N(R7)R7a, alkoxy, alkyl, or aryl, wherein each of the alkyl and aryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, C1-C6 alkoxy, or -C(O)OR6; or R5a and R4 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R7)R7a, C1-C6 alkoxy, and -C(O)OR6; R6 and R9 are independently hydrogen, hydroxy, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, either alone or as part of another group within R6 and R9, is independently optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from amino, hydroxy, alkoxy, alkyl, and halo; and R7, R7a R7b, R7c, R7d, R8, and R8a are independently hydrogen, alkyl, alkenyl, hydroxy, alkyloxy, alkenyloxy, -0-C0-C6 alkyl-aryl, -C0-C6 alkyl-C(O)OR6, -C0-C6 alkyl- C(O)R6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl, either alone or part of another group within R7, R7a
R7b, R7c, R7d, R8, and R8a is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, -S-C1-C6 alkyl, cyano, nitro, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, halo, aryl, heterocycloalkylalkyl, and heteroaryl optionally substituted with one or two C1-C6 alkyl.
[00596] One embodiment (P-A) of the PI3K compound is directed to a compound of Formula I(P) where W1, W2, W3, and W4 are -C(R1)-; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1)=; where each R1 is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino; and all other groups are as defined in the
Summary of the Invention. Specifically, W1, W2, W3, and W4 are -C(R1)= and each R1 is independently hydrogen or alkyl; or one of W1 and W4 is -N= and the other is -C(H)=. More specifically, W1, W2, W3, and W4 are -C(R1)= where each R1 is independently hydrogen or alkyl. Even more specifically, R1 is hydrogen. [00597] Another embodiment (P-B) is a Compound of Formula I(P) where R50 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C1-C6-alkylene- N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R553, or alkylcarbonylamino; where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention. Specifically, R50 is hydrogen. [00598] Another embodiment (P-C) is a Compound of Formula I(P) where R51 is hydrogen or alkyl; and all other groups are as defined in the Summary of the Invention. Specifically, R51 is alkyl. More specifically, R51 is methyl. [00599] Another embodiment (P-D) of the invention is a Compound of Formula I(P) where R52 is hydrogen or halo; and all other groups are as defined in the Summary of the Invention. Specifically R is hydrogen or fluoro. More specifically, R is hydrogen. [00600] Another embodiment (P-E) is a Compound of Formula 1(P) where R53 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R^)C(O)-C1 -C6-alkylene- N(R55a)R55 , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R553, or alkylcarbonylamino; where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention. Specifically, R53 is hydrogen, alkoxy, nitro, amino, or -N(R55)C(O)-C1-C6-alkylene-N(R55a)R55b. More specifically, R53 is hydrogen, methoxy, nitro, amino, or -NHC(O)CH2N(CHs)2. Even more specifically, R53 is hydrogen or methoxy.
[00601] Another embodiment (P-F) is a Compound of Formula 1(P) where R54 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C1-C6-alkylene- N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R553, or alkylcarbonylamino; where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention. Specifically, R is hydrogen, alkyl, alkoxy, or halo. More specifically, R54 is hydrogen, methyl, methoxy, bromo, or chloro. Even more specifically, R54 is hydrogen, methoxy, or chloro. [00602] Another embodiment (P-G) is directed to a compound of Formula I(P) where R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention. More specifically, R50, R52, and R53 are hydrogen and R54 is chloro or methoxy; R50, R52, and R54 are hydrogen and R53 is methoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form pyridinyl. Even more speicfically, R50, R52, and R53 are hydrogen and R54 is chloro or methoxy; or R50, R52, and R54 are hydrogen and R53 is methoxy. [00603] In a more specific embodiment (P-Gl) of embodiment G is a compound of Formula I(P) where R51 is methyl.
[00604] Another embodiment (P-H) of the invention is a compound of Formula I(P) where B is phenyl substituted with R3a and optionally further substituted with one, two, or three R3; and all other groups are as defined in the Summary of the Invention. Specifically, B is phenyl substituted with R3a. More specifically the Compound is of Formula I(P)a:
Figure imgf000447_0001
I(P)a
[00603] Even more specifically, B is phenyl substituted with R3a as depicted in I(P)a and is not further substituted with R3.
[00604] Another embodiment (P-J) is directed to a compound of Formula I(P) where B is heteroaryl optionally substituted with one, two, or three R3. Specifically, B is thien-3- yl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, or thiazolyl, each of which is optionally substituted with one or two R3. More specifically, B is thien-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, imidazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl, each of which is optionally substituted with one or two R3. Even more specifically, B is thien-3-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R3. Yet even more specifically, B is pyridin-3-yl, 2-hydroxy-pyridin-5-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R3. [00605] Another embodiment (P-K) provides a compound of Formula 1(P) or I(P)a where R3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy ; dialkylaminoalkyloxy ; -N(R7)C(O)-C , -C6-alkylene-N(R7a)(R7b); -C(O)NR8R83; -NR9C(O)R9"; -C(O)N(Rl0)-C1-C6-alkylene-N(Rl0a)Rl0b;
-NR11C(O)NR118R11" where Rl la; -C(O)R12; -NR13C(O)OR13"; -C(O)N(R14)N(Rl4a)(R14b); -S^^R'^-d.Ce-alkylene-^R15^15";
-C(O)N(R16)-C1.C6-alkylene-C(O)OR16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)- C(=N(Rl7b)(R17a))(NR17cR17d); -N(R18)C(O)-C1-C6-alkylene-N(R18b)C(O)Rl8a;
-C(O)N(R ' 9)-C , -Ce-alkylene-C^R19a; -N(R22)C(O)-C , .C6-alkylene-N(R22b)-
N(R22c)(R22a); -CcCό-alkylene-N^^-CCe-alkylene-N^23^233; or -NR24C(O)-C1-C6- alkylene-OR24a; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and all other groups are as defined in the Summary of the Invention. [00606] Specifically, R3a is -NHC(O)CH2NII(CH3), -NHC(O)CH2NII(CH2CH3), -NHC(O)CII(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CH3)2,
-NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(CH3)NII(CH3), -NHC(O)CH2NH2, -NHC(O)H, -NHC(O)CH2(azetidin-1-yl), -NHC(O)(pyrrolidin-2-yl),
-NHC(O)CII(NH2)CH2OH, -NHC(O)(azetidin-4-yl), -NHC(O)C(CH3)2NII(CH3), -NH2, -NHC(O)CH2NII(CH2CH2CH3), -NHC(O)CH2CH2NH2, -NHOH, -NHC(0)(piperidin-3- yl), -NHC(O)CH2(4-methyl-1,4-diazepan-1-yl), -NHC(O)CII(NH2)(CH2CH3), -NHC(O)CH2NII(CH2CII(OH)(CH3)), -NHC(O)CH2NHCH2CH2F,
-NHC(O)CH2NII(OCH2CII(CH3)2), -NHC(O)(I -aminocycloprop-1-yl),
-NHC(O)CH2NII(CH2cyclopropyl), -NHC(O)CH2(3-(dimethylamino)-azetidin- 1 -yl), -NHC(0)(piperidin-2-yl), -NHC(O)(morpholin-4-yl), -NHC(O)CH2(pyrrolidin- 1 -yl), -NHC(O)CII(NH2)CH2CH2CH2CH2N(CH3);,, -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)CH2(imidazol-5-yl), -NHC(O)(I -aminocyclopent-1-yl),
-NHC(O)CH2NII(CH2CII(CH3)2), -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)(N- (imidazol-4-ylmethyl)-azetidin-3-yl), -NHC(0)(N-ethyl-azetidin-3-yl),
-NHCH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH2N(CH3)(N-methyl-pyrrolidin-3-yl), -ΝHC(O)CH2Ν(CH3)(CH2CH2Ν(CH3)2), -NHC(O)CH2(3-hydroxy-pyrrolidin-1-yl), -NHC(O)(I -amino-cyclobut-1-yl), -NHC(O)CH2NII(CH2)3CH3, -NHC(O)CH2(3- piperidin- 1 -ylazetidin- 1 yl), -NHC(O)NH2, -NHC(0)( 1 -hydroxycyclopropyl),
-NHC(O)CH2NHN(CH3)2, -NHC(O)NII(CH2)2N(CH3)2, -NHC(O)CH2OH,
-NHC(O)(pyridazin-4-yl), -NHC(0)(N-methyl-piperidin-4-yl),
-NHC(O)CH2NHCII(CH3)3, -NHC(O)CH2(3-dimethylamino-pyrrolidin-lyl), -NHC(O)CH2NII(CH2)2N(CH3)2, -NHC(O)(l-cyclopropylmethyl-azetidin-3-yl),
-NHC(O)CH2NII(CH3)3, -NHC(O)(imidazol-2-yl), -NHC(O)(imidazol-4-yl),
-NHC(O)(1, 2-oxazol-5-yl), -NHC(O)CH2NHCH2CF3, -NHC(O)CH2CH2(piperidin-1-yl), -NHC(O)(3-oxo-cyclopent- 1 -yl), -NHC(O)(2-hydroxy-pyridin-6-yl), -NHC(O)CH2NII(3-fluoro-4-hydroxyphenyl), -NHC(O)(CH2)3N(CH3)2, -NHC(O)(I- (ftiran-2-ylmethyl)-azetidin-3-yl), -NHC(O)(pyrimidin-5-yl), -NHC(O)(pyrrol-2-yl), -NHC(O)CH2N(CH3)CII(CH3)2, -NHC(O)CH2N(CH2CH3)2, -NHC(O)CH2(3-methyl- 1 ,2-oxazol-5-yl), -NHC(O)CH2NHCH2(3-hydroxyphenyl), -NHC(O)(N-methyl-pyrrol-2- yl), -NHC(O)(2-amino-tetrahydropyran-2-yl), -NHC(O)CH2(4-methylamino-piperidin-1- yl), -NHC(O)(piperidin-1-yl), -NHC(O)(N-methyl-pyrrolidin-2yl), -NHC(O)(thien-3yl), -NHC(O)(N-(cyclopropylcarbonyl)azetidin-3-yl), -NHC(O)CH2(4-methylpiperazin-1-yl), -NHC(O)(N-benzylazetidin-3-yl), -NHC(O)(2-chloro-pyridin-3-yl),
-NHC(O)CH2(pyridin-4-yl), -NHC(O)CH2N(CH3)(CH2CH=CH2), -NHC(O)CH2NII(benzyl), -NHC(O)CH2OCH3, -NHC(O)[I -(C(O)CH2CH3)-azetidin-3- yl], -NHC(O)(pyridin-3-yl), -NHC(O)CH2NHCH2CH2OCH3,
-NHC(O)(l-[C(O)CH3]piperidin-4-yl), -NHC(O)CH2(2-methyl-pyrrolidin-1-yl),
-NHC(O)(furan-3-yl), -NHC(O)CH2N(CH3)2, -NHC(O)(2-chloro-pyridin-5-yl), -NHC(O)(2-chlorophenyl), -NHC(O)CH2(pyridin-2-yl), -NHC(O)CH2(3-dimethylamino- azetidin-1-yl), -NHC(O)CH2(pyridin-3-yl), -NHC(O)CH2(2-chlorophenyl),
-NHC(O)CH2N(CH3)CH2CH2CH2N(CH3)2, -NHC(O)CH2N(CH2CH3)CH2CH2OH,
-NHC(O)CH2(2-benzyl-pyrrolidin- 1 -yl), -NHC(0)(furan-2-yl, -NHC(O)(2-chloro- pyridin-4-yl), -NHC(O)CH2NHC(O)CH3, -NHC(O)CH2CH2CH3,
-NHC(O)(4-chlorophenyl), -NHC(0)(4-methyl-phenyl), -NHC(O)CH2NHC(O)O(CH3)3, -NHC(O)(benzo[d][l ,3]dioxol-5-yl), -NHC(O)CH2NHOCH2(2-methoxyphenyl),
-NHC(0)(pyridin-4-yl), -NHC(O)CH2 [4-(3,4-dichlorophenyl)-piperazin-1-yl],
-NHC(O)CH2CH2(pyridin-3-yl), -NHC(O)(tetrahydrofiiran-3-yl),
-NHC(O)CH2NHCH2(2-methylphenyl), -NHC(O)CII(CH3)CH2CH3, -NHC(O)CH2(3- fluorophenyl), -NHC(O)CH2C(CH3)2phenyl, -NHC(O)(2-methyl-cycloprop- 1 -yl), -NHC(O)(2-methyl-4-methoxyphenyl), -NHC(O)(2-methylpyridin-3-yl), -NHC(0)(4- methoxyphenyl), -NHC(O)CH2(4-ethylpiperazin- 1 -yl), -NHC(0)(thien-2-yl),
-NHC(O)(3-fluoro-2-methylphenyl), -NHC(O)(2-bromo-thien-3-yl), -NHC(0)(4- fluorophenyl), -NHC(O)CH2(3-methylpiperidin-l -yl), -NHC(O)CII(CH3)2,
-NHC(O)(CH2)3CH3, -NHC(O)CH2OCH2CH3, -NHC(O)CH2NII(2-fluorophenyl), -NHC(O)(3-dimethylaminophenyl), -NHC(O)CH2(4-methylpiperidin-1-yl),
-NHC(O)CH2NII(2-n-propylphenyl), -NHC(O)phenyl, -NHC(O)(pyrazin2-yl), -NHC(O)(3-fluoro-4-methoxyphenyl), -NHC(O)C(CH3)2CH2CH3,
-NHC(O)CH2O(4-fluorophenyl), -NHC(O)(I -methylcarbonyl-azetidin-3-yl), -NHC(O)CH2NII(4-methylphenyl), -NHC(O)CH2NII(phenyl), -NHC(O)CH2(4-allyl- piperazin-1-yl), -NHC(O)(2-methylphenyl), -NHC(O)CH2CH2OCH3,
-NHC(O)(3-methyl-furan-2-yl), -NHC(O)C(CH3)3, -NHC(O)CH2NHObenzyl, -NHC(O)CH2NII(3-chlorophenyl), -NHC(O)cyclobutyl, -NHC(O)CH2(3-methoxyphenyl), -NHC(O)(I -methylcycloprop-1-yl),
-NHC(O)(3-flurophenyl), -NHC(O)(4-dimethylaminophenyl), -NHC(O)(3,4- dichlorophenyl), -NHC(O)CH2NHCH2(2-methylthiophenyl), -NHC(O)CH2(2- fluorophenyl), -NHC(O)CH2N(CH2CH3)CII(CH3)2, -NHC(O)(thiazol-4-yl),
-NHC(O)CH2N(CH3)benzyl, -NHC(O)CH2NHCH2(thien-2-yl), -NHC(O)CH2NHCH2(pyridin-2-yl), -NHC(O)(3-methoxyphenyl),
-NHC(O)CH2NHCH2(3-chloro-4-methylphenyl), -NHC(O)CII(CH3)CH2CH2CH3,
-NHC(O)CH2(4-chlorophenyl), -NHC(O)(3-fluoro-4-methylphenyl), -NHC(O)CH2O(2- methylphenyl), -NHC(O)CH2(cyclohexyl), -NHC(O)(2-phenyl-cycloprop- 1 -yl), -NHC(O)(3-chlorophenyl), -NHC(O)CH2(2-methoxyphenyl), -NHC(O)CH2CH2Q- methoxyphenyl), -NHC(O)CH2NII(2-fluoro-4-methyl-phenyl), -NHC(O)CH2NHCH2(3- fluoro-phenyl), -NHC(O)CH2(4-methoxy-phenyl), -NHC(O)benzyl, -NHC(O)(2,4- dichlorophenyl), -NHC(O)(3-oxo-cyclohex-1-yl), -NHC(O)CH2NII(3-fluorophenyl), -NHC(O)CH2(3-chlorophenyl), -NHC(O)CH2NHCH2CII(CH3)phenyl,
-NHC(O)CH2NHCH2(2,4-dimethylphenyl), -NHC(O)CH2(2-methyl-piperidin- 1 -yl), -NHC(O)CH2NII(2-methoxyphenyl), -NHC(O)CH2(1, 2,3,4-tetrahydroisoquinolin-2-yl), -NHC(O)CH2CH2CH=CH2, -NHC(O)CH2NII(2-methylphenyl), -NHC(O)CH2(4-oxo- piperidin-1-yl), -NHC(O)(2-fluorophenyl), -NHC(O)CH2NHCII(CH3)phenyl,
-NHC(O)(2-fluoro-6-methoxyphenyl), -NHC(O)CH2NII(2-isopropylphenyl),
-NHC(O)CH2CH2(2-methoxyphenyl), -NHC(O)CH2CH2CII(CH3)2, -NHC(O)CH2(2- phenyl-morpholin-4-yl), -NHC(O)CH2CH2(4-methoxyphenyl),
-NHC(O)CH2N(allyl)cyclopentyl, -NHC(O)CH2N(CH3)CH2CH2OCH3,
-NHC(O)CH2CH2C(O)cyclopropyl, -NHC(O)CH2NII(3-tert-butylphenyl),
-NHC(O)CH2N(n-propyl)(cyclopropylmethyl), -NHC(O)CH2(2-oxo-cyclopentyl),
-NHC(O)CH2NII(4-chlorophenyl), -NHC(O)CH2(4-piperidin- 1 -ylpiperidin- 1 -yl), -NHC(O)CH2(4-cyclopentylpiperazin- 1 -yl), -NHC(O)CH2(2-methylphenyl),
-NHC(O)CH2NHCH2(3-fluoro-6-methylphenyl), -NHC(O)CH2C(CHj)3,
-NHC(O)CH2NII(2-chlorophenyl), -NHC(O)(3-fluoro-6-methylphenyl), -NHC(0)(4- fluoro-3-methylphenyl), -NHC(O)(2,3-dichlorophenyl), -NHC(O)CH2Ophenyl, -NHC(O)CH2NII(2,3-dimethylphenyl), -NHC(O)(2-fluoro-5-methylphenyl),
-NHC(O)CH2NHOCH2(4-methylphenyl), -NHC(O)CH2(4-isopropylpiperazin- 1 -yl), -NHC(O)CH2(4-fluorophenyl), -NHC(O)CH2CII(CH3)2, -NHC(O)(2-methoxy- 4-methylphenyl), -NHC(O)CH2(4-n-propylpiperidin-l -yl), -NHC(O)CH2O(3- methylphenyl), -NHC(O)(tetrahydrofuran-2-yl), -NHC(O)CH2(3- hydroxymethylpiperidin- 1 -yl), -NHC(0)( 1 -tert-butoxycarbonylpiperidin-2-yl),
-NHC(O)CH2N(CH3)CH2(pyridin-3-yl), -NHC(O)CH2N(CH2CH3)phenyl,
-NHC(O)CH2OCH2CH2OCH3, -NHC(O)CH2CH2(cyclopentyl), -NHC(O)(2,5- dichlorophenyl), -NHC(O)CH2(4-methylcarbonylpiperazin-l -yl), -NHC(O)(5-fluoro-2- methoxyphenyl), -NHC(O)CH2N(CH2CH3)cyclohexyl, -NHC(O)(5-methyl-1,2-oxazol- 3-yl), -NHC(O)(3-methylpyridin-3-yl), -NHC(O)(2-methoxypyridin-3-yl), -NHC(O)(3,5- dichlorophenyl), -NHC(O)CH2(thiazolidin3-yl), -NHC(O)CH2(4- [C(O)H] -piperazin-1- yl), -NHC(O)CH2(2-pyridin-4-ylpiperidin- 1 -yl), -NHC(O)(2-methoxyphenyl),
-NHC(O)CH2N(CH3)CH2CII(CH3)2, -NHC(O)CH2(4-[C(O)H]-homopiperazin-1-yl), -NHC(O)(I -phenylcycloprop- 1 -yl), -NHC(O)CH2(2,6-dimethylmorpholin-4-yl),
NHC(O)CH2(2-phenylpyrrolidin- 1 -yl), -NHC(O)CH2(morpholin-4-yl),
-C(O)NHCII(CH3)CH2N(CH3)2, -C(O)NHCH2CH2N(CH3)2, -C(O)NII(pyrrolidin-3-yl), -C(O)NHCH2CH2(pyrrolidin- 1 -yl), -C(O)NHCH2CH2NH2,
-C(O)N(CH3)CH2CH2N(CH3)2, -C(O)NHCH2(piperidin-2-yl), -C(O)NII(I- methylazetidin-3-yl), -C(O)NHCH2CH2(piperidin-1-yl), -C(O)NHCH2CH2N(CH2CH3)2, -C(O)NII( I -methylpiperidin-3-yl), -C(O)NII(piperidin-3-yl), -C(O)NHCH2(I- methylpiperidin-3-yl), -C(O)NHCH2CH2N(CH2CH2OH)2, -C(O)NII( I -ethylpiperidin-3- yl), -C(O)NH2, -C(O)(3-aminopyrrolidin-1-yl), -C(O)(3-methylaminopyrrolidin-1-yl), -C(O)OH, -C(O)NHCH2CH2(morpholin-4-yl), -C(O)NHCH2(I -ethylpyrrolidin-2-yl), -C(O)(4-amino-3-oxo-pyrazolidin-1-yl), -C(O)NHCH3, -C(O)(3-aminocyclobut-1-yl), -C(O)NHCH2(pyridin-3-yl), -C(O)NHCH2CH2OH, -C(O)NII(3-oxo-pyrazolidin-4-yl), -NHCH2CH2(imidazol-4-yl), -C(O)(3-dimethylaminopyrrolidin-1-yl),
-C(O)NHCH2(pyridin-4-yl), -C(O)N(CH3)(I -methyl-pyrrolidin-3-yl), -C(0)(3- diethylaminopyrrolidin- 1 -yl), -C(O)NII(pyrrol- 1 -yl), -C(O)NHCH2CH2CH2(pyrrolidin- 1-yl), -C(O)N(CH3)CH2CH2CN, -C(O)NHCH2CH2OCH3, -C(O)N(CH2CH3)CH2CH2CN, -C(O)(3-aminopiperidin- 1 -yl), -C(O)NHCH2CH2CH2N(CH3)2, -C(O)NII(morpholin-4- yl), -C(O)NHN(CH3)2, -C(O)NHCH2CH2CH2(imidazol-1-yl),
-C(O)NHCH2CH2CH2N(CH2CH3)Z, -C(O)NHCH2CH2CN, -C(O)NHCH2CH2C(O)OCH3, -C(O)NHCH2CH2SCH3, -C(O)NHCH2CH2SCH2CH3, -C(O)N(CH2CH3)CH2CH2N(CH3)2, -C(O)NHCH2CH2CH2(2-oxo-pyrrolidin- 1 -yl),
-C(O)NHCH2CH2(pyridin-4-yl), -C(O)NHCH2CH2CH2OCH2CH3,
-C(O)NHCH2CH2CH2(morpholin-4-yl), -C(O)NHCH2CH2CH2OCH3, -C(O)N(CH3)CH2CH2CH2N(CH3)2, -C(O)NHCH2CH2CH2OCH2CH2CH3,
-C(O)NHCH2CH2C(O)OCH2CH3, -C(O)NHCH2CH2CH2OCII(CH3)2,
-C(O)NHC(CH3)2CH2(piperidin- 1 -yl), -C(O)N(CH3)CH2CH2CH3, -C(O)NII(piperidin- 1 - yl), -C(O)NHCII(CH3)CH2OCH3, -C(O)NHC(CH3)2CH2(rnorpholin-4-yl), -C(O)(2- dimethylaminomethylpiperidin-1-yl), -C(O)NII(CH2)3O(CH2)3CH3, -C(O)NHCII(CH3)(CH2)3N(CH2CH3)2, -C(O)NHC(CH3)2C(O)(piperidin-1-yl), -C(O)(4- methylpiperazin-1-yl), -C(O)(2-piperidin-1-ylmethyl-piperidin-1-yl), cyano, -NHCH3, -CII(CH3)NHCH2CH2N(CH3)2, -C(O)CH3, -S(O)2NHCH2CH2N(CH3)2,
-S(O)2NII(CH2)3N(CH3)2, 5-(JV,N-dimethylaminomethyl)- 1 ,3,4-oxadiazol-2-yl,
-NHCH2CH2N(CH3)2, -N(CH3)2, -OCH2CH2N(CH3),, -NHC[N(CHj)2] [=N(CH3)2], -OCHF2, -S(O)2CH3, -OCF3, or -NHC(O)CH2(4-dimethylaminopiperidin- 1 -yl).
[00607] In a more specific embodiment (P-L), the compound of Formula I(P) or I(P)a is that where R3a is hydroxyamino, -N(R7)C(O)-C1-C6-alkylene-N(R7a)(R7b), -C(O)NR8R83 , -NR9C(O)R93, -C(O)N(R10)-C1-C6-alkylene-N(R10a)R10b,
-NR1 1C(O)NR1 laR* lb, -N(R22)C(O)-C,.C6-alkylene-N(R22b)-N(R22c)(R22a), -NR13C(O)OR133, -N(R18)C(O)-C1-C6-alkylene-N(R18b)C(O)R18a , -NR24C(O)-C1-C6- alkylene-OR24a, or -N(R20)C(O)-C1-C6-alkylene-C(O)R20a; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention. Specifically, R3a is -NHC(O)CH2NII(CH3), -NHC(O)CII(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2,
-NHC(O)CII(CH3)NII(CH3), -NHC(O)H, -NHC(O)CH2(azetidin-1-yl),
-NHC(O)(pyrrolidin-2-yl), -NHC(O)CII(NH2)CH2OH, -NHC(0)(azetidin-4-yl), -NHC(O)C(CH3)2NII(CH3), -NH2, -NHC(O)CH2NII(CH2CH2CH3), -NHC(O)CH2CH2NH2, -NHOH, or -NHC(0)(piperidin-3-yl).
[00608] In a more specific embodiment (P-M) the compound is of Formula I(P) or
I(P)a and R3a -N(R7)C(O)-C1-C6-alkylene-N(R7a)(R7b); and R7 is hydrogen or alkyl and R7a and R7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in the Summary of the Invention. More specifically, R3a is -NHC(O)CH2NII(CH3), -NHC(O)CII(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CHS)2, -NHC(O)CII(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, or -NHC(O)CII(CH3)NII(CH3).
[00609] Embodiment (P-N) provides a compound of Formula I(P) where each R3 is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R7)C(O)- C,-C6-alkylene-N(R7a)(R7b); -C(O)NR8R83; -NR9C(O)R93; -C(O)N(R10)-C,-C6-alkylene- N(R1Oa)R1Ob; -NR11C(O)NR1 13R11" where R1 '3; -C(O)R12; -NR13C(O)OR133; -C(O)N(R14)N(R14a)(R14b); -S(O)2N(R15)-C1.C6-alkylene-N(R15a)R15b;
-C(O)N(R16)-C1.C6-alkylene-C(O)ORl6a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)- C(=N(Rl7b)(R17a))(NR17cR17d); -N(R18)C(O)-C1-C6-alkylene-N(R18b)C(O)R18a; -C(O)N(R19)-C,-C6-alkylene-C(O)Rl9a; -N(R22)C(O)-C,-C6-alkylene-N(R22b)-
N(R22c)(R22a); -Co-C6-alkylene-N(R23)-C,-C6-alkylene-N(R23b)R23a; or -NR24C(O)-C1-C6- alkylene-OR24a; where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and all other groups are as defined in the Summary of the Invention. [00610] Specifically, each R3 is independently methyl, bromo, chloro, fluoro, NHC(O)CH2NII(CH3), -NHC(O)CH2NII(CH2CH3), -NHC(O)CII(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(CH3)NII(CH3), -NHC(O)CH2NH2, -NHC(O)H, -NHC(O)CH2(azetidin-1- yl), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CII(NH2)CH2OH, -NHC(O)(azetidin-4-yl), -NHC(O)C(CH3)2NII(CH3), -NH2, -NHC(O)CH2NII(CH2CH2CH3), -NHC(O)CH2CH2NH2, -NHOH, -NHC(0)(piperidin-3-yl), -NHC(O)CH2(4-methyl-1,4- diazepan- 1 -yl), -NHC(O)CII(NH2)(CH2CH3), -NHC(O)CH2NII(CH2CII(OH)(CH3)), -NHC(O)CH2NHCH2CH2F, -NHC(O)CH2NII(OCH2CII(CH3)2), -NHC(O)(I- aminocycloprop- 1 -yl), -NHC(O)CH2NII(CH2cyclopropyl), -NHC(O)CH2(3-
(dimethylamino)-azetidin- 1 -yl), -NHC(0)(piperidin-2-yl), -NHC(O)(morpholin-4-yl), -NHC(O)CH2(pyrrolidin- 1 -yl), -NHC(O)CII(NH2)CH2CH2CH2CH2N(CH3)2, -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)CH2(imidazol-5-yl), -NHC(O)(I- aminocyclopent- 1 -yl), -NHC(O)CH2NII(CH2CII(CH3)2),
-NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)(N-(imidazol-4-ylmethyl)-azetidin-3-yl), -NHC(0)(N-ethyl-azetidin-3-yl), -NHCH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH2N(CH3)(N-methyl-pyrrolidin-3-yl), -NHC(O)CH2N(CH3)(CH2CH2N(CH3)2), -NHC(O)CH2(3-hydroxy-pyrrolidin- 1 -yl), -NHC(O)(I -amino-cyclobut-1-yl), -NHC(O)CH2NII(CH2)3CH3, -NHC(O)CH2(3- piperidin- 1 -ylazetidin- 1 yl), -NHC(O)NH2, -NHC(0)( 1 -hydroxycyclopropyl), -NHC(O)CH2NHN(CH3)2, -NHC(O)NII(CH2)2N(CH3)2, -NHC(O)CH2OH, -NHC(O)(pyridazin-4-yl), -NHC(O)(N-methyl-piperidin-4-yl), -NHC(O)CH2NHCII(CH3)3, -NHC(O)CH2(3-dimethylamino-pyrrolidin-lyl), -NHC(O)CH2NII(CH2)2N(CH3)2, -NHC(O)(l-cyclopropylmethyl-azetidin-3-yl), -NHC(O)CH2NII(CH3)3, -NHC(O)(imidazol-2-yl), -NHC(O)(imidazol-4-yl), -NHC(O)(1 ,2-oxazol-5-yl), -NHC(O)CH2NHCH2CF3, -NHC(O)CH2CH2(piperidin-1-yl), -NHC(O)(3-oxo-cyclopent-1-yl), -NHC(O)(2-hydroxy-pyridin-6-yl), -NHC(O)CH2NII(3-fluoro-4-hydroxyphenyl), -NHC(O)(CH2)3N(CH3)2, -NHC(O)(I - (fiiran-2-ylmethyl)-azetidin-3 -yl), -NHC(0)(pyrimidin-5 -yl), -NHC(O)(pyrrol-2-yl), -NHC(O)CH2N(CH3)CII(CH3)2, -NHC(O)CH2N(CH2CH3)2, -NHC(O)CH2(3-methyl- 1 ,2-oxazol-5-yl), -NHC(O)CH2NHCH2(3-hydroxyphenyl), -NHC(O)(N-methyl-pyrrol-2- yl), -NHC(O)(2-amino-tetrahydropyran-2-yl), -NHC(O)CH2(4-methylamino-piperidin- 1 - yl), -NHC(O)(piperidin-l -yl), -NHC(O)(N-methyl-pyrrolidin-2yl), -NHC(O)(thien-3yl), -NHC(O)(N-(cyclopropylcarbonyl)azetidin-3-yl), -NHC(O)CH2(4-methylpiperazin- 1 -yl), -NHC(O)(N-benzylazetidin-3-yl), -NHC(O)(2-chloro-pyridin-3-yl), -NHC(O)CH2(pyridin-4-yl), -NHC(O)CH2N(CH3)(CH2CH=CH2), -NHC(O)CH2NII(benzyl), -NHC(O)CH2OCH3, -NHC(O)[I -(C(O)CH2CH3)-azetidin-3- yl], -NHC(0)(pyridin-3-yl), -NHC(O)CH2NHCH2CH2OCH3,
-NHC(O)(I -[C(O)CH3]piperidin-4-yl), -NHC(O)CH2(2-methyl-pyrrolidin-l -yl), -NHC(0)(furan-3-yl), -NHC(O)CH2N(CHj)2, -NHC(O)(2-chloro-pyridin-5-yl), -NHC(O)(2-chlorophenyl), -NHC(O)CH2(pyridin-2-yl), -NHC(O)CH2(3-dimethylamino- azetidin- 1 -yl), -NHC(O)CH2(pyridin-3-yl), -NHC(O)CH2(2-chlorophenyl), -NHC(O)CH2N(CH3)CH2CH2CH2N(CH3);!, -NHC(O)CH2N(CH2CH3)CH2CH2OH, -NHC(O)CH2(2-benzyl-pyrrolidin- 1 -yl), -NHC(0)(furan-2-yl, -NHC(O)(2-chloro- pyridin-4-yl), -NHC(O)CH2NHC(O)CH3, -NHC(O)CH2CH2CH3, -NHC(O)(4-chlorophenyl), -NHC(0)(4-methyl-phenyl), -NHC(O)CH2NHC(O)O(CH3)3, -NHC(O)(benzo[d] [ 1 ,3]dioxol-5-yl), -NHC(O)CH2NHOCH2(2-methoxyphenyl), -NHC(O)(pyridin-4-yl), -NHC(O)CH2[4-(3,4-dichlorophenyl)-piperazin-1-yl], -NHC(O)CH2CH2(pyridin-3-yl), -NHC(O)(tetrahydrofuran-3-yl), -NHC(O)CH2NHCH2(2-methylphenyl), -NHC(O)CII(CH3)CH2CH3, -NHC(O)CH2(3- fluorophenyl), -NHC(O)CH2C(CH3)2phenyl, -NHC(O)(2-methyl-cycloprop-1-yl), -NHC(O)(2-methyl-4-methoxyphenyl), -NHC(O)(2-methylpyridin-3-yl), -NHC(0)(4- methoxyphenyl), -NHC(O)CH2(4-ethylpiperazin- 1 -yl), -NHC(O)(thien-2-yl), -NHC(O)(3-fluoro-2-methylphenyl), -NHC(O)(2-bromo-thien-3-yl), -NHC(0)(4- fluorophenyl), -NHC(O)CH2(3-methylpiperidin- 1 -yl), -NHC(O)CII(CH3)2, -NHC(O)(CH2)3CH3, -NHC(O)CH2OCH2CH3, -NHC(O)CH2NH(2-fluorophenyl), -NHC(O)(3-dimethylaminophenyl), -NHC(O)CH2(4-methylpiperidin- 1 -yl), -NHC(O)CH2NII(2-n-propylphenyl), -NHC(O)phenyl, -NHC(O)(pyrazin2-yl), -NHC(O)(3-fluoro-4-methoxyphenyl), -NHC(O)C(CH3)2CH2CH3, -NHC(O)CH2O(4-fluorophenyl), -NHC(0)( 1 -methylcarbonyl-azetidin-3-yl), -NHC(O)CH2NII(4-methylphenyl), -NHC(O)CH2NII(phenyl), -NHC(O)CH2(4-allyl- piperazin-1-yl), -NHC(O)(2-methylphenyl), -NHC(O)CH2CH2OCH3, -NHC(O)(3-methyl-furan-2-yl), -NHC(O)C(CH3)3, -NHC(0)CH2NH0benzyl, -NHC(O)CH2NII(3-chlorophenyl), -NHC(O)cyclobutyl, -NHC(O)CH2(3-methoxyphenyl), -NHC(O)(I -methylcycloprop-1-yl), -NHC(O)(3-flurophenyl), -NHC(O)(4-dimethylaminophenyl), -NHC(O)(3,4- dichlorophenyl), -NHC(O)CH2NHCH2(2-methylthiophenyl), -NHC(O)CH2(2- fluorophenyl), -NHC(O)CH2N(CH2CH3)CII(CH3)2, -NHC(O)(thiazol-4-yl), -NHC(O)CH2N(CH3)benzyl, -NHC(O)CH2NHCH2(thien-2-yl), -NHC(O)CH2NHCH2(pyridin-2-yl), -NHC(O)(3-methoxyphenyl), -NHC(O)CH2NHCH2(3-chloro-4-methylphenyl), -NHC(O)CII(CH3)CH2CH2CH3,
-NHC(O)CH2(4-chlorophenyl), -NHC(O)(3-fluoro-4-methylphenyl), -NHC(O)CH2O(2- methylphenyl), -NHC(O)CH2(cyclohexyl), -NHC(O)(2-phenyl-cycloprop-l -yl), -NHC(O)(3-chlorophenyl), -NHC(O)CH2(2-methoxyphenyl), -NHC(O)CH2CH2(3- methoxyphenyl), -NHC(O)CH2NII(2-fluoro-4-methyl-phenyl), -NHC(O)CH2NHCH2(3- fluorophenyl), -NHC(O)CH2(4-methoxy-phenyl), -NHC(O)benzyl, -NHC(O)(2,4- dichlorophenyl), -NHC(O)(3-oxo-cyclohex- 1 -yl), -NHC(O)CH2NII(3-fluorophenyl), -NHC(O)CH2(3-chlorophenyl), -NHC(O)CH2NHCH2CII(CH3)phenyl, -NHC(O)CH2NHCH2(2,4-dimethylphenyl), -NHC(O)CH2(2-methyl-piperidin- 1 -yl), -NHC(O)CH2NII(2-methoxyphenyl), -NHC(O)CH2(1,2,3,4-tetrahydroisoquinolin-2-yl), -NHC(O)CH2CH2CH=CH2, -NHC(O)CH2NII(2-methylphenyl), -NHC(O)CH2(4-oxo- piperidin- 1 -yl), -NHC(O)(2-fluorophenyl), -NHC(O)CH2NHCII(CH3)phenyl, -NHC(O)(2-fluoro-6-methoxyphenyl), -NHC(O)CH2NII(2-isopropylphenyl), -NHC(O)CH2CH2(2-methoxyphenyl), -NHC(O)CH2CH2CII(CH3)2, -NHC(O)CH2(2- phenyl-morpholin-4-yl), -NHC(O)CH2CH2(4-methoxyphenyl), -NHC(O)CH2N(allyl)cyclopentyl, -NHC(O)CH2N(CH3)CH2CH2OCH3, -NHC(O)CH2CH2C(O)cyclopropyl, -NHC(O)CH2NII(3-/ert-butylphenyl), -NHC(O)CH2N(n-propyl)(cyclopropylmethyl), -NHC(O)CH2(2-oxo-cyclopentyl), -NHC(O)CH2NII(4-chlorophenyl), -NHC(O)CH2(4-piperidin- 1 -ylpiperidin- 1 -yl), -NHC(O)CH2(4-cyclopentylpiperazin- 1 -yl), -NHC(O)CH2(2-methylphenyl), -NHC(O)CH2NHCH2(3-fluoro-6-methylphenyl), -NHC(O)CH2C(CH3)3, -NHC(O)CH2NII(2-chlorophenyl), -NHC(O)(3-fluoro-6-methylphenyl), -NHC(O)(4- fluoro-3-methylphenyl), -NHC(O)(2,3-dichlorophenyl), -NHC(O)CH2Ophenyl, -NHC(O)CH2NII(2,3-dimethylphenyl), -NHC(O)(2-fluoro-5-methylphenyl),
-NHC(O)CH2NHOCH2(4-methylphenyl), -NHC(O)CH2(4-isopropylpiperazin- 1 -yl), -NHC(O)CH2(4-fluorophenyl), -NHC(O)CH2CII(CH3)2, -NHC(O)(2-methoxy- 4-methylphenyl), -NHC(O)CH2(4-n-propylpiperidin- 1 -yl), -NHC(O)CH2O(3- methylphenyl), -NHC(O)(tetrahydrofuran-2-yl), -NHC(O)CH2(3- hydroxymethylpiperidin-1-yl), -NHC(O)(I -tert-butoxycarbonylpiperidin-2-yl), -NHC(O)CH2N(CH3)CH2(pyridin-3-yl), -NHC(O)CH2N(CH2CH3)phenyl, -NHC(O)CH2OCH2CH2OCH3, -NHC(O)CH2CH2(cyclopentyl), -NHC(O)(2,5- dichlorophenyl), -NHC(O)CH2(4-methylcarbonylpiperazin- 1 -yl), -NHC(O)(5-fluoro-2- methoxyphenyl), -NHC(O)CH2N(CH2CH3)cyclohexyl, -NHC(0)(5-methyl-l ,2-oxazol- 3-yl), -NHC(O)(3-methylpyridin-3-yl), -NHC(O)(2-methoxypyridin-3-yl), -NHC(O)(3,5- dichlorophenyl), -NHC(O)CH2(thiazolidin3-yl), -NHC(O)CH2(4-[C(O)H]-piperazin-l - yl), -NHC(O)CH2(2-pyridin-4-ylpiperidin- 1 -yl), -NHC(O)(2-methoxyphenyl), -NHC(O)CH2N(CH3)CH2CII(CH3)2, -NHC(O)CH2(4-[C(O)H]-homopiperazin-1-yl), -NHC(O)(I -phenylcycloprop-1-yl), -NHC(O)CH2(2,6-dimethylmorpholin-4-yl), NHC(O)CH2(2-phenylpyrrolidin- 1 -yl), -NHC(O)CH2(morpholin-4-yl),
-C(O)NHCII(CH3)CH2N(CH3)2, -C(O)NHCH2CH2N(CH3)2, -C(O)NII(pyrrolidin-3-yl), -C(O)NHCH2CH2(pyrrolidin- 1 -yl), -C(O)NHCH2CH2NH2, -C(O)N(CH3)CH2CH2N(CH3)2, -C(O)NHCH2(piperidin-2-yl), -C(O)NII( I- methylazetidin-3-yl), -C(O)NHCH2CH2(piperidin- 1 -yl), -C(O)NHCH2CH2N(CH2CH3);,, -C(O)NII( 1 -methylpiperidin-3-yl), -C(O)NII(piperidin-3-yl), -C(O)NHCH2( 1 - methylpiperidin-3-yl), -C(O)NHCH2CH2N(CH2CH2OH)2, -C(O)NII(I -ethylpiperidin-3- yl), -C(O)NH2, -C(O)(3-aminopyrrolidin-1-yl), -C(O)(3-methylaminopyrrolidin-1-yl), -C(O)OH, -C(O)NHCH2CH2(morpholin-4-yl), -C(O)NHCH2(I -ethylpyrrolidin-2-yl), -C(O)(4-amino-3-oxo-pyrazolidin- 1 -yl), -C(O)NHCH3, -C(O)(3-aminocyclobut- 1 -yl), -C(O)NHCH2(pyridin-3-yl), -C(O)NHCH2CH2OH, -C(O)NII(3-oxo-pyrazolidin-4-yl), -NHCH2CH2(imidazol-4-yl), -C(O)(3-dimethylaminopyrrolidin-1-yl), -C(O)NHCH2(pyridin-4-yl), -C(O)N(CH3)(I -methyl-pyrrolidin-3-yl), -C(0)(3- diethylaminopyrrolidin- 1 -yl), -C(O)NII(pyrrol- 1 -yl), -C(O)NHCH2CH2CH2(pyrrolidin- 1-yl), -C(O)N(CH3)CH2CH2CN, -C(O)NHCH2CH2OCH3, -C(O)N(CH2CH3)CH2CH2CN, -C(O)(3-aminopiperidin- 1 -yl), -C(O)NHCH2CH2CH2N(CH3)2, -C(O)NII(morpholin-4- yl), -C(O)NHN(CH3)2, -C(O)NHCH2CH2CH2(imidazol-1-yl), -C(O)NHCH2CH2CH2N(CH2CH3)2, -C(O)NHCH2CH2CN, -C(O)NHCH2CH2C(O)OCH3, -C(O)NHCH2CH2SCH3, -C(O)NHCH2CH2SCH2CH3, -C(O)N(CH2CH3)CH2CH2N(CH3)2, -C(O)NHCH2CH2CH2(2-oxo-pyrrolidin- 1 -yl), -C(O)NHCH2CH2(pyridin-4-yl), -C(O)NHCH2CH2CH2OCH2CH3, -C(O)NHCH2CH2CH2(rnorpholin-4-yl), -C(O)NHCH2CH2CH2OCH3, -C(O)N(CH3)CH2CH2CH2N(CH3)2, -C(O)NHCH2CH2CH2OCH2CH2CH3, -C(O)NHCH2CH2C(O)OCH2CH3, -C(O)NHCH2CH2CH2OCII(CH3)2,
-C(O)NHC(CH3)2CH2(piperidin- 1 -yl), -C(O)N(CH3)CH2CH2CH3, -C(O)NII(piperidin- 1 - yl), -C(O)NHCII(CH3)CH2OCH3, -C(O)NHC(CH3)2CH2(morpholin-4-yl), -C(0)(2- dimethylaminomethylpiperidin-1-yl), -C(O)NII(CH2)3O(CH2)3CH3, -C(O)NHCII(CH3)(CH2)3N(CH2CH3)2, -C(O)NHC(CH3)2C(O)(piperidin- 1 -yl), -C(0)(4- methylpiperazin-1-yl), -C(0)(2-piperidin-1-ylmethyl-piperidin-1-yl), cyano, -NHCH3, -CII(CH3)NHCH2CH2N(CH3)2, -C(O)CH3, -S(O)2NHCH2CH2N(CH3)2, -S(O)2NII(CH2)3N(CH3)2, 5-(N,N-dimethylaminomethyl)- 1 ,3,4-oxadiazol-2-yl, -NHCH2CH2N(CH3)2, -N(CH3)2, -OCH2CH2N(CH3)2, -NHC[N(CH3)2][=N(CH3)2], -OCHF2, -CF3, -S(O)2CH3, -OCF3, -NHC(O)CH2(4-dimethylaminopiperidin-1-yl), or methoxy.
[00611] In a more specific embodiment (P-P), the Compound of Formula I(P) is that where each R3 is independently halo, alkyl, hydroxyamino, -N(R7)C(O)-C1-C6-alkylene- N(R7a)(R7b), -C(O)NR8R83 , -NR9C(O)R93, -C(O)N(R 10)-C, -C6-alkylene- N(R1Oa)R1Ob-NR' 1C(O)NR1 laR' lb, -N(R22)C(O)-C1-C6-alkylene-N(R22b)-N(R22c)(R22a), -NR13C(O)OR13a, -N(R18)C(O)-C1-C6-alkylene-N(R18b)C(O)R18a , -NR24C(O)-C1-C6- alkylene-OR24a, or -N(R20)C(O)-C,-C6-alkylene-C(O)R20a; where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention. Specifically, each R3 is independently methyl, chloro, -NHC(O)CH2NII(CH3), -NHC(O)CII(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CHs)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(CH3)NII(CH3), -NHC(O)H, -NHC(O)CH2(azetidin- 1 -yl),
-NHC(O)(pyrrolidin-2-yl), -NHC(O)CII(NH2)CH2OH, -NHC(0)(azetidin-4-yl), -NHC(O)C(CH3)2NII(CH3), -NH2, -NHC(O)CH2NII(CH2CH2CH3), -NHC(O)CH2CH2NH2, -NHOH, or -NHC(0)(piperidin-3-yl). [00612] In a more specific embodiment (P-Q), the Compound of Formula 1(P) is that where R3 is alkyl or -N(R7)C(O)-C1-C6-alkylene-N(R7a)(R7b); and R7 is hydrogen or alkyl and R7a and R7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in herein. More specifically, each R3 is independently methyl, -NHC(O)CH2NII(CH3), -NHC(O)CII(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CII(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, or -NHC(O)CII(CH3)NII(CH3).
[00613] In another specific embodiment (P-R), the Compound of Formula I(P) is that where B is phenyl, R3 is not present or R3 is halo, alkyl, or alkoxy; R3a is -C(O)NR8R83, -NR9C(O)R93, -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b), or -C(O)N(R10)-C1-C6-alkylene- N(R1Oa)R1Ob where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined herein.
[00614] In a more specific embodiment (P-Rl) of embodiment (P-R), the compound is that where R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention. Specifically, R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy.
[00615] In a more specific embodiment of (P-R2) of embodiment (P-R), the compound is that where R51 is methyl. [00616] In a more specific embodiment (P-S), the compound of Formula I(P)a:
Figure imgf000459_0001
I(P)a is that where R3 is not present or R3 is alkyl and R3a is -N(R7)C(O)-C1-C6-alkylene- N(R7a)(R7b), -C(O)NR8R83 , -NR9C(O)R93, or -C(O)N(Rl0)-C1-C6-alkylene-N(R10a)R10b; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention. Specifically, R3 is is not present or is methyl. More specifically, R3 is is not present. [00617] In a more specific embodiment (P-Sl) of embodiment (P-S) is that where R7 is hydrogen or alkyl and R7a, and R7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R8 is hydrogen or alkyl and R8a is heterocycloalkyl or heterocycloalkylalkyl; R9 is hydrogen or alkyl and R9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; and R10, R1Oa, and RIOb are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl. [00618] In a more specific embodiment (P-S2) of embodiment (P-S) is that where R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl. Specifically, R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy.
[00619] In a more specific embodiment of (P-S3) of embodiment (P-S), the compound is that where R51 is methyl. [00620] In another specific embodiment (P-T), the Compound of Formula 1(P) is that where B is heteroaryl, one R3 is halo, alkyl, or alkoxy and a second R3 is -C(O)NR8R8a, -NR9C(O)R98, -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b), or -C(O)N(R10)-C,-C6-alkylene- N(R1Oa)R1Ob where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined herein.
[00621] In another specific embodiment (P-Tl) of embodiment (P-T), the compound is that where R7 is hydrogen or alkyl and R7a, and R7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R8 is hydrogen or alkyl and R8a is heterocycloalkyl or heterocycloalkylalkyl; R9 is hydrogen or alkyl and R9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; R10, R1Oa, and R1Ob are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl. [00622] In another specific embodiment (P-U), the compound of Formula I(P) is that where B is
Figure imgf000460_0001
present) is independently halo, alkyl, alkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkylamino, dialkylamino, -C(O)NR8R8a, -NR9C(O)R93, -N(R7)C(O)-C,-C6-alkylene-N(R7aXR7b), or -C(O)N(R10)-C1-C6-alkylene-N(R10a)R10b; and all other groups are as defined herein.
[00623] In a more specific embodiment (P-Ul) of embodiment (P-U), the compound of Formula I(P) is that where R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention.
Specifically, R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy.
[00624] In a more specific embodiment (P-U2) of embodiment (P-Ul), the compound of Formula I(P) is that where R51 is methyl. [00625] In another specific embodiment (P-U3) of embodiment (P-U), the compound of Formula 1(P) is that where R7 is hydrogen or alkyl and R7a, and R7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R8 is hydrogen or alkyl and R8a is heterocycloalkyl or heterocycloalkylalkyl; R9 is hydrogen or alkyl and R9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; R10, R1Oa, and R1Ob are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl
[00626] In another embodiment of the Invention (P-V) the Compound of Formula I(P) is that where: W1, W2, W3, and W4 are -C(H)=; or W2 and W3 are -C(H)= and one of W1 and W4 is -N= and the other is -C(H)=; R50 is hydrogen; R51 is hydrogen or alkyl; R52 is hydrogen; R53 is hydrogen, alkoxy, nitro, amino, or -N(R55)C(O)-C,-C6-alkylene-N(R55a)R55b; and
R54 is hydrogen, alkyl, alkoxy, or halo; or R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl;
B is phenyl substituted with R3a and optionally further substituted with one R3; or B is heteroaryl optionally substituted with one or two R ; R3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R7)C(O)-C i -C6-alkylene-
N(R7a)(R7b); -C(O)NR8R83; -NR9C(O)R92; -C(O)N(R10)-C1-C6-alkylene-N(R10a)R10b;
-NR1 1C(O)NR113R11" where Rl la; -C(O)R12; -NR13C(O)OR133;
-C(O)N(R14)N(R14a)(R14b); -S(O)2N(R15)-C1.C6-alkylene-N(R15a)R15b; -C(O)N(R16)-C1.C6-alkylene-C(O)OR16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)-
C(=N(R' 7O(R173X)(NR17CR' 7d); -N(R18)C(O)-C i -Ce-alkylene-N^18b)C(O)R' 8a;
-C(O)N(R19)-C,-C6-alkylene-C(O)R19a; -N(R22)C(O)-C1.C6-alkylene-N(R22b)-
N(R22c)(R22a); -C0-C6-alkylene-N(R23)-C1.C6-alkylene-N(R23b)R23a; or -NR24C(O)- C1.Q-alkylene-OR243; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; each R3 (when R3 is present) is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b); -C(O)NR8R88; -NR9C(O)R93; -C(O)N(R10)-C,-C6-alkylene-N(R10a)Rl0b; -NR11C(O)NR118R11" where R1 la; -C(O)R12; -NR13C(O)OR138; -C(O)N(R14)N(R14a)(R14b); -S(O)2N(R15)- C1-C6-alkylene-N(R15a)Rl5b; -C(O)N(R16)-C1.C6-alkylene-C(O)OR16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)-C(=N(R17b)(R17a))(NR17cR17d); -N(R18)C(O)-C1-C6- alkylene-N(R' 8b)C(O)R' 8a; -C(O)N(R19)-C , -C6-alkylene-C(O)R' 9a; -N(R22)C(O)- C1-C6-alkylene-N(R22b)-N(R22c)(R22a); -C0-C6-alkylene-N(R23)-C1-C6-alkylene-
N(R 23b )R 23a. or .NR 24 C(O)-C1-C6-alkylene-OR24a; where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; provided that when R50 and R52 are hydrogen, R51 is hydrogen or methyl, R53 is hydrogen or methoxy, and R54 is hydrogen or methoxy, then B is not 2,3-dihydro-1,4- benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R3 where R3 is halo. [00627] Another embodiment (P-W) of the invention is a Compound of Formula I(P) where R50, R53, and R54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C1-C6-alkylene-N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R55a, or alkylcarbonylamino and where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R5 a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R53 and R54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl.
[00628] Another embodiment (P-X) of the invention is a Compound of Formula I(P) where R53 and R54 together with the carbons to which they are attached form a 5- or 6- membered heteroaryl or 5- or 6-membered heterocycloalkyl.
Representative Compounds [00629] Representative PI3K compounds of Formula I(P) and/or II(P), or pharmaceutically acceptable salts thereof, are depicted below in Table P. These compounds in Table P, and pharmaceutically acceptable salts thereof, are merely illustrative and do not limit the scope of the POK compounds or PBK modulators in any way.
Table P
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Figure imgf000470_0001
Figure imgf000471_0001
Figure imgf000473_0001
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0001
Figure imgf000477_0001
Figure imgf000478_0001
Figure imgf000479_0001
Figure imgf000480_0001
Figure imgf000481_0001
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0001
Figure imgf000487_0001
Figure imgf000488_0001
Figure imgf000489_0001
Figure imgf000490_0001
Figure imgf000491_0001
Figure imgf000492_0001
Figure imgf000493_0001
Definitions for PI3K Compounds
[00630] The following terms apply to PI3K compounds described above only. These definitions are not to be considered when determining the scope and meaning of any of the other compounds described herein that are not PI3K compounds. To the same extent, the definitions for all of the other compounds described herein that are not PI3K compounds are not to be considered when determining the scope and meaning of the PI3K compounds.
[00631] "Alkenyl" or "lower alkenyl" means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one double bond and includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like. [00632] "Alkenylcarbonyl" means a C(O)R group where R is alkenyl, as defined herein.
[00633] "Alkenyloxy" or "lower alkenyloxy" means an -OR group where R is alkenyl, as defined herein. Representative examples include methoxy, ethoxy, 1- methoxyprop-1-en-3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
[00634] "Alkoxy" or "lower alkoxy" means an -OR group where R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, 1-methoxyprop-1-en-
3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. [00635] "Alkoxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three alkoxy groups, as defined herein.
[00636] "Akoxycarbonyl" means a -C(O)OR group where R is alkyl as defined herein.
[00637] "Alkoxyycarbonylalkyl" means an alkyl group, as defined herein, substituted with one, two, or three alkoxycarbonyl groups, as defined herein.
[00638] "Alkyl" or "lower alkyl" means a linear or branched hydrocarbon group having one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. A "C0" alkyl (as in "C0-C6-alkyl") is a covalent bond. "C6 alkyl" refers to, for example, n-hexyl, /ΛO-hexyl, and the like.
[00639] "Alkylamino" means a -NHR radical where R is alkyl as defined herein, or an
N-oxide derivative thereof, e.g., methylamino, ethylamino, n-, /sø-propylamino, n-, iso-,
/ert-butylamino, or methylamino-N-oxide, and the like.
[00640] "Alkylaminoalkyl" means an alkyl group substituted with one or two alkylamino groups, as defined herein.
[00641] "Alkylaminoalkyloxy" means an -OR group where R is alkylaminoalkyl, as defined herein.
[00642] "Alkylcarbonyl" means a C(O)R group where R is alkyl, as defined herein.
[00643] "Alkylcarbonylamino" means a -NRC(O)R' group where R is hydrogen or alkyl, as defiend herein, and R' is alkyl, as defiend herein.
[00644] "Alkylene" refers to straight or branched divalent hydrocarbon, containing no unsaturation and having from two to eight carbon atoms. Examples of alkylene include ethdiyl (-CH2CH2-), prop-1,3-diyl (-CH2CH2CH2-), 2,2-dimethylprop-1,3-diyl
(-CH2C(CHj)2CH2-), and the like.
[00645] "Alkylsulfonyl" means a -S(O)2R group where R is lakyl, as defined herien.
[00646] "Alkylthio" means a -SR group where R is alkyl, as defined herein. Examples of alkylthio include methylthio and ethylthio, and the like.
[00647] "Alkylthioalkyl" means an alkyl group substituted with one or two alkylthio groups, as defined herein, e.g. 2-(methylthio)-ethyl and 2-(ethylthio)-ethyl.
[00648] "Alkynyl" or "lower alkynyl" means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
[00649] "Amino" means a -NH2.
[00650] "Aminoalkyl" means an alkyl group subsitutted with at least one, specifically one, two, or three, amino groups.
[00651] "Aminoalkyloxy" means an -OR group where R is aminoalkyl, as defined herein.
[00652] "Aryl" means a monovalent six- to fourteen-membered, mono- or bi- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenyl, naphthyl, and indanyl, and the like. [00653] "Arylalkyl" means an alkyl group, as defined herein, subsituted with one or two aryl groups, as defined herein. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like.
[00654] "Aryloxy"means a -OR group where R is aryl as defined herein.
[00655] "Arylalkyloxy" means a -OR group where R is arylalkyl as defined herein. [00656] "Arylsulfonyl" means a -SO2R group where R is aryl as defined herein.
[00657] "Carboxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three -C(O)OH groups.
[00658] "Carboxy ester" means a -C(O)OR group where 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.
[00659] "Cyanoalkyl" means an alkyl, alkenyl, or alkynyl radical, as defined herein, substituted with at least one, specifically one, two, or three, cyano groups. [00660] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon radical having three to thirteen carbon atoms. The cycloalkyl can be saturated or partially unsaturated, but cannot contain an aromatic ring. Cycloalkyl includes fused, bridged, and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[00661] "Cycloalkylalkyl" means alkyl group substituted with one or two cycloalkyl group(s), as defined herein. Representative examples include cyclopropylmethyl and 2- cyclobutyl-ethyl, and the like. [00662] "Cycloalkylcarbonyl" means a -C(O)R group where R is cycloalkyl as defined herein.
[00663] "Dialkylamino" means a -NRR' radical where R and R' are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, 7V,N-methylpropylamino or 7V,N-methylethylamino, and the like. [00664] "Dialkylaminoalkyl" means an alkyl group substituted with one or dialkylamino group(s), as defined herein.
[00665] "Dialkylaminoalkyloxy" means an -OR group where R is dialkylaminoalkyl, as defined herein. [00666] "Fused ring system" and "fused ring" refer 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. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, 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. In some examples, as appreciated by one of ordinary skill in the art, 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.
[00667] "Haloaloxy" means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like. [00668] "Haloalkoxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three haloalkoxy, as defined herein. [00669] "Halogen" or "halo" means fluoro, chloro, bromo and iodo. [00670] "Haloalkenyl means an alkenyl group, as defined herein, substituted with one or more halogens, specifically one to five halo atoms.
[00671] "Haloalkyl" means an alkyl group, as defined herein, substituted with one or more halogens, specifically one to five halo atoms. Representative examples includes 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-1-fluoroethyl, and the like. [00672] "Heteroaryl" means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing 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")-, 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. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Rx is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, 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, Rx is absent. More specifically, the term 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-1H-indolyl (including, for example, 2,3-dihydro-l//-indol- 2-yl or 2,3-dihydro-1H-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, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof. [00673] "Hetereoarylalkyl" means an alkyl group substituted with one or two heteroaryl group(s) as defined herein.
[00674] "Heterocycloalkyl" means a saturated or partially unsaturated monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated 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(Ry)- (where Ry is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. 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. In particular, when the point of valency is located on a nitrogen atom, Ry is absent. More specifically the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2- oxopyrrolidinyl, 2,5-dihydro-1H-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, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and the derivatives thereof and N-oxide or a protected derivative thereof.
[00675] "Ηeterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with one or two heterocycloalkyl group(s), as defined herein.
[00676] "Ηydroxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, specifically 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 -hydroxy butyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl, 2,3- dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, specifically 2-hydroxyethyl, 2,3-dihydroxypropyl, or l-(hydroxymethyl)-2-hydroxyethyl, and the like. [00677] "Ηydroxyamino" means a -NΗ(OΗ) group. [00678] "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. So, for example, in the term "optionally substituted arylCj.g alkyl," both the "Cj.g alkyl" portion and the "aryl" portion of the molecule may or may not be substituted. A list of exemplary optional substitutions is presented below in the definition of "substituted." But where a first optionally substituted group can be substituted by a second optionally substituted group, the second substituent cannot be further substituted.
[00679] "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, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)0-2-, alkenyl-S(O)0-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc- (where Rc is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NRaRb (where Ra and Rb are independently hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).
[00680] "Optionally substituted alkenyl" means an alkenyl radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, or three groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(0)o-2-, alkenyl-S(0)o-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc- (where Rc is hydrogen, optionally substituted alkyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NRaRb (where Ra and Rb are independently hydrogen, optionally substituted alkyl, alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy). [00681] "Optionally substituted aryl" means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, -C(O)NR5R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR5C(O)R" (where R' is hydrogen or alkyl and R" is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)2R5 (where R5 is alkyl, aryl, or heteroaryl). [00682] "Optionally substituted heteroaryl55 means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, -C(O)NR5R55 (where R5 is hydrogen or alkyl and R55 is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR5C(O)R5' (where R5 is hydrogen or alkyl and R55 is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)2R5 (where R5 is alkyl, aryl, or heteroaryl).
[00683] "Optionally substituted heterocycloalkyl55 means a heterocycloalkyl, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, -C(O)NR5R55 (where R5 is hydrogen or alkyl and R55 is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR5C(O)R55 (where R5 is hydrogen or alkyl and R" is alkyl, aryl, heteroaryl, or heterocycloalkyl), amino, alkylamino, dialkylamino, and -NHS(O)2R' (where R' is alkyl, aryl, or heteroaryl).
[00684] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a- hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro- naphthalene are all included in the class "saturated bridged ring system."
Synthetic Procedures for PI3K Compounds [00685] Compounds of Formula 1(P) and/or II(P) can be made by the synthetic schemes and examples described in publication WO 2007/044729, which is incorporated herein by reference in its entirety. The utility of these compounds are also described in WO 2007/044729.
[00686] The PI3K compounds of Formula I(P) and II(P), or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of Formula 1(P) 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 may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention.
[00687] In particular, B can be 2-hydroxy-pyridinyl, also described as its structure:
Figure imgf000501_0001
14.
Both 2-hydroxy-pyridinyl and the above structure 14 include, and are equivalent to, pyridin-2(1H)-one and its structure 15:
Figure imgf000502_0001
15.
Regardless of which structure or which terminology is used, each tautomer is included within the scope of the compounds of Formula I(P) and II(P). [00688] Compounds of Formula 1(P) and II(P) also includes N-oxide derivatives and protected derivatives of compounds of Formula I(P). For example, when compounds of Formula I(P) and II(P) contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula I(P) and U(P) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable "protecting group" or "protective group". A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula I(P) and II(P) can be prepared by methods well known in the art.
[00689] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization. [00690] In addition, the compounds of Formula I(P) and II(P) 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. [00691] In compounds of Formula I(P) and II(P)
Figure imgf000503_0001
the hydrogen on the -NHS(O)2- group is highly acidic. Thus, intermediates leading to compounds of Formula I(P) and II(P), as well as compounds of Formula I(P) and II(P) themselves, can be recovered as uncharged or zwitterionic molecules, or cationic salts such a sodium or potassium, depending on the substitutions on the B ring and on reaction conditions. In the representative compounds provided herein, unless otherwise specified, the final form of the compound was assumed to be the uncharged molecule in the absence of analytical techniques that would have determined otherwise. [00692] The PI3K compounds of Formula I(P) and II(P), or their pharmaceutically acceptable salts, can have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.
[00693] The PI3K compounds of of Formula 1(P) and II(P) 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. [00694] It is assumed that when considering generic descriptions of POK compounds of Formula 1(P) and II(P) for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that theoretically some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra).
[00695] In addition, it is intended that the PI3K compounds of Formula I(P) and II(P) 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. Pharmaceutical Composition Examples
[00696] The following are representative pharmaceutical Formulations containing a PI3K compound of Formula I(P) or II(P).
Tablet Formulation
[00697] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet, mg
PI3K compound 400
Cornstarch 50 croscarmellose sodium 25
Lactose 120
Magnesium stearate 5
Capsule Formulation
[00698] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantity per tablet, mg
PI3K compound 200 lactose, spray-dried 148
Magnesium stearate 2 Suspension Formulation
[00699] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount
PBK compound l .O g fumaric acid 0.5 g sodium chloride 2.O g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) l.O g
Flavoring 0.035 mL
Colorings 0.5 mg distilled water q.s. to 100 mL
Injectable Formulation [00700] The following ingredients are mixed to form an injectable Formulation.
Ingredient Amount
PI3K compound 1.2 g sodium acetate buffer solution 0.4 M 2.0 mL
HCl (1 N) or NaOH (1 M) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL
[00701] All of the above ingredients, except water, are combined and heated to 60-70° C with stirring. A sufficient quantity of water at 60 ° C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.
Suppository Formulation
[00702] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Quantity per tablet, mg
PI3K compound 500
Witepsol®H-15 Balance [00703] Aspect (32) 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) (including pharmaceutically acceptable salts 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a PI3K compound of Formula 1(P), II(P), I(P)a, (P- A), (P-B), (P-C), (P-D), (P-E), (P-F), (P-G), (P-Gl), (P-H), (P-J), (P-K), (P-L), (P-M), (P-N), (P-P), (P-Q), (P-R), (P-Rl), (P-R2), (P-S), (P-Sl), (P-S2), (P-S3), (P-T), (P-Tl), (P-U), (P-Ul), (P-U2), (P-U3), (P-V), or (P-X), or a pharmaceutical composition comprising a therapeutically effective amount of the PI3K compound of Formula I(P), II(P), I(P)a, (P-A), (P-B), (P-C), (P-D), (P-E), (P-F), (P-G), (P-Gl), (P-H), (P-J), (P-K), (P-L), (P-M), (P-N), (P-P), (P-Q), (P-R), (P-Rl), (P-R2), (P-S), (P-Sl), (P-S2), (P-S3), (P-T), (P-Tl), (P-U), (P-Ul), (P-U2), (P-U3), (P-V), or (P-X), and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment.
[00704] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, R2 of Formula I(J) is
Figure imgf000506_0001
[00705] In another embodiments of aspect ( 1 ), aspect ( 16) and aspect (32) of this invention, R2 of Formula I(J) is
Figure imgf000506_0002
wherein R28a is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl. [00706] In another embodiments of aspect ( 1 ), aspect ( 16) and aspect (32) of this invention, R2 of Formula I(J) is
Figure imgf000507_0001
[00707] In another embodiments of aspect (1), aspect (16) and aspect (32) of this
^ - R26 invention, L of Formula I(J) is a bond, Z is R26a , R25 is hydrogen and E and D are hydrogen.
[00708] In another embodiments of aspect (1), aspect (16) and aspect (32) of this
^ - R26 invention, Z of Formula I(J) is R26a , R26a is -C(O)R32, R26 is hydrogen, and R32 is selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R32 is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl and halo.
[00709] In another embodiments of aspect (1), aspect (16) and aspect (32) of this
invention, R2 of Formula I(J) is
Figure imgf000507_0002
_
[00710] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, R32 of Formula I(J) is U or -CH2-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- 1 H-indolyl.
[00711] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, R11 of Formula I(J), when present, is halo or lower alkyl.
[00712] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, R35 of Formula I(J) is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl. [00713] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, n2 of Formula I(J) is 0.
[00714] In another embodiments of aspect (1), aspect (16) and aspect (32) of this
invention, R2 of Formula I(J) is
Figure imgf000508_0001
, and wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. [00715] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, the JAK-2 compound has Formula IV(J):
Figure imgf000508_0002
wherein and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00716] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, the JAK-2 compound has Formula V(J):
Figure imgf000508_0003
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00717] In another embodiments of aspect (1), aspect (16) and aspect (32) of this invention, the JAK-2 compound has Formula VI(J):
Figure imgf000509_0001
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00718] In other embodiments of the method of combining the PDK inhibitors with the JAK-2 inhibitors of Formula I(J), any of the embodiments described above for the PI3K compounds can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the method of combining the PI3K inhibitors with the JAK-2 inhibitors of Formula I(J), one or more of any of the PI3K compounds in Table P can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the above method of combining the PI3K compounds with the JAK-2 inhibitors of Formula I(J), one or more of any of the PI3K compounds in Table P can be combined with one or more of any of the compounds in Table I(J).
PBKα INHIBITORS
[00719] The PI3Kα compounds inhibit, regulate and/or modulate the signal transduction of PI3Kα, and are expected to be useful in the treatment of hyperproliferative diseases, such as cancer, in humans. In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with any of the PI3Kα inhibitors known in the art. The PI3Kα compounds described below are non-limiting examples of "PI3Kα inhibitors" that fall within the scope of aspect (2) of this invention. All of the substituents for the PI3Kα compounds described below are defined separately from all of the other compounds described herein that are not PI3Kα compounds so that every substituent in the PI3Kα compounds that also appears in any of the other compounds described herein has a separate and distinct meaning for each of these two compounds. For instance, R1 for the JAK-2 compounds has a separate and distinct meaning from R1 for the PBKα compounds.
[00720] All of the POKα compounds disclosed herein include either their free base form or their pharmaceutically acceptable salts whether it is stated in the specification that these compounds can exist as their pharmaceutically acceptable salts or not. All of the PBKα compounds disclosed herein fall within the scope of aspect (17) of this invention.
[00721] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with PDKα compounds of Formula 1(K):
R4 R5
R R1
I(K) or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
R is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R groups;
X is -NR3-; R3 hydrogen;
R4 is optionally substituted alkyl; R5 is hydrogen; and R6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R9 groups; each R8, when present, is independently hydroxy, halo, alkoxy, haloalkoxy, amino, alkylamino, dialkylaminoalkyl, or alkoxyalkylamino; and each R9, when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either alone or as part of another group within R9, are independently optionally substituted with 1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkxy, amino, alkylamino, and dialkylamino.
[00722] In another embodiment, the PBKα compound is a compound of Formula
II(K):
Figure imgf000511_0001
II(K) or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; X is S, SO2, or -NR3-; R2 is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyl-aryl- or optionally substituted heteroaryl;
R2 is optionally further substituted with one or more R8 groups; R3, R3a, and R3b are independently hydrogen, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R4 is hydrogen, halo, haloalkyl, haloalkoxy, -NR3a-, optionally substituted alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R5 is hydrogen, halo, haloalkyl, haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl or optionally substituted heteroaryl; and
R6 is hydrogen, halo, haloalkyl, haloalkoxy, -NR3b-, optionally substituted Cj-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted Cj-C6 alkoxyalkyl, optionally substituted acyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; substitutable R6 groups are optionally further substituted with 1, 2, 3, 4, or 5 R9 groups; each R8, when present, is independently hydroxy, halo, haloalkyl, haloalkoxy, optionally substituted alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 alkoxyalkylaminoalkyl, C1-C6 alkylcarboxyheterocycloalkyl, oxy C1-C6alkylheterocycloalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; each R9, when present, is independently halo, haloalkyl, haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 carboxyalkyl, optionally substituted alkoxycarbonyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted aryloxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In a specific embodiment (K-A) of the PDKα compound of Formula I(K) is a compound of Formula I(K) where R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl. Specifically, R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, or optionally substituted heterocycloalkylalkyl. More specifically, R1 is hydrogen, alkyl, alkyl substituted with one or two hydroxy, alkyl substituted with alkoxy, cycloalkyl, arylalkyl, or heterocycloalkylalkyl. Even more specifically, R1 is hydrogen, methyl, ethyl, propyl, isopropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-ethoxyethyl, 3-methoxypropyl,
3-ethoxypropyl, 3-isopropoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-piperidin-1-ylethyl. Yet even more specifically, R1 is ethyl, isopropyl, cyclopentyl, or cyclohexyl. Yet even more specifically, R1 is ethyl. [00723] Another embodiment (K-B) of the compound of Formula 1(K) is a Compound of Formula I(K) where R2 is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R8 groups. Specifically, R2 is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three R8 groups. More specifically, R2 is hydrogen or alkyl where the alkyl is optionally substitued with one, two, or three R groups; and each R8, when present, is independently selected from amino, alkylamino, dialkylamino, and halo. Even more specifically, R2 is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl, 3-(/V-methylamino)-propyl, 3-(N1N- dimethylamino)-propyl, 2-fluoroethyl, or 2,2,2-trifluoroethyl. Yet even more specifically, R2 is hydrogen or ethyl. Yet even more preferably, R is hydrogen. [00724] In another embodiment, R2 is hydrogen. [00725] In another embodiment, R2 is alkyl optionally substituted with 1, 2, 3, 4, or 5, R8 groups. Specifically, R2 is alkyl where the alkyl is optionally substituted with one, two, or three R8 groups; and each R8, when present, is independently selected from amino, alkylamino, dialkylamino, and halo. Even more specifically, R2 is methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl, 3-(N-methylamino)-propyl, 3-(N1N- dimethylamino)-propyl, 2-fluoroethyl, or 2,2,2-trifluoroethyl. Yet even more specifically, R2 is ethyl.
[00726] Another embodiment (K-C) of the PDKα compound of Formula I(K) is a Compound of Formula 1(K) where R4 is optionally substituted alkyl. Specifically, R4 is methyl or ethyl. More specifically, R4 is methyl. [00727] Another embodiment (K-D) of the PI3Kα compound of Formula I(K) is directed to a Compound of Formula I(K) where R6 is acyl. More specifically, R6 is alkylcarbonyl. Even more specifically, R6 is acetyl. [00728] Another embodiment (K-E) of the PI3Kα compound of Formula 1(K) is directed to a Compound of Formula 1(K) where R6 is phenyl optionally substituted with 1, 2, 3, 4, or 5 R9 groups. Specifically, R6 is phenyl optionally substituted with one or two R9 groups; and each R9, when present, is independently selected from aryl, halo, alkoxy, aryloxy, and haloalkyl. More specifically, R6 is phenyl optionally substituted with one or two R9 groups; and each R9, when present, is independently selected from phenyl, fluoro, chloro, methoxy, phenyloxy, and trifluoromethyl. Even more specifically, R6 is phenyl, phenyl substituted with phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, phenyl substituted with chloro and fluoro, methoxyphenyl, dimethoxyphenyl, phenyloxyphenyl, or trifluoromethylphenyl. Yet even more specifically, R6 is phenyl, 2-phenyl-phenyl, 3 -phenyl-phenyl, 4-phenyl- phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-methoxyphenyl, 3 -methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2, 5 -dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-phenyloxyphenyl, 2-trifluoromethylphenyl, 3 -trifluoromethylphenyl, or 4-trifluoromethylphenyl. [00729] Another embodiment (K-F) of the compound of Formula I(K) is directed to a Compound of Formula I(K) where R6 is phenyl subtituted with 1, 2, 3, 4, or 5 R9 groups. [00730] Another embodiment (K-G) of the compound of Formula I(K) is directed to a Compound of Formula I(K) where R6 is heteroaryl optionally substituted with 1, 2, 3, 4, or 5 R9 groups. [00731] A more specific embodiment (K-Gl) of embodiment (K-G) is a Compound of Formula 1(K) where R6 is a 6-membered heteroaryl optionally substituted with one or two R9. More specifically, R6 is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with one R9 where R9, when present, is halo. Even more specifically, R6 is pyridW-2-yl, pyridW-3-yl, pyridi/V-4-yl, 3-fluoropyridiN-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3- yl, or pyridazin-4-yl, each of which is optionally substituted with one or two R9. [00732] In an even more specific embodiment (K-G2) of embodiment (K-G) is a Compound of Formula 1(K) where R6 is pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with one R where R9, when present, is halo. Even more specifically, R6 is pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin- 5-yl, pyridazin-3-yl, or pyridazin-4-yl.
[00733] A more specific embodiment (K-G3) of embodiment (K-G) is a Compound of Formula I(K) where R6 is 5-membered heteroaryl optionally substituted with one or two R9. Specifically R6 is pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with one R9 where R9, when present, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo. More specifically, R6 is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4- yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1 ,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl,. triazol-1-yl, triazol-4-yl, triazol-5-yl, tetrazol-1-yl, or tetrazol-5-yl; each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, TV-tert-butoxycarbonyl, or chloro. Even more specifically, R6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4- yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro. [00734] A more specific embodiment (K-G4) of embodiment (K-G) is a Compound of Formula 1(K) where R6 is thienyl, pyrrolyl, furanyl, pyrazolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with one R where R9, when present, is methyl, benzyl, cyano, phenyl, N-te/Y-butoxycarbonyl, or chloro. Specifically, R6 is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, tetrazol-5-yl, each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, JV-tert-butoxycarbonyl, or chloro. More specifically, R6 is thien-2-yl, thien-3-yl, 5-cyano-thien-2-yl, 4-methyl- thien-2-yl, 4-methyl-thien-3-yl, 5-chloro-thien-5-yl, 5-phenyl-thien-2-yl, pyrrol-2-yl, N-/erM)utoxycarbonyl-pyπOl-2-yl, N-methyl-pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol- 3-yl, pyrazol-4-yl, N-benzyl-pyrazol-4-yl, pyτazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, tetrazol-5-yl,
[00735] A more specific embodiment (K-G5) of embodiment (K-G) is a Compound of Formula I(K) where R6 is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, or tetrazol-5-yl, each of which is optionally substituted with one R where R , when present, is methyl, benzyl, cyano, phenyl, iV-tert-butoxycarbonyl, or chloro. [00736] A more specific embodiment (K-G6) of embodiment (K-G) is a Compound of Formula I(K) where R6 is indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, or benzoisoxazolyl each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups. Specifically, R6 is indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, benzoisoxazol-6-yl, or benzoisoxazol-7-yl; each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups. More specifically, R6 is indol-6-yl. [00737] Another embodiment (K-H) of the compound of Formula l(K) is a Compound of Formula I(K) where R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkylalkyl, or optionally substituted arylalkyl; X is -NH-; R2 is hydrogen or alkyl where the alkyl is optionally substituted with one or two R8 groups; R4 is alkyl; R5 is hydrogen; R is phenyl or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with one, two, or three R9 groups; each R8, when present, is independently amino, alkylamino, dialkylamino, or halo; and each R9, when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo. [00738] Another embodiment (K-J) is a Compound of Formula I(K) where R6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3- oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1 ,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2- yl, ftiran-3-yl, pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which is optionally substituted with 1 , 2, 3, 4, or 5 R9 groups.
[00739] Another embodiment (K-K) is a Compound of Formula 1(K) where R1 is alkyl or cycloalkyl; R4 is methyl; and R6 is heteroaryl optionally substituted with one or two R9 groups. Specifically, each R9, when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo. Specifically, R6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-
2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1 ,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol- 2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, or N- tert-butoxycarbony 1.
[00740] A more specific embodiment (K-Kl) of embodiment (K-K) is a Compound of Formula 1(K) where R2 is hydrogen.
[00741] A more specific embodiment (K-K2) of embodiment (K-K) is a Compound of Formula 1(K) where R2 is methyl or ethyl.
[00742] Another embodiment (K-L) of a Compound of Formula I(K) is a Compound of Formula I(K) where R1 is alkyl or cycloalkyl; R4 is methyl; and R6 is phenyl optionally substituted with one or two R9 groups. Specifically each R9, when present, is independently halo, alkoxy, or haloalkyl.
[00743] Another embodiment (K-M) is a Compound of Formula I(K) where R1 is alkyl or cycloalkyl; R4 is methyl; and R2 is hydrogen.
[00744] Another embodiment (K-N) is a Compound of Formula 1(K) where R1 is alkyl or cycloalkyl; R4 is methyl; and R2 is optionally subtituted alkyl.
Representative Compounds
[00745] Representative PI3Kα compounds, including pharmaceutically acceptael salts thereof, are depicted below in Table K. These PI3Kα compounds are merely illustrative and do not limit the scope of the PBKα compounds or PBKα inhibitors in any way. Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS). Names were generated using ACD/Labs naming software 8.00 release, product version 8.08.
TABLE K
Figure imgf000518_0001
Figure imgf000519_0001
Figure imgf000520_0001
Figure imgf000521_0001
Definitions for PI3Kα Compounds
[00746] The following abbreviations and terms apply to PBKα compounds described above only. These definitions are not to be considered when determining the scope and meaning of any of the other compounds described herein that are not PI3Kα compounds. To the same extent, any of the other compounds described herein are not to be considered when determining the scope and meaning of the PI3Kα compounds. [00747] "Acyl" means a -C(O)R radical where R is optionally substituted alkyl, optionally substituted alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g., acetyl, trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like. [00748] "Acylamino" means a -NRR' radical where R is hydrogen, hydroxy, alkyl, or alkoxy and R' is acyl, as defined herein.
[00749] "Acyloxy" means an -OR radical where R is acyl, as defined herein, e.g. cyanomethylcarbonyloxy, and the like.
[00750] "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, and l-pent-3-enyl, and the like.
[00751] "Alkoxy" means an -OR group where R is alkyl group as defined herein.
Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like. [00752] "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.
[00753] "Alkoxyalkylamino" means an -NRR' group where R is hydrogen, alkyl, or alkoxyalkyl and R' is alkoxyalkyl, as defined herein. [00754] "Alkoxyalkylaminoalkyl" means an alkyl group substituted with at least one, specifcially one or two, alkoxyalkylamino group(s), as defined herein.
[00755] "Alkoxycarbonyl" means a -C(O)R group where R is alkoxy, as defined herein.
[00756] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.
[00757] "Alkylamino" means an -NHR group where R is alkyl, as defined herein.
[00758] "Alkylaminoalkyl" means an alkyl group substituted with one or two alkylamino groups, as defined herein.
[00759] "Alkylaminoalkyloxy" means an -OR group where R is alkylaminoalkyl, as defined herein.
[00760] "Alkylcarbonyl" means a -C(O)R group where R is alkyl, as defined herein. [00761] "Alkynyl" 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 triple bond, e.g., ethynyl, propynyl, butynyl, pentyN-
2-yl and the like. [00762] "Amino" means -NH2.
[00763] "Aminoalkyl" means an alkyl group substiuted with at least one, specifically one, two or three, amino groups.
[00764] "Aminoalkyloxy" means an -OR group where R is aminoalkyl, as defined herein. [00765] "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. [00766] "Arylalkyl" means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl and phenethyl, and the like.
[00767] "Aryloxy" means an -OR gorup where R is aryl, as defined herein.
[00768] "Carboxyalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, -C(O)OH group(s). [00769] "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. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. More specifically, the term cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.
[00770] "Cycloalkylalkyl" means an alkyl group substituted with at least one, specificallyone or two, cycloalkyl group(s) as defined herein. [00771] "Dialkylamino" means a -NRR' radical where R and R' are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, iV,N-methylpropylamino or N,N-methylethylamino, and the like. [00772] "Dialkylaminoalkyl" means an alkyl group substituted with one or two dialkylamino groups, as defined herein.
[00773] "Dialkylaminoalkyloxy" means an -OR group where R is dialkylaminoalkyl, as defined herein. Representative examples include 2-(jV,JV-diethylamino)-ethyloxy, and the like.
[00774] "Fused-polycyclic" or "fused ring system" means a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, 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. In some examples, as appreciated by one of ordinary skill in the art, 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. [00775] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. [00776] "Haloalkoxy" means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
[00777] "Haloalkyl" mean an alkyl group substituted with one or more halogens, specifically one to five halo atoms, e.g., trifluoromethyl, 2-chloroethyl, and 2,2- difluoroethyl, and the like. [00778] "Heteroaryl" means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms independently selected from -O-, -S(OV- (n is 0> 1, or 2), -N-, -N(RX)-, 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. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Rx is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. When the point of valency is located on the nitrogen, Rx is absent. More specifically, the term 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-l//-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridiN-3- yl, phthalazW-3-yl, phthalaziN-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinoliN-4-yl or tetrahydroisoquinolLN-6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridLN-2-yl or pyrrolo[3,2-c]pyridiN-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof.
[00779] "Ηeteroarylalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two heteroaryl group(s), as defined herein.
[00780] "Ηeteroatom" refers to O, S, N, or P.
[00781] "Ηeterocycloalkyl" 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(Ry) (where Ry is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NΗ)- group. 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, Ry is absent. More specifically the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2- oxopyrrolidinyl, 2,5-dihydro-1H-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, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and the derivatives thereof and N-oxide or a protected derivative thereof. [00782] "Heterocycloalkylalkyl" means an alkyl radical, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein, e.g., morpholinylmethyl, N-pyrrolidinylethyl, and 3-(N-azetidinyl)propyl, and the like. [00783] "Heterocycloalkylalkyloxy means an -OR group where R is heterocycloalkylalkyl, as defined herein. [00784] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a- hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro- naphthalene are all included in the class "saturated bridged ring system. [00785] "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. So, for example, in the term "optionally substituted arylC1-8 alkyl," optional substitution may occur on both the "C1-8 alkyl" portion and the "aryl" portion of the molecule may or may not be substituted. But where a first optionally substituted group can be substituted by a second optionally substituted group, the second substituent cannot be further substituted. A list of exemplary optional substitutions is presented below in the definition of "substituted."
[00786] "Optionally substituted alkoxy" means an -OR group where R is optionally substituted alkyl, as defined herein. [00787] "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, hydroxy, hydroxyalkoxy, halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)0-2-, alkenyl-S(0)o-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc- (where Rc is hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NRaRb (where Ra and Rb are independently hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl). [00788] "Optionally substituted alkenyl" 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, hydroxy, hydroxyalkoxy, halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)0-2-, alkenyl-S(O)0-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc- (where Rc is hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NRaRb (where Ra and Rb are independently hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl). [00789] "Optionally substituted amino" refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, acyl, carboxy, alkoxycarbonyl, -S(O)2-(optionally substituted alkyl), -S(O)2-optionally substituted aryl), -S(O)2-(optionally substituted heterocycloalkyl), -S(O)2-(optionally substitutted heteroaryl), and -S(O)2-(optionally substituted heteroaryl). For example, "optionally substituted amino" includes diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino. [00790] "Optionally substituted aminoalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted amino group(s), as defined herein.
[00791] "Optionally substituted aryl" means an aryl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Within the optional substituents on "aryl", the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo. [00792] "Optionally substituted arylalkyl" means an alkyl group, as defined herein, substituted with optionally substituted aryl, as defined herein.
[00793] "Optionally substituted cycloalkyl" means a cycloalkyl group, as defined herein, substituted with one, two, or three groups independently selected from acyl, acyloxy, acylamino, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, carboxy, and cyano. Within the above optional substitutents on "cycloalkyl", the alkyl and alkenyl,, either alone or as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl. [00794] "Optionally substituted cycloalkylalkyl" means an alkyl group substituted with at least one, specifically one or two, optionally substituted cycloalkyl groups, as defined herein.
[00795] "Optionally substituted heteroaryl" means a heteroaryl group optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy. Within the optional substituents on "heteroaryl", the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo. [00796] "Optionally substituted heteroarylalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heteroaryl group(s), as defined herein.
[00797] "Optionally substituted heterocycloalkyl" means a heterocycloalkyl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Within the optional substituents on "heterocycloalkyl", the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[00798] "Optionally substituted heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heterocycloalkyl group(s) as defined herein.
Synthetic Procedures for PI3Kα Compounds
[00799] Compounds of Formula I(K) and II(K) can be made by the synthetic schemes and examples described in publication WO 2007/044813, which is incorporated herein by reference in its entirety. The utility of these compounds are also described in WO 2007/044813.
[00800] The PI3Kα compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of Formula I(K) and II(K) 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 of the invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention. In particular, imidazol- 5-yl and pyrazol-5-yl each can also exist in their respective tautomeric forms imidazol-4- yl and pyrazol-3-yl. Regardless of which structure or which terminology is used, each tautomer is included within the scope of the Invention.
[00801] Compounds of Formula I(K) and II(K) also includes N-oxide derivatives and protected derivatives of compounds of Formula I(K) and II(K). For example, when compounds of Formula I(K) and II(K) contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula I(K) and II(K) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable "protecting group" or "protective group". A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John
Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula I(K) and II(K) can be prepared by methods well known in the art.
[00802] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
[00803] In addition, the compounds of Formula I(K) and II(K) 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. [00804] In addition, it is intended that the PBKα 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.
Pharmaceutical Composition Examples [00805] The following are representative pharmaceutical Formulations containing a PBKα compound of Formula I(K) or II(K).
Tablet Formulation
[00806] The following ingredients are mixed intimately and pressed into single scored tablet^
Ingredient Quantity per tablet, mg
PBKα compound 400
Cornstarch 50 croscarmellose sodium 25
Lactose 120 magnesium stearate 5 Capsule Formulation
[00807] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantity per tablet, mg
PBKα compound 200 lactose, spray-dried 148 magnesium stearate 2
Suspension Formulation
[00808] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount
PBKα compound 1.0 g fumaric acid 0.5 g sodium chloride 2.O g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g
Flavoring 0.035 mL
Colorings 0.5 mg distilled water q.s. to 10O mL
Injectable Formulation
[00809] The following ingredients are mixed to form an injectable Formulation.
Ingredient Amount
PDKα compound 1-2 g sodium acetate buffer solution 0.4 M 2.0 mL HCl (l N) or NaOH (l M) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL
[00810] All of the above ingredients, except water, are combined and heated to 60- 70° C with stirring. A sufficient quantity of water at 60° C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.
Suppository Formulation [00811] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol®. H- 15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: Ingredient Quantity per tablet, mg
POKα compound 500
Witepsol®H-15 Balance
[00812] Aspect (33) of this ivention 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 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a PI3Kα compound of Formula I(K), H(K), (K-A), (K-B), (K-C), (K-D), (K-E), (K-F), (K-G), (K- Gl), (K-G2), (K-G3), (K-G4), (K-G5), (K-G6), (K-H), (K-J), (K-K), (K-Kl), (K-K2), (K-L), (K-M), or (K-N), or a pharmaceutical composition comprising a therapeutically effective amount of the PI3Kα compound of Formula 1(K), II(K), (K-A), (K-B), (K-C), (K-D), (K-E), (K-F), (K-G), (K-Gl), (K-G2), (K-G3), (K-G4), (K-G5), (K-G6), (K-H), (K-J), (K-K), (K-Kl), (K-K2), (K-L), (K-M), or (K-N), and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment. [00813] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, R2 of Formula I(J) is
Figure imgf000533_0001
[00814] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, R of Formula I(J) is
Figure imgf000533_0002
wherein R28a is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl. [00815] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, R2 of Formula I(J) is
Figure imgf000534_0001
[00816] In another embodiment of the above method of combining the PI3Kα inhibitors of Formula I(K), II(K), (K-A), (K-B), (K-C), (K-D), (K-E), (K-F), (K-G), (K-Gl), (K-G2), (K-G3), (K-G4), (K-G5), (K-G6), (K-H), (K-J), (K-K), (K-Kl), (K-K2), (K-L), (K-M), or (K-N), with the JAK-2 inhibitors of Formula I(J), L of Formula I(J) is a
bond, Z is R a , R25 is hydrogen and E and D are hydrogen. In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention,
Z of Formula I(J) is R26a , R26a is -C(O)R32, R26 is hydrogen, and R32 is selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R32 is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl and halo. [00817] In other embodiments of aspect (2), aspect (17), and aspect (33) of this
invention, R2 of Formula I(J) is
Figure imgf000534_0002
[00818] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, R32 of Formula I(J) is U or -CH2-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- 1 H-indolyl .
[00819] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, R1 1 of Formula I(J), when present, is halo or lower alkyl. [00820] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, R35 of Formula I(J) is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl.
[00821] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, n2 of Formula I(J) is 0.
[00822] In other embodiments of aspect (2), aspect (17), and aspect (33) of this
invention, R2 of Formula I(J) is
Figure imgf000535_0001
, and wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
[00823] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, the JAK-2 compound has Formula IV(J):
Figure imgf000535_0002
wherein and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31. [00824] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, the JAK-2 compound has Formula V(J):
Figure imgf000535_0003
wherein R28 and R28a, 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 [00825] In other embodiments of aspect (2), aspect (17), and aspect (33) of this invention, the JAK-2 compound has Formula VI(J):
Figure imgf000536_0001
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00826] In other embodiments of the method of combining the PI3Kα inhibitors with the JAK-2 inhibitors of Formula I(J), any of the embodiments described above for the PI3Kα compounds can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the method of combining the PI3Kα inhibitors with the JAK-2 inhibitors of Formula I(J), one or more of any of the PDKα compounds in Table K can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the above method of combining the PI3Kα compounds with the JAK-2 inhibitors of Formula I(J), one or more of any of the PI3Kα compounds in Table K can be combined with one or more of any of the compounds in Table I(J).
Src and BCR-AbI COMPOUNDS
[00827] The Src and/or BCR-AbI compounds (inhibitors of Src and/or BCR-AbI) described herein regulate and/or modulate Src and/or BCR-AbI and/or IGFlR protein kinase enzymatic activity. In another embodiment of the methods described herein, the
JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J),
IV(J), V(J), VI(J), and VII(J)] can be combined with any of the Src and/or BCR-AbI inhibitors known in the art. Non-limiting examples of Src inhibitors that fall within the scope of aspect (7) of this invention are the Src and/or BCR-AbI compounds described below that inhibit Src. Non-limiting examples of BCR-AbI inhibitors that fall within the scope of aspect (9) of this invention are the Src and/or BCR-AbI compounds described below that inhibit BCR-AbI. Non-limiting examples of IGFlR inhibitors that fall within the scope of aspect (15) of this invention are the Src and/or BCR-AbI compounds described below that inhibit IGFlR. All of the substituents for the Src and/or BCR-AbI compounds described below are defined separately from all of the other compounds described herein that are not Src and/or BCR-AbI compounds so that every substituent that appear in all of the other compounds described herein that also appears in the Src and/or BCR-AbI compounds has a separate and distinct meaning for each of these two compounds. For instance, R1 for the JAK-2 compounds has a separate and distinct meaning from R1 for the Src and/or BCR-AbI compounds. [00828] All of the compounds disclosed herein include either their free base form or their pharmaceutically acceptable salts whether it is stated in the specification that these compounds can exist as their pharmaceutically acceptable salts or not. All of the BCR- AbI compounds disclosed herein fall within the scope of aspect (24) of this invention.
[00829] In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with Src and/or BCR-AbI compounds represented by Formula I(S):
Figure imgf000537_0001
I(S)
or a pharmaceutically acceptable salt thereof, wherein:
V is NRiRia, or O-Ri, wherein
R1 is H, CN, halo, -NRi3Ri4, C(O)NR13R14, C1-C6 alkyl, -C(O)-C1-C6 alkyl, -C0-C6 alkyl-
R20, wherein R20 is aryl, heteroaryl, heterocyclyl, or a 5-12 membered fused bicyclical or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from N, O, and S, wherein aryl, heteroaryl, C3- C7 heterocyclyl, or the 5-12 membered ring system are optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, and -C0-C6 alkyl-R2i; Ria is H or C1-C6 alkyl; or when V is NRiRi3, Ri and Rj3 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing, in addition to the nitrogen, up to two additional heteroatoms independently selected from O, N, and
S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two of C1-C6 alkyl, -NRI3RH or C3-C7 cycloalkyl;
X is H, halo, C1-C6 alkyl, NO2, mono-, di-, or tri-halo substituted methyl, NRI3RH,
C(O)O-C1-C6 alkyl, or N(Rn)-C(O)-C, -C6 alkyl;
Y is H, halo, OH, C-C6 alkyl, C0-C6 alkyl-NR,5Ri6, C1-C6 alkoxy, -N(R,3)-(CH2)n-
NRi5Ri6, -C(O)O-C1-C6 alkyl, -O-(CH2)n-NR15R16, -C(O)-C1-C6 alkyl, -C0-C6- alkyl-R21, -0-R21, -C(O)-R21, -O-(CH2)n-R21, -C(O)-NR13R14, -C(O)-N(R13)-aryl,
-C(O)-N(R13)-(CH2)n-NR15R16, -C(O)-N(R13)-(CH2)n-aryl, -C(O)-N(R13)-(CH2)n- heterocyclyl; or X and Y together with the atoms to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing one or two heteroatoms independently selected from O, N, and S, wherein the heterocyclyl or heteroaryl group is optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, aryl-C,-C6 alkyl-, aryl-(CH2)n-O-(CH2)n-aryl-, arylOH, C3-C7 cycloalkyl, heterocyclyl, -aryl-N(R13)C(O)-C3-C7 cycloalkyl-C(O)-N(R,4)- aryl, or a group of the Formula -L-M-Q, wherein L is a bond or C3-C7 cycloalkyl,
M is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl,
Q is NRi3Ri4, N(Ri3)C(O)-C1-C6 alkyl, heterocyclyl, or a saturated fused bicyclic ring containing one or two heteroatoms independently selected from O, N, and S, wherein each aryl, heteroaryl, or heterocyclyl substituent on the group formed by X and Y is optionally further substituted with one or two moieties independently selected from halo, C(O)O-(CH2)n-phenyl, and C(O)-C1-C6 alkyl;
Z is H, NR2R3, -S-R23, or -O-R2a, wherein
R2 is -C1-C6 alkyl, -C1-C6 alkyl-NRi3RH, -C(O)-aryl, -C0-C6-alkyl-aryl, -C0-C6-alkyl- heteroaryl, -C0-C6-alkyl-(C3-C7-cycloalkyl), -C0-C6-alkyl-heterocyclyl, or -C0-C6 alkyl-5-12 membered fused bicyclic or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from N, O, and S, wherein each alkyl is optionally substituted with phenyl, and each aryl, heteroaryl, C3-C7 cycloalkyl, heterocyclyl, or 5-12 membered ring system is optionally . substituted with one, two, or three groups independently selected from halo, mono-, di-, or tri-halo substituted methyl or methoxy, CN, NO2, NRi3Ri4, C(O)O- C-C6 alkyl, N(R13)C(O)-C1-C6 alkyl, -SO2NR13R14, -0-C(O)-NR13R14, -C0-C6 alkyl-C(O)NRi5R16, C1-C6 alkoxy, C1-C6 thioalkoxy, -0-(CH2VNRi5Ri6, -C1-C6 alkyl-NR,3RI4, -N(R13)-C(O)-C1-C6 alkyl, -N(R13)-C(O)-aryl, -C0-C6 alkyl-C(O)- N(R,3)-(CH2)n-NR,5R,6, -C0-C6 alkyl-C(O)-N(R,3)-(CH2)n-aryl, -0-(CH2)n-C(0)- N(R,3)-(CH2)n-NR15Ri6, -O-(CH2)n-C(O)-NR15R16, -C0-C6 alkyl-C(O)-N(R,3)- (CH2VO-C1-C6 alkyl, -C0-C6 alkyl-N(Ri3)-C(O)O-C,-C6 alkyl, -C0-C6alkyl- C(O)-heterocyclyl, -C0-C6alkyl-C(O)-heteroaryl, -C0-C6alkyl-C(O)-aryl, -C0-C6- alkyl-R2,, aryloxy, -O-(CH2)n-R2i, -SO2-heterocyclyl, N(R13)-C(O)-C3-C7- cycloalkyl, -C0-C6alkyl C(O)O-R2J ,C3-C7-cycloalkyl, -C0-C6alkylR2], -SC1- C6alkyl or C1-C6 alkyl optionally substituted with halo or cyano, wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl substituent is further optionally substituted with 1-3 groups independently selected from halo, CF3, C1-C6 alkyl,
C1-C6 haloalkoxy, NR13R14 and C1-C6 alkoxy; R3 is H or C1-C6 alkyl; or R2 and R3 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing up to three heteroatoms independently selected from O, N, and S, and wherein the heterocyclyl or heteroaryl group is optionally substituted with one or two of halo or C1-C6 alkyl; R2a is aryl or C0-C6 alkyl-heteroaryl, wherein the aryl and heteroaryl are optionally substituted with aryl, -N(R,3)-C(O)-C3-C7 cycloalkyl or -C(O)NRi3R]4; Ri3 and R14 are independently H or C1-C6 alkyl; R15 and Rj6 are independently H, C1-C6 alkyl, heteroaryl, or heterocyclyl, or Ri5 and Ri6 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two moieties independently selected from halo, Cj-C6 alkyl, or -C(O)O-
C1-C6 alkyl;
R21 is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, -S(O)2-Co-C1 alkyl, -C(O)-Co- C1 alkyl, -C(O)-H, -C0-C1 alkyl-aryl, C1-C6 alkyl, NRnRi4, and heterocyclyl; n is 0-6; provided that when V is NH2, X, Y and Z are not simultaneously H. [00830] In a specific embodiment of the protein kinase modulator compound of
Formula I(S), is a compound of Formula I(S) wherein V is NHRi .
[00831] In another specific embodiment of the protein kinase modulator compound of Formula I(S), is a compound of Formula I(S) wherein Z is NR2R3.
[00832] In another specific embodiment of the protein kinase modulator compound of Formula I(S), is a compound of Formula I(S) wherein V is NHR] and Z is NR2R3.
[00833] Another specific embodiment of the Src and/or BCR-AbI compounds is a compound having Formula II(S):
Figure imgf000540_0001
H(S) or a pharmaceutically acceptable salt thereof, wherein:
Ri is H, CN, halo, -NRnR14, C(O)NRnRi4, C1-C6 alkyl, -C(O)-C1-C6 alkyl, -C0-C6 alkyl- R20, wherein R20 is aryl, heteroaryl, heterocyclyl, or a 5-12 membered fused bicyclical or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from N, O, and S, wherein aryl, heteroaryl, C3-C7 heterocyclyl, or the 5-12 membered ring system are optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, and -C0- C6 alkyl-R21;
X is H, halo, C1-C6 alkyl, NO2, mono-, di-, or tri-halo substituted methyl, NRnRn, C(O)O-C1-C6 alkyl, or N(Rn)-C(O)-C1-C6 alkyl; Y is H, halo, OH, C1-C6 alkyl, NR15Ri6, C1-C6 alkoxy, -N(Rn)-(CH2)n-NR15Ri6, - C(O)O-C1-C6 alkyl, -O-(CH2)n-NRi5R,6) -C(O)-C1-C6 alkyl, -Co-C6-alkyl-R2,, - 0-R21, -C(O)-R21, -O-(CH2)n-R2i, -C(O)-NRnR14, -C(O)-N(Rn)-aryl, -C(O)- N(Rn)-(CH2)n-NR15R16, -C(O)-N(Rn)-(CH2)n-aryl, -C(O)-N(R13)-(CH2)n- heterocyclyl, wherein R21 is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, NRi3R]4, and heterocyclyl; or X and Y together with the atoms to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing one or two heteroatoms independently selected from O, N, and S, wherein the heterocyclyl or heteroaryl group is optionally substituted with one or two moieties independently selected from halo, C-C6 alkyl, aryl-C,-C6 alkyl-, aryl-(CH2)n-O-(CH2)n-aryl-, arylOH, C3-C7 cycloalkyl, heterocyclyl, -aryl-N(R13)C(O)-C3-C7 cycloalkyl-C(O)-N(RH)- aryl, and a group of the Formula -L-M-Q, wherein L is a bond or C3-C7 cycloalkyl,
M is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl,
Q is NRi3Ri4, N(R]3)C(O)-C1-C6 alkyl, heterocyclyl, or a saturated fused bicyclic ring containing one or two heteroatoms independently selected from O, N, and S, wherein each aryl, heteroaryl, or heterocyclyl substituent on the group formed by
X and Y is optionally further substituted with one or two moieties independently selected from halo, C(O)O-(CH2)n-phenyl, and C(O)-C1-C6 alkyl;
R2 is -C1-C6 alkyl, -C1-C6 alkyl-NR]3Ri4, -C(O)-aryl, -Co-Q-alkyl-aryl, -C0-C6-alkyl- heteroaryl, -C0-C6-alkyl-(C3-C7-cycloalkyl), -C0-C6-alkyl-heterocyclyl, or -C0-C6 alkyl-5-12 membered fused bicyclic or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from N, O, and S, wherein each alkyl is optionally substituted with phenyl, and each aryl, heteroaryl, C3-C7 cycloalkyl, heterocyclyl, or 5-12 membered ring system is optionally substituted with one, two, or three groups independently selected from halo, mono-, di-, or tri-halo substituted methyl or methoxy, CN, NO2, NR]3R]4, C(O)O-C1-C6 alkyl, N(R13)C(O)-C-C6 alkyl, -SO2NR13R]4, -0-C(O)-NR]3R14, -C0-C6 alkyl-C(O)NR]5R16, C1-C6 alkoxy, C-C6 thioalkoxy, -O-(CH2)n-NR]5R]6, -C-C6 alkyl-NR,3R,4, -N(Ru)-C(O)-C1-C6 alkyl, -N(R,3)-C(O)-aryl, -C0-C6 alkyl-C(O)-N(R,3)-(CH2)n-NR,5R,6, -C0-C6 alkyl-C(O)-N(R,3)-(CH2)n-aryl, -O-
(CH2)n-C(O)-N(R13)-(CH2)n-NR,5R,6, -O-(CH2)n-C(O)-NR,5R,6, -C0-C6 alkyl- C(O)-N(R, 3)-(CH2)n-O-C, -C6 alkyl, -C0-C6 alkyl-N(R,3)-C(O)O-C-C6 alkyl, -C0-C6alkyl-C(O)-heterocyclyl, -Co-C6alkyl-C(0)-heteroaryl, -C0-C6alkyl-C(0)- aryl, -C0-C6-alkyl-R2i, aryloxy, -O-(CH2)n-R2i, -SO2-heterocyclyl, N(Rn)-C(O)- C3-C7-cycloalkyl, -C0-C6alkyl C(O)O-R2] ,C3-C7-cycloalkyl, -C0-C6alkylR2i, -SC1-C6alkyl or C1-C6 alkyl optionally substituted with halo or cyano, wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl substituent is further optionally substituted with 1 -3 groups independently selected from halo, mono-, di-, or tri-halo substituted methyl, C1-C6 alkyl, C1-C6 haloalkoxy, NRi3Rj4 and C1-C6 alkoxy;
Ri3 and R]4 are independently H or C1-C6 alkyl, or R]3 and RM together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two of halo, C1-C6 alkyl, or C1-C6 alkoxy; Ri5 and Rj6 are independently H, C1-C6 alkyl, heteroaryl, or heterocyclyl, or R]5 and Ri6 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two of halo, C1-C6 alkyl, or -C(O)O-C1-C6 alkyl; and n is 1-6.
[00834] In a specific embodiment of the compound according to Formula II(S), X is H, C1-C6 alkyl, or halo.
[00835] In another specific embodiment of the compound according to Formula II(S), X is H or halo.
[00836] In another specific embodiment of the compound according to Formula II(S),
X is halo. For example, the halo is Cl or Br; or Br.
[00837] In another specific embodiment of the compound according to Formula II(S),
Y is H, halo, C-C6 alkyl, C-C6 alkoxy, NRi5R16, -C(O)O-C1-C6 alkyl, -O-(CH2)n- NR15Ri6, -N(Rn)-(CHz)n-NRi5R16, -0-R2,, -0-(CH2VR21, or aryl.
[00838] In another specific embodiment of the compound according to Formula I(S),
Y is H. [00839] In another specific embodiment of the compound according to Formula II(S),
Y is halo, for example, bromo or chloro; or bromo.
[00840] In another specific embodiment of the compound according to Formula II(S),
Y is C1-C6 alkyl, for example, Cj-C3 alkyl; or methyl. [00841] In another specific embodiment of the compound according to Formula II(S), Ri is aryl or heteroaryl optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, and heteroaryl. [00842] In another specific embodiment of the compound according to Formula II(S), Ri is heteroaryl, optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, and heteroaryl.
[00843] In another specific embodiment of the compound according to Formula II(S), Ri is pyrazolyl or isoxazolyl, optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, and heteroaryl. [00844] In another specific embodiment of the compound according to Formula II(S), R2 is aryl or -C1-C6-alkyl-heteroaryl, wherein aryl or heteroaryl are optionally substituted as defined above for compounds of Formula II.
[00845] In another specific embodiment of the compound according to Formula II(S), R2 is C1-C6-alkyl-heteroaryl, optionally substituted as defined above for compounds of Formula II. In a further specific embodiment, R2 is C1-C2-isoxazolyl, optionally substituted with aryl, heterocyclyl, or C1-C6 alkyl.
[00846] In another specific embodiment of the compound according to Formula II(S), R2 is aryl, optionally substituted as defined above for compounds of Formula II. In a further specific embodiment, R2 is phenyl, optionally substituted with -O-(CH2)n- NRi5Ri6, NR13Ri4, -C0-C6 alkyl-C(O)NR15Ri6, -C0-C6 alkyl-C(O)-N(R,3)-(CH2)n- NRi5R16, N(Ri3)C(O)-C1-C6 alkyl, halo, -C, -C6 alkyl-NR,3Ri4, C1-C6 alkoxy, or heterocyclyl.
[00847] Another specific embodiment of the Src and/or BCR-AbI compounds is a compound according to Formula III(S):
Figure imgf000543_0001
1H(S) or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2;
R5 at each occurrence is independently H, C1-C6 alkyl, C3-C7 cycloalkyl, aryl, or heteroaryl;
X is H, halo, C1-C6 alkyl, NO2, mono-, di-, or tri-halo substituted methyl, NRi3R]4, C(O)O-C-C6 alkyl, or N(Rn)-C(O)-C1-C6 alkyl;
Y is H, halo, OH, C1-C6 alkyl, NRi5R16, C1-C6 alkoxy, -N(R13)-(CH2)n-NRi5Ri6s
-C(O)O-C1-C6 alkyl, -O-(CH2)n-NRI5R16, -C(O)-C1-C6 alkyl, -C0-C6-alkyl-R21, -0-R21, -C(O)-R21, -O-(CH2)n-R2i, -C(O)-NR13R14, -C(O)-N(R13)-aryl, -C(O)-
N(R13)-(CH2)n-NRI5R16, -C(O)-N(R13)-(CH2)n-aryl, -C(O)-N(R13)-(CH2)n- heterocyclyl, wherein R21 is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, NR13R14, and heterocyclyl; or X and Y together with the atoms to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing one or two heteroatoms independently selected from O, N, and S, wherein the heterocyclyl or heteroaryl group is optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, aryl-d-C6 alkyl-, aryl-(CH2)n-O-aryl-, C3-C7 cycloalkyl, heterocyclyl, -aryl-N(R13)C(O)-C3-C7 cycloalkyl-C(O)-N(R14)-aryl, and a group of the Formula -L-M-Q, wherein L is a bond or C3-C7 cycloalkyl, M is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, Q is NR13R14, N(R13)C(O)-C1-C6 alkyl, heterocyclyl, or a saturated fused bicyclic ring containing one or two heteroatoms independently selected from O, N, and S, wherein each aryl, heteroaryl, or heterocyclyl substituent on the group formed by X and
Y is optionally further substituted with one or two moieties independently selected from halo, C(O)O-(CH2)n-phenyl, and C(O)-C1-C6 alkyl; R2 is -C1-C6 alkyl, -C1-C6 alkyl-NR13RH, -C(O)-aryl, -C0-C6-alkyl-aryl, -C0-C6-alkyl- heteroaryl, -C0-C6-alkyl-(C3-C7-cycloalkyl), -C0-C6-alkyl-heterocyclyl, or -C0-C6 alkyl-5-12 membered fused bicyclic or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from N, O, and S, wherein each alkyl is optionally substituted with phenyl, and each aryl, heteroaryl, C3-C7 cycloalkyl, heterocyclyl, or 5-12 membered ring system is optionally substituted with one, two, or three groups independently selected from halo, mono-, di-, or tri-halo substituted methyl or methoxy, CN,
NO2, NR13Ri4, C(O)O-C-C6 alkyl, N(R13)C(O)-C1-C6 alkyl, -SO2NRi3Ri4, - OC(O)-NR]3R14, -C0-C6 alkyl-C(O)NRi5Ri6, C1-C6 alkoxy, C1-C6 thioalkoxy, -O-(CH2)n-NR,5R,6, -C1-C6 alkyl-NR13R14, -N(Rn)-C(O)-C1-C6 alkyl, -N(R13)- C(O)-aryl, -C0-C6 alkyl-C(O)-N(R13)-(CH2)n-NR15R16, -C0-C6 alkyl-C(O)- N(R13)-(CH2)n-aryl, -O-(CH2)n-C(O)-N(R13)-(CH2)n-NR15R16, -O-(CH2)n-C(O)-
NRi5Ri6, -C0-C6 alkyl-C(O)-N(Ri3)-(CH2)n-O-C,-C6 alkyl, -C0-C6 alkyl-N(R,3)- C(O)O-C1-C6 alkyl, -C0-C6alkyl-C(O)-heterocyclyl, -C0-C6alkyl-C(O)- heteroaryl, -C0-C6alkyl-C(O)-aryl, -C0-C6-alkyl-R2i, aryloxy, -O-(CH2)n-R2i, -SO2-heterocyclyl, N(R]3)-C(O)-C3-C7-cycloalkyl, or C1-C6 alkyl optionally substituted with halo or cyano,wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl substituent is further optionally substituted with 1 -3 groups independently selected from halo, mono-, di-, or tri-halo substituted methyl, C1- C6 alkyl, and Cj-C6 alkoxy; Ri3 and Ri4 are independently H or C1-C6 alkyl, or Ri3 and Ri4 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two of halo, Cj-C6 alkyl, or C1-C6 alkoxy; Ri5 and Rj6 are independently H, C1-C6 alkyl, heteroaryl, or heterocyclyl, or Ri5 and R]6 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, and -C(O)O-
C1-C6 alkyl; and n is 1-6. [00848] In one specific embodiment of the compound according to Formula III(S), X is H, C1-C6 alkyl, or halo.
[00849] In another specific embodiment of the compound is according to Formula
III(S), X is H or halo. [00850] In another specific embodiment of the compound according to Formula III(S), X is halo, such as Cl or Br,or Br.
[00851] In another specific embodiment of the compound according to Formula III(S), Y is H, halo, C1-C6 alkyl, C1-C6 alkoxy, NR15Ri6, -C(O)O-C1-C6 alkyl, -O-(CH2)n-
NR,5R,6, -N(R,3)-(CH2)n-NR15R,6, -O-(CH2)n-R21, -0-R21, or aryl. [00852] In another specific embodiment of the compound according to Formula III(S), Y is H.
[00853] In another specific embodiment of the compound according to Formula III(S), Y is halo;such as bromo or chloro; or bromo.
[00854] In another specific embodiment of the compound according to Formula III(S), Y is C1-C6 alkyl; such as C1-C3 alkyl; or methyl.
[00855] In another specific embodiment of the compound according to Formula III(S), R2 is aryl or -C!-C6-alkyl-heteroaryl, wherein aryl or heteroaryl are optionally substituted as defined above for compounds of Formula III(S).
[00856] In another specific embodiment of the compound according to Formula III(S), R2 is Cj-Cό-alkyl-heteroaryl, optionally substituted as defined above for compounds of Formula III(S). For example, R2 is C1-C2-isoxazolyl, optionally substituted with 1 or 2 of aryl, heterocyclyl, or C1-C6 alkyl.
[00857] In another specific embodiment of the compound according to Formula III(S), R2 is aryl, optionally substituted as defined above for compounds of Formula III(S). For example, R2 is phenyl, optionally substituted with 1 or 2 of -O-(CH2)n-
NR15Ri6, NR13R14, -C0-C6 alkyl-C(O)NR15R16, -C0-C6 alkyl-C(O)-N(R13)-(CH2)n-
NRi5Ri6, N(R13)C(O)-C1-C6 alkyl, halo, -C1-C6 alkyl-NR13Ri4, C1-C6 alkoxy, or heterocyclyl.
[00858] Another specific embodiment of the Src and/or BCR-AbI compounds, is a compound according to Formula IV(S):
Figure imgf000547_0001
IV(S) or a pharmaceutically acceptable salt thereof, wherein:
Ri is H, CN, halo, -NRnRi4, C(O)NRi3Ri4, C1-C6 alkyl, -C(O)-C1-C6 alkyl, -C0-C6 alkyl- R20, wherein R20 is aryl, heteroaryl, heterocyclyl, or a 5-12 membered fused bicyclical or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from N, O, and S, wherein aryl, heteroaryl,
C3-C7 heterocyclyl, or the 5-12 membered ring system are optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, and -C0- C6 alkyl-R2i;
X is H, halo, C1-C6 alkyl, NO2, mono-, di-, or tri-halo substituted methyl, NRj3Ri4,
C(O)O-C-C6 alkyl, or N(R,3)-C(O)-C,-C6 alkyl;
Y is H, halo, OH, C1-C6 alkyl, NRi5Ri6, C1-C6 alkoxy, -N(R,3)-(CH2)n-NRi5R,6, -
C(O)O-C1-C6 alkyl, -O-(CH2)n-NR15R16, -C(O)-C1-C6 alkyl, -C0-C6-alkyl-R21, - 0-R21, -C(O)-R2I, -O-(CH2)n-R2i, -C(O)-NRnR14, -C(O)-N(Rn)-aryl, -C(O)-
N(Rn)-(CH2)n-NR,5R,6, -C(O)-N(Rn)-(CH2)n-aryl, -C(O)-N(R13)-(CH2)n- heterocyclyl, wherein R21 is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, NRnRi4, and heterocyclyl; or X and Y together with the atoms to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing one or two heteroatoms independently selected from O, N, and S, wherein the heterocyclyl and heteroaryl group is optionally substituted with one or two moieties selected from halo, C1-C6 alkyl, aryl-C1-C6 alkyl-, aryl-(CH2)n-O-aryl-, C3-C7 cycloalkyl, heterocyclyl, - aryl-N(R13)C(O)-C3-C7 cycloalkyl-C(O)-N(R,4)-aryl, and a group of the Formula -L-M-Q, wherein L is a bond or C3-C7 cycloalkyl, M is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, Q is NRi3Ri4, N(Ri3)C(O)-C1-C6 alkyl, heterocyclyl, or a saturated fused bicyclic ring containing one or two heteroatoms independently selected from O, N, and S, wherein each aryl, heteroaryl, and heterocyclyl substituent on the group formed by X and Y is optionally further substituted with one or two moieties selected from halo, C(O)O-(CH2)n-phenyl, and C(O)-C1-C6 alkyl;
R6 at each occurrence is independently H, halo, mono-, di-, or tri-halo substituted methyl or methoxy, CN, NO2, NRnR14, C(O)O-C1-C6 alkyl, N(R13)C(O)-C1-C6 alkyl, -SO2NR13R14, -0-C(O)-NR13R14, -C0-C6 alkyl-C(O)NRi5R,6, C1-C6 alkoxy, C1- C6 thioalkoxy, -O-(CH2)n-NR15R16, -C1-C6 alkyl-NR13R14, -N(R,3)-C(O)-C,-C6 alkyl, -N(R13)-C(O)-aryl, -C0-C6 alkyl-C(O)-N(R13)-(CH2)n-NR,5R,6, -C0-C6 alkyl-C(O)-N(R13)-(CH2)n-aryl, -O-(CH2)n-C(O)-N(Ri3)-(CH2)n-NR15R16, -O- (CH2)n-C(O)-NR,5R16, -C0-C6 3^yI-C(O)-N(Rn)-(CH2)H-O-C1-C6 alkyl, -C0-C6 alkyl-N(R13)-C(O)O-C1-C6 alkyl, -C0-C6alkyl-C(O)-heterocyclyl, -C0-C6alkyl- C(O)-heteroaryl, -C0-C6alkyl-C(O)-aryl, -C0-C6-alkyl-R21, aryloxy, -0-(CH2)n- R21, -SO2-heterocyclyl, N(R)3)-C(O)-C3-C7-cycloalkyl, or C1-C6 alkyl optionally substituted with halo or cyano, wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl substituent is further optionally substituted with 1 -3 groups independently selected from halo, mono-, di-, or tri-halo substituted methyl, C1- C6 alkyl, and C1-C6 alkoxy; Ri3 and Ri4 are independently H or C1-C6 alkyl, or R]3 and R14 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two of halo, C1-C6 alkyl, or C1-C6 alkoxy;
R15 and R)6 are independently H, C1-C6 alkyl, heteroaryl, or heterocyclyl, or R!5 and Rt6 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two moieties selected from halo, C1-C6 alkyl, or -C(O)O-C1-C6 alkyl; and m is 1 or 2; and n is 1-6. In one specific embodiment of the compound according to Formula IV(S), X is
H, C1-C6 alkyl, or halo.
[00859] In another specific embodiment of the compound according to Formula
IV(S), X is H or halo. [00860] In another specific embodiment of the compound according to Formula
IV(S), X is halo. For example, the halo is Cl or Br, or Br.
[00861] In another specific embodiment of the compound according to Formula
IV(S), Y is H, halo, C1-C6 alkyl, C1-C6 alkoxy, NR15Ri6, -C(O)O-C-C6 alkyl, -O-
(CH2)n-NR15R16, -N(R13MCH2VNR15R16, -O-(CH2)n-R21, -0-R21, or aryl. [00862] In another specific embodiment of the compound according to Formula
IV(S), Y is H.
[00863] In another specific embodiment of the compound according to Formula I(S),
Y is halo; bromo or chloro; or bromo.
[00864] In another specific embodiment of the compound according to Formula IV(S), Y is C1-C6 alkyl, such as C-C3 alkyl; or methyl.
[00865] In another specific embodiment of the compound according to Formula
IV(S), Ri is aryl or heteroaryl optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, or heteroaryl.
[00866] In another specific embodiment of the compound according to Formula IV(S), Ri is heteroaryl, optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, or heteroaryl.
[00867] In another specific embodiment of the compound according to Formula
IV(S), Ri is pyrazolyl or isoxazolyl, optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, or heteroaryl. [00868] In another specific embodiment of the compound according to Formula
IV(S), m is 1 and R6 is aryl, heterocyclyl, or C1-C6 alkyl.
[00869] Another embodiment of the Src and/or BCR-AbI compounds is a compound according to Formula V(S):
Figure imgf000550_0001
V(S) or a pharmaceutically acceptable salt thereof, wherein: m is independently 1 or 2; R5 at each occurrence is independently H, C1-C6 alkyl, C3-C7 cycloalkyl, aryl, or heteroaryl; X is H, halo, Cj-C6 alkyl, NO2, mono-, di-, or tri-halo substituted methyl, NR)3Ri4, C(O)O-C1-C6 alkyl, Or N(Rn)-C(O)-C1-C6 alkyl;
Y is H, halo, OH, C1-C6 alkyl, NRi5R16, C-C6 alkoxy, -N(Ri3)-(CH2)n-NR,5Ri6, .
C(O)O-C-C6 alkyl, -O-(CH2)n-NRi5R16, -C(O)-C1-C6 alkyl, -C0-C6-alkyl-R21, - 0-R21, -C(O)-R21, -O-(CH2)n-R21, -C(O)-NR13R14, -C(O)-N(R13)-aryl, -C(O)-
N(R13)-(CH2)n-NR15R16, -C(O)-N(R13)-(CH2)n-aryl, -C(O)-N(R, 3)-(CH2)n- heterocyclyl, wherein R21 is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, NR13R14, and heterocyclyl; or X and Y together with the atoms to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing one or two heteroatoms independently selected from O, N, and S, wherein the heterocyclyl and heteroaryl group is optionally substituted with one or two moieties selected from halo, C1-C6 alkyl, aryl-d-C6 alkyl-, aryl-(CH2)n-O-aryl-, C3-C7 cycloalkyl, heterocyclyl, - aryl-N(Ri3)C(O)-C3-C7 cycloalkyl-C(O)-N(Ri4)-aryl, and a group of the Formula -L-M-Q, wherein L is a bond or C3-C7 cycloalkyl, M is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, Q is NRi3Ri4, N(R)3)C(O)-C1-C6 alkyl, heterocyclyl, or a saturated fused bicyclic ring containing one or two heteroatoms independently selected from O, N, and S, wherein each aryl, heteroaryl, or heterocyclyl substituent on the group formed by X and Y is optionally further substituted with one or two moieties selected from halo,
C(O)O-(CH2)n-phenyl, and C(O)-C1-C6 alkyl;
R6 at each occurrence is independently H, halo, mono-, di-, or tri-halo substituted methyl or methoxy, CN, NO2, NRnR14, C(O)O-C1-C6 alkyl, N(R13)C(O)-C1-C6 alkyl, -
SO2NRi3Ri4, -0-C(O)-NRi3Ri4, -C0-C6 alkyl-C(O)NRi5Ri6, C,-C6 alkoxy, C,-C6 thioalkoxy, -O-(CH2)n-NRi5Ri6, -C,-C6 alkyl-NRi3Ri4, -N(Rn)-C(O)-C1-C6 alkyl, -N(R,3)-C(O)-aryl, -C0-C6 alkyl-C(O)-N(R13)-(CH2)n-NR15R16, -C0-C6 alkyl- C(O)-N(R,3HCH2)n-aryl, -O-(CH2)n-C(O)-N(R,3)-(CH2)n-NR,5R,6, -O-(CH2)n- C(O)-NR15R16, -C0-C6 alkyl-C(O)-N(R13)-(CH2)n-O-C1-C6 alkyl, -C0-C6 alkyl-
N(Rn)-C(O)O-C1-C6 alkyl, -C0-C6alkyl-C(O)-heterocyclyl, -C0-C6alkyl-C(O)- heteroaryl, -C0-C6alkyl-C(O)-aryl, -C0-C6-alkyl-R21, aryloxy, -O-(CH2)n-R21, - SO2-heterocyclyl, N(R13)-C(O)-C3-C7-cycloalkyl, or C1-C6 alkyl optionally substituted with halo or cyano, wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with 1 -3 groups independently selected from halo, mono-, di-, or tri-halo substituted methyl, C1-C6 alkyl, and C1-C6 alkoxy;
Rn and Ri4 are independently H or C1-C6 alkyl, or Rn and R]4 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two of halo, Cj-C6 alkyl, or C1-C6 alkoxy;
Ri5 and Ri6 are independently H, C1-C6 alkyl, heteroaryl, or heterocyclyl, or Ri5 and Ri6 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O, N, and S, and wherein each heterocyclyl and heteroaryl group is optionally substituted with one or two moieties selected from halo, C1-C6 alkyl, and -C(O)O-C1-C6 alkyl; and n is 1-6. [00870] In one specific embodiment of the compound according to Formula V(S), X is H, C1-C6 alkyl, or halo.
[00871] In another specific embodiment of the compound according to Formula V(S), X is H or halo. [00872] In another specific embodiment of the compound according to Formula V(S), X is halo. For example, X is Cl or Br; or Br.
[00873] In another specific embodiment of the compound according to Formula V(S),
Y is H, halo, C1-C6 alkyl, C1-C6 alkoxy, NRi5Ri6, -C(O)O-C1-C6 alkyl, -O-(CH2)n- NR15Ri6, -N(R13HCH2)H-NR15Ri6, -O-(CH2)n-R21, -0-R2,, or aryl. [00874] In another specific embodiment of the compound according to Formula V(S),
Y is H.
[00875] In another specific embodiment of the compound according to Formula V(S),
Y is halo. For example, Y is bromo or chloro; or bromo.
[00876] In another specific embodiment of the compound according to Formula V(S), Y is C1-C6 alkyl, such as C1-C3 alkyl, or methyl.
[00877] In another specific embodiment of the compound according to Formula V(S), m is 1 and R6 is aryl, heterocyclyl, or C1-C6 alkyl.
[00878] Another specific embodiment of a compound for modulating protein kinase enzymatic activity, is a compound according to Formula 1(S)I, wherein, V is NR1R18,
R1 is -C0-C6 alkyl-R20, wherein R2o heteroaryl, wherein the heteroaryl is optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, and -C0-C6 alkyl-R21; Ria is H; X is H, or halo;
Y is H, C1-C6 alkyl, NR15R16, C0-C6 alkyl-NR15R16, -N(R13)-(CH2)n-NRI5R16, -O-(CH2)n-
NR15R16, -C0-C6-alkyl-R21, -0-R21 or -O-(CH2)n-R2l; Z is NR2R3, or -O-R2a, wherein
R2 is -C0-C6-alkyl-heteroaryl, wherein the heteroaryl is optionally substituted with one, two, or three groups independently selected from -C0-C6-alkyl-R2i or C1-C6 alkyl;
R3 is H; R2a is Co-C6 alkyl-heteroaryl, wherein the heteroaryl is optionally substituted with aryl;
Ri3 is H;
Ri5 and Ri6 are independently H, C1-C6 alkyl or heterocyclyl optionally substituted with
C1-C6 alkyl; R2i is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, -S(O)2-C0-C1 alkyl, -C(O)-C0- C1 alkyl, -C(O)-H, -C0-C1 alkyl-aryl, C-C6 alkyl Or NRnRi4; and n is 1-4. [00879] In another specific embodiment of the compound according to Formula 1(S)I, Z is NR2R3, wherein R2 is -C)-C3-alkyl-heteroaryl, wherein the heteroaryl is optionally substituted with R2] or C1-C4 alkyl. For example, the C1-C4 alkyl is methyl, propyl or isopropyl. Also specific are compounds wherein the R21 is heteroaryl or aryl wherein the heteroaryl and aryl are optionally substituted with halo or NH2; for example, fluoro.
[00880] In another specific embodiment of the compound according to Formula 1(S)I, Z is -O-R2a, wherein R2a is C1-C2 alkyl-heteroaryl, wherein the heteroaryl is optionally substituted with phenyl.
[00881] In another specific embodiment of the compound according to Formula 1(S)I, Ri is heteroaryl optionally substituted with C1-C4 alkyl or R21. For example, the C1-C4 alkyl is methyl, propyl, isopropyl. Also specific are compounds wherein R2] is C3- C4 cycloalkyl. For example, R2] is cyclopropyl.
[00882] In another specific embodiment of the compound according to Formula I(S)l, X is chloro. [00883] In another specific embodiment of the compound according to Formula 1(S)I, Y is C1-C4 alkyl, NR15Ri6, C1-C4 alkyl-NR,5Ri6, -N(H)-(CH2)2.3-NRi5R,6, -O- (CH2)2-NR,5R,6, -R2,, -O-R2i or -O-(CH2)2-R2i. For example, R15 and R!6 are independently H, C1-C4 alkyl or heterocyclyl optionally substituted with C1-C3 alkyl; such as, for example, R15 and R16 are independently methyl, ethyl, propyl, or heterocyclyl optionally substituted with methyl, ethyl or propyl. Also specific are compounds wherein R21 is heterocyclyl optionally substituted with one or two moieties independently selected from -S(O)2-C,-C3 alkyl, -C(O)-C1-C3 alkyl, -C(O)-H, C1-C2 alkyl-aryl, or C)-C4 alkyl. For example, R21 is optionally substituted with one or two moieties independently selected from -S(O)2-CH3, -C(O)-CH3, -CH2-phenyl, methyl, ethyl or propyl.
[00884] Another embodiment of a Src and/or BCR-AbI compound is a compound according to Formula VI(S):
Figure imgf000554_0001
VI(S) or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2 or 3;
R5 is C1-C6 alkyl, and -C0-C6 alkyl-R2j; X is H, or halo;
Y is -C0-C6-alkyl-R21;
R6 is -C0-C6-alkyl-R21 or C1-C6 alkyl;
R2I is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, -S(O)2-C0-C1 alkyl, -C(O)-C0-
C, alkyl, -C(O)-H, -C0-C1 alkyl-aryl, C1-C6 alkyl or NR,3RM.
[00885] In another specific embodiment of the compound according to Formula
VI(S), Y is heterocyclyl optionally substituted with C1-C3 alkyl, X is H or halo, R5 is C3-
C4 cycloalkyl and R6 is C1-C4 alkyl. For example, Y is heterocyclyl optionally substituted with methyl, ethyl, propyl or isopropyl, X is H, R5 is cyclopropyl and R6 is methyl, ethyl, propyl or isopropyl.
[00886] Representative Src and BCR-AbI compounds of Formula I(S), and pharmaceutically acceptable salts thereof, are depicted below in Table S. The compounds in Table S are merely illustrative and do not limit the scope of BCR-AbI compounds of Formula I(S).
Table S
NAME
NM~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-methyl-N~2~-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
Figure imgf000555_0001
NAME
3-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl dimethylcarbamate;
5-bromo-N~4~-(5-cyclopropyl-1 H^yrazol-3-yl)-N~2H1-phenylethyl)pyrimidine-2,4- diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-{4-[2-(4-^ oxoethyl]phenyl}pyrimidine-2,4-diamine;
3-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[2- (diethylamino)ethyl]benzamide;
4-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[2- (diethylamino)ethyl]benzamide;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-(2-pyrrolidin-1-ylethyl)propanamide;
NM~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~6~-[3-(diethylamino)propyl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
NM~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-(4-methylpiperazin-1-yl)-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(2- piperidin-1-ylethyl)propanamide;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~6~-[2-(diethylamino)ethyl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-morpholin-4-yl-N~2~-[(3-phenylisoxa yl)methyl]pyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(2- pyrrolidin-1-ylethyl)propanamide;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-(3-pyrrolidin-1-ylpropyl)propanamide;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-(3-piperidin-1-ylpropyl)propanamide;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-[2-(diethylamino)ethyl]propanamide;
N~2~-[3,5-bis(methyloxy)phenyl]-5-bromo-N~4~-(5-methylisoxazol-3-yl)pyrimidine-2,4- diamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2~-[(3- phenylisoxazol-5-yl)methyllpyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(3- piperidin-1-ylpropyl)propanamide;
N-[3-({5-bromo-4-[(5-methylisoxazol-3-yl)amino]pyrimidin-2-yl}amino)-4- chlorophenyl]acetamide;
3-[4-({5-bromo-4-[(5-methylisoxazol-3-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-[2- (diethylamino)ethyl]propanamide;
5-bromo-N~4~-(3-nnethylisoxazol-5-yl)-N~2~-(4-morpholin-4-ylphenyl)pyrimidine-2,4- diamine;
3-[4-({5-bromo-4-[(5-cyclopropyl-1 H-pyrazol-3-yl)amino]pyrimidin-2-yl}amino)phenyl]- N-methylpropanamide;
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[4- (dimethylamino)phenyl]pyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[(3R)- pyrrolidin-3-yl]benzamide;
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine;
5-chloro-N~2~-(2-chlorophenyl)-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~6~-[3- (diethylamino)propyl]pyrimidine-2,4,6-triamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-(2-morpholin-4-ylethyl)propanamide;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(3- pyrrolidin-1-ylpropyl)propanamide; NAME
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-[2- (diethylamino)ethyl]propanamide;
5-bromo-NM~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-{4-[(3-morpholin-4- ylpropyl)oxy]phenyl}pyrimidine-2,4-diamine;
5-bromo-N~2~-[4-(dimethylamino)phenyl]-N~4~-phenylpyrimidine-2,4-diamine;
5-bromo-N~2~-[(3-bromoisoxazol-5-yl)methyl]-N~4~-(3-cyclopropyl-1 H-pyrazol-5- yl)pyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)benzamide;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-[3-(1H-imidazol-1-yl)propyl]propanamide;
4-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[3- (diethylamino)propyl]benzamide;
3-[4-({5-bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}amino)phenyl]- N-[3-(diethylamino)propyl]propanamide;
NM~-(5-cyclopropyl-1 H^yrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine;
2-[4-({5-bromo-4-[(5-cyclopropyl-1 H-pyrazol-3-yl)amino]pyrimidin-2-yl}amino)phenyl]- N-[3-(diethylamino)propyl]acetamide;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(6-morpholin-4-ylpyridin-3- yl)pyrimidine-2,4-diamine;
N~2~-[(3-cyclohexylisoxazol-5-yl)methyl]-NM~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6- methylpyrimidine-2,4-diamine;
5-bromo-N~2~-(2-bromophenyl)-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)pyrimidine-2,4- diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-{2- [(trifluoromethyl)oxy]phenyl}pyrimidine-2,4-diamine;
5-bromo-N~4—(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{4-[3-(4-methylpiperazin-1-yl)-3- oxopropyl]phenyl}pyrimidine-2,4-diamine;
5-bromo-N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-(2-methylphenyl)pyrimidine-2,4- diamine;
N~2~-(4-aminophenyl)-5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)pyrimidine-2,4- diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[4-(methyloxy)phenyl]pyrimidine- 2,4-diamine;
3-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[(3S)- pyrrolidin-3-yl]benzamide;
5-bromo-N~4~-(3-methyl-1 H-pyrazol-5-yl)-N~2~-phenylpyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2- yl}amino)benzenesulfonamide;
1 ,1-dimethylethyl {[4-({5-bromo-4-[(5-cyclopropyl-1 H-pyrazol-3-yl)amino]pyrimidin-2- yl}amino)phenyl]methyl}carbamate;
S-^δ-bromo^-^S-cyclopropyl-I H-pyrazol-δ-yOaminolpyrimidin^-ylJamino)^- chlorobenzamide;
5-bromo-N~2~-(2-chlorophenyl)-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)pyrimidine-2,4- diamine;
5-bromo-N~2~-[2-chloro-5-(methyloxy)phenyl]-N~4~-(3-cyclopropyl-1 H-pyrazol-5- yl)pyrimidine-2,4-diamine;
3-[3-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]- N-(1-methylethyl)propanamide;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-{3-[3-(4-methylpiperazin-1-yl)-3- oxopropyl]phenyl}pyrimidine-2,4-diamine;
5-chloro-N~2~-(2-chlorophenyl)-N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)pyrimidine-2,4- diamine; NAME
5-bromo-N~4— (3-cyclopropyl-1H-pyrazol-5-yl)-N~2— [2-(methyloxy)phenyl]pyrimidine- 2,4-diamine;
2-[4-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]- N-methylacetamide;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(2,3-dihydro-1 ,4-benzodioxin-6- yl)pyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(2- morpholin-4-yletnyl)propanamide;
S-K-^-^S-cyclopropyl-1 H-pyrazol-S-yOaminoJpyrimidin^-ylJaminoJphenylJ-N-IS-tiH- imidazol-1-yl)propyl]propanamide;
S-IS-^S-bromo^-^S-cyclopropyl-I H-pyrazol-δ-yOaminolpyrimidin^-ylJaminoJphenyl]- N-[3-(diethylamino)propyl]propanamide;
5-bromo-N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2—[(1S)-1-phenylethyl]pyrimidine- 2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-(3-morpholin-4-ylpropyl)propanamide;
N~6— (5-cyclopropyl-1 H-pyrazol-3-yl)-NM~,N~4~-dimethyl-N~2~-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4,6-triamine;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N,N-dimethylpropanamide;
5-bromo-N~4~-(2-chlorophenyl)-N~2~-(3-cyclopropyl-1 H-pyrazol-5-yl)pyrimidine-2,4- diamine;
2-[4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]- N-(1-methylethyl)acetamide;
5-bromo-N~4~-[5-(1 , 1 -dimethylethyl)-1 H-pyrazol-3-yl]-N~2~-phenylpyrimidine-2,4- diamine;
4-({5-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}amino)benzonitrile;
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-(2-methylpropyl)pyrimidine-2,4- diamine;
N~2~-[2,5-bis(methyloxy)phenyl]-5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5- yl)pyrimidine-2,4-diamine;
5-bromo-N,N'-diphenylpyrimidine-2,4-diamine;
5-bromo-N~2~-(2-bromo-4-fluorophenyl)-N~4~-(3-cyclopropyl-1 H-pyrazol-5- yl)pyrimidine-2,4-diamine;
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-phenylpyrimidine-2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[3-(methyloxy)phenyl]pyrimidine- 2,4-diamine;
5-bromo-N-4—(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}pyrimidine-2,4-diamine;
3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[3- (diethylamino)propyl]benzamide;
3-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)aπnino]pyπmidin-2-yl}amino)benzamide;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-{3-[(4-methylpiperazin-1- yl)carbonyl]phenyl}pyrimidine-2,4-diamine;
5-bromo-N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-naphthalen-1-ylpyrimidine-2,4- diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[2-(methylthio)phenyl]pyrimidine- 2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N-2~-1H-indol-5-ylpyrimidine-2,4- diamine;
5-bromo-N,N'-bis(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine; NAME
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(2-methyl-1 ,3-thiazol-5- yl)methyl]pyrimidine-2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-(2,3-dichlorophenyl)pyrimidine- 2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2— (furan-2-ylmethyl)pyrinnidine-2,4- diamine;
N~2~-(2-chlorophenyl)-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-5-methylpyrimidine-2,4- diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[4-(morpholin-4- ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
1 ,1-dimethylethyl (3S)-3-({[3-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5- yl)amino]pyrimidin-2-yl}amino)phenyl]carbonyl}amino)pyrrolidine-1 -carboxylate;
5-bromo-N~4~-(3-cyclopropyM H-pyrazol-5-yl)-N~2~-[(5-methylfuran-2- yl)methyl]pyrimidine-2,4-diamine;
5-bromo-N~2~-(4-bromo-2-chlorophenyl)-N~4~-(5-cyclopropyl-1 H-pyrazol-3- yl)pyrimidine-2,4-diamine;
5-bromo-N~4~-(5-cyclopropyl-1 H^yrazol-3-yl)-N~2~-[2-(1 H-pyrrol-1- yl)phenyl]pyrimidine-2,4-diamine;
1 , 1 -dimethylethyl (3R)-3-({[4-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5- yl)amino]pyrimidin-2-yl}amino)phenyl]carbonyl}amino)pyrrolidine-1 -carboxylate;
3-[4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(3- morpholin-4-ylpropyl)propanamide;
5-bromo-N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-[5-methyl-2- (methyloxy)phenyl]pyrimidine-2,4-diamine; ethyl 2-[(2-chlorophenyl)amino]-6-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-5- nitropyrimidine-4-carboxylate;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-{[3- (methyloxy)phenyl]methyl}pyrimidine-2,4-diamine;
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(1S)-1-phenylpropyl]pyrimidine- 2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-(2-phenylethyl)pyrimidine-2,4- diamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-6-methylpyrimidin-2-yl}amino)phenyl]- N-[3-(4-methylpiperazin-1-yl)propyl]propanamide;
5-bromo-N~2~-[(4-chlorophenyl)methyl]-N~4~-(3-cyclopropyl-1 H-pyrazol-5- yl)pyrimidine-2,4-diamine;
N~2~-(2-chlorophenyl)-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine;
4-[(3-amino-1 H-pyrazol-5-yl)oxy]-5-bromo-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine;
4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-5-methylpyrimidin-2-yl}amino)-N-(1- methylpiperidin-4-yl)benzamide;
5-bromo-N-4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-(1-methylethyl)pyrimidine-2,4- diamine;
5-chloro-N~4—(2-chlorophenyl)-N~6~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[3- (diethylamino)propyl]pyrimidine-2,4,6-triamine;
5-bromo-N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-(pyridin-3-ylmethyl)pyrimidine- 2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-(2,4-dibromophenyl)pyrimidine- 2,4-diamine;
4-({4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-(1-methylpiperidin- 4-yl)benzamide;
5-bromo-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[2-methyl-5-(1- methylethyl)phenyl]pyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1 H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)benzonitrile;
Figure imgf000560_0001
Figure imgf000561_0001
NAME
N~4— (5-cyclopropyl-1 H-pyrazol-3-yl)-6-[(1-methylpiperidin-3-yl)oxy]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
6-{[2-(dimethylamino)ethyl]oxy}-N~4~-[5-(1-methylethyl)-1 H-pyra2ol-3-yl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2— {[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- (4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;
IM~4~-(5-cyC | OprOpy|.-| H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- morpholin-4-ylpyrimidine-2,4-diamine;
6-[(5-cyclopropyl-1 H-pyrazol-3-yl)amino]-2-{[(3-phenylisoxazol-5-yl)methyl]amino}-N- (2-pyrrolidin-1-ylethyl)pyrimidine-4-carboxamide;
NMH3-cyclopropyl-1 H-pyrazol-5-yl)-6-methyl-N~2~-[(5-phenylisoxazol-3- yl)methyl]pyrimidine-2,4-diamine;
5-bromo-N~2~-(4-morpholin^-ylphenyl)-N~4~-[4-(2-pyrrolidin-1- ylethyl)phenyl]pyrimidine-2,4-diamine;
6-methyl-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(1-methylethyl)-1 H- pyrazol-3-yl]pyrimidine-2,4-diamine;
5-bromo-N~2~-(4-morpholin-4-ylphenyl)-N~4~-[4-(2-piperidin-1- ylethyl)phenyl]pyrimidine-2,4-diamine;
6-chloro-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(1-methylethyl)-1 H- pyrazol-3-yl]pyrimidine-2,4-diamine;
N~2~-(2-amino-2,3-dihydro-1 H-inden-5-yl)-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6- methylpyrimidine-2,4-diamine;
N~2~-[4-(2-aminoethyl)phenyl]-N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6- methylpyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-methyl-N~2~-[4-(2-pyrrolidin-1- ylethyl)phenyl]pyrimidine-2,4-diamine;
N~4--(3-cyclopropyl-1 H-pyrazol-5-yl)-6-methyl-N~2~-(4-piperidin-4- ylphenyl)pyrimidine-2,4-diamine;
N~4~.(5-CyC|OprOpy|.-| H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- [(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;
N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(1-methylethyl)-1 H-pyrazol-3- yl]-N~6~-[2-(4-methylpiperazin-1-yl)ethyl]pyrimidine-2,4,6-triamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-( 1 -methylethyl)isoxazol-5-yl]methyl}- N~6~-[2-(4-methylpiperazin-1-yl)ethyllpyrimidine-2,4,6-triamine;
N~4~-[5-(1-methylethyl)-1 H-pyrazol-3-yl]-N~6~-[2-(4-methylpiperazin-1-yl)ethyl]-N~2~- [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
N-4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~6~-[2-(diethylamino)ethyl]-N~2~-{[3-(1- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4,6-triamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2~-{[3-(1- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4— [3-( 1 -methylethyl)-1 H-pyrazol-5-yl]-6-[( 1 -methylpyrrolidin-3-yl)oxy]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~.(3.CyCloprOpy|-i H-pyrazol-5-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]nnethyl}-6- [(1-methylpyrrolidin-3-yl)oxy]pyrimidine-2,4-diamine;
N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~4~-[3-(1-methylethyl)-1 H-pyrazol-5- yl]-6-[(1-methylpyrrolidin-3-yl)oxylpyrimidine-2,4-diamine;
N~4~-[2-(diethylamino)ethyl]-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N-6~-[5-(1- methylethyl)-1 H-pyrazol-3-yllpyrimidine-2,4,6-triamine;
N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(1-methylethyl)-1H-pyrazol-3- yl]-6-[(1-methylpiperidin-3-yl)oxy]pyrimidine-2,4-diamine;
6-{[2-(dimethylamino)ethyl]oxy}-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5- (1 -methylethyl)-1 H-pyrazol-3-yl]pyrimidine-2,4-diamine;
N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N-4~-[5-(1-methylethyl)-1H-pyrazol-3- yll-6-f(2-morpholin-4-ylethyl)oxyipyrimidine-2,4-diamine;
N~4— [3-(1-methylethyl)-1 H-pyrazol-5-yl]-N~2~-[(3-phenylisoxazol-5-yl)methyl]-6-[(2- piperidin-1-ylethyl)oxy]pyrimidine-2,4-diamine; NAME
N~4~-[3-(diethylamino)propyl]-N~2— {[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~6~-[5- (1-methylethyl)-1 H-pyrazol-3-yl]pyrimidine-2,4,6-triamine;
N~4~-[5-(1-methylethyl)-1 H-pyrazol-3-yl]-6-[(3S)-3-methylpiperazin-1-yl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-[5-(1-methylethyl)-1H-pyrazol-3-yl]-6-[(1-methylpiperidin-4-yl)oxy]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- [(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4-diamine;
N~2~-{[3-(1 -methylethyl)isoxazol-5-yl]methyl}-N~4~-[3-(1 -methylethyl)-1 H-pyrazol-5- yl]-6-[(2-piperidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
NM^3-cyclopropyl-1 H^yrazol-5-yl)-6-[3-(diethylamino)propyl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
NMH3-cyclopropyl-1 H^yrazol-5-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- [(2-piperidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-N~4~-[3-(1-methylethyl)-1 H-pyrazol-5- yl]-6-[(1-methylpiperidin-4-yl)oxy]pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-methyl-N~2~-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N~4— (3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[(3-methylisoxazol-5-yl)methyl]-6- morpholin-4-ylpyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[(3-methylisoxazol-5-yl)methyl]-6-(4- methylpiperazin-1-yl)pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- [(1-methylpiperidin-4-yl)oxy]pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6- morpholin-4-ylpyrimidine-2,4-diamine;
N~4~.(5-CyC|Oprθpy|.-) |-|-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N~2~-[(3-pyridin-2- ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-N~2~-[(3-pyridin-2-yliso yl)methyl]pyrimidine-2,4-diamine;
N~4~.(5-CyClopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- piperazin-1-ylpyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- [4-(methylsulfonyl)piperazin-1-yl]pyrimidine-2,4-diamine;
4-{6-[(5-cyclopropyl-1 H-pyrazol-3-yl)amino]-2-({[3-(1-methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4-yl}piperazine-1-carbaldehyde;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-methyl-N~2~-[(3-pyrazin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N~2~-[(3-methylisoxazol-5-yl)methyl]-6-(4-methylpiperazin-1-yl)-N~4~-(3-methyl-1H- pyrazol-5-yl)pyrimidine-2,4-diamine;
N~2~-[(3-methylisoxazol-5-yl)methyl]-N~4~-(3-methyl-1 H-pyrazol-5-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N~2~-[(3-pyrimidin-4- ylisoxazol-5-yl) m ethyllpyrim id i ne-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N-2~-[(3-furan-3-ylisoxazol-5-yl)methyl]-6-(4- methylpiperazin-1 -yl)pyrimidine-2,4-diamine; _^_^
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N-6~-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)- N~2~-[(3-methylisoxazol-5-yl)methyllpyrimidine-2,4,6-triamine;
N~4~.(5.CyC|oprθpy|.-1H-pyrazol-3-yl)-6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)- N~2~-[(3-methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-(5-methyl-2,5-diaza N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diaπnine;
N~4~-bicyclo[2.2.1]hept-2-yl-N-6~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-(1- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4,6-triamine;
N~4~-bicyclo[2.2.1]hept-2-yl-N-6~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine; NAME
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2— [(3-methylisoxazol-5-yl)methyl]-6-[(1 R,4R)- 5-(phenylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimicline-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- [(1 R,4R)-5-(phenylmethyl)-2,5-diazabicyclo[2,2.1]hept-2-yl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-morpholin-4-yl-N~2~-[(3-pyrimidin-4-ylisoxazol- 5-yl)methyl]pyrimidine-2,4-diamine;
NM~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2~-[(3- pyrimidin-4-ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
NM~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N~2~-{[3-(2- thienyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-6-{[2-(diethylamino)ethyl]oxy}-N~2~-{[3-(1- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1 H-pyrazol-3-yl)-N~2~-{[3-(1-methylethyl)isoxazol-5-yl]methyl}-6- [(2-pyrrolidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
N~4H5-cyclopropyl-1 H-pyrazol-3-yl)-6-{[2-(diethylamino)ethyl]oxy}-N~2~-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
NMH5-cyclopropyl-1 H^yrazol-3-yl)-N~2~-[(3-methylisoxazol-5-yl)methyl]-6-[(2- pyrrolidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
NM~-(5-cyclopropyl-1 H^yrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N~2~-{[3-(1 ,3-thiazol- 2-yl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1 H^yrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2~-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4— (3-cyclopropyl-1 H-pyrazol-5-yl)-N~2~-[(3-ethylisoxazol-5-yl)methyl]-6-(4- methylpiperazin-1-yl)pyrimidine-2,4-diamine;
NM-^S-cyclopropyl-I H-pyrazol-S-yO-N^—KS-ethylisoxazol-S-yOmethyll-δ-morpholin- 4-ylpyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2~-[(3- ethylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-6-{[2-(diethylamino)ethyl]oxy}-N~2~-[(3- ethylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine; and
N~4~-(3-cyclopropyl-1 H-pyrazol-5-yl)-N~2— [(3-ethylisoxazol-5-yl)methyl]-6-[(2- pyrrolidin-1-ylethyl)oxy]pyrimidine-2,4-diamine,
[00887] For puφoses of this application, in the above table (Table S), any compound that has "N~4~" and/or "N~2~" mean the same thing as "N4" and "N2", respectively. For example, N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}- N~2~-[(3-ethylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine is exactly the same compound as N4-(3-cyclopropyl-1H-pyrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N2- [(3-ethylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine.
Definitions for Compounds of Formula I(S), 1(S)I, II(S), 1H(S), IV(S), V(S), and VI(S)
[00888] The following definitions apply to the compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), and VI(S) described hereinabove only. These definitions are not to be considered when determining the scope and meaning of any of the other compounds described herein. To the same extent, all of the other compounds described herein that are not compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), and VI(S) are not to be considered when determining the scope of the compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), and VI(S). [00889] "Alkyl" is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively. For example, "Cg alkyl" may mean an /7-octyl, iso-octyl, cyclohexylethyl, and the like. "Lower alkyl" means an alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. "Higher alkyl" means alkyl groups containing more that eight carbon atoms. A "C0" alkyl (as in "Co-C6-alkyl") is a covalent bond. Exemplary alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. In this application, "alkyl" means an alkanyl, alkenyl, and alkynyl residues (and combinations thereof). "Alkyl" includes cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either "butyl" or "C4 alkyl" is meant to include n- butyl, .sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-ynyl groups; and for example, "propyl" or "C3 alkyl" each include n-propyl, propenyl, and isopropyl.
[00890] "Alkylene" means a 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. Examples of alkylene include ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CH3)2CH2-), and cyclohexylpropylene (-CH2CH2CII(C6H13)). [00891] "Alkylidene" means 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. [00892] "Alkylidyne" means 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.
[00893] Any of the above groups, "alkylene," "alkylidene" and "alkylidyne," when optionally substituted, may contain alkyl substitution which itself contains unsaturation. For example, 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an n- butylid-3-ynyl group with a vinyl substituent at the 2-position of said group.
[00894] "Alkoxy" or "alkoxyl" means the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons. [00895] "Substituted alkoxy" means the group -O-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy). One exemplary substituted alkoxy group is "polyalkoxy" or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH2CH2OCH3, and glycol ethers such as polyethyleneglycol and -0(CH2CH2O)xCH3, where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five. Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
[00896] "Acyl" means groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons. [00897] "α-Amino Acids" means naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available α- amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A "side chain of an α-amino acid" refers to the group found on the α-carbon of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like. [00898] "Amino" means the group -NH2. "Substituted amino," means the group
-N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino. [00899] "Aryl" means an aromatic six- to fourteen-membered carbocyclic ring, for example, benzene, naphthalene, indane, tetralin, fluorene and the like, univalent substituents. As univalent substituents, the aforementioned ring examples are named, phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl. [00900] "Arylene" means any aryl that has at least two groups attached thereto. For a more specific example, "phenylene" refers to a divalent phenyl ring group. A phenylene, thus may have more than two groups attached, but is defined by a minimum of two non- hydrogen groups attached thereto.
[00901] "Arylalkyl" means a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Both the aryl and the corresponding alkylene, alkylidene, or alkylidyne group portion of an arylalkyl group may be optionally substituted. "Lower arylalkyP'means an arylalkyl where the "alkyl" portion of the group has one to six carbons; this can also be referred to as C1-6 arylalkyl. [00902] "Exo-alkenyl" means a double bond that emanates from an annular carbon, and is not within the ring system, for example the double bond depicted in the Formula below.
Figure imgf000568_0001
[00903] In some examples, as appreciated by one of ordinary skill in the art, 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. [00904] "Fused-polycyclic" or "fused ring system" means a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, 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. [00905] "Halogen" or "halo" means fluorine, chlorine, bromine or iodine. "Haloalkyl" and "haloaryl" refer generically to alkyl and aryl groups that are substituted with one or more halogens, respectively. Thus, "dihaloaryl," "dihaloalkyl," "trihaloaryl" etc. mean an aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
[00906] "Heteroarylene" means any heteroaryl that has at least two groups attached thereto. For a more specific example, "pyridylene" means a divalent pyridyl ring group. A pyridylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto. [00907] "Heteroatom" means O, S, N, or P.
[00908] "Heterocyclyl" means a stable three- to fifteen-membered ring substituent that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclyl substituent may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl group may be optionally oxidized to various oxidation states. In a specific example, the group -S(0)o-2-, refers to - S- (sulfide), -S(O)- (sulfoxide), and -SO2- (sulfone). For convenience, 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. Thus, for a compound of the invention having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included as another compound of the invention. In addition, annular nitrogen atoms may be optionally quaternized; and the ring substituent may be partially or fully saturated or aromatic. Examples of 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl. [00909] "Heteroalicyclic" means specifically a non-aromatic heterocyclyl group. A heteroalicyclic may contain unsaturation, but is not aromatic.
[00910] "Heteroaryl" means specifically an aromatic heterocyclyl group. [00911] "Heterocyclylalkyl" means a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include (4-methylpiperazin-1-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. Both the heterocyclyl and the corresponding alkylene, alkylidene, or alkylidyne portion of a heterocyclylalkyl group may be optionally substituted. "Lower heterocyclylalkyl" refers to a heterocyclylalkyl where the "alkyl" portion of the group has one to six carbons. "Heteroalicyclylalkyl" means specifically a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and "heteroarylalkyl" means specifically a heterocyclylalkyl where the heterocyclyl portion of the group is aromatic Such terms may be described in more than one way, for example, "lower heterocyclylalkyl" and "heterocyclyl Chalky!" are equivalent terms. Additionally, for simplicity, the number of annular atoms (including heteroatoms) in a heterocycle may be denoted as "Cx-Cy" (as in "Cx-Cy-heterocyclyl" and "Cx-Cy-heteroaryl" (and the like)), where x and y are integers. So, for example, Cs-Cn-heterocyclyl refers to a 5 to 14 membered ring system having at least one heteroatom and not a ring system containing 5 to 14 annular carbon atoms. [00912] Preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, and xanthenyl. [00913] "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, for example in the term "optionally substituted arylC1.g alkyl," optional substitution may occur on both the "C1-8 alkyl" portion and the "aryl" portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups. But where a first optionally substituted group can be substituted by a second optionally substituted group, the second substituent cannot be further substituted. A list of exemplary optional substitutions is presented below in the definition of "substituted." [00914] Unless otherwise specified, the term "optionally substituted" applies to the chemical moiety immediately preceding it. For instance, if a variable group (such as R) is defined as aryl, optionally substituted alkyl, or cycloalkyl, then only the alkyl group is optionally substituted. [00915] In the case where there is a point of attachment for a monovalent substituent, such as -CH3, -NH2, or -OH, the indication of where the point of attachment is is not necessary. That is, -CH3 has the same meaning as CH3, -NH2 has the same meaning as NH2, and -OH has the same meaning as OH.
[00916] In Table S, where there appears to be an empty valence for oxygen or nitrogen for any of the compounds listed in this table, where the name of the structure requires that the empty valence is filled with hydrogen, it is assumed that the missing valence is filled with hydrogen for each of these cases.
[00917] "Saturated bridged ring system" means a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a- hexahydro-1H-indene, 7-aza-bicyclo-[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro- naphthalene are all included in the class "saturated bridged ring system.
Synthetic Procedures of Formula 1(S)I, H(S), 1H(S), IV(S), V(S), and VI(S) [00918] Compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), and VI(S) can be made by the synthetic schemes and examples described in publication WO 2005/074057, which is incorporated herein by reference in its entirety. The utility of these compounds are also described in WO 2005/074057.
[00919] Compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), and VI(S) and their pharmaceutically acceptable salts can 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.
[00920] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
[00921] In addition, the compounds of Formula I(S), I(S) 1 , II(S), III(S), IV(S), V(S), and VI(S) 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. [00922] In addition, it is intended that the protein kinase modulator 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. Pharmaceutical Composition Examples
[00923] The following are representative pharmaceutical Formulations containing a compound of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), or VI(S).
Tablet Formulation
[00924] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet, mg
Compound of Formula I(S),
1(S)I, II(S), III(S), IV(S), V(S), 400 or VI(S)
Cornstarch 50 croscarmellose sodium 25
Lactose 120
Magnesium stearate 5
Capsule Formulation
[00925] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantity per tablet, mg
Compound of Formula I(S),
1(S)1, 11(S), III(S), IV(S), V(S), 200 or VI(S) lactose, spray-dried 148
Magnesium stearate 2
Suspension Formulation
[00926] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount
Compound of Formula I(S),
1(S)I, II(S), III(S), IV(S), V(S), 1.0 g or VI(S) fumaric acid 0.5 g sodium chloride 2.O g methyl paraben 0.15 g propyl paraben 0.05 g Ingredient Amount granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.O g
Flavoring 0.035 mL
Colorings 0.5 mg
Distilled water q.s. to 100 mL
Injectable Formulation [00927] The following ingredients are mixed to form an injectable Formulation.
Ingredient Amount
Compound of Formula I(S),
1(S)IJI(S), III(S), IV(S), V(S), 1 -2 g or VI(S) sodium acetate buffer solution 0.4 M 2.0 mL
HCl (l N) or NaOH (l M) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL
[00928] All of the above ingredients, except water, are combined and heated to 60- 70° C with stirring. A sufficient quantity of water at 60° C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.
Suppository Formulation
[00929] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol®. H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Quantity per tablet, mg
Compound of Formula I(S), i(S)i, ii(S), iii(S), iv(S), V(S), 500 or VI(S)
Witepsol® H- 15 Balance
[00930] Aspect (34) 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 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a protein kinase modulator compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), or VI(S) or a pharmaceutical composition comprising a therapeutically effective amount of the protein kinase modulator compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), or VI(S), and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment.
[00931] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, R2 of Formula I(J) is
Figure imgf000575_0001
[00932] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, R2 of Formula I(J) is
Figure imgf000575_0002
wherein R28a is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl. [00933] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, R2 of Formula I(J) is
Figure imgf000575_0003
[00934] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24),
^ -R26 and aspect (34) of this invention, L of Formula I(J) is a bond, Z is R26a , R25 is hydrogen and E and D are hydrogen. [00935] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24),
^ -R26 and aspect (34) of this invention, Z of Formula I(J) is R26a , R26a is -C(O)R32, R26 is hydrogen, and R32 is selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R32 is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl and halo.
[00936] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, R2 of Formula I(J) is
Figure imgf000576_0001
[00937] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, R32 of Formula I(J) is U or -CH2-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. [00938] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, R1 ' of Formula I(J), when present, is halo or lower alkyl.
[00939] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, R35 of Formula I(J) is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl.
[00940] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, n2 of Formula I(J) is 0.
[00941] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24),
and aspect (34) of this invention, R2 of Formula I(J) is
Figure imgf000576_0002
, and wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. [00942] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, the JAK-2 compound has Formula IV(J):
Figure imgf000577_0001
wherein and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[00943] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, the JAK-2 compound has Formula V(J):
Figure imgf000577_0002
wherein R , 28 and i n R28a , 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
[00944] In another embodiments of aspect (7), aspect (9), aspect (15), aspect (24), and aspect (34) of this invention, the JAK-2 compound has Formula VI(J):
Figure imgf000577_0003
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31. [00945] In other embodiments of the methods of combining compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), or VI(S) with the JAK-2 inhibitors of Formula I(J), any of the embodiments described above for the compounds of Formula I(S), 1(S)I, U(S), III(S), IV(S), V(S), or VI(S) can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the methods of combining compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), or VI(S) with the JAK-2 inhibitors of Formula I(J), one or more of any of the compounds Table S can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the methods of combining compounds of Formula I(S), 1(S)I, II(S), III(S), IV(S), V(S), or VI(S) with the JAK-2 inhibitors of Formula I(J), one or more of any of the compounds in Table S can be combined with one or more of any of the compounds in Table I(J).
Raf COMPOUNDS
[00946] The Raf compounds inhibit, regulate and/or modulate the signal transduction of protein kinases, particularly Raf, and are expected to be useful in the treatment of hyperproliferative diseases, such as cancer, in humans. In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with any of the Raf inhibitors known in the art. The Raf compounds described below are non-limiting examples of "Raf inhibitors" that are within the scope of aspect (12) of this invention. All of the substituents for the Raf compounds described below are defined separately from all of the other compounds described herein that are not Raf compound so that every substituent in the Raf compounds that also appears in any of the other compounds described herein has a separate and distinct meaning for each of these two compounds. For instance, R1 for the JAK-2 compounds has a separate and distinct meaning from R1 for the Raf compounds.
[00947] All of the Raf compounds disclosed herein include either their free base form or their pharmaceutically acceptable salts whether it is stated in the specification that these compounds can exist as their pharmaceutically acceptable salts or not. [00948] All of the Raf compounds disclosed herein fall within the scope of aspect (27) of this invention. [00949] The Raf compound is a compound for modulating kinase activity, particularly Raf, of Formula 1(R),
Figure imgf000579_0001
1(R)
or a tautomer thereof, or a pharmaceutically acceptable salt the compound of Formula I(R) or tautomere thereof, wherein:
A is a three- to seven-membered alicyclic, a five- to six-membered ortho-arylene or a five- to six-membered ortho-heteroarylene containing between one and three heteroatoms, either of the aforementioned optionally substituted with up to four R; each R is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; optionally two of R, together with the atoms to which they are attached, form a first ring system fused with A, said first ring system substituted with zero to three of R1;
Xi, X2 and X3 are independently selected from -CR1= or -N=; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl;
Z and X are each independently selected from -C(R2)=, -N=, -N(R2)-, -S(O)0-2-, and -0-; E and Y are each independently selected from absent, -C(R2)(R2)-, -C(=0)-, -C(R2)= and -N=, but E and Y are not both absent, and E and Y are not both -N= when both Z and X are -N=; each R2 is independently selected from R3, -N(R3)(R3), -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted C3-7alicyclic, optionally substituted aryl, optionally substituted aryl C1^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1.3a.kyl; optionally two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
G is selected from -CO2R3, -C(O)R3, -C(O)N(R3)R3, -C(O)(NR3), -C(O)NR3 [C(R3)2]0. ,R3, -C(O)NR3O[C(R3)2]0.,R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -N(R3)C(O)R3, -N(R3)R3, -S(0)o-2R3, -SO2N(R3)R3, optionally substituted aryl C0-3alkyl, and optionally substituted heterocyclyl C0-3alkyl; with the proviso, however, that the compound is not CAS Registry No. 439096-29-4,
439107-32-1 or 439107-34-3.
[00950] In one embodiment(IR-A), the Raf compound is a compound of Formula I(R) wherein A is a six-membered ortho-arylene.
[00951] In another embodiment (IR-B), the Raf compound of (IR-A) is a compound of Formula I(R) wherein A is ortho-phenylene.
[00952] In another embodiment (IR-C), the Raf compound is according to embodiment (IR-B), wherein G is -C(O)R3, -C(O)N(R3)R3, -C(O)(NR3), - C(O)NR3[C(R3)2]0-,R3, -C(O)NR3O[C(R3)2]0-1R3.
[00953] In another embodiment (IR-D), the Raf compound is according to embodiment (IR-C), wherein G is -C(O)N(R3)R3.
[00954] In another embodiment (IR-E), the Raf compound is according to embodiment (IR-D), wherein G is -C(O)NHR3. [00955] In another embodiment (IR-F), the Raf compound is according to embodiment (IR-E), wherein R3 is optionally substituted Chalky!. [00956] In another embodiment (IR-G), the Raf compound is according to embodiment (IR-E), wherein R3 is optionally substituted aryl.
[00957] In another embodiment (IR-H), the Raf compound is according to embodiment (IR-E), wherein R is optionally substituted aryl C1-3alkyl.
[00958] In another embodiment (IR-J), the Raf compound is according to embodiment (IR-E), wherein R3 is optionally substituted heterocyclyl.
[00959] In another embodiment (IR-K), the Raf compound is according to embodiment (IR-E), wherein R3 is optionally substituted heterocyclyl C1-3alkyl.
[00960] In another embodiment (IR-L), the Raf compound is according to embodiment (IR-E), wherein Xi, X2 and X3 are -CR1=.
[00961] In another embodiment (IR-M), the Raf compound is according to embodiment (IR-L), wherein E is absent.
[00962] In another embodiment (IR-N), the Raf compound is according to embodiment (IR-M), wherein Z is -N=; Y is -C(R2)=; and X is selected from -N(R2)-,
-S-, and -O-.
[00963] In another embodiment (IR-O), the Raf compound is according to embodiment (IR-E), wherein it is recognized that the Raf compound includes tautomeric interconversions of each compound.
[00964] In another embodiment (IR-P), the Raf compound is a compound according to Formula I(R), wherein it is recognized that the Raf compound includes tautomeric interconversions of each compound according to the following Formula I(R)a, wherein
R3, A, Xi, X2, X3, Z, E, Y and X are as defined above according to Formula I(R), or embodiment (IR-A), (IR-B), (IR-C), (IR-D), (IR-E), (IR-F), (IR-G), (IR-H), (IR-J),
(IR-K), (IR-L), (IR-M), (IR-N), or (IR-O),
Figure imgf000581_0001
I(R)a [00965] In another embodiment (IR-Q), the Raf compound is according to Formula
I(R), wherein the compound is a pharmaceutically acceptable salt.
[00966] In another embodiment (IR-S), the Raf compound is according to Formula
1(R), wherein the compound is a prodrug.
[00967] In another embodiment, the Raf compounds are according to of Formula ii(R),
Figure imgf000582_0001
ii(R)
or a pharmaceutically acceptable salt thereof, wherein:
A is either a five- to six-membered ortho-arylene or a five- to six-membered ortho- heteroarylene containing between one and three heteroatoms, either of the aforementioned optionally substituted with up to four R; each R is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl
Figure imgf000582_0002
optionally substituted heterocyclyl, and optionally substituted heterocyclyl C].6alkyl; optionally two of R, together with the atoms to which they are attached, form a first ring system fused with A, said first ring system substituted with zero to three of R1; n is zero to three; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl;
Z and X are each independently selected from -C(R2)=, -N=, -N(R2)-, -S(O)0-2-, and -O-;
E and Y are each independently selected from absent, -C(R2)(R2)-, -C(=O)-, -C(R2)= and -N=, but E and Y are not both absent, and E and Y are not both -N= when both Z and X are -N=; each R2 is independently selected from R3, -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl
Figure imgf000583_0001
optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-3alkyl; optionally two of R , when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
G is selected from -C(O)R3, -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -N(R3)C(O)R3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, optionally substituted aryl d.3alkyl, and optionally substituted heterocyclyl C1^alkyl; with the proviso, however, that the compound is not CAS Registry No. 439096-29-4, 439107-32- 1 or 439107-34-3.
[00968] In another embodiment (IIR-A), the Raf compound is according to Formula II(R), wherein E is absent.
[00969] In another embodiment (HR-B), the Raf compound is according to embodiment (IR-A), wherein A is ortho-phenylene.
[00970] In an example of embodiment (HR-B), the Raf compound is of Formula III(R):
Figure imgf000584_0001
HI(R) or a pharmaceutically acceptable salt thereof, wherein Z, Y, and X are as defined in any of the Raf compound embodiments described above; G is selected from -C(O)R3, -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -N(R3)C(O)R3, -N(R3)R3, -SO2N(R3)R3, optionally substituted aryl
Figure imgf000584_0002
and optionally substituted heterocyclyl C1-3alkyl; R is selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -SR3, -CO2R3, and optionally substituted C^aHcyl; and R1 is selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted Chalky., optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl.
[00971] In another embodiment (IIIR-A), the Raf compound is according to Formula III(R), wherein Z is -N=; Y is -C(R2)=; and X is selected from -N(R2)-, -S-, and -O-. [00972] In another embodiment (1HR-B), the Raf compound is according to embodiment (IIIR-A), wherein R and R1 are -H.
[00973] In another example of embodiment (1HR-B), the Raf compound is a Raf compound of Formula IV(R)a or IV(R)b:
Figure imgf000584_0003
or a pharmaceutically acceptable salt thereof, wherein G is selected from -C(O)R3, -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -N(R3)C(O)R3, -N(R3)R3,
-SO2N(R3)R3, optionally substituted aryl C1-3alkyl, and optionally substituted heterocyclyl C1-3alkyl; wherein R3 is as defined above; R2 is either -H or optionally substituted it being understood that when R2 is -H and all other groups are the same, IVa and IVb represent tautomers of a single molecule; R3a is either -H or optionally substituted
Figure imgf000585_0001
R3b is selected from optionally substituted C]-6alkyl, optionally substituted aryl, optionally substituted aryl C1-3alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C]-3alkyl. [00974] In another embodiment (IVR-A), the Raf compound is a compound of Formula IV(R)a or IV(R)b wherein R3a is -H.
[00975] In another embodiment (IVR-B), the Raf compound is according to embodiment (HR-A), wherein R2 is -H.
[00976] In another embodiment (IVR-C), the Raf compound is according to embodiment (HR-B), wherein G is selected from -C(O)R3, -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3.
[00977] In another example of embodiment (IVR-C), the Raf compound is according to Formula V(R):
Figure imgf000585_0002
or a pharmaceutically acceptable salt thereof, wherein W is R3 or -N(R3)R3; and R3b is selected from optionally substituted Chalky., optionally substituted aryl, and optionally substituted aryl C]-3alkyl.
[00978] In another embodiment (VR-A), the Raf compound is a compound of
Formula V(R), wherein W is -N(H)R3.
[00979] In another embodiment (VR-B), the Raf compound is according to embodiment (VR-A), wherein R3 is optionally substituted aryl. [00980] In another embodiment (VR-C), the Raf compound is according to embodiment (VR-B), wherein R3b is optionally substituted
Figure imgf000586_0001
[00981] In another embodiment (VR-D), the Raf compound is according to embodiment (VR-C), wherein R3b is C1-6alkyl.
[00982] In another embodiment (IIR-C), the Raf compound is a Raf compound of
Formula II(R), wherein the compound is a pharmaceutically acceptable salt.
[00983] In another embodiment (IIR-D), the Raf compound is a Raf compound of
Formula II(R), wherein the compound is a prodrug.
[00984] In another embodiment, the Raf compound is a compound of Formula VI(R),
Figure imgf000586_0002
VI(R) or a pharmaceutically acceptable salt thereof, wherein:
each R5 and R6 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl;
m is 1 or 2 dependent upon the presence or absence of saturation of the carbon bond between R5 and R6; Xi, X2 and X3 are independently selected from -CR1= or -N=; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C|-6alkyl, optionally substituted aryl, optionally substituted aryl C|-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; Z and X are each independently selected from -C(R2)=, -N=, -N(R2)-, -S(O)0-2-, and -0-;
E and Y are each independently selected from absent, -C(R2)(R2)-, -C(=0)-, -C(R2)= and -N=, but E and Y are not both absent, and E and Y are not both -N= when both Z and X are -N=; each R2 is independently selected from R3, -N(R3)(R3), -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted C3-7alicyclic, optionally substituted aryl, optionally substituted aryl C1.3a.kyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-3alkyl; optionally two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
G is selected from -CO2R3, -C(O)R3, -C(O)N(R3)R3, -C(O)(NR3), -C(O)NR3 [C(R3)2]0- ,R3, -C(O)NR3O[C(R3)2]0-iR3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -N(R3)C(O)R3,
-N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, optionally substituted aryl C0-3alkyl, and optionally substituted heterocyclyl Co^alkyl.
[00985] In one embodiment (VIR-A), the Raf compound is a compound according to
Formula VI(R), wherein R4 is -OH. [00986] In another embodiment (VIR-B), the Raf compound is according to embodiment (VIR-A), wherein G is -C(O)R3, -C(O)N(R3)R3, -C(O)(NR3), -
C(O)NR3 [C(R3)2]o-iR3, -C(O)NR3O[C(R3)2]0-1R3.
[00987] In another embodiment (VIR-C), the Raf compound is according to embodiment (VIR-B), wherein G is -C(O)N(R3)R3. [00988] In another embodiment (VIR-D), the Raf compound is according to embodiment (VIR-C), wherein G is -C(O)NHR3.
[00989] In another embodiment (VIR-E), the Raf compound is a compound of
Formula VI(R), wherein R3 is optionally substituted C1-6alkyl.
[00990] In another embodiment (VIR-F), the Raf compound is a compound of Formula VI(R), wherein R3 is optionally substituted aryl. [00991] In another embodiment (VIR-G), the Raf compound is a compound of
Formula VI(R), wherein R3 is optionally substituted aryl C1-3alkyl.
[00992] In another embodiment (VIR-H), the Raf compound is a compound of
Formula VI(R), wherein R3 is optionally substituted heterocyclyl. [00993] In another embodiment (VIR-J), the Raf compound is a compound of
Formula VI(R), wherein R3 is optionally substituted heterocyclyl C1-3alkyl.
[00994] In another embodiment (VIR-K), the Raf compound is a compound of
Formula VI(R), wherein Xi, X2 and X3 are -CR1=.
[00995] In another embodiment (VIR-L), the Raf compound is according to embodiment (VIR-K), wherein E is absent.
[00996] In another embodiment (VIR-M), the Raf compound is according to embodiment (VIR-L), wherein Z is -N=; Y is -C(R2)=; and X is selected from -N(R2)-,
-S-, and -O-.
[00997] In another embodiment (VIR-N), the Raf compound is according to embodiment (VIR-M), wherein R5 and R6 are optionally substituted C1-6alkyl.
[00998] In another embodiment (VIR-O), the Raf compound is according to embodiment (VIR-N), wherein m is 1.
[00999] In another embodiment (VIR-P), the Raf compound is a compound of
Formula VI(R), wherein the compound is a pharmaceutically acceptable salt. [001000] In another embodiment (VIR-Q), the Raf compound is a compound of
Formula VI(R),, wherein the compound is a prodrug.
[001001] In another embodiment, the Raf compound is a compound of Formula
VII(R),
Figure imgf000588_0001
VII(R)
or a pharmaceutically acceptable salt thereof, wherein: A is a three- to seven-membered alicyclic, a five- to six-membered ortho-arylene or a five- to six-membered ortho-heteroarylene containing between one and three heteroatoms, either of the aforementioned optionally substituted with up to four R; each R is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C)-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl
Figure imgf000589_0001
optionally two of R, together with the atoms to which they are attached, form a first ring system fused with A, said first ring system substituted with zero to three of R1;
Xi, X2 and X3 are independently selected from -CR1= or -N=; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl;
Z and X are each independently selected from -C(R2)=, -N=, -N(R2)-, -S(O)0-2-, and -0-;
E and Y are each independently selected from absent, -C(R2)(R2)-, -C(=0)-, -C(R2)= and -N=, but E and Y are not both absent, and E and Y are not both -N= when both Z and X are -N=; each R2 is independently selected from R3, -N(R3)(R3), -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted C3-7alicyclic, optionally substituted aryl, optionally substituted aryl C1-3alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-3alkyl; optionally two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and R4 is selected from -H, -OH, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy; with the proviso, however, that the compound is not CAS Registry No. 439096-29-4, 439107-32-1 or 439107-34-3. [001002] In one embodiment (VIIR-A), the Raf compound is a compound of Formula VII(R), wherein A is a six-membered ortho-arylene.
[001003] In another embodiment (VIIR-B), the Raf compound is according to embodiment (VIIR-A), , wherein A is ortho-phenylene.
[001004] In another embodiment (VIIR-C), the Raf compound is according to embodiment (VIIR-B), wherein R4 is -OH.
[001005] In another embodiment (VIIR-D), the Raf compound is a compound of Formula VII(R), wherein R3 is optionally substituted C1-6alkyl.
[001006] In another embodiment (VIIR-E), the Raf compound is a compound of Formula VII(R), wherein R3 is optionally substituted aryl. [001007] In another embodiment (VIIR-F), the Raf compound is a compound of Formula VII(R), wherein R3 is optionally substituted aryl C1-3alkyl.
[001008] In another embodiment (VIIR-G), the Raf compound is a compound of Formula VII(R), wherein R3 is optionally substituted heterocyclyl.
[001009] In another embodiment (VIIR-H), the Raf compound is a compound of Formula VII(R), wherein R3 is optionally substituted heterocyclyl C1-3alkyl.
[001010] In another embodiment (VIIR-J), the Raf compound is according to embodiment (VIIR-H), wherein Xi, X2 and X3 are -CR1=.
[001011] In another embodiment (VIIR-K), the Raf compound is according to embodiment (VIIR-J), wherein E is absent. [001012] In another embodiment (VIIR-L), the Raf compound is according to embodiment (VIIR-K), wherein Z is -N=; Y is -C(R2)=; and X is selected from -N(R2)-, -S-, and -O-.
[001013] In another embodiment (VIIR-M), the Raf compound is a compound of Formula VII(R), wherein the compound is a pharmaceutically acceptable salt. [001014] In another embodiment (VIIR-N), the Raf compound is a compound of
Formula VII(R), wherein the compound is a prodrug.
[001015] In another embodiment, the Raf compound is a compound of Formula
VIII(R):
Figure imgf000591_0001
VIII(R)
or a pharmaceutically acceptable salt thereof, wherein:
A is either a five- to six-membered ortho-arylene or a five- to six-membered ortho- heteroarylene containing between one and three heteroatoms, either of the aforementioned optionally substituted with up to four R; each R is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C,-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; optionally two of R, together with the atoms to which they are attached, form a first ring system fused with A, said first ring system substituted with zero to three of R1; n is zero to three; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl
Figure imgf000591_0002
Z and X are each independently selected from -C(R2)=, -N=, -N(R2)-, -S(O)0-2-, and -O-; E and Y are each independently selected from absent, -C(R2)(R2)-, -C(=0)-, -C(R2)= and -N=, but E and Y are not both absent, and E and Y are not both -N= when both Z and X are -N=; each R2 is independently selected from R3, -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1.3a.kyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C].3alkyl; optionally two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
R4 is selected from -H, -OH, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy; with the proviso, however, that the compound is not CAS Registry No. 439096-29-4,
439107-32-1 or 439107-34-3.
[001016] In another embodiment (VIIIR-A), the Raf compound is a compound of
Formula VIII(R), wherein E is absent.
[001017] In another embodiment (VIIIR-B), the Raf compound is according to embodiment (VIIIR-A), wherein A is ortho-phenylene.
[001018] In another example of embodiment (VIII-B), the Raf compound is a compound of Formula IX(R):
Figure imgf000592_0001
IX(R) or a pharmaceutically acceptable salt thereof, wherein A, n, R, R1, R2, R3, R4, Z, Y, and X are as defined in any of the embodiments of the Raf compounds above. [001019] In another embodiment (IXR-A), the Raf compound is a compound of Formula IX(R), wherein Z is -N=; Y is -C(R2)=; and X is selected from -N(R2)-, -S-, and -O-.
[001020] In another embodiment (IXR-B), the Raf compound is according to embodiment (IXR-A), wherein R and R1 are -H.
[001021] In another example of embodiment (IXR-B), the Raf compound is a compound of Formula X(R)a or X(R)b:
Figure imgf000593_0001
or a pharmaceutically acceptable salt thereof, wherein:
A, R3 and R4 are as defined in any of the embodiments of the Raf compounds above; R2 is either -H or optionally substituted C1-6alkyl (it being understood that when R2 is -H and all other groups are the same, Xa and Xb represent tautomers of a single molecule);
R3a is either -H or optionally substituted C1-6alkyl; R3b is selected from optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-3alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-3alkyl.
[001022] In another embodiment (XR-A), the Raf compound is a compound of
Formula X(R)a or X(R)b, wherein R3a is -H.
[001023] In another embodiment (XR-B), the Raf compound is according to embodiment (XR-A), wherein R2 is -H.
[001024] In another embodiment (XR-C), the Raf compound is according to embodiment (XR-B), wherein R3 is optionally substituted aryl.
[001025] In another example of embodiment (XR-C), the Raf compound is a compound of Formula XI(R):
Figure imgf000593_0002
XI(R) or a pharmaceutically acceptable salt thereof, wherein:
R3 is as defined in any of the embodimets of the Raf compounds described above; and R3b is selected from optionally substituted C1-6alkyl, optionally substituted aryl, and optionally substituted aryl C1oalkyl.
[001026] In another embodiment (XIR-A), the Raf compound is a compound of
Formula XI(R), wherein R3 is disubstituted aryl.
[001027] In another embodiment (XIR-B), the Raf compound is according to embodiment (XIR-A), wherein R3 is aryl disubstituted with alkyl and halogen. [001028] In another embodiment (VIIIR-C), the Raf compound is a compound of
Formula VIII(R), wherein the compound is a pharmaceutically acceptable salt.
[001029] In another embodiment (VIIIR-D), the Raf compound is a compound of
Formula VIII(R), wherein the compound is a prodrug.
[001030] In another embodiment, the Raf compound is a compound of Formula XII(R):
Figure imgf000594_0001
or a pharmaceutically acceptable salt thereof, wherein: each R5 and R6 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C].6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; m is 1 or 2 dependent upon the presence or absence of saturation of the carbon bond between R5 and R6;
Xi, X2 and X3 are independently selected from -CR1= or -N=; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C,.6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Chalky.;
Z and X are each independently selected from -C(R2)=, -N=, -N(R2)-, -S(O)0-2-, and -0-;
E and Y are each independently selected from absent, -C(R2)(R2)-, -C(=O)-, -C(R2)= and -N=, but E and Y are not both absent, and E and Y are not both -N= when both Z and X are -N=; each R2 is independently selected from R3, -N(R3)(R3), -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted C3-7alicyclic, optionally substituted aryl, optionally substituted aryl C1-3alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1^alkyl; optionally two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
R4 is selected from -H, -OH, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy.
[001031] In another embodiment (XIIR-A), the Raf compound is a compound of Formula XII(R), wherein R4 is -OH.
[001032] In another embodiment (XIIR-B), the Raf compound is according to embodiment (XIIR-A), wherein G is -C(O)R3, -C(O)N(R3)R3, -C(O)(NR3), - C(O)NR3[C(R3)2]0-,R3, -C(O)NR3O[C(R3)2]0-1R3.
[001033] In another embodiment (XIIR-C), the Raf compound is according to embodiment (XIIR-B), wherein G is -C(O)N(R3)R3.
[001034] In another embodiment (XIIR-D), the Raf compound is according to embodiment (XIIR-C), wherein G is -C(O)NHR3. [001035] In another embodiment (XIIR-E), the Raf compound is a compound of Formula XII(R), wherein R3 is optionally substituted C1-6alkyl.
[001036] In another embodiment (XIIR-F), the Raf compound is a compound of Formula XII(R), wherein R3 is optionally substituted aryl. [001037] In another embodiment (XIIR-G), the Raf compound is a compound of Formula XII(R), wherein R3 is optionally substituted aryl C1^alkyL
[001038] In another embodiment (XIIR-H), the Raf compound is a compound of Formula XII(R), wherein R3 is optionally substituted heterocyclyl.
[001039] In another embodiment (XIIR-J), the Raf compound is a compound of Formula XII(R), wherein R3 is optionally substituted heterocyclyl C1-3alkyl.
[001040] In another embodiment (XIIR-K), the Raf compound is a compound of Formula XII(R), wherein X1, X2 and X3 are -CR1=.
[001041] In another embodiment (XIIR-L), the Raf compound is according to embodiment (XIIR-K) [00111], wherein E is absent. [001042] In another embodiment (XIIR-M), the Raf compound is according to embodiment (XIIR-L), wherein Z is -N=; Y is -C(R2)=; and X is selected from -N(R2)-, -S-, and -O-.
[001043] In another embodiment (XIIR-N), the Raf compound is according to embodiment (XIIR-M) wherein R5 and R6 are optionally substituted C1-6alkyl. [001044] In another embodiment (XIIR-O), the Raf compound is according to embodiment (XIIR-N) wherein m is 1.
[001045] In another embodiment (XIIR-P), the Raf compound is a compound of Formula XII(R), wherein the compound is a pharmaceutically acceptable salt.
[001046] In another embodiment (XIIR-Q), the Raf compound is a compound of Formula XII(R), wherein the compound is a prodrug.
[001047] In another embodiment, the Raf compound is a compound of Formula XIII(R):
Figure imgf000597_0001
XIII(R)
or a pharmaceutically acceptable salt thereof, wherein:
A is either a five- to six-membered ortho-arylene or a five- to six-membered ortho- heteroarylene containing between one and three heteroatoms, either of the aforementioned optionally substituted with up to four R; each R is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C^aHcyl; optionally two of R, together with the atoms to which they are attached, form a first ring system fused with A, said first ring system substituted with zero to three of R1; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-3alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C].3alkyl; optionally two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and R4 is selected from -H, -OH, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy; with the proviso, however, that the compound is not CAS Registry No. 439096-29-4, 439107-32-1 or 439107-34-3. [001048] In another embodiment (XIIIR-A), the Raf compound is a compound of Formula XIII(R), wherein A is ortho-phenylene.
[001049] In another embodiment (XIIIR-B), the Raf compound is according to embodiment (XIIIR-A), wherein R4 is -OH.
[001050] In another embodiment (XIIIR-C), the Raf compound is according to embodiment (XIIIR-B), wherein R3 is optionally substituted aryl.
[001051] In another embodiment (XIIIR-D), the Raf compound is according to embodiment (XIIIR-C), wherein R3 is mono- or di-substituted phenyl.
[001052] In another embodiment (XIIIR-E), the Raf compound is according to embodiment (XIIIR-B), wherein R3 is optionally substituted aryl C1-3alkyl. [001053] In another embodiment (XIIIR-F), the Raf compound is according to embodiment (XIIIR-B), wherein R3 is optionally substituted heterocyclyl.
[001054] In another embodiment (XIIIR-G), the Raf compound is according to embodiment (XIIIR-B), wherein R3 is optionally substituted heterocyclyl C1-3alkyl.
[001055] In another embodiment (XIIIR-H), the Raf compound is a compound of Formula XIII(R), wherein the compound is a pharmaceutically acceptable salt.
[001056] In another embodiment (XIIIR-J), the Raf compound is a compound of Formula XIII(R), wherein the compound is a prodrug.
[001057] Representative Raf compounds of Formula I(R), II(R), III(R), IV(R)a, IV(R)b, V(R), VI(R), VII(R), VIII(R), IX(R), X(R)a, X(R)b, XI(R), XII(R), or XIII(R), or pharmaceutically acceptable salts thereof, are depicted below in Table R. These compound in Table R are merely illustrative and do not limit the scope of the Raf compounds or Raf inhibitors in any way.
Table R
No. Name
1 6-(2-butyl- 1 -hydroxy-3-oxo-2,3-dihydro- 1H-isoindol- 1 -yl)- 2H- 1 ,4-benzoxazin-3(4H)-one
Figure imgf000599_0001
Figure imgf000600_0001
Figure imgf000601_0001
Figure imgf000602_0001
Figure imgf000603_0001
Figure imgf000604_0001
Figure imgf000605_0001
Figure imgf000606_0001
Figure imgf000607_0001
Figure imgf000608_0001
Figure imgf000609_0001
Figure imgf000610_0001
Figure imgf000611_0001
Figure imgf000612_0001
Figure imgf000613_0001
Figure imgf000614_0001
Figure imgf000615_0001
Figure imgf000616_0001
Figure imgf000617_0001
Figure imgf000618_0001
Figure imgf000619_0001
Figure imgf000620_0001
Figure imgf000621_0001
No. Name methyl {6-[(2-{[(2-fluoro-5-
419 methylphenyl)amino]carbonyl } phenyl)carbonyl] - 1 H- benzimidazol-2-yl}carbamate
Raf Compound Definitions
[001058] The following definitions apply to the Raf compounds described above only. These definitions are not to be considered when determining the scope and meaning of the JAK-2 compounds. To the same extent, the JAK-2 definitions are not to be considered when determining the scope and meaning of the Raf compounds. [001059] Chemical Formulae use descriptors such as "R1" accompanied by a list of Formulae or verbage describing the scope of what is meant by the descriptor. A subsequent descriptor such as "Rla" is used to describe some subset of the scope of R1, and "Rlb" is used to describe another subset of the scope of R1, and so on. In such subsequent cases, all other Formulae containing simply "R1" are meant to include the entire scope of the descriptor.
[001060] "Alkyl" is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively. For example, "C8 alkyl" may refer to an tt-octyl, /sø-octyl, cyclohexylethyl, and the like. Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. Higher alkyl refers to alkyl groups containing more that eight carbon atoms. Exemplary alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus, when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either "butyl" or "C4alkyl" is meant to include n-butyl, sec-butyl, isobutyl, t- butyl, isobutenyl and but-2-yne radicals; and for example, "propyl" or "C3alkyl" each include n-propyl, propenyl, and isopropyl. Otherwise, if alkenyl and/or alkynyl descriptors are used in a particular definition of a group, for example "C4alkyl" along "C4alkenyl," then C4alkenyl geometric isomers are not meant to be included in "C4alkyl," but other 4-carbon isomers are, for example C4alkynyl. For example, a more general description, may describe a particular group as "C1-8alkyl" while a preferred species may describe the same group as including, "C1-8alkyl," "C1-6alkenyl" and "C1-salkynyl." [001061] "Alkylene" refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, n-butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CHj)2CH2-), and cyclohexylpropylene (-CH2CH2CII(C6H13)). [001062] "Alkylidene" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to ten carbon atoms, for example, ethylidene, propylidene, /7-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.
[001063] "Alkylidyne" refers to a straight or branched chain unsaturated divalent radical 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. [001064] Any of the above radicals, "alkylene," "alkylidene" and "alkylidyne," when optionally substituted, may contain alkyl substitution which itself contains unsaturation. For example, 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an n-butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical. [001065] "Alkoxy" or "alkoxyl" refers to the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons. [001066] "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). One exemplary substituted alkoxy group is "polyalkoxy" or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH2CH2OCH3, and glycol ethers such as polyethyleneglycol and -0(CH2CH2O)xCH3, where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five. Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
[001067] "Acyl" refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower- acyl refers to groups containing one to six carbons.
[001068] "α-Amino Acids" refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available α- amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A "side chain of an α-amino acid" refers to the radical found on the α-carbon of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like. [001069] "Amino" refers to the group -NH2. "Substituted amino," refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino. [001070] "Aryl" refers to aromatic six- to fourteen-membered carbocyclic ring, for example, benzene, naphthalene, indane, tetralin, fluorene and the like, univalent radicals. As univalent radicals, the aforementioned ring examples are named, phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl.
[001071] "Arylene" generically refers to any aryl that has at least two non-hydrogen groups attached thereto. For a more specific example, "phenylene" refers to a divalent phenyl ring radical. A phenylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto. The terms "ortho- arylene," "meta-arylene" or "para-arylene" refer to geometrical isomers of a particular arylene wherein, two groups attached to an aryl as depicted in a Formula are situated in an ortho, meta or para geometrical relationship about the aryl, respectively. [001072] Arylalkyl" refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Both the aryl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted. "Lower arylalkyl" refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons; this can also be refered to as aryl C1-6alkyl. [001073] "Exo-alkenyl" refers to a double bond that emanates from an annular carbon, and is not within the ring system, for example the double bond depicted in the Formula below.
Figure imgf000625_0001
[001074] In some examples, as appreciated by one of ordinary skill in the art, 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. [001075] "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. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, 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 may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
[001076] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. "Haloalkyl" and "haloaryl" refer generically to alkyl and aryl radicals that are substituted with one or more halogens, respectively. Thus, "dihaloaryl," "dihaloalkyl," "trihaloaryl" etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3 -fluorophenyl is within the scope of dihaloaryl. [001077] "Heteroarylene" generically refers to any heteroaryl that has at least two groups attached thereto. For a more specific example, "pyridylene" refers to a divalent pyridyl ring radical. A pyridylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto. For the purposes of this application, the term "ortho-heteroarylene" refers to a geometrical isomer of a particular heteroarylene wherein two groups attached to a heteroaryl as depicted in a Formula are situated on contiguous atoms of the heteroaryl. [001078] "Heteroatom" refers to O, S, N, or P.
[001079] "Heterocyclyl" refers to a stable three- to fifteen-membered ring radical that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. The heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states. In a specific example, the group -S(O)0-2-, refers to -S- (sulfide), -S(O)- (sulfoxide), and -SO2- (sulfone). For convenience, 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. Thus, for a Raf compound having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included as another Raf compound of the invention. In addition, annular nitrogen atoms may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. Examples of heterocyclyl radicals 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl. [001080] "Heteroalicyclic" refers specifically to a non-aromatic heterocyclyl radical. A heteroalicyclic may contain unsaturation, but is not aromatic. [001081] "Heteroaryl" refers specifically to an aromatic heterocyclyl radical. [001082] "Heterocyclylalkyl" refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. 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 radical portion of a heterocyclylalkyl group may be optionally substituted. "Lower heterocyclylalkyl" refers to a heterocyclylalkyl where the "alkyl" portion of the group has one to six carbons. "Heteroalicyclylalkyl" refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and "heteroarylalkyl" refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is aromatic Such terms may be described in more than one way, for example, "lower heterocyclylalkyl" and "heterocyclyl C1-6alkyl" are equivalent terms. [001083] "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, that only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted" refers to all subsequent modifiers in a term, for example in the term "optionally substituted aryl C1-8alkyl," optional substitution may occur on both the "C1-galkyl" portion and the "aryl" portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups. But where a first optionally substituted group can be substituted by a second optionally substituted group, the second substituent cannot be further substituted. A list of exemplary optional substitutions is included below in the definition of "substituted."
[001084] Unlesss otherwise specified, the term "optionally substituted" applies to the chemical moiety immediately preceding it. For instance, if a variable group (such as R) is defined as aryl, optionally substituted alkyl, or cycloalkyl, then only the alkyl group is optionally substituted.
[001085] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a- hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro- naphthalene are all included in the class "saturated bridged ring system. [001086] "Substituted" alkyl, aryl, and heterocyclyl, refer respectively to alkyl, aryl, and heterocyclyl, wherein 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: optionally substituted alkyl (for example, fluoromethyl, hydroxypropyl, nitromethyl, aminoethyl and the like.), optionally substituted aryl (for example, 4- hydroxyphenyl, 2,3-difluorophenyl, and the like), optionally substituted arylalkyl (for example, 1 -phenyl -ethyl, /?αrø-methoxyphenylethyl and the like), optionally substituted heterocyclylalkyl (for example, l-pyridin-3-yl-ethyl, N-ethylmorphonlino and the like), optionally substituted heterocyclyl (for example, 5-chloro-pyridin-3-yl, 1-methyl- piperidin-4-yl and the like), optionally substituted alkoxy (for example methoxyethoxy, hydroxypropyloxy, methylenedioxy and the like), optionally substituted amino (for example, methylamino, diethylamino, trifluoroacetylamino and the like), optionally substituted amidino, optionally substituted aryloxy (for example, phenoxy, para- chlorophenoxy, metø-aminophenoxy, /?αrø-phenoxyphenoxy and the like), optionally substituted arylalkyloxy (for example, benzyloxy, 3-chlorobenzyloxy, meta- phenoxybenzyloxy and the like), carboxy (-CO2H), optionally substituted carboalkoxy (that is, acyloxy or -OC(=O)R), optionally substituted carboxyalkyl (that is, esters or -CO2R), optionally substituted carboxamido, optionally substituted benzyloxycarbonylamino (CBZ-amino), cyano, optionally substituted acyl, halogen, hydroxy, nitro, optionally substituted alkylsulfanyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, thiol, oxo, carbamyl, optionally substituted acylamino, optionally substituted hydrazino, optionally substituted hydroxylamino, and optionally substituted sulfonamide.
[001087] "Sulfanyl" refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), and -S-(optionally substituted heterocyclyl). [001088] "Sulfinyl" refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-optionally substituted aryl), and -S(O)-(optionally substituted heterocyclyl). [001089] "Sulfonyl" refers to the groups: -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-optionally substituted aryl), -S(O2)-(optionally substituted heterocyclyl), -S(O2)-(optionally substituted alkoxy), -S(O2)-optionally substituted aryloxy), and -S(O2)-(optionally substituted heterocyclyloxy). [001090] Some of the Raf compounds described herein may 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 may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
Synthetic Procedures for Raf Compounds [001091] Raf compounds of Formula I(R), U(R), III(R), IV(R)a, IV(R)b, V(R), VI(R), VII(R), VIII(R), IX(R), X(R)a, X(R)b, XI(R), XII(R), and XIII(R) can be made by the synthetic schemes and examples described in publication WO 2005/112932, which is incorporated herein by reference in its entirety. The utility of these compounds are also described in WO 2005/112932. [001092] The Raf 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 the Raf compounds described herein. [001093] It is assumed that when considering generic descriptions of Raf compounds for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that theoretically some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra).
[001094] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) 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. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can be required to liberate the desired enantiomeric form. Alternatively, specific 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. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization.
[001095] In addition, the Raf 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 Raf compounds described herein.
[001096] In addition, it is intended that the Raf 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. Pharmaceutical Composition Examples
[001097] The following are representative pharmaceutical Formulations containing a Raf compound, such as, for example, a Raf compound of Formula 1(R), II(R), III(R), IV(R)a, IV(R)b, V(R), VI(R), VII(R), VIII(R), IX(R), X(R)a, X(R)b, XI(R), XII(R), or XIII(R).
Tablet Formulation
[001098] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet, mg
Raf compound 400
Cornstarch 50 croscarmellose sodium 25
Lactose 120 magnesium stearate 5 Capsule Formulation
[001099] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantity per tablet, mg
Raf compound 200 lactose, spray-dried 148 magnesium stearate 2
Suspension Formulation
[001100] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount
Raf compound 1.0 g fumaric acid 0.5 g sodium chloride 2.O g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) l.O g
Flavoring 0.035 mL
Colorings 0.5 mg distilled water q.s. to 10O mL Injectable Formulation [001101] The following ingredients are mixed to form an injectable Formulation.
Ingredient Amount
Raf compound 1.2 g sodium acetate buffer solution 0.4 M 2.0 mL
HCl (1 N) or NaOH (1 M) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL
[001102] All of the above ingredients, except water, are combined and heated to 60-70° C with stirring. A sufficient quantity of water at 60° C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.
Suppository Formulation [001103] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol®. H- 15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Quantity per tablet, mg
Raf compound 500
Witepsol® H- 15 Balance
[001104] Aspect (35) 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 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a Raf compound of Formula I(R), II(R), III(R), IV(R)a, IV(R)b, V(R), VI(R), VII(R), VIII(R), IX(R), X(R)a, X(R)b, XI(R), XII(R), or XIII(R) or a pharmaceutical composition comprising a therapeutically effective amount of the Raf compound of Formula I(R), II(R), III(R), IV(R)a, IV(R)b, V(R), VI(R), VII(R), VIII(R), IX(R), X(R)a, X(R)b, XI(R), XII(R), or XIII(R), and a pharmaceutically acceptable carrier, wherein the mammal is in need of the treatment. [001105] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, R2 of Formula I( J) is
Figure imgf000633_0001
[001106] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, R2 of Formula I(J) is
Figure imgf000633_0002
wherein R28a is selected from lower alkyl, dialkylaminoalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, and hetercycloalkylalkyl.
[001107] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, R2 of Formula I(J) is
Figure imgf000633_0003
[001108] In other embodiments of aspect (12), aspect (27), and aspect (35) of this
^ - R26 invention, L of Formula I(J) is a bond, Z is R26a , R25 is hydrogen and E and D are hydrogen.
[001109] In other embodiments of aspect (12), aspect (27), and aspect (35) of this
5^- N invention, Z of Formula I(J) is R26a , R26a is -C(O)R32, R26 is hydrogen, and R32 is selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R32 is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl and halo. [001110] In other embodiments of aspect (12), aspect (27), and aspect (35) of this
} (CH2)n4-NH-C(O)— <f~^ invention, R2 of Formula I(J) is >J (Ri1>nz .
[001111] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, R32 of Formula I(J) is U or -CH2-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- 1 H-indolyl .
[001112] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, R11 of Formula I(J), when present, is halo or lower alkyl.
[001113] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, R35 of Formula I(J) is heterocycloalkylalkyl, wherein the heterocyloalkyl is selected from piperazinyl, piperidinyl, morpholinyl and dioxanyl.
[001114] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, n2 of Formula I( J) is 0.
[001115] In other embodiments of aspect (12), aspect (27), and aspect (35) of this
invention, Rz of Formula I(J) is
Figure imgf000634_0001
, and wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. [001116] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, the JAK-2 compound has Formula IV(J):
Figure imgf000634_0002
wherein and R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31. [001117] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, the JAK-2 compound has Formula V(J):
Figure imgf000635_0001
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31.
[001118] In other embodiments of aspect (12), aspect (27), and aspect (35) of this invention, the JAK-2 compound has Formula VI(J):
Figure imgf000635_0002
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R31. Akt Compounds
[001119] The Akt compounds described below regulate and/or modulate the signal transduction of protein kinases, such as Akt kinase and the enzyme p70S6K (a serine- theoronine kinase that is a component of the phosphatidylinositol 3 kinase (PI3K)/Akt kinase (AktK) pathway). In another embodiment of the methods described herein, the JAK-2 compounds described hereinabove [e.g., compounds of Formula I(J), II(J), III(J), IV(J), V(J), VI(J), and VII(J)] can be combined with any of the Akt inhibitors known in the art. The Akt compounds described below are non-limiting examples of "Akt" or "p70S6K" inhibitors" that fall within the scope of aspect (3) of this invention. [001120] Representative Akt compounds, or pharmaceutically acceptable salts thereof, are depicted below in Table Al. The Akt compounds below fall within the scope of aspect (18) of this invention. These Akt compounds are merely illustrative and do not limit the scope of the Akt compounds or Akt/p70S6 inhibitors in any way
Table A2
Figure imgf000636_0001
Figure imgf000637_0001
Figure imgf000638_0001
Figure imgf000639_0001
Figure imgf000640_0001
Figure imgf000641_0001
Figure imgf000642_0001
Figure imgf000643_0001
Figure imgf000644_0001
Figure imgf000645_0001
Figure imgf000646_0001
Figure imgf000647_0001
Figure imgf000648_0001
Figure imgf000649_0001
Figure imgf000650_0001
Figure imgf000651_0001
Synthetic Procedures for Akt Compounds
[001121] The Akt compounds listed above can be made by the synthetic schemes and examples described in publication WO 2005/1 17909, which is incorporated herein by reference in its entirety. The utility of these compounds are also described in WO 2005/117909.
[001122] Another aspect 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 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), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a Akt compound. [001123] Another aspect 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 pharmaceutical composition comprising a therapeutically effective amount of the JAK-2 compound of Formula I(J), U(T), III(J), IV(J), V(J), or VI(J), and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of an Akt compound.
[001124] In other embodiments of the above method of combining the Akt compounds with the JAK-2 inhibitors of Formula I(J), one or more of any of the Akt compounds in Table A2 can be combined with any one of the embodiments of the compound of Formula I(J) described hereinabove. In other embodiments of the above method of combining the Akt compounds with the JAK-2 inhibitors of Formula I(J), one or more of any of the Akt compounds in Table A2 can be combined with one or more of any of the compounds in Table I(J). [001125] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

What is claimed is:
1. A method of treating a disease in a mammal, wherein the mammal is in need of the treatment, comprising administering to the mammal a therapeutically effective amount of a JAK-2 compound of Formula I(J), 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 an active agent selected from of a Raf inhibitor, an EGFR inhibitor, a VEGFR inhibitor, a ErbB2 inhibitor, a BCR-AbI, inhibitor, a Flt3 inhibitor, a Src inhibitor, a c-Kit inhibitor, an Akt inhibitor, a Ret inhibitor, an IFGlR inhibitor, an m-Tor inhibitor, a PI3K inhibitior, a PI3Kα inhibitor, and a taxane, wherein the JAK-2 compound of Formula I(J) is defined as follows:
Figure imgf000653_0001
KJ) or a pharmaceutically acceptable salt thereof, wherein: D is hydrogen, halo, -CF3, heterocycloalkyl or alkyl; E is hydrogen, halo, -CF3, 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, -C(O)OR26, -C(=N-OH)alkyl, -C(O)R8, -C(O)NR30R30a, -CH2R2,
-(CH2)H5NR26R26VCF3, -CN,-SO2R12, -S-R12a, -OR32a, -NHC(O)R32, aryl, and heterocycloalkyl optionally substituted with 1 or 2 oxo, or Z and R25, 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 R25 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; R1 is hydrogen;
R2 is selected from one of the following groups:
Figure imgf000655_0001
(a) (b) (c-1) ,
Figure imgf000655_0002
(i) (j)
Figure imgf000655_0003
or R is selected from one of the following groups:
Figure imgf000656_0001
(W)
(V) or (X)
ring X in Formula (d) of R 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; R7, R7', R9, R10, R12 and R15 are each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl;
R8 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, hydroxyalkyl, alkoxyalkyl, dihydroxyalkyl, alkylamino, dialkylamino, aminoalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkylaminoalkyl, dialkylaminoalkyl, -(CH2)r-
C(O)OR7, -(CH2)r-C(O)NR7R7', aryl, heteroaryl, cycloalkyl, arylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with one, two, three, four or five groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; each R11, when R1 1 is present, is independently selected from alkyl, alkenyl, lower alkynyl,
-CF3, alkoxy, halo, haloalkoxy, haloalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkyl, dialkylaminoalkoxy, oxo, thioalkyl, alkylthioalkyl, -(CH2)P-OR17, -CN, -0-CH2-C(O)-R17, -C(O)R16, -(CH2)p-C(O)OR17, -S(O)2R17, -S(O)2NR15R17, aryl, heteroaryl, cycloalkyl, arylalkyl, arylalkoxy, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at any ring position with 1, 2, 3 or 4 R21; R12 is hydrogen or alkyl; R12a is hydrogen or alkyl;
R13 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, -(CH2)r-C(O)OR7, -(CH2)r-C(O)NR7R7', aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with 1, 2, 3, 4 or 5 groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; and wherein the alkyl of cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl are independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from halo and hydroxy;
R14 is a bond, heterocycloalkyl or cycloalkyl; R16 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, dialkylaminoalkyl,
-(CH2)r-C(O)OR7, aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with one, two, three, four or five groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; and wherein the alkyl of cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from halo and hydroxy; R17 is selected from hydrogen, hydroxy, alkyl, alkenyl, lower alkynyl, hydroxyamino, haloalkyl, alkyl substituted with halo and hydroxy, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, dialkylaminoalkyl,
-(CH2)r-C(O)OR7, -(CH2)r-C(O)NR7R7>, aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein the aryl, heteroaryl, cycloalkyl, arylalkyl, diarylalkyl, aryloxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are each independently optionally substituted at the ring position with one, two, three, four or five groups independently selected from alkyl, alkenyl, lower alkynyl, halo, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, haloalkyl, haloalkoxy, lower alkoxy, amino, aryl, alkylamino, dialkylamino, heterocyclylalkoxy, oxo and haloalkyl; and wherein the alkyl of cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from halo and hydroxy; each R21, when R21 is present, is independently selected from alkyl, alkenyl, lower alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyloxy, haloalkyl, oxo, - OR13, -NHS(O)2R17, -S(O)2R17, -C(O)R17, -C(O)OR17, -C(O)NR15R17, -NR15C(O)R17, aryl, arylalkyl, heteroarylalkyl, aryloxy, and heteroaryl; wherein each of the aryl, arylalkyl, heteroarylalkyl, aryloxy, and heteroaryl within R21 are optionally substituted at any ring position with 1, 2, or 3 groups selected from alkyl, lower alkoxy halo, phenyl, heteroaryl and alkylheteroalkyl; R25 is selected from alkyl, alkenyl, lower alkyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, -OR12, cyano, -CH2NHC(O)OR7, -CH2NHC(O)R7, -SR7, -S(O)2R7, -S(O)2NR7R8, -C(O)OR8, -C(O)NR7R8, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one, two or three groups independently selected from alkyl, alkenyl, halo, haloalkoxy, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, -OR8, -NHS(O)2R8, cyano, -C(O)R8, -CH2NHC(O)OR7, -CH2NHC(O)R7, -SR7, -S(O)2R7, -S(O)2NR7R8, -C(O)OR8, -C(O)NR7R8, -NRrC(O)-CHR3-OR8, -NR7 C(O)-CHR3-NR7-R8, and -NR7C(O)R8; R26 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;
R26a is hydrogen, alkyl, heteroaryl, -C(O)R32, -C(O)NHR32a, -S(O)2R9, -SR9, -C(O)OR32, or -C(O)NR323R32;
R27 and R28 are each independently selected from alkyl, alkenyl, hydroxy, alkoxy, and alkoxyalkyl; R27a and R28a are independently selected from hydrogen, alkyl, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminoalkyl, arylcarbonylalkyl, aryloxyalkyl, dialkylaminoalkyl, alkyl-O-
C(O)heterocylcoalkyl, -(CH2)n4heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -(CH2)n4-C(O)R29, -(CH2)n4NR28R28a, -(CH2)n4NHR28a, -CII(phenyl)2, -S(O)2R29, -C(O)R29, -C(O)OR29, and -C(O)NR293R29, wherein the aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl groups within R27a and R28a 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, -CF3, oxo, -OCF3, alkoxyphenyl, and heteroaryl optionally substituted with alkyl or halo; or R27 and R27a, together with the nitrogen to which they are attached, form heterocycloalkylamino, heterocycloalkyl or heteroaryl, wherein the heterocycloalkylamino and heteroaryl are each independently optionally substituted with 1, 2, 3, 4, or 5 R31; or R28 and R28a 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 R31; R29a is hydrogen or alkyl; R29 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 R29 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, -CF3, oxo, -OCF3, alkoxyphenyl, and heteroaryl optionally substituted with alkyl or halo;
R3Oa is hydrogen or alkyl; R3 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 groups within R30 are each independently optionally substituted at any ring position with 1, 2, 3, 4, or 5 groups selected from halo, alkyl, alkoxy, alkoxyalkyl, -C(O)OCH3, -CF3, -OCF3, alkylcarbonyl, phenyl, phenoxy, alkylphenoxy, dialkylaminoalkoxy and heteroaryl; R31 is selected from alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthioalkyl,
-C(O)R30, -C(O)NR30R30a, -C(O)OR30, -S(O)2R30, 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, spirocyclic heterocycloalkyl, and heterocycloalkylalkyl, wherein the aryl, arylalkyl, cycloalkyl, arylheteroarylalkyl, arylalkoxyalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl groups within R31 are each independently optionally substituted at any ring position with 1, 2, 3, 4, or 5 groups selected from halo, alkyl, -CF3, -OCF3> cyano, alkoxy, alkoxyalkyl, -C(O)OCH3, alkylcarbonyl, phenyl optionally substituted at any ring position with halo, phenoxy, alkylphenoxy, arylalkoxyalkyl, dialkylaminoalkoxy and heteroaryl; R32a is hydrogen, -OCF3, -CF3, or alkyl;
R32 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, -CF3, -OCF3, aminoalkyl, alkylaminoalkyl, aryl and dialkylaminoalkyl, and wherein the alkyl portion of the heteroarylalkyl can be substituted with amino; or R32 is alkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from hydroxy, alkoxycarbonyl, alkoxy, -CF3, halo, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonylalkylamino, dialkylaminocarbonyl, -NR34R343 and phenyl optionally substituted with 1, 2, or 3 halo; or R32 is alkylamino or arylalkylamino; R34 is hydrogen or alkyl; R34a 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
R35 is selected from halo, -(CH2)PC(O)OR|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, wherein the mammal is in need of the treatment.
2. The method according to Claim 1 , wherein the Raf inhibitor is sorafenib, the PI3K inhibitor is BEZ, the Akt inhibitor is GSK, the BCR-AbI inhibitor is imatinib, rituximab, axitinib, nilotinib, or dasatinib, the Flt3 inhibitor is sunitinib, the Src inhibitor is dasatinib or AZ, the mTor/Raptor inhibitor is rapamycin, the VEGFR inhibitor is bevacizumab or axitinib, and the c-Kit inhibitor is imatinib or axitinib. 3. The method according to claim 1, wherein the active agent is a compound of Formula I(V2):
Figure imgf000662_0001
I(V2) or a pharmaceutically acceptable salt thereof, wherein, •
R1 is C1-C3 alkyl optionally substituted with between one and three R50 substituents;
R2 is selected from halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -N(R3)R4,
-S(O)0-2R4, -SO2N(R3)R4, -CO2R3, -C(=O)N(R3)R4, -N(R3)SO2R4, -N(R3)C(=O)R3, -N(R3)CO2R4, -C(=O)R3, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted lower alkynyl; R3 is -H or R4;
R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or
R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; q is 0, 1, 2, 3, 4, or 5;
Z is selected from -OCH2-, -O-, -S(O)0-2-, -N(R5)CH2-, and -NR5-;
R is -H or optionally substituted lower alkyl;
R50 is -H, halo, trihalomethyl, -OR3, -N(R3)R4, -S(O)0-2R4, -SO2N(R3)R4, -CO2R3,
-C(=O)N(R3)R4, -C(=NR25)N(R3)R4, -C(=NR25)R4, -N(R3)SO2R4, -N(R3)C(O)R3, -NCO2R3, -C(=O)R3, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or two of R50, when taken together on the same carbon are oxo; or two of R50, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; R25 is selected from -H, -CN, -NO2, -OR3, -S(O)0-2R4, -CO2R3, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted lower alkynyl; M'-M2-M3-M4- together are according to Formula II(V2):
Figure imgf000663_0001
II(V2) wherein X1, X , and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system containing up to three annular heteroatoms represented by any of X1, X2, and X ; wherein, each X1 is independently selected from -C(R6)R7-, -O-, -S(O)0-2-, and -NR8-; each X2 is independently a bridgehead methine optionally substituted with R , or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -O-, -S(O)0-2-, and -NR8-; provided, for X1, X2, and X3, there are no nitrogen-nitrogen annular bonds nor geminal di-nitrogen substitutions; E is selected from -NR9-, -O-, and absent;
Y is either: a C i-3 alkylene linker, between the oxygen at the 7-position of the quinazoline ring system of I(V2) and either E, or when E is absent, any ring atom of the saturated bridged ring system except X2, when X2 is a bridgehead nitrogen; provided there are at least two carbon atoms between the oxygen at the 7-position of the quinazoline ring system of I(V2) and either E, or when E is absent, any heteroatom represented by X1, X2 or X3; or Y is absent, when Y is absent, E is also absent; said saturated bridged ring system is directly attached to the oxygen at the 7-position of the quinazoline ring system of I(V2) via a carbon atom of said saturated bridged ring system; m and p are each independently from one to four; n is from zero to two, when n is zero, then there is a direct single bond between the two bridgehead X2 's;
R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -N(R3)R4, -S(O)0-2R4, -SO2N(R3)R4, -CO2R3, -C(O)N(R3)R4, -N(R3)SO2R4, -N(R3)C(O)R3, -NCO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl; or R6 and R7, when taken together are oxo; or
R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
R8 is selected from R3, -SO2N(R3)R4, -CO2R3, -C(O)N(R3)R4, -SO2R4, and -C(O)R3;
R9 is -H or optionally substituted lower alkyl; with the proviso that when Y is a C1-3 alkylene linker, E is absent, Z is -NH- or -N(CH3)-, R1 is a C1-3 alkyl, R2 is -H or halogen, n = O, and the atoms X1 of one bridge of the saturated bridged ring system, when combined with both bridgehead atoms, X2, of the saturated bridged ring system, represent: either a pyrrolidine ring or a piperidine ring, and any atom, X1 or X2, of either of said pyrrolidine ring or said piperidine ring is attached to Y; then the other bridge of said saturated bridged ring system cannot be any one of -OC(O)CH2-, -CH2OC(O)-, -OC(O)CH2CH2-, -CH2OC(O)CH2-, -CH2CH2OC(O)-, -OC(O)CH2NH-, -OC(O)CH2N(C, -4alkyl)-, and
-OC(O)CH2O-; or either a piperazine ring or a 4-(C1-4 alkyl)-piperazine ring, and any atom, X1 or X2, of either of said piperazine ring or said 4-(C1-4 alkyl)-piperazine ring is attached to Y; then the other bridge of said saturated bridged ring system, only when attached via the 2- and the 3-position of either of said piperazine ring or said 4-(C1-4 alkyl)-piperazine ring, cannot be one of -CH2OC(O)CH2-, -CH2CH2OC(O)-, and either of the two aforementioned bridges cannot be optionally substituted by one or two C1-2alkyl groups; or a piperazine ring, and any atom, X1 or X2, of said piperazine ring is attached to Y; then the other bridge of said saturated bridged ring system, only when attached via the 3- and the 4-position of said piperazine ring, cannot be one of -C(O)OCH2CH2- or -CH2OC(O)CH2- (and only when either of -C(O)OCH2CH2- or -CH2OC(O)CH2- is attached to the 3-position of said piperazine ring via their left-hand end as depicted above), and either of the two aforementioned bridges cannot be optionally substituted by one or two C1.2 alkyl groups, and ; or a 2-oxomorpholine ring, said 2-oxomorpholine ring attached to Y via its 4-position; then the other bridge of said saturated bridged ring system, only when attached via the 5- and the 6-position of said 2-oxomorpholine ring, cannot be one of -(CH2)g-, -CH2WCH2-, -CH2WCH2CH2-, and -CH2CH2WCH2-, wherein W is -0-, -S(O)0-2-, -NH-, or
-N(C1-4 alkyl)- and wherein g is 2,
3, or 4.
4. The method according to claim 1, wherein the active agent is according to Formula A-B-C (version 3), or a pharmaceutically acceptable salt thereof, wherein: A is selected from:
Figure imgf000665_0001
R3
,/ ■-> — Λ
R3-' N>< ' 2-44 and . -R D 33;.
B is selected from:
Figure imgf000666_0001
C is selected from:
Figure imgf000666_0002
wherein:
R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl; q is 0 to 2; each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl; or, two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5 and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=O)R3, -C(=O)OR3, -C(K))SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; or, two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R60; A1 is selected from =N- and =C(H)-;
A2 is either =N- or =C(H)-; R is -H or optionally substituted lower alkyl;
R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3 and -C(O)R , or an R is absent and the alkylene linker of A is covalently bonded to the nitrogen atom in which R8 is absent;
E1 is selected from -0-, -CH2-, -N(R5)- and -S(O)0-2-;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3 and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted arylalkyl; or, two of
R , 60 , when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above Formulae is independently optionally substituted with one or two R25; and each R25 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or two of R25 on a single carbon can be oxo; with the proviso that the conditions of:
C contains
Figure imgf000668_0001
; and the remaining portion of C contains one of:
Figure imgf000668_0002
are not met at the same time; and
with the proviso that when C
Figure imgf000668_0003
attached to
Figure imgf000669_0001
and R70 is selected from -H, CMalkyl, and C1-4alkoxyl, then A2 is N.
5. The method according to claim 1, wherein the active agent is a compound according to A-B-C (version 4) or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
Figure imgf000669_0002
B is selected from:
Figure imgf000669_0003
C is selected from:
Figure imgf000669_0004
Figure imgf000670_0001
wherein:
R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is 0 to 2; each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or, two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5, and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=0)R3, -C(=0)0R3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; or, two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R60;
A1 is selected from =N- and =C(H)-; A2 is either =N- or =C(H)-;
R5 is -H or optionally substituted lower alkyl;
R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3, and
-C(O)R , or an R is absent and the alkylene linker of A is covalently bonded to the nitrogen atom in which R is absent; E1 is selected from -O-, -CH2-, -N(R5)-, and -S(O)0-2-;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3,
-NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3,
-N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; or, two of R , when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above Formulae is independently optionally substituted with one or two R25; and each R25 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; or two of R , together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or two of R25 on a single carbon can be oxo; with the proviso that the conditions of:
C contains
Figure imgf000672_0001
; and the remaining portion of C contains one of:
Figure imgf000672_0002
are not met at the same time; and
with the proviso that when C contains
Figure imgf000672_0003
attached to
Figure imgf000672_0004
and R70 is selected from -H, CMalkyl, and C)-4alkoxyl, then A2 is N.
6. The method according to claim 1, wherein the active agent is according to Formula A-B-C (version 5), or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
Figure imgf000672_0005
B is selected from:
Figure imgf000673_0001
C is selected from:
Figure imgf000673_0002
wherein:
R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is O to 2; each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or, two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5, and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=0)R3, -C(=O)OR3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; or, two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R60; A1 is selected from =N- and =C(H)-;
A2 is either =N- or =C(H)-; R5 is -H or optionally substituted lower alkyl;
R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3, or wherein the A group contains at least one R8, R8 is absent and the alkylene linker is bonded to the corresponding nitrogen atom;
E1 is selected from -O-, -CH2-, -N(R5)-, and -S(O)0-2-;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3,
-NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3,
-N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, or two of
R60, when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above Formulae is independently optionally substituted with one or two R25; and each R25 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3,
-N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of
R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or, two of R on a single carbon can be oxo.
7. The method according to claim 1, wherein the active agent is a compound according to Formula I(P):
Figure imgf000675_0001
I(P) or a pharmaceutically acceptable salt thereof, where W1, W2, W3, and W4 are -C(R1)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1)=; and where each R1 is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino; R51 is hydrogen or alkyl; R52 is hydrogen or halo;
R50, R53, and R54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C , -C6-alkylene-N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R55a, or alkylcarbonylamino and where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R53 and R54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl;
B is phenyl substituted with R3a and optionally further substituted with one, two, or three R3; or
B is heteroaryl optionally substituted with one, two, or three R3; R a is cyano; hydroxyamino; carboxy; alkoxycarbonyl; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR8R88 where R8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R9a where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(R10)-C,-C6-alkylene-N(R10a)R10b where R1Oa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl and R10 and R1Ob are independently hydrogen, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl; e) -NR11C(O)NR118R1 lb where R1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R11 and Rl lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl ; g) -NR13C(O)OR133 where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl; h) -C(O)N(R14)N(R14a)(R14b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-C1-C6-alkylene-N(R15a)R15b where R15, R15a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-C1-C6-alkylene-C(O)OR16a where R16 is hydrogen, alkyl, or alkenyl and R16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; 1) -N(R17)-C(=N(R17b)(R17a))(NR17cR17d) where R17, R17a, R17b, R17c, and R17d are independently hydrogen, alkyl, or alkenyl; m) -N(R18)C(O)-C,-C6-alkylene-N(R18b)C(O)R18a where R18a is hydrogen, alkyl, alkenyl, or alkoxy and R18 and R18b are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(R19)-C,-C6-alkylene-C(O)R19a where R19 is hydrogen, alkyl, or alkenyl and R19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-C1-C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and R20a is cycloalkyl or heterocycloalkyl; p) -NR21 S(O)2R-C1. C6-alkylene-N(R2lb)R21a where R21 is hydrogen, alkyl, or alkenyl and R21a and R21b are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-C1-C6-alkylene-N(R22b)-N(R22c)(R22a) where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0.C6-alkylene-N(R23)-C,-C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C,.C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and
R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; and where each of the alkylene in R3a is independently optionally further substituted with
1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and each R3 (when R3 is present) is independently alkyl; alkenyl; alkynyl; halo; hydroxy; oxo; alkoxy; cyano; hydroxyamino; carboxy; alkoxycarbonyl; amino; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C , -C6-alkylene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR8R83 where R8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R9" where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(R10)-C,-C6-alkylene-N(R10a)R10b where R1Oa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or hydroxyalkyl and R10 and R1Ob are independently hydrogen, alkyl, alkenyl, haloalkyl, or hydroxyalkyl; e) -NR11C(O)NR113R1 lb where R1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R11 and Rl lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminooalkyl, dialkylaminoalkyl; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl ; g) -NR13C(O)OR133 where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl); h) -C(O)N(R14)N(R14a)(R14b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-C,-C6-alkylene-N(R15a)R15b where R15, Rl5a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-C1.C6-alkylene-C(O)OR16a where R16 is hydrogen, alkyl, or alkenyl and R16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; 1) -N(Rl 7)-C(=N(R17b)(Rl7a))(NR17cR17d) where R17, R17a, R17b, R17c, and Rl7d are independently hydrogen, alkyl, or alkenyl; m) -N(Rl 8)C(O)-C,-C6-alkylene-N(R18b)C(O)R18a where R18a is hydrogen, alkyl, alkenyl, or alkoxy and R18 and R18b are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(R19)-C1-C6-alkylene-C(O)R19a where R19 is hydrogen, alkyl, or alkenyl and R19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-C,-C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and R20a is cycloalkyl or heterocycloalkyl; p) -NR21S(O)2R-C1.C6-alkylene-N(R21b)R2la where R21 is hydrogen, alkyl, or alkenyl and R2 la and R lb are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-CI-C6-alkylene-N(R22b)-N(R22c)(R22a), where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0-C6-alkylene-N(R23)-C,.C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C i.C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and
R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; wherein each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and provided that when R50 and R52 are hydrogen, R51 is hydrogen or methyl, R53 is hydrogen or methoxy, and R54 is hydrogen or methoxy, then B is not 2,3-dihydro- 1 ,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R3 where R3 is halo.
8. The method according to claim 1, wherein the active agent is according to Formula II(P):
Figure imgf000680_0001
II(P) or a pharmaceutically acceptable salt thereof, wherein: W1, W2, W3, and W4 are -C(Rla)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(Rla)=;
X1 is -N(R5a)-; A is aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, or -alkyl-N(R7)R7a, where each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl and alkoxy groups, each either alone or as part of another group within A, are independently optionally substituted with one, two, three, or four R2a; or
B1 is aryl, arylalkyl, alkyl, heteroaryl, or heteroaryalkyl, wherein each of the aryl, heteroaryl and alkyl groups are independently optionally substituted with one, two, three, or four R3d; each RIa is independently selected from hydrogen, alkoxy, alkyl, nitro, halo, cyano, and -C0-C6-alkyl-N(R7)R7a, wherein each of the alkyl and alkoxy groups is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, and -C(O)OR6; each R2a (when R2a is present) is independently selected from alkyl, alkenyl, -alkenyl- C(O)OR6, -OR6, -N(R7)C(O)R6, -N(R7)C(O)-C0-C6 alkyl-N(R7b)R7a, -OC(O)-C0-
C6 alkyl-N(R7)R7a, -N(R7)C(O)-C,-C6 alkylC(O)OR6, C0-C6-alkyl-C(O)R6 > oxo, dioxo, -S(O)2-N(R7)R7a, -C(O)OR6, -CII(R6)2-C(O)OR6, -S(O)2R6, cycloalkyl, heterocycloalkyl, heteroaryl, -C(O)N(R7)-alkyl-OR6, -C0-C6 alkyl-C(O)N(R7)-C0- C6-alkyl-C(O)OR6, -C0-C6-alkyl-C(O)N(R7)R7a, aryl, arylalkyl, -S-(C1-C6 alkyl), halo, oxo, nitro, -SCN, cyano, and -C0-C6 alkyl-N(R7)R7a, wherein each of the alkyl (including, for example the alkyl within alkoxy), aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R2, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, oxo, nitro, cyano, hydroxy, -N(R8)R8a, alkoxy, and -C(O)OR9; each R3d (when R3d is present) is independently oxo, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, C3-C6-cycloalkyl, -C0-C6-alkyl-heterocycloalkyl, -C0-C6 alkyl- N(R7)C(0)-Co-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)C(O)-C0-C6-alkyl- N(R7b)C(O)R7a, -C0-C6 alkyl-C(O)-C0-C6-alkyl-N(R7)R7a, -C0-C6-alkyl- C(O)N(R7)-C0-C6-alkyl-N(R7b)R7a, -C0-C6-alkyl-C(O)N(R7)-
C,-C6alkylC(O)OR7a, -C0-C6 alkyl-N(R7)C(O)-C0-C6-alkyl-(R7a), -C0-C6 alkyl- N(R7)-C0-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)C(O)-C0-C6-alkyl-N(R7b)- N(R7c)R7a, -C0-C6 alkyl-N(R7)C(O)O-C0-C6-alkyl-aryl, -C0-C6 alkyl-C(O)N(R7)- C0-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)-C0-C6 alkyl- C(=N(R7b)(R7a))(NR7cR7d), -Co-Q-alkyl-aryl, -C0-C6-alkyl-heteroaryl, -C0-C6 alkyl-heterocycloalkyl, -0-C0-C6 alkyl-N(R7)R7a, -C0-C6 alkyl-ORe, -C0-C6 alkyl- C(O)OR6, C0-C6-alkyl-N(R7)R7a, -C0-C6 alkyl-C(O)NR7R7a, -C0-C6 alkyl-C(O)R7, -SR7, -S(O)2R7, -S(O)3R7, -S(O)R7, -SO2N(R7)R7a, -SO2N(R7)-C0-C6 alkyl- N(R7b)R7a, -C0-C6-alkyl-N(R7)-aryl, -C0-C6-alkyl-N(R7)-heteroaryl, -C0-C6-alkyl-
N(R7)-heterocycloalkyl, -Co-C6-alkyl-C(0)N(R7)-C0-C6-alkyl-cycloalkyl, C0-C6- alkyl-C(O)N(R7)-C0-C6-alkyl-aryl, C0-C6 alkyl-C(O)N(R7)-C0-C6 alkyl- heteroaryl, C0-C6 alkyl-C(O)N(R7)-C0-C6-alkyl-heterocycloalkyl, -C0-C6-alkyl- N(R7)C(O)-C0-C6-alkyl-cycloalkyl, -C0-C6-alkyl-N(R7)C(O)-C0-C6-alkyl-aryl, C0-C6-alkyl-N(R7)C(0)-Co-C6-alkyl-heteroaryl, -C0-C6-alkyl-N(R7)C(O)-C0-C6- alkyl-heterocydoalkyl, C0-C6-alkyl-N(R7)C(O)-C0-C6-alkyl-heterocycloalkyl- aryl, -N(R7)C(O)OR6, or -NHC(O)H, wherein each of the alkyl, alkenyl, cycloalkyl, aryl, (including, for example the alkyl within alkoxy), heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R3d, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkenyl, -C0-C6-alkyl-OR9, cycloalkyl, halo, haloalkyl, haloalkoxy, -C(O)R9, nitro, cyano, oxo, -C0-C6-alkyl-N(R8)R8a, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)OR9, alkylthio, and hydroxyalkyl; R4 is hydrogen, aryl, -C0-C6-alkyl-N(R7)R7a, alkoxy, or C1-C6 alkyl, wherein each of the alkyl and aryl groups, either alone or as part of another group in R4, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, alkoxy, and -C(O)OR6; or R4 and X1 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein R5a is absent when X is -N(R5a)-, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R7)R7a, alkoxy, and -C(O)OR6; R5a is hydrogen, -C1-C6 alkyl-N(R7)R7a, alkoxy, alkyl, or aryl, wherein each of the alkyl and aryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, C1-C6 alkoxy, or -C(O)OR6; or R5a and R4 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R7)R7a, C1-C6 alkoxy, and -C(O)OR6; R6 and R9 are independently hydrogen, hydroxy, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, either alone or as part of another group within R6 and R9, is independently optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from amino, hydroxy, alkoxy, alkyl, and halo; and
R7, R7a R7b, R7c, R7d, R8, and R8a are independently hydrogen, alkyl, alkenyl, hydroxy, alkyloxy, alkenyloxy, -0-C0-C6 alkyl-aryl, -C0-C6 alkyl-C(O)OR6, -C0-C6 alkyl- C(O)R6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl, either alone or part of another group within R7,
R 7a R 7b ; R 7c ? R 7d, R 8 and R 8a is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, -S-C1-C6 alkyl, cyano, nitro, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, halo, aryl, heterocycloalkylalkyl, and heteroaryl optionally substituted with one or two C1-C6 alkyl.
9. The method according to claim 1, wherein the active agent is a compound according to Formula I(K):
Figure imgf000683_0001
I(K) or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
R2 is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5
R8 groups; X is -NR3-; R3 hydrogen; R4 is optionally substituted alkyl; R5 is hydrogen; and
R6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R9 groups; each R , when present, is independently hydroxy, halo, alkoxy, haloalkoxy, amino, alkylamino, dialkylaminoalkyl, or alkoxyalkylamino; and each R9, when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either alone or as part of another group within R9, are independently optionally substituted with 1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkxy, amino, alkylamino, and dialkylamino; or the PI3Kα inhibitor is a compound of Formula II(K):
Figure imgf000684_0001
II(K) or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
X is S, SO2, or -NR3-;
R2 is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyl-aryl- or optionally substituted heteroaryl; R2 is optionally further substituted with one or more R8 groups; R3, R3a, and R3b are independently hydrogen, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R4 is hydrogen, halo, haloalkyl, haloalkoxy, -NR3a-, optionally substituted alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R5 is hydrogen, halo, haloalkyl, haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl or optionally substituted heteroaryl; and
R6 is hydrogen, halo, haloalkyl, haloalkoxy, -NR3b-, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted acyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; substitutable R6 groups are optionally further substituted with 1, 2, 3, 4, or 5 R9 groups; each R8, when present, is independently hydroxy, halo, haloalkyl, haloalkoxy, optionally substituted alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 alkoxyalkylaminoalkyl, C1-C6 alkylcarboxyheterocycloalkyl, oxy C1- C6alkylheterocycloalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; each R9, when present, is independently halo, haloalkyl, haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 carboxyalkyl, optionally substituted alkoxycarbonyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted aryloxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.
10. The method according to claim 1, wherein the active agent is a compound according to Formula I(S):
Figure imgf000686_0001
I(S) or a pharmaceutically acceptable salt thereof, wherein:
V is NRjRia, or O-Ri, wherein
R, is H, CN, halo, -NR13R14, C(O)NRi3Ri4, C1-C6 alkyl, -C(O)-C-C6 alkyl, -C0-C6 alkyl-R2o, wherein R20 is aryl, heteroaryl, heterocyclyl, or a 5-12 membered fused bicyclical or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from N, O, and S, wherein aryl, heteroaryl, C3-C7 heterocyclyl, or the 5-12 membered ring system are optionally substituted with one, two, or three groups independently selected from C1-C6 alkyl, and -C0-C6 alkyl-R2i; Ria is H or C1-C6 alkyl; or when V is NRIRJ3, RI and Rj8 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing, in addition to the nitrogen, up to two additional heteroatoms independently selected from O, N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two of C1-C6 alkyl, - NRnRi4 or C3-C7 cycloalkyl;
X is H, halo, C1-C6 alkyl, NO2, mono-, di-, or tri-halo substituted methyl, NRI 3RH, C(O)O-C-C6 alkyl, or N(Rn)-C(O)-C-C6 alkyl;
Y is H, halo, OH, C,-C6 alkyl, C0-C6 alkyl-NR,5Ri6, C, -C6 alkoxy, -N(R13)-(CH2)n-
NRi5R16, -C(O)O-C1-C6 alkyl, -O-(CH2)n-NR,5R,6, -C(O)-C1-C6 alkyl, -C0-C6- alkyl-R21, -0-R21, -C(O)-R21, -O-(CH2)n-R21, -C(O)-NR13R14, -C(O)-N(R13)- aryl, -C(O)-N(R13)-(CH2)n-NR15R16, -C(O)-N(R13)-(CH2)n-aryl, -C(O)-N(R13)-
(CH2)n-heterocyclyl ; or X and Y together with the atoms to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing one or two heteroatoms independently selected from O, N, and S, wherein the heterocyclyl or heteroaryl group is optionally substituted with one or two moieties independently selected from halo, C1-C6 alkyl, aryl-C1-Cό alkyl-, aryl-(CH2)n-
O-(CH2)n-aryl-, arylOH, C3-C7 cycloalkyl, heterocyclyl, -aryl-N(Ri3)C(O)-C3- C7 cycloalkyl-C(O)-N(Ri4)-aryl, or a group of the Formula -L-M-Q, wherein L is a bond or C3-C7 cycloalkyl, M is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, Q is NRI3RH, N(RI3)C(O)-CI-C6 alkyl, heterocyclyl, or a saturated fused bicyclic ring containing one or two heteroatoms independently selected from O, N, and S, wherein each aryl, heteroaryl, or heterocyclyl substituent on the group formed by X and Y is optionally further substituted with one or two moieties independently selected from halo, C(O)O-(CH2)n-phenyl, and C(O)-C1-C6 alkyl;
Z is H, NR2R3, -S-R2a, or -Q-R2a, wherein
R2 is -C1-C6 alkyl, -C1-C6 alkyl-NRi3Ri4, -C(O)-aryl, -C0-C6-alkyl-aryl, -C0-C6-alkyl- heteroaryl, -C0-C6-alkyl-(C3-C7-cycloalkyl), -Co-C6-alkyl-heterocyclyl, or -C0- C6 alkyl-5-12 membered fused bicyclic or tricyclic saturated, partially saturated, or unsaturated ring system containing 0-4 ring atoms selected from
N, O, and S, wherein each alkyl is optionally substituted with phenyl, and each aryl, heteroaryl, C3-C7 cycloalkyl, heterocyclyl, or 5-12 membered ring system is optionally substituted with one, two, or three groups independently selected from halo, mono-, di-, or tri-halo substituted methyl or methoxy, CN, NO2, NRi3R14, C(O)O-C1-C6 alkyl, N(Rn)C(O)-C1-C6 alkyl, -SO2NR,3R14, -
O-C(O)-NR,3RM, -C0-C6 alkyl-C(O)NR,5Ri6, C1-C6 alkoxy, C1-C6 thioalkoxy, -O-(CH2)n-NR,5R,6, -C-C6 alkyl-NR13R,4, -N(R,3)-C(O)-C,-C6 alkyl, - N(R,3)-C(O)-aryl, -C0-C6 alkyl-C(O)-N(R13)-(CH2)n-NR15R16, -C0-C6 alkyl- C(O)-N(R,3)-(CH2)n-aryl, -O-(CH2)n-C(O)-N(R,3)-(CH2)n-NR15R,6, -O- (CH2VC(O)-NRi5R16, -C0-C6 alkyl-C(O)-N(R,3HCH2)n-O-C,-C6 alkyl, -C0-
C6 alkyl-N(R,3)-C(O)O-C1-C6 alkyl, -C0-C6alkyl-C(O)-heterocyclyl, -C0- C6alkyl-C(O)-heteroaryl, -C0-C6alkyl-C(O)-aryl, -C0-C6-alkyl-R2b aryloxy, - O-(CH2)n-R21, -SO2-heterocyclyl, N(R13)-C(O)-C3-C7-cycloalkyl, -C0-C6alkyl C(O)O-R21 ,C3-C7-cycloalkyl, -C0-C6alkylR21, -SC1-C6alkyl or C1-C6 alkyl optionally substituted with halo or cyano, wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl substituent is further optionally substituted with 1-3 groups independently selected from halo, CF3, C1-C6 alkyl, C1-C6 haloalkoxy, NRnRi4 and C1-C6 alkoxy; R3 is H or C ,-C6 alkyl; or R2 and R3 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group containing up to three heteroatoms independently selected from O, N, and S, and wherein the heterocyclyl or heteroaryl group is optionally substituted with one or two of halo or C1-C6 alkyl;
R2a is aryl or C0-C6 alkyl-heteroaryl, wherein the aryl and heteroaryl are optionally substituted with aryl, -N(R,3)-C(O)-C3-C7 cycloalkyl or -C(O)NR)3Ri4;
Ri3 and Ri4 are independently H or C1-C6 alkyl;
Ri5 and Ri6 are independently H, C1-C6 alkyl, heteroaryl, or heterocyclyl, or Ri5 and Ri6 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl or heteroaryl group wherein one or two ring carbons are each optionally replaced with a heteroatom independently selected from O,
N, and S, and wherein each heterocyclyl or heteroaryl group is optionally substituted with one or two moieties independently selected from halo, Cj-C6 alkyl, or -C(O)O-C , -C6 alkyl;
R2I is heterocyclyl, aryl, heteroaryl, or C3-C7 cycloalkyl, and wherein alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, and heterocyclyl are optionally substituted with one or two moieties independently selected from halo, -S(O)2-C0-C1 alkyl,
-C(O)-C0-C, alkyl, -C(O)-H, -C0-C, alkyl-aryl, C-C6 alkyl, NRnRi4, and heterocyclyl; n is 0-6; provided that when V is NH2, X, Y and Z are not simultaneously H.
11. The method according to claim 1 , wherein the active agent is a compound according to Formula I(R):
Figure imgf000688_0001
I(R)
or a pharmaceutically acceptable salt thereof, wherein: A is a three- to seven-membered alicyclic, a five- to six-membered ortho-arylene or a five- to six-membered ortho-heteroarylene containing between one and three heteroatoms, either of the aforementioned optionally substituted with up to four R;
each R is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; optionally two of R, together with the atoms to which they are attached, form a first ring system fused with A, said first ring system substituted with zero to three of R1; Xi, X2 and X3 are independently selected from -CR1= or -N=; each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl;
Z and X are each independently selected from -C(R2)=, -N=, -N(R2)-, -S(O)0-2-, and -0-;
E and Y are each independently selected from absent, -C(R2)(R2)-, -C(=0)-, -C(R2)= and -N=, but E and Y are not both absent, and E and Y are not both -N= when both Z and X are -N=; each R2 is independently selected from R3, -N(R3)(R3), -C(O)N(R3)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, and -N(R3)C(O)R3; each R3 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted C3-7alicyclic, optionally substituted aryl, optionally substituted aryl C1-3alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Cualkyl; optionally two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P; and
G is selected from -CO2R3, -C(O)R3, -C(O)N(R3)R3, -C(O)(NR3), -C(O)NR3[C(R3)2]0-,R3, -C(0)NR30[C(R3)2]o-iR\ -N(R3)CO2R3,
-N(R3)C(O)N(R3)R3, -N(R3)C(O)R3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, optionally substituted aryl C0-3alkyl, and optionally substituted heterocyclyl Co^alkyl; with the proviso, however, that the compound is not CAS Registry No. 439096-29-4, 439107-32-1 or 439107-34-3.
12. The method according to claim 1, wherein R2 of Formula I(J) is
Figure imgf000690_0001
13. The method according to claim 1, wherein Z of Formula I(J) is R26a , R26a is -C(O)R32, R26 is hydrogen, and R32 is selected from tetrahydrofuran, pyrrolidinyl or pryimidinyl, wherein R is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydroxyl, oxo, alkyl, alkoxy, amino, hydroxyalkyl and halo.
14. The method according to claim 13, wherein R32 of Formula I(J) is U or -CH2-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.
15. The method according to claim 1 , wherein the JAK-2 compound has Formula IV(J):
16. The method according to claim 1, wherein the JAK-2 compound has Formula V(J):
Figure imgf000691_0001
wherein R28 and R a, 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
17. The method according to claim 1, wherein the JAK-2 compound has Formula VI(J):
Figure imgf000691_0002
wherein R28 and R28a, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two R3 ' .
18. The method according to claim 1, wherein 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.
19. The method according to claim 1, wherein the JAK-2 compound is selected from one or more of the following compounds: N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2,6- dichlorobenzamide ; 2,6-dichloro-N-(3-{[4-(2,3-dihydro-1-benzofuran-6-yl)pyrimidin-2- yl] amino } propyl)benzamide; N- [3 -( {4- [4-(acetylamino)phenyl]pyrimidin-2-yl } amino)propyl] -2-fluoro-6- iodobenzamide;
N-(3-{[4-(4-aminophenyl)pyrimidin-2-yl]amino}propyl)-2,6-dichlorobenzamide; N-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide; N-{4-[2-({3-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2- (dimethylamino)ethyl]benzamide;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-fluorobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-fluoro-6- iodobenzamide;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6- dimethylbenzamide;
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]pyridine-4- carboxamide;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,3,4,5,6- pentafluorobenzamide;
4-(4-chlorophenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide ;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; 4-(2,4-dichlorophenyl)-N-{3-[(2-piperidin-1-ylethyl)oxy]phenyl}pyrimidin-2-amine; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-chlorobenzamide; N-(4-{2-[(3-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4-{2-[(3-piperidin-1-ylphεnyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-bromobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-3-fluorobenzamide; N-[3-({4-[4-(acetylamino)phenyl]-5-methylpyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide ; N-(4-{2-[(3-{[(2,6-dichlorophenyl)sulfonyl]amino}phenyl)amino]-5- methylpyrimidin-4-yl}phenyl)acetamide;
2,6-dichloro-N-(3-{[4-(l//-indol-5-yl)pyrimidin-2-yl]amino}phenyl)benzamide; N-[3-({4-[4-(acetylamino)phenyl]-5-fluoropyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-methylbenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,4- dichlorobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,3- dichlorobenzamide ; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,5- dichlorobenzamide ;
N- [4-(2- { [4-(4-ethylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide; N-(4-{2-[(4-piperidin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4-{2-[(2-methyl-4-piperazin-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)thiophene-2-carboxamide; N-(4-{5-methyl-2-[(3-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)acetamide ;
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)-2-(phenyloxy)acetamide; N-(4-{6-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)-2-morpholin-4-ylacetamide;
N-[4-(2-{[3-(methyloxy)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N-[3-({4-[4-(acetylamino)-2-chlorophenyl]pyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide; 2,6-dichloro-N-{3-[(4-phenylpyrimidin-2-yl)amino]phenyl}benzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6- difluorobenzamide;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,4,5- trifluorobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]benzamide; N-(4-{6-morpholin-4-yl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-3,5- difluorobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2-chloro-6-fluoro-3-
(methyloxy)benzamide ;
N-[3-( {4-[4-(acetylamino)phenyl]pyrimidin-2-yl } amino)phenyl] -2-chloro-6-fluoro-4- methylbenzamide;
N-(4-{2-[(3-{[(2,6-dimethylphenyl)methyl]amino}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
4-(2,4-dichlorophenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; 4-(2,4-dichlorophenyl)-N-{3-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}pyrimidin-2- amine;
N-(3- { [4-(4-aminophenyl)pyrimidin-2-yl] amino } phenyl)-2,6-dichlorobenzamide; 4-(4-aminophenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; 4-[4-(ethylamino)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; N-(4-{2-[(4-aminophenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-[4-(2- { [4-(methyloxy)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide ;
N- { 4- [2-( { 3- [4-(pyridin-4-ylmethyl)piperazin- 1 -yl]phenyl } amino)pyrimidin-4- yljphenyl} acetamide; N-[5-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-2-morpholin-4-ylphenyl]-
2,6-dichlorobenzamide; N-(4-{5-fluoro-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4- { 2- [(4- { [2-(4-ethylpiperazin- 1 -yl)-2-oxoethyl] oxy } phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; N- [4-(2- { [3-(morpholin-4-ylcarbonyl)phenyl] amino } pyrimidin-4- yl)phenyl]acetamide; N-{3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-5-[(4-ethylpiperazin-1- yl)carbonyl]phenyl}-2,6-dichlorobenzamide;
4-[4-(dimethylamino)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; 2,6-dichloro-N-(3-{[4-(2,4-dichlorophenyl)pyrimidin-2-yl]amino}phenyl)benzamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}phenyl)acetamide;
N-(3-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)thiophene-2-carboxamide;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-1-methylpiperidine- 4-carboxamide; N-{4-[2-({3-[(phenylmethyl)amino]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide; N-(4- { 2- [(3 -aminophenyl)amino] -5-methylpyrimidin-4-yl } phenyl)acetamide; N-(4- { 2- [(3 -aminophenyl)amino] -5-fluoropyrimidin-4-yl } phenyl)acetamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(2-ethylphenyl)benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(phenylmethyl)benzamide; N-{4-[2-({3-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide; N-{4-[2-({3-[(4-phenylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-(3-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(2-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-{4-[2-({3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl} acetamide; N-(4- { 2- [(3 - { [4-(3 -chlorophenyl)piperazin- 1 -yl] carbonyl } phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(l-methyl-l//- benzimidazol-2-yl)methyl] benzamide ;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-propylbenzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-cyclopropylbenzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(3- fluorophenyl)methyl]benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(naphthalen-1- ylmethyl)benzamide ; 3 -( {4- [4-(acetylamino)phenyl] pyrimidin-2-yl } amino)-//- [2-(dimethylamino)ethyl] -N- methylbenzamide ; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2- methylphenyl)methyl]benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(3- chlorophenyl)methyl] benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(2-phenylethyl)benzamide; N-{4-[2-({3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(tetrahydrofuran-2- ylmethyl)benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[3-(2-oxopyrrolidin-1- yl)propyl]benzamide; o
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(3s,5s,7s)- tricyclo[3.3.1.1~3,7~]dec-1-yl]benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2- (methyloxy)ethyl]benzamide;
N-[4-(2-{[3-(1,3-thiazolidin-3-ylcarbonyl)phenyl]amino}pyrimidin-4- yl)pheny 1] acetamide ; N-{4-[2-({3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[2-
(methyloxy)phenyl] methyl } benzamide ; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[3-
(methyloxy)phenyl]methyl}benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2- fluorophenyl)methyl]benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(4- fluoropheny l)methy 1] benzam ide ; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(3,3- dimethylbutyl)benzamide; N-[4-(2-{[3-(thiomorpholin-4-ylcarbonyl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(2-thienylmethyl)benzamide; 3-({4-[4-(acetylamino)pheny]]pyrimidin-2-yl}amino)-N-[3-
(dimethylamino)propyl]benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-jV-{[2-
(trifluoromethyl)phenyl]methyl}benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{[3-
(trifluoromethyl)phenyl]methyl}benzamide; 3-({4-[4-(acetyiamino)phenyl]pyrimidin-2-yl}amino)-N-{[4- (trifluoromethyl)phenyl]methyl}benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2,4- difluorophenyl)methyl] benzamide ; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-ethyl-N-methylbenzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-({4-
[(trifluoromethyl)oxy]phenyl}methyl)benzamide; N-{4-[2-({3-[(4-acetylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N- (cyclopropylmethy^benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2-(2- fluoropheny l)ethyl] benzamide ; N-[4-(2-{[3-(pyrrolidin-1-ylcarbonyl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide; O N-{4-[2-({3-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4- { 2- [(4-morpholin-4-ylpheny l)amino] pyrimidin-4-yl } phenyl)benzamide; N-[4-(2-{[3-(1,3-dioxan-2-yi)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N- [4-(2- { [3 -(morpholin-4-ylmethyl)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide ; N-{4-[2-({3-[(4-ethylpiperazin-1-yl)methyl]phenyl}amino)pyrimidin-4- yl] phenyl } acetam ide ;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-3-[(2-morpholin-4- ylethyl)oxy] benzamide;
4-[4-(methylamino)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine;
N-[4-(2-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N-(4-{2-[(3-amino-2,4,5,6-tetrafluorophenyl)amino]pyrimidin-4- yl } phenyl)acetamide; N-(4- {2- [(3 - { [4-(2-fluorophenyl)piperazin- 1 -yl] carbony 1 } phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; 3 -( {4- [4-(acetylamino)pheny l]pyrimidin-2-yl } amino)-JV- [2-
(phenyloxy)ethyl]benzamide; methyl l-{[3-({4-[4-(acetylamino)phenyl]pyrimidin-2- yl}amino)phenyl]carbonyl}piperidine-4-carboxylate;
N-[4-(2-{[3-({4-[3-(methyloxy)phenyl]piperazin-1- yl}carbonyl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-{2-[2-
(methy loxy)pheny 1] ethyl } benzam ide ; N-[4-(2-{[3-(1,3-dihydro-2//-isoindol-2-ylcarbonyl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(biphenyl-4- ylmethyl)benzamide;
N-(4-{2-[(3-{[4-(phenylcarbonyl)piperazin-1-yl]carbonyl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-[4-(2- { [3 -( {4- [4-(methyloxy)phenyl] piperazin- 1 - yl}carbonyl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-methyl-N-{[2-
(methyloxy)phenyl]methyl}benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2-fluorophenyl)methyl]-N- methylbenzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(diphenylmethyl)benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(2-pyridin-2- ylethyl)benzamide ; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(pyridin-2- ylmethyl)benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[2-(2- chlorophenyl)ethyl]benzamide;
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-5-fluoropyrimidin-4- yl)phenyl] acetamide ;
N2-[3-(1H-imidazol-1-yl)propyl]-N-(4-{2-[(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)glycinamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- N2-(2-pyridin-3- ylethyl)glycinamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(pyridin-3- ylmethyl)benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(pyridin-4- ylmethyl)benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-methyl-N-
(phenylmethyl)benzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-cyclopentylbenzamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(2- chloropheny l)methy 1] benzamide ; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(4- chlorophenyl)methyl]benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(furan-2- y lmethy l)benzamide ;
3 -( { 4-[4-(acetylamino)phenyl]pyrimidin-2-yl } amino)-N- { [4-
(methyloxy)phenyl]methyl}benzamide; N-[4-(2-{[3-({4-[2-(methyloxy)phenyl]piperazin-1- yl}carbonyl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[3-
(methyloxy)propyl] benzamide ; N-(4-{2-[(3-{[(2/?,65)-2,6-dimethylmorpholin-4- yl]carbonyl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; 3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-[(6-chloropyridin-3- yl)methyl]benzamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-butylbenzamide;
N-(4- { 2- [(3 - { [4-(2-chlorophenyl)piperazin- 1 -yl] carbonyl } phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-ethyl-N-[2- (methyloxy)ethyl]benzamide;
N-(4-(2-(3-(3-morpholinopropoxy)phenylamino)pyrimidin-4-yl)phenyl)acetamide; N-(4-(2-(3-(2-(dimethylamino)ethoxy)phenylamino)pyrimidin-4-yl)phenyl)acetamide;
N-[3-({4-[4-(acetylamino)phenyl]-5-methylpyrimidin-2-yl}amino)phenyl]-2,6- dimethylbenzamide; N-[4-(2-{[4-(phenyloxy)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; 4-(4-aminophenyl)-N-[4-(phenyloxy)phenyl]pyrimidin-2-amine; N-{4-[2-({4-[(phenylmεthyl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide; 4-(4-aminophenyl)-N-[3-(morpholin-4-ylsulfonyl)phenyl]pyrimidin-2-amine; N-(4-{2-[(3,5-dimorpholin-4-ylphenyl)amino]-5-fluoropyrimidin-4- yl}phenyl)acetamide;
N-{4-[2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-(4-{2-[(4-{4-[(5-methyl-3-phenylisoxazol-4-yl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4- {2-[(4- {4-[(5-methyl- 1 -phenyl- 1 H-pyrazol-4-yl)methyl]piperazin- 1 - yl }phenyl)amino]pyrimidin-4-yl } phenyl)acetamide; N-(4-{2-[(4-{4-[(2-phenyl-1,3-thiazol-4-yl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-[4-(2- { [4-(4- { [6-(phenyloxy)pyridin-3-yl]methyl }piperazin- 1 - yl)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide ; N- { 4- [2-( {4- [4-(cyclohexylmethyl)piperazin- 1 -yl] phenyl } amino)pyrimidin-4- yl]pheny 1 } acetamide ; N-(4-{2-[(4-{4-[(15,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethyl]piperazin-1- yl } phenyl)amino] pyrim idin-4-yl } phenyl)acetamide ;
N-[4-(2-{[4-(4-pentylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(4-{4-[(2-chlorophenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; N- [4-(2- { [4-(4- { [3 ,5 -bis(methy loxy)pheny 1] methy 1 } piperazin- 1 - yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N-(4-{2-[(4-{4-[(4-fluorophenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ;
N-(4- { 2-[(4- { 4- [( 1 -methyl- 1 //-pyrrol-2-yl)methyl] piperazin- 1 - yl } phenyl)amino]pyrimidin-4-yl } phenyl)acetamide;
N-(4-{2-[(4-{4-[(2,4-dichlorophenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-
4-yl}phenyl)acetamide; N- {4- [2-( { 4- [4-(9H-fluoren-2-ylmethy l)piperazin- 1 -yljphenyl } amino)pyrimidin-4- yl]phenyl} acetamide; N-(4-{2-[(4-{4-[(3-methyl-2-thienyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-
4-yl } phenyl)acetam ide ; N-(4-{2-[(4-{4-[(5-ethylfuran-2-yl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl } phenyl)acetam ide;
N-(4.{2-[(4-{4-[(3-{[4-(l,l-dimethylethyl)phenyl]oxy}phenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N- { 4- [2-( { 4- [4-(3-thieny lmethyl)piperazin- 1 -yl]pheny 1 } amino)pyrimidin-4- yl]phenyl} acetamide; methyl 4-({4-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]piperazin-
1 -yl } methyl)benzoate ; N-(4-{2-[(4-{4-[3-(methylthio)propyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(4-{4-[(4-{[3-(dimethylamino)propyl]oxy}phenyl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-[4-(2- { [4-(4- { 2- [(phenylmethyl)oxy] ethyl } piperazin- 1 -yl)phenyl] amino } pyrimidin-
4-yl)phenyl]acetamide;
N-(4-{2-[(4-{4-[(2-chloroquinolin-3-yl)methyl]piperazin-1- yl } phenyl)amino]pyrimidin-4-yl } phenyl)acetamide; N-(4-{2-[(4-{4-[(4-chloro-2,6-dimethylphenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-{l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]pyrrolidin-3- yl}acetamide;
N2-[3-(4-methylpiperazin-1-yl)propyl]-N-(4-{2-[(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)glycinamide;
N2-(l-methylpiperidin-4-yl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)glycinamide; N-{4-[2-({4-[(pyridin-4-ylmethyl)oxy]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide ; N-(4-{2-[(4-{[2-(methyloxy)ethyl]amino}phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; 2-(dimethylamino)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)acetamide ;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)furan-2- carboxamide;
2-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)cyclobutanecarboxamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)azetidine-3- carboxamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)piperidine-2- carboxamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)piperidine-3- carboxamide;
N-[4-(2-{[4-(dimethylamino)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(4-chlorophenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4- { 2- [(3- { [(2-fluorophenyl)methyl] amino } phenyl)amino] pyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)piperidine-4- carboxamide;
2-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)propanamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)glycinamide; N-(4- {2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl } phenyl)morpholine-2- carboxamide; N2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)glycinamide ;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-beta-alaninamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)phenylalaninamide; N-[4-(2-{[4-(3-oxopiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-[4-(2-{[4-(4-{[5-(3-chlorophenyl)furan-2-yl]methyl}piperazin-1- yl)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide; N- [4-(2- { [4-(4- { [4-fluoro-2-(trifluoromethy l)phenyl] methyl } piperazin- 1 - yl)phenyl] amino } pyrimidin-4-yl)phenyl]acetamide ;
-V-[4-(2- { [4-(4- { [4-( 1 H-imidazol- 1 -yl)phenyl]methyl } piperazin- 1 - yl)phenyl]amino}pyiϊmidin-4-yl)phenyl]acetamide; N-[4-(2-{[4-(4-{[2,5-bis(trifluoromethyl)phenyl]methyl}piperazin-1- yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(4-{4-[(2,6-dimethylphenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-
4-yl}phenyl)acetamide; N-(4-{2-[(4-{4-[(2,3-dimethylphenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-
4-yl } phenyl)acetam ide ;
N-[4-(2- { [4-(4- { [2,4-bis(ethyloxy)phenyl]methyl } piperazin- 1 - yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N-[4-(2-{[4-(4-{[3-(ethyloxy)phenyl]methyl}piperazin-1-yl)phenyl]amino}pyrimidin- 4-yl)phenyl] acetamide ; N-{4-[2-({4-[4-(2,2'-bithien-5-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N- [4-(2- { [4-(4- { [4-(2-thienyl)pheny l]methyl } piperazin- 1 - yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N-(4-{2-[(4-{4-[(4-cyanophenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-[4-(2- { [4-(4- { [2,5-bis(methyloxy)phenyl]methyl }piperazin- 1 - yl)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide; N-{4-[2-({4-[4-(2,2-diphenylethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide ; N-{4-[2-({4-[4-(1H-pyrrol-2-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-{4-[2-(1H-indazol-6-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; N-{4-[2-(1H-indol-5-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; N-[4-(2-{[4-(morpholin-4-ylmethyl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(3-{[(3-fluorophenyl)methyl]amino}phenyl)amino]pyrimidin-4- yl } phenyl)acetamidε ; N-(4- { 2- [(3 - { [(4-fluorophenyl)methyl] amino } pheny l)amino] pyrimidin-4- yl}phenyl)acetamide;
4-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-N-ethylpiperazine-1- carboxamide;
N-{4-[2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide ;
N-{4-[2-(1H-indazol-5-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; N-[4-(2-{[4-(4-propylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-[4-(2-{[4-(4-butylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-{4-[2-({4-[4-(cyclopropylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl} acetamide;
4-[4-(methylsulfonyl)phenyl]-jV-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; ethyl N-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-N- methylglycmate;
4-[3-(methylsulfonyl)phenyi]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine;
4-[4-(methylthio)phenyl]-ΛL(4-morpholin-4-ylphenyl)pyrimidin-2-amine;
N-(4-{2-[(4-cyclohexylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-{4-[2-({4-[(tetrahydrofuran-2-ylmethyl)amino]phenyl}amino)pyrimidin-4- yljphenyl } acetamide;
N-{4-[2-({4-[(phenylmethyl)amino]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide; N- [4-(2- { [4-(acetylamino)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide ; methyl (4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)carbamate; l-ethyl-3-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)urea; ethyl l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]piperidine-3- carboxylate; ethyl [4-( {4- [4-(acety lam ino)phenyl]pyrimidin-2-yl } amino)phenyl] acetate ; 4-[4-(methyloxy)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; 4-[3-(methyloxy)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; 4-(1H-indol-5-yl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; 2-[(2-amino-2-oxoethyl)amino]-ΛL(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-
4-yl}phenyl)acetamide;
2-morpholin-4-yl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
2,6-dichloro-N-{3-[(4-{4-[(cyclopropylcarbonyl)amino]phenyl}pyrimidin-2- yl)amino]phenyl}benzamide; N2-(2-aminoethyl)- N2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)glycinamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- N2-1H-pyrazol-5- ylglycinamide; phenylmethyl N-{2-[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl }phenyl)amino] -2-oxoethyl } -L-alaninate; 4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}benzamide; 1,1-dimethylethyl [(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)methyl]carbamate;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)propanamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-phenylacetamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3- phenylpropanamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)tetrahydrofuran-2- carboxamide; 5-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyrazine-
2-carboxamide; 2-(ethyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- y 1 } pheny l)acetam ide ;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2- (phenyloxy)acetamide;
N-[4-(2-{[4-(1H-pyrrol-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N-[4-(2-{[4-(2,6-dimethylmorpholin-4-yl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide; ethyl l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]piperidine-4- carboxylate;
2-cyclopentyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3-pyridin-3- ylpropanamide; 6-(methyloxy)-N-(4-{2-[(4-inorpholin-4-ylphenyl)amino]pyrimidin-4- yl } pheny l)pyridine-3 -carboxamide ; methyl 4-[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)amino]-4- oxobutanoate; jV-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)butanamide; N-(4-{2-[(4-{bis[2-(methyloxy)ethyl]amino}phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; N-[4-(2-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide;
4-(4-(aminomethyl)phenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine; N-[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)methyl]acetamide; N-(4-morpholin-4-ylphenyl)-4- { 4- [(propylamino)methyl]phenyl } pyrimidin-2-amine ; N-(4-{2-[(4-piperidin-1-yIphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4-{2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; 2-(2-methylphenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)cyclopentanecarboxamide; N^V-dimethyl-N1-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)butanediamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- N2-pyrimidin-4- ylglycinamide;
3-chloro-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridine-4- carboxamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-piperidin-1- ylacetamide; N2-ethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)glycinamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-pyrrolidin-1- ylacetamide; 2-(1H-imidazol-1-yl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; jV-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-piperazin-1- ylacetamide;
N-[4-(2-{[4-(4-phenylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(3-chloro-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4-{2-[(4-piperazin-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; W-[6-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)pyridin-2-yl]-2,6- dichlorobenzamide;
'N- [6-( { 4- [4-(acetylam ino)phenyl] pyrimidin-2-yl } amino)pyrimidin-4-yl] -2,6- dichlorobenzamide;
W-(4-{2-[(6-aminopyridin-2-yl)amino]pyrimidin-4-yl}phenyl)acetamide; W-(4-{2-[(6-aminopyrimidin-4-yl)amino]pyrimidin-4-yl}phenyl)acetamide; '5-fluoro- N4-[2-(methyloxy)phenyl]- N2-[3-(methyloxy)phenyl]pyrimidine-2,4- diamine; '2,6-dichloro-N- { 3 - [(4- { [3 -chloro-4-(methyloxy)phenyl] oxy } pyrimidin-2- yl)amino]phenyl } benzamidc;
'4-{[2-chloro-4-(methyloxy)phenyl]oxy}-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine;
W-[4-({2-[(4-morpholin-4-ylphenyl)amino]-7H-pyπOlo[2,3-d]pyrimidin-4- yl}amino)phenyl]acetamide; W-[4-({2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}oxy)phenyl]acetamide; N-{4-[2-({4-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-{4-[2-({4-[(2/?,65)-2,6-dimethylmorpholin-4-yl]phenyl}amino)pyrimidin-4- yl] phenyl } acetamide ;
N-(4-{2-[(4-{4-[(2-methylphenyl)carbonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-{4-[2-({4-[4-(1H-pyrazol-4-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yljphenyl} acetamide;
N-(4-{2-[(3-piperazin-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N- [4-(2- { [3-(4- { [2-(methyloxy)phenyl] methyl } piperazin- 1 - yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N- { 4- [2-( { 3 - [4-( 1 ,3 -thiazol-2-ylmethyl)piperazin- 1 -yl]phenyl } amino)pyrimidin-4- yljphenyl} acetamide;
N-(4-{2-[(3-bromo-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-[4-(2-{[4-{[2-(diethylamino)ethyl]oxy}-3-(4-ethylpiperazin-1- yl)phenyl] amino } pyrirr.idin-4-yl)phenyl] acetamide ;
4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}benzoic acid;
4-(4-fiiran-2-ylphenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine;
4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine; 4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}benzonitrile; methyl 4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}benzoate;
4-(4-fluorophenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine;
N-[3-({2-[(4-morpholin-4-ylphenyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4- yl}amino)phenyl]acetamide; N-(4-morpholin-4-ylphenyl)-4-[4-(pyridin-3-ylamino)phenyl]pyrimidin-2-amine; N-(4-mθrpholin-4-ylphenyl)-4-[4-(pyridin-2-ylamino)phenyl]pyrimidin-2-amine; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)methanesulfonamide; l-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3- (phenylmethyl)urea;
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4- yl}phenyl)acetamide; N-(4-morpholin-4-ylphenyl)-4-quinolin-6-ylpyrimidin-2-amine;
4-[4-(5-methyl-1,3,4-oxadiazol-2-y4)phenyl]-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine;
N-(4-morpholin-4-y.lphenyl)-4-(4-pyrimidin-5-ylphenyl)pyrimidin-2-amine; N-(4-morpholin-4-ylphenyl)-4-quinoxalin-6-ylpyrimidin-2-amine; 2-chloro-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)benzamide ; 2-(2-fluorophenyl)-N-(4- { 2- [(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)acetamide;
N-(4- { 2- [(4-morpholin-4-y lphenyl)amino] pyrimidin-4-yl } phenyl)pyrimidine-5- carboxamide;
(25)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)azetidine-2- carboxamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)- N2- phenylglycinamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L-prolinamide; jV-(4-(2-(3-methoxy-4-morpholino-phenylamino)pyrimidin-4-yl)phenyl)acetamide; N-(4-(2-(4-(4-isobutyrylpiρεrazin-1-yl)phenylamino)-pyrimidin-4- yl)phenyl)acetamide ;
N-(4-(2-(4-(4-(3-methylbutanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide;
N-(4-(2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide ; N-(4-(2-(4-(4-(cyclobutanecarbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-(cyclopentanecarbonyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-(2-methoxybenzoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide ;
N-(4-(2-(4-(4-pentanoy!piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide;
N-(4-(2-(4-(4-picolinoylpipcrazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-isonicotinoylpiperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-( 1 -acetylpiperidine-4-carbonyl)piperazin- 1 -yl)phenylamino)pyrimidin-
4-yl)phenyl)acetamide;
N-(4-(2-(4-(4-(2-cyclopropylacetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide;
N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-(2-(2-methoxyethoxy)acetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-(2-(pyridin-3 -yl)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-(3-(pyridin-3-yl)propanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide;
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)tetrahydrofiiran-3- carboxamide;
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-2-(pyridin-3- yl)acetamide;
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)isonicotinamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D-prolinamide; N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4-yl)phenyl]-D- prolinamide; O-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- serinamide;
(5)-3-hydroxy-N-(4-(2-(4-morpholino-phenylamino)-pyrimidin-4-yl)-phenyl)- butanamide;
(i?)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamiάe; (/?)-2-amino-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide; 2-Hydroxy-2-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide ;
2-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2- carboxamide; (Λ)-N-(4-(2-(4-((J/?)-3-(dimethylamino)pyrrolidin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; 4-amino- 1 , 1 -dioxo-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)tetrahydro-2H-thiopyran-4-carboxamide;
(/?)-4-(4-aminophenyl)-N-(4-(3 -(dimethylamino)-pyrrolidin- 1 -yl)phenyl)-pyrimidin- 2-amine;
(i?)-N-(4-(2-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenylamino)-pyrimidin-4- yl)phenyl)-3-methoxy-propanamide; N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)piperazine-2- carboxamide; 2-amino-N-(4-(2-(4-morphoiinophenylamino)pyrimidin-4-yl)phenyl)- 1 ,2,3,4- tetrahydronaphthalene-2-carboxamide; 4-(4-( 1 , 1 -dioxo-isothiazolidin-2-yl)phenyl)-N-(4-morpholinophenyl)-pyrimidin-2- amine;
4-(4-(1H-tetrazol-1-yl)phenyl)-N-(4-morpholinophenyl)-pyrimidin-2-amine; (/?)-N-(4-(2-(3-(benzyloxy)-4-morpholino-phenylamino)-pyrimidin-4-yl)phenyl)- pyrrolidine-2-carboxamide; (5)-2-amino-3-hydroxy-N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4- yl)pheny l)propanam i de ;
N-(4-(2-(4-morpholinopheny lamino)pyrimidin-4-y l)phenyl)-2-( 1 H-tetrazol- 1 - yl)acetamide;
(/?)-N-(4-(2-(3-ethoxy-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-pyrrolidine-
2-carboxamide; (/?)-N-(4-(2-(1,2,3,4-tetrahydroquinolin-6-ylamino)-pyrimidin-4-yl)phenyl)- pyrrolidine-2-carboxamide; 3-hydroxy-N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-3- methylbutanamide ; (35',75)-7-(hydroxymethyl)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)quinuclidine-3-carboxamide; l-hydroxy-N-(4-(2-(4-morpholino-phenylamino)-pyrimidin-4- yl)phenyl)cyclopropanecarboxamide;
(iS)-2-amino-N-(4-(2-(3-methyl-4-morpholinophenylamino)pyrimidin-4- yl)pheny l)propanam ide ; (i?)-//-(4-(2-(3-methyl-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyπOlidine-
2-carboxamide; (Λ)-N-(4-(2-(4-morpholino-3-(trifluoromethyl)-phenylamino)pyrimidin-4-yl)-phenyl)- pyrτolidine-2-carboxamide;
(/?)-N-(4-(2-(4-(4-((5)-tetrahydrofuran-2-carbonyl)-piperazin-1-yl)-phenylamino)- pyrimidin-4-yl)phenyl)-pyπOlidine-2-carboxamide;
(7?)-N-(4-(2-(4-(4-((/?)-tetrahydrofuran-2-carbonyl)-piperazin-1-yl)-phenylamino)- pyrimidin-4-yl)phenyl)-pyrrolidine-2-carboxamide; 4-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)piperazine-1- carboxamide; 3-methoxy-N-(4-(2-(4-morpholino-3-(trifluoromethyl)phenylamino)pyrimidin-4- yl)phenyl)propanamide; 3-methoxy-N-(4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)phenyl)-propane-1- sulfonamide;
2-methoxy-N-(4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)phenyl)- ethanesulfonamide;
(iS)-3-hydroxy-N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide; (i?)-3-hydroxy-N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide ; N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-2,5-dihydro-1H-pyπOle-
2-carboxamide; l-(3-(dimethylamino)propyl)-3-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)urea;
(i?)-N-(4-(2-(4-(4-((5)-pyrrolidin-2-ylmethyl)piperazin-1-yl)phenylamino)pyrimidin- 4-yl)phenyl)pyrrolidine-2-carboxamide;
(7?)-2-amino-N-(4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)-5-methylpyrimidin-4- yl)pheny l)propanam i de ; l-(3-methoxypropyl)-3-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)urea; (Λ)-N-(4-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)-5-methylpyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide;
(5)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1-yl)-3- fluorophenylamino)pyrimidin-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide; (i?)-N-(4-(2-(3-chloro-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine- 2-carboxamide; l-(2-morpholinoethyl)-3-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)urea; l-(2-(dimethylamino)ethyl)-3-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)urea;
(S)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-2-(pyrrolidin-2- yl)acetamide; 2,3-dihydroxy-N-(4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)phenyl)- propanamide; (5)-2-amino-4-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)penlanamide; (i?)-2-amino-4-methyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pentanamide;
N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)isoindoline-1- carboxamide;
N-ethyl-4-(4-(4-(4-(tetrahydrofiiran-2-carboxamido)phenyl)pyrimidin-2- ylamino)phenyl)piperazine-l -carboxamide; N-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-2-carboxamide; (R)-N-(4-(2-(4-(4-((R) -2-aminopropanoyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (i?)-N-(4-(2-(4-(4-((5)-2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; N-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-3-carboxamide;
3-methoxy-N-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; N-(4-(2-(4-(4-pivaloylpiperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-3 -carboxamide ; (Λ)-N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-1- methylpyrrolidine-2-carboxamide; (7?)-N-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)pyrτolidine-2-carboxamide; (i?)-4-(4-(4-(4-(2-aminopropanamido)phenyl)-pyrimidin-2-ylamino)phenyl)-N- ethylpiperazine- 1 -carboxamide; (Λ)-2-amino-N-(4-(2-(4-(4-((/?)-pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (Λ)-2-amino-N-(4-(2-(4-(4-((5)-pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide;
(i?)-2-amino-N-(4-(2-(4-(4-((5)-2-aminopropanoyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (/?)-N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (5)-N-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin-l -yl)phenylamino)pyrimidin-4- yl)phenyl)cyciopropaπecarboxamide;
N-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide;
(/?)-N-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide; l-ethyl-3-(4-(5-methyl-2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)urea; (5)-N-(4-(2-(4-(4-(2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopiopanecarboxamide;
(/?)-N-(4-(2-(4-(4-(2-aminopiOpanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)-3-rr.ethoxypropanamide;
(5)-3-methoxy-N-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (i?)-N-(4-(2-(4-(4-(2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide; N-(4-(2-(4-(4-(cyclobutanecarbonyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide; N-(4-(2-(4-(4-isobutyrylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide;
N-(4-(2-(4-(l-butyryl-1,2,4-triazinan-4-yl)phenylamino)pyrimidin-4- yl)phenyl)butyramide;
1 -(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)-3 -ethy lui ea; N-(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)-3-methoxypropanamide; N-(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide;
N-(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)butyramide;
1 -ethyl-3-(4-(2-(4-(4-pivaloylpiperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)urea; 1 -(4-(2-(4-(4-(cyclobutanecarbonyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)-3-ethylurea; 1 -ethyl-3-(4-(2-(4-(4-isobutyrylpiperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)urea; jV-ethyl-4-(4-(4-(4-(3-ethylureido)phenyl)pyrimidin-2-ylamino)phenyl)piperazine-1- carboxamide;
(5)-1-ethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyiτolidine-2- carboxamide;
(7?)-1-(2-hydroxyethyl)-N-(4-(2-(4-morpholinobenzyl)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (i?)-1-isopropyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (5)-2-(dimethylamino)-vV-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)acetamide; 1 -(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)-3-ethylurea;
(i?)-1-ethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2- carboxamide;
4-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)tetrahydro-2H- pyran-4-carboxamide; (/?)-2-amino-N-(4-(2-(4-(4-isobutyrylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)propanamide; (i?)-2-amino-N-(4-(2-(4-(4-((/?)-2-aminopropanoyl)piperazin-1- yl)phenylartiino)pyrimidin-4-yl)phenyl)propanamide;
(i?)-N-(4-(5-methyl-2-(4-(4-(( 1 -methyl- 1 H-imidazol-2-yl)methyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (Λ)-2-amino-N-(4-(§-methyl-2-(4-(4-((l-methyl-1H-imidazol-2-yl)methyl)piperazin-
1 -yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (/?)-2-(dimethylamino)-N-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)acetamide;
(/?)-N-(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide;
(S)-_V-(4-(5-methyl-2-(4-(4-((l -methyl- 1H-imidazol-2-yl)methyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (i?)-2-amino-N-(4-(2-(4-(4-(2-(piperazin-1-yl)acetyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (2i?)-N-(4-(2-(4-(4-(tetrahydrofuran-3-carbonyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (5)-1-ethyl-3-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)urea;
(S)- 1 -(4-(2-(4-(4-(2-aminopropanoyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)-3 -ethylurea;
N-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)butyramide; (5)-N-(4-(2-(4-(4-(2-aminopropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)butyramide; 3-methoxy-N-(4-(5-methyl-2-(4-morpholinophenylamino)pyrimidin-4- yl)pheny l)propan am ide ; (/?)-2-amino-N-(4-(5-methyl-2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide;
2-(dimethylamino)-N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)acetamide;
1 -ethyl-3-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)urea;
3-methoxy-N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (/?)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-5-oxopyπOlidine-2- carboxamide;
(5)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-5-oxopyrrolidine-2- carboxamide; (iS)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-3- carboxamide; (2i?,35)-2-amino-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide;
(i?)-2-amino-N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide;
N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide;
N-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butyramide; N-(4-(2-(4-(4-(3 -methoxypropanoyl)piperazin- 1 -yl)pheny lamino)pyrimidin-4- yl)phenyl)butyramide;
N-(4-(2-(4-(4-(3-methcxypropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)cyclopropanεcarboxamide;
(i?)-2-amino-N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (2iS',37?)-2-amino-3-hydroxy-//-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide; (7?)-jV-(4-(2-(4-((25',6Λ)-2,ό-dimethylmorpholino)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide;
(/?)-N-(4-(2-(4-(4-(3-hydroxyρropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide;
1 -ethyl-3-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)urea; (i?)-1-ethyl-3-(4-(2-(4-(4-(pyrrolidine-2-carbonyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)urea; 3,3,3-trifluoro-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyriniidin-4- yl)phenyl)propanamide; (R)- 1 -(4-(2-(4-(4-(2-amiπoprcpanoyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)-3 -ethyl area;
2-(dimethylamino)-N-(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)acetamide;
(/?)-2-amino-N-(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; (Λ)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino.)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (i?)-2-amino-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide; N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)-3-methoxypropanamide;
N-(4-(2-(4-(4-(3-(diraethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)butyr amide; N-(4-(2-(4-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-3-carboxamide; N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamii;o)pyrirriidin-4-yl)phenyl)tetrahydrofuran-3-carboxamide; (/?)-JV-(4-(2-(4-(4-(2- (dimethylainino)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)teirahydrofuran-2-carboxamide;
2-(dimethylamino)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin- l-yl)phenylamino)pyrimidin-4-yl)phenyl)acetamide;
(/?)-N-(4-(2-(4-(4-(piperidine-4-carbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; 3-methoxy-N-(4-(2-(4-(4-(piperidine-4-carbonyl)piperazin-1- yl)phenylam:no)pyrimidin-4-yl)phenyl)propanamide; l-ethyl-3-(4-(2-(4-(4-(piperidine-4-carbonyl)piperazin-1-yl)phenylamino)pyrimidin-
4-yl)phenyl)urea; N-(4-(2-(4-(4-(3-(dimethyiamino)-2,2-dimethylpropanoyl)piperazin-1- yl)benzyl)pyrirri idin-4-y l)phenyl)acetamide ;
(S)-N-(4-(2-(4-(4-(2-(dimethy]amino)acetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-2-carboxamide;
(/?)-N-(4-(2-(4-(4-(3- methoxypropanoyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-2-carboxamide; (4iS)-4-hydroxy-N-(4-(2-(4-mcrpholinophenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (/?)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)tetrahydrofuran-2-carboxamide; (iS)-N-(4-(2-(4-(4-(3-niethoxypropanoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-2-carboxamide; N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)cyclopropanecarboxamide; N-(4-(2-(4-(4-(3 -methoxypropanoyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-3-carboxamide;
(5)-N-(4-(2-(4-(4-(pyrro!idine-2-carbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)butyramide ;
(2Λ)-N-(4-(2-(4-(4-(tetrεhydrofuran-2-carbonyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (i?)-N-(4-(5-chloro-2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-
2-carboxamidε; N-(4-(2-(4-(4-(3-(diethylamino)propanoyl)piperazin- 1 -yl)benzyl)pyrimidin-4- yl)phenyl)acetamide ; (5)-1-(2-hydroxyetbyl)-N-('4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-3-carboxamide;
(5)-2-amino-Nl-(4-(2-(4-morphoϊinophenylamino)pyrimidin-4- yl)phenyl)pentanediamide;
(Λ)-2-amino-Nl-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pentanediamide ; (/?)-2-amino-Nl-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)succjnamide; (i?)-N-(4-(2-(4-(4-((4-chloro- 1 -methyl- 1 H-pyrazol-3-yl)methyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (S)-I -ethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyπOlidine-3- carboxamide;
(i?)-N-(4-(2-(4-(4-(2-ethoxyacetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrciiάine-2-carboxamide;
(Λ)-N-(4-(2-(4-(4-(2-(pyrrolidin- 1 -yl)acetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (i?)-N-(4-(2-(4-(4-(2-morpholinoacetyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-1H-imidazole-4- carboxamide;
2-(dimethy lamino)-Λ^-(4-(2-(4-(4-(2-(piperazin- 1 -yl)acetyl)piperazin- 1 - yl)phenylami no)pyrim idin-4-yl)phenyl)acetamide ; o (5)-N-(4-(2-(4-(4-(3-(dimethylamino)-2,2-dimethylpropyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)tetrahydrofuran-2-carboxamide;
(i?)-2-hydroxy-2-methyl-yV-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)butanamide;
(5)-2-hydroxy-2-methyl-7^-(4-(2-(4-morpholinobenzyl)pyrimidin-4- υ yl)phenyl)butanam'de;
(i?)-2-methoxy-N-(4-C2-(4-rnorpholinophenylamino)pyrimidin-4- yl)phenyl)prcpanamide; (5)-2-methoxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide; (Λ)-N-(4-(2-(4-(4-(2-methoxyacetyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (i?)-N-(4-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide;
(5)-2-amino-N-(4-(5-methyl-2-(4-(4-((l -methyl- 1 H-imidazol-2-yl)methyl)piperazin- 1 -yl)phenylamino)pyrimidin-4-yl)phenyl)propanamide;
N-(4-(2-(4-(4-(piperidine-4 -carbonyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)tetrahydrofuran-3-carboxamide; (2i?,4iS)-4-hydroxy-N-(4-(2-(4-(4-(3-methoxypropanoyl)piperazin-1- yl)phenylamino)pyrimidiΗ-4-yl)phenyl)pyrrolidine-2-carboxamide; 1 -amino-N-(4-(2-(4-rnorpholinophenylamino)pyrimidin-4- yl)phenyl)cyclopentanecarboxamide; (7?)-N-(4-(2-(4-(4-formylpiperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)p>-riOlidine-2-carboxamide;
(i?)-1-(2-hydroxyethyl)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-3-carboxamide; l-amino-N-(4-(2-(4jmorpholinophenylamino)pyrimidin-4- yl)phenyl)cyclopropanecarboxamide; N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-l//-pyrrole-2- carboxamide; N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)-1H-imidazole-2- carboxamidε;
(5)-2-hydroxy-3,3-dimethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)pheny l)butanam i ae ; (i?)-2-cyclohexyl-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)acetamide; (5)-2-cyclohexyl-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)acetamide;
(5)-2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide; l-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)cyc!obutanecarboxamide; (i?)-N-(4-(2-(6-morpholinopyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2- carboxamide; (5)-N-(4-(2-(3-chloro-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-
2-carboxamide; (2i?,3i?)-2-amino-3-inethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)peritanamide; l-hydroxy-N-(4-(2-(4-moipholinophenylamino)pyrimidin-4- yl)phenyl)cyclopentanecarboxamide;
(/?)-N-(4-(2-(4-(4-(4-(dimεthylamino)butanoyl)piperazin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (i?)-N-(4-(2-(4-(2-methoxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- ylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (i?)-2-amino-N-(4-(2-(4-rnorpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide; (i?)-2-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pentanamide;
(Λ)-2-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)hexanamide; (Λ)-2-amino-3-methoxy-.V-(4-(2-(3-methoxy-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide;
(25,3i?)-2-amino-3-rpethyl-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)pentanamide ; (i?)-N-(4-(2-(3-fluoro-4-niorpholinophenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-
2-carboxamide; N-(4-(2-(3-methoxy-4-morphϋlinophenylamino)pyrimidin-4-yl)phenyl)-2-(1H- tetrazol- 1 -yl)acetamide;
(5)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)indoline-2- carboxamidc; (/?)-tert-butyl 2-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenylcarbamoyl)ρyrrolidine- 1 -carboxylate; l-acetyl-4-amino-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)piperidine-4-carboxamide;
(/?)-2-amino-3-methoxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide;
(5)-N-(4-(2-(3-fluoro-4-morpholinophenylamino)pyrimidin-4-yl)phenyl)pyπOlidine-
2-carboxamide; (i?)-2-amino-N-(4-(2-(3-fluoro-4-morpholinophenylamino)pyrimidin-4- yl)phenyl)propanamide; 2-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)acetamide; (7?)-N-(4-(2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)pyrrolidine-2-carboxamide; (Λ)-N-(4-(2-(4-(4-((l -methyl- 1H-pyrrol-2-yl)methyl)piperazin-1- yl)phenylamino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide; (i?)-N-(4-(2-(4-(4-((i?)-pyrrolidin-2-ylmethyl)piperazin- 1 -yl)phenylamino)pyrimidin-
4-yl)phenyl)pyrrolidine-2-carboxamide; (2iS',3aS',7a5)-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)octahydro- 1H-indole-2-carboxamide;
N-(4-{2-[(4-morphoϋn-4-ylphenyl)amino]pyrimidin-4- yllpheny^cyclopropanecarboxamide;
N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)cyclopiopanecarboxamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)valinamide; N-(4-{2-[(4-{4-[(l-melhyl-1H-imidazol-2-yl)methyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-(4-{2-[(3,5-dimorpholin-4-ylphenyl)amino]-5-methylpyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D-alaninamide; N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
2-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2- phenylacetamide; N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide; 3-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)propanamide ;
N-(4-{2-[(4-morpholin-4-y!phenyl)amino]pyrimidin-4-yl}phenyl)prolinamide; N-(4-{2-[(4-morpho!in-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L-alaninamide; N-(4-{2-[(4-{4-[3-(dimethylamino)-2,2-dimethylpropyl]piperazin-1- yl}phenyl)amincjpyrimidin-4-yl}phenyl)acetamide; N-(4-{2-[(4-{4-[3-(methyioxy)propanoyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-(4- { 2- [(4-morphol in-4-ylphenyl)amino]pyrimidin-4-yl } phenyl)- 1 ,3-thiazole-4- carboxamide; N-(4-{2-[(2-methyl-4-moipholin-4-ylphenyl)amino]pyrimidin-4- yl } pheny l)acetamide ;
N-(4-{2-[(4-pyrrolidin-1-y!phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-[4-(2- { [4-(diethy laminc)phenyl] amino } pyrim idin-4-yl)phenyl] acetamide ; N-(4-{2-[(4-azepan-1-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-{4-[2-({4-[methyl(2-phenylethyl)amino]phenyl}amino)pyrimidin-4- yl]phenyl} acetamide;
N-[4-(2-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]amino}pyrimidin-4- yl)phenyl] acetamide;
N-[4-(2-{[4-(2-oxopiperidin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-[4-(2-{[4-(2-methylpipεridin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L-valinamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D-valinamide; 2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)aianinamide
N-(4-{2-[(4-morphoiin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)tryptophanamide; N-(4-{2-[(4-morpholin-4-yiphenyl)amino]pyrimidin-4-yl}phenyl)-l, 2,3,4- tetrahydroisoquinoline- 1 -carboxamide; O-(l,l-dimethylethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-L-serinamide
3-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)tetiahydrofuran-3-carboxamide; bis( 1 , 1 -dimethylethy!) (2R)-2- { [(4- {2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)aminc]carbonyl}piperazine-1,4-dicarboxylate; N-(4-{2-[(4-{4-[2-(2-fluorophenyl)acetyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(4-{4-[2-(2-methy!phenyl)acetyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(4-{4-[2-(2-fluoiOphenyl)acetyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N- { 4-[2-( { 4- [4-(3 -thieny] carbonyl)piperazin- 1 -yl] phenyl } amino)pyrimidin-4- yl]phenyl } acctam ide; N-(4-{2-[(4-{4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4-{2-[(4-{4-[(3-methylfuran-2-yl)carbonyl]piperazin-1- yl}phenyl)amino]ρyrimidin-4-yl}phenyl)acetamide;
N-(4-(2-(4-(4-(3-fluoro-2 -methylbenzoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide;
N-(4-(2-(4-(4-(1H-imidazole-4-carbonyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-(2-methoxynicotinoyl)piperazin-1-yl)phenylamino)pyrimidin-4- yl)phenyl)acetamide; N-(4-(2-(4-(4-(4-fluoro-3 -methylbenzoyl)piperazin- 1 -yl)phenylamino)pyrimidin-4- yl)phenyl)acetarnide; N-{4-[2-({4-[4-(naphthalen-2-ylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acotamidc;
N-{4-[2-({4-[4-(quinolin-8-ylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N- [4-(2- { [4-(4- { [4-( 1 , 1 -dimethylethyl)phenyl] sulfonyl } piperazin- 1 - yl)phenyl] am ino } pyrimidin-4-yl)phenyl] acetamide; N- [4-(2- { [4-(4- { [5-bronio-2-(methyloxy)phenyl] sulfonyl } piperazin- 1 - yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(4-{4-[(phenylmethyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-[4-(2- { [4-(4- { [3-(trifluoromethyl)phenyl]sulfonyl } piperazin- 1 - yl)phenyl]amiπo}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(4-{4-[(2-methylphenyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- y 1 } phenyl)acetam ide ; N-(4-{2-[(4-{4-[(3-fmorophenyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- y 1 } pheny l)acetam ide;
N-(4-{2-[(4-{4-[(2,4-difluorophenyl)sulfonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-{4-[2-({3-[4-({4-[(trifluoromethyl)oxy]phenyl}methyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide; N-(4- {2-[(3- {4-[( 1 -methyl- 1 H-imidazol-2-yl)methyl]piperazin- 1 - yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-{4-[2-({3-[4-({2-[(trifluoromethyl)oxy]phenyl}methyl)piperazin-1- yl]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide; N-(4- { 2-[(3 - { 4- [(3 -chlorophenyl)methy l]piperazin- 1 -yl } phenyl)amino] pyrimidin-4- yl } phenyl)acetamide ;
N-{4-[2-({3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N- { 4-[2-( { 3 - [4-( 1 ,3 -benzodioxol-5 -ylmethyl)piperazin- 1 -yljphenyl } amino)pyrimidin-
4-yl]phenyl} acetamide; N-{4-[2-({3-[4-(pyridin-2-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-{4-[2-({3-[4-(pyridin-3-yimethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-{4-[2-({3-[4-(1H-pyrroi-2-ylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
4-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-N- (phenylmethyl)piperazine-1-carboxamide;
N-[4-(2-{[3-(4-{[2-(methylcxy)phenyl]carbonyl}piperazin-1- yl)phenyl] am ino } pyrimidin-4-yl)phenyl] acetamide; N-{4-[2-({3-[4-(1H-pyrazol-4-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yljphenyl } acetamide ; N-{4-[2-({3-[4-(3-pyridin-3-ylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-(4-{2-[(3-{4-[3-(methyloxy)propanoyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl } phenyl)acetamide; N- [4-(2- { [3-(4- { 2- [(4-fluorophenyl)oxy] acetyl } piperazin- 1 - yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-{4-[2-({3-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-{4-[2-({3-[4-(pyridin-4-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-{4-[2-({3-[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-(4-{2-[(3-{4-[(2-methylphenyl)carbonyl]piperazin-1-yl}phenyl)amino]pyrimidin-
4-yl } phenyl)acetamide ; N-{4-[2-({3-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yljphenyl } acexamide; N-{4-[2-({3-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-{4-[2-({3-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N- [4-(2- { [3-(methyloxy)-4-morpholin-4-ylphenyl] amino } pyrimidin-4- yl)phenyl]tetrahydrofuran-3-carboxamide; (2R)-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-2-carboxamide; (2S)-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-2-carboxamide; N-(4-{2-[(4-{4-[(2-fluoropbenyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- y 1 } phenyl)acetami de ;
N-(4-{2-[(3-{4-[(3,5-dichlorophenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; ethyl 3-[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)amino]-3- oxopropanoatc; N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}tetrahydrofuran-3-carboxamide; N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}tetrahydrofuran-3-carboxamide;
N-ethyl-4-{4-[(4-{4-[(tetrahydrofuran-3-ylcarbonyl)amino]phenyl}pyrimidin-2- yl)amino]phenyl}piperazine-1-carboxamide; N- [4-(2- { [4-(4-D-alanylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4- yl)phenyl]tetrahydrofiiran-3-carboxamide; N-[4-(2- { [4-(4-L-alanylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4- yl)phenyl]tetrahydrofuran-3-carboxamide;
N-[4-(2-{[4-(4-D-proly!piperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-3-carboxamide;
N-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4- y l)pheny 1] tetrahydrofur an-3 -carboxamide;
N-{4-[2-(1H-benzim5dazo!-6-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; 4-(4-furan-2-ylphenyl)-N-(4-morpholin-4-ylphenyl)pyrimidin-2-amine; N-(4-morpholin-4-ylphenyl)-4-[4-(pyrimidin-2-ylamino)phenyl]pyrimidin-2-amine; N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-5-methylpyrimidin-4- yl)phenyl]cycloproρanecarboxamide; N-[4-(2- { [4-(4-ethylpiperazin- 1 -yl)phenyl]amino}pyrimidin-4- yl)phenyl]cyclopropanecarboxamide; N-(4-{2-[(3,5-dimorpholin-4-ylphenyl)amino]-5-methylpyrimidin-4-yl}phenyl)- N2,
N2-dimethylglycinamide; N2, N2-dimethyl-N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)glycinamide;
N-(4-{5-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide;
N-{4-[2-({4-[4-(2-methylρropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-D-prolinamide; N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-D-prolinamide; N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-D-ρrolinamide; N-ethyl-4-[4-({4-[4-(D-piOlylamino)phenyl]pyrimidin-2-yl}amino)phenyl]piperazine-
1 -carboxamide;
N-[4-(2-{[4-(4-D-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-D- prolinamide;
N-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-D- prolinamide; l-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)piperidine-2-carboxamide; N-{4-[2-({4-[4-(piperidin-4-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; l-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- prolinamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-pyridin-4- ylacetamide; 2-(3-fluorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; 3-(4-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)propanamide; 2-(3-chlorophenyl)-N^(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetemide;
2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3- phenylpropanamide;
(lR,2R)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2- phenylcyclopropanecarboxamide ; 2-(4-fluorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide; 3-(2-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)propanamide; 3-(3-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)propanamide;
3-(2-fluorophenyl)-N-(4- (2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)propanamide;
Nalpha,Nalpha-dimethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-L-phenylalaninamide; 2-(2-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-pyridin-2- ylacetamide;
2-(4-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)acetarr) ide ; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2-{4- o
[(trifluoromethyl)oxy]phenyl}acetamide; 2-[2-(methyloxy)phenyi]-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
2-[3-(methyloxy)phenyl]-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
2-[4-(methyloxy)pheiiy?]-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N- [4-(2- { [4-(4-ethy lpiperazin- 1 -yl)pheny 1] amino } pyrimidin-4-yl)phenyl] -D- alaninamide; N- {4-[2-( {4-[4-(N,N-dimethylglycyl)piperazin- 1 -yljphenyl } amino)pyrimidin-4- yl]phenyl}acetamide; N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-3-
(methy loxy)propanamide ;
(2R)-2-amino-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-2- phenylethanamide;
N2, N2-dimethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-
D-alaninamide; l-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- prolinamide; N2, N2-dimethyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- alaninamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-1- phenylcycloprcpanecarboxamide;
2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)butanamide;
(2S)-1-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)azetidine-2-carboxamide; 2,4,6-trichloro-N-(3-{[4-(4-methyl-2-thienyl)pyrimidin-2- yl] amino } propyl)benzamide ; N-[3-({4-[3,4-bis(methyloxy)phenyl]pyrimidin-2-yl}amino)propyl]-2,6- dichlorobenzamide; 2,6-dichloro-N-[3-({4-[(4-morpholin-4-ylphenyl)amino]pyrimidin-2- yl } amino)propyl] benzamide; 2,6-dichloro-N-(3- { [4-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-5-fluoropyrimidin-2- yl]amino}prcpyl)benzamide; 2,6-dichloro-N- {3-[(4-{3- [(dimethylamino)methyl] phenyl } pyrimidin-2- yl)amino]propyl}benzamide;
2,6-dichloro-N-[3-({4-[3-(l-methylethyl)phenyl]pyrimidin-2- yl}amino)propyl]benzamide;
2,6-dichloro-N-{3-[(4-{4-[(l-methylethyl)oxy]phenyl}pyrimidin-2- yl)amino]propyl } benzamide; N-[3-({4-[3-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2,6- dichlorobenzam i de ; 2,6-dichloro-N-[3-({4-[(E)-2-phenylethenyl]pyrimidin-2- yl}amino)propyljbenzamide; phenyl (4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)carbamate; phenylmethyl (4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)carbamate; N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-3-(methyloxy)propanamide; N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}cyclopropanecarboxamide;
4- { 4- [(4- { 4- [(cyclopropy icarbonyl)amino]phenyl } pyrimidin-2-yl)amino]phenyl } -N- ethylpiperazine-1 -carboxamide;
N- { 4- [2-( { 4- [4-(cyclobutylcarbonyl)piperazin- 1 -yljphenyl } amino)pyrimidin-4- yl]phenyl}-3-(methyloxy)propanamide; 3-(methyloxy)-N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1- yl]phenyl } araino)pyrimidin-4-yl]phenyl } propanamide; N-ethyl-4-(4- { [4-(4- { [3 -(methyloxy)propanoy 1] amino } phenyl)pyrimidin-2- yl]amino}pher.yl)piperazine-l -carboxamide; N-[4-(2-{[4-(4-ethylpipcrazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-2- phenylacetamide; ° l-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyrrolidin-2-one; N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl } -D-alaninamide;
N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-D-alaninamide; (2S)-2-hydroxy-3-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- y 1 } phenyl)butanamide ; (2R)-2-hydroxy-3-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } pheny l)butanamide ;
N- {4-[2-( {4-[4-(cyclopropylcarbonyl)piperazin- 1 -yl]phenyl } amino)pyrimidin-4- yl]phenyl}-D-alaninamide;
(2 S)-2-amino-N-(4- { 2 - [(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl } pheny l)-2- phenylethanamide ; 2-amino-2-(4-chlorophenyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } pheny l)acetamide ; N-(4-{2-[(4-morpholiri-4-ylphenyl)aniino]pyrimidin-4-yl}phenyl)morpholine-3- carboxamide: 1 -ethyl-3- [4-(2- { [4-(4-ethylpiperazin- 1 -yl)-3 -(methyloxy)phenyl] amino } pyrimidin-4- yl)phenyl]urea;
N- [4-(2- { [4-(4-ethylpipεrazin- 1 -yl)-3-(methy loxy)phenyl] amino } pyrimidin-4- yl)phenyl]-D-ρrolinamide;
N-[4-(2-{[4-(4-ethyipiperazin-1-yl)-3-(methyloxy)phenyl]amino}pyrimidin-4- yl)phenyl] acetam ide ; 1 -(2,6-dichlorophenyl)-3 -(3- { [4-(4-methyl-2-thienyl)pyrimidin-2- yl]amino}propyl)urea; l-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-(4-methyl-2-thienyl)pyrimidin-2- yl] amino } propyi)urea; 2,6-dichloro-N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2- yl}amino)proρyl]benzenesulfonamide;
N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2,6- difluorobenzenesulfonamide;
N-[3-({4-[4-(dimethyJamino)phenyl]pyrimidin-2-yl}amino)propyl]naphthalene-2- sulfonamide; N- [3-( { 4- [4-(dimethylam ino)phenyl] pyrimidin-2-yl } amino)propyl] -3 ,4- bis(methyloxy)'oenzenesulfonamide; 3-chloro-N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2-yl}amino)propyl]propane-
1 -sulfonamide;
N-[3-({4-[4-(dimethylamino)phenyl]pyrimidin-2-yl}amino)propyl]propane-1- sulfonamide; methyl (3-{[4-(2,4-dichlorophenyl)pyrimidin-2-yl]amino}propyl)carbamate;
1 -methylethyl (3-{ [4-(2,4-dichlorophenyl)pyrimidin-2-yl]amino}propyl)carbamate; phenylmethyl (3-{[4-(2,4-dichlorophenyl)pyrimidin-2-yl]amino}propyl)carbamate; N- {4- [2-( { [3 -(3-chlorophenyl)isoxazol-5 -yl] methyl } amino)pyrimidin-4- yl]phenyl}acet?mide; ethyl 4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)piperidine-1-carboxylate; 1 , 1 -dimethylethyl 4-( {4-[4-(acetylamino)pheny l]pyrimidin-2-yl } amino)piperidine- 1 - carboxylate;
N-(4-{2-[(4-cyanophenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4-{2-[(4-morpholm-4-ylphenyl)amino]pyridin-4-yl}phenyl)acetamide; 1,1 -dimethylethyl { l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2- yl } amino)phenyl]piperidin-4-y 1 } carbamate ; N-{4-[2-({4-[4-(cyclopropylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}cyclopropanecarboxamide;
N-{ l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]piperidin-4- yl}acetamide;
4-(4-aminophenyl)-N-[4 (4-aminopiperidin-1-yl)phenyl]pyrimidin-2-amine;
N- [4-(2- { [4-(4-ethylpiperazin- 1 -yl)phenyl] amino } -5-methylpyrimidin-4-yl)phenyl] -3-
(methyloxy)proρanamide ;
N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}tetrahydroflιran-2-carboxamide;
N-{4-[2-({4-[4-(cyclobυtylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}tetrahydrofuran-2-carboxamide; N- {4- [2-( { 4- [4-(2,2 -dimethylpropanoyl)piperazin- 1 -yl]phenyl } amino)pyrimidin-4- yl]phenyl}tetrahydrofuran-2-carboxamide; N-cyclopropyl-4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}benzamide; N-[2-(methyloxy)ethyl]-4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}benzamidε;
2,6-dichloro-N-{3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]propyl}benzamide; 2,6-dichloro-N-(3-{[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)pyrimidin-2- yl]amino}propyi)benzamide;
2,6-dichloro-N-(3-{[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-methylpyrimidin-2- yl] amino } propyl)benzamide; N-(4-{2-[(3-{[(2,6-dichlorophenyl)carbonyl]amino}propyl)amino]pyrimidin-4- yl}phenyl)morpholine-4-carboxamide; 2,6-dichloro-N-{3-[(4-{4-[(cyclopropylcarbonyl)amino]phenyl}pyrimidin-2- yl)amino]propyl } benzamide;
N-(4-{2-[(3-{[(2,6-dichlorophenyl)carbonyl]amino}propyl)amino]pyrimidin-4- yl}phenyl)thiophene-2-carboxamide;
2,6-dichloro-N-(3-{[4-(4-{[N-(2-morpholin-4- ylethyl)glycyl]amino}phenyl)pyrimidin-2-yl]amino}propyl)benzamide; l-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)ethanone; ( 1 E)- 1 -(4- { 2- [(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl } phenyl)ethanone oxime;
N-{4-[2-({4-[4-(cyclopiOpylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-2-phc:nylacetamide;
N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2-bromobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2-fluorobenzamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)propyl]-2-chlorobenzamide; N-[4-(2-{[3-(morpholin-4-ylsulfonyl)phenyl]amino}pyrimidin-4- yl)phenyl] acetamide ; N-{4-[2-({3-[(cyclohexylmethyl)amino]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide; N-(4- { 2-[(3 - { [(5 -bromo-2-fluorophenyl)methy 1] amino } phenyl)amino]pyrimidin-4- yl}phenyl)acetdmide; N-(4-{2-[(3-{[(2,5-dimethylphenyl)methyl]amino}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(3,4-dimorpho!in-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-{4-[2-({4-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}cycloρropanecarboxamide; N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}butanamide;
N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}butanamide;
N-{4-[2-({4-[4-(cyclobutylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}butsnamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridine-2- carboxamide; 2-hydroxy-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)benzamide;
3-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)benzamide;
4-(methyloxy)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)benzamide; 4-chloro-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)benzamide; (2R)-N- [4-(2- { [4-(4-ethylpiperazin- 1 -yl)pheny 1] amino } pyrimidin-4- yl)phenyl] tetrahydrofuran-2-carboxamide ; (2S)-N-[4-(2-{[4-(4-echylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-2-carboxamide; l-(2-hydroxyethyl)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)-L-prolinamide;
N-(4-{2-[(4-morphGlin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)thiophene-2- carboxamide; N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-3-carboxamide; 2-phenyl-N-{4-[2-({4-[4-(pyridin-3-ylcarbonyl)piperazin-1- yl]phenyl } amino)pyrimidin-4-yl]phenyl } acetamide;
3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-N-(diphenylmethyl)benzamide; N-[4-(2- { [4-(4-me thylpiperazin- 1 -y l)pheny 1] amino } pyrimidin-4-yl)pheny 1] acetamide ; N-{4-[2-({4- [4-(phenylcarbonyl)piperazin- 1 -y 1] phenyl } amino)pyrimidin-4- yljphenyl} acetamide;
N-{4-[2-({4-[4-(2-cyclopentylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-{4-[2-({4-[4-(cyclohexylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- y 1] phenyl } acet am ide ; N-(4-{2-[(4-{4-[(2-chlorophenyl)carbonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl } pheny l)acetamide;
N-(4-{2-[(4-{4-[(3-fluorophenyl)carbonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-(4- {2-[(4- {4-[(3-fluoro-4-methylphenyl)carbonyl]piperazin- 1 - yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-(4-{2-[(4-{4-[(3,4-dichlorophenyl)carbonyl]piperazin-1- yl}phenyl)anii!io]pyrimidin-4-yl}phenyl)acetamide;
N-(4-{2-[(4-{4-[(3,5-dichlorophenyl)carbonyl]piperazin-1- yl } phenyl)amino] pyrimidin-4-y 1 } phenyl)acetamide;
N- [4-(2- { [4-(4- { [3 -(methy loxy)phenyl] carbonyl } piperazin- 1 - yl)phenyl] amino } pyrimidin-4-yl)phenyl] acetamide ; N-(4-{2-[(4-{4-[(4-chlorophenyl3carbonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl } phenyl)acetamide ; N-(4-{2-[(4-{4-[(4-methylphenyl)carbonyl]piperazin-1-yl}phenyl)amino]pyrimidin-
4-yl}phenyl)acetamide; N-(4-{2-[(4-{4-[(l-methyl-1H-pyrrol-2-yl)carbonyl]piperazin-1- yl}phenyl)amiπo]pyrimidin-4-yl}phenyl)acetamide;
N- {4-[2-( {4-[4-(furan-2-ylcarbonyl)piperazin- 1 -yljphenyl } amino)pyrimidin-4- yl]phenyl} acetamide;
N-[4-(2- { [4-(4- { 2- [(4-fluorophenyl)oxy] acetyl } piperazin- 1 - yl)phenyl]ainino}pyrimidin-4-yl)phenyl]acetamide; N-(4-{2-[(4-morpholin~4-ylphenyl)amino]pyrimidin-4-yl}phenyl)furan-3- carboxamide; N-{4-[2-({4-[4-(phenylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-{4-[2-({4-[4-(2-thienylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl} acetamide;
N-(4-{2-[(4-{4-[(4-fluorophenyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N- [4-(2- { [4-(4- { [4-(m ethyloxy)phenyl] sulfonyl } piperazin- 1 - yl)phenyl] am ino } pyrimidin-4-yl)phenyl] acetamide; N-(4-{2-[(4-{4-[(4-chlorophenyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl } phenyl)acctamide ; N-(4-{2-[(4-{4-[(3^chlorophenyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)aceιamide;
N-{4-[2-({4-[4-(biphenyl-4-ylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide; N- {4-[2-({4-[4-(naphthalen- 1 -ylsulfonyl)piperazin- 1 -yl]phenyl } amino)pyrimidin-4- yl]phenyl}acetamide; N-(4-{2-[(3-{4-[(2-chlorophenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-[4-(2-{[3-(4-{[3-(mεthyloxy)phenyl]methyl}piperazin-1- yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide;
N-{4-[2-({3-[4-(3-methylbutyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-{4-[2-({3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazin-1- yl]phenyl } amino)pyrimidin-4-yl]phenyl } acetamide; N-{4-[2-({3-[4-(cyc!opropylmethyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yljphenyl } acei amide; N-(4-{2-[(3-{4-[3-(n"iethylthio)propyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide;
N-(4- { 2- [(3- {4- [(4s { [3 -(dimethy lamino)propyl]oxy } phenyl)methyl]piperazin- 1 - yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N-{4-[2-({3-[4-({3-[(trifluoromethyl)oxy]phenyl}methyl)piperazin-1- yl]phenyl } amino)pyrimidin-4-yl]phenyl } acetamide; 4-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-N-phenylpiperazine-
1-carboxamide; N-[4-(2- { [3-(4-proρanoylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4- yl)pheny 1] acetamide ; N-{4-[2-({3-[4-(phenylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl} acetamide;
N-{4-[2-({3-[4-(2 -phenyl acety l)piperazin- 1 -y 1] phenyl } amino)pyrimidin-4- yljphenyl} acetamide;
N-{4-[2-({3-[4-(cyclopentylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide N-{4-[2-({3-[4-(2-pyridin-3-ylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl } acetamide ; N- {4- [2-( { 3 - [4-(2-cyc J openty lacety l)piperazin- 1 -y l]phenyl } amino)pyrimidin-4- yljphenyl} acetamide;
N-(4-{2-[(3-{4-[(2-ch!orophenyl)carbonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N-(4-{2-[(3-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}phenyl)amino]pyτimidin-4- yl}phenyl)acetamide;
N-(4-{2-[(3-{4-[(3,4-dichlorophenyl)carbonyl]piperazin-1- yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-(4- {2-[(3- {4-[( 1 -methyl- 1 H-pyrrol-2-yl)carbonyl]piperazin- 1 - yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide;
N2, N -dimethyl-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-
4-yl)phenyl]glycinamide; 3-(methyloxy)-N-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4- y l)pheny 1] propanamide ; N-(4-{2-[(4-{4-[(2-chlorophenyl)sulfonyl]piperazin-1-yl}phenyl)amino]pyrimidin-4- yl}phenyl)acetamide; N- {4- [2-( { 3 - [4-(cyclopropylcarbonyl)piperazin- 1 -yljphenyl } amino)pyrimidin-4- yl]phenyl}acεiamide;
N-{4-[2-({3-[4-(2-cyclopropylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-[4-(2- { [3-(4- { [3-(methyloxy)phenyl]carbonyl}piperazin- 1 - yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- y 1] phenyl } acε tam ide ; l-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]piperidine-3- carboxylic acid; 1,1-dimethylethyl methyl {2-[(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl }phenyl)amlno] -2-oxoethyl } carbamate;
1 , 1 -dimethylethyl [4-(2-{ [4-(4-ethylpiperazin- 1 -yl)phenyl] amino }pyrimidin-4- yl)phenyl]carbamate;
N- [4-(2- { [4-(4-ethylpiperazjn- 1 -yl)phenyl] amino } pyrimidin-4-yl)phenyl] -N2, N2- dimethylglycinamide;
4-(4-aminophenyl)-N-[4-(4-ethylpiperazin-1-yl)phenyl]pyrimidin-2-amine;
Nalpha- {[(1,1 -dimethylethyl)oxy] carbonyl } -N-(4- { 2-[(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)-L-phenylalaninamide;
Nalpha- {[(1,1 -dimethy lelhyl)oxy] carbonyl } -N-(4- { 2- [(4-morpholin-4- ylphenyl)amino]pyrimidin-4-yl}phenyl)-D-phenylalaninamide; N-(4-{2-[(4-morphoIin-4 -ylphenyl)amino]pyrimidin-4-yl}phenyl)-D- phenylalaninamide; N-(4-{2-[(4-morphoϋn-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-L- phenylalaninεmide;
N-[4-(2-{[4-(4-ethylρiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-L- valinamide;
N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]-D- valinamide; l-ethyl-3-[4-(2-{[3-(methyloxy)-4-morpholin-4-ylphenyl]amino}pyrimidin-4- yl)phenyl]ureH; (2R)-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)piperidine-2- carboxamide; N-[4-(2- { [4-(4-ethylρiperazin- 1 -yl)phenyl] amino } -5 -methylpyrimidin-4- yl)phenyl] acetam ide ;
4-{4-[(4-{4-[(N,N-dirnεthylglycyl)amino]phenyl}pyrimidin-2-yl)amino]phenyl}-N- ethylpiperazine-1 -carboxamide;
N-{4-[2-({4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-N2, N2-dimethylglycinamide; N- { 4- [2-( { 4- [4-(cyclobuty lcarbonyl)piperazin- 1 -y l]phenyl } amino)pyrimidin-4- yl]phenyl} -N2, N2-dimethylglycinamide; N2, N2-dimethyl-N-{4-[2-({4-[4-(2-methylpropanoyl)piperazin-1- yl]phenyl } amino)pyrimidin-4-yl] phenyl } glycinamide; N-{4-[2-({4-[4-(cyclopropylcarbonyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yl]phenyl}-N2,N2-dimethylglycinamide;
N- [4-(2- { [4-(4-D-alany lpiperazin- 1 -yl)phenyl] amino } pyrimidin-4-yl)pheny 1] -N2, N2- dimethylglycinamide;
N- [4-(2- { [4-(4-L-alanylpiperazin- 1 -yl)pheny 1] amino } pyrimidin-4-yl)pheny 1] -N2, N2- dimethylglycinamide; N-(4-{2-[({ l-[(2,6-dichlorophenyl)carbonyl]azetidin-3-yl}methyl)amino]pyrimidin-
4-yl}phenfl)acetamide; N-(4-{2-[(3-morpho!in-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide; N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)cyclohexyl]-2,6- dichlorobenzam ide; N-{4-[2-({[4-(4-methylpiperazin-1-yl)phenyl]methyl}amino)pyrimidin-4- yl]phenyl}acetamide; N-[4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6- dichlorobenzamide;
N-{4-[2-(piperidin-4-ylamino)pyrimidin-4-yl]phenyl}acetamide; N-{4-[2-({l-[(2,6-dichlorophenyl)carbonyl]piperidin-4-yl}amino)pyrimidin-4- yl]phenyl}acetamide;
N-{4-[2-({4-[(2-hydroxyethyl)(5xy]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide; l-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-3-phenylurea; N-[5-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)-2-(4-ethylpiperazin-1- yl)phenyl] -2,ό-dichlorobenzamide;
1 - [4-(2- { [4-(4-ethylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4-yl)phenyl] -3-
(phenylmethyl)urea; N2, N2-dimethyl-N- { 4- [2-( { 4-[4-(pyridin-3 -ylcarbonyl)piperazin- 1 - yl]phenyl } amino)pyrimidin-4-yl]phenyl } glycinamide; N-(3-fluoro-4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)cyciopropanecarboxamide; N-(4- {2-[(4-{4-[( 1 -methyl- 1 H-imidazol-2-yl)methyl]piperazin- 1 - ylJphenyOaminoJpyrimidin^-ylJpheny^cyclopropanecarboxamide; N-[4-(2-{[4-(4-L-alaiiylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]acetamide;
N-[4-(2- { [4-(4-L-proly Ipiperazin- 1 -yl)phenyl] amino } pyrimidin-4- yl)phenyl]acetamide; N- [4-(2- { [4-(4-D-alanylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4- yl)phenyl]acelamide; N-[4-(2-{[4-(4-D-proiylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)pheny 1] acetamide ; N-{4-[2-({4-[4-(2-piperazin-1-ylacetyl)piperazin-1-yl]phenyl}amino)pyrimidin-4- yljphenyl } acetamide ;
N-[4-(2-{[4-(4-L-alar.ylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-2-carboxamide;
N-[4-(2-{[4-(4-L-prolylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-2-carboxamide; N- [4-(2- { [4-(4-D-,alanylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4- yl)phenyl]tetrahydrofuran-2-carboxamide; N-[4-(2-{[4-(4-D-proIylpiperazin-1-yl)phenyl]amino}pyrimidin-4- yl)phenyl]tetrahydrofuran-2-carboxamide; l-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)-1H- pyrrole-2-carboxamide;
3-fluoro-N-(4-{2-[(4-moipholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridine-4- carboxamide; 6-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridine-
3-carboxamide; N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridazine-4- carboxamide; 2-cyclopropyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl}phenyl)acctamide;
N-(4-{2-[(4-morpho'-in-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)isoxazole-5- carboxamide;
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)pyridine-3- carboxamide; 4-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4- yl } phenyl)benzamide ; N- [4-(2- { [4-(4-ethylpiperazin- 1 -yl)phenyl] amino } pyrimidin-4-yl)phenyl] -D- prolinamide; N-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]butanamide; and l-ethyl-3-[4-(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)phenyl]urea; and the active agent is selected from one or more of the following compounds:
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(l- methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;
N-(4-bromo-3-chlorG-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(l- methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;
7-({[(3aR,5r,6aS)-2-af;etyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-N-(4- bromo-3-chloro-2-fluoiOphenyl)-6-(methyloxy)quinazolin-4-amine; N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)- octahydrocyclopenta[c]pyiτol-5-ylmethyl]oxy}quinazolin-4-aniine; ethyl (3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazol\n-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyπOle-2(1H)- carboxylate;
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2- (methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine;
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- ethyloctahydrocyclopenta[c]pyiτol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(3,4-dichloro-1-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2- methylpropyl)octahydrocyclopenta[c]pyiτol-5-yl]methyl}oxy)quinazolin-4-amine;
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- aminej
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyc)openta[c]pyπOl-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4-bromo-2,3-dichlorcphenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyc!openta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(3,4-dichlorophenyi)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl] methyl } oxy)-6-(methyloxy)quinazolin-4-amine ;
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2- methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine;
N-(4-bromo-2,3-dich)orophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3-ylmetlιyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(4,5-dichloro-2-flucrophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- ][1,4]oxazin-3-ylmetl\yi]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(4-bromo-5-chloro-2-fl uorophenyl)-7- { [(3R,9aS)-hexahydro- 1H-[1 ,4]oxazino[3,4- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine; -(3-chloro-2,4-difluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c] [ 1 ,4]oxazin-3-ylmethyl]oxy } -6-(methyloxy)quinazolin-4-amine;
N-(4-bromo-3-chloro-2-fluorophenyl)-7- { [(3 S ,9aS)-hexahydro- 1H-[1 ,4] oxazino[3 ,4- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(3-chloro-2,4-difluorophenyl)-7- { [(3 S ,9aS)-hexahydro- 1 H- [ 1 ,4] oxazino [3 ,4- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(3,4-dichlorophenyl)-7-[(hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3- ylmethyl)oxy]-6-(methyloxy)quinazolin-4-amine;
N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- ] [ 1 ,4]oxazin-3-ylmethyl]oxy} -6-(methyloxy)quinazolin-4-amine;
-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c] [ 1 ,4] oxazin-3 -ylmethyljoxy} -6-(methyloxy)quinazolin-4-amine ;
N-(4-bromo-5-chloro-2-fluorophenyl)-7- { [(3 S ,9aS)-hexahydro- 1 H- [ 1 ,4] oxazino[3 ,4- c] [ 1 ,4]oxazin-3-ylmethyl]oxy } -6-(methyloxy)quinazolin-4-amine;
N-(3 ,4-dichloro-2-fluorophenyl)-7- { [(3R,9aS)-hexahydro- 1 H- [ 1 ,4] oxazino [3 ,4- c] [1 ,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(4-bromo-3-chloro-2-fluorophenyl)-7- { [(3R,9aS)-hexahydro- 1 H- [ 1 ,4] oxazino[3 ,4- c] [ 1 ,4]oxazin-3-ylmethyl]oxy} -6-(methyloxy)quinazolin-4-amine;
N-(3 ,4-dichlorophenyl)-7- { [(3R,8aR)-hexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4] oxazin-3 - ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(4-bromo-5 -chloro-2-fluorophenyl)-7- { [(3 S ,8aS)-hexahydro- 1 H-pyrτolo [2, 1 - c] [1 ,4]oxazin-3-ylmethyl]oxy} -6-(methyloxy)quinazolin-4-amine;
N-(3,4-dichlorophenyl)-7-{[(3S,8aR)-hexahydro-1H-pyrrolo[2,l-c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(3 ,4-dichlorophenyl)-7- { [(3 S ,8aS)-hexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4] oxazin-3 - ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(3,4-dichlorophenyl)-7-{[(3R,8aS)-hexahydro-1H-pyrrolo[2,l-c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,l- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,l- ] [ 1 ,4] oxazin-3-ylmethyl] oxy } -6-(methy loxy)quinazolin-4-amine ;
N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,l- ][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine;
Figure imgf000742_0001
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,6aS)- octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-amine; ethyl (3aR,5r,6aS)-5-[({4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl}oxy)methyl]hexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate;
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,6aS)-2- (methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine;
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol- 5-yl] methyl } oxy)-6-(methyloxy)quinazolin-4-amine ;
N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,6aS)-2-(2- methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine;
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;
N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta- [c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;
N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;
N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;
N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;
N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;
Figure imgf000744_0001
1 , 1 -dimethylethyl (3 aR,6aS)-5 -( { [4-[(4-bromo-2,3 -dichlorophenyl)amino] -6- (methyloxy)quinazolin-7-yl]oxy}methyl) hexahydrocyclopenta-[c]pyrrole-2(1H)- carboxylate;
N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5r,6aS)-octahydrocyclo-penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;
1, 1 -dimethylethyl (3aR,6aS)-5-({ [4-[(3 ,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl) hexahydrocyclopenta-[c]pyrrole-2(1H)- carboxylate;
N-(3,4-dichlorophenyl)-7-({[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5- yl]methyl } oxy)-6-(methyloxy)quinazolin-4-amine;
7-{[(3-eni/o)-8-azabicyclo[3.2.1]oct-3-ylmethyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine;
1 , 1 -dimethylethyl (3-e«fi?o)-3-(2-{[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate;
7-( { 2- [(3 -en dø)-8-azabicyclo[3.2.1] oct-3-yl] ethyl } oxy)-N-(3 ,4-dichlorophenyl)-6- (methyloxy) quinazolin-4-amine;
N- { [(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy } -3- fluorophenyl)(methyl)amino]carbonothioyl}-2-phenylacetamide; l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl) imidazolidin-2-one ;
N'-(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3-fiuorophenyl)-N-methyl-N-(2- phenylethyl)sulfamide;
1 -(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } -3-fluoropheny l)piperidin-2-one ;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4-phenyl-1,3-thiazol-2- amine;
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(phenylmethyl) B enzenesulfonamide ;
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(2-phenylethyl) Benzenesulfonamide;
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(3-phenylpropyl) Benzenesulfonamide;
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (phenylmethyl)carbamate;
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N-(3-phenylpropyl) Benzenesulfonamide;
N- [(Z)- [(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } -3 - fluorophenyl)amino](imino)methyl]-2-phenylacetamide; N,N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-bis-(3- phenylpropane- 1 -sulfonamide);
N2- [(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } -3 -fluorophenyl)sulfonyl] -N 1 - phenylglycinamide ;
N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)amino]carbonothioyl}-2- pheny 1 acetam ide ;
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-amine; benzyl-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-methyl}- carbamic acid tert-butyl ester;
N2-acetyl-Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2- (phenylmethyl)glycinamide; benzyl- { [6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylcarbamoyl] -methyl } - carbamic acid tert-butyl ester;
N2-acetyl-Nl-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-4-phenylbutanamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2- (phenylmethyl)glycinamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-3- pheny lpropanam ide ;
N'-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-(2-phenylethyl)-N- (phenylmethyl)sulfamide;
N-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-methyl}- benzamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N,N'- bis(phenylmethyl)sulfamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(4- fluorophenyl)propanediamide; l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-[(4- methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-2-[3- (trifluoromethyl)phenyl]acetamide;
6- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } -5 -fluoro-N-(2-piperidin- 1 -ylethyl)- 1,3- benzothiazol-2-amine; 6- { [6,7-bis(methyloxy)quinolin-4-yl]oxy } -5-fluoro-N-(2-pyrrolidin- 1 -ylethyl)- 1 ,3- benzothiazol-2-amine ;
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{2-[3- (trifluoromethyl)phenyl] ethyl} - 1 ,3-benzothiazol-2-amine;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[3- (trifluoromethyl)phenyl] acetamide ;
N 1 -(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N2-(2- pheny lethyl)glycinamide ; benzyl-{[5-chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylcarbamoyl]- methyl}-carbamic acid tert-butyl ester;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[3,5- bis(trifluoromethyl)phenyl]acetamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2-{[3- (trifluoromethyl)phenyl]methyl}glycinamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2-(2- phenylethyl)glycinamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridazin-3-yl)-N'-(4- fluorophenyl)propanediamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(3- chlorophenyl)propanediamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(4- chloropheny l)propanediamide ;
(2E)-N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-[(ethyloxy)imino] propanamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-1-(phenylmethyl)prolinamide;
1 -(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy }phenyl)-4-(phenylmethyl) imidazolidin-2-one;
6,7-bis(methyloxy)-4-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}oxy)quinoline;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-(phenylmethyl)alaninamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-(phenylmethyl)leucinamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-(phenylmethyl)valinamide;
2-(Benzyl-methyl-amino)-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-methyl- butyramide; 2-Benzyloxyimino-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-2-phenyl- acetamide;
4-(4-{3-Chloro-5-[2-(4-fluoro-phenylcarbamoyl)-acetylamino]-pyridin-2-yloxy}-6- methoxy-quinolin-7-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester;
N - { 5-Chloro-6-[6-methoxy-7-( 1 -methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy] - P) yridin-3-yl}-Nl-(4-fluoro-phenyl)-malonamide;
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N'-(2,4-difluoro- phenyl)-malonamide;
-{5-Chloro-6-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-pyridin-3- yl } -N'-(4-fluoro-phenyl)-malonamide;
N-{5-Chloro-6-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-pyridin-3- yl}-N'-(4-fluoro-phenyl)-malonamide;
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N'-phenyl-malonamide;
1 , 1 -dimethylethyl 4-(3- { [4- [(2-fluoro-4- { [( 1 - { [(4- fluorophenyl)amino] carbonyl } cyclopropyl)carbonyl] amino } phenyl)oxy] -6-
(methyloxy)quinolin-7-yl]oxy}propyl)piperazine- 1 -carboxylate;
-(4- { [7- { [3-(diethylamino)propyl] oxy } -6-(methyloxy)quinazolin-4-yl] oxy } -3 - fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide;
N-(4-{ [7- { [3-(4-acetylpiperazin- 1 -yl)propyl]oxy} -6-(methyloxy)quinolin-4-yl]oxy } -3- fluorophenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
N-(3-fluoro-4- { [7-( { 3-[4-( 1 -methylethyl)piperazin- 1 -yl]propyl } oxy)-6- (methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide;
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)cyclobutane- 1,1 -dicarboxamide;
N- [3 -fluoro-4-( { 6-(methyloxy)-7- [(3-morpholin-4-ylpropyl)oxy] quinazolin-4- y 1 } oxy)phenyl] -N'-(4-fluorophenyl)cyclobutane- 1 , 1 -dicarboxamide;
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2,2-dimethylcyclopropane- 1 , 1 -dicarboxamide;
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)-2,2-dimethylcyclopropane- 1 , 1 -dicarboxamide ;
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2,2-dimethylcyclopropane- 1,1 -dicarboxamide;
(lR,2R,3S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}- 3-fluorophenyl)-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane- 1 , 1 -dicarboxamide; N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)-2,2-dimethylcyclopropane- 1 , 1 -dicarboxamide ;
N-(4- { [7- { [2-(diethylamino)ethyl] oxy } -6-(methyloxy)quinazolin-4-yl] oxy } -3 - fluorophenyl)-N'-(4-fluorophenyl)-2,2-dimethylcyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2,2-dimethylcyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)cyclobutane- 1 , 1 -dicarboxamide;
N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl } -N'-(4-fluorophenyl)cyclobutane- 1 , 1 -dicarboxamide;
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinazolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)cyclobutane- 1 , 1 -dicarboxamide ;
N-(4- { [7- { [3 -(diethylamino)propyl] oxy} -6-(methyloxy)quinolin-4-yl] oxy } -3 - fluorophenyl)-N'-(4-fluorophenyl)cyclobutane- 1 , 1 -dicarboxamide;
N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclobutane-l,l -dicarboxamide;
-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4- yl }oxy)phenyl] -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1-ylpropyl)oxy]quinolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
- [3-fluoro-4-( { 6-(methyloxy)-7- [(3 -piperidin- 1 -ylpropyl)oxy] quinolin-4- yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclobutane-l , 1 -dicarboxamide;
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
N - { 5-chloro-6-[(6-(methyloxy)-7- { [( 1 -methylpiperidin-4-yl)methyl]oxy } quinolin-4- yil)oxy]pyridin-3-yl}-N'-(4 fluorophenyl)cyclopropane- 1,1 -dicarboxamide;
N- [5 -chloro-6-( { 6-(methyloxy)-7- [(piperidin-4-ylmethyl)oxy] quinolin-4- yl}oxy)pyridin-3-yl]-N'-(4-fluorophenyl)cyclopropane- 1,1 -dicarboxamide;
N- [5-chloro-6-( { 6-(methyloxy)-7- [(phenylmethyl)oxy] quinolin-4-yl } oxy)pyridin-3 -yl] ■ N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide; N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)cyclobutane- 1 , 1 -dicarboxamide;
N- { 3-fluoro-4- [(6-(methyloxy)-7- { [( 1 -methylpiperidin-4-yl)methyl] oxy } quinazolin-4- yl)oxy]phenyl } -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
N-(4-fluorophenyl)-N'- [2-methyl-6-( { 6-(methyloxy)-7- [(3 -morpholin-4- ylpropyl)oxy] quinolin-4-yl } oxy )pyridin-3 -yl] cyclopropane- 1 , 1 -dicarboxamide ;
-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4-ylpropyl)oxy]quinolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
N- { 3 -fluoro-4- [(7-(methyloxy)-6- { [( 1 -methylpiperidin-4-yl)methy 1] oxy } quinazolin-4- yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane- 1,1 -dicarboxamide;
N- [5 -fluoro-2-methyl-4-( { 6-(methyloxy)-7- [(3 -morpholin-4-ylpropyl)oxy] quinolin-4- yl } oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4-fluorophenyl)-N'-[2-methyl-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy] quinolin-4-yl } oxy)phenyl]cyclopropane- 1 , 1 -dicarboxamide ;
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N- { 3 -fluoro-4- [(6-(methyloxy)-7- { [3 -(4-methylpiperazin- 1 -yl)propy 1] oxy } quinolin-4- yl)oxy] phenyl} -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N- { 3 -fluoro-4- [(6-(methyloxy)-7- { [( 1 -methylpiperidin-4-yl)methy 1] oxy } quinolin-4- yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide;
N-(4-fluorophenyl)-N'- [4-( { 6-(methyloxy)-7- [(3-morpholin-4-ylpropyl)oxy] quinolin-4- yl } oxy )phenyl] cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4- { [6- { [3 -(diethylamino)propyljoxy } -7-(methyloxy)quinolin-4-yl] oxy } -3 - fluorophenyl)-N'-(4-fluorophenyl)cyclopropane- 1,1 -dicarboxamide;
N-(4- { [6- { [2-(diethylamino)ethyl]oxy } -7-(methyloxy)quinolin-4-yl]oxy } -3- fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-l , 1 -dicarboxamide;
( 1 S ,2R)-N- [3-fluoro-4-( { 6-(methyloxy)-7- [(3 -morpholin-4-ylpropy l)oxy] quinolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)-2-methylcyclopropane- 1 , 1 -dicarboxamide ;
(lR,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)-2-methylcyclopropane- 1 , 1 -dicarboxamide ; ( 1 R,2R)-N- [3-fluoro-4-( { 6-(methyloxy)-7- [(3-morpholin-4-ylpropy l)oxy] quinazolin-4- yl}oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcyclopropane-l,l-dicarboxamide;
( 1 R,2R)-N-(4- { [7- { [2-(diethylamino)ethyl]oxy } -6-(methyloxy)quinazolin-4-yl]oxy } -3 fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane-l,l-dicarboxamide;
1 , 1 -dimethylethyl 4-(3- { [4-[(2-fluoro-4- { [(( 1 R,2R)- 1 - { [(4-fluorophenyl)amino] carbonyl}-2-methylcyclopropyl)carbonyl]amino}phenyl)oxy]-6-(methyloxy)quinolin- 7-yl]oxy}propyl)piperazine-1-carboxylate;
(lR,2S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1- yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)-2-methylcyclopropane-
1,1-dicarboxamide;
( 1 R,2R)-N- { 3 -fluoro-4- [(6-(methyloxy)-7- { [3-(4-methylpiperazin- 1 - y l)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)-2-methylcyclopropane- 1,1-dicarboxamide;
( 1 R,2R)-N- [3 -fluoro-4-( { 6-(methyloxy)-7- [(3 -piperazin- 1 -y lpropyl)oxy] quinolin-4- yl } oxy)phenyl] -N'-(4-fluorophenyl)-2-methylcyclopropane- 1 , 1 -dicarboxamide;
(lR,2R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane- 1 , 1 -dicarboxamide;
(lR,2R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane- 1 , 1 -dicarboxamide;
(lR,2S)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane- 1 , 1 -dicarboxamide;
(lR,2S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane- 1,1 -dicarboxamide;
(lR,2S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinolin-4- yl } oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcyclopropane- 1 , 1 -dicarboxamide;
(lR,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin- 4-yl } oxy)phenyl] -N'-(4-fluorophenyl)-2,3 -dimethylcyclopropane- 1 , 1 -dicarboxamide ;
( 1 R,2R,3 S)-N- { 3 -fluoro-4- [(6-(methyloxy)-7- { [3-(4-methylpiperazin- 1 ■ yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1 , 1 -dicarboxamide;
(lR,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1 , 1 -dicarboxamide;
( 1 R,2R,3 S)-N- { 3-fluoro-4-[(6-(methyloxy)-7- { [3-(4-methylpiperazin- 1 ■ yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)-2,3- dimethylcyclopropane-1 , 1 -dicarboxamide;
(2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane- 1,1 -dicarboxamide;
(2R,3R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-l , 1 -dicarboxamide;
Figure imgf000752_0001
l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)pyrrolidin-2-one;
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (2-phenylethyl)carbamate;
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-[2-(phenyloxy)ethyl] Benzenesulfonamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-phenylpropane-1- sulfonamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-2-phenylacetamide;
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2-amine;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2- phenylacetamide ;
N 1 -(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy } -3-fluorophenyl)-N2- (phenylmethyl)glycinamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2-yl)-2- phenylacetamide;
Nl-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide ;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-3-phenylpropanamide;
Nl-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2-methyl-N2- (phenylmethyl)glycinamide;
4-[(2-amino-1,3-benzothiazol-6-yl)oxy]-6,7-bis(methyloxy)-1-(2-oxo-2-phenylethyl) quinolinium;
N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)amino]carbonothioyl}-2-phenylacetamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2- (trifluoroacetyl)glycinamide ;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N'-(4- fluorophenyl)propanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N,N'-bis(2- phenylethyl)sulfamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-hydroxy-1- (phenylmethyl)ethyl]urea;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-3-oxo-4- pheny lbutanam ide ;
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-[2-(phenyloxy)ethyl]-1,3- benzothiazol-2-amine; 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-methyl-N-(2-phenylethyl)-1,3- benzothiazol-2-amine;
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{[3-(trifluoromethyl)phenyl] methyl }-1,3-benzothiazol-2-amine;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-[3- (trifluoromethyl)phenyl]propanediamide;
Nl -(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N2- { [3- (trifluorom ethyl )phenyl] methyl } glycinamide ;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-{2-[3- (trifluoromethyl)phenyl] ethyl } glycinamide ;
Nl-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N2- (phenylmethyl)glycinamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[2- chloro-5-(trifluoromethyl)phenyl]acetamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2-{2-[3- (trifluoromethyl)phenyl]ethyl}glycinamide; l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4- (phenylmethyl)imidazolidin-2-one;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(2- chlorophenyl)propanediamide;
Nl-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N2-methyl-N2- (phenylmethyl)glycinamide;
(2E)-N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-[(methyloxy)imino] propanamide;
(2E)-N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2- { [(phenylmethyl)oxy] imino } propanamide ; l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-3-[(4-methylphenyl)sulfonyl]-4- (phenylmethyl)imidazolidin-2-one;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-(phenylmethyl)-4,5-dihydro- 1 ,3-oxazol-2-amine;
1 -(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-(phenylmethyl)piperazin-2-one;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl-N2-(phenylmethyl) alaninamide;
Nl-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl-N2-(phenylmethyl) eucinamide; 4-benzyl-1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-tetrahydro-pyrimidin-2-one;
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-2-phenoxyimino-propionamide;
4-[4-(4-Benzyl-piperidin-1-yl)-phenoxy]-6,7-dimethoxy-quinoline;
- { 5 -Chloro-6- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -pyridin-3 - yl}-N'-(4-fluoro-phenyl)-malonamide;
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-2,2-difluoro-N'-(4- fluoro-phenyl)-malonamide;
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N'-(4-fluoro-phenyl)- N'-methyl-malonamide;
N- { 5 -Chloro-6- [6-methoxy-7-(3 -morpholin-4-yl-propoxy)-quinolin-4-y loxy] -pyridin- 3-yl}-N'-(4-fluoro-phenyl)-malonamide;
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N'-(3-fluoro-phenyl)- malonamide;
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N'-(4-fluoro-phenyl)- 2,2-dimethyl-malonamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(4- fluorophenyl)cyclobutane- 1 , 1 -dicarboxamide ;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'- (phenylmethyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'- phenylcyclopropane- 1 , 1 -dicarboxamide ;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(2- phenylethyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylpyridin-3-yl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-{4-[(7-chloroquinolin-4-yl)oxy]-3-fluorophenyl} -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
N-{4-[(7-chloroquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide ;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide; N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylphenyl)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloro-2-methylpyridin-3-yl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,5-difluorophenyl)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,3,5-trifluorophenyl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-2-methylphenyl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ;
N-(4- { [6,7-bis(methyloxy)quinolin-4-yl]oxy } -2-chloro-5-methylphenyl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(3-fluoro-4-{[6-hydroxy-7-(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4- fluoropheny l)cyclopropane- 1 , 1 -dicarboxamide ;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-chloro-5-fluorophenyl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4- { [6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl] oxy } -3 -fluoropheny l)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4-fluorophenyl)-N'-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4- fluoropheny l)cyclopropane- 1 , 1 -dicarboxamide ;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-1- (phenylmethyl)azetidine-3,3-dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)azetidine-3,3- dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-[(4-fluorophenyl)methyl] yclopropane- 1 , 1 -dicarboxamide; N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(2-morpholin-4- ylethyl)cyclopropane- 1 , 1 -dicarboxamide;
N-(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } phenyl)-N'- [2-(piperidin- 1 - ylmethyl)phenyl]cyclopropane- 1,1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Nl-[2-(pyrrolidin-1-ylmethyl) phenyljcyclopropane- 1,1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-[3-(morpholin-4-ylmethyl) phenyl] cyclopropane- 1 ,1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-[2-(morpholin-4-ylmethyl) phenyl] cyclopropane- 1 , 1 -dicarboxamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-phenylcyclopropane-l,l- dicarboxamide;
N-[3-(aminomethyl)phenyl]-N'-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl) cyclopropane- 1 , 1 -dicarboxamide;
N-(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } phenyl)-N'- [3 -(piperidin- 1 - ylmethyl)phenyl] cyclopropane- 1 , 1 -dicarboxamide;
N-(4- { [6,7-bis(methyloxy)quinolin-4-yl] oxy } phenyl)-N'- [3 -(pyrrolidin- 1 - ylmethyl)phenyl] cyclopropane- 1 , 1 -dicarboxamide; ethyl [(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl) amino] (oxo)acetate ;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'- (phenylmethyl)ethanediamide ;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2- phenylethyl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'- phenylethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2-morpholin-4- ylethyl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-{2-[4-(methyloxy) phenyl]ethyl}ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2,3-dihydro-1H- nden- 1 -yl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2,3-dihydro-1H- nden-2-yl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(l , 2,3,4- etrahydronaphthalen- 1 -yl)ethanediamide; N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[(2S)-1,2,3,4- tetrahydronaphthalen-2-yl]ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-(4-methylphenyl) ethyl]ethanediamide;
-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(2-phenylpropyl) Ethanediamide;
-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-(4-chlorophenyl) ethyl]ethanediamide; ethyl [(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)amino](oxo)acetate;
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N'-(2- phenylethyl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(l, 2,3,4- tetrahydronaphthalen-2-yl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-(l- methylpyrrolidin-2-yl)ethyl]ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[2-(phenyloxy) ethyl] ethanediam ide ;
N'-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-N-(2- phenylethyl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-{[3- (trifluoromethyl)phenyl]methyl}ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolm-4-yl]oxy}-3-fluorophenyl)-N'-{2-[3- (trifluoromethyl)phenyl]ethyl } ethanediamide;
N- { 3 -fluoro-4- [(6-(methyloxy)-7- { [( 1 -methylpiperidin-4-yl)methyl] oxy } quinolin-4- yl)oxy]phenyl}-N'-(2-phenylethyl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(1,2,3,4- tetrahydroisoquinolin-1-ylmethyl)ethanediamide;
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-[(2-methyl-l, 2,3,4- tetrahydroisoquinolin- 1 -yl)methyl]ethanediamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- phenethyl-oxalamide;
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N'-(2-isopropyl-1,2,3,4- tetrahydro-isoquinolin-1-ylmethyl)-oxalamide;
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N'-(2-ethyl-l, 2,3,4- tetrahydro-isoquinolin- 1 -ylmethyl)-oxalamide ; N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-N'- phenethyl-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}- '-phenethyl-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}- '-phenethyl-oxalamide;
N-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-N'- phenethyl-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-N'-methyl-N'-phenethyl-oxalamide;
2-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-{3-fluoro-4-[6-methoxy-7-(l-methyl-piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo-acetamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -2- oxo-2-(3-phenyl-pyrrolidin- 1 -yl)-acetamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2- oxo-2-(2-phenyl-morpholin-4-yl)-acetamide;
N-(2-Dimethylamino-2-phenyl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-oxo-2-phenyl-ethyl)-oxalamide;
N-Benzyl-N'-{3-fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -oxalamide ;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- [2-(2-fluoro-phenyl)-ethyl]-oxalamide;
N-[2-(3-Chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl} -oxalamide;
N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- [2-(2-methoxy-phenyl)-ethyl]-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-pyridin-3 -yl-ethyl)-oxalamide ;
N-Benzyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -oxalamide ;
N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N' [2-(2-trifluoromethyl-phenyl)-ethyl]-oxalamide; N-[2-(2-Ethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(2,4-Dimethyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (IS -phenyl-2-p-tolyl-ethyl)-oxalamide;
-[2-(4-Chloro-phenyl)-ethyl] -N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-oxalamic acid;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- [2-(3-fluoro-phenyl)-ethyl]-oxalamide;
N-[2-(2-Chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- [2 -(3 -methoxy-phenyl)-ethy 1] -oxalamide ;
N-(1,2-Diphenyl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl} -oxalamide;
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(4-Ethyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide ;
N-[2-(4-Ethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(4-Ethoxy-3-methoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- [2-(4-phenoxy-phenyl)-ethyl]-oxalamide;
N- [2-(3 -Ethoxy-4-methoxy-phenyl)-ethyl] -N'- { 3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl} -oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-pyridin-2-yl-ethyl)-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-pyridin-4-yl-ethyl)-oxalamide; N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl } -N'- [2-(4-fluoro-phenyl)-ethyl]-oxalamide;
N- [2-(2-Bromo-phenyl)-ethyl] -N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (2R-phenyl-propyl)-oxalamide ;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- indan- 1 -yl-oxalamide ;
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-N'-isobutyl-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-N'-(3-methyl-butyl)-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(2R-phenyl-propyl)-oxalamide;
N- {3 -Fluoro-4- [6-methoxy-7-( 1 -methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl}-N'-(2-phenyl-propyl)-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-( 1 -methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-indan-2-yl-oxalamide ;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- ( 1 R-phenyl-ethyl)-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- ( 1 S-phenyl-ethyl)-oxalamide;
N-[2-(3-Bromo-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N-[2-(2,6-Dichloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide ;
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(3-Bromo-4-methoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide; N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (2-o-tolyl-ethyl)-oxalamide ;
N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- (2-m-tolyl-ethyl)-oxalamide;
N-[2-(3-Ethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(3,4-Dimethyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide ;
N-[2-(2,5-Dimethyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide ;
N-[2-(3-Chloro-4-propoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N-[2-(4-Butoxy-3-chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide ;
N-[2-(4-tert-Butyl-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide ;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- [2-(4-sulfamoyl-phenyl)-ethyl]-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- [2-(4-hydroxy-3 -methoxy-phenyl)-ethyl] -oxalamide ;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- [2-(3-hydroxy-4-methoxy-phenyl)-ethyl]-oxalamide;
N-(2,4-Dichloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide ;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (4-fluoro-2-trifluoromethyl-benzyl)-oxalamide;
N- { 3 -Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- (l-p-tolyl-ethyl)-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (3-fluoro-4-trifluoromethyl-benzyl)-oxalamide;
N-(3-Chloro-4-fluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- [ 1 -(3-methoxy-phenyl)-ethyl]-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- ( 1 -naphthalen-2-yl-ethyl)-oxalamide; N-(4-Chloro-3-trifluoromethyl-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N - { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- ( (11 -p-tolyl-ethyl)-oxalamide;
N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (6-trifluoromethyl-pyridin-3-ylmethyl)-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-methyl-benzyl)-oxalamide;
- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (3-methyl-benzyl)-oxalamide;
- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (4-fluoro-3-trifluoromethyl-benzyl)-oxalamide;
N-(3,5-Dichloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (lR,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (lS,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide;
N-Cyclopentyl-N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -oxalamide ;
N-[I -(4-Bromo-phenyl)-ethy 1] -N'- { 3-fluoro-4- [6-methoxy-7-(piperidin-4-y lmethoxy)- quinolin-4-y loxy] -phenyl } -oxalamide ;
N-(2-Fluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -oxalamide ;
N-[2-(3,4-Dichloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide;
N-(4-Fluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyl } -oxalamide;
N-(2,3-Difluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (2-phenoxy-ethyl)-oxalamide;
N-(2,2-Diphenyl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl } -oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- 2-(4-methoxy-phenyl)-ethyl]-oxalamide; -{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-phenyl-propyl)-oxalamide;
N-[2-(4-Bromo-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N-{4-[7-(l-Ethyl-piperidin-4-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (3-fluoro-5-trifluoromethyl-benzyl)-oxalamide;
N-(3,5-Difluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl} -oxalamide;
N-(2-Chloro-5-trifluoromethyl-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N'-(2-dimethylamino-2- phenyl-ethyl)-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (4-methoxy-benzyl)-oxalamide;
N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (4-trifluoromethyl-benzyl)-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N' (3 -methoxy-benzyl)-oxalamide ;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (3-trifluoromethyl-benzyl)-oxalamide;
N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- (3-trifluoromethoxy-benzyl)-oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (2-methoxy-benzyl)-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-trifluoromethyl-benzyl)-oxalamide;
N-(3-Chloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin- 4-yloxy] -phenyl} -oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-trifluoromethoxy-benzyl)-oxalamide;
N-(2-Chloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin- 4-yloxy] -phenyl } -oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (4-trifluoromethoxy-benzyl)-oxalamide; N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(4-methoxy-benzyl)-oxalamide ;
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-(4-trifluoromethyl-benzyl)-oxalamide;
N-{4-[7-(Azetidin-3-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-N'- phenethyl-oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-( 1 -methyl-azetidin-3-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N'-phenethyl-oxalamide;
-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-hydroxy-2-phenyl-ethyl)-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N' ( 1 R-phenyl-propyl)-oxalamide;
- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- ( 1 R-phenyl-propyl)-oxalamide;
N-(3 ,4-Difluoro-benzyl)-N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide;
N-(2,6-Difluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide ;
N- { 3-Fluoro-4-[6-methoxy-7-( 1 -methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy] - phenyl } -N1- [2-(4-fluoro-phenyl)-ethyl] -oxalamide ;
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -N'-phenyl-oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (3 -fluoro-phenyl)-oxalamide ;
N-(4-Chloro-3-fluoro-phenyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide ;
N-(3,4-Dimethoxy-phenyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (3 -methyl-buty l)-oxalamide ;
N-(3,3-Dimethyl-butyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -oxalamide;
N-(4-Chloro-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin- 4-yloxy] -phenyl } -oxalamide ;
N-(3,5-Dimethoxy-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl} -oxalamide; N-(4-Butyl-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yl oxy] -phenyl } -oxalam ide ;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (2-p-tolyl-ethyl)-oxalamide;
N-(3,5-Bis-trifluoromethyl-benzyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- pyrazin-2-ylmethyl-oxalamide;
- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N1- yridin-2-ylmethyl-oxalamide;
- { 3 -Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy] -phenyl } - '-phenethy 1-oxalamide ;
N-{3-Fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinazolin-4-yloxy]- phenyl}-N'-phenethyl-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (2-fluoro-3-trifluoromethyl-benzyl)-oxalamide;
N-[2-(2-Bromo-6-methoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -oxalamide ;
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl } -N-methyl-oxalamide ;
N-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- (2-fluoro-5-trifluoromethyl-benzyl)-oxalamide;
N- { 3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- 1 -(4-fluoro-phenyl)-ethy 1] -oxalamide ;
N-( 1 S-Benzyl-2-oxo-2-pyrrolidin- 1 -yl-ethyl)-N'- { 3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide;
N- [2-(4- Amino-phenyl)-ethy 1] -N'- { 3 -fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl} -oxalamide;
2-(4-Benzyl-piperidin-1-yl)-N-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy] -phenyl } -2-oxo-acetamide;
N-Ethyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -oxalamide ;
N- { 3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -N'- sopropyl-oxalamide; N-Butyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl } -oxalamide ;
-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-methoxy-ethyl)-oxalamide;
N-Cyclopropylmethyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin- 4-yloxy] -phenyl } -oxalamide;
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'- (2-morpholin-4-yl-ethyl)-oxalamide;
N- { 3 -Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl } -2- oxo-2-pyrrolidin- 1 -yl-acetamide;
N-Ethyl-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]- phenyl}-N-methyl-oxalamide;
N-(4- { [(3- { [4-(methoxy)phenyl] amino } quinoxalin-2-yl) ami no] sulfonyl } phenyl) acetamide;
4-bromo-N-[3-(phenylamino)quinoxalin-2-yl] benzene sulfonamide;
4-bromo-N- { 3 - [(2-methy lphenyl)amino] quinoxalin-2-yl } benzene sulfonamide ;
4-bromo-N-(3-{ [4-(methoxy)phenyl] amino} quinoxalin-2-yl) benzene sulfonamide;
4-chloro-N-{3-[(4-chlorophenyl)amino]-6-(methoxy)quinoxalin-2- y 1 } benzenesulfonamide ;
N-(4-{[3-{[(4-chlorophenyl)sulfonyl]amino}-7-(methoxy)quinoxalin-2-yl]amino} phenyl) acetamide;
4-chloro-N-{6-(methoxy)-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-5- yl)amino] quinoxalin-2-yl } benzenesulfonamide ;
N- { 4- [(3 - { [(4-chlorophenyl)sulfonyl] amino } quinoxalin-2-yl) amino]phenyl } acetamide ;
N-(3-{ [4-(ethyloxy) phenyl]amino}quinoxalin-2-yl)-4-methylbenzene sulfonamide;
N-{3-[(3,4-dimethylphenyl)amino]-6-methylquinoxalin-2-yl}-4-methylbenzene sulfonamide;
N-(3-{[3-(dimethylamino)phenyl]amino}quinoxalin-2-yl)-4-methylbenzene sulfonamide;
4-methyl-N-{6-methyl-3-[(4-methylphenyl)amino]quinoxalin-2-yl} benzene sulfonamide; N-{3-[(4-hydroxyphenyl)amino]-6-methylquinoxalin-2-yl}-4-methylbenzene sulfonamide;
N-{3-[(2,5-dimethylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
4-chloro-N-[3-(naphthalen-2-ylamino)quinoxalin-2-yl]benzenesulfonamide;
N-{3-[(3-aminophenyl)amino]quinoxalin-2-yl}-4-chlorobenzenesulfonamide;
N-(3-{[4-(aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;
4-chloro-N-{3-[(4-chlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-chloro-N-{3-[(4-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-chloro-N-{3-[(2-methylphenyl)amino]quinoxalin-2-yl} benzenesulfonamide; methyl 4-[(3-{[(4-chlorophenyl)sulfonyl]amino} quinoxalin-2-yl) amino]benzoate; methyl 2-chloro-5-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl) aminojbenzoate;
N-{4-[(7-methyl-3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl) amino]phenyl}acetamide;
4-methyl-N-(6-methyl-3-{[2-(methoxy)phenyl]amino} quinoxalin-2- yl)benzenesulfonamide ;
N-{3-[(phenylmethyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-( { 3 - [(phenylsulfony l)amino] quinoxalin-2-yl } amino)benzoic acid;
3-({3-[(phenylsulfonyl)amino]quinoxalin-2-yl}amino)benzenesulfonamide;
N-{3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]quinoxalin- 2-yl } benzenesulfonamide;
N- { 3- [(4-hydroxyphenyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
N- { 3- [(4-hydroxyphenyl)amino] quinoxalin-2-yl } -4-methylbenzenesulfonamide ;
N-(3- { [4-(aminosulfonyl)phenyl] amino } quinoxalin-2-yl)-4- methylbenzenesulfonamide;
3-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
N-[4-({[3-(phenylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide;
N-(4-{[(3-{[4-(aminosulfonyl)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } pheny l)acetamide ; N-[4-({[3-(naphthalen-1-ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide;
Sf- { 4-[(3 - { [(4-methylphenyl)sulfonyl] amino } quinoxalin-2- /l)amino]phenyl } acetam ide ;
N-(3 - { [3 -(aminosulfonyl)phenyl] amino } quinoxalin-2-yl)-4- bromobenzenesulfonamide;
N-{3-[(3-hydroxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
4-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-2-hydroxybenzoic acid;
N-(3-{[4-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;
3 - [(3 - { [(4-chlorophenyl)sulfony 1] amino } quinoxalin-2-y l)amino] benzoic acid ;
N-(3-{[4-(aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide
N-(3-{[3-(aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide;
N-[3-(naphthalen-2-ylamino)quinoxalin-2-yl]-4-nitrobenzenesulfonamide;
N-(3-{[3-(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N- { 3 - [(4-bromophenyl)amino] quinoxalin-2-yl } -3 -nitrobenzenesulfonamide ;
3-[(3-{[(4-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
4-nitro-N-[3-(phenylamino)quinoxalin-2-yl]benzenesulfonamide;
4-chloro-N-[3-(phenylamino)quinoxalin-2-yl]benzenesulfonamide;
3-nitro-N-[3-(phenylamino)quinoxalin-2-yl]benzenesulfonamide;
4-[(3-{[(4-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
N-[3-(naphthalen-2-ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;
4-methyl-N-(3-{[3-(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[3-chloro-4-(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N- { 3 - [(3-chloro-4-fluorophenyl)amino] quinoxalin-2-yl } benzenesulfonamide ; methyl 2-chloro-5-({3-[(phenylsulfonyl)amino]quinoxalin-2-yl}amino)benzoate;
4-chloro-N-{3-[(3-hydroxyphenyl)amino]quinoxalin-2-yl} benzenesulfonamide;
4-methyl-N-[6-methyl-3-(phenylamino)quinoxalin-2-yl]benzenesulfonamide; - {4-[( { 3 - [(4-methylphenyl)amino] quinoxalin-2- yl}amino)sulfonyl]phenyl}acetamide;
1-methylethyl 4-[(3-{[(4-chlorophenyl)sulfonyl]amino}-7-methylquinoxalin-2- yl)amino] benzoate ;
N-{3-[(4-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(3-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(4-bromophenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
4-methyl-N-{3-[(3-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-methyl-N-[3-(naphthalen-1-ylamino)quinoxalin-2-yl]benzenesulfonamide;
N- {4- [( { 3 - [(4-chlorophenyl)amino] quinoxalin-2-yl } amino)sulfonyl]pheny 1 } acetamide ;
-(4-{[(3-{[3-(aminosulfonyl)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)acetamide;
4-methyl-N- { 3 - [(phenylmethyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
4-[(3-{[(4-bromophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-2-hydroxybenzoic acid;
4-bromo-N- { 3 - [(4-methylphenyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
4-bromo-N-{3-[(3-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{4-[({3-[(2-hydroxyethyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide;
4-bromo-N-[3-(naphthalen-1-ylamino)quinoxalin-2-yl]benzenesulfonamide;
4- [(3 - { [(4-chlorophenyl)sulfonyl] amino } quinoxalin-2-yl)amino] benzoic acid;
3-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
N-{3-[(2-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-({3-[(phenylsulfonyl)amino]quinoxalin-2-yl}amino)benzenesulfonamide;
N- [3 -(naphthalen- 1 -ylamino)quinoxalin-2-yl]-3 -nitrobenzenesulfonam ide ;
N-(3-{[3-(aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;
N-{3-[(4-bromophenyl)amino]quinoxalin-2-yl}-4-nitrobenzenesulfonamide;
4-chloro-N-[3-(naphthalen-1-ylamino)quinoxalin-2-yl]benzenesulfonamide; N-{4-[({3-[(phenylmethyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide;
N- [4-( { [3 -(buty lamino)quinoxalin-2-yl] amino } sulfonyl)pheny 1] acetamide;
N-[3-(butylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide;
N-[3-(cyclohexylamino)quinoxalin-2-yl]benzenesulfonamide;
1 -(phenylsulfonyl)-3-[4-(pyrrolidin- 1 -ylsulfonyl)phenyl]-2,3-dihydro- 1 H-imidazo[4,5- b]quinoxaline; l-(phenylsulfonyl)-3-[4-(piperidin-1-ylsulfonyl)phenyl]-2,3-dihydro-1H-imidazo[4,5- b]quinoxaline;
2,5-dichloro-N-[3-(3,4-dihydroquinolin-l(2H)-yl)quinoxalin-2-yl]benzenesulfonamide;
ethyl 2-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7- tetrahydro- 1 -benzothiophene-3-carboxylate;
2,5-dichloro-N-{3-[(2-morpholin-4-ylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide;
-{4-[({3-[(3-methylphenyl)amino]quinoxalin-2- yl } amino)sulfonyl]phenyl } acetamide;
4-chloro-N-{3-[(3-chloro-4-piperidin-1-ylphenyl)amino]-6-methylquinoxalin-2- yl }benzenesulfonamide;
3-nitro-N-[3-(quinolin-6-ylamino)quinoxalin-2-yl]benzenesulfonamide; butyl N- { [4-( { 3 -[(phenyl sulfony l)amino] quinoxalin-2- yl } amino)phenyl] carbonyl } glycinate;
4-nitro-N-(3-{[3-(trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-[4-( { 3 - [(phenylsulfonyl)amino]quinoxalin-2-yl } amino)phenyl] acetamide ;
N- { 3 - [(3 - { [(4-methylphenyl)sulfonyl] amino } quinoxalin-2- yl)amino]phenyl}acetamide; ethyl 3,3,3-trifluoro-2-hydroxy-2-{4-[(3-{[(4- methylphenyl)sulfony 1] amino } quinoxalin-2-y l)amino]phenyl } propanoate ;
N-{3-[(4-{[(2,6-dimethylpyrimidin-4-yl)amino]sulfonyl}phenyl)amino]quinoxalin-2- yl}-3-nitrobenzenesulfonamide;
4-chloro-N- { 3 - [(3 ,4-dimethylphenyl)amino] -6-methylquinoxalin-2- yl}benzenesulfonamide;
4-chloro-N-(6-methyl-3-{[3-(methoxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide; butyl 4- [(3- { [(4-chlorophenyl)sulfonyl] amino } -7-methylquinoxalin-2- yl)amino]benzoate;
4-chloro-N-{3-[(3-chloro-4-methylphenyl)amino]quinoxalin-2- y 1 } benzenesulfonamide ;
1 -methylethyl 4- [(3- { [(4-chlorophenyl)sulfonyl] amino } quinoxalin-2- yl)amino]benzoate;
N-{3-[(2,5-dimethylphenyl)amino]-6-nitroquinoxalin-2-yl}-4- methylbenzenesulfonamide;
N-[3-(cyclohexylamino)-6-nitroquinoxalin-2-yl]-4-methylbenzenesulfonamide;
N-{3-[(2,4-dimethylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
N-(3-{[4-(ethyloxy)phenyl]amino}-6-methylquinoxalin-2-yl)-4- methylbenzenesulfonamide;
3 -( { 3- [( { 4-[hydroxy(oxido)amino]phenyl } sulfonyl)amino] quinoxalin-2- yl}amino)benzoic acid;
N- { [4-( { 3 - [(phenylsulfonyl)amino] quinoxalin-2-yl } amino)phenyl] carbonyl } glycine ;
N-{3-[(3-{[(4-chlorophenyl)sulfonyl]amino}-7-methylquinoxalin-2- yl)amino]phenyl } acetamide;
4-chloro-N-{3-[(3,5-dimethyl-1H-pyrazol-4-yl)amino]-6-methylquinoxalin-2- yl} benzenesulfonamide;
4-bromo-N- { 3 - [(4'-nitrobiphenyl-3 -yl)amino] quinoxalin-2-yl } benzenesulfonamide ;
4-bromo-N-{3-[(2-chlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N- { 3 - [(4-butylphenyl)amino] -6-methylquinoxalin-2-yl } -4-chlorobenzenesulfonamide ;
• { 4- [(3 - { [(4-chloropheny l)sulfonyl] amino } -7-methylquinoxal in-2- l)amino] phenyl} acetamide;
4-chloro-N- { 6-methyl-3 - [(2-oxo-2,3 -dihydro- 1 H-benzimidazol-5 -yl)amino] quinoxalin- 2-yl}benzenesulfonamide; propyl 4-[(3-{[(4-chlorophenyl)sulfonyl]amino}-7-methylquinoxalin-2- yl)amino] benzoate ;
4-chloro-N- {3-[(4-fluorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-[4-({[3-(naphthalen-2-ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide;
4-bromo-N-(3-{[4-(phenylamino)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
2-hydroxy-4-({3-[(phenylsulfonyl)amino]quinoxalin-2-yl}amino)benzoic acid; N-(3-{[3-(aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4- methylbenzenesulfonamide;
4-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
N-(3 - { [3 -(butyloxy)phenyl] amino } quinoxalin-2-y l)-4-methylbenzenesulfonamide;
N- { 3- [(4-fluorophenyl)amino] quinoxalin-2-yl } -3 -nitrobenzenesulfonamide ;
4-{[3-({[4-(acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-2- hydroxybenzoic acid;
N-[3-(naphthalen-1-ylamino)quinoxalin-2-yl]-4-nitrobenzenesulfonamide;
4- [(3 - { [(4-bromophenyl)sulfonyl] amino } quinoxalin-2-yl)amino] benzoic acid ;
- { 4- [( { 3- [(3 -hydroxypheny l)amino]quinoxalin-2- yl } amino)sulfonyl]phenyl } acetamide;
3-[(3-{[(4-bromophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
4-bromo-N-(3-{[3-(butyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
4-bromo-N-(3-{[3-(trifluoromethyl)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
4-methyl-N-{3-[(4'-nitrobiphenyl-3-yl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-chloro-N- { 3- [(3 -fluorophenyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
N-{3-[(2-chlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-bromo-N-[3-(quinolin-5-ylamino)quinoxalin-2-yl]benzenesulfonamide;
N- { 3 - [(3 -fluorophenyl)amino]quinoxalin-2-yl } -4-methylbenzenesulfonam ide ;
N-{3-[(4-fluorophenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
3-nitro-N-(3-{[3-(trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
2-hydroxy-4-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
N- { 3- [(3 -chlorophenyl)amino] quinoxalin-2-yl } -4-methylbenzenesulfonamide ;
N-[3-(1,3-benzodioxol-5-ylamino)quinoxalin-2-yl]-4-bromobenzenesulfonamide;
N-{3-[(3-acetylphenyl)amino]quinoxalin-2-yl}-4-chlorobenzenesulfonamide;
3-nitro-N-(3-{[4-(9H-xanthen-9-yl)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide; 4-chloro-N-{3-[(4'-nitrobiphenyl-3-yl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-tolylsulfonamide;
N-{3-[(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]quinoxalin-2- y 1 } benzenesulfonamide ;
4-methyl-N-[3-(quinolin-5-ylamino)quinoxalin-2-yl]benzenesulfonamide;
4-methyl-N-{3-[(l-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]quinoxalin-2- yl } benzenesulfonamide ;
4-chloro-N- { 3 - [(2-chlorophenyl)amino] quinoxalin-2-yl } benzenesulfonamide;
2-hydroxy-5-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
N-(3- { [3,5-bis( 1 , 1 -dimethylethyl)-4-hydroxyphenyl] amino } quinoxalin-2- yl)benzenesulfonamide;
N-[3-({2-[(trifluoromethyl)thio]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide;
- {4- [( { 3- [(4-hydroxyphenyl)amino] quinoxalin-2- 1 } amino)sulfonyl]phenyl } acetamide;
N-[3-(1,3-benzodioxol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide;
N-(3 - { [2,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)benzenesulfonamide ;
N-{3-[(2,4-dichlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-[4-({[3-(2,3-dihydro-l ,4-benzodioxin-6-ylamino)quinoxalin-2- yl]amino}sulfonyl)phenyl]acetamide;
4-chloro-N-{3-[(3,4-dimethylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;
4-bromo-N- { 3 - [(3 ,4-dimethylphenyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
5-{[3-({[4-(acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-2- hydroxybenzoic acid;
N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide;
N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide;
N-{3-[(2,4-dichlorophenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
4-bromo-N-{3-[(3-fluorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide; 4-{[3-({[4-(acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}benzoic acid;
N- { 3 - [(2-fluorophenyl)amino] quinoxalin-2-yl } -4-methylbenzenesulfonamide ;
N-[3-(2,3-dihydro-1,4-benzodioxin-6-ylamino)quinoxalin-2-yl]-4- methylbenzenesulfonamide;
N- { 3- [(3 ,4-dimethylphenyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
4-methyl-N-(3 - { [3-(trifluoromethyl)phenyl] amino } quinoxalin-2- yl)benzenesulfonamide;
5-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-2-hydroxybenzoic acid;
3-nitro-N-{3-[(l-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]quinoxalin-2- yl} benzenesulfonamide;
-{4-[({3-[(2-bromo-4-methylphenyl)amino]quinoxalin-2- l}amino)sulfonyl]phenyl}acetamide;
N- { 3 - [(2-fluorophenyl)amino] quinoxalin-2-yl } -4-nitrobenzenesulfonamide ;
N-{3-[(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]quinoxalin-2-yl}-3- nitrobenzenesulfonamide;
4-chloro-N-{3-[(l-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]quinoxalin-2- yl}benzenesulfonamide;
N-{3-[(l-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]quinoxalin-2- y 1 } benzenesulfonamide ;
N- { 3 - [(2-fluorophenyl)amino] quinoxalin-2-yl } -3 -nitrobenzenesulfonamide ;
N-[2-(butyloxy)-2-hydroxyethyl]-4-({3-[(phenylsulfonyl)amino]quinoxalin-2- yl}amino)benzamide;
3 -nitro-N-(3 - { [4-(phenylamino)phenyl] amino } quinoxalin-2-yl)benzenesulfonamide ;
4-bromo-N-{3-[(4-fluorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-methyl-N-[3-({2-[(trifluoromethyl)thio]phenyl}amino)quinoxalin-2- yljbenzenesulfonamide;
N-[4-({3-[2-(methoxy)phenyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- y 1 } sulfonyl)pheny 1] acetamide ;
4-(3-{[4-(acetylamino)phenyl]sulfonyl}-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl)benzoic acid; l-naphthalen-2-yl-3-[(3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5- bjquinoxaline; N-[4-({3-[4-(methoxy)phenyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl}sulfonyl)phenyl]acetamide; l-(3-methylphenyl)-3-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5- b]quinoxaline;
N-(4-{[3-(4-methylphenyl)-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl] sulfonyl }phenyl)acetamide;
-{4-[(3-phenyl-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl)sulfonyl]phenyl}acetamide;
-(4-{[3-(3-methylphenyl)-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl] sulfonyl } phenyl)acetamide ;
1 - [4-(methoxy)phenyl] -3 - [(4-methylphenyl)sulfonyl] -2,3 -dihydro- 1 H-imidazo [4,5 - bjquinoxaline;
N-(4-{[3-(2-methylphenyl)-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl] sulfonyl } phenyl)acetamide ; l-(3-methylphenyl)-3-[(3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5- bjquinoxaline; l-(4-methylphenyl)-3-[(3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5- b]quinoxaline;
N- { 3- [(4-methylphenyl)amino] quinoxalin-2-yl } -3 -( 1 H-tetrazol- 1 - yl)benzenesulfonamide;
N-(3-{[2-(ethyloxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide;
N-{4-[({3-[(4-ethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide;
4-bromo-N-(3-{[3-(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide
N-(4- { [(3 - { [4-(ethyloxy)pheny 1] amino } quinoxalin-2- yl)amino]sulfonyl}phenyl)acetamide;
N-{4-[({3-[(2-ethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide;
N-(4- { [(3 - { [2-(ethyloxy)pheny 1] amino } quinoxalin-2- yl)amino] sulfonyl } pheny l)acetamide ;
N- { 3 - [(4-nitrophenyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
4-(ethyloxy)-N-(3-{[4-(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide; methyl N-acetyl-N-[4-({3-[(phenylsulfonyl)amino]quinoxalin-2-yl}amino)phenyl]- beta-alaninate; methyl N-acetyl-N-{4-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]phenyl}-beta-alaninate; N-{3-[(3-chloro-5-methylphenyl)amino]quinoxalin-2-yl}-4- methylbenzenesulfonamide;
N-{3-[(3-acetylphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;
4-{[3-({[4-(acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-N-[4- (methoxy)phenyl]benzamide;
2-hydroxy-5 -( { 3 - [(pheny lsulfonyl)amino] quinoxalin-2-yl } amino)benzoic acid;
N-[3-(2,3-dihydro-1,4-benzodioxin-6-ylamino)quinoxalin-2-yl]-3- nitrobenzenesulfonamide;
N- [4-(methoxy)phenyl] -4- [(3 - { [(4-nitrophenyl)sulfonyl] amino } quinoxalin-2- yl)amino]benzamide;
4-chloro-N-{3-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]quinoxalin-2- yl}benzenesulfonamide;
4-methyl-N- { 3 - [methyl (phenylmethyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
N-[3-(3,4-dihydroisoquinolin-2(1H)-yl)quinoxalin-2-yl]-2-methylbenzenesulfonamide;
N-[4-({[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2- yl]amino}sulfonyl)phenyl]acetamide;
4-bromo-N-{3-[(4-phenylquinolin-8-yl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-methyl-N-{3-[(4-phenylquinolin-8-yl)amino]quinoxalin-2-yl}benzenesulfonamide;
1 - [(4-chlorophenyl)sulfonyl] -3- [4-(pyrrolidin- 1 -ylsulfonyl)phenyl] -2,3 -dihydro- 1 H- imidazo[4,5-b]quinoxaline; l-(4-morpholin-4-ylphenyl)-3-(phenylsulfonyl)-2,3-dihydro-1H-imidazo[4,5- bjquinoxaline; methyl 4,5-dimethyl-2-({3-[(phenylsulfonyl)amino]quinoxalin-2-yl}amino)thiophene- 3-carboxylate; thyl 6-methyl-2-[(3-{[(2-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]- 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate; ethyl 2-{[3-({[4-(acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-6- phenyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate; ethyl 6-methyl-2-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]- 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate; propyl 4-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoate;
N-{3-[(4-butylphenyl)amino]quinoxalin-2-yl}-4-chlorobenzenesulfonamide;
N-{3-[(2-chlorophenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide; N- { 3 -[(2,3 -dimethylphenyl)amino] quinoxalin-2-yl } -4-methylbenzenesulfonamide ;
N-{3-[(3,4-dimethylphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;
-{4-[({3-[(2,3-dimethylphenyl)amino]quinoxalin-2- y 1 } amino)sulfonyl] phenyl } acetamide;
4-chloro-N-{3-[(2,3-dimethylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
3-nitro-N-(3-{[3,4,5-tris(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
4-chloro-N-{3-[(2,4-dichlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(2,3-dimethylphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;
N-{4-[({3-[(3,4-dimethylphenyl)amino]quinoxalin-2- yl } amino)sulfonyl]phenyl } acetamide; ethyl 2- [(3- { [(4-chlorophenyl)sulfonyl] amino } quinoxalin-2-yl)amino] -5 ,6-dihydro-4H- cyclopenta[b]thiophene-3-carboxylate;
4-chloro-N-(3 - { [4-chloro-3 -(morpholin-4-ylsulfonyl)phenyl] amino } quinoxalin-2- yl)benzenesulfonamide; thyl 2-[(3-{[(2-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7- tetrahydro-1-benzothiophene-3-carboxylate;
4-bromo-N-{3-[(2,4-dichlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide; ethyl 5-ethyl-2-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]thiophene- 3-carboxylate;
N-(3-{[3-(morpholin-4-ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide; ethyl 2-[(3-{[(4-bromophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4, 5,6,7- tetrahydro- 1 -benzothiophene-3-carboxylate;
4-methyl-N-(3 - { [3-(piperidin- 1 -ylsulfonyl)phenyl] amino } quinoxalin-2- yl)benzenesulfonamide;
4-chloro-N-(3-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
4-chloro-N-(3-{[3-(morpholin-4-ylsulfonyl)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
4-methyl-N-[3-(quinolin-6-ylamino)quinoxalin-2-yl]benzenesulfonamide;
N-(3-{[3-(piperidin-1-ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[4-(phenylamino)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-bromobenzenesulfonamide; ethyl 2- [(3- { [(3 -nitrophenyl)sulfonyl] amino } quinoxalin-2-yl)amino] -5 ,6-dihydro-4H- cyc lopenta [b] thiophene-3 -carboxy late ;
N-{3-[(4'-nitrobiphenyl-4-yl)amino]quinoxalin-2-yl}benzenesulfonamide; ethyl 2-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4, 5,6,7- tetrahydro-1-benzothiophene-3-carboxylate;
N-(3-{[4-chloro-3-(morpholin-4-ylsulfonyl)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide; thyl 5 -ethyl-2-( { 3- [(phenylsulfonyl)amino]quinoxalin-2-yl } amino)thiophene-3 - carboxylate;
N-[4-({[3-(quinolin-6-ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide; ethyl 2-[(3-{[(2-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-5,6-dihydro- 4H-cyclopenta[b]thiophene-3-carboxylate;
3,4-dichloro-N-[3-(naphthalen-1-ylamino)quinoxalin-2-yl]benzenesulfonamide; ethyl 2-{[3-({[4-(acetylamino)-3,5-dibromophenyl]sulfonyl}amino)quinoxalin-2- yl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate;
:thyl 2-[(3-{[(2-chloro-5-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7- tetrahydro- 1 -benzothiophene-3-carboxylate;
N- { 3 - [(3 -fluorophenyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
N-(3-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide; ethyl 2-{[3-({[4-(acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-4, 5,6,7- tetrahydro- 1 -benzothiophene-3-carboxylate; ethyl 2-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-5- ethylthiophene-3-carboxylate;
N,N-diethyl-4-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzenesulfonamide; ethyl 2- { [3 -( { [4-(acetylamino)phenyl] sulfonyl } amino)quinoxalin-2-yl] amino } -5 - ethylthiophene-3-carboxylate; thyl 2-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4, 5,6,7- tetrahydro- 1 -benzothiophene-3-carboxylate; thyl 2-({3-[(phenylsulfonyl)amino]quinoxalin-2-yl}amino)-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate;
N- [4-(methoxy)phenyl] -4- [(3 - { [(3 -nitrophenyl)sulfonyl] amino } quinoxalin-2- yl)amino]benzamide;
N-[3-({4-[(4-aminophenyl)oxy]phenyl}amino)quinoxalin-2-yl]-4- hlorobenzenesulfonamide; N- [4-( { [3 -( {4- [(4-aminophenyl)oxy]phenyl } amino)quinoxalin-2- yl]amino}sulfonyl)phenyl]acetamide;
(2E)-3- { 3 - [(3- { [(4-methylphenyl)sulfonyl] amino } quinoxalin-2-yl)amino]phenyl } prop- 2-enoic acid;
N-{3-[(9-ethyl-9H-carbazol-3-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;
N-[3-({4-[(4-aminophenyl)oxy]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide;
4-bromo-N-{3-[(9-ethyl-9H-carbazol-3-yl)amino]quinoxalin-2- yl}benzenesulfonamide;
N- { 3 - [(9-ethyl-9H-carbazol-3 -yl)amino] quinoxalin-2-yl } benzenesulfonamide;
N- { 3 - [(2-iodophenyl)amino] quinoxalin-2-yl } benzenesulfonamide;
N- { 3 - [( 1 -phenylethyl)amino] quinoxalin-2-yl } benzenesulfonamide ;
4-bromo-N-{3-[(4-bromophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-bromo-N-{3-[(4-chlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-bromo-N- [3 -(naphthalen-2-ylamino)quinoxalin-2-yl] benzenesulfonamide ;
N-{3-[(2,3-dimethylphenyl)amino]-6-methylquinoxalin-2-yl}-4- methylbenzenesulfonamide;
4-chloro-N-{3-[(2-iodophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-(3-{[4-(octyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-[3-(2,l ,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;
N-{3-[(2-bromo-4-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-[3-({4-[(3-aminophenyl)sulfonyl]phenyl}amino)quinoxalin-2-yl]-4- chlorobenzenesulfonamide ;
N- [3 -( { 2- [(difluoromethyl)oxy]phenyl } amino)quinoxalin-2-yl] -3- nitrobenzenesulfonamide ;
8-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]quinoline-2- carboxylic acid; ethyl 3,3,3-trifluoro-2-hydroxy-2-{4-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin- 2-yl)amino]phenyl } propanoate ;
N- [3 -(quinolin-6-ylamino)quinoxalin-2-yl] benzenesulfonamide ;
4- { [3 -( { [4-(acetylamino)phenyl] sulfonyl } amino)quinoxalin-2-yl] am ino } phenyl thiocyanate;
1 - [3 -( { [4-(acetylamino)phenyl] sulfonyl } amino)quinoxalin-2-yl] -4-methylpyridinium ; N- { 3 - [(2-chlorophenyl)amino]quinoxalin-2-yl } -3 -nitrobenzenesulfonamide ;
4-methyl-N-[3-(phenylamino)quinoxalin-2-yl]benzenesulfonamide;
4-methyl-N-{3-[(2-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-methyl-N-{3-[(4-methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(4-chlorophenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
4-methyl-N-[3-(naphthalen-2-ylamino)quinoxalin-2-yl]benzenesulfonamide;
N- { 4- [( { 3- [(4-bromophenyl)amino] quinoxalin-2-yl } amino)sulfonyl]pheny 1 } acetamide ;
N- { 4- [( { 3 - [(2-methylphenyl)amino] quinoxalin-2-yl } amino)sulfonyl] - phenyl } acetamide;
N- { 3 - [bis(phenylmethyl)amino] quinoxalin-2-yl } benzenesulfonamide;
4-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
2-hydroxy-4-[(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid;
4-bromo-N-(3 - { [2-(methoxy)phenyl] amino } quinoxalin-2-yl)benzenesulfonamide ;
N-{3-[(3-hydroxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-[3-(naphthalen- 1 -ylamino)quinoxalin-2-yl]benzenesulfonamide;
3-methyl-1-(3-{[(4-methylphenyl)sulfonyl]amino}quinoxalin-2-yl)pyridinium;
-(3 - { [3 - { [(4-chlorophenyl)sulfonyl] amino } -7-(methoxy)quinoxalin-2- 1] amino } phenyl)acetamide ;
N-{3-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide;
N- { 3 - [(4-bromopheny l)amino] quinoxalin-2-yl } -4-chlorobenzenesulfonamide ;
N- { 3 - [(2,4-dimethylphenyl)amino] -6-methylquinoxalin-2-yl } -4- methylbenzenesulfonamide;
N-{3-[(3,4-dimethylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide;
N-{3-[(2,5-dimethylphenyl)amino]-6-methylquinoxalin-2-yl}-4- methylbenzenesulfonamide;
:thyl 4-[(3-{[(4-chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoate;
4-chloro-N-{3-[(4-ethylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-chloro-N-(6-methyl-3-{[4-(methoxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide; -chloro-N- { 3 - [(4-chloropheny l)amino] -6-methy lquinoxalin-2- l}benzenesulfonamide;
N-(3-{[4-chloro-2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide;
N-(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-3-nitrobenzenesulfonamide ;
N-(3-{[2-methyl-5-(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-[3-(2-Chloro-5-methoxy-phenylamino)-quinoxalin-2-yl]-benzensulfonamide;
3-amino-N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide;
-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- l)amino]sulfonyl}phenyl)acetamide;
N-(3 - { [4-chloro-3 -(methoxy)phenyl] amino } quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[4-fluoro-3-(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
3-amino-N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-bromobenzenesulfonamide;
N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3- nitrobenzenesulfonamide ;
3-amino-N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-,N-2-dimethylglycinamide;
N-(3-{[2,5-bis(methoxy)phenyl]amino}-7-methylquinoxalin-2-yl)benzenesulfonamide;
N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4- (methoxy)benzenesulfonamide;
N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-bromobenzenesulfonamide;
N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-fluorobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-2-fluorobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4- (methoxy)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-bromobenzenesulfonamide; N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- l-methylpiperidine-4-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3-piperidin-1-ylpropanamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 4-(dimethylamino)butanamide;
N-(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-3 - (hydroxyamino)benzenesulfonamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfony 1 } pheny I)- 2-morpholin-4-ylacetamide;
N-(3 - { [(3- { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfony 1 } -4- methylphenyl)-N-2-methylglycinamide;
N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4- methylphenyl)-L-alaninamide;
N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4- methylphenyl)-2-methylalaninamide;
N-(3-{[(3-{ [2-chloro-5 -(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfony 1 } -4- methylphenyl)-N-2-,N-2-dimethylglycinamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- D-alaninamide;
N-(3 - { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2-methylglycinamide;
N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4- methylphenyl)-D-alaninamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- N-2-methylglycinamide;
-(3 - { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2- l)amino] sulfonyl} pheny l)-L-alaninamide ;
N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-D-alaninamide;
N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)-2-methylalaninamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- 2-methylalaninamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4- methylphenyl)-N-2-,N-2-dimethylglycinamide;
N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2-[2-(dimethylamino)ethyl]-N-2-methylglycinamide; (2S)-2-amino-N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- y l)am ino] sulfonyl } phenyl)butanam ide ; sf-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino} quinoxalin-2-yl)amino] sulfonyl } phenyl)- vf-2- [2-(dimethylamino)ethyl] -N-2-methylglycinamide ;
M-(3- { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2- ^l)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;
H3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- J-2-methyl-L-alaninamide ;
N-(3 - { [(3- { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2- yl)amino] sulfonyl } phenyl)glycinamide;
-(3 - { [(3- { [3 , 5-bis(methoxy)phenyl] amino } quinoxalin-2- l)amino]sulfonyl}phenyl)glycinamide; s«J-(2-chloro-5-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- /l)amino] sulfonyl } phenyl)-N-2-methylglycinamide ;
2-(dimethylamino)-N-(3-(N-(3-(3-(2-(dimethylamino)acetamido)-5- methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide;
N-(3-{[(3-{[2-acetyl-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)-N-2-,N-2-dimethylglycinamide ;
N-(3- { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)-3 - (formylamino)benzenesulfonamide;
N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)-N-2-ethylglycinamide ;
N-(5-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2- methylphenyl)glycinamide;
2-azetidin-1-yl-N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)acetamide ;
N-(3- { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2- yl)amino]sulfonyl}phenyl)-L-prolinamide;
N-(3 - { [(3 - { [2-bromo-5 -(methoxy)phenyl] amino } quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2-methylglycinamide;
N-2-,N-2-dimethyl-N-(3-{[(3-{[6-(methoxy)quinolin-8-yl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- -alaninamide;
N-(3 - { [(3 - { [2-chloro-5 -(methoxy)phenyl]amino } quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2-methyl-D-alaninamide;
Figure imgf000785_0001
Figure imgf000786_0001
Figure imgf000787_0001
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-( 1 , 1 -dimethylethyl)glycinamide;
N-2-methyl-N-(3-{[(3-{[3-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 1 H-imidazole-2-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)isoxazole-5-carboxamide;
-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2-(2,2,2-trifluoroethyl)glycinamide;
3 -amino-N-(3 - { [2-methyl-5-(methoxy)phenyl] amino } quinoxalin-2- yl)benzenesulfonamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3-oxocyclopentanecarboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 6-hydroxypyridine-2-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-(3-fluoro-4-hydroxyphenyl)glycinamide;
N-(3- { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- l-(furan-2-ylmethyl)azetidine-3-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)pyrimidine-5-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 1 H-pyrrole-2-carboxamide;
N-(3- { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- N-2-methyl-N-2-( 1 -methylethyl)glycinamide;
N-(3- { [(3 - { [3 -fluoro-5 -(methoxy)phenyl] amino} quinoxalin-2- yl)amino] sulfonyl } phenyl)-N-2-,N-2-dimethy lglycinamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 1 H-imidazole-4-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-,N-2-diethylglycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(3-methylisoxazol-5-yl)acetamide;
N-2-,N-2-dimethyl-N-(3-{[(3-{[2-methyl-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)glycinamide; N -(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N -2-[(3-hydroxyphenyl)methyl]glycinamide;
N-(3- { [(3 - { [3 ,5-bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 1 -methyl- 1 H-pyrrole-2-carboxamide;
4-amino-N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)tetrahydro-2H-pyran-4-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-[4-(methylamino)piperidin-1-yl]acetamide;
N-(3- { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-piperidin- 1 -ylacetamide;
N-(4- { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-,N-2-dimethylglycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 1 -methyl-L-prolinamide;
-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } pheny l)thiophene-3 -carboxamide ;
3 -amino-N- { 3 - [(2-chloro-5-hydroxyphenyl)amino] quinoxalin-2- yl } benzenesulfonamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- l-(cyclopropylcarbonyl)azetidine-3-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-methylpiperazin- 1 -y l)acetamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- l-(phenylmethyl)azetidine-3-carboxamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-chloropyridine-3 -carboxamide ;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-pyridin-4-ylacetamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-methyl-N-2-prop-2-en- 1 -ylglycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-(phenylmethyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(methoxy)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 1 -propanoylazetidine-3 -carboxamide; -(3 - { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2- l)amino] sulfonyl } phenyl)pyridine-3-carboxamide ;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-[2-(methoxy)ethyl]glycinamide;
1 -acetyl-N-(3- { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2- yl)amino]sulfonyl}phenyl)piperidine-4-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(2-methylpyrrolidin- 1 -yl)acetamide;
N-(3-{[(3-{ [3 ,5 -bis(methoxy)phenyl]amino } quinoxalin-2- yl)amino] sulfonyl } phenyl)furan-3 -carboxamide;
-2-,N-2-dimethyl-N-(3-{[(3-{[3-(methoxy)phenyl]amino}quinoxalin-2- l)amino]sulfonyl}phenyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 6-chloropyridine-3 -carboxamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-chlorobenzamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-pyridin-2-ylacetamide ;
N-(3- { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2- [3 -(dimethylamino)azetidin- 1 -yl] acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-pyridin-3-ylacetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(2-chlorophenyl)acetamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-[3-(dimethylamino)propyl]-N-2-methylglycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-ethyl-N-2-(2-hydroxyethyl)glycinamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-[2-(phenylmethyl)pyrrolidin-1-yl]acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)propanamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)furan-2-carboxamide;
N-(3- { [(3- { [3,5-bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-chloropyridine-4-carboxamide;
Figure imgf000791_0001
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-methylpyridine-3-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 4-(methoxy)benzamide;
-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-ethylpiperazin- 1 -yl)acetamide;
N -(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yil)amino] sulfonyl } pheny l)thiophene-2-carboxamide;
N-(3 - { [(3- { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 3-fluoro-2-methylbenzamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-bromothiophene-3-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 4-fluorobenzamide;
N-(3 - { [(3- { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- 2-(3 -methylpiperidin- 1 -y l)acetamide ;
N-(3 - { [(3- { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2 -methy lpropanamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)pentanamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(ethyloxy)acetamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-(2-fluorophenyl)glycinamide;
N-(3- { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 3-(dimethylamino)benzamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-methylpiperidin- 1 -yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-(2-propylphenyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)benzamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2- yl)amino]sulfonyl}phenyl)pyrazine-2-carboxamide;
N-(3- { [(3- { [3 ,5-bis(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } phenyl)- 3 -fluoro-4-(methoxy)benzamide ;
Figure imgf000793_0001
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3,4-dichlorobenzamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-{[2-(methylthio)phenyl]methyl}glycinamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(2-fluorophenyl)acetamide;
-(3 -{ [(3 -{ [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- -2-ethyl-N-2-(l-methylethyl)glycinamide;
N-(3 - { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 1 ,3-thiazole-4-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-methyl-N-2-(phenylmethyl)glycinamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-(2-thienylmethyl)glycinamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-(pyridin-2-ylmethyl)glycinamide;
N-(3 - { [(3 - { [3 ,5 -bis(methoxy)pheny 1] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 3-(methoxy)benzamide;
N-(3- { [(3- { [3 ,5-bis(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl }phenyl)- N-2-[(3-chloro-4-methylphenyl)methyl]glycinamide;
N-(3- { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-methylpentanamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-chlorophenyl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3-fluoro-4-methylbenzamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-[(2-methylphenyl)oxy]acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-cyclohexylacetamide;
(lR,2R)-N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-2-phenylcyclopropanecarboxamide;
N-(3- { [(3- { [3 ,5-bis(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } phenyl)- 3-chlorobenzamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)pheny 1] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2- [2-(methoxy)phenyl] acetamide; N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3-[3-(methoxy)phenyl]propanamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-(2-fluoro-4-methylphenyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-[(3-fluorophenyl)methyl]glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2- [4-(methoxy)pheny 1] acetamide;
-(3 - { [(3- { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-phenylacetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2,4-dichlorobenzamide;
N-(3 - { [(3- { [3 ,5 -bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 3-oxocyclohexanecarboxamide;
-(3- { [(3- { [3 ,5-bis(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } phenyl)- -2-(3 -fluorophenyl)glycinamide ;
-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(3-chlorophenyl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-(2-phenylpropyl)glycinamide;
N-(3 - { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- N-2- [(2,4-dimethylphenyl)m ethyl] glycinamide ;
N-(3 - { [(3- { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- 2-(2-methylpiperidin- 1 -yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-[2-(methoxy)phenyl]glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(3 ,4-dihydroisoquinolin-2( 1 H)-yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)pent-4-enamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-(2-methylphenyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-oxopiperidin- 1 -yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-fluorobenzamide; N -(3 - { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfony 1 } phenyl)- -2-( 1 -phenylethyl)glycinamide;
-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-fluoro-6-(methoxy)benzamide;
-(3 - { [(3 - { [3 , 5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfony 1 } phenyl)- -2-[2-(l-methylethyl)phenyl]glycinamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfony 1 } phenyl)- 3-[2-(methoxy)phenyl]propanamide;
-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl }phenyl)- 4-methylpentanamide;
N-(3- { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(2-phenylmorpholin-4-yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3 - [4-(methoxy)phenyl]propanamide ;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- N-2-cyclopentyl-N-2-prop-2-en-1-ylglycinamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-methyl-N-2-[2-(methoxy)ethyl]glycinamide;
N-(3-{ [(3- {[3, 5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino] sulfonyl }phenyl)- 4-cyclopropyl-4-oxobutanamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-[3-( 1 , 1 -dimethylethyl)phenyl] glycinamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- N-2-(cyclopropylmethyl)-N-2-propylglycinamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(2-oxocyclopentyl)acetamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2-(4-chlorophenyl)glycinamide;
2-(1,4'-bipiperidin-r-yl)-N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-cyclopentylpiperazin- 1 -yl)acetamide;
N-(3 - { [(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(2-methylphenyl)acetamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-[(5-fluoro-2-methylphenyl)methyl]glycinamide; N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3 , 3 -dimethy lbutanamide ;
N-(3 - { [(3- { [3 ,5 -bis(methyloxy)phenyl] amino } quinoxalin-2- yl)amino] sulfonyl } phenyl)-N2-(2-chlorophenyl)glycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 5-fluoro-2-methylbenzamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 4-fluoro-3 -methylbenzamide ;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2 , 3 -dichlorobenzamide ;
N-(3- { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(phenyloxy)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-(2,3-dimethylphenyl)glycinamide;
3-amino-N-(3-{[3,5-bis(methoxy)phenyl]amino}pyrido[2,3-b]pyrazin-2- yl)benzenesulfonamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- 2-fluoro-5 -methylbenzamide ;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- N-2- { [(4-methylphenyl)methyl]oxy} glycinamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2- [4-( 1 -methylethyl)piperazin- 1 -yl] acetamide ;
N-(3- { [(3- { [3 ,5-bis(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(4-fluorophenyl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3 -methylbutanamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 4-methyl-2-(methoxy)benzamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-propylpiperidin- 1 -yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-[(3-methylphenyl)oxy]acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)tetrahydrofuran-2-carboxamide;
N-(3- { [(3- { [3 ,5-bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl }phenyl)- 2-[3-(hydroxymethyl)piperidin-1-yl]acetamide; l,l-dimethylethyl2-{[(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)amino]carbonyl}piperidine-1-carboxylate;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-methyl-N-2-(pyridin-3-ylmethyl)glycinamide;
J-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- J-2-ethyl-N-2-phenylglycinamide;
N-(3- { [(3- { [3 ,5-bis(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-{[2-(methoxy)ethyl]oxy}acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3-cyclopentylpropanamide;
-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2 , 5 -dichlorobenzamide ;
2-(4-acetylpiperazin- 1 -yl)-N-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2- y l)amino] sulfonyl } phenyl)acetamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 5-fluoro-2-(methoxy)benzamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-cyclohexyl-N-2-ethylglycinamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 5-methylisoxazole-3-carboxamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3-methylpyridine-2-carboxamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(methoxy)pyridine-3 -carboxamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 3,5-dichlorobenzamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino} quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(1,3-thiazolidin-3-yl)acetamide;
N-(3- { [(3 - { [3 ,5-bis(methoxy)phenyl] amino} quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(4-formylpiperazin- 1 -yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(2-pyridin-4-ylpiperidin- 1 -yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(methoxy)benzamide ;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N-2-methyl-N-2-(2-methylpropyl)glycinamide; N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-(4-formyl- 1 ,4-diazepan-l -yl)acetamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 1 -phenylcyclopropanecarboxamide;
N-(3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)- 2-(2,6-dimethylmorpholin-4-yl)acetamide;
-(3 - { [(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } pheny I)- 2-(2-phenylpyrrolidin-1-yl)acetamide;
3- { [(3- { [2-chloro-5-(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } -N-[2- (dimethylamino)- 1 -methylethyl]benzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]benzamide;
5-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-2-fluorobenzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N- pyrrolidin-3-ylbenzamide;
3 - { [(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- [2- (dimethylamino)ethyl]benzamide;
3 - { [(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N-(2- pyrrolidin- 1 -ylethyl)benzamide;
N-(2-aminoethyl)-3 - { [(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2- yl)amino] sulfonyl } benzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-N-methylbenzamide;
3 - { [(3- { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- (piperidin-2-ylmethyl)benzamide ;
3 - { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N-( 1 ■ methylazetidin-3-yl)benzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2- piperidin-1 -ylethyl)benzamide;
3- { [(3- { [2-chloro-5-(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } -N-[2- (diethylamino)ethyl]benzamide;
3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-N-methylbenzamide;
3- { [(3- { [2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl } -N-( 1 • methylpiperidin-3-yl)benzamide;
Figure imgf000800_0001
3 - { [(3- { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfony 1 } -N- [2- ( 1 H-imidazol-4-yl)ethyl] benzamide ;
N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-{[3- (dimethylamino)pyrrolidin- 1 -yljcarbonyl } benzenesulfonamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N- (pyridin-4-ylmethyl)benzamide ;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N- methyl-N-(l-methylpyrrolidin-3-yl)benzamide;
N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-{[3- (diethylamino)pyrrolidin- 1 -yl]carbonyl}benzenesulfonamide;
3- { [(3- { [2-chloro-5-(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } -N- 1 H- pyrrol-1 -ylbenzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3- pyrrolidin- 1 -ylpropyl)benzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2- cyanoethyl)-N-methylbenzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (methoxy)ethyl]benzamide;
3- { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N-(2- cyanoethyl)-N-ethy lbenzamide ;
3 - [(3 -aminopiperidin- 1 -yl)carbonyl] -N-(3 - { [2-chloro-5 - (methoxy)phenyl] amino } quinoxalin-2-yl)benzenesulfonamide ;
3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid;
3 - { [(3- { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- [3 - (dimethylamino)propyl]benzamide;
3- { [(3- { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- morpholin-4-ylbenzamide ;
N-(3 - { [2-chloro-5-(methoxy)pheny 1] amino } quinoxalin-2-yl)-3 - [(2 ,2- dimethylhydrazino)carbonyl]benzenesulfonamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (1H-imidazol-1-yl)propyl]benzamide;
3- { [(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- [3 - (diethylamino)propyl]benzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2- cyanoethyl)benzamide; methylN- [(3 - { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2- y l)amino] sulfonyl } phenyl)carbonyl] -beta-alaninate;
3- { [(3- { [2-chloro-5-(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } -N-[2- (methylthio)ethyl]benzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (ethy lthio)ethyl] benzam ide ;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-N-ethylbenzamide;
3 - { [(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N-[3 - (2-oxopyrrolidin- 1 -yl)propyl] benzamide ;
3 - { [(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N-(2- pyridin-4-ylethyl)benzamide;
3 - { [(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- [3 - (ethyloxy)propyl]benzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3- morpholin-4-ylpropyl)benzamide;
3- { [(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- [3 - (methoxy)propy 1] benzamide ;
3- { [(3- { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- [3- (dimethylamino)propyl]-N-methylbenzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (propyloxy)propyl]benzamide; thylN-[(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino] sulfonyl } phenyl)carbonyl] -beta-alaninate;
3 - { [(3- { [2-chloro-5 -(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } -N- { 3 - [( 1 -methylethyl)oxy]propyl } benzamide;
3 - { [(3- { [2-chloro-5 -(methoxy)phenyl]amino } quinoxalin-2-yl)amino] sulfonyl } -N-( 1 , 1 - dimethyl-2-piperidin- 1 -ylethyl)benzamide;
3- { [(3- { [2-chloro-5-(methoxy)phenyl]amino} quinoxalin-2-yl)amino] sulfonyl } -N- methyl-N-propylbenzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N- piperidin- 1 -ylbenzamide;
3-{ [(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl} -N-[I- methyl-2-(methoxy)ethyl] benzamide ;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(l,l- dimethyl-2-morpholin-4-ylethyl)benzamide; N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-({2- [(dimethylamino)methyl]piperidin-1-yl}carbonyl)benzenesulfonamide;
- [3 -(butyloxy)propyl] -3 - { [(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2- yl)amino]sulfonyl}benzamide;
3- { [(3- { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } -N- [4- (diethylamino)- 1 -methylbutyljbenzamide;
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(l,l- dimethyl-2-oxo-2-piperidin- 1 -ylethyl)benzamide;
-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-[(4-methylpiperazin-1- yl)carbonyl]benzenesulfonamide;
N-(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)-3 - { [2-(piperidin- 1 - ylmethyl)piperidin- 1 -yl]carbonyl}benzenesulfonamide;
N-(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)-6-oxo- 1,6- dihydropyridine-3-sulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3- sulfonamide;
3-amino-N-(3-{[6-(methoxy)quinolin-8-yl]amino}quinoxalin-2- yl)benzenesulfonamide;
N-(3 - { [3 ,5 -bis(methoxy)phenyl]amino } quinoxalin-2-yl)thiophene-2-sulfonamide ;
N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3- cyanobenzenesulfonamide;
N-(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-3 - (methylamino)benzenesulfonamide;
-(2-{[3,5-bis(methoxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)-3- nitrobenzenesulfonamide ;
N-(3 - { [2-chloro-5-(methoxy)phenyl] amino } quinoxalin-2-yl)-3-( 1 - { [2- (dimethylamino)ethyl] amino } ethyl)benzenesulfonamide ;
3 -amino-N-(3 - { [3 -(methoxy)-5-nitrophenyl] amino } quinoxalin-2- yl)benzenesulfonamide;
3-acetyl-N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
3-amino-N-(3-{[3-fluoro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
N-(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)-N'- [2- (dimethylamino)ethyl]benzene-1,3-disulfonamide;
N-(3 - { [2-chloro-5 -(methoxy)phenyl] amino } quinoxalin-2-yl)-N'- [3 - (dimethylamino)propyl]benzene-1,3-disulfonamide; N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-6-chloropyridine-3- sulfonamide;
N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-{5- [(dimethylamino)methyl] - 1 ,3 ,4-oxadiazol-2-yl } benzenesulfonamide ;
-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-6-{[2- (dimethylamino)ethyl]amino}pyridine-3-sulfonamide;
3-amino-N-(3-{[3-amino-5-(methoxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide ;
N-(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)-3 - (dimethylamino)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-6-{[2- (dimethylamino)ethyl] oxy } pyridine-3 -sulfonamide ;
-(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)-6-(dimethylamino)pyridine-3 - sulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-cyanobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-fluorobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4-fluoro-2- methylbenzenesulfonamide;
N-(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)-2-methylbenzenesulfonamide ;
N-(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-3-cyanobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3,5- difluorobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-2-chlorobenzenesulfonamide;
N-(4- { [(3- { [3 ,5-bis(methoxy)phenyl]amino} quinoxalin-2- yl)amino]sulfonyl}phenyl)acetamide;
N-(3-{[6-(methoxy)quinolin-8-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5- yl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)naphthalene-l -sulfonamide;
N-{[(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4- methylphenyl)amino] (dimethylamino)methylidene } -N-methylmethanaminium ;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-fluorobenzenesulfonamide; N-(3-{[2-bromo-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3- nitrobenzenesulfonamide;
N-(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)-4- [(difluoromethyl)oxy]benzenesulfonamide;
N-(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-2- (trifluoromethyl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-chloro-4- fluorobenzenesulfonamide;
N-(3- { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-4- (trifluoromethyl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3- (methylsulfonyl)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-2,5-dichlorothiophene-3- sulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3,5- dichlorobenzenesulfonamide;
N-(3-{[2-methyl-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3- nitrobenzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4- [(trifluoromethyl)oxy]benzenesulfonamide;
N-(3-{[(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- 2-[4-(dimethylamino)piperidin-1-yl]acetamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-5-chloro-2- (methoxy)benzenesulfonamide;
N-(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-3- (trifluoromethyl)benzenesulfonamide;
N-(3 - { [3 ,5 -bis(methoxy)phenyl] amino } quinoxalin-2-yl)-2,5 - bis(methoxy)benzenesulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3,5-dimethylisoxazole-4- sulfonamide;
N-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-5-bromo-2- (methoxy)benzenesulfonamide ;
N-(3 - { [3 ,5-bis(methoxy)phenyl] amino } quinoxalin-2-yl)-4-fluoro-3 - (trifluoromethyl)benzenesulfonamide;
N-(3-{[3-fluoro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3- nitrobenzenesulfonamide;
Figure imgf000806_0001
Figure imgf000807_0001
Figure imgf000808_0001
Figure imgf000809_0001
Figure imgf000810_0001
Figure imgf000811_0001
Figure imgf000812_0001
6- { 2- [(2-bromophenyl)methyl] - 1 -hydroxy-3-oxo-2,3 -dihydro- 1 H-isoindol- 1 -yl } -2H- 1 ,4-benzoxazin-3(4H)-one;
6-{2-[(2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H- 1 ,4-benzoxazin-3(4H)-one;
6-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4- benzoxazin-3(4H)-one;
6- [ 1 -hydroxy-2-(3 -iodophenyl)-3 -oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] -2H- 1 ,4- benzoxazin-3(4H)-one;
6-[2-(3-bromophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] -2H- 1 ,4- benzoxazin-3 (4H)-one ;
6-[l-hydroxy-2-(3-nitrophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4- benzoxazin-3(4H)-one;
6- { 1 -hydroxy-2- [3 -(methyloxy)phenyl] -3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 -y 1 } -2H- 1 ,4- benzoxazin-3(4H)-one;
6-[l-hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4- benzoxazin-3(4H)-one;
3-hydroxy-3-(1H-indol-5-yl)-2-(phenylmethyl)-2,3-dihydro-l H-isoindol- 1 -one; methyl [6-(l-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-1H- benzimidazol-2-yl] carbamate ;
6-[2-(2-aminophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1 -yl]-2H- 1 ,4- benzoxazin-3(4H)-one;
6-{[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one;
6- { [2-( 1 H-benzimidazol-2-yl)phenyl] carbonyl } -2H- 1 ,4-benzoxazin-3 (4H)-one;
6-( 1 -hydroxy-3-oxo-2- { [2-(trifluoromethyl)phenyl]methyl } -2,3-dihydro- 1 H-isoindol- l-yl)-2H-1,4-benzoxazin-3(4H)-one;
6- {2-[(5-bromo-2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl}-2H-1,4-benzoxazin-3(4H)-one;
6- { 1 -hydroxy-2-[(3-nitrophenyl)methyl]-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl } -2H- 1 ,4- benzoxazin-3(4H)-one;
6-( 1 -hydroxy-3-oxo-2- { [3-(trifluoromethyl)phenyl]methyl } -2,3-dihydro- 1 H-isoindol- 1 -yl)-2H- 1 ,4-benzoxazin-3(4H)-one;
6-(2-{[2,3-bis(methyloxy)phenyl]methyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl)-2H- 1 ,4-benzoxazin-3(4H)-one;
6- { 1 -hydroxy-2-[(3-iodophenyl)methyl] -3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl } -2H- 1 ,4- benzoxazin-3(4H)-one; 6-[l-hydroxy-3-oxo-2-({3-[(trifluoromethyl)oxy]phenyl}-methyl)-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one;
6-(l-hydroxy-2-{[2-(methylthio)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)- 2H- 1 ,4-benzoxazin-3(4H)-one;
6-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-l ,4- benzoxazin-3(4H)-one;
6-{ l-hydroxy-2-[3-(l-methylethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H- 1 ,4-benzoxazin-3(4H)-one;
6-( 1 -hydroxy-3 -oxo-2- { 3 - [(trifluoromethyl)oxy] phenyl } -2,3 -dihydro- 1 H-isoindol- 1 - yl)-2H- 1 ,4-benzoxazin-3(4H)-one;
6-{ l-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-2H- 1 ,4-benzoxazin-3(4H)-one;
3-[ 1 -hydroxy-3-oxo- 1 -(3-oxo-3,4-dihydro-2H-l ,4-benzoxazin-6-yl)- 1 ,3-dihydro-2H- isoindol-2-yl]benzene-sulfonamide;
6-{2-[5-chloro-2-(methyloxy)phenyl]- l-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1-yl}- 2H-1 ,4-benzoxazin-3(4H)-one;
6-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl } -2H- 1 ,4-benzoxazin-3(4H)-one;
3-hydroxy-3-( 1 H-indol-6-yl)-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -one;
6-[2-(3-fluoro-5-iodophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4- benzoxazin-3(4H)-one;
6-[2-(3-aminophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] -2H- 1 ,4- benzoxazin-3(4H)-one;
6- [2-(3 ,5-difluoropheny I)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 -yl] -2H- 1 ,4- benzoxazin-3(4H)-one;
6-{ l-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H- 1 ,4-benzoxazin-3(4H)-one; thyl 3-[l -hydroxy-3-oxo- l-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro- 2H-isoindol-2-yl]benzoate;
3-[ 1 -hydroxy-3-oxo- 1 -(3-oxo-3,4-dihydro-2H-l ,4-benzoxazin-6-yl)- 1 ,3-dihydro-2H- soindol-2-yl]benzonitrile;
6-[2-(2-chlorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] -2H- 1 ,4- benzoxazin-3 (4H)-one ;
6-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- l-yl]-2H- 1 ,4-benzoxazin-3(4H)-one;
Figure imgf000815_0001
methyl { 5-[ 1 -(ethyloxy)-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl}carbamate;
Phenylmethyl 2-[(2-{ [(methyloxy)carbonyl]- amino } - 1 H-benzimidazol-5-yl)carbonyl] - benzoate;
3-hydroxy-3-(1H-indazol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one;
3-hydroxy-3-(l H-indazol-6-yl)-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -one; ethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl} carbamate;
2-methylpropyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[l-hydroxy-3-oxo-2-(2-thienylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl} carbamate; methyl {5-[l-hydroxy-3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl} carbamate;
3-[2-amino- 1 -(1 , 1 -dimethylethyl)- 1 H-benzimidazol-5-yl]-3-hydroxy-2- (phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -one;
3-(2-amino- 1 H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro- 1 H- isoindol-1-one; methyl [5-( 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl)- 1 H-benzimidazol-2- yl] carbamate;
3-(methyloxy)butyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (5-{ l-hydroxy-3-oxo-2-[(lR)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-yl}- 1 H-benzimidazol-2-yl)carbamate; methyl (5 - { 1 -hydroxy-3 -oxo-2- [( IS)-I -phenylethyl] -2,3 -dihydro- 1 H-isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate;
2-(methyloxy)ethyl {5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-l H-isoindol- 1 yl] - 1 H-benzimidazol-2-yl } carbamate; methyl { 6-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 - methyl- 1 H-benzimidazol-2-yl } carbamate ; prop-2-yn- 1 -yl { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; but-2-yn- 1 -yl {5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate ;
1 -methylethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(2,3-dihydro-1H-inden-2-yl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- l-yl]-1H-benzimidazol-2-yl}carbamate; methyl {5-[l-hydroxy-3-oxo-2-(pyridin-4-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[l-hydroxy-3-oxo-2-(pyridin-3-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl (6- {2-[(3-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- y 1 } - 1 H-benzimidazol-2-yl)carbamate ; methyl { 5-[ 1 -hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-l H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl } carbamate ; methyl [5-( 1 -hydroxy-2- { [2-(methy loxy)phenyl] methyl } -3 -oxo-2,3 -dihydro- 1 H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate; methyl [5-( 1 -hydroxy-2- { [3-(methyloxy)phenyl]methyl} -3-oxo-2,3-dihydro- 1 H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate; methyl [5-(l -hydroxy-2- { [4-(methyloxy)phenyl]methyl } -3-oxo-2,3-dihydro- 1 H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate; methyl (6-{2-[(4-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (6-{2-[(3-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{ l-hydroxy-2-[(3-iodophenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}- 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[(3-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[(2-fluorophenyl)methyl]- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 - yl } - 1 H-benzimidazol-2-yl)carbamate; methyl {5-[l-hydroxy-3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro-l H-isoindol- 1-yl]- 1 H-benzimidazol-2-yl } carbamate; phenylmethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate ;
2-fluoroethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; propyl { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl}carbamate; methyl (5-{ l-hydroxy-2-[4-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}- 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[(2-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[(2-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{l-hydroxy-2-[(3-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{ l-hydroxy-2-[(4-methylphenyl)methyl]-3-oxo-2,3-dihydro-l H-isoindol- 1- yl } - 1 H-benzimidazol-2-y l)carbamate; methyl (5-{l-hydroxy-2-[(2-methylphenyl)methyl]-3-oxo-2,3-dihydro-l H-isoindol- 1- yl}-1H-benzimidazol-2-yl)carbamate; methyl { 5-[2-(3-bromophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl} carbamate; methyl { 5-[2-(3-chlorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl}carbamate; methyl {5-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dmydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl}carbamate; methyl (5-{l-hydroxy-2-[3-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}- 1H-benzimidazol-2-yl)carbamate; methyl {5-[2-(4-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl } carbamate; methyl { 5-[2-(4-chlorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl } carbamate ; methyl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl } carbamate ; methyl {5-[2-(3,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl } carbamate; methyl {5-[2-(2-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl } carbamate; methyl {5-[l-hydroxy-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl} carbamate; methyl (5-{l-hydroxy-2-[2-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}- 1 H-benzimidazol-2-yl)carbamate; methyl { 5-[ 1 -hydroxy-2-(4-methylphenyl)-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl}carbamate; methyl (5-{l-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-isoindol-l yl } - 1 H-benzimidazol-2-yl)carbamate; but-2-yn- 1 -yl (5 - { 1 -hydroxy-3 -oxo-2- [( 1 R)- 1 -phenylethyl] -2,3-dihydro- 1 H-isoindol- 1 ■ 1 } - 1 H-benzimidazol-2-yl)carbamate;
N-ethyl-N'-{5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl } urea; phenylmethyl (5-{l-hydroxy-3-oxo-2-[(lR)-1-phenylethyl]-2,3-dihydro-1H-isoindol-l yl } - 1 H-benzimidazol-2-yl)carbamate; methyl {6-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-1H-benzimidazol-2-yl} carbamate; piperidin-4-ylmethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(cyclopropylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl} carbamate; methyl {5-[2-(2,2-dimethylpropyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(3,5-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl}carbamate; methyl {5-[2-(3,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate;
N-ethyl-N'-CS-l l-hydroxy-S-oxo^-fClR^l-phenylethy^^^-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)urea;
N'- { 5- [ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl } -N,N-dimethylurea; methyl {5-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
3-(4-methylpiperazin-1-yl)propyl {6-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ; methyl {5-[2-(cyclohexylmethyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl} carbamate; methyl { 5-[ 1 -hydroxy-2-(2-methylpropyl)-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl} carbamate; methyl {5-[l-hydroxy-3-oxo-2-(1,3-thiazol-2-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl} carbamate; methyl (5- {2-[l-(3,5-difluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[l-(3-fluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl [5-(2-cyclohexyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H- benzimidazol-2-yl]carbamate; methyl {5-[2-(2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate;
N- { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl}-N'-(phenylmethyl)urea; piperidin-4-yl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate ;
N- { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl } -N'-methylurea; methyl (5-{2-[ 1 -(2-fluorophenyl)ethyl]-l -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 - yl}-1H-benzimidazol-2-yl)carbamate; methyl (5-{ l-hydroxy-3-oxo-2-[l-(2-thienyl)ethyl]-2,3-dihydro-1H-isoindol-1-yl}-1H- benzimidazol-2-yl)carbamate; methyl (5-{2-[l-(3-chlorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{ 1 -hydroxy-2-[3-methyl-5-(trifluoromethyl)phenyl]-3-oxo-2,3-dihydro- 1 H- soindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate;
N- { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl}propanamide; methyl {5-[2-(3,4-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(3-ethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1-yl]- 1H- benzimidazol-2-yl } carbamate; methyl {5-[2-(3-ethynylphenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl } carbamate; methyl { 5-[2-(4-chloro-3-methylphenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 - yl]-1H-benzimidazol-2-yl}carbamate; methyl [S-Cl-hydroxy-S-oxo^-ll-tS-Ctrifluoromethy^phenylJethyll^^-dihydro-1H- soindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate; methyl (5-{ 1 -hydroxy-3-oxo-2-[(lR)- 1 -phenylpropyl]-2,3-dihydro- 1 H-isoindol- 1 -yl } ■ 1 H-benzimidazol-2-yl)carbamate; methyl [5-(l-hydroxy-3-oxo-2-{2-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate; methyl { 5-[2-(2,3-difluorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; cyclohexyl {5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-l H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl } carbamate; tetrahydrofiiran-2-ylmethyl { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; cyclopropylmethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1- yl] - 1 H-benzimidazol-2-yl } carbamate;
N- { 5 - [ 1 -hydroxy-3 -oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl}morpholine-4-carboxamide; methyl { 5 - [2-(cyclopentylmethyl)- 1 -hydroxy-3 -oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl } carbamate ; methyl {5-[2-(2,3-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1-yl]- 1 H-benzimidazol-2-yl } carbamate ; methyl {5-[2-(2,3-dihydro-1H-inden-1-yl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (2S)-cyclohexyl[ 1 -hydroxy- 1 -(2- { [(methyloxy)carbonyl] amino } - 1 H- benzimidazol-5-yl)-3-oxo-1,3-dihydro-2H-isoindol-2-yl]ethanoate; methyl {5-[2-(2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl { 5-[2-(3-chloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl]- 1 H-benzimidazol-2-yl } carbamate; but-3-en- 1 -yl { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate;
2,2,2-trifluoroethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1- yl]-1H-benzimidazol-2-yl}carbamate; methyl {5-[2-(5-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (5 - { 2- [ 1 -(5 -chloro-2-methylphenyl)ethyl] - 1 -hydroxy-3 -oxo-2 ,3 -dihydro- 1 H- soindol-1-yl}-1H-benzimidazol-2-yl)carbamate; methyl (5-{ l -hydroxy-3-oxo-2-[(l S)-1-phenylpropyl]-2,3-dihydro-1H-isoindol-1-yl}- 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[l-(3-chloro-2-methylphenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5- { 1 -hydroxy-2- [ 1 -(5-methyl-2-thienyl)ethyl]-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[l-(5-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- l-yl}-1H-benzimidazol-2-yl)carbamate; methyl { 5-[ 1 -hydroxy-2-(3-iodophenyl)-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl } carbamate; methyl (5-{ l-hydroxy-2-[3-(l-methylethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl {5-[2-(furan-2-ylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- l-yl]-l H- benzimidazol-2-yl } carbamate; methyl { 5-[ 1 -hydroxy-3-oxo-2-(3-thienylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl}carbamate; methyl {5-[2-(cyclobutylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl}carbamate;
3,3,3-trifluoro-2-hydroxy-N-{5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl} -2-(trifluoromethyl)propanamide; methyl (5-{ l-hydroxy-2-[l-(4-methyl-2-thienyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{2-[l-(4-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate ; methyl {5-[l-hydroxy-2-(3-{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; tetrahydrofuran-3-ylmethyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ;
N- { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl } piperidine- 1 -carboxamide ; methyl {5-[2-(3-bromo-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-1H-benzimidazol-2-yl}carbamate;
2,3-dihydroxypropyl {5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl {5-[l-hydroxy-3-oxo-2-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (5-{2-[3-(aminocarbonyl)phenyl]- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 ■ yl}-1H-benzimidazol-2-yl)carbamate;
4,4,4-trifluoro-3-hydroxy-N-{5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- soindol-1-yl]-1H-benzimidazol-2-yl}-3-(trifluoromethyl)butanamide; methyl (5-{ l-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-y l)carbamate; methyl (5-{ l-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}- 1H-benzimidazol-2-yl)carbamate; methyl [5-(l-hydroxy-3-oxo-2-{3-[(phenylmethyl)oxy]phenyl}-2,3-dihydro-1H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl] carbamate ; methyl [5-(2-biphenyl-3-yl- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl)- 1 H- benzimidazol-2-yl]carbamate;
2,2-dimethyl-3-[(phenylmethyl)oxy]propyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)- 2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl}carbamate; methyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-1H-benzimidazol-2-yl}carbamate; methyl {5-[2-(3-cyanophenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1-yl]- 1H- benzimidazol-2-yl } carbamate ; methyl { 5 - [2-(3 -ethynyl-4-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 - yl] - 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(4-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-l H-benzimidazol-2-yl} carbamate; methyl {6-[2-(3,4-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)- 2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl }carbamate; methyl {5-[2-(5-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (5-{2-[3-(acetylamino)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{ l-hydroxy-3-oxo-2-[3-(phenylmethyl)phenyl]-2,3-dihydro-l H-isoindol- 1- yl}-1H-benzimidazol-2-yl)carbamate; methyl (5-{2-[l-(4-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5- { l-hydroxy-3-oxo-2-[3-(phenylcarbonyl)phenyl]-2,3-dihydro-l H-isoindol- 1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl [5 -(2- { 3 - [(dimethylamino)methyl]phenyl } - 1 -hydroxy-3 -oxo-2,3-dihydro- 1 H- soindol-1-yl)-1H-benzimidazol-2-yl]carbamate; methyl (5-{2-[3-(aminosulfonyl)phenyl]-l -hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl } - 1 H-benzimidazol-2-yl)carbamate; methyl {5-[2-(3-acetylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl} carbamate; methyl { 5-[2-(3-ethyl-4-fluorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 - yl] - 1 H-benzimidazol-2-y 1 } carbamate; methyl { 5 - [2-(3 -chloro-5 -fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 - yl] - 1 H-benzimidazol-2-yl } carbamate ;
N- { 6-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl}-2-methylpropanamide; methyl (5-{2-[l-(3-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl [5-(l-hydroxy-3-oxo-2-pyridin-3-yl-2,3-dihydro-l H-isoindol- 1-yl)- 1H- benzimidazol-2-yl]carbamate; methyl (5-{l-hydroxy-3-oxo-2-[3-(phenylamino)phenyl]-2,3-dihydro-l H-isoindol- 1- yl}-1H-benzimidazol-2-yl)carbamate; methyl {5-[2-(5-bromo-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- l-yl]-1H-benzimidazol-2-yl}carbamate; methyl {5-[2-(5-chloro-2,4-difluorophenyl)-l -hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ; methyl {5-[2-(3,5-dichloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2,2-dimethyl-3-(methyloxy)propyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate;
3-hydroxy-2,2-dimethylpropyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (5-{2-[l-(5-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl} - 1 H-benzimidazol-2-yl)carbamate; methyl {5-[2-(4,5-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ; methyl {5-[2-(3-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- y 1] - 1 H-benzimidazol-2-yl } carbamate ; methyl {5-[2-(3-chloro-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -y 1] - 1 H-benzimidazol-2-yl } carbamate;
N- { 6- [ 1 -hydroxy-3 -oxo-2-(phenylmethyl)-2,3 -dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl}pent-4-ynamide; methyl (6-{ l-methyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l H-isoindol- 1- yl } - 1 H-benzimidazol-2-y l)carbamate; methyl [5-(l-hydroxy-3-oxo-2-{3-[(l,1,2,2-tetrafluoroethyl)oxy]phenyl}-2,3-dihydro- 1 H-isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate; methyl {5-[l-hydroxy-3-oxo-2-(3-piperidin-4-ylphenyl)-2,3-dihydro-1H-isoindol-1- yl] - 1 H-benzimidazol-2-y 1 } carbamate; methyl {5-[2-(3-ethenylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1-yl] -1H- benzimidazol-2-yl } carbamate; methyl (5-{2-[3-(dimethylamino)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl } - 1 H-benzimidazol-2-y l)carbamate ;
2,2-difluoro-N-{6-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl}cyclopropanecarboxamide;
N-ethyl-N'- { 6- [2-(4-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } urea; methyl {5-[2-(3-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl } carbamate;
N- { 5 - [ 1 -hydroxy-3 -oxo-2-(phenylmethyl)-2, 3 -dihydro- 1 H-isoindol- 1 -y 1] - 1 H- benzimidazol-2-yl}-4-[(phenylmethyl)oxy]butanamide;
N-{5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-l H-isoindol- 1-yl]- 1H- benzimidazol-2-yl } -4-piperidin- 1 -ylbutanamide;
N-{5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl } -4-(4-methylpiperazin- 1 -yl)butanamide ;
- { 6- [2-(4-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl } butanamide ; methyl {6-[2-(3-bromophenyl)-5,6-dichloro-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate; methyl [5-(l-hydroxy-2-{3-[methyl(phenyl)amino]phenyl}-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate; methyl {5-[l-hydroxy-3-oxo-2-(phenylsulfonyl)-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl} carbamate; methyl { 5- [(2- { [(phenylamino)carbonyl] amino } phenyl)carbonyl] - 1 H-benzimidazol-2- yl} carbamate; methyl (5 - { [2-( { [(phenylmethyl)oxy] carbonyl } amino)phenyl] carbonyl } - 1 H- benzimidazol-2-yl)carbamate; methyl [5-({2-[(2-phenylhydrazino)carbonyl]phenyl}carbonyl)-1H-benzimidazol-2- yl]carbamate; methyl { 5 - [(2- { [(phenyloxy)amino] carbonyl } phenyl)carbonyl] - 1 H-benzimidazol-2- yl} carbamate; but-2-yn-1-yl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate;
N- { 5 - [ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3 -dihydro- 1 H-isoindol- 1 -y 1] - 1 H- benzimidazol-2-yl } -3 -piperidin- 1 -ylpropanamide ;
N- { 6- [2-(4-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl } propanamide;
N-(4-fluorophenyl)-2- { [2-(pent-4-ynoylamino)- 1 H-benzimidazol-6- yl]carbonyl}benzamide;
4-(diethylamino)-N-{5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } butanamide;
N- { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl}-4-pyrrolidin-1-ylbutanamide;
3 -piperidin- 1-ylpropyl {6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
3-(4-methylpiperazin- 1 -yl)propyl {6-[2-(4-fluorophenyl)- 1 -hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl} carbamate; methyl {5-[2-(3-bromophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol- 2-yl} carbamate; methyl {5-[2-(3-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl] - 1 H-benzimidazol-2-yl } carbamate;
2-piperidin-1-ylethyl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate; methyl { 5 - [2-(3-chloro-2-methylphenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 - yl]-l H-benzimidazol-2-yl} carbamate; methyl {5-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-1H-benzimidazol-2-yl}carbamate;
N-{6-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl } -2,2-dimethyl-3-piperidin- 1 -ylpropanamide;
N-{5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl}-4-piperidin-1-ylbutanamide;
N- {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1-yl]- 1 H-benzimidazol-2-yl } -4-piperidin- 1 -ylbutanamide; methyl [6-({2-[(phenylcarbonyl)amino]phenyl}carbonyl)-1H-benzimidazol-2- yl]carbamate; methyl {5-[l-hydroxy-2-(3-morpholin-4-ylphenyl)-3-oxo-2,3-dihydro-l H-isoindol- 1- yl]-1H-benzimidazol-2-yl}carbamate; 2-(dimethylamino)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2-(diethylamino)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2-piperidin- 1 -ylethyl { 5 - [2-(3 -chloro-2-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
3-piperidin-1-ylpropyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2-piperidin- 1 -ylethyl {6-[2-(3-bromophenyl)-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H- benzimidazol-2-yl } carbamate ; methyl {6-[2-(3-bromophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- l-yl]-1H-benzimidazol-2-yl}carbamate;
2-[methyl(phenylmethyl)amino]ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[ 1 -hydroxy-3 -oxo-2-(3-pyrrolidin- 1 -ylphenyl)-2,3-dihydro- 1 H-isoindol- 1 - yl] - 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(5-chloro-2,3-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- l-yl]-l H-benzimidazol-2-yl} carbamate; methyl {5-[ 1 -hydroxy-3-oxo-2-(pyrrolidin-2-ylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; methyl { 5-[l-hydroxy-3-oxo-2-(pyrrolidin-3-ylmethyl)-2,3-dihydro-l H-isoindol- 1-yl]- 1 H-benzimidazol-2-yl} carbamate;
(l-methylpiperidin-2-yl)methyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl} carbamate;
[(2S)-1-methylpyrrolidin-2-yl]methyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; octahydro-2H-quinolizin-1-ylmethyl { 6- [2-(3-chloro-2-fluorophenyl)-l -hydroxy-3 - oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate; methyl {5-[2-(5-bromo-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl] - 1 H-benzimidazol-2-yl } carbamate ;
5-[2-(3-chloro-2-fluorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 ,3- dihydro-2H-benzimidazol-2-one; methyl {5-[2-(3-bromo-2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2-morpholin-4-ylethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate; (l-methylpiperidin-3-yl)methyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (5-{2-[5-chloro-2-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate; methyl [S-^-P-tcyclohexylCmethyOaminoJphenylJ-1-hydroxy-S-oxo^^-dihydro-1H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate;
8-azabicyclo [3.2.1 ] oct-3 -ylmethyl { 6- [2-(3-chloro-2-fluorophenyl)- 1 -hydroxy-3 -oxo- 2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ; methyl {6-[l-(3-bromophenyl)-5-oxopyrrolidin-2-yl]-1H-benzimidazol-2- yl} carbamate;
(l-methylpiperidin-4-yl)methyl {5-[l-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ;
1 , 1 -dimethylethyl 4-( { [( { 5-[ 1 -hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1 H- isoindol- 1 -yl]- 1 H-benzimidazol-2-yl }amino)carbonyl]oxy}methyl)piperidine- 1 - carboxylate;
( 1 -methylpiperidin-4-yl)methyl { 5-[2-(3-chloro-2-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3- dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ;
2-(l-methylpiperidin-4-yl)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl ( { 6- [2-(3 -chloro-2-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 - yl] - 1 H-benzimidazol-2-yl } amino)(oxo)acetate;
N-(5- { 1 -hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro- 1 H-isoindol- 1 -yl} - 1 H- benzimidazol-2-yl)-4-piperidin- 1 -ylbutanamide ; methyl {6-[2-(3-bromophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl} carbamate;
4-(diethylamino)but-2-yn-1-yl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ; methyl {5-[2-(3-chloro-2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2-(2-oxopyrrolidin-1-yl)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ;
2-(2,5-dioxopyrrolidin-1-yl)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate;
2,2,3,3-tetrafluorocyclobutyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; l-acetyl-N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- l-yl]-1H-benzimidazol-2-yl}piperidine-4-carboxamide; N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl}cyclobutanecarboxamide; methyl [5-(2-{3-[ethyl(phenyl)amino]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl)- 1 H-benzimidazol-2-yl]carbamate;
N-{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl}-2,2-difluorocyclopropanecarboxamide; cyclobutyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ;
2,2-difluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2 -(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyridin-2-ylamino)-1H-benzimidazol-5- y l]-2,3-dihydro-l H-isoindol- 1 -one;
1 -methylethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; yclopropylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
N- { 5-[2-(3-chloro-2-fluorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } cyclopropanecarboxamide;
2-(methyloxy)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; tetrahydrofuran-2-ylm ethyl { 6- [2-(3 -chloro-2-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 - dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ;
N- {5-[2-(3-chloro-2-fluorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl }-2-(2-thienyl)acetamide; methyl {6-[2-(3-chloro-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H- soindol- 1 -yl]- 1 H-benzimidazol-2-yl} carbamate; thyl { 6-[2-(3-chloro-2-fluorophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate;
2-fluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- soindol-1-yl]-1H-benzimidazol-2-yl}carbamate; methyl (5-{ l-hydroxy-3-oxo-2-[2-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}- 1H-benzimidazol-2-yl)carbamate;
N'-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl}-N,N-diethylpentanediamide; jyclobutylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- soindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ; 2,2,2-trifluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl]-l H-benzimidazol-2-yl}carbamate; methyl (5-{2-[3-(l,l-dimethylethyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl {6-[2-(3-chloro-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate;
2-(3 -chloro-2-fluorophenyl)-3-hydroxy-3 - [2-(phenylamino)- 1 H-benzimidazol-5 -yl] - 2,3-dihydro- 1 H-isoindol- 1 -one; methyl {6-[4,7-dichloro-2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ; phenylmethyl 2-[(2-{[(ethyloxy)carbonyl]amino}-1,3-benzoxazol-5- y l)carbonyl] benzoate ; methyl {5-[2-(5-chloro-3-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(5-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(3-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate;
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-benzirnidazol- 5-yl]-2,3-dihydro- 1 H-isoindol- 1 -one; methyl {5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate ;
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(1,3-thiazol-2-ylamino)-1H-benzimidazol- 5-yl] -2,3-dihydro- 1 H-isoindol- 1 -one; ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 ,3-benzoxazol-2-yl}carbamate; methyl {5-[2-(5-chloro-3-iodo-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate; methyl { 5-[2-(3-ethyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl] - 1 H-benzimidazol-2-yl } carbamate; methyl { 5 - [2-(5 -ethyny 1-2-methylphenyl)- 1 -hydroxy-3 -oxo-2,3-dihydro- 1 H-isoindol- 1 yl]-1H-benzimidazol-2-yl}carbamate;
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-5- yl]-2,3-dihydro- 1 H-isoindol- 1 -one; methyl { 5-[2-(2-fluoro-3-iodophenyl)- 1 -hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl]- 1H-benzimidazol-2-yl}carbamate; methyl {6-[2-(5-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl] - 1 H-benzimidazol-2-y 1 } carbamate;
2-(3-ethynyl-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol 5-yl]-2,3-dihydro-1H-isoindol-1-one; methyl {5-[2-(2,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1 H-benzimidazol-2-yl } carbamate; methyl { 5- [2-(3 -ethenyl-2-fluorophenyl)- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 - yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (6-{2-[2-fluoro-3-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl (5-{ l-hydroxy-2-[2-methyl-5-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate; methyl {5-[2-(3-ethynyl-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl { 5 - [2-(2-fluoro-3 -prop- 1 -yn- 1 -ylphenyl)- 1 -hydroxy-3-oxo-2,3 -dihydro- 1 H- isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(5-chloro-2-methylphenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl]- 1 H-benzimidazol-2-yl } carbamate; methyl {5-[2-(3-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-l yl] - 1 H-benzimidazol-2-yl } carbamate;
3 -hydroxy-2- [3 -(methyloxy)phenyl] -3 -[2-(pyrimidin-2-ylamino)- 1 H-benzimidazol-6- yl] -2,3-dihydro- 1 H-isoindol- 1 -one;
3-hydroxy-2-(3-methylphenyl)-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-6-yl]- 2,3-dihydro- 1 H-isoindol- 1 -one;
2-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol- 6-yl] -2,3 -dihydro- 1 H-isoindol- 1 -one ; methyl {6-[2-(5-chloro-2-methylphenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H-benzimidazol-2-yl } carbamate; methyl { 5-[2-(3-ethynyl-2-fluorophenyl)-3-oxo-2,3-dihydro- 1 H-isoindol- 1 -yl] - 1 H- benzimidazol-2-yl} carbamate;
2-(3-chloro-2-fluorophenyl)-3 - { 2- [(6-chloropyridazin-3 -yl)amino] - 1 H-benzimidazol-5 ■ yl } -3-hydroxy-2,3-dihydro- 1 H-isoindol- 1 -one;
2-(3-chloro-2-fluorophenyl)-4,7-difluoro-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H- benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one; methyl {5-[2-(2-fluoro-5-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-l H-isoindol- 1- yl] - 1 H-benzimidazol-2-yl } carbamate; methyl (5-{2-[2-fluoro-5-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate ; methyl (5-{ l-hydroxy-2-[5-methyl-2-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H- isoindol- 1 -yl } - 1 H-benzimidazol-2-yl)carbamate; methyl {5-[2-(3-ethynyl-5-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-l yl] - 1 H-benzimidazol-2-yl } carbamate;
2-(3-chloro-2-fluorophenyl)-3-{2-[(5-chloropyrimidin-2-yl)amino]-1H-benzimidazol- 5 -yl } -3 -hydroxy-2,3 -dihydro- 1 H-isoindol- 1 -one;
2-(3 -chloro-2-fluorophenyl)-3-hydroxy-3 - { 2-[(4-methylpyrimidin-2-yl)amino] - 1 H- benzimidazol-5-yl } -2,3-dihydro- 1 H-isoindol- 1 -one;
3-(2- { [4,6-bis(methyloxy)pyrimidin-2-yl]amino}- 1 H-benzimidazol-5-yl)-2-(3-chloro- 2-fluorophenyl)-3-hydroxy-2,3-dihydro- 1 H-isoindol- 1 -one;
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-(2-{[4-methyl-6-(methyloxy)pyrimidin-2- yl]amino}-1H-benzimidazol-5-yl)-2,3-dihydro-l H-isoindol- 1 -one;
3-hydroxy-2-(3-methylphenyl)-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-6-yl]-2,3- dihydro- 1 H-isoindol- 1 -one;
2-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-6- yl] -2,3-dihydro- 1 H-isoindol- 1 -one ; methyl {6-[2-(2-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl] - 1 H-benzimidazol-2-yl } carbamate ;
3-hydroxy-2-[3-(methyloxy)phenyl]-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-5-yl]- 2,3-dihydro- 1 H-isoindol- 1 -one; methyl { 6- [(2- { [(2-thienylmethyl)amino] carbonyl } phenyl)carbonyl] - 1 H-benzimidazol- 2-yl}carbamate; methyl { 6- [(2- { [(3-methylphenyl)amino]carbonyl } phenyl)carbonyl] - 1 H-benzimidazol- 2-yl}carbamate; methyl {6-[(2-{[(3-bromophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol- 2-yl}carbamate; methyl {6-[(2-{[(3-chlorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol- 2-yl} carbamate; methyl {6-[(2-{[(3-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol- 2-yl} carbamate; methyl (6- { [2-( { [3-(methyloxy)phenyl]amino } carbonyl)phenyl] carbonyl } - 1 H- benzimidazol-2-yl)carbamate; methyl (6- { [2-( { [3 -(trifluoromethy l)phenyl]amino } carbonyl)phenyl]carbonyl } - 1 H- benzimidazol-2-yl)carbamate; methyl { 6- [(2- { [(3 -ethylphenyl)amino]carbonyl } phenyl)carbonyl] - 1 H-benzimidazol-2- yl}carbamate; methyl { 6- [(2- { [(3-ethynylphenyl)amino]carbonyl } phenyl)carbonyl] - 1 H- benzimidazol-2-yl}carbamate; methyl { 6- [(2- { [(3-chloro-4-fluorophenyl)amino] carbonyl } pheny l)carbonyl] - 1 H- benzimidazol-2-yl } carbamate; methyl { 6- [(2- { [(5-chloro-2-fluorophenyl)amino] carbonyl } pheny l)carbonyl] - 1 H- benzimidazol-2-yl } carbamate; methyl {6-[(2-{[(3-iodophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2- yl} carbamate; methyl (6- { [2-( { [3-( 1 -methylethyl)phenyl] amino } carbonyl)phenyl] carbonyl } - 1 H- benzimidazol-2-yl)carbamate; methyl {6-[(2-{[(3-thienylmethyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol- 2-yl} carbamate; methyl {6-[(2-{[(3-bromo-4-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H- benzimidazol-2-yl} carbamate; methyl {6-[(2-{[(3-chloro-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H- benzimidazol-2-yl} carbamate; methyl {6-[(2-{[(4-fluoro-3-methylphenyl)amino]carbonyl}phenyl)carbonyl]-1H- benzimidazol-2-yl} carbamate; methyl {6-[(2-{[(5-bromo-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H- benzimidazol-2-yl} carbamate; methyl {6-[(2-{[(5-bromo-2,4-difluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H- benzimidazol-2-yl} carbamate; methyl { 6- [(2- { [(5-chloro-2,4-difluorophenyl)amino] carbonyl } phenyl)carbonyl] - 1 H- benzimidazol-2-yl} carbamate; methyl { 6- [(2- { [(3-bromo-2-fluorophenyl)amino] carbonyl } phenyl)carbonyl] - 1 H- benzimidazol-2-yl} carbamate; methyl { 6- [(2- { [(3 -ethenylphenyl)amino] carbonyl } phenyl)carbonyl] - 1 H-benzimidazol- 2-yl} carbamate; methyl { 6- [(2- { [(3 -ethyny l-2-fluorophenyl)amino] carbonyl } phenyl)carbony 1] - 1 H- benzimidazol-2-yl} carbamate; methyl { 6- [(2- { [(5 -chloro-2-methylphenyl)amino]carbonyl } phenyl)carbonyl] - 1 H- benzimidazol-2-yl } carbamate; methyl { 6- [(2- { [(5 -bromo-2-methylphenyl)amino]carbonyl } phenyl)carbonyl] - 1 H- benzimidazol-2-yl} carbamate; methyl { 6- [(2- { [(2-fluoro-3-iodophenyl)amino]carbonyl } phenyl)carbonyl] - 1 H- benzimidazol-2-yl } carbamate ;
methyl {6-[(2-{[(3-ethenyl-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H- benzimidazol-2-yl } carbamate ; methyl { 6-[(2- { [(2-fluoro-5 -methylphenyl)amino] carbonyl } phenyl)carbonyl] - 1H- benzimidazol-2-yl } carbamate;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N6-[3-(diethylamino)propyl]-N2-{[3-(l- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4,6-triamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N6-[2-(diethylamino)ethyl]-N2-{[3-(l- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4,6-triamine;
N2- { [3 -( 1 -methylethyl)isoxazol-5 -yl]methyl } -N4- [5-( 1 -methylethyl)- 1 H-pyrazol-3 - yl] -6- [(3 S)-3 -methylpiperazin- 1 -yl]pyrimidine-2,4-diamine ;
N4-(5-cyclopropyl- 1 H-pyrazol-3-yl)-6- { [2-(dimethylamino)ethyl]oxy } -N2- { [3-( 1 - methylethyl)isoxazol-5 -yl] methyl } pyrimidine-2,4-diamine;
N4- [3 -( 1 -methylethyl)- 1 H-pyrazol-5-yl] -6- [( 1 -methylpyrrolidin-3 -yl)oxy] -N2- [(3 - phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-6- (l-methylpyrrolidin-3-yl)oxy]pyrimidine-2,4-diamine;
N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N4-[3-(l-methylethyl)-1H-pyrazol-5- yl]-6-[(l-methylpyrrolidin-3-yl)oxy]pyrimidine-2,4-diamine;
N4-[2-(diethylamino)ethyl]-N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N6-[5-(l- methylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4,6-tri amine;
N2- { [3-( 1 -methylethyl)isoxazol-5-yl]methyl } -N4-[5-( 1 -methylethyl)- 1 H-pyrazol-3- yl]pyrimidine-2,4-diamine;
N4-[5-(l-methylethyl)-1H-pyrazol-3-yl]-6-[(l-methylpiperidin-3-yl)oxy]-N2-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N2- { [3 -( 1 -methylethyl)isoxazol-5 -yljmethyl } -N4- [5 -( 1 -methylethyl)- 1 H-pyrazol-3 - yl]-6-[(l-methylpiperidin-3-yl)oxy]pyrimidine-2,4-diamine;
N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-2-{[(3-phenylisoxazol-5- l)methyl]oxy}pyrimidin-4-amine;
N4-(5-cyclopropyl- 1 H-pyrazol-3-yl)-6-methyl-N2-[(4-phenyl- 1 H-imidazol-2- yl)methyl]pyrimidine-2,4-diamine;
6-{[2-(dimethylamino)ethyl]oxy}-N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N4- 5-( 1 -methylethyl)- 1 H-pyrazol-3-yl]pyrimidine-2,4-diamine;
N2- { [3-( 1 -methylethyl)isoxazol-5-yl]methyl } -N4- [5-( 1 -methylethyl)- 1 H-pyrazol-3- l]-6-[(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4-diamine; N4-[5-(l-methylethyl)-1H-pyrazol-3-yl]-6-[(2-morpholin-4-ylethyl)oxy]-N2-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-[3-(l-methylethyl)-1H-pyrazol-5-yl]-N2-[(3-phenylisoxazol-5-yl)methyl]-6-[(2- piperidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine;
N4-[3-(diethylamino)propyl]-N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N6-[5-(l- methylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4,6-triamine;
N4-[5-(l-methylethyl)-1H-pyrazol-3-yl]-6-[(3S)-3-methylpiperazin-1-yl]-N2-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-[2-(diethylamino)ethyl]-N6-[5-(l-methylethyl)-1H-pyrazol-3-yl]-N2-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
N4- [5 -( 1 -methylethyl)- 1 H-pyrazol-3 -yl] -6- [( 1 -methylpiperidin-4-yl)oxy] -N2- [(3 - phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-6- [(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4-diamine;
2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N4-[3-(l-methylethyl)-1H-pyrazol-5- l]-6-[(2-piperidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
4-(3-cyclopropyl-1H-pyrazol-5-yl)-6-[3-(diethylamino)propyl]-N2-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-6- [(2-piperidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine;
N4-(5 -cyclopropyl- 1 H-pyrazol-3 -yl)-N2- { [3 -( 1 -methylethyl)isoxazol-5-yl] methyl } -6- [(l-methylpiperidin-3-yl)oxy]pyrimidine-2,4-diamine;
2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N4-[3-(l-methylethyl)-1H-pyrazol-5- l]-6-[(l-methylpiperidin-4-yl)oxy]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methyl-N2-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-[(3-methylisoxazol-5-yl)methyl]-6- moηDholin-4-ylpyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-[(3-methylisoxazol-5-yl)methyl]-6-(4- methylpiperazin- 1 -yl)pyrimidine-2,4-diamine;
N4-(5-cyclopropyl- 1 H-pyrazol-3-yl)-N2- { [3-( 1 -methylethyl)isoxazol-5-yl]methyl } -6- [(l-methylpiperidin-4-yl)oxy]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6- morpholin-4-ylpyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6- (4-methylpiperazin- 1 -yl)pyrimidine-2,4-diamine; N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6- [(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4-diamine;
N2-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N4-[3-(l-methylethyl)-1H-pyrazol-5- yl]-6-morpholin-4-ylpyrimidine-2,4-diamine;
N2-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N4-[3-(l-methylethyl)-1H-pyrazol-5- yl] -6-(4-methylpiperazin- 1 -yl)pyrimidine-2,4-diamine ;
N2-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N4-[3-(l-methylethyl)-1H-pyrazol-5- yl] -6- [(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4-diamine ;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-N2-[(3-pyridin-3-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N2-[(3-pyridin-2- ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-N2-[(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl- 1 H-pyrazol-3 -yl)-N2- { [3 -( 1 -methylethyl)isoxazol-5 -yl] methyl } -6- piperazin- 1 -ylpyrimidine-2,4-diamine;
6-(4-acetylpiperazin-1-yl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-{[3-(l- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N4-(5-cyclopropyl- 1 H-pyrazol-3 -yl)-N2- { [3 -( 1 -methylethyl)isoxazol-5 -y 1] methyl } -6- [4-(methylsulfonyl)piperazin-1-yl]pyrimidine-2,4-diamine;
4-{6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-({[3-(l-methylethyl)isoxazol-5- 1] methyl } amino)pyrimidin-4-yl } piperazine- 1 -carbaldehyde;
N4-(3-methyl-1H-pyrazol-5-yl)-6-morpholin-4-yl-N2-[(3-phenylisoxazol-5- l)methyl]pyrimidine-2,4-diamine;
6-(4-methylpiperazin-1-yl)-N4-(3-methyl-1H-pyrazol-5-yl)-N2-[(3-phenylisoxazol-5- l)methyl]pyrimidine-2,4-diamine;
N4-(3-methyl-1H-pyrazol-5-yl)-6-[(2-morpholin-4-ylethyl)oxy]-N2-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-N2-[(3-pyridin-4-ylisoxazol-5- l)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-{[3-(3,4-difluorophenyl)isoxazol-5- l]methyl}-6-methylpyrimidine-2,4-diamine; s>J4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-{[3-(2,4-difluorophenyl)isoxazol-5- l]methyl}-6-methylpyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-N2-[(3-pyrazin-2-ylisoxazol-5- l)methyl]pyrimidine-2,4-diamine;
Figure imgf000837_0001
N4-(3-cyclopropyl- 1 H-pyrazol-5-yl)-6-(4-methylpiperazin- 1 -yl)-N2-[(3-pyrimidin-5- ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-6-morpholin-4-yl-N2-[(3-pyrimidin-5-ylisoxazol- 5-yl)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl- 1 H-pyrazol-3-yl)-6- { [2-(diethylamino)ethyl]oxy } -N2- { [3-( 1 - methylethyl)isoxazol-5 -y ljmethyl } pyrimidine-2,4-diamine ;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-6- [(2-pyrrolidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-{[2-(diethylamino)ethyl]oxy}-N2-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[(3-methylisoxazol-5-yl)methyl]-6-[(2- pyπOlidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N2-{[3-(1,3-thiazol-2- yl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N4-(3-cyclopropyl- 1 H-pyrazol-5 -yl)-6- [2-(dimethylamino)ethoxy] -N2- [(3 - methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
6-{[2-(dimethylamino)ethyl]oxy}-N2-[(3-methylisoxazol-5-yl)methyl]-N4-(3-methyl- 1H-pyrazol-5-yl)pyrimidine-2,4-diamine;
6-{[2-(diethylamino)ethyl]oxy}-N2-[(3-methylisoxazol-5-yl)methyl]-N4-(3-methyl- 1H-pyrazol-5-yl)pyrimidine-2,4-diamine;
N2-[(3-methylisoxazol-5-yl)methyl]-N4-(3-methyl-1H-pyrazol-5-yl)-6-[(2-pyrrolidin- l-ylethyl)oxy]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methyl-N2-[2-(3-phenylisoxazol-5- yl)ethyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl- 1 H-pyrazol-5-yl)-6-methyl-N2-[ 1 -(3-phenylisoxazol-5- yl)ethyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-[(3-ethylisoxazol-5-yl)methyl]-6-(4- methylpiperazin- 1 -yl)pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-[(3-ethylisoxazol-5-yl)methyl]-6-morpholin- 4-ylpyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N2-[(3- thylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-6-{[2-(diethylamino)ethyl]oxy}-N2-[(3- thylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N4-(3-cyclopropyl-1H-pyrazol-5-yl)-N2-[(3-ethylisoxazol-5-yl)methyl]-6-[(2- pyiτolidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
Figure imgf000839_0001
5-bromo-N~4~-(3-methyl-1H-pyrazol-5-yl)-N~2 — [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N~2~-[4-(aminomethyl)phenyl]-5-bromo-N~4 — (S-cyclopropyl-1H-pyrazol-S- yl)pyrimidine-2,4-diamine;
~2~-(2-chlorophenyl)-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidine- 2,4-diamine;
N-[3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-4- chlorophenyl]acetamide;
5-bromo-N~4 — (5-methylisoxazol-3-yl)-N~2~-(4-morpholin-4-ylphenyl)pyrimidine- 2,4-diamine;
3-[4-({5-bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl}amino)phenyl]-N-[2-(diethylamino)ethyl]propanamide;
5-bromo-N~4 — (5-cyclopropyl- 1 H-pyrazol-3-yl)-N~2~-(2,3-dihydro- 1 H-inden- 1 - yl)pyrimidine-2,4-diamine;
5-bromo-N~2 — (4-morpholin-4-ylphenyl)-N~4~-phenylpyrimidine-2,4-diamine;
3-[4-({5-bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl } amino)phenyl] -N-(I -methylethyl)propanamide ;
4-( { 5-bromo-4-[(3-cyclopropyl- 1 H-pyrazol-5-yl)amino]pyrimidin-2-yl } amino)-N-( 1 - methylpiperidin-4-yl)benzamide;
2 — (3-aminophenyl)-5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine- 2,4-diamine;
3-[3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl}amino)phenyl]-N-[2-(diethylamino)ethyl]propanamide;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(4-{[2- (dimethylamino)ethyl]oxy}phenyl)pyrimidine-2,4-diamine;
5-bromo-N~4— (3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-{[2- (methyloxy)phenyl]methyl}pyrimidine-2,4-diamine;
2-[4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl } amino)phenyl] -N- [2-(diethylamino)ethyl] acetamide;
5-bromo-N~4 — (5-cyclopropyl- 1H-pyrazol-3-yl)-N~2~-( 1,2,3, 4-tetrahydronaphthalen- 1 -yl)pyrimidine-2,4-diamine;
3-( { 5 -bromo-4- [(3 -cyclopropyl- 1 H-pyrazol-5-yl)amino]pyrimidin-2-yl } am ino)phenyl dimethylcarbamate;
5-bromo-N~4 — (5-cyclopropyl- 1H-pyrazol-3-yl)-N~2—(l-phenylethyl)pyrimidine-2,4- diamine; 5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — {4-[2-(4-methylpiperazin-1- yl)-2-oxoethyl]phenyl } pyrimidine-2,4-diamine;
3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[2- (diethylamino)ethyl]benzamide;
4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[2- (diethylamino)ethyl]benzamide;
3 - [4-( { 4- [(3 -cyclopropy 1- 1 H-pyrazol-5-yl)amino] -6-methylpyrimidin-2- yl}amino)phenyl]-N-(2-pyrrolidin-1-ylethyl)propanamide;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~6— [3-(diethylamino)propyl]-N~2— [(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-6-(4-methylpiperazin-1-yl)-N~2 — [(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(2- piperidin- 1 -ylethyl)propanamide;
■4~- (5-cyclopropyl-1H-pyrazol-3-yl)-N~6— [2-(diethylamino)ethyl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-6-morpholin-4-yl-N~2 — [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
3 - [4-( {4- [(3 -cyclopropyl- 1 H-pyrazol-5-yl)amino]pyrimidin-2-yl } amino)phenyl] -N-(2- pyrrolidin- 1 -ylethyl)propanamide;
3- [4-( {4- [(3 -cyclopropyl- 1 H-pyrazol-5 -yl)amino] -6-methylpyrimidin-2- y 1 } amino)phenyl] -N-(3 -pyrrolidin- 1 -ylpropyl)propanamide;
3 - [4-( { 4- [(3 -cyclopropyl- 1 H-pyrazol-5 -yl)amino] -6-methylpyrimidin-2- yl } amino)phenyl] -N-(3 -piperidin- 1 -ylpropyl)propanamide;
3 - [4-( {4- [(3 -cyclopropyl- 1 H-pyrazol-5-yl)amino] -6-methylpyrimidin-2- yl}amino)phenyl]-N-[2-(diethylamino)ethyl]propanamide;
N~2~-[3,5-bis(methyloxy)phenyl]-5-bromo-N~4— (5-methylisoxazol-3-yl)pyrimidine- 2,4-diamine;
N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2 — [(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(3- piperidin- 1 -ylpropyl)propanamide;
N-[3-({5-bromo-4-[(5-methylisoxazol-3-yl)amino]pyrimidin-2-yl}amino)-4- chlorophenyl] acetamide ;
3-[4-({5-bromo-4-[(5-methylisoxazol-3-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-[2- diethylamino)ethyl]propanamide; 5-bromo-N~4 — (3-methylisoxazol-5-yl)-N~2~-(4-morpholin-4-ylphenyl)pyrimidine- 2,4-diamine;
3-[4-({5-bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl}amino)phenyl]-N-methylpropanamide;
5-bromo-N~4~-(5-cyclopropyl- 1 H-pyrazol-3-yl)-N~2~-[4- (dimethylamino)phenyl]pyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N- [(3R)-pyrrolidin-3-yl]benzamide;
5-bromo-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-{[3-(l-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine;
5-chloro-N~2~-(2-chlorophenyl)-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~6~-[3- (diethylamino)propyl]pyrimidine-2,4,6-triamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-6-methylpyrimidin-2- 1 } amino)phenyl] -N-(2-morpholin-4-ylethyl)propanamide;
3 - [4-( {4- [(3 -cyclopropyl- 1 H-pyrazol-5-yl)amino]pyrimidin-2-yl } amino)phenyl] -N-(3 - pyrrolidin- 1 -ylpropyl)propanamide;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-[2- (diethylamino)ethyl]propanamide;
5 -bromo-N~4 — (3 -cyclopropyl- 1 H-pyrazol-5-yl)-N~2 — { 4- [(3 -morpholin-4- ylpropyl)oxy]phenyl}pyrimidine-2,4-diamine;
5-bromo-N~2 — [4-(dimethylamino)phenyl]-N~4 — phenylpyrimidine-2,4-diamine;
5-bromo-N~2 — [(3-bromoisoxazol-5-yl)methyl]-N~4~-(3-cyclopropyl-1H-pyrazol-5- yl)pyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl } amino)benzamide;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-6-methylpyrimidin-2- yl}amino)phenyl]-N-[3-(1H-imidazol-1-yl)propyl]propanamide;
4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[3- (diethylamino)propyl]benzamide;
3-[4-({5-bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl}amino)phenyl]-N-[3-(diethylamino)propyl]propanamide;
N~4— (5-cyclopropyl-1H-pyrazol-3-yl)-N~2—{[3-(l-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine;
2-[4-({5-bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl}amino)phenyl]-N-[3-(diethylamino)propyl]acetamide; 5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(6-morpholin-4-ylpyridin-3- yl)pyrimidine-2,4-diamine;
N~2 — [(3-cyclohexylisoxazol-5-yl)methyl]-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-6- methylpyrimidine-2,4-diamine;
5-bromo-N~2 — (2-bromophenyl)-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine- 2,4-diamine;
5 -bromo-N~4 — (3 -cyclopropyl- 1 H-pyrazol-5 -yl)-N~2 — { 2- [(trifluoromethyl)oxy]phenyl}pyrimidine-2,4-diamine;
5 -bromo-N~4 — (5 -cyclopropyl- 1 H-pyrazol-3 -yl)-N~2~- { 4-[3 -(4-methylpiperazin- 1 - yl)-3-oxopropyl]phenyl}pyrimidine-2,4-diamine;
5-bromo-N~4~- (5 -cyclopropyl- 1 H-pyrazol-3 -yl)-N~2 — (2-methylphenyl)pyrimidine- 2,4-diamine;
N~2 — (4-aminophenyl)-5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine- 2,4-diamine;
5-bromo-N~4 — (3 -cyclopropyl- 1 H-pyrazol-5 -yl)-N~2 — [4- (methyloxy)phenyl]pyrimidine-2,4-diamine;
3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N- [(3S)-pyrrolidin-3-yl]benzamide;
5-bromo-N~4 — (3-methyl-1H-pyrazol-5-yl)-N~2 — phenylpyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl } amino)benzenesulfonamide ;
1 , 1 -dimethylethyl { [4-( { 5 -bromo-4- [(5 -cyclopropyl- 1 H-pyrazol-3-yl)amino]pyrimidin- 2-yl}amino)phenyl] methyl} carbamate;
3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-4- chlorobenzamide;
5-bromo-N~2 — (2-chlorophenyl)-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine- 2,4-diamine;
5-bromo-N~2 — [2-chloro-5-(methyloxy)phenyl]-N~4 — (3-cyclopropyl-1H-pyrazol-5- yl)pyrimidine-2,4-diamine;
3-[3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl }amino)phenyl]-N-( 1 -methylethyl)propanamide;
5 -bromo-N~4 — (3 -cyclopropyl- 1 H-pyrazol-5 -yl)-N~2— { 3 - [3-(4-methy lpiperazin- 1 ■ yl)-3-oxopropyl]phenyl}pyrimidine-2,4-diamine;
5-chloro-N~2 — (2-chlorophenyl)-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine- 2,4-diamine; 5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-[2- (methyloxy)phenyl]pyrimidine-2,4-diamine;
2-[4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- l}amino)phenyl]-N-methylacetamide;
5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — (2,3-dihydro-1,4-benzodioxin- 6-yl)pyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(2- morpholin-4-ylethyl)propanamide;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-[3- (1H-imidazol-1-yl)propyl]propanamide;
3-[3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- y 1 } amino)phenyl] -N- [3 -(diethylamino)propyl]propanamide ;
5-bromo-N~4~-(5 -cyclopropyl- 1 H-pyrazol-3 -yl)-N~2~- [(1S)-I- phenylethyl]pyrimidine-2,4-diamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-6-methylpyrimidin-2- yl } amino)phenyl] -N-(3 -morpholin-4-ylpropyl)propanamide ;
N~6 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~4~,N~4 — dimethyl-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-6-methylpyrimidin-2- y 1 } amino)phenyl] -N,N-dimethylpropanamide ;
5-bromo-N~4 — (2-chlorophenyl)-N~2 — (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine- 2,4-diamine;
2-[4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- 1 } amino)phenyl] -N-( 1 -methylethyl)acetamide ;
5-bromo-N~4~-[5-(l,l-dimethylethyl)-1H-pyrazol-3-yl]-N~2 — phenylpyrimidine-2,4- diamine;
4-({5-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl } amino)benzonitrile ;
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2— (2-methylpropyl)pyrimidine- 2,4-diamine;
N~2~-[2,5-bis(methyloxy)phenyl]-5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5- yl)pyrimidine-2,4-diamine;
5-bromo-N,N'-diphenylpyrimidine-2,4-diamine;
5-bromo-N~2~-(2-bromo-4-fluorophenyl)-N~4 — Q-cyclopropyl-1H-pyrazol-S- yl)pyrimidine-2,4-diamine; 5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-phenylpyrimidine-2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-[3- (methyloxy)phenyl]pyrimidine-2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}pyrimidine-2,4-diamine;
3 -( { 5-bromo-4- [(3 -cyclopropyl- 1 H-pyrazol-5-yl)amino]pyrimidin-2-yl } am ino)-N- [3 - (diethylamino)propyl]benzamide;
3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl } amino)benzamide;
5-bromo-N~4— (3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-{3-[(4-methylpiperazin-1- yl)carbonyl]phenyl}pyrimidine-2,4-diamine;
5-bromo-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-naphthalen-1-ylpyrimidine-2,4- diamine;
5-bromo-N~4— (3-cyclopropyl- 1 H-pyrazol-5-yl)-N~2~-[2- (methylthio)phenyl]pyrimidine-2,4-diamine;
5-bromo-N~4 — (3-cyclopropyl- 1 H-pyrazol-5-yl)-N~2 — 1 H-indol-5-ylpyrimidine-2,4- diamine;
5-bromo-N,N'-bis(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine;
5-bromo-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2 — [(2-methyl-1,3-thiazol-5- yl)methyl]pyrimidine-2 ,4-diamine ;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(2,3- dichlorophenyl)pyrimidine-2,4-diamine;
5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2—(furan-2-ylmethyl)pyrimidine- 2,4-diamine;
N~2~-(2-chlorophenyl)-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-5-methylpyrimidine- 2,4-diamine;
5-bromo-N~4 — (3-cyclopropyl- 1H-pyrazol-5-yl)-N~2 — [4-(morpholin-4- ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
1 , 1 -dimethy lethyl (3 S)-3 -( { [3 -( { 5-bromo-4- [(3 -cyclopropyl- 1 H-pyrazol-5 - yl)amino]pyrimidin-2-yl } amino)phenyl]carbonyl } amino)pyrrolidine- 1 -carboxylate;
5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — [(5-methylfuran-2- yl)methyl]pyrimidine-2,4-diamine;
5-bromo-N~2 — (4-bromo-2-chlorophenyl)-N~4 — (5-cyclopropyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine; 5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[2-(1H-pyrrol-1- yl)phenyl]pyrimidine-2,4-diamine; l,l-dimethylethyl (3R)-3-({[4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5- yl)amino]pyrimidin-2-yl}amino)phenyl]carbonyl}amino)pyrrolidine-1-carboxylate;
3-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)phenyl]-N-(3- morpholin-4-ylpropyl)propanamide;
5-bromo-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[5-methyl-2- (methyloxy)phenyl]pyrimidine-2,4-diamine; ethyl 2- [(2-chlorophenyl)amino] -6- [(3 -cyclopropy 1- 1 H-pyrazol-5 -y l)amino] -5 - nitropyrimidine-4-carboxylate;
5-bromo-N~4— (3-cyclopropyl- 1 H-pyrazol-5-yl)-N~2~- { [3- (methyloxy)phenyl]methyl}pyrimidine-2,4-diamine;
5-bromo-N~4~-(5-cyclopropyl- 1 H-pyrazol-3 -yl)-N~2~- [(I S)- 1 - phenylpropyl]pyrimidine-2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(2-phenylethyl)pyrimidine-2,4- diamine;
3- [4-( { 4- [(3-cyclopropyl- 1 H-pyrazol-5 -yl)amino] -6-methylpyrimidin-2- 1 } amino)phenyl] -N- [3 -(4-methylpiperazin- 1 -yl)propyl]propanamide ;
5-bromo-N~2~-[(4-chlorophenyl)methyl]-N~4 — (3-cyclopropyl-1H-pyrazol-5- yl)pyrimidine-2,4-diamine ;
N~2 — (2-chlorophenyl)-N~4 — (3-cyclopropyl- 1 H-pyrazol-5 -yl)-5 - (trifluoromethyl)pyrimidine-2,4-diamine;
4-[(3-amino-1H-pyrazol-5-yl)oxy]-5-bromo-N-(4-morpholin-4-ylphenyl)pyrimidin-2- amine;
4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-5-methylpyrimidin-2-yl}amino)-N-(l- methylpiperidin-4-yl)benzamide;
5 -bromo-N~4 — (5 -cyclopropyl- 1 H-pyrazol-3 -yl)-N~2~-( 1 -methylethyl)pyrimidine-2,4- diamine;
5-chloro-N~4~-(2-chlorophenyl)-N~6 — (3-cyclopropyl- 1H-pyrazol-5-yl)-N~2 — [3- (diethylamino)propyl]pyrimidine-2,4,6-triamine;
5 -bromo-N~4~-(5 -cyclopropy 1- 1 H-pyrazol-3 -yl)-N~2~-(pyridin-3 - ylmethyl)pyrimidine-2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(2,4- dibromophenyl)pyrimidine-2,4-diamine;
4-( { 4-[(3 -cyclopropyl- 1 H-pyrazol-5-yl)amino]pyrimidin-2-yl } amino)-N-( 1 - methylpiperidin-4-yl)benzamide; 5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-[2-methyl-5-(l- methylethyl)phenyl]pyrimidine-2,4-diamine;
4-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl}amino)benzonitrile;
4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-5-methylpyrimidin-2-yl}amino)-N-[2- (diethylamino)ethyl]benzamide;
~2~-(2-chlorophenyl)-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidine- 2,4-diamine;
5-bromo-N~4 — (3-cyclopropyl- 1H-pyrazol-5-yl)-N~2~-[2-(2-thienyl)ethyl]pyrimidine- 2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(2,5- dibromophenyl)pyrimidine-2,4-diamine;
~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — [4-(dimethylamino)phenyl]-5- methylpyrimidine-2,4-diamine;
5-bromo-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-{[4- (methyloxy)phenyl]methyl}pyrimidine-2,4-diamine;
5-bromo-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2 — (2,3-dihydro-1H-inden-5- yl)pyrimidine-2,4-diamine;
4-( {4- [(3-cyclopropyl- 1 H-pyrazol-5 -yl)amino] -5 -methylpyrimidin-2-yl } amino)-N- [3 - (diethylamino)propyl]benzamide;
N~2 — (2-chlorophenyl)-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~6 — [3- (diethylamino)propyl]pyrimidine-2,4,6-triamine;
4-( { 4- [(3 -cyclopropyl- 1 H-pyrazol-5-yl)amino]pyrimidin-2-yl } amino)-N- [2- (diethylamino)ethyl]benzamide;
5 -bromo-N~2~- [(2-chlorophenyl)m ethyl] -N~4~-(3 -cyclopropyl- 1 H-pyrazol-5 - yl)pyrimidine-2,4-diamine;
5 -bromo-N~4~-(3 -cyclopropyl- 1 H-pyrazol-5-yl)-N~2~- { [4-(4-methy lpiperazin- 1 - yl)phenyl]methyl}pyrimidine-2,4-diamine;
N~2 — {[3,5-bis(methyloxy)phenyl]methyl}-5-bromo-N~4 — (5-cyclopropyl-1H- pyrazol-3-yl)pyrimidine-2,4-diamine;
5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(phenylmethyl)pyrimidine-2,4- diamine;
5-bromo-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2 — (3-phenylpropyl)pyrimidine- 2,4-diamine;
N~4 — (3-cyclopropyl- 1H-pyrazol-5-yl)-5-methyl-N~2— (4-morpholin-4- ylphenyl)pyrimidine-2,4-diamine; 5-bromo-N~2~-(2-chlorophenyl)-N~4~-1H-pyrazol-3-ylpyrimidine-2,4-diamine;
5-bromo-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — {[4- (dimethylamino)phenyl] methyl } pyrimidine-2,4-diamine ;
4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-N-[3- (diethylamino)propyl]benzamide;
3-({5-bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2- yl}amino)benzonitrile;
5-bromo-N~2~-(4-chlorophenyl)-N~4~— (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine- 2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-(piperidin-4- ylmethyl)pyrimidine-2,4-diamine;
5 -bromo-N~4~-(5 -cyclopropyl- 1 H-pyrazol-3 -yl)-N~2~- [( 1 R)- 1 - phenylethyl]pyrimidine-2,4-diamine;
N~2 — {[2,5-bis(methyloxy)phenyl]methyl}-5-bromo-N~4 — (5-cyclopropyl-1H- pyrazol-3-yl)pyrimidine-2,4-diamine;
N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-N~2 — {[2- (methyloxy)phenyl]methyl}pyrimidine-2,4-diamine;
5-bromo-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — (2,4- dichlorophenyl)pyrimidine-2,4-diamine;
N~2 — (2-chlorophenyl)-N~6~-(3-cyclopropyl-1H-pyrazol-5-yl)-9H-purine-2,6- diamine;
N~2 — (2-chlorophenyl)-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4- diamine;
5-bromo-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2 — {[2-(2-thienyl)-1,3-thiazol-4- 1] methyl } pyrimidine-2,4-diamine ;
N~2 — (2-chlorophenyl)-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4,5- triamine;
5-bromo-N~4 — (5-cyclopropyl- 1 H-pyrazol-3-yl)-N~2—methyl-N~2 — phenylpyrimidine-2,4-diamine;
2-[(2-chlorophenyl)amino]-6-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-N-(2- morpholin-4-ylethyl)-5-nitropyrimidine-4-carboxamide;
5-bromo-N~4~-(5-cyclopropyl- 1 H-pyrazol-3-yl)-N-τ'2—[2-( 1 - methylethyl)phenyl]pyrimidine-2,4-diamine;
5-bromo-N~2~-(3-chlorophenyl)-N~4— (3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine- 2,4-diamine; N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(3-phenylisoxazol-5-yl)methyl]-7- (phenylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-N~2~-({3-[4- (methyloxy)phenyl] isoxazol-5 -yl } methyl )pyrimidine-2,4-diamine ;
2-[(2-chlorophenyl)amino]-6-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-N-(l- methylethyl)-5-nitropyrimidine-4-carboxamide;
N~2 — [3,5-bis(methyloxy)phenyl]-N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-6- methylpyrimidine-2,4-diamine;
N-[4-({4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidin-2- y 1 } thio)phenyl] cyclopropanecarboxamide ;
N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methyl-N~2~-[3-(methyloxy)-5- nitropheny 1] pyrim idine -2 ,4-di amine ;
N-{[3-(4-amino-5-{3-[(phenylmethyl)oxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclobutyl]methyl}acetamide;
N~4~-[5-(l-methylethyl)-1H-pyrazol-3-yl]-6-morpholin-4-yl-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-[5-(l-methylethyl)-1H-pyrazol-3-yl]-6-(4-methylpiperazin-1-yl)-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-N~2~-[(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-6-[(2-morpholin-4-ylethyl)oxy]-N~2— [(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-6-({[(2S)-1-methylpyrrolidin-2- yl]methyl}oxy)-N~2 — [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
~4~- (5 -cyclopropyl- 1 H-pyrazol-3 -yl)-6- [(3 S)-3 -methylpiperazin- 1 -yl] -N~2~- [(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl- 1 H-pyrazol-3 -yl)-6- [( 1 -methylpiperidin-4-y l)oxy] -N~2~- [(3 - phenylisoxazol-5 -yl)methyl] pyrimidine-2,4-diamine ;
N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N~4— [5-(l-methylethyl)-1H-pyrazol- 3-yl]-6-morpholin-4-ylpyrimidine-2,4-diamine;
N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — [(3-phenylisoxazol-5-yl)methyl]-6-[(2- piperidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine;
N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(l-methylethyl)-1H-pyrazol- 3-yl]-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~6~-[2-(4-methylpiperazin-1-yl)ethyl]-N~2- (3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine; N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(3-phenylisoxazol-5-yl)methyl]-N~6~- (2-pyrrolidin- 1 -ylethyl)pyrimidine-2,4,6-triamine;
N~4~-(5 -cyclopropyl- 1 H-pyrazol-3 -yl)-6- [(3R)-3 -methy lpiperazin- 1 -y 1] -N~2~- [(3 - phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-[(3-phenylisoxazol-5-yl)methyl]-6-[(2- pyrrolidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine;
N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-6-[(l-methylpyrrolidin-3-yl)oxy]-N~2 — [(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine
N~4— (5-cyclopropyl-1H-pyrazol-3-yl)-6-[(l-methylpiperidin-3-yl)oxy]-N~2—[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
6-{[2-(dimethylamino)ethyl]oxy}-N~4~-[5-(l-methylethyl)-1H-pyrazol-3-yl]-N~2" [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl- 1 H-pyrazol-3-yl)-N~2~- { [3-( 1 -methylethyl)isoxazol-5- yl]methyl}-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;
~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2 — {[3-(l-methylethyl)isoxazol-5- yl]methyl}-6-morpholin-4-ylpyrimidine-2,4-diamine;
6- [(5-cyclopropyl- 1 H-pyrazol-3 -yl)amino] -2- { [(3-phenylisoxazol-5 -yl)methyl] amino } ■ N-(2-pyrrolidin- 1 -ylethyl)pyrimidine-4-carboxamide;
N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-6-methyl-N~2 — [(5-phenylisoxazol-3- yl)methyl]pyrimidine-2,4-diamine;
5 -bromo-N~2 — (4-morpholin-4-ylphenyl)-N~4~- [4-(2-pyrrolidin- 1 - ylethyl)phenyl]pyrimidine-2,4-diamine;
6-methyl-N~2~- { [3 -( 1 -methylethyl)isoxazol-5 -yl]methyl } -N~4~- [5 -( 1 -methylethyl)- 1H-pyrazol-3-yl]pyrimidine-2,4-diamine;
5-bromo-N~2 — (4-morpholin-4-ylphenyl)-N~4 — [4-(2-piperidin- 1 - ylethyl)phenyl]pyrimidine-2,4-diamine;
6-chloro-N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(l-methylethyl)- 1H-pyrazol-3-yl]pyrimidine-2,4-diamine;
N~2~-(2-amino-2,3-dihydro-1H-inden-5-yl)-N~4— (3-cyclopropyl-1H-pyrazol-5-yl)-6- methylpyrimidine-2,4-diamine;
N~2— [4-(2-aminoethyl)phenyl]-N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-6- methylpyrimidine-2,4-diamine;
N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-6-methyl-N~2— [4-(2-pyrrolidin-1- ylethyl)phenyl]pyrimidine-2,4-diamine;
N~4—(3-cyclopropyl-1H-pyrazol-5-yl)-6-methyl-N~2~-(4-piperidin-4- ylphenyl)pyrimidine-2,4-diamine; N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-{[3-(l-methylethyl)isoxazol-5- yl]methyl}-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;
N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(l-methylethyl)-1H-pyrazol- 3-yl]-N~6~-[2-(4-methylpiperazin-1-yl)ethyl]pyrimidine-2,4,6-triamine;
N~4— (5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-{[3-(l-methylethyl)isoxazol-5- yl]methyl}-N~6 — [2-(4-methylpiperazin-1-yl)ethyl]pyrimidine-2,4,6-triamine;
N~4~-[5 -( 1 -methylethyl)- 1 H-pyrazol-3 -yl] -N~6— [2-(4-methylpiperazin- 1 -yl)ethyl] - N~2 — [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~6~-[2-(diethylamino)ethyl]-N~2~-{[3-(l- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4,6-tri amine;
N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2 — {[3- (l-methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4~-[3-(l-methylethyl)-1H-pyrazol-5-yl]-6-[(l-methylpyrrolidin-3-yl)oxy]-N~2~- [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — {[3-(l-methylethyl)isoxazol-5- yl]methyl}-6-[(l-methylpyrrolidin-3-yl)oxy]pyrimidine-2,4-diamine;
2— { [3-( 1 -methylethy l)isoxazol-5 -yl] methyl } -N~4~- [3 -( 1 -methylethyl)- 1 H-pyrazol- 5-yl]-6-[(l-methylpyrrolidin-3-yl)oxy]pyrimidine-2,4-diamine;
N~4~-[2-(diethylamino)ethyl]-N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N~6~- [5-(l -methylethyl)- 1H-pyrazol-3-yl]pyrimidine-2,4,6-triamine;
N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N~4~-[5-(l-methylethyl)-1H-pyrazol- 3-yl]-6-[(l-methylpiperidin-3-yl)oxy]pyrimidine-2,4-diamine;
6-{[2-(dimethylamino)ethyl]oxy}-N~2 — {[3-(l-methylethyl)isoxazol-5-yl]methyl}- ~4 — [5-(l-methylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4-diamine;
N~2~- { [3-( 1 -methylethyl)isoxazol-5-yl]methyl } -N~4~-[5-( 1 -methylethyl)- 1 H-pyrazol- 3-yl]-6-[(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4-diamine;
N~4—[3-(l-methylethyl)-1H-pyrazol-5-yl]-N~2~-[(3-phenylisoxazol-5-yl)methyl]-6- [(2-piperidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine;
N~4~- [3-(diethylamino)propyl] -N~2~- { [3-( 1 -methylethyl)isoxazol-5 -yl] methyl } - N~6 — [5-(l-methylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4,6-triamine;
N~4~-[5-(l-methylethyl)-1H-pyrazol-3-yl]-6-[(3S)-3-methylpiperazin-1-yl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-[5 -( 1 -methylethyl)- 1 H-pyrazol-3 -yl] -6- [( 1 -methylpiperidin-4-y l)oxy] -N~2~- [(3 - phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-{[3-(l-methylethyl)isoxazol-5- yl]methyl}-6-[(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4-diamine; N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}-N~4~-[3-(l-methylethyl)-1H-pyrazol- 5-yl]-6-[(2-piperidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
N~4~- (3-cyclopropyl-1H-pyrazol-5-yl)-6-[3-(diethylamino)propyl]-N~2~-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-{[3-(l-methylethyl)isoxazol-5- yl]methyl}-6-[(2-piperidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
N~2~- { [3-(l -methylethyl)isoxazol-5-yl]methyl } -N~4—[3-( 1 -methylethyl)- 1 H-pyrazol- 5-yl]-6-[(l-methylpiperidin-4-yl)oxy]pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methyl-N~2~-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N~4~- (3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-[(3-methylisoxazol-5-yl)methyl]-6- morpholin-4-ylpyrimidine-2,4-diamine;
N~4~- (3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-[(3-methylisoxazol-5-yl)methyl]-6-(4- methylpiperazin- 1 -yl)pyrimidine-2,4-diamine;
N~4~-(5 -cyclopropyl- 1 H-pyrazol-3 -yl)-N~2~- { [3 -( 1 -methylethyl)isoxazol-5 - yl]methyl}-6-[(l-methylpiperidin-4-yl)oxy]pyrimidine-2,4-diamine;
N~4 — (3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — {[3-(4-fluorophenyl)isoxazol-5- yl] methyl } -6-morpholin-4-ylpyrimidine-2,4-diamine ;
N~4 — (5 -cyclopropyl- 1 H-pyrazol-3-yl)-6-(4-methylpiperazin- 1 -yl)-N~2 — [(3 -pyridin- 2-ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4— (5-cyclopropyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-N~2— [(3-pyridin-2- ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
~4~-(5-cyclopropyl- 1 H-pyrazol-3-yl)-N~2— { [3-( 1 -methylethyl)isoxazol-5- yl]methyl}-6-piperazin-1-ylpyrimidine-2,4-diamine;
N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2 — {[3-(l-methylethyl)isoxazol-5- yl]methyl}-6-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine-2,4-diamine;
4- { 6- [(5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino] -2-( { [3-( 1 -methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4-yl}piperazine-1-carbaldehyde;
N~4— (5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-N~2 — [(3-pyrazin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine;
N~2~-[(3-methylisoxazol-5-yl)methyl]-6-(4-methylpiperazin-1-yl)-N~4 — (3-methyl- 1H-pyrazol-5-yl)pyrimidine-2,4-diamine;
N~2~-[(3-methylisoxazol-5-yl)methyl]-N~4~-(3-methyl-1H-pyrazol-5-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N~4— (5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N~2~-[(3- pyrimidin-4-ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine; N~4 — (5-cyclopropyl-1H-pyrazol-3-yl)-N~2~- [(3-furan-3-ylisoxazol-5-yl)methyl]-6- (4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~6~-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)- N~2~-[(3-methylisoxazol-5-yl)methyl]pyrimidine-2,4,6-tri amine;
N~4— (5-cyclopropyl-1H-pyrazol-3-yl)-6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)- N~2~-[(3-methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~- (5-cyclopropyl-1H-pyrazol-3-yl)-6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)- N~2~-{[3-(l-methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4~-bicyclo[2.2.1]hept-2-yl-N~6~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-{[3-(l- methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4,6-triamine;
N~4~-bicyclo[2.2.1]hept-2-yl-N~6~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4,6-triamine;
N~4~- (5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(3-methylisoxazol-5-yl)methyl]-6- [(lR,4R)-5-(phenylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;
N~4— (5-cyclopropyl- 1 H-pyrazol-3-yl)-N~2~- { [3-( 1 -methylethyl)isoxazol-5- yl]methyl}-6-[(lR,4R)-5-05henylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine- 2,4-diamine;
N~4 — (5-cyclopropyl- 1H-pyrazol-3-yl)-6-morpholin-4-yl-N~2 — [(3-pyrimidin-4- ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2—[(3- pyrimidin-4-ylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N~2 — {[3-(2- thienyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4— (5-cyclopropyl- 1 H-pyrazol-3-yl)-6- { [2-(diethylamino)ethyl]oxy } -N~2~- { [3-( 1 ■ methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2— {[3-(l-methylethyl)isoxazol-5- yl]methyl}-6-[(2-pyrrolidin-1-ylethyl)oxy]pyrimidine-2,4-diamine;
N~4 — (5-cyclopropyl- 1H-pyrazol-3-yl)-6-{[2-(diethylamino)ethyl]oxy}-N~2 — [(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2—[(3-methylisoxazol-5-yl)methyl]-6-[(2- pyrrolidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine;
N~4— (5-cyclopropyl- 1 H-pyrazol-3-yl)-6-(4-methylpiperazin- 1 -yl)-N~2 — { [3-( 1 ,3- thiazol-2-yl)isoxazol-5-yl]methyl}pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-6-{[2-(dimethylamino)ethyl]oxy}-N~2~-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
]vj~4~-(3-CyClOprOpyl.1H-pyrazol-5-yl)-N~2~-[(3-ethylisoxazol-5-yl)methyl]-6-(4- methylpiperazin- 1 -yl)pyrimidine-2,4-diamine; N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2~-[(3-ethylisoxazol-5-yl)methyl]-6- morpholin-4-ylpyrimidine-2,4-diamine;
N~-4~- (3 -cyclopropyl- 1 H-pyrazol-5 -yl)-6- { [2-(dimethylamino)ethyl] oxy } -N~2~- [(3- ethylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine;
N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-6-{[2-(diethylamino)ethyl]oxy}-N~2~-[(3- ethylisoxazol-5-yl)methyl]pyrimidine-2,4-diamine; and
N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)-N~2 — [(3-ethylisoxazol-5-yl)methyl]-6-[(2- pyrrolidin- 1 -ylethyl)oxy]pyrimidine-2,4-diamine.
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