WO2021159993A1 - Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 (irak)/tyrosine kinase du récepteur de type fms (flt3), leurs produits pharmaceutiques et leurs procédés - Google Patents

Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 (irak)/tyrosine kinase du récepteur de type fms (flt3), leurs produits pharmaceutiques et leurs procédés Download PDF

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WO2021159993A1
WO2021159993A1 PCT/CN2021/074803 CN2021074803W WO2021159993A1 WO 2021159993 A1 WO2021159993 A1 WO 2021159993A1 CN 2021074803 W CN2021074803 W CN 2021074803W WO 2021159993 A1 WO2021159993 A1 WO 2021159993A1
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pyridin
pyrimidin
amino
trifluoromethoxy
diazaspiro
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PCT/CN2021/074803
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English (en)
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Zuozhong PENG
Yizhou WU
Jilin JIA
Yonghua LEI
Ming Xu
Keke DONG
Youfei MA
Liu Liu
Lisha Wang
Jiaqi Hu
Minmin Yang
Lin Wang
Liang RONG
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Pharmablock Sciences (Nanjing) , Inc.
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Priority to CN202180012966.5A priority Critical patent/CN115151534B/zh
Publication of WO2021159993A1 publication Critical patent/WO2021159993A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure generally relates to inhibitors of interleukin-1 receptor associated kinase (IRAK) /FMS-like receptor tyrosine kinase (FLT3) , pharmaceutical products thereof, productions thereof, and applications thereof.
  • IRAK interleukin-1 receptor associated kinase
  • FLT3 FMS-like receptor tyrosine kinase
  • the present disclosure can also include applications of the compounds and derivatives thereof in prophylaxis and/or treatment of a broad range of disorders or diseases related to or mediated by IRAK /FLT3, or associated with aberrant IRAK /FLT3 activity, for example, inflammatory diseases, infections such as viral, bacterial, fungal, and parasitic infections, HIV-1 infection, sepsis, autoimmune disorders or diseases such as rheumatoid arthritis and multiple sclerosis, gout, juvenile idiopathic arthritis, Muckle-Wells disease, familial
  • inflammatory diseases infections such as viral, bacterial, fungal, and
  • kinases are very important targets for the development of medicines for the prophylaxis and/or treatment of various diseases and disorders, simply because kinases are involved in many essential processes of cell physiology, for example protein phosphorylation.
  • protein and lipid kinases are involved in the activation, growth, differentiation, and survival of cells. Protein kinases can be divided between those preferentially phosphorylating tyrosine residues, and those preferentially phosphorylating serine and/or threonine residues.
  • IRAK kinases and more particularly IRAK-4, have been identified as playing a role in inflammation and autoimmune diseases.
  • IRAKs are expressed in many cell types and mediate signals from various cell receptors including interleukin-1 (IL-1) and toll-like receptors (TLRs) .
  • IL-1R and Toll-like receptors sharing the conserved Toll/IL-1R domain, function as a crucial part in innate immunology.
  • Toll/IL-1 receptors Upon binding with LPS or cytokines, Toll/IL-1 receptors recruit adaptor molecule MyD88 through TIR domain, initiating downstream protein complex assembling and phosphorylation cascade, resulting in induction of inflammation cytokines and chemokines such as TNF- ⁇ , IL-1 ⁇ , IL-6 and IL-8.
  • the IL-1R-associated kinase (IRAK) family plays an important role, both in scaffold and kinase function.
  • the IL-1R associated kinase (IRAK) family consists of four members, IRAK1, IRAK2, IRAKM, and IRAK4.
  • IRAK1 and IRAK4 are active kinases and the other two are not. However, they all regulate the nuclear factor- ⁇ B (NF- ⁇ B) and mitogen-activated protein kinase (MAPK) pathways.
  • NF- ⁇ B nuclear factor- ⁇ B
  • MAPK mitogen-activated protein kinase
  • IRAK4 represents an attractive therapeutic target.
  • IRAK4 is a threonine/serine protein kinase made up of 460 amino acids, containing a kinase domain and a death domain.
  • the N-terminal lobe and the C-terminal lobe can be found in the kinase domain, which meet together to form the ATP binding site.
  • the death domain exists to bind and interact with MyD88 during protein recruitment.
  • IRAK4 is believed to be the key protein kinase activated early downstream of the IL-1 receptor and TLRs, initiating signaling via rapid activation of IRAK1 and IRAK2, leading to innate immune responses. Also, other interleukins, such as IL-18 and IL-33, are dependent on IRAK4 for signaling. As such, diseases for which these cytokines are involved in the pathogenic process (e.g., fibrosis) and atopic dermatitis are potential target diseases for treatment by IRAK4 inhibitors.
  • mice expressing an inactive IRAK4 mutant instead of wild type complete resistance to septic shock triggered by several TLR agonists as well as impaired response to IL-1 is observed. Furthermore, mice expressing an inactive IRAK4 mutant instead of wild type are partially protected in several models of auto-immune diseases, such as rheumatoid arthritis and multiple sclerosis. Interestingly, the serum of rheumatoid arthritis and systemic lupus erythematosus patients has been shown to activate plasmacytoid dendritic cells in an IRAK4 dependent manner. Finally, recurring pyogenic bacterial infection has been observed in children suffering from genetic defects leading to IRAK4 inactivity.
  • IRAK4 is regarded as the “Master IRAK” , since it acts as the central component in the signaling pathway.
  • IRAK4 binds to MyD88 with the death domain, recruiting IRAK1 and IRAK2, to form the MyD88–IRAK4–IRAK2 complex or so called ‘myddosome’ .
  • Crystal structure reveals that it consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 death domains, exhibiting as a left-handed helical oligomer.
  • IRAK4 phosphorylates IRAK1 or IRAK2 in the myddosome, resulting in the recruitment of TNF receptor associated factor 6 (TRAF6) , triggering the initiation of signal transduction events for NF- ⁇ B-mediated transcription activation.
  • TNF receptor associated factor 6 TNF receptor associated factor 6
  • IRAK4 is important for innate immunity.
  • their whole blood cells or PBMCs do not respond to IL-1 ⁇ , in terms of IL-6 secretion, or to IL-18, in terms of IFN- ⁇ production.
  • stimulating TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 do not induce the production of major inflammatory cytokines (TNF- ⁇ , IL-6, and IL-12) and growth factors (G-CSF and GM-CSF) in whole blood cells and PBMCs.
  • TNF- ⁇ , IL-6, and IL-12 major inflammatory cytokines
  • G-CSF and GM-CSF growth factors
  • adult patients with the deficiency are not prone to chronic infections indicating that there might be some certain mechanisms for bypassing the deficiency in TLR signaling.
  • IRAK4 is also associated with cancer due to the downstream pathway it regulates.
  • the discovery of oncogenically active MyD88 mutations in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) reveals the cancer-specific dependencies on IRAK signaling.
  • Sequence analysis of the MyD88 coding region in a large amount of tumor biopsies indicated that 29%of ABC DLBCL tumors harbor the L265P single amino acid substitution within the MyD88 TIR domain, which is absent in other DLBCL subtypes.
  • the L265P MyD88 mutant promotes cell survival through spontaneous assembly of a protein-signaling complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activation, IRAK1 phosphorylation, and activated JAK-STAT and NF- ⁇ B signaling. Moreover, the common somatic L265P mutation of MyD88 occurs in 91%of patients with Macroglobulinaemia, a kind of lymphocytic hematological malignancy.
  • MYD88 an adaptor molecule downstream of the TLR and IL-1R, which activates IRAK4.
  • Activating MYD88 mutations have been identified in e.g., diffuse large B-cell lymphomas (DLBCL) , and in Waldenstrom macroglobulinemia.
  • DLBCL diffuse large B-cell lymphomas
  • T-ALL T-cell acute lymphoblastic leukemia
  • the pharmacological inhibition of IRAK-4 has been shown to enhance the sensitivity of T-ALL to chemotherapeutic agents.
  • IL-33 has been shown to play a role in the development of fibrotic and allergic diseases, asthma and atopic dermatitis in particular. As this cytokine signals through an IRAK4 dependent pathway, these diseases might also represent a target for IRAK4 inhibitors. Furthermore, several auto-inflammatory diseases have been shown to be dependent on IL-1 activity and, as a consequence, IL-1 blocking biologicals show some benefit to these patients. Gout, juvenile idiopathic arthritis, Muckle-Wells disease, familial Mediterranean fever, Behcet's disease, adult onset Still's disease are examples of such auto-inflammatory diseases.
  • One aspect of the present disclosure provides a compound represented by Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate, or isomer thereof, in any crystalline form or in amorphous form.
  • X, X 1 , X 2 is selected from N and C; and U, V and W groups are independently of each other a non-hydrogen monovalent group.
  • Another aspect of the disclosure provides a pharmaceutical composition, a kit, or a packaged pharmaceutical product comprising a therapeutically effective amount of the compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form, and a pharmaceutically acceptable carrier or excipient.
  • Still another aspect of the disclosure provides a method of inhibiting interleukin-1 receptor associated kinase (IRAK) enzyme such as interleukin-1 receptor associated kinase-4 (IRAK4) .
  • the method includes contacting the IRAK such as IRAK4 with an effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form.
  • Still another aspect of the disclosure provides a method of altering gene expression or altering transcription comprising contacting a cell in vitro or in a subject with an effective amount of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form.
  • Formula (I) or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form.
  • Still another aspect of the disclosure provides a method for prophylaxis and/or treatment of a disorder or disease mediated by IRAK such as IRAK4 or associated with aberrant IRAK such as IRAK4 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form; or a pharmaceutical composition thereof.
  • Still another aspect of the disclosure provides a method of inhibiting FMS-like receptor tyrosine kinase (FLT3) .
  • the method includes contacting the FLT3 with an effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form.
  • a further aspect of the disclosure provides a method for prophylaxis and/or treatment of a disorder or disease mediated by FLT3 or associated with aberrant FLT3 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form; or a pharmaceutical composition thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form; or a pharmaceutical composition thereof.
  • substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual sub-combination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to include C 1 alkyl (methyl) , C 2 alkyl (ethyl) , C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • a numerical range is disclosed herein, unless otherwise specified, such range is continuous, inclusive of both the minimum and maximum values of the range as well as every value between such minimum and maximum values.
  • a range refers to integers, only the integers from the minimum value to and including the maximum value of such range are included.
  • multiple ranges are provided to describe a feature or characteristic, such ranges can be combined.
  • the present disclosure provides a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, or hydrate thereof.
  • X, X 1 , X 2 is selected from N and C; and U, V and W groups are independently of each other a non-hydrogen monovalent group.
  • non-hydrogen monovalent group may include, but is not limited to, groups in the following 8 classes.
  • R is independently of each other any suitable group e.g. alkyl group.
  • -OR may be an alkoxy or alkyloxy group, i.e. an -O-alkyl group.
  • C 1-6 alkoxy/alkyloxy is an -O- (C 1-6 alkyl) group.
  • alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , tert-butoxy, and the like.
  • the alkoxy or alkyloxy group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
  • Class (2) Alkyl group, i.e. saturated aliphatic hydrocarbon including straight chains and branched chains.
  • the alkyl group has 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • C 1-6 alkyl refers to linear or branched radicals of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl) .
  • An alkyl group optionally can be substituted by one or more (e.g., 1 to 5) suitable substituents.
  • Class (3) Alkenyl group, i.e. aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chains and branched chains having at least one carbon-carbon double bond.
  • the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • C 2-6 alkenyl includes straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl) , isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
  • An alkenyl group optionally can be substituted by one or more (e.g., 1 to 5) suitable substituents.
  • the alkenyl group may exist as the pure E form, the pure Z form, or any mixture thereof.
  • Class (4) Alkynyl group, i.e. aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight chains and branched chains having at least one carbon-carbon triple bond.
  • the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms.
  • C 2-6 alkynyl includes straight or branched hydrocarbon chain alkynyl radicals as defined above, having 2 to 6 carbon atoms.
  • An alkynyl group optionally can be substituted by one or more (e.g., 1 to 5) suitable substituents.
  • Cycloalkyl group may be saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclics such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclics including spiro, fused, or bridged systems (such as bicyclo [1.1.1] pentanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.2.1] octanyl or bicyclo [5.2.0] nonanyl, decahydronaphthalenyl, etc.
  • monocyclics such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl
  • bicyclics including s
  • the cycloalkyl group has 3 to 15 carbon atoms. In some embodiments the cycloalkyl may optionally contain one, two or more non-cumulative non-aromatic double or triple bonds and/or one to three oxo groups. In some embodiments, the bicycloalkyl group has 6 to 14 carbon atoms.
  • C 3-14 cycloalkyl includes saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 14 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentanyl, or cyclodecanyl) .
  • the cycloalkyl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
  • Class (6) Aryl group, i.e. all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system.
  • the aryl group may have 6 or 10 carbon atoms in the ring (s) . Most commonly, the aryl group has 6 carbon atoms in the ring.
  • C 6-10 aryl is an aromatic radical containing from 6 to 10 carbon atoms such as phenyl or naphthyl.
  • the aryl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
  • Heteroaryl group i.e. monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatom ring members (ring-forming atoms) each independently selected from O, S and N in at least one ring.
  • the heteroaryl group has 5 to 14 ring-forming atoms, including 1 to 13 carbon atoms, and 1 to 8 heteroatoms selected from O, S, and N.
  • the heteroaryl group has 5 to 10 ring-forming atoms including one to four heteroatoms.
  • the heteroaryl group has 5 to 8 ring-forming atoms including one, two or three heteroatoms.
  • 5-membered heteroaryl group is a monocyclic heteroaryl group as defined above with 5 ring-forming atoms in the monocyclic heteroaryl ring
  • 6-membered heteroaryl is a monocyclic heteroaryl group as defined above with 6 ring-forming atoms in the monocyclic heteroaryl ring
  • 5 ⁇ 10-membered heteroaryl is a monocyclic or bicyclic heteroaryl group as defined above with 5, 6, 7, 8, 9 or 10 ring-forming atoms in the monocyclic or bicyclic heteroaryl ring.
  • a heteroaryl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
  • suitable substituents include those with 5 ring-forming atoms including one to three heteroatoms or those with 6 ring-forming atoms including one, two or three nitrogen heteroatoms.
  • fused bicyclic heteroaryls include two fused 5-and/or 6-membered monocyclic rings including one to four heteroatoms.
  • heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1, 3-oxazolyl, 1, 2-oxazolyl) , thiazolyl (e.g., 1, 2-thiazolyl, 1, 3-thiazolyl) , pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl) , tetrazolyl, triazolyl (e.g., 1, 2, 3-triazolyl, 1, 2, 4-triazolyl) , oxadiazolyl (e.g., 1, 2, 3-oxadiazolyl) , thiadiazolyl (e.g., 1, 3, 4-thiadiazolyl) , quinolyl, isoquinolyl, benzothieny
  • Class (8) Heterocycloalkyl group, i.e. monocyclic or polycyclic (including 2 or more rings that are fused together, including spiro, fused, or bridged systems, for example, a bicyclic ring system) , saturated or unsaturated, non-aromatic 4-to 15-membered ring system including 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms each independently selected from O, S, N, P and B.
  • 4-to 12-membered heterocycloalkyl is a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4-to 12-membered ring system that comprises one or more ring-forming heteroatoms.
  • heterocycloalkyl rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, 2-oxaspiro [3.3]
  • heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl) , imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1, 3-oxazolidin-3-yl, 1, 4-oxazepan-1-yl, isothiazolidinyl, 1, 3-thiazolidin-3-yl, 1, 2-pyrazolidin-2-yl, 1, 2-tetrahydrothiazin-2-yl, 1, 3-thiazinan-3,
  • aromatic-fused heterocycloalkyl groups include indolinyl, isoindolinyl, isoindolin-1-one-3-yl, 5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridin-6-yl, 6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-6-yl, 4, 5, 6, 7-tetrahydrothieno [2, 3-c] pyridine-5-yl, 5, 6-dihydrothieno [2, 3-c] pyridin-7 (4H) -one-5-yl, 1, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrazol-5-yl, and 3, 4-dihydroisoquinolin-1 (2H) -one-3-yl groups.
  • heterocycloalkyl group is optionally substituted by 1 or more (e.g., 1 to 5) suitable substituents.
  • suitable substituents include 5-or 6-membered monocyclic rings and 9-or 10-membered fused bicyclic rings.
  • non-hydrogen monovalent group may include a combination of any number of groups selected from the above 8 classes.
  • a combination of two groups it means that one group (G1) is substituted with another group (G2) to form a new group -G1-G2.
  • combination of three groups it means that a first group (G1) is substituted with a second group (G2) which is substituted with a third group (G3) , forming a new group -G1-G2-G3.
  • a group from Classes (2) - (8) may be substituted with a group from Class (1) : (i) Haloalkyl group such as fluoroalkyl, i.e.
  • C1-6 haloalkyl is a C1-6 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom) .
  • C1 haloalkyl is a methyl group having one, two, or three halogen substituents.
  • Cyanoalkyl group i.e an alkyl group having one or more (e.g., 1, 2, or 3) OH substituents.
  • Cyanoalkyl group i.e an alkyl group having one or more (e.g., 1, 2, or 3) -CN substituents.
  • a group from Class (1) may be substituted with another group from Class (1) , e.g. haloalkoxy group such as fluoroalkoxy, i.e. an-O-haloalkyl group.
  • C1-6 haloalkoxy refers to an -O- (C1-6 haloalkyl) group.
  • U in Formula (I) may be selected from phenyl, pyridinyl amino, piperidin-4-ylidenemethyl, (tetrahydro-2H-pyran-4-yl) oxy, (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) amino, a five-membered or six-membered cycloalkyl non aromatic group, a five-membered heterocyclic non-aromatic group containing 1-2 hetero atom (e.g. N, O, or S) , a six-membered heterocyclic non-aromatic group containing 1-2 hetero atom (e.g.
  • N, O, S or 2N a five-membered heterocyclic aromatic group containing 1-2 hetero atoms (e.g. 1N, 1S, 2N, or 1N1O) , a six-membered heterocyclic aromatic group containing 1-2 hetero atom (e.g.
  • N, O, or S a bicyclic group containing a 4-, 5-or 6-membered ring with 0-2 member hetero atom fused with with another 4-, 5-or 6-membered ring with 0-2 member hetero atom, and a bicyclic group containing a 4-, 5-or 6-membered ring with 0-1 member N atom spiro-twisted with another 4-, 5-or 6-membered ring with 0-1 member N atom.
  • One or more non-aromatic moieties of U in Formula (I) may be saturated or unsaturated (e.g. including double or tripe bonds) .
  • the point of attachment of the non-hydrogen monovalent group can be from any suitable position.
  • piperidinyl can be piperidin-1-yl (attached through the N atom of the piperidinyl) , piperidin-2-yl (attached through the C atom at the 2-position of the piperidinyl) , piperidin-3-yl (attached through the C atom at the 3-position of the piperidinyl) , or piperidin-4-yl (attached through the C atom at the 4-position of the piperidinyl) .
  • pyridinyl can be 2-pyridinyl (or pyridin-2-yl) , 3-pyridinyl (or pyridin-3-yl) , or 4-pyridinyl (or pyridin-4-yl) .
  • the point of attachment of the non-hydrogen monovalent group can be specified to indicate the position where the non-hydrogen monovalent group is attached to another moiety.
  • “-C 1-2 alkyl- (C 3-4 cycloalkyl) ” means the point of attachment occurs at the “C 1-2 alkyl” part.
  • (C 3-4 cycloalkyl) -C 1-2 alkyl- also means the point of attachment occurs at the “C 1-2 alkyl” part.
  • substituent may be bonded to any of the ring-forming atoms in that ring that are substitutable (i.e., one or more hydrogen atoms) , unless otherwise specified or otherwise implicit from the context.
  • group U of Formula (I) may be selected from:
  • group V in Formula (I) may be selected from -Cl, -OH, -N (CH 3 ) 2 , N- (tetrahydropyranyl) amino, N- (methylcarbonylpiperrazinylethyl) amino, tert-butoxycarbonyl 8-azazpiro [4, 5] decanyl amino, a four-membered heterocyclic group containing 1 hetero atoms, a four-membered heterocyclic aromatic group containing 1 hetero atoms (e.g. 1N azetidinyl) , a six-membered heterocyclic non-aromatic group containing 1-2 hetero atoms (e.g.
  • group V of Formula (I) may be selected from -Cl, -OH,
  • group W in Formula (I) may be selected from -Cl, pyridinyl, and -NHR 1 , where R 1 is selected from -Cl, pyridinyl, and -NHR 1 , where R 1 is selected from phenyl, cyclohexyl, a five-membered heterocyclic aromatic or non-aromatic group containing 1-2 hetero atoms (e.g. 1N, 2N, 1N1O, 1N1S) , a six-membered heterocyclic aromatic or non-aromatic group containing 1-2 hetero atoms (e.g.
  • R 1 may be saturated or unsaturated.
  • W is selected from -Cl
  • Formula (I) may be Formula (Ia-1) or Formula (Ia-2) :
  • the compound of Formula (I) may be selected from the following:
  • the present disclosure may include all pharmaceutically acceptable isotopically labelled compounds of Formula (I) or salts thereof, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically labelled compounds of Formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and detection. Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron-emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Stereoisomers of Formula (I) include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, atropisomers, and conformational isomers of the compounds of Formula (I) , including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs) .
  • the compounds of Formula (I) may exist in the form of pharmaceutically acceptable salts such as acid addition salts and/or base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts e.g. hydrochloride/chloride.
  • Suitable base salts are formed from bases which form non-toxic salts such as calcium and sodium salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof include all forms of the compound of Formula (I) or pharmaceutically salt thereof, including hydrates, solvates, isomers (e.g. rotational stereoisomers) , crystalline and non-crystalline forms, isomorphs, polymorphs, metabolites, and prodrugs thereof.
  • Compounds of Formula (I) may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions.
  • the compounds of Formula (I) may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • amorphous refers to a state in which the material lacks long-range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from apparent solid to a material with liquid properties occurs, which is characterized by a change of state, typically second order ( “glass transition” ) .
  • crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ( “melting point” ) .
  • the compounds of the disclosure may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) .
  • the disclosure also relates to prodrugs of the compounds of Formula (I) .
  • Some compounds of Formula (I) may have little or no pharmacological activity themselves, but they can, when administered into or onto the body, be converted into compounds of Formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs” .
  • Prodrugs in accordance with the disclosure can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula (I) with certain moieties known to those skilled in the art as “pro-moieties” .
  • certain compounds of Formula (I) may themselves act as prodrugs of other compounds of Formula (I) . Metabolites of compounds of Formula (I) formed in vivo upon administration of the drug are also included within the scope of the disclosure.
  • Compounds of the disclosure can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
  • the reactions for preparing compounds of the disclosure can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the disclosure may involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • a -CN group can be hydrolyzed to afford an amide group;
  • a carboxylic acid can be converted to an amide;
  • a carboxylic acid can be converted to an ester, which in turn can be reduced to an alcohol, which in turn can be further modified.
  • an OH group can be converted into a better leaving group such as a methanesulfonate, which in turn is suitable for nucleophilic substitution, such as by a cyanide ion.
  • an unsaturated bond such as C-C double bond or C-C triple bond can be reduced to a saturated bond by hydrogenation.
  • Functional (reactive) groups can be protected/deprotected in the course of the synthetic scheme, if appropriate and/or desired.
  • an OH group can be protected by a benzyl, methyl, or acetyl group, which can be deprotected and converted back to the OH group in a later stage of the synthetic process.
  • an NH 2 group can be protected by a benzyloxycarbonyl (Cbz) or BOC group; conversion back to the NH 2 group can be carried out at a later stage of the synthetic process via deprotection.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC) .
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC) .
  • HPLC high-performance liquid chromatography
  • TLC thin layer chromatography
  • the compounds may exist as stereoisomers, such as atropisomers, racemates, enantiomers, or diastereomers.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high-performance liquid chromatography (HPLC) .
  • HPLC high-performance liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization, and one or both of the diastereoisomers converted to the corresponding pure enantiomer (s) by means well known to one skilled in the art.
  • Chiral compounds (and chiral precursors thereof) may be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0%to 50%2-propanol, typically from 2%to 20%, and from 0%to 5%of an alkylamine, typically 0.1%diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. Suitable stereoselective techniques are well known to those of ordinary skill in the art.
  • geometric cis/trans (or Z/E) isomers are possible.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form, a pharmaceutically acceptable carrier or excipient, and optionally comprising at least one additional medicinal or pharmaceutical agent.
  • the pharmaceutically acceptable carrier or excipient may comprise any conventional pharmaceutical carrier or excipient.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents such as hydrates and solvates.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • a therapeutically effective amount refers to that amount of the compound (including a pharmaceutically acceptable salt thereof) being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • a therapeutically effective amount refers to that amount which has the effect of relieving to some extent or eliminating one or more symptoms associated with the IRAK4 (e.g. IRAK4) -mediated disease or disorder.
  • a therapeutically effective amount refers to that amount which has the effect of relieving to some extent or eliminating one or more symptoms associated with the FLT3-mediated disease or disorder.
  • the term “treating” /” treatment” means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • the term “treating” /” treatment” also includes adjuvant and neo-adjuvant treatment of a subject.
  • Administration of the compounds of Formula (I) may be effected by any method that enables delivery of the compounds to the site of action. These methods include, for example, enteral routes (e.g., oral routes, buccal routes, sublabial routes, and sublingual routes) , oral routes, intranasal routes, inhaled routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) , intrathecal routes, epidural routes, intracerebral routes, intracerbroventricular routes, topical, and rectal administration.
  • the compounds of Formula (I) may be administered/effected by parenteral injection routes (e.g., intravenous injection route) .
  • the compounds of Formula (I) may be administered or effected by oral routes.
  • Dosage of the compounds of Formula (I) may be adjusted to provide the desired response. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
  • kits or packaged pharmaceutical product comprising a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form, and instructions for use thereof.
  • kits may include a provided pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container) .
  • the kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of the pharmaceutical composition or compound.
  • a pharmaceutical composition or compound is provided in two containers, and when it is needed, the contents in the two containers are combined to form one unit dosage form.
  • the present disclosure provides a method of inhibiting interleukin-1 receptor associated kinase (IRAK) enzyme such as interleukin-1 receptor associated kinase-4 (IRAK4) , comprising: contacting the IRAK such as IRAK4 with an effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form.
  • IRAK interleukin-1 receptor associated kinase
  • IRAK4 interleukin-1 receptor associated kinase-4
  • the present disclosure also provides a method of inhibiting FMS-like receptor tyrosine kinase (FLT3) , comprising: contacting the FLT3 with an effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form.
  • FLT3 FMS-like receptor tyrosine kinase
  • the step of inhibiting may be carried out in vitro or in vivo.
  • “In vitro” refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
  • “In vivo” refers to procedures performed within a living organism such as, without limitation, a human, a mouse, dog, rat or rabbit.
  • IC50 refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50%IC, or IC50) .
  • IC50 refers to the plasma concentration required for obtaining 50%> of a maximum effect in vivo.
  • the method of the disclosure utilizes the IRAK (e.g. IRAK4) or FLT3 inhibitor of Formula (I) with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro assay.
  • the inhibitor inhibits IRAK (e.g.
  • IRAK4 or FLT3 with an IC50 value of about 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 150 nM or less, 200 nM or less, 300 nM or less, 400 nM or less, 500 nM or less, 600 nM or less, 700 nM or less, 800 nM or less, 900 nM or less, 1000 nM or less or >1000nM, 1500 nM or less, 2000 nM or less, or 2500 nM or less (or a number in the range defined by and including any two numbers above) .
  • the present disclosure provides a method of altering gene expression or altering transcription comprising contacting a cell in vitro or in a subject with an effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form.
  • the cell is in culture in vitro.
  • the cell is in an animal, e.g., a human.
  • the cell is in a subject in need of treatment.
  • a compound of Formula (I) is useful in somatic cell reprogramming, such as reprogramming somatic cells into stem cells.
  • a compound of Formula (I) is useful in germ cell development, and are thus envisioned useful in the areas of reproductive technology and regenerative medicine.
  • the present disclosure provides a method for prophylaxis and/or treatment of a disorder or disease mediated by IRAK such as IRAK4 or associated with aberrant IRAK such as IRAK4 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form; or a pharmaceutical composition thereof.
  • IRAK such as IRAK4
  • IRAK4 activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form; or a pharmaceutical composition thereof.
  • IRAK e.g. IRAK4 -mediated disorder
  • the term “IRAK (e.g. IRAK4) -mediated disorder” means any disease, disorder, or other pathological condition in which IRAK (e.g. IRAK4) is known to play a role.
  • the present disclosure relates to treating or lessening the severity of one or more diseases in which IRAK (e.g. IRAK4) is known to play a role.
  • the methods of the disclosure are useful for treating a disease condition associated with IRAK (e.g. IRAK4) .
  • Any disease condition that results directly or indirectly from an abnormal activity or expression level of IRAK (e.g. IRAK4) can be an intended disease condition. Different disease conditions associated with IRAK (e.g. IRAK4) have been reported.
  • the present disclosure also provides a method for prophylaxis and/or treatment of a disorder or disease mediated by FLT3 or associated with aberrant FLT3 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form; or a pharmaceutical composition thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, isomer, or hydrate thereof, in any crystalline form or in amorphous form; or a pharmaceutical composition thereof.
  • the term “FLT3-mediated disorder” means any disease, disorder, or other pathological condition in which FLT3 is known to play a role. Accordingly, in some embodiments, the present disclosure relates to treating or lessening the severity of one or more diseases in which FLT3 is known to play a role. The methods of the disclosure are useful for treating a disease condition associated with FLT3. Any disease condition that results directly or indirectly from an abnormal activity or expression level of FLT3 can be an intended disease condition. Different disease conditions associated with FLT3 have been reported.
  • the disorder or disease includes inflammatory diseases, infections such as viral, bacterial, fungal, and parasitic infections, HIV-1 infection, sepsis, autoimmune disorders or diseases such as rheumatoid arthritis and multiple sclerosis, gout, juvenile idiopathic arthritis, Muckle-Wells disease, familial Mediterranean fever, Behcet’s disease, adult onset Still’s disease, proliferative diseases such as cancer, hyperplasia, restenosis, cardiac hypertrophy, leukemia, intravascular coagulation, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, fibrotic and allergic diseases, asthma, atopic dermatitis, Alzheimer's disease, hormone-related diseases, trauma (surgery) , hemodialysis, ischemic diseases (myocardial infarction) , noninfectious hepatitis, UV radiation, closed head injury, pancreatitis, periodontitis, graft-versus-host disease, and/or transplant rejection.
  • infections such as viral, bacterial, fungal
  • Compounds of Formula (I) can be administered to treat any of the described diseases, alone or in combination with a medical therapy.
  • Medical therapies include, for example, surgery and radiotherapy (e.g. gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes) .
  • Example 1 9- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 9-diazaspiro [5.5] undecan-1-one (IRAK-052) (#2)
  • Step 1 6-chloro-2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-061) (#1)
  • Step 2 9- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 9-diazaspiro [5.5] undecan-1-one (IRAK-052) (#2)
  • 6-chloro-2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (50.00 mg , 0.13 mmol, 1.0 eq. ) , 2, 9-diazaspiro [5.5] undecan-1-one (53.30 mg, 0.26 mmol, 2.0 eq. ) , Pd 2 (dba) 3 (11.90 mg, 0.01 mmol, 0.1 eq. ) , BINAP (16.17mg, 0.26 mmol, 0.2 eq. ) and CS 2 CO 3 (127.14 mg, 0.39 mmol, 3.0 eq.
  • Example 2 8- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 8-diazaspiro [4.5] decan-1-one (IRAK-037) (#3)
  • Example 5 1-methyl-8- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4 -yl) -1, 8-diazaspiro [4.5] decan-2-one (IRAK-028) (#6)
  • Example 8 9- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -1, 9-diazaspiro [5.5] undecan-2-one (IRAK-054) (#9)
  • Example 9 8- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 8-diazaspiro [4.5] decan-3-one (IRAK-051) (#10)
  • Example 12 8- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-oxa-8-azaspiro [4.5] decan-4-one (IRAK-053) (#13)
  • Example 14 6- (piperidin-1-yl) -2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-024) (#15)
  • 6-morpholino-2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-059) was obtained as a white powdery solid.
  • Example 17 1- (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-071) (#18)
  • Example 18 6- (4- (2-methoxyethyl) piperidin-1-yl) -2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-077) (#19)
  • N- (3- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -3-azaspiro [5.5] undecan-8-yl) cyclopropanecarboxamide (IRAK-094) was obtained as a white powdery solid.
  • Example 20 1- (9- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 9-diazaspiro [5.5] undecan-2-yl) ethan-1-one (IRAK-093) (#21)
  • Example 21 1- (9- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -3, 9-diazaspiro [5.5] undecan-3-yl) ethan-1-one (IRAK-086) (#22)
  • Example 22 6- (2- (methylsulfonyl) -2, 9-diazaspiro [5.5] undecan-9-yl) -2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-134) (#23)
  • Example 23 1- (8- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 8-diazaspiro [4.5] decan-2-yl) ethan-1-one (IRAK-125) (#24)
  • Example 24 1- (4- (2- ( (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) amino) ethyl) piperazin-1-yl) ethan-1-one (IRAK-084) (#25)
  • N- (2- (1- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) piperidin-4-yl) ethyl) acetamide (IRAK-085) was obtained as a white powdery solid.
  • N- (8- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -8-azaspiro [4.5] decan-2-yl) acetamide (IRAK-087) was obtained as a white powdery solid.
  • N- (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decan-8-yl) acetamide (IRAK-088) was obtained as a white powdery solid.
  • N- (3- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -3-azaspiro [5.5] undecan-9-yl) acetamide (IRAK-090) was obtained as a white powdery solid.
  • N-methyl-2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.5] nonane-7-carboxamide (IRAK-089) was obtained as a white powdery solid.
  • N-methyl-2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-8-carboxamide (IRAK-092) was obtained as a white powdery solid.
  • Example 31 1- (6- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.5] nonan-2-yl) ethan-1-one (IRAK-147) (#32)
  • Example 32 1- (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.5] nonan-6-yl) ethan-1-one (IRAK-149) (#33)
  • Example 33 1- (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one (IRAK-144) (#34)
  • Example 34 1- (6- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-2-yl) ethan-1-one (IRAK-143) (#35)
  • N- (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.4] octan-6-yl) acetamide (IRAK-142) was obtained as a white powdery solid.
  • Example 36 1- (6- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (IRAK-135) (#37)
  • N- (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.3] heptan-6-yl) acetamide (IRAK-141) was obtained as a white powdery solid.
  • Example 38 1- (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decan-7-yl) ethan-1-one (IRAK-140) (#39)
  • Example 40 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-7-one (IRAK-174) (#41)
  • Example 41 4- (1- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) azetidin-3-yl) thiomorpholine 1, 1-dioxide (IRAK-176) (#42)
  • Example 44 1- (3- (1- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) piperidin-4-yl) phenyl) ethan-1-one (IRAK-191) (#45)
  • Example 45 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -8-oxa-2, 5-diazaspiro [3.5] nonan-6-one (IRAK-192) (#46)
  • Example 46 6-methyl-2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-5-one (IRAK-193) (#47)
  • Example 47 1- (4- (1- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) azetidin-3-yl) piperidin-1-yl) ethan-1-one (IRAK-195) (#48)
  • Example 48 (7- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -7-azaspiro [3.5] nonan-2-yl) methanol (IRAK-196) (#49)
  • Example 50 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -7-thia-2-azaspiro [3.5] nonane-7, 7-dioxide (IRAK-198) (#51)
  • Example 51 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-5-one (IRAK-214) (#52)
  • Example 52 7- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2- thia-7-azaspiro [4.4] nonane-2, 2-dioxide (IRAK-215) (#53)
  • Example 53 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -8-thia-2-azaspiro [4.5] decane 8, 8-dioxide (IRAK-216) (#54)
  • Example 54 6- (7- (methylsulfonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-220) (#55)
  • Example 55 1- (3- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) ethan-1-one (IRAK-221) (#56)
  • Example 56 6- (3-morpholinoazetidin-1-yl) -2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-222) (#57)
  • 6- (3-morpholinoazetidin-1-yl) -2- (pyridin-3-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (IRAK-222) was obtained as a white powdery solid.
  • N- (6- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -6-azaspiro [3.4] octan-1-yl) acetamide (IRAK-145) was obtained as a white powdery solid.
  • Example 58 1- (7- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-2-yl) ethan-1-one (IRAK-171) (#59)
  • Example 60 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.5] nonan-7-ol (IRAK-173) (#61)
  • Example 61 tert-butyl 2- ( (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) amino) -8-azaspiro [4.5] decane-8-carboxylate (IRAK-055) (#62)
  • Example 62 tert-butyl (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decan-8-yl) carbamate (IRAK-056) (#63)
  • tert-butyl (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decan-8-yl) carbamate (IRAK-056) was obtained as a white powdery solid.
  • Example 63 tert-butyl (3- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -3-azaspiro [5.5] undecan-9-yl) carbamate (IRAK-057) (#64)
  • tert-butyl (3- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -3-azaspiro [5.5] undecan-9-yl) carbamate (IRAK-057) was obtained as a white powdery solid.
  • Example 64 tert-butyl 9- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -2, 9-diazaspiro [5.5] undecane-2-carboxylate (IRAK-072) (#65)
  • Example 65 tert-butyl 9- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -3, 9-diazaspiro [5.5] undecane-3-carboxylate (IRAK-073) (#66)
  • Example 66 tert-butyl 8- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -2, 8-diazaspiro [4.5] decane-2-carboxylate (IRAK-074) (#67)
  • Example 68 3- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -3-azaspiro [5.5] undecan-9-amine hydrochloride (IRAK-076) (#69)
  • Example 70 2- (pyridin-3-yl) -6- (2, 7-diazaspiro [4.5] decan-2-yl) -N- (4- (trifluoromethoxy) pyridin-2 -yl) pyrimidin-4-amine hydrochloride (IRAK-105) (#71)
  • Example 71 tert-butyl (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.3] heptan-6-yl) carbamate (IRAK-106) (#72)
  • tert-butyl (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.3] heptan-6-yl) carbamate (IRAK-106) was obtained as a white powdery solid.
  • Example 72 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.3] heptan-6-amine hydrochloride (IRAK-108) (#73)
  • tert-butyl (2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.4] octan-6-yl) carbamate (IRAK-109) was obtained as a white powdery solid.
  • Example 74 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [3.4] octan-6-amine hydrochloride (IRAK-111) (#75)
  • Example 75 tert-butyl 6- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (IRAK-112) (#76)
  • Example 77 tert-butyl 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -2, 6-diazaspiro [3.4] octane-6-carboxylate (IRAK-115) (#78)
  • Example 78 2- (pyridin-3-yl) -6- (2, 6-diazaspiro [3.4] octan-2-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine hydrochloride (IRAK-117) (#79)
  • Example 80 6- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -6-azaspiro [3.4] octan-1-amine hydrochloride (IRAK-120) (#81)
  • Example 81 tert-butyl 6- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -2, 6-diazaspiro [3.5] nonane-2-carboxylate (IRAK-121) (#82)
  • Example 82 tert-butyl 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -2, 6-diazaspiro [3.5] nonane-6-carboxylate (IRAK-122) (#83)
  • Example 83 2- (pyridin-3-yl) -6- (2, 9-diazaspiro [5.5] undecan-9-yl) -N- (4- (trifluoromethoxy) pyridin -2-yl) pyrimidin-4-amine hydrochloride (IRAK-124) (#84)
  • Example 84 2- (pyridin-3-yl) -6- (2, 6-diazaspiro [3.5] nonan-6-yl) -N- (4- (trifluoromethoxy) pyridin-2 -yl) pyrimidin-4-amine (IRAK-146) (#85)
  • Example 86 methyl 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (IRAK-150) (#87)
  • Example 88 tert-butyl 2- (2- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin -4-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (IRAK-178) (#89)
  • Step 1 tert-butyl 7- (methylcarbamoyl) -2-azaspiro [4.5] decane-2-carboxylate (#94)
  • Step 4 2-chloro-6- (pyridin-4-yl) -N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (#97)
  • Step 5 N-methyl-2- (4- (pyridin-4-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-2-yl) -2-azaspiro [4.5] decane-7-carboxamide (#93)
  • Step 1 6-chloro-2-phenyl-N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (#99)
  • Step 2 ethyl 2- (2-phenyl-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (#100)
  • Step 3 N-methyl-2- (2-phenyl-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxamide (#98)
  • Example 94 2-methyl-8- (2-phenyl-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 8-diazaspiro [4.5] decan-1-one (IRAK-082) (#101)
  • Step 1 2-methyl-8- (2-phenyl-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 8-diazaspiro [4.5] decan-1-one (#101)
  • 6-chloro-2-phenyl-N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (0.1 g, 0.27 mmol) in THF (15 mL) was added 2-methyl-2, 8-diazaspiro [4.5] decan-1-one (0.09 g, 0.540 mmol) , DIPEA (0.5 mL) , BINAP (0.03 mmol) and Pd (dba) 2 (0.03 mmol) , and the resultant mixture was heated to 110 °C under nitrogen gas atmosphere for 10 hours. The reaction mixture was concentrated to dryness.
  • Step 1 ethyl 2- (2-chloro-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (#103)
  • Step 2 ethyl2- (2- (6- (methylamino) pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (#104)
  • Step 3 N-methyl-2- (2- (6- (methylamino) pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxamide (#102)
  • Step 1 ethyl 2- (4-chloro-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-2-yl) -2-azaspiro [4.5] decane-7-carboxylate (#106)
  • Step 2 ethyl2- (4- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-2-yl) -2-azaspiro [4.5] decane-7-carboxylate (IRAK-153) (#107)
  • Step 3 N-methyl-2- (4- (pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-2-yl) -2-azaspiro [4.5] decane-7-carboxamide (#105)
  • Step 1 ethyl 2- (4- (4-methylpyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-2 -yl) -2-azaspiro [4.5] decane-7-carboxylate (IRAK-138) (#109)
  • Step 2 N-methyl-2- (4- (4-methylpyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-2-yl) -2-azaspiro [4.5] decane-7-carboxamide (#108)
  • Step 1 ethyl 2- (2- (6-aminopyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (IRAK-158) (#111)
  • Step 2 2- (2- (6-aminopyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -N-methyl-2-azaspiro [4.5] decane-7-carboxamide (#110)
  • Step 1 ethyl 2- (2- (5- (morpholinosulfonyl) pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (IRAK-160) (#113)
  • Step 2 N-methyl-2- (2- (5- (morpholinosulfonyl) pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxamide (#112)
  • Example 100 N-methyl-2- (2- (1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxamide (IRAK-163) (#114)
  • Step 1 methyl 2- (2-chloro-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (#115)
  • Step 2 methyl 2- (2- (1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (IRAK-162) (#116)
  • Step 3 N-methyl-2- (2- (1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxamide (#114)
  • Step 1 ethyl 2- (2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (#118)
  • Step 2 N-methyl-2- (2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -6- ( (4- (trifluoro methoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxamide (#117)
  • Example 102 1- (2- (2- (6- (methylsulfonyl) pyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-180) (#119)
  • Step 1 1- (2- (2-chloro-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (#120)
  • Example 103 1- (2- (2- (1- (methylsulfonyl) -1H-pyrazol-4-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-181) (#121)
  • Example 102 A synthetic method similar to that in Example 102 was used to afford a white solid (10 mg, 17.6 %yield) .
  • Example 104 1- (2- (6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) -2- (5- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-188 ) (#122)
  • Example 105 1- (2- (6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) -2- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-206) (#123)
  • Example 106 1- (2- (2- (3, 3-difluoropyrrolidin-1-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-207) (#124)
  • Example 107 1- (2- (2- (1-methylpiperidin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-209) (#125)
  • Step 1 1- (2- (2- (1-methyl-1, 2, 5, 6-tetrahydropyridin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-208) (#126)
  • Step 2 1- (2- (2- (1-methylpiperidin-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-209) (#125)
  • Example 108 1- (2- (2- (6-methyl-2, 6-diazaspiro [3.3] heptan-2-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-210) (#127)
  • Example 106 A synthetic method similar to that in Example 106 was used, replacing 3, 3-difluoro pyrrolidine with 2-Methyl-2, 6-diaza-spiro [3.3] heptane dihydrochloride, to afford a white solid (20 mg, 37.5 %yield) .
  • Example 109 1- (2- (6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) -2- (4- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-218) (#128)
  • Example 110 1- (2- (2- (thiophen-3-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-219) (#129)
  • Example 111 1- (2- (2- (1H-pyrazol-4-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-223) (#130)
  • Example 112 1- (2- (2- (pyridin-2-yl) -6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (IRAK-224) (#131)
  • Step 2 2, 6-dichloro-N- (4- (trifluoromethoxy) pyridin-2-yl) pyrimidin-4-amine (#134)
  • Step 3 ethyl 2- (2-chloro-6- ( (4- (trifluoromethoxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-azaspiro [4.5] decane-7-carboxylate (#135)

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Abstract

La présente invention concerne des inhibiteurs de l'enzyme de kinase associée au récepteur de l'interleukine 1 (IRAK)/tyrosine kinase du récepteur de type FMS (FLT3) de formule (I), un sel, un ester, un promédicament, un complexe, un solvate, un hydrate ou un isomère pharmaceutiquement acceptable de ceux-ci, sous toute forme cristalline ou amorphe. Dans la formule (I), X, X 1, X 2 est choisi parmi N et C ; et U, V et W sont indépendamment l'un de l'autre un groupe monovalent non-hydrogène. L'invention concerne également des produits pharmaceutiques comprenant les inhibiteurs d'IRAK ainsi que la prophylaxie et/ou le traitement de maladies inflammatoires, de maladies auto-immunes et de maladies prolifératives, entre autres. La kinase associée au récepteur de l'interleukine-1 (IRAK) mentionnée ci-dessus peut être l'IRAK4.
PCT/CN2021/074803 2020-02-14 2021-02-02 Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 (irak)/tyrosine kinase du récepteur de type fms (flt3), leurs produits pharmaceutiques et leurs procédés WO2021159993A1 (fr)

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US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11945798B2 (en) * 2021-08-27 2024-04-02 Yuhan Corporation Substituted aminopyridine compounds as EGFR inhibitors
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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