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WO2025174879A1 - Procédés pour réduire ou supprimer une maladie résiduelle mesurable - Google Patents

Procédés pour réduire ou supprimer une maladie résiduelle mesurable

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Publication number
WO2025174879A1
WO2025174879A1 PCT/US2025/015585 US2025015585W WO2025174879A1 WO 2025174879 A1 WO2025174879 A1 WO 2025174879A1 US 2025015585 W US2025015585 W US 2025015585W WO 2025174879 A1 WO2025174879 A1 WO 2025174879A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
inhibitor
irak4
heterocyclyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/015585
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English (en)
Inventor
Mariano SEVERGNINI
Maureen E. LANE
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Curis Inc
Original Assignee
Curis Inc
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Publication of WO2025174879A1 publication Critical patent/WO2025174879A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Interleukin-1 (IL-1) Receptor-Associated Kinase 4 is a serine/threonine kinase enzyme that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs).
  • TIRs Toll/IL-1 receptors
  • IRAK enzymes are key components in the signal transduction pathways mediated by interleukin-1 receptor (IL-1R) and Toll-like receptors (TLRs) (Janssens, S, et al. Mol. Cell. 11, 2003, 293-302).
  • IRAK-1 interleukin-1 receptor
  • TLRs Toll-like receptors
  • IRAK proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain.
  • the IRAK proteins, as well as MyD88, have been shown to play a role in transducing signals other than those originating from IL-1R receptors, including signals triggered by activation of IL-18 receptors (Kanakaraj, et al. J. Exp. Med. 189(7): 1999, 1129-38) and LPS receptors (Yang, et al., J. Immunol. 163, 1999, 639-643).
  • IRAK4 is considered to be the “master IRAK”.
  • IRAK4 KI Inactivation of IRAK4 kinase (IRAK4 KI) in mice leads to resistance to EAE due to reduction in infiltrating inflammatory cells into CNS and reduced antigen specific CD4+ T-cell mediated IL-17 production (Kirk A et al. The Journal of Immunology, 183(1), 2009, 568-577).
  • MRD Measurable residual disease
  • MRD can be assessed through various modalities, including multiparameter flow cytometry (MFC), real-time quantitative polymerase chain reaction (RT- qPCR) and next-generation sequencing (NGS)-based assay (Leukemia & Lymphoma Society, Measurable Residual Disease (MRD) Facts, April 2021, 1-11).
  • MFC multiparameter flow cytometry
  • RT- qPCR real-time quantitative polymerase chain reaction
  • NGS next-generation sequencing
  • MRD can be detected via next generation sequencing of circulating tumor DNA (ctDNA) in the blood, a method that is gaining widespread utilization to better define risk stratification and improve patient outcomes (Front Oncol. 2021; 11 : 763790).
  • Detecting cell or blast numbers is related to flow cytometry while NGS and PCR methods (RT-qPCR) are used for clonal rearrangements and mutation detection in hematological malignancies.
  • RT-qPCR NGS and PCR methods
  • the present disclosure provides methods of reducing or eliminating MRD in a subject, comprising administering to the subject an IRAK4 inhibitor or an IRAK4 degrader. In some aspects, the present disclosure provides methods of reducing MRD in a subject. In some aspects, the present disclosure provides methods of eliminating MRD in a subject. In some embodiments, the method comprises conjointly administering a nucleoside analog. In some embodiments, the method comprises conjointly administering a BCL-2 inhibitor.
  • emavusertib in combination with azacitidine and venetoclax demonstrated synergistic antileukemic effects in AML cell lines, including azacitidine- or venetoclax-resistant cell lines.
  • Adding emavusertib to azacitidine and venetoclax combinations as a first line therapy in MRD+ patients at the time of CR may enhance conversion to MRD- without adding significant toxicity.
  • MRD is often associated with treatment resistant cancers and/or genetic mutations in the cancer cells that make them less susceptible to treatment with frontline therapies.
  • oncogenic mutations associated with MRD include mutations in FLT3, NPM1, NRAS, DNMT3A, IDH2, RUNX1, IDH1, TET2, SF3B1, PTPN11, WT1, CEBPA, ASXL1, TP53, KRAS, and U2AGP Accordingly, compounds that can inhibit cancer cell growth or kill cancer cells with such mutations can have improved efficacy in reducing or eliminating MRD.
  • Compounds as disclosed herein have demonstrated efficacy against cancers that have developed resistance against treatment with FLT3 inhibitors.
  • Compounds as disclosed herein also have demonstrated efficacy against cancers that have a mutation in SF3B1 and/or U2AG1. Accordingly, therapies that include compounds as disclosed herein can be used as effective frontline or maintenance therapies for preventing, reducing, or eliminating MRD.
  • the present disclosure provides methods of reducing measurable residual disease (MRD) in a subject, comprising administering to the subject an IRAK4 inhibitor or an IRAK4 degrader.
  • the IRAK4 inhibitor is
  • the methods reduce the MRD in the subject (e.g., as compared to a subject who has not received an IRAK4 inhibitor or degrader, and/or a nucleoside analog, and/or a BCL-2 inhibitor). In other embodiments, the methods eliminates the MRD in the subject.
  • the IRAK4 inhibitor is the BCL-2 inhibitor is venetoclax; and the nucleoside analog is azacitidine.
  • the IRAK4 inhibitor has a structure represented by formula (I) or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof; wherein Zi is an optionally substituted heteroaryl;
  • Z2 is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;
  • Ri is alkyl, cyano, -NRaRb, or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH 2 -O-alkyl, -OP(O)(O-alkyl) 2 or -CH 2 -OP(O)(O-alkyl) 2 ;
  • R 2 at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;
  • R3 at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NRaRb, hydroxyl or hydroxy alkyl;
  • Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SO 2 -alkyl or optionally substituted cycloalkyl; and ‘m’ and ‘n’ are independently 1 or 2.
  • Zi is a 5- or 6-membered optionally substituted heteroaryl.
  • the IRAK4 inhibitor has a structure represented by formula (IC): or a pharmaceutically acceptable salt thereof.
  • Z2 is pyridyl
  • Z2 is pyrazolyl
  • Z2 is pyrrolidinyl
  • Ri is optionally substituted heterocyclyl; wherein the substituent is halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, -OCO-CH2-O-alkyl, - OP(O)(O-alkyl) 2 or -CH 2 -OP(O)(O-alkyl) 2 .
  • Ri is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl; wherein the substituent is amino, halogen, hydroxyl, hydroxyalkyl, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2.
  • Ri is optionally substituted piperidinyl, wherein the substituent is hydroxyl.
  • Ri is optionally substituted phenyl, wherein the substituent is halogen.
  • Ri is cycloalkyl
  • Ri is cyclopropyl or cyclohexyl.
  • Ri is -NRaRb; Ra is hydrogen; Rb is optionally substituted cycloalkyl, wherein the substituent is hydroxyl.
  • Ri is cyano
  • R2 is optionally substituted alkyl, wherein the substituent is alkoxy.
  • R2 is cycloalkyl
  • R3 is hydrogen, halogen, alkyl, alkoxy, -NRaRb, hydroxyl or hydroxyalkyl; Rais hydrogen or alkyl; and Rb is hydrogen, alkyl, acyl, hydroxyalkyl or -SO2- alkyl.
  • Zi is optionally substituted pyridyl
  • Ring Z2 is pyridyl, pyrazolyl, pyrrolidinyl or direct bond
  • Ri is an optionally substituted group selected from cyclopropyl, piperidinyl, morpholinyl or pyrrolidinyl
  • R2 is optionally substituted alkyl or cycloalkyl
  • R3 is hydrogen, halogen, alkyl, alkoxy, -NRaRb, hydroxyl or hydroxyalkyl
  • Ra is hydrogen or alkyl
  • Rb is hydrogen or hydroxy alkyl.
  • Zi is oxazolyl
  • Z2 is pyridyl, pyrazolyl or pyrrolidinyl
  • Ri is cyano, -NRaRb, or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl
  • R2 is optionally substituted alkyl or cycloalkyl
  • R3 is hydrogen, halogen, alkyl, alkoxy, -NRaRb, hydroxyl or hydroxyalkyl
  • Ra is hydrogen or alkyl
  • Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SCh-alkyl or optionally substituted cycloalkyl.
  • R3 is -NRaRb; Ra is hydrogen or alkyl; and Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SCh-alkyl or optionally substituted cycloalkyl, wherein the optional substituent is hydroxyl;
  • ‘n’ is 1.
  • ‘n’ is 2.
  • ‘m’ is 1.
  • ‘m’ is 2.
  • the IRAK4 inhibitor is: _ or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the IRAK4 inhibitor is represented by formula (II): or a pharmaceutically acceptable salt thereof; wherein,
  • Xi and X3 independently are CH or N; X2 is CR2 or N; provided one and not more than one of Xi, X2 or X 3 is N;
  • A is O or S
  • Y is -CH2- or O
  • Z is aryl or heterocyclyl
  • Ri at each occurrence, is independently halo or optionally substituted heterocyclyl, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NRaRb;
  • R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the optional substituent is alkyl, amino, halo or hydroxyl;
  • R3 at each occurrence, is alkyl or hydroxyl
  • R and Rb are independently hydrogen, alkyl, acyl or heterocyclyl
  • ‘m’ and ‘n’ are independently 0, 1 or 2;
  • ‘p’ is 0 or 1.
  • Z is aryl or 5- or 6-membered heterocyclyl.
  • Z is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, IH-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,l,4-dioxanyl, dioxidothiomorpholin
  • Z is phenyl, oxazolyl, furanyl, thienyl or pyridyl; each of which is optionally substituted with one or more Ri.
  • the IRAK4 inhibitor has a structure represented by formula
  • the IRAK4 inhibitor has a structure represented by formula (IIB): (IIB) or a pharmaceutically acceptable salt thereof.
  • Y is O or CH2.
  • Ri is optionally substituted heterocyclyl, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NRaRb; Ra and Rb are independently hydrogen, alkyl or acyl.
  • Ri is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl; each of which is optionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or -NRaRb; Ra and Rb are independently hydrogen or acyl.
  • R2 is hydrogen
  • R2 is optionally substituted heterocyclyl, wherein the substituent is alkyl, amino, halo or hydroxyl.
  • R2 is optionally substituted piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, pyridyl, azepanyl or azabicyclo[3.2.1]octanyl; wherein the optional substituent is alkyl, amino, halo or hydroxyl.
  • R2 is optionally substituted aryl, wherein the substituent is halo.
  • R2 is optionally substituted phenyl, wherein the substituent is fluoro.
  • A is O or S;
  • Y is -CH2- or O;
  • Ri is halo, pyridyl, pyrazolyl, pyrrolidinyl each of which is optionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or -NRaRb;
  • R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the optional substituent is alkyl, amino, halo or hydroxyl;
  • Ra and Rb are independently hydrogen or alkyl.
  • A is O or S; Y is -CH2- or O; Ri is pyridyl, pyrazolyl, pyrrolidinyl, each of which is optionally substituted with alkyl, hydroxyl, hydroxyalkyl or - NRaRb; Ra and Rb are independently hydrogen; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the optional substituent is alkyl, amino, halo or hydroxyl; R a and Rb are independently hydrogen, alkyl, acyl or heterocyclyl.
  • ‘n’ is 0, 1 or 2. In certain embodiments, ‘p’ is 0 or 1.
  • ‘m’ is 0 or 2.
  • the IRAK4 inhibitor is selected from: or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the IRAK4 inhibitor is emavusertib) or a pharmaceutically acceptable salt thereof.
  • the IRAK4 inhibitor has a structure represented by formula (III): or a pharmaceutically acceptable salt thereof; wherein,
  • Zi represents optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or is absent;
  • Z2 represents optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl;
  • Ri is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;
  • R2 at each occurrence is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;
  • R3 at each occurrence is hydroxy, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or -NRaRb;
  • Ra and Rb independently for each occurrence, are hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;
  • m, at each occurrence, is 0, 1 or 2; and n, at each occurrence, is 0, 1, or 2.
  • Zi represents cycloalkyl, aryl, or heterocyclyl, optionally substituted by one or more substituents selected, independently for each occurrence, from hydroxy, halo, alkyl, cycloalkyl, or NRaRb.
  • Zi is an optionally substituted heteroaryl, wherein the optional substituent is alkyl or cycloalkyl.
  • Zi is tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H
  • Zi is pyridyl or oxazolyl, wherein the oxazolyl group is optionally substituted with alkyl.
  • the alkyl is methyl.
  • Zi is absent.
  • Z2 is cycloalkyl, aryl or heterocyclyl.
  • Z2 is heterocyclyl.
  • Z2 is azetidinyl, oxetanyl, furanyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,4-dioxanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolidinyl, imidazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, oxazolidinyl, pyrazolidin
  • Z2 is pyridyl, piperazinyl, pyrimidyl, pyrrolidinyl, 1, 2,3,4- tetrahydropyridyl, piperidinyl, pyrazolopyrimidyl or pyrrol opyridyl.
  • the IRAK4 inhibitor has a structure represented by formula (IIIA):
  • Z2 is piperidinyl, piperazinyl, tetrahydropyridyl, pyrimidyl or pyrazolopyridyl.
  • Ri is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl.
  • Ri is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl.
  • R2 at each occurrence, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl.
  • R2 is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heterocyclylalkyl, optionally substituted with one or more substituents selected, independently for each occurrence, from alkyl, cycloalkyl, or heterocyclyl.
  • R2 is optionally substituted alkyl, preferably methyl. In certain embodiments, R2 is optionally substituted cycloalkyl, preferably, cyclopropyl.
  • Zi is oxazolyl
  • Z2 is pyridyl, pyrimidyl or pyrrolidinyl, piperidinyl, tetrahydropyridyl, piperazinyl, pyrrolopyridyl
  • Ri is an optionally substituted group selected from piperidinyl or pyrrolidinyl
  • R2 is optionally substituted alkyl or cyclopropyl
  • R3 is halogen, alkyl, alkoxy, -NRaRb, hydroxyl, hydroxyalkyl optionally substituted cyclopropyl
  • Ra is hydrogen or alkyl
  • Rbis hydrogen, alkyl, acyl, hydroxyalkyl, -SCh-alkyl or optionally substituted cycloalkyl.
  • ‘m’ is 2.
  • ‘n’ is 0.
  • ‘n’ is 1.
  • ‘n’ is 2.
  • the IRAK4 inhibitor is selected from: or a pharmaceutically acceptable salt thereof.
  • the IRAK4 inhibitor is In other preferred embodiments, the IRAK4 inhibitor is , inhibitor yet other preferred embodiments, the
  • the IRAK4 inhibitor is PF-06650833, BAY1830839, BAY1834845, R835, GS-5718, or ND-2158.
  • the IRAK4 inhibitor may be administered in any amount or manner that elicits the desired response in the subject.
  • 100 - 400 mg of the IRAK4 inhibitor can be administered to the subject twice per day or 200 - 1000 mg of the IRAK4 inhibitor can be administered to the subject once per day.
  • 100 - 400 mg of the IRAK4 inhibitor is administered to the subject twice per day.
  • 200 - 400 mg of the IRAK4 inhibitor is administered to the subject twice per day.
  • 250 - 350 mg of the IRAK4 inhibitor is administered to the subject twice per day.
  • about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of the IRAK4 inhibitor is administered to the subject twice per day.
  • about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the IRAK4 inhibitor is administered to the subject twice per day. In certain embodiments, about 50 mg of the IRAK4 inhibitor is administered to the subject twice per day. In other embodiments, about 200 mg of the IRAK4 inhibitor is administered to the subject twice per day. In other embodiments, about 225 mg of the IRAK4 inhibitor is administered to the subject twice per day. In other embodiments, about 250 mg of the IRAK4 inhibitor is administered to the subject twice per day. In other embodiments, about 275 mg of the IRAK4 inhibitor is administered to the subject twice per day. In particularly preferred embodiments, about 300 mg of the IRAK4 inhibitor is administered to the subject twice per day.
  • about 325 mg of the IRAK4 inhibitor is administered to the subject twice per day. In other embodiments, about 350 mg of the IRAK4 inhibitor is administered to the subject twice per day. In other embodiments, about 375 mg of the IRAK4 inhibitor is administered to the subject twice per day. In other embodiments, about 400 mg of the IRAK4 inhibitor is administered to the subject twice per day.
  • about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the IRAK4 inhibitor is administered to the subject once per day.
  • about 50 mg of the IRAK4 inhibitor is administered to the subject once per day.
  • about 75 mg of the IRAK4 inhibitor is administered to the subject once per day.
  • about 100 mg of the IRAK4 inhibitor is administered to the subject once per day.
  • about 125 mg of the IRAK4 inhibitor is administered to the subject once per day.
  • about 150 mg of the IRAK4 inhibitor is administered to the subject once per day.
  • the IRAK4 inhibitor is orally administered to the subject. In certain embodiments, about 50 mg of the IRAK4 inhibitor is orally administered to the subject twice per day. In other embodiments, about 200 mg of the IRAK4 inhibitor is orally administered to the subject twice per day. In other embodiments, about 250 mg of the IRAK4 inhibitor is orally administered to the subject twice per day. In particularly preferred embodiments, about 300 mg of the IRAK4 inhibitor is orally administered to the subject twice per day. In other embodiments, about 325 mg of the IRAK4 inhibitor is orally administered to the subject twice per day. In other embodiments, about 350 mg of the IRAK4 inhibitor is orally administered to the subject twice per day.
  • about 375 mg of the IRAK4 inhibitor is orally administered to the subject twice per day. In other embodiments, about 400 mg of the IRAK4 inhibitor is orally administered to the subject twice per day. In other embodiments, about 50 mg of the IRAK4 inhibitor is orally administered to the subject once per day. In yet other embodiments, about 75 mg of the IRAK4 inhibitor is orally administered to the subject once per day. In yet other embodiments, about 100 mg of the IRAK4 inhibitor is orally administered to the subject once per day. In yet other embodiments, about 125 mg of the IRAK4 inhibitor is orally administered to the subject once per day. In yet other embodiments, about 150 mg of the IRAK4 inhibitor is orally administered to the subject once per day.
  • the method comprises administering an IRAK4 degrader.
  • the IRAK4 degrader is KT-474, KYM-001, or IRAKMiD.
  • the IRAK4 degrader is an IRAK4 degrader disclosed in US 2019/0151295 Al, WO 2019/133531 Al, WO 2020/113233 Al, and WO 2021/011868 Al, the contents of each of which is hereby incorporated by reference in its entirety.
  • reducing MRD in the subject comprises reducing the number of cancer cells in a patient sample.
  • reducing MRD in the subject comprises reducing the count of residual blasts in a patient sample.
  • reducing MRD in the subject comprises reducing the count of residual blasts per leukocyte in a patient sample.
  • eliminating MRD in the subject comprises reducing the number of cancer cells in a patient sample below a threshold. In certain preferred embodiments, eliminating MRD in the subject comprises reducing the count of residual blasts in a patient sample below a threshold. In certain particularly preferred embodiments, eliminating MRD in the subject comprises reducing the count of residual blasts per leukocyte in a patient sample below a threshold.
  • eliminating MRD in the subject comprises reducing the count of residual blasts per leukocyte in a patient sample to below about 1 in 1,000; below about 1 in 10,000; below about 1 in 100,000; or below about 1 in 1,000,000, most preferably below 0.001 (z.e., 1 in 1,000). In some embodiments, the count of residual blasts per leukocyte is below 0.0001 (z.e., 1 in 10,000). In some embodiments, the count of residual blasts per leukocyte is below 0.00001 (i.e., 1 in 100,000). In some embodiments, the threshold is the threshold of detection of a measurement or diagnostic technique. The threshold can be determined by a medical professional and can vary according to measurement or diagnostic technique.
  • cancer cells are counted or measured by flow cytometry.
  • the count of residual blasts per leukocyte is measured by flow cytometry.
  • the flow cytometry is preferably multiparameter flow cytometry.
  • reducing MRD in the subject comprises reducing the number or type of residual mutations in a patient sample, or preferably eliminating MRD in the subject, e.g., by reducing the number or type of residual mutations in a patient sample below a threshold.
  • the number and/or type of residual mutations are assessed by polymerase chain reaction (PCR).
  • the number and/or type of residual mutations are assessed by next-generation sequencing (NGS).
  • the number and/or type of residual mutations are measured from circulating tumor DNA (ctDNA). Residual mutations can be sorted by mutation type (e.g., point mutations, translocations, or chromosomal mutations) and by the gene(s) affected.
  • the patient sample comprises peripheral blood.
  • the patient sample comprises bone marrow cells.
  • the patient sample comprises at least 1,000; at least 10,000; or at least 100,000 cells.
  • reducing or eliminating MRD leads to a subject’s MRD- negative test.
  • the MRD is detected by bone marrow sampling (e.g., bone marrow biopsy).
  • the MRD is detected by multiparameter flow cytometry (MFC).
  • the MRD is detected molecular via polymerase chain reaction (PCR) or next-generation sequencing (NGS).
  • the MRD is detected via circulating tumor DNA (ctDNA).
  • the method reduces the MRD in the subject (e.g., as compared to a subject who has not received an IRAK4 inhibitor or degrader, and/or a nucleoside analog, and/or a BCL-2 inhibitor).
  • the method eliminates the MRD in the subject.
  • the BCL-2 inhibitor is venetoclax.
  • 400 mg of venetoclax is administered daily.
  • the venetoclax is administered orally.
  • the method comprises orally administering 400 mg of venetoclax daily.
  • the subject’s tumor volume is reduced by 35%. In certain embodiments, the subject’s tumor volume is reduced by 40%. In certain embodiments, the subject’s tumor volume is reduced by 45%. In certain embodiments, the subject’s tumor volume is reduced by 50%. In certain embodiments, the subject’s tumor volume is reduced by 55%. In certain embodiments, the subject’s tumor volume is reduced by 60%. In certain embodiments, the subject’s tumor volume is reduced by 65%. In certain embodiments, the subject’s tumor volume is reduced by 70%. In certain embodiments, the subject’s tumor volume is reduced by 80%. In certain embodiments, the subject’s tumor volume is reduced by 85%. In certain embodiments, the subject’s tumor volume is reduced by 90%. In certain embodiments, the subject’s tumor volume is reduced by 95%.
  • the IRAK4 inhibitor or IRAK4 degrader may be administered first, the BCL-2 inhibitor third, and the nucleoside analog second. In yet other embodiments, the IRAK4 inhibitor or IRAK4 degrader may be administered second, the BCL- 2 inhibitor first, and the nucleoside analog third. In yet other embodiments, the IRAK4 inhibitor or IRAK4 degrader may be administered second, the BCL-2 inhibitor third, and the nucleoside analog first. In yet other embodiments, the IRAK4 inhibitor or IRAK4 degrader may be administered third, the BCL-2 inhibitor first, and the nucleoside analog second.
  • the IRAK4 inhibitor or IRAK4 degrader may be administered third, the BCL-2 inhibitor second, and the nucleoside analog first.
  • the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analog are administered within about 5 minutes to within about 168 hours of each other.
  • the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog are administered simultaneously.
  • the IRAK4 inhibitor may be administered first, the BCL-2 inhibitor third, and the nucleoside analog second.
  • the IRAK4 inhibitor may be administered second, the BCL-2 inhibitor first, and the nucleoside analog third.
  • the IRAK4 inhibitor may be administered second, the BCL-2 inhibitor third, and the nucleoside analog first.
  • the IRAK4 inhibitor may be administered third, the BCL-2 inhibitor first, and the nucleoside analog second.
  • the IRAK4 inhibitor may be administered third, the BCL-2 inhibitor second, and the nucleoside analog first. In certain embodiments, the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog are administered within about 5 minutes to within about 168 hours of each other.
  • the subject following administration of the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analog, the subject achieves a partial response. In some embodiments, following administration of the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog, the subject achieves a partial response. In some embodiments, following administration of the IRAK4 inhibitor or IRAK4 degrader, the BCL- 2 inhibitor, and the nucleoside analog, the subject achieves a good partial response. In some embodiments, following administration of the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog, the subject achieves a good partial response.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxy -2-naphthoic acid, 2, 2-di chloroacetic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • carboxylate is art-recognized and refers to a group wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • fused carbocycle refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH- indene and bicyclo[4.1.0]hept-3-ene.
  • “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-.
  • carboxy refers to a group represented by the formula -CO2H.
  • cycloalkyl includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings.
  • cycloalkyl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R 100 ) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl.
  • sulfoxide is art-recognized and refers to the group-S(O)-.
  • sulfonate is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 9 or -SC(O)R 9 wherein R 9 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • modulate includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non- pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • Log of solubility is used in the art to quantify the aqueous solubility of a compound.
  • the aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
  • LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
  • partial response means an objective response in at least one organ or tissue in the subject with no evidence of progression elsewhere.
  • a partial response may refer to a 50% or more reduction in the disease state (e.g., tumor volume).
  • complete response means a complete disappearance of the measurable evidence of the disease in the subject.
  • a complete response may refer to the complete measurable disappearance of the subject’s cancer.
  • a complete response may refer to the complete measurable disappearance of the subject’s symptoms (e.g., the subject’s cytokine count may return to normal).

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Abstract

La présente divulgation concerne des procédés pour réduire ou supprimer une maladie résiduelle mesurable (MRD) chez un sujet, comprenant l'administration au sujet d'un inhibiteur d'IRAK4 ou d'un agent de dégradation d'IRAK4.
PCT/US2025/015585 2024-02-12 2025-02-12 Procédés pour réduire ou supprimer une maladie résiduelle mesurable Pending WO2025174879A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022216379A1 (fr) * 2021-04-08 2022-10-13 Curis, Inc. Polythérapies pour le traitement du cancer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022216379A1 (fr) * 2021-04-08 2022-10-13 Curis, Inc. Polythérapies pour le traitement du cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CERCHIONE CLAUDIO, SCHOLL SEBASTIAN, MIDDEKE JAN MORITZ, NITIKA NITIKA, LANE MAUREEN E, ZHAO WANYING, ANGELIDES STEVEN, ROEMELING : "A phase 1 single-arm, open-label study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in patients (pts) with acute myeloid leukemia (AML) in complete response (CR) with measurable residual disease (MRD)", JOURNAL OF CLINICAL ONCOLOGY, AMERICAN SOCIETY OF CLINICAL ONCOLOGY, UNITED STATES, vol. 42, no. 16_suppl, 1 June 2024 (2024-06-01), United States, pages TPS6587 - TPS6587, XP093345830, ISSN: 0732-183X, DOI: 10.1200/JCO.2024.42.16_suppl.TPS6587 *
GARCIA-MANERO GUILLERMO, PLATZBECKER UWE, LIM KIAN-HUAT, NOWAKOWSKI GRZEGORZ, ABDEL-WAHAB OMAR, KANTARJIAN HAGOP, VERMA AMIT, STAR: "Research and clinical updates on IRAK4 and its roles in inflammation and malignancy: themes and highlights from the 1st symposium on IRAK4 in cancer", FRONTIERS IN HEMATOLOGY, vol. 3, XP093345832, ISSN: 2813-3935, DOI: 10.3389/frhem.2024.1339870 *
GUMMADI VENKATESHWAR RAO, BORUAH ANIMA, AINAN BHARATHI RAJA, VARE BRAHMA REDDY, MANDA SRINIVAS, GONDLE HARI PRAKASH, KUMAR SHIVA N: "Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies", ACS MEDICINAL CHEMISTRY LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 11, no. 12, 10 December 2020 (2020-12-10), US , pages 2374 - 2381, XP055907105, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.0c00255 *

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