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  • 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
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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  • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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  • 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
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  • A61K31/00—Medicinal preparations containing organic active ingredients
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  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
  • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
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  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• Interleukin- 1 (IL-1) Receptor- Associated Kinase 4 (IRAK4) 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”.
• IRAKs Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor-kB (NF-KB) and stress-induced mitogen activated protein kinase (MAPK)-signaling cascades.
• NF-KB nuclear factor-kB
• MAPK mitogen activated protein kinase
• IRAK-1 and IRAK4 have been shown to have active kinase activity. While IRAK-1 kinase activity could be dispensable for its function in IL-l-induced NF-kB activation (Kanakaraj et al, J. Exp. Med. 187(12), 1998, 2073-2079) and (XiaoxiaLi, et al. Mol. Cell. Biol.
• IRAK4 requires its kinase activity for signal transduction (Li S, et al. Proc. Natl. Acad. Sci. USA 99(8), 2002, 5567-5572) and (Lye, E et al, J. Biol. Chem. 279(39); 2004, 40653-8).
• IRAK4 inhibitors Given the central role of IRAK4 in Toll-like/IL-lR signalling and immunological protection, IRAK4 inhibitors have been implicated as valuable therapeutics in inflammatory diseases, sepsis and autoimmune disorders (Wietek C, et al, Mol. Interv. 2: 2002, 212-215).
• mice lacking IRAK4 are viable and show complete abrogation of inflammatory cytokine production in response to IL-1, IL-18 or LPS (Suzuki et al. Nature, 416(6882), 2002, 750-756). Similarly, human patients lacking IRAK4 are severely immune-compromised and are not responsive to these cytokines (Medvedev et al. J. Exp. Med., 198(4), 2003, 521-531 and Picard et al. Science 299(5615), 2003, 2076-2079). Knock-in mice containing inactive IRAK4 were completely resistant to lipopolysaccharide- and CpG-induced shock ( Kim TW, et al.
• 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).
• Non-Hodgkin lymphoma is the most common hematologic malignancy in adults with approximately 78 thousand new cases and 20 thousand deaths estimated for 2020 in the United States.
• the molecular pathology driving NHL is varied, although a common theme is over activity of the NFKB signaling pathway. Specific molecular changes have been identified that drive this pathway is subsets of NHL.
• Diffuse large B-cell lymphoma (hereafter also referred to as “DLBCL”) is an aggressive lymphoma that can arise in lymph nodes or outside of the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain.
• DLBCL is a cancer of B cells, a type of white blood cell responsible for producing antibodies.
• DLBCL non-Hodgkin
• GCB germinal center B-cell-like
• ABSC activated B-cell-like
• WM Waldenstrom’s macroglobulinemia
• IgM immunoglobulin M
• Non-Hodgkin’s lymphoma include mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), CNS lymphoma, and testicular lymphoma.
• MCL mantle cell lymphoma
• MZL marginal zone lymphoma
• FL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• CNS lymphoma CNS lymphoma
• testicular lymphoma testicular lymphoma.
• Non- Hodgkin’s lymphoma can be caused by a variety of factors such as infections agents (Epstein- Barr virus, hepatitis C virus and human T-Cell leukemia virus), radiation and chemotherapy treatments, and autoimmune diseases.
• infections agents Epstein- Barr virus, hepatitis C virus and human T-
• the present disclosure provides methods of treating cancer in a subject, comprising conjointly administering to the subject an IRAK4 inhibitor or an IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analog.
• the present disclosure provides methods of treating cancer in a subject, comprising conjointly administering to the subject an IRAK4 inhibitor or an IRAK4 degrader and a nucleoside analog.
• FIG. 1A shows the efficacy of certain therapies in a venetoclax resistant THP-1 cell line.
• Cells were treated continuously with clinically relevant drug concentration for 96 hrs.
• Relative cell viability was measured by CellTiter Glo assay (Promega, Madison, WI) at 0 and at 96 hrs according to manufacturer’s instructions. All values are presented as mean ⁇ SE.
• Cell viability assay data were analyzed with one-way ANOVA. P values less than 0.05 were considered significant.
• Statistical analysis was performed using GraphPad Prism 8.0 software. The combination of Compound 1, azacitidine, and venetoclax showed synergistic efficacy.
• FIG. IB shows the efficacy of certain therapies in a azacitidine resistant OCI-AML2 cell line.
• Cells were treated continuously with clinically relevant drug concentration for 96 hrs.
• Relative cell viability was measured by CellTiter Glo assay (Promega, Madison, WI) at 0 and at 96 hrs according to manufacturer’s instructions. All values are presented as mean ⁇ SE.
• Cell viability assay data were analyzed with one-way ANOVA. P values less than 0.05 are considered significant.
• Statistical analysis was performed using GraphPad Prism 8.0 software. The combination of Compound 1, azacitidine, and venetoclax showed synergistic efficacy.
• IL-1R associated kinase 4 is a serine/threonine kinase that is a key component of the myddosome complex.
• the myddosome a key component of the innate immune system, transmits intracellular signals from IL-1R and Toll-Like Receptors (TLR), resulting in NFKB activation.
• TLR Toll-Like Receptors
• This pathway is also oncogenic in a number of malignancies.
• MYD88 Myeloid Differentiation Primary Response 88
• MYD88 is composed of a death domain at the N terminus, an intermediate linker domain, and a Toll/interleukin- 1 receptor domain at the C terminus (FIG. 2). Toll-like receptor (TLR) and the interleukin 1 family of receptors (IL-1R) signaling occurs through MYD88. MYD88 is involved in the assembly and activation of IL-IR associated kinase 4 (IRAK4) which stimulates NF-KB mediated anti-apoptotic signaling cascades. IL-IR associated kinase 1 (IRAKI) is recruited by MYD88 via direct interaction with IRAK4, the most proximal IRAK.
• IRAK4 IL-IR associated kinase 4
• TRAF6-TAK1-IKK tumor necrosis factor receptor associated factor 6- transforming growth factor beta-activated kinase 1-IkB kinase
• activation of the NF-KB pathway and promotion of cell survival.
• Oncogenic signaling is transmitted by the myddosome, which requires IRAK4 for activation.
• TLRs are widely expressed on tumor cells, regulating growth and other tumor functions.
• MYD88 is a known oncogene which is mutated in a number of malignancies and requires IRAK4.
• the long form of IRAK4 (IRAK4-L) is itself known to be oncogenic in AML and MDS, where over half of cases overexpress IRAK4-L.
• Compound 1 is the first clinical candidate targeting IRAK4 to be evaluated in cancer patients and disclosed herein is evidence that targeting IRAK4 results in anti-cancer activity in a patient.
• the present disclosure provides methods of treating cancer in a subject, comprising conjointly administering to the subject an IRAK4 inhibitor or an IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analog.
• the methods comprise conjointly administering to the subject an IRAK4 inhibitor, a BCL-2 inhibitor, and a nucleoside analog.
• the present disclosure provides methods of treating cancer in a subject, comprising conjointly administering to the subject an IRAK4 inhibitor or an IRAK4 degrader and a nucleoside analog.
• the methods comprise conjointly administering to the subject an IRAK4 inhibitor and a nucleoside analog.
• the IRAK4 inhibitor is , inhibitor yet other preferred embodiments, the IRAK4 inhibitor
• the BCL-2 inhibitor is venetoclax.
• the nucleoside analog is azacitidine.
• the IRAK4 inhibitor is the BCL-2 inhibitor is venetoclax; and the nucleoside analog is azacitidine.
• the IRAK4 inhibitor is the nucleoside analog is azacitidine.
• the IRAK4 inhibitor has as structure represented by formula (I) or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof; wherein
• Zi is an optionally substituted heteroaryl
• L ' l is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond
• Ri is alkyl, cyano, -NR a Rb, 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-CHz-O-alkyl, -0P(0)(0-alkyl)2 or -CH2-0P(0)(0-alkyl)2; III, 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;
• Ra is hydrogen or alkyl
• R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SCk-alkyl or optionally substituted cycloalkyl;
• ‘m’ and ‘n’ are independently 1 or 2.
• Zi is a 5- or 6-membered optionally substituted heteroaryl.
• Zi is an optionally substituted heteroaryl; wherein the optional substituent is alkyl.
• Zi is selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl and pyrazolyl.
• Zi is selected from pyridyl, oxazolyl and furanyl; wherein the pyridyl group is optionally substituted with alkyl; in particular alkyl is methyl.
• Z2 is a 5- or 6-membered heteroaryl selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.
• Z2 is a 5- or 6-membered heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,4-dioxanyl.
• Z2 is pyridyl, pyrazolyl or pyrrolidinyl.
• Z2 is a direct bond
• the IRAK4 inhibitor has a structure represented by formula
• the IRAK4 inhibitor has a structure represented by formula
• 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-CHz-O-alkyl, - 0P(0)(0-alkyl) 2 or -CH 2 -0P(0)(0-alkyl)2.
• Ri is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl; wherein the substituent is amino, halogen, hydroxyl, hydroxyalkyl, aminoalkyl, -OCO-CHz-O-alkyl, -0P(0)(0-alkyl)2 or -CH2-0P(0)(0-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 substituent is alkoxy.
• R2 is cycloalkyl
• R3 is hydrogen, halogen, alkyl, alkoxy, -NRaRb, hydroxyl or hydroxyalkyl;
• R a is hydrogen or alkyl; and
• R b 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
• R b is hydrogen or hydroxyalkyl.
• Zi is oxazolyl
• Z 2 is pyridyl, pyrazolyl or pyrrolidinyl
• Ri is cyano, -NRaR b , or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl
• R 2 is optionally substituted alkyl or cycloalkyl
• R 3 is hydrogen, halogen, alkyl, alkoxy, -NRaR b , hydroxyl or hydroxyalkyl
• Ra is hydrogen or alkyl
• R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SCk-alkyl or optionally substituted cycloalkyl.
• R3 is -NR a Rb;
• Ra is hydrogen or alkyl; and
• Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SCk-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 X3 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 substituent is alkyl, amino, halo or hydroxyl;
• R 3 at each occurrence, is alkyl or hydroxyl
• Ra and Rb are independently hydrogen, alkyl, acyl or heterocyclyl
• ‘nf and ‘n’ are independently 0, 1 or 2; and ‘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, lH-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,l,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl
• 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
• the IRAK4 inhibitor has a structure represented by formula
• Y is O or Cfb.
• 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 cycloalkyl.
• R2 is cyclopropyl
• R2 is optionally substituted heterocyclyl; wherein the substituent is alkyl, amino, halo or hydroxyl.
• R2 is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, pyridyl, azepanyl or azabicyclo[3.2.1]octanyl; wherein the 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.
• R2 is -NR a Rb; wherein Ra and Rb are independently hydrogen or heterocyclyl.
• R2 is -NR a Rb; wherein Ra and Rb are independently hydrogen or pyrrolidinyl.
• 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 -NR a Rb;
• R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NR a Rb; wherein the 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 substituent is alkyl, amino, halo or hydroxyl; Ra and Rb are independently hydrogen, alkyl, acyl or heterocyclyl.
• ‘n’ is 0, 1 or 2.
• ‘p’ is 0 or 1.
• ‘m’ is 0 or 2.
• the IRAK4 inhibitor is selected from:
• the IRAK4 inhibitor is Compound 1) or a pharmaceutically acceptable salt thereof.
• the IRAK4 inhibitor has a structure represented by formula
• 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 -NR a Rb;
• 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 ach occurrence, is 0, 1 or 2; and n, at each occurrence, is 0, 1, or 2.
• Zi is an optionally substituted heterocyclyl.
• 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 tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.
• Zi is pyridyl or oxazolyl; wherein the oxazolyl group is optionally substituted with alkyl; in particular alkyl is methyl. In certain embodiments, Zi is absent.
• Z2 is cycloalkyl, aryl or heterocyclyl.
• Z2 represents cycloalkyl, aryl, or heterocyclyl, optionally substituted by one or more substituents selected from hydroxy, halo, alkyl, alkoxyl, cycloalkyl, -NRaRb, or cycloalkoxy.
• 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, pyrazolidinyl, benzisoxazolyl, be
• Z2 is pyridyl, piperazinyl, pyrimidyl, pyrrolidinyl, 1, 2,3,4- tetrahydropyridyl, piperidinyl, pyrazolopyrimidyl or pyrrolopyridyl.
• the IRAK4 inhibitor has a structure represented by formula
• the IRAK4 inhibitor has a structure represented by formula
• Z2 is pyridyl
• Z2 is pyrrolidinyl
• 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.
• the present methods include a compound of formula (III) or a pharmaceutically acceptable salt, wherein Ri is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, optionally substituted with one or more substituents selected, independently for each occurrence, from hydroxy, halo, alkyl, or hydroxyalkyl.
• Ri is heterocyclyl; optionally substituted with halogen, hydroxyl or hydroxyalkyl.
• Ri is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl.
• Ri is piperidinyl, optionally substituted with hydroxyl.
• Ri is pyrrolidinyl, optionally substituted with hydroxyl.
• 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.
• R2 is optionally substituted cycloalkyl, preferably, cyclopropyl.
• R3, at each occurrence, is hydroxy, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or -NRaRb; wherein R a is hydrogen or optionally substituted alkyl; and Rb is hydrogen, optionally substituted alkyl, optionally substituted acyl, hydroxyalkyl or -SCte-alkyl.
• 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, -SCk-alkyl or optionally substituted cycloalkyl.
• ‘m’ is 0.
• ‘m’ is 1.
• ‘m’ is 2.
• ‘n’ is 0.
• ‘n’ is 1.
• ‘n’ is 2.
• the IRAK4 inhibitor is selected from:
• the IRAK4 inhibitor is PF-06650833, BAY1830839, BAY1 834845, R835, GS-5718, or ND-2158.
• the IRAK4 inhibitor (e.g., Compound 1) 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.
• 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 to the subject once per day. In yet other embodiments, about 75 mg of the IRAK4 inhibitor to the subject once per day. In yet other embodiments, about 100 mg of the IRAK4 inhibitor to the subject once per day. In yet other embodiments, about 125 mg of the IRAK4 inhibitor to the subject once per day. In yet other embodiments, about 150 mg of the IRAK4 inhibitor to the subject once per day.
• IRAK4 Degraders of the Disclosure about 50 mg of the IRAK4 inhibitor to the subject once per day. In yet other embodiments, about 75 mg of the IRAK4 inhibitor to the subject once per day. In yet other embodiments, about 100 mg of the IRAK4 inhibitor to the subject once per day. In yet other embodiments, about 125 mg of the IRAK4
• 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.
• the combinations disclosed herein may be utilized in connection with any BCL-2 inhibitor.
• the BCL-2 inhibitor is ventoclax.
• 400 mg of venetoclax is administered daily.
• the venetoclax is administered orally.
• the nucleoside analog is an analog of cytidine.
• the nucleoside analog is azacitidine, decitabine, cytarabine, gemcitabine, 5’- deoxy-5-fluorouridine, fludarabine, cladribine, troxacitabine, or clofarabine.
• the nucleoside analog is azacitidine.
• the azacitidine is administered at a dose of 75 mg/m 2 daily.
• the azacitidine is administered at a dose of 100 mg/m 2 daily.
• the azacitidine is administered subcutaneously.
• the azacitidine is administered at a dose of 300 mg daily.
• the azacitidine is administered orally.
• the cancer is a hematological malignancy, such as a leukemia or lymphoma, for example a non-Hodgkin’s lymphoma.
• the hematological malignancy is myelogenous leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt’s lymphoma, non-Burkitt high grade B
• the hematological malignancy is myelogenous leukemia. In other embodiments, the hematological malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In certain embodiments, the hematological malignancy is acute myeloid leukemia (e.g., AML). In certain embodiments, the AML is primary AML. In other embodiments, the AML is secondary AML. In certain embodiments, the AML is resistant to treatment with an fms related receptor tyrosine kinase 3 (FLT3) inhibitor. In certain embodiments, the AML is associated with a mutation in FLT3 kinase. In certain embodiments, the mutation is an internal tandem duplication (ITD).
• ITD internal tandem duplication
• the mutation is a D835H, D835V, D835Y, K663Q, N841L, or F691L mutation. In certain embodiments, the mutation is a D835Y mutation.
• the hematological malignancy is myelodysplastic syndromes (MDS). In certain embodiments, the MDS is high grade. In other embodiments, the MDS is low grade. In certain embodiments, the MDS is high risk.
• the hematological malignancy is lymphoblastic leukemia (e.g., acute lymphoblastic leukemia). In yet other embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL).
• the CLL is high risk CLL.
• the hematological malignancy is small lymphocytic lymphoma (SLL).
• the hematological malignancy is follicular lymphoma.
• the hematological malignancy is diffuse large B-cell lymphoma (DLBCL).
• the hematological malignancy is activated B cell-like (ABC) DLBCL.
• the hematological malignancy is germinal center B cell-like (GCB) DLBCL.
• the DLBCL is extranodal.
• the DLBCL is extranodal leg lymphoma, extranodal testicle lymphoma, or extra nodal not otherwise specified (NOS) type lymphoma.
• the hematological malignancy is mantle cell lymphoma.
• the hematological malignancy is Waldenstrom’s macroglobulinemia.
• the DLBCL or WM is characterized by a L265P mutation in MYD88.
• the hematological malignancy is multiple myeloma.
• the hematological malignancy is marginal zone lymphoma.
• the hematological malignancy is Burkitt’ s lymphoma. In yet other embodiments, the hematological malignancy is non-Burkitt high grade B cell lymphoma. In still other embodiments, the hematological malignancy is extranodal marginal zone B cell lymphoma. In yet other embodiments, the hematological malignancy is transformed high grade B-cell lymphoma (HGBL). In yet other embodiments, the hematological malignancy is lymphoplasmacytic lymphoma (LPL). In yet other embodiments, the hematological malignancy is CNS lymphoma. In yet other embodiments, the CNS lymphoma is primary CNS lymphoma (PCNSL).
• PCNSL primary CNS lymphoma
• the hematological malignancy is MALT lymphoma.
• the hematological malignancies described above may be relapsed or refractory.
• the hematological malignancies described above are resistant to treatment with a BTK inhibitor.
• the hematological malignancies described above are resistant to treatment with a BTK inhibitor as a monotherapy.
• the hematological malignancies is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM7 1224.
• the hematological malignancy is resistant to treatment with ibrutinib.
• the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, gastric cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, prostate cancer, head or neck cancer.
• the cancer is pancreatic cancer.
• the cancer is colon cancer.
• the cancer is a solid tumor. In various such embodiments, the cancer may be relapsed or refractory.
• the combinations disclosed herein may be used as a first line therapy or they may be administered to patients who have failed to achieve a response, either partial or full, using one or more previous anti-cancer therapies or anti-inflammatory therapies.
• the subject has previously received at least one anti-cancer therapy.
• the patient has previously received one anti-cancer therapy.
• the patient has previously received two anti-cancer therapies.
• the patient has previously received three anti-cancer therapies.
• the patient has previously received four anti-cancer therapies.
• the patient has previously received five anti-cancer therapies.
• the at least one anti cancer therapy is selected from an anti-CD20 antibody, a nitrogen mustard, a steroid, a purine analog, a DNA a topoisomerase inhibitor, a DNA intercalator, a tubulin inhibitor, a BCL-2 inhibitor, a proteasome inhibitor, a toll-like receptor inhibitor, a kinase inhibitor, an SRC kinase inhibitor, a PI3K kinase inhibitor, BTK inhibitor, a glutaminase inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor and a methylating agent; or a combination thereof.
• the anti-cancer therapy is selected from ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, oprozomib, ixazomib, acalabrutinib, zanubrutinib, IMO- 08400, idelalisib, umbrelasib, CB-839, fludarabine, and thalidomide; or a combination thereof.
• the anti-cancer therapy is ibrutinib. In certain embodiments, the anti- cancer therapy is ibrutinib and rituximab. In certain embodiments, the anti-cancer therapy is bendamustine. In certain embodiments, the anti-cancer therapy is bendamustine and rituximab. In certain embodiments, the anti-cancer therapy is bortezomib. In certain embodiments, the anti-cancer therapy is bortezomib and dexamethasone. In certain embodiments, the anti-cancer therapy is bortezomib and rituximab.
• the anti-cancer therapy is bortezomib, rituximab, and dexamethasone. In certain embodiments, chlorambucil. In certain embodiments, the anti-cancer therapy is cladribine. In certain embodiments, the anti-cancer therapy is cladribine and rituximab. In certain embodiments, the anti-cancer therapy is cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R).
• the anti-cancer therapy is cyclophosphamide, prednisone, and rituximab (i.e., CPR).
• the anti-cancer therapy is fludarabine.
• the anti-cancer therapy is fludarabine and rituximab.
• the anti-cancer therapy is fludarabine, cyclophosphamide, and rituximab.
• the anti-cancer therapy is rituximab.
• the anti cancer therapy comprises rituximab.
• the anti-cancer therapy is rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).
• the anti-cancer therapy is thalidomide.
• the anti-cancer therapy is thalidomide and rituximab.
• the anti-cancer therapy is venetoclax.
• the anti-cancer therapy is cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD).
• the anti-cancer therapy is a hypom ethylating agent.
• the subject has previously received at least 6 cycles of a hypomethylating agent.
• the anti-cancer therapy is a combination of any of the foregoing, for example the subject may first receive rituximab and then at a later date receive a combination of rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).
• the subject may also have received or been prepared for other, non-chemotherapeutic treatments, such as surgery, radiation, or a bone marrow transplant.
• the subject has previously received etoposide chemo-mobilization therapy.
• the subject has previously received a bone marrow transplant.
• he subject has previously received a stem cell transplant.
• the subject has previously received an autologous cell transplant.
• the subject has previously received an allogenic stem cell transplant.
• the subject has previously received a hematopoietic cell transplantation.
• the subject has previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning).
• the subject has previously received re-induction therapy.
• the subject may have also previously exhibited a favorable outcome to prior therapy only to require additional treatment at a later date.
• the subject has previously achieved a partial response.
• the subject has previously achieved a good partial response.
• the subject has previously achieved a complete response.
• the cancer is relapsed.
• the cancer is refractory.
• the subject may also have preexisting or developed one or more genetic mutations that render the subjects cancer more or less resistant to therapy.
• the subject has a mutation in RICTOR.
• the subject has a N1065S mutation in RICTOR.
• the subject has a mutation in MYD88.
• the subject has a L265P mutation in MYD88.
• the subject has a mutation in TET2.
• the subject does not have a mutation in CXCR4.
• the subject has a mutation in CXCR4.
• the subject shows early progression.
• the subject has not previously received a BTK inhibitor.
• the subject achieves a partial response. In certain embodiments, following administration of the combinations, the subject achieves a good partial response. In other embodiments, following administration of the combinations, the subject achieves a complete response. In certain embodiments, the subject achieves a partial response within 7 days of receiving the combinations. In certain embodiments, the subject achieves a good partial response within 7 days of receiving the combinations. In certain embodiments, the subject achieves a complete response within 7 days of receiving the combinations.
• the subject’s tumor volume is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.
• the subject’s tumor volume is reduced by 5%.
• the subject’s tumor volume is reduced by 10%.
• the subject’s tumor volume is reduced by 15%.
• the subject’s tumor volume is reduced by 20%.
• the subject’s tumor volume is reduced by 25%.
• the subject’s tumor volume is reduced by 30%.
• 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, the BCL-2 inhibitor, and the nucleoside analog may be administered in a number of ways.
• the IRAK4 inhibitor or IRAK4 degrader, BCL-2 inhibitor, and the nucleoside analog may be administered simultaneously.
• the IRAK4 inhibitor or IRAK4 degrader may be administered first, the BCL-2 inhibitor second, and the nucleoside analog third.
• 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 IRAK4 inhibitor or IRAK4 degrader and the nucleoside analog are administered simultaneously. In other embodiments, the IRAK4 inhibitor and the nucleoside analog are administered within about 5 minutes to within about 168 hours of each other.
• the IRAK4 inhibitor and the nucleoside analog are administered simultaneously. In other embodiments, the IRAK4 inhibitor and the nucleoside analog are administered within about 5 minutes to within about 168 hours of each other.
• compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
• the individual is a mammal such as a human, or a non-human mammal.
• the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
• the aqueous solution is pyrogen-free, or substantially pyrogen-free.
• the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
• the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
• the composition can also be present in a transdermal delivery system, e.g., a skin patch.
• the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
• a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
• physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
• the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
• the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
• the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
• Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
• 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.
• 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.
• Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
• Compositions or compounds may also be administered as a bolus, electuary or paste.
• 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), surface- active 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.
• Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art,
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
• the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• 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.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
• the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other 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, lH-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-dichloroacetic 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, dodecyl sulfuric acid, ethan
• the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
• the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BEIT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (
• agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
• Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.
• a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
• Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
• Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
• Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
• preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
• a condition such as a local recurrence (e.g., pain)
• a disease such as cancer
• a syndrome complex such as heart failure or any other medical condition
• prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
• administering or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
• a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
• a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
• Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
• a compound or an agent is administered orally, e.g., to a subject by ingestion.
• the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
• the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
• the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
• an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
• a “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
• the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
• a therapeutically effective amount may be administered in one or more administrations.
• the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
• the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
• “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
• substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
• the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O- alkyl, -0P(0)(0-alkyl)2 or -CH2-0P(0)(0-alkyl)2.
• “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
• alkyl refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups.
• the “alkyl” group refers to C1-C6 straight-chain alkyl groups or C1-C6 branched- chain alkyl groups.
• the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups.
• alkyl examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3 -pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3-octyl or 4-octyl and the like.
• the “alkyl” group may be optionally substituted.
• acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
• acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(0)NH-.
• acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
• alkoxy refers to an alkyl group having an oxygen attached thereto.
• Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
• alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
• alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
• a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci- 30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer.
• 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.
• Cx- y or “Cx-C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
• Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
• a Ci-6alkyl group for example, contains from one to six carbon atoms in the chain.
• 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-.
• amide refers to a group wherein R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
• amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
• R 10 R 10 ' wherein R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
• aminoalkyl refers to an alkyl group substituted with an amino group.
• aralkyl refers to an alkyl group substituted with an aryl group.
• aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
• the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
• aryl 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 aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
• carbocycle 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-.
• 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.
• esters refers to a group -C(0)0R 9 wherein R 9 represents a hydrocarbyl group.
• 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.
• hydroxy alkyl 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.
• substitution 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(0)SR 9 or -SC(0)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
• R 9 R 9 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.
• pharmaceutically acceptable is art-recognized.
• the term includes 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.
• Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I).
• Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
• Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
• prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
• the prodrugs of this disclosure are metabolized to produce a compound of Formula I.
• the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
• 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 subj ect’ 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).
• Example I Exemplary Treatment of Cancer with a Combination of an IRAK-4 Inhibitor, a Bcl-2 Inhibitor, and a Nucleoside Analog
• CellTiter Glo cell viability assay was used to evaluate the antitumor effects of Compound 1 in combination with AML SOC drugs daunorubicin, Ara-C, decitabine, azacitidine and venetoclax in FLT3-WT AML cell lines THP-1, F-36P, OC1-AML2 and GDM- 1.
• GLo the concentration for 50% of maximal inhibition of cell proliferation
• THP-1 and F-36P cell lines were identified as resistant to clinically relevant concentrations of venetoclax, whereas OC1-AML2 cell line was resistant to the treatment with azacytidine (Table 1).
• Synergistic effect of combining Compound 1 with Ara-C was observed in THP-1 cell line.
• Compound 1 potentiated antitumor effects of azacitidine in 3 of 4 FLT3-WT AML cell lines whereas we did not observe any additive or synergistic effect of combining Compound 1 with decitabine (Table 2).
• the combination of venetoclax and Compound 1 inhibited the cell growth in 2 of 4 AML FLT3-WT cell lines more effectively than either of the two agents alone.
• Compound 1 significantly potentiated antitumor effects of azacitidine+venetoclax in all AML FLT3-WT cell lines (Table 2) ⁇

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